Pertussis outbreak investigation of Mekdela district, South Wollo zone, Amhara region, North-West Ethiopia

Pertussis is a highly contagious respiratory illness caused by Bordetella pertussis. It is one of the most common vaccine-preventable bacterial infections that affects all susceptible individuals, regardless of a...

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Tourette syndrome: a disorder of the social decision-making network

Abstract

Tourette syndrome is a common neurodevelopmental disorder defined by characteristic involuntary movements, tics, with both motor and phonic components. Tourette syndrome is usually conceptualized as a basal ganglia disorder, with an emphasis on striatal dysfunction. While considerable evidence is consistent with these concepts, imaging data suggest diffuse functional and structural abnormalities in Tourette syndrome brain. Tourette syndrome exhibits features that are difficult to explain solely based on basal ganglia circuit dysfunctions. These features include the natural history of tic expression, with typical onset of tics around ages 5 to 7 years and exacerbation during the peri-pubertal years, marked sex disparity with higher male prevalence, and the characteristic distribution of tics. The latter are usually repetitive, somewhat stereotyped involuntary eye, facial and head movements, and phonations. A major functional role of eye, face, and head movements is social signalling. Prior work in social neuroscience identified a phylogenetically conserved network of sexually dimorphic subcortical nuclei, the Social Behaviour Network, mediating many social behaviours. Social behaviour network function is modulated developmentally by gonadal steroids and social behaviour network outputs are stereotyped sex and species specific behaviours. In 2011 O'Connell and Hofmann proposed that the social behaviour network interdigitates with the basal ganglia to form a greater network, the social decision-making network. The social decision-making network may have two functionally complementary limbs: the basal ganglia component responsible for evaluation of socially relevant stimuli and actions with the social behaviour network component responsible for the performance of social acts. Social decision-making network dysfunction can explain major features of the neurobiology of Tourette syndrome. Tourette syndrome may be a disorder of social communication resulting from developmental abnormalities at several levels of the social decision-making network. The social decision-making network dysfunction hypothesis suggests new avenues for research in Tourette syndrome and new potential therapeutic targets.

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The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists.

Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5-year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator's choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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AhR activation increases IL-2 production by alloresponding CD4+ T cells initiating the differentiation of mucosal-homing Tim3+Lag3+ Tr1 cells

Activation of the aryl hydrocarbon receptor (AhR) by immunosuppressive ligands promotes the development of regulatory T (Treg) cells. Although AhR-induced Foxp3⁺ Treg cells have been well studied, much less is known about the development and fate of AhR-induced Type 1 Treg (AhR-Tr1) cells. In the current study, we identified the unique transcriptional and functional changes in murine CD4⁺ T cells that accompany the differentiation of AhR-Tr1 cells during the CD4⁺ T-cell-dependent phase of an allospecific cytotoxic T lymphocyte (allo-CTL) response. AhR activation increased the expression of genes involved in T-cell activation, immune regulation and chemotaxis, as well as a global downregulation of genes involved in cell cycling.  Increased IL-2 production was responsible for the early AhR-Tr1 activation phenotype previously characterized as CD25⁺CTLA4⁺GITR⁺ on day 2. The AhR-Tr1 phenotype was further defined by the coexpression of the immunoregulatory receptors Lag3 and Tim3 and non-overlapping expression of CCR4 and CCR9. Consistent with the increased expression of CCR9, real-time imaging showed enhanced migration of AhR-Tr1 cells to the lamina propria of the small intestine and colon. The discovery of mucosal imprinting of AhR-Tr1 cells provides an additional mechanism by which therapeutic AhR ligands can control immunopathology.

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A two-stage temperature control strategy enhances extracellular secretion of recombinant α-cyclodextrin glucosyltransferase in Escherichia coli

The effects of temperature on extracellular secretion of the α-cyclodextrin glucosyltransferase (α-CGTase) from Paenibacillus macerans JFB05-01 by Escherichia coli were investigated. When protein expression was i...

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Identification, heterologous expression and characterization of a dye-decolorizing peroxidase of Pleurotus sapidus

The coding sequence of a peroxidase from the secretome of Pleurotus sapidus was cloned from a cDNA library. Bioinformatic analyses revealed an open reading frame of 1551 bp corresponding to a primary translation ...

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Survey of methanotrophic diversity in various ecosystems by degenerate methane monooxygenase gene primers

Methane is the second most important greenhouse gas contributing to about 20% of global warming. Its mitigation is conducted by methane oxidizing bacteria that act as a biofilter using methane as their energy ...

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Development of a circulation direct sampling and monitoring system for O2 and CO2 concentrations in the gas–liquid phases of shake-flask systems during microbial cell culture

Monitoring the environmental factors during shake-flask culture of microorganisms can help to optimise the initial steps of bioprocess development. Herein, we developed a circulation direct monitoring and samp...

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A comment on ‘An assessment of the variation in the concentrations of acetylcysteine in infusions for the treatment of paracetamol overdose’

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Pharmacokinetic variability of valproate in women of childbearing age

Summary

The purpose was to investigate pharmacokinetic variability of valproic acid (VPA) in women of childbearing age by therapeutic drug monitoring (TDM) data to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of VPA. Anonymized retrospective data from the TDM database (2006–2015) at the National Center for Epilepsy in Norway were used. Trough total concentrations of VPA at assumed steady state in women aged 14–46 years were analyzed. Data from 643 nonpregnant women of childbearing age (mean age = 27 years) were included. Mean dose and serum concentration of VPA were 968 (standard deviation [SD] = 453) mg/day and 411 (SD = 138) μmol/L, respectively, and 59% used polytherapy. The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive. For doses <700 mg/day (n = 202; 32%; 150–625 mg/day), mean serum concentration was 336 μmol/L and variability in C/D ratio was 10-fold. The variability decreased with increasing dose to eightfold (≥700 to <1,500 mg/day, n = 358) and fourfold (≥1,500 mg/day, n = 96). This study demonstrates the extensive pharmacokinetic variability of VPA among women of childbearing age, which is most pronounced at low doses. In future studies, serum concentrations of VPA, rather than dosage, should be used as a guide for exposure of VPA and possible risks of teratogenicity to evaluate safety aspects of VPA in women.

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Editorial Board

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The Impact of Waiting List Bmi Changes on the Short-Term Outcomes of Lung Transplantation.

Background: Obesity and underweight are associated with a higher postlung transplantation (LTx) mortality. This study aims to assess the impact of the changes in BMI during the waiting period for LTx on early postoperative outcomes. Methods: Medical records of 502 consecutive cases of LTx performed at our institution between 1999 and 2015 were reviewed. Patients were stratified per change in BMI category between pre-LTx assessment (candidate BMI) and transplant BMI as follows: A-Candidate BMI=30 and Transplant BMI18.5-29.9 and E-Candidate BMI>=30 or 18.5-29.9 and Transplant BMI>=30. Our primary outcome was in-hospital (H) mortality and secondary outcomes were length of mechanical ventilation (MV), intensive care unit (ICU) length of stay (LOS), H LOS and postoperative complications. Results: BMI variation during the waiting time was common, as 1/3 of patients experienced a change in BMI category. Length of MV (21 vs. 9 d; p=0.018), ICU LOS (26 vs. 15 d; p=0.035) and rates of surgical complications (76 vs. 44%; p=0.018) were significantly worse in patients of group E vs. D. Obese candidates who failed to decrease BMI

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Cytoreductive nephrectomy for metastatic renal cell carcinoma: inequities in access exist despite improved survival

Abstract

The use of cytoreductive nephrectomy (CRN) in the targeted therapy era is still debated. We aimed to determine factors associated with reduced use of CRN and determine the effect of CRN on overall survival in patients with metastatic renal cell carcinoma (RCC). All advanced RCC diagnosed between 2001 and 2009 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment and death were electronically linked. Follow-up was to the end of 2011. Multivariable logistic regression analysis was used to determine factors associated with the receipt of CRN. Cox proportional hazards model was used to determine factors associated with survival. A total of 1062 patients were identified with metastatic RCC of whom 289 (27%) received CRN. There was no difference in the use of CRN over the time period of the study. Females (OR 0.68 (95% CI: 0.48–0.96)), unmarried individuals (OR 0.68 (95% CI: 0.48–0.96)), treatment in a nonteaching hospital (OR 0.26 (95% CI: 0.18–0.36)) and individuals without private insurance (OR 0.29 (95% CI: 0.20–0.41)) all had reduced likelihood of receiving CRN. On multivariable analysis, not receiving CRN resulted in a 90% increase in death (HR 1.90 (95% CI: 1.61–2.25)). In addition, increasing age (P < 0.001), increasing Charlson comorbidity status (P = 0.002) and female gender also had a significant independent association with death. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or have no private insurance have a reduced likelihood of receiving CRN.

Cytoreductive nephrectomy is commonly used in conjunction with systemic therapy to treat advanced renal cell carcinoma. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or do not have private insurance have a reduced likelihood of receiving this surgery.

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The colorectal cancer immune microenvironment and approach to immunotherapies

Future Oncology, Ahead of Print.


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The evolutionary nature of the cancer immunotherapy revolution

Future Oncology, Ahead of Print.


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Should we be combining local tumor therapies with immunotherapies as standard?

Future Oncology, Ahead of Print.


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Docetaxel or abiraterone in addition to androgen deprivation therapy in metastatic castration-sensitive prostate cancer

Future Oncology, Ahead of Print.


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How and when adjuvant treatment should be intensified in stage III colorectal cancers?

Future Oncology, Ahead of Print.


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Intravascular Lymphoma in the CNS: Options for Treatment

Abstract

Purpose of review The purpose of this review was to discuss therapeutic manipulations and effective current interventions available to treat intravascular lymphoma in the central nervous system.

Recent findings Patients experienced resolution and remission of disease for 14 months and up to 2 years after eight cycles of R-CHOP and four courses of intrathecal therapy with MTX, cytarabine, and prednisolone. Intravascular use of unfractionated heparin during therapy may contribute to better outcome.

Summary Series of therapeutic avenues were analyzed and compared. The effective current treatment of intravascular lymphoma in the CNS is considered to be a combinational intrathecal methotrexate-based chemotherapy with rituximab. Since intrathecal administration bypasses the blood–brain barrier, lower doses can be given, which thereby minimizes systemic toxicity. Practical use of intrathecal chemotherapy is also justified for prophylaxis in intravascular lymphoma-diagnosed patients without CNS involvement.

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Functional MRI for Surgery of Gliomas

Abstract

Purpose of Review

Advanced neuroimaging techniques such as functional MRI (fMRI) and diffusion MR tractography have been increasingly used at every stage of the surgical management of brain gliomas, as a means to improve tumor resection while preserving brain functions. This review provides an overview of the last advancements in the field of functional MRI techniques, with a particular focus on their current clinical use and reliability in the preoperative and intraoperative setting, as well as their future perspectives for personalized multimodal management of patients with gliomas.

Recent Findings

fMRI and diffusion MR tractography give relevant insights on the anatomo-functional organization of eloquent cortical areas and subcortical connections near or inside a tumor. Task-based fMRI and diffusion tensor imaging (DTI) tractography have proven to be valid and highly sensitive tools for localizing the distinct eloquent cortical and subcortical areas before surgery in glioma patients; they also show good accuracy when compared with intraoperative stimulation mapping data. Resting-state fMRI functional connectivity as well as new advanced HARDI (high angular resolution diffusion imaging) tractography methods are improving and reshaping the role of functional MRI for surgery of gliomas, with potential benefit for personalized treatment strategies.

Summary

Noninvasive functional MRI techniques may offer the opportunity to perform a multimodal assessment in brain tumors, to be integrated with intraoperative mapping and clinical data for improving surgical management and oncological and functional outcome in patients affected by gliomas.

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Ciliated muconodular papillary tumors of the lung with KRAS/BRAF/AKT1 mutation

Ciliated muconodular papillary tumors (CMPTs) are newly recognized rare peripheral lung nodules that are histologically characterized by ciliated columnar, goblet, and basal cells. Although recent studies have...

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Comprehensive catwalk gait analysis in a chronic model of multiple sclerosis subjected to treadmill exercise training

Multiple sclerosis (MS) is a demyelinating disease with a wide range of symptoms including walking impairment and neuropathic pain mainly represented by mechanical allodynia. Noteworthy, exercise preconditioni...

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The Gulf War era multiple sclerosis cohort: 3. Early clinical features

Objectives

To present clinical features at diagnosis for a large nationwide incident cohort of multiple sclerosis (MS) among those serving in the US military during the Gulf War era (GWE).

Materials & Methods

Medical records and databases from the Department of Veterans Affairs (VA) for cases of MS with onset in or after 1990, active duty between 1990 and 2007 and service connection by the VA, were reviewed for diagnosis and demographic variables. Neurological involvement was summarized by the Kurtzke Disability Status Scale (DSS) and the Multiple Sclerosis Severity Score (MSSS).

Results

Among 1919 cases of clinically definite MS, 94% had a relapsing-remitting course and 6% were primary progressive at diagnosis. More males of all races and blacks of both sexes were progressive. At diagnosis, functional system involvement was pyramidal 69%, cerebellar 58%, sensory 55%, brainstem 45%, bowel/bladder 23%, cerebral 23%, visual 18%, and other 5%. Mean DSS scores were: white males, females 2.9, 2.7; black males, females 3.3, 2.8; and other-race males, females 3.2, 2.6. Mean and median MSSS were marginally greater in black males and other males compared to the other sex-race groups.

Conclusions

In this incident cohort, males and blacks had significantly higher proportions of primary progressive MS. DSS at diagnosis was significantly more severe in blacks and significantly less so in whites and in women vs men, but MSSS was only marginally greater in black males and other-race males. This morbidity assessment early in the course of MS provides population-based data for diagnosis, management, and prognosis.

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Cognitive complaint in early Parkinson's disease: A pilot study

Background

Subjective cognitive complaint (SCC) is a criterion recommended by the Movement Disorder Society (MDS) task force for the diagnosis of mild cognitive impairment (MCI). Until now there were few specific tools for detecting SCC in PD. We sought to develop a new tool to assess SCC specifically dedicated for PD.

Materials and Methods

We set a group of experts in movements disorders and neurocognition to develop an easy-to-use tool based on a visual analogue scale (VAS) for five cognitive domains: memory, executive functions, spatial orientation, attention, and language. We use it to assess SCC twice (at a one-month interval) in PD patients with disease duration of less than 5 years. Comprehensibility of the VAS was assessed. Controls were assessed with the same VAS. Patients with PD also underwent neuropsychological testing.

Results

VAS was easily understandable by the 70 patients with PD. We found significant SCC for the patients with PD vs controls in three cognitive domains: executive functions (1.7 ± 1.9 vs 0.8 ± 1.1; P < .001), language (2.3 ± 2.5 vs 1.0 ± 1.3, P < .001), and attention (2.1 ± 2.2 vs 1.2 ± 1.2; P < .01). Reproducibility between the two evaluations of patients with PD was good. There was no relationship between SCC and the results of neuropsychological testing.

Conclusions

SCC seems to appear early in PD, in three cognitive domains (executive functions, language, and attention), and VAS might be a good way to detect SCC in PD, but need to be validated.

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Genetic characterization of novel class 1 Integrons In0, In1069 and In1287 to In1290, and the inference of In1069-associated integron evolution in Enterobacteriaceae

This study aims to characterize genetically related class 1 integrons In1069, In893 and In1287 to In1290, and to further propose a scheme of stepwise integration or excision of individual gene cassettes (GCs) ...

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Abstracts

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Just for Women? Feminist Multicultural Therapy with Male Clients

Abstract

Feminist multicultural therapy is an integrative approach to psychotherapy that emphasizes a systems-level understanding of psychological distress and the process of therapeutic change. In the present exploratory study, the experiences of feminist multicultural therapists working with male clients were studied using Consensual Qualitative Research (CQR) (Hill et al. 1997). Phone interviews were conducted with eight female practicing licensed or license-eligible therapists who had worked with at least one male client in the past 6 months. Consistent with the theoretical approach, all of the therapists interviewed expressed their belief that psychological symptoms can be seen as a reaction to a loss of power or related to the effects of an oppressive system. Additionally, the therapists believed that this theoretical model is broad enough to be used with varying types of intersecting social identities. The findings illustrate the ways in which the counseling approach may work similarly across genders, as well as ways in which one's therapeutic approach may be altered when working specifically with men. Implications for therapists who work with male clients (both the rewards and the challenges) as well as for researchers who wish to study the application of therapeutic interventions with men are discussed.

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Signs

Not long after my mother died, my father lay disconsolate in a darkened hotel room begging his deceased wife to send him a sign. Wherever she was in her ghostly habitat, would she please smuggle him some affirmation of their enduring love? Suddenly, the overhead light switched on. Other people…

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Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer

Abstract

Background

Emerging studies show that long noncoding RNAs (lncRNAs) play important roles in carcinogenesis and cancer progression. The lncRNA ZEB1 antisense 1 (ZEB1-AS1) derives from the promoter region of ZEB1 and we still know little about its expressions, roles and mechanisms.

Methods

RACE was used to obtain the sequence of ZEB1-AS1. RNA interference was used to decrease ZEB1-AS1 expression. Adenovirus expression vector was used to increase ZEB1-AS1 expression. CHIP and RIP were used to detect the epigenetic mechanisms by which ZEB1-AS1 regulated ZEB1. CCK8 assay, wound healing assay and transwell assay were used to measure proliferation and migration of prostate cancer cells.

Results

In this study, in prostate cancer cells, we found that RNAi-mediated downregulation of ZEB1-AS1 induced significant ZEB1 inhibition while artificial overexpression of ZEB1-AS1 rescued ZEB1 expression, which means that ZEB1-AS1 promotes ZEB1 expression. Also, ZEB1-AS1 indirectly inhibited miR200c, the well-known target of ZEB1, and upregulated miR200c's target BMI1. Mechanistically, ZEB1-AS1 bound and recruited histone methyltransferase MLL1 to the promoter region of ZEB1, induced H3K4me3 modification therein, and activated ZEB1 transcription. Biologically, ZEB1-AS1 promoted proliferation and migration of prostate cancer cells.

Conclusions

Collectively, ZEB1-AS1 functions as an oncogene in prostate cancer via epigenetically activating ZEB1 and indirectly regulating downstream molecules of ZEB1.

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Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition

Purpose: Despite advances in multimodal therapy, neuroblastomas with hemizygous deletion in chromosome 11q (20-30%) undergo consecutive recurrences with poor outcome. We hypothesized that patients with 11q loss may share a druggable molecular target(s) that can be exploited for a precision medicine strategy to improve treatment outcome. Experimental Design: SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma aetiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models. Results: We detected that ATM haploinsufficiency and ATM allelic variants are common genetic hallmarks of 11q-loss neuroblastomas. Based on the distinct DNA repair pathways triggered by ATM and PARP, we postulated that 11q-loss may define a subgroup of neuroblastomas with higher sensitivity to PARP inhibitors. Noteworthy, concomitant treatment with olaparib and DNA alkylating agent temozolomide potently inhibited growth of cell lines harboring 11q-loss. This drug synergism was less potent when temozolomide was exchanged for cisplatin or irinotecan. Intact 11q cells concomitantly treated with ATM inhibitor displayed growth arrest and enhanced apoptosis, revealing a role for ATM in the mechanism that mediates sensitivity to temozolomide-olaparib. Interestingly, functional TP53 is required for efficacy of this treatment. In an in vivo model, co-administration of temozolomide-olaparib resulted in sustained xenograft regression. Conclusions: Our findings reveal a potent synergism between temozolomide and olaparib in treatment of neuroblastomas with 11q loss and provide a rationale for further clinical investigation.

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Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma indicate the potential for CDK4/6 Inhibitors in Targeted Therapy

Purpose: Effective therapies for the majority of metastatic acral melanoma (AM) patients has not been established. Thus, we investigated genetic aberrations of CDK4 pathway in AM and evaluate the efficacy of CDK4/6 inhibitors in targeted therapy of AM. Experimental Design: A total of 514 primary AM samples were examined for the copy number variations (CNVs) of CDK4 pathway-related genes, including Cdk4, Ccnd1 and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established AM cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated. Results: Among the 514 samples, 203 cases, 137 cases and 310 cases respectively showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%) and p16INK4a loss (60.3%). The overall frequency of AMs that contain at least one aberration in Cdk4, Ccnd1 and P16INK4a was 82.7%. The median overall survival time for AM patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations P = .005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of AM cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss and Ccnd1 gain plus P16INK4a loss. Conclusions: Genetic aberration of CDK4 pathway is a frequent event in AM. AM cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in AM patients.

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Separating Pathways in the Extracellular ESCRT Service

We have known for a long time that cells communicate with their neighbors by secreting a wide array of small molecules and macromolecules. However, in the past three decades, it has become increasingly apparent that cells also release membrane-bounded vesicles not merely to discard selected cellular contents but as an extension of the intercellular communication network. Indeed, there is now vigorous and widespread interest in the roles of these extracellular vesicles (ECVs) as purveyors between cells of growth factors, selected receptors, cytoplasmic signaling proteins, transcription factors, a range of nucleic acid transcripts, DNA, and selected lipids (1).

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Duplication and Sub/Neofunctionalization of Malvolio, an Insect Homolog of Nramp, in the Subsocial Beetle Nicrophorus vespilloides

With growing numbers of sequenced genomes, increasing numbers of duplicate genes are uncovered. Here we examine Malvolio, a gene in the natural resistance-associated macrophage protein (Nramp) family, that has been duplicated in the subsocial beetle, Nicrophorus vespilloides, which exhibits advanced parental behavior. There is only one copy of Mvl in honey bees and Drosophila, whereas in vertebrates there are two copies that are subfunctionalized. We first compared amino acid sequences for Drosophila, beetles, mouse and humans. We found a high level of conservation between the different species, though there was greater variation in the C-terminal regions. A phylogenetic analysis across multiple insect orders suggests that Mvl has undergone several independent duplications. To examine the potential for different functions where it has been duplicated, we quantified expression levels of Mvl1 and Mvl2 in eight tissues in N. vespilloides. We found that while Mvl1 was expressed ubiquitously, albeit at varying levels, expression of Mvl2 was limited to brain and midgut. Because Mvl has been implicated in behavior, we examined expression during different behavioral states that reflected differences in opportunity for social interactions and expression of parental care behaviors. We found differing expression patterns for the two copies, with Mvl1 increasing in expression during resource preparation and feeding offspring, and Mvl2 decreasing in these same states. Given these patterns of expression, along with the protein analysis, we suggest that Mvl in N. vespilloides has experienced sub/neofunctionalization following its duplication, and may be evolving differing and tissue-specific roles in behavior and physiology.

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CONE: Community Oriented Network Estimation Is a Versatile Framework for Inferring Population Structure in Large Scale Sequencing Data

Estimation of genetic population structure based on molecular markers is a common task in population genetics and ecology. We apply a generalized linear model with LASSO regularization to infer relationships between individuals and populations from molecular marker data. Specifically, we apply a neighborhood selection algorithm to infer population genetic structure and gene flow between populations. The resulting relationships are used to construct an individual-level population graph. Different network substructures known as communities are then dissociated from each other using a community detection algorithm. Inference of population structure using networks combines the good properties of: (i) network theory (broad collection of tools, including aesthetically pleasing visualization) (ii) principal component analysis (dimension reduction together with simple visual inspection) (iii) model-based methods (e.g. ancestry coefficients estimates). We have named our process as CONE (Community Oriented Network Estimation). CONE has fewer restrictions than conventional assignment methods in that properties such as the number of subpopulations need not be fixed before the analysis, the sample may include close relatives or involve uneven sampling. Applying CONE on simulated data sets resulted in more accurate estimates of the true number of subpopulations and provided comparable ancestry coefficient estimates than model-based methods. Inference of empirical data sets of teosinte single nucleotide polymorphism, bacterial disease outbreak, and human genome diversity panel illustrate that population structures estimated with CONE are consistent with the earlier findings.

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Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns

Abstract

Background

In Parkinson's disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [¹⁸F]FDG-PET (to demonstrate brain metabolism in awake animals), [¹⁸F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model.

Results

We found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [¹⁸F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation.

Conclusions

Our results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

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Evaluation of HIV-DNA and inflammatory markers in HIV-infected individuals with different viral load patterns

Persistent residual viremia (RV) and low grade inflammation and immune activation have been associated with non-AIDS defining events. The impact of persistent RV and HIV-DNA load on immune activation/inflammat...

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Tuberculosis active case finding in Cambodia: a pragmatic, cost-effectiveness comparison of three implementation models

Globally, almost 40% of tuberculosis (TB) patients remain undiagnosed, and those that are diagnosed often experience prolonged delays before initiating correct treatment, leading to ongoing transmission. While...

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Rates of switching to second-line antiretroviral therapy and impact of delayed switching on immunologic, virologic, and mortality outcomes among HIV-infected adults with virologic failure in Rakai, Uganda

Switch from first to second-line ART is recommended by WHO for patients with virologic failure. Delays in switching may contribute to accumulated drug resistance, advanced immunosuppression, increased morbidit...

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Emergence and clonal transmission of multi-drug-resistant tuberculosis among patients in Chad

Emergence of Multidrug-resistant (MDR) strains constitutes a significant public health problem worldwide. Prevalence of MDR tuberculosis from Chad is unavailable to date.

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Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics

Abstract

Background

Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer.

Methods

The drug effects on cell proliferation were measured by CellTiter 96® AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by Radius™ 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry.

Results

We show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCa cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation.

Conclusion

This study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development.

http://ift.tt/2inxbjs

Constitutive signaling from an engineered IL-7 receptor promotes durable tumor elimination by tumor redirected T-cells [Research Briefs]

Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but are associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL-7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Co-expressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and anti-tumor activity during repeated exposure to tumor cells, without T cell dysfunction or autonomous T cell growth. Furthermore, C7R co-expressing CAR-T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.

http://ift.tt/2g3PuJY

Intermediate-term outcome after PSMA-PET guided high-dose radiotherapy of recurrent high-risk prostate cancer patients

Abstract

Background

By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far.

Methods

Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0).

Result

Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up.

Conclusion

PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed.

Trial registration

No trial registration was performed due to retrospective evaluation.

http://ift.tt/2vX5liG

Cognitive Function in a Randomized Trial of Evolocumab

Statin therapy, ezetimibe, and the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab have been shown to reduce the rate of cardiovascular events among patients with established cardiovascular disease. These therapies may result in very low levels of low-density lipoprotein…

http://ift.tt/2uS3dWw

Signs

Not long after my mother died, my father lay disconsolate in a darkened hotel room begging his deceased wife to send him a sign. Wherever she was in her ghostly habitat, would she please smuggle him some affirmation of their enduring love? Suddenly, the overhead light switched on. Other people…

http://ift.tt/2wi2H7Q

Human pluripotent stem cell-derived TSC2-haploinsufficient smooth muscle cells recapitulate features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both Tuberous Sclerosis Complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSCs), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/- mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributed to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM which can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM.

http://ift.tt/2wCBYTO

Esophageal Cryoablation Using Retrograde Per-Gastrostomy Ventilation in A Patient with Pharyngoesophageal Stenosis

http://ift.tt/2vmE2uF

Stent migration into the abdominal cavity after EUS-guided hepaticogastrostomy

http://ift.tt/2v4aFC5

GIE: At the Focal Point Direct Visualization of IgG4-related Cholangiopathy

http://ift.tt/2vmpOKv

Acute suppurative cholangitis due to an impacted pancreatic stone: a rare adverse event in the setting of chronic calcified pancreatitis

http://ift.tt/2v412mQ

Complex Reproductive Traits and Whole-Organism Performance

Synopsis

Arnold's 1983 path-analytic paradigm, considering "morphology, performance, and fitness," has been elaborated in several ways. For example, current versions recognize the level of "behavior" (including aspects of motivation) as a filter between performance abilities (only measurable if motivation is maximal) and fitness components. Performance abilities constrain behavior, but behavioral choices may shield performance from selection. Conceptual and empirical issues remain, such as the extent to which individual variation in lower-level subordinate traits (e.g., circulating hormone concentrations) might directly affect behavior, growth rates, sexual maturation, etc., rather than having effects only through paths involving some aspect of performance. Moreover, empirical studies have yet to encompass more than a few possible paths in a given system, in part because life-history researchers rarely communicate with those focused on performance. Most life-history studies ponder trade-offs associated with reproductive effort, but studies of locomotor performance (e.g., maximal sprint speed) have rarely considered trade-offs with reproduction. This lack of connection is surprising because both life history (e.g., clutch size) and locomotor performance (e.g., locomotor stamina) traits require allocation of energy and other resources, so trade-offs between these trait types may be expected. These perspectives and cultures could be bridged by a focus on the ability of organisms to perform components of reproductive biology (e.g., lactation performance could be studied in animals maximally "motivated" by manipulation of litter size or endocrine function). Alternatively, one could study impacts of reproduction on performance, as when bats and live-bearing fishes lose maneuverability during gestation. We also consider sperm performance in the context of the paradigm and illustrate that the paradigm can easily be utilized as a frame-work within which to consider key aspects of sperm biology.

http://ift.tt/2w1AjoB

Physiological Trade-Offs in Lizards: Costs for Individuals and Populations

Synopsis

The immune system is a critical component of health and fitness, whereby organisms must maintain sufficient health to survive to reproduce. Because of the key role of immunity in an organism's fitness, the use of immunological indices is widespread. However, there is a paucity of empirical support for the best way to interpret immunological data, and the internal energetic state of the organism, as well as the external environmental pressures it faces, are often not considered concurrently. A stronger immune response is not always beneficial to the organism; a more attenuated response may ultimately lead to improved fitness if the animal incurs fewer performance costs on competing systems, especially reproduction. Additionally, the external pressures animals encounter (such as anthropogenic disturbance) must be considered along with the animal's internal state. A synthesis of results addressing resource allocation between the immune and reproductive systems is presented using a well-studied organism, the side-blotched lizard, from a combination of field and laboratory studies under varying environmental conditions. Specifically, experiments involving specific immune, reproductive, metabolic, and performance costs in a laboratory setting are discussed, as well as associated demographic trade-offs between survival and reproductive success, demonstrating essential links between immunity and the population.

http://ift.tt/2w1AmAN

Predicting Life-History Trade-Offs with Whole-Organism Performance

Synopsis

Whole-organism performance traits are key intermediaries between the organism and the environment. Because performance traits are energetically costly to both build and maintain, performance will compete with other life-history traits over a limited pool of acquired energetic resources at any given time, potentially leading to trade-offs in performance expression. Although these trade-offs can have important implications for organismal fitness we currently lack a conceptual framework for predicting both where trade-offs might be expected, and which traits may be especially prone to trade-offs with other fitness-related life-history traits. We propose such a framework based on an estimate of the energetic requirements of locomotion in vertebrates, the ecological cost of transport. By analyzing existing data on mammalian energetic budgets and life-history, we found that species with higher costs of locomotion also tended to be those with "slow" life histories that invest relatively less in current reproduction than "fast" life-history species. We discuss the potential implications of ectothermy for masking such relationships, and how this framework might be expanded upon in the future.

http://ift.tt/2wlL4Eu

Performance Tradeoffs, Ontogenetic Conflict, and Multisport Athletes: How is an Ironman Triathlete Like a Frog?

Synopsis

Life-history theory is a cornerstone of modern evolutionary biology that addresses myriad phenomena ranging from demography and population structure to the evolution of aging and senescence. Trade-offs may arise in a number of contexts, from allocation-based (e.g., egg size vs. egg number) to genomic conflicts (e.g., intralocus sexual conflict in which genes that perform well in males perform poorly in females). Here we test for performance tradeoffs in human athletes. We show that in Ironman triathletes, swimming performance trades off with cycling and running performance. The tradeoff appears to be plastic, in that only highly trained athletes experience the tradeoff. We then investigate whether wood frogs (Rana sylvatica) experience similar locomotor performance tradeoffs, to ask whether the divergent environments experienced by tadpoles and frogs leads to ontogenetic conflict (tradeoffs over development). We show that although swimming and jumping performance are positively correlated, antagonistic natural selection may still favor alternative adaptive optima in the two life history stages. However, "adaptive decoupling" of the life stages during metamorphosis may resolve ontogenetic conflict and facilitate independent adaptation to both environments. Thus, whereas performance tradeoffs are general in both systems, the unique selective environment of amphibians has favored the evolution of mechanisms to alleviate the costs of those tradeoffs.

http://ift.tt/2w1sjDO

Does Hormonal Pleiotropy Shape the Evolution of Performance and Life History Traits?

Synopsis

Hormonal pleiotropy occurs when a part of the endocrine system (e.g., hormone concentrations) influences the expression of two or more phenotypes. Although hormonal pleiotropy may have similar evolutionary consequences as genetic pleiotropy, most conceptual and empirical work on its putative evolutionary consequences to date has focused on identifying whether the different components of an endocrine axis (titer, receptor expression, etc.) that affect trait expression are themselves able to evolve independently from one another. This is important because if these different components evolve together, the expression of two traits affected by the same hormone may be yoked and evolve non-independently. Here, we first describe methodological approaches used to identify how hormonal pleiotropy could cause the co-evolution of performance and life history traits. We then focus on a similar but less studied concept about how hormonal pleiotropy can affect phenotypic responses to selection. If the expression of two traits is affected by the same hormone, the magnitude of the phenotypic response to selection may be exacerbated or retarded compared to the absence of this hormonal pleiotropy. We use classical concepts from quantitative genetics to discuss an approach for identifying whether hormonal pleiotropy has such evolutionary consequences using data collected from longitudinal studies of wild animals. We develop a simple quantitative genetics model to derive predictions about the conditions under which hormonal pleiotropy would affect the response to selection. We focus on performance and life history traits and how the effects of hormonal pleiotropy on the evolution of these traits depend upon the genetic correlations between the hormone and traits as well as the direction and strength of selection on the two traits. Finally, we review the literature for examples that have estimated these model parameters to characterize the studies that have or have not found support for these model predictions.

http://ift.tt/2wlPR96

Merging the “Morphology–Performance–Fitness” Paradigm and Life-History Theory in the Eagle Lake Garter Snake Research Project

Synopsis

The morphology–performance–fitness paradigm for testing selection on morphological traits has seen decades of successful application. At the same time, life-history approaches using matrix methods and perturbation studies have also allowed the direct estimate of selection acting on vital rates and the traits that comprise them. Both methodologies have been successfully applied to the garter snakes of the long-term Eagle Lake research project to reveal selection on morphology, such as color pattern, number of vertebrae, and gape size; and life-history traits such as birth size, growth rates, and juvenile survival. Here we conduct a reciprocal transplant study in a common laboratory environment to study selection on morphology and life-history. To place our results in the ecomorphology paradigm, we measure performance outcomes (feeding rates, growth, insulin-like growth factor 1 titers) of morphological variation (body size, condition) and their fitness consequences for juvenile survival—a trait that has large fitness sensitivities in these garter snake populations, and therefore is thought to be subject to strong selection. To better merge these two complementary theories, we end by discussing our findings in a nexus of morphology–performance–fitness–life history to highlight what these approaches, when combined, can reveal about selection in the wild.

http://ift.tt/2w1DBIf

Epigenetic Potential as a Mechanism of Phenotypic Plasticity in Vertebrate Range Expansions

Synopsis

During range expansions, organisms are often exposed to multiple pressures, including novel enemies (i.e., predators, competitors and/or parasites) and unfamiliar or limited resources. Additionally, small propagule sizes at range edges can result in genetic founder effects and bottlenecks, which can affect phenotypic diversity and thus selection. Despite these obstacles, individuals in expanding populations often thrive at the periphery of a range, and this success may be mediated by phenotypic plasticity. Increasing evidence suggests that epigenetic mechanisms may underlie such plasticity because they allow for more rapid phenotypic responses to novel environments than are possible via the accumulation of genetic variation. Here, we review how molecular epigenetic mechanisms could facilitate plasticity in range-expanding organisms, emphasizing the roles of DNA methylation and other epigenetic marks in the physiological regulatory networks that drive whole-organism performance. We focus on the hypothalamic-pituitary-adrenal (HPA) axis, arguing that epigenetically-mediated plasticity in the regulation of glucocorticoids in particular might strongly impact range expansions. We hypothesize that novel environments release and/or select for epigenetic potential in HPA variation and hence organismal performance and ultimately fitness.

http://ift.tt/2wlBpOr

Locomotion, Energetics, Performance, and Behavior: A Mammalian Perspective on Lizards, and Vice Versa

Synopsis

Animals are constrained by their abilities and by interactions with environmental factors, such as low ambient temperatures. These constraints range from physical impossibilities to energetic inefficiencies, and may entail trade-offs. Some of the constraints related to locomotion and activity metabolism can be illustrated through allometric comparisons of mammals and lizards, as representative terrestrial vertebrate endotherms and ectotherms, respectively, because these lineages differ greatly in aerobic metabolic capacities, resting energetic costs, and thermoregulatory patterns. Allometric comparisons are both useful and unavoidable, but "outlier" species (unusual for their clade) can also inform evolutionary scenarios, as they help indicate extremes of possible adaptation within mammalian and saurian levels of organization. We compared mammals and lizards for standard metabolic rate (SMR), maximal oxygen consumption during forced exercise (VO_2max), net (incremental) cost of transport (NCT), maximal aerobic speed (MAS), daily movement distance (DMD), daily energy expenditure (DEE) during the active season, and the ecological cost of transport (ECT = percentage of DEE attributable to locomotion). (Snakes were excluded because their limbless locomotion has no counterpart in terrestrial mammals.) We only considered lizard SMR, VO_2max, NCT, MAS, and sprint speed data if measured at 35–40 °C. On average, MAS is ∼7.4-fold higher in mammals, whereas SMR and VO_2max are ∼6-fold greater, but values for all three of these traits overlap (or almost overlap) between mammals and lizards, a fact that has not previously been appreciated. Previous studies show that sprint speeds are similar for smaller mammals and lizards, but at larger sizes lizards are not as fast as some mammals. Mammals move ∼6-fold further each day than lizards, and DMD is by far the most variable trait considered here, but their NCT is similar. Mammals exceed lizards by ∼11.4-fold for DEE. On average for both lineages, the ECT is surprisingly low, somewhat higher for lizards, and positively allometric. If a lizard and mammal of 100 g body mass were both to move their entire DMD at their MAS, they could do so in ∼21 and 17 min, respectively, thus de-emphasizing the possible importance of time constraints. We conclude that ecological-energetic constraints related to locomotion are relatively more likely to occur in large, carnivorous lizards. Overall, our comparisons support the idea that the (gradual) evolution of mammalian endothermy did not necessarily require major changes in locomotor energetics, performance, or associated behaviors. Instead, we speculate that the evolution of thermoregulatory responses to low temperatures (e.g., shivering) may have been a key and "difficult" step in this transition.

http://ift.tt/2w0XWxr

Physiological and Biomechanical Mechanisms of Distance Specific Human Running Performance

Synopsis

Running events range from 60-m sprints to ultra-marathons covering 100 miles or more, which presents an interesting diversity in terms of the parameters for successful performance. Here, we review the physiological and biomechanical variations underlying elite human running performance in sprint to ultramarathon distances. Maximal running speeds observed in sprint disciplines are achieved by high vertical ground reaction forces applied over short contact times. To create this high force output, sprint events rely heavily on anaerobic metabolism, as well as a high number and large cross-sectional area of type II fibers in the leg muscles. Middle distance running performance is characterized by intermediates of biomechanical and physiological parameters, with the possibility of unique combinations of each leading to high-level performance. The relatively fast velocities in mid-distance events require a high mechanical power output, though ground reaction forces are less than in sprinting. Elite mid-distance runners exhibit local muscle adaptations that, along with a large anaerobic capacity, provide the ability to generate a high power output. Aerobic capacity starts to become an important aspect of performance in middle distance events, especially as distance increases. In distance running events, V˙O_2max is an important determinant of performance, but is relatively homogeneous in elite runners. V˙O₂ and velocity at lactate threshold have been shown to be superior predictors of elite distance running performance. Ultramarathons are relatively new running events, as such, less is known about physiological and biomechanical parameters that underlie ultra-marathon performance. However, it is clear that performance in these events is related to aerobic capacity, fuel utilization, and fatigue resistance.

http://ift.tt/2w1oFK7

Does the Treadmill Support Valid Energetics Estimates of Field Locomotion?

Synopsis

Quantifying animal energy expenditure during locomotion in the field is generally based either on treadmill measurements or on estimates derived from a measured proxy. Two common proxies are heart rate (ƒ_H) and dynamic body acceleration (accelerometry). Both ƒ_H and accelerometry have been calibrated extensively under laboratory conditions, which typically involve prompting the animal to locomote on a treadmill at different speeds while simultaneously recording its rate of oxygen uptake (V̇o₂) and the proxy. Field estimates of V̇o₂ during locomotion obtained directly from treadmill running or from treadmill-calibrated proxies make assumptions about similarities between running in the field and in the laboratory. The present study investigated these assumptions, focusing on humans as a tractable species. First we investigated experimentally if and how the rate of energy expenditure during treadmill locomotion differs to that during field locomotion at the same speeds, with participants walking and running on a treadmill, on tarmac, and on grass, while wearing a mobile respirometry system. V̇o₂ was substantially higher during locomotion in both of the field conditions compared with on a level treadmill: 9.1% on tarmac and 17.7% on grass. Second, we included these data in a meta-analysis of previous, related studies. The results were influenced by the studies excluded due to particulars of the experiment design, suggesting that participant age, the surface type, and the degree of turning during field locomotion may influence by how much treadmill and field locomotion V̇o₂ differ. Third, based on our experiments described earlier, we investigated the accuracy of treadmill-calibrated accelerometry and ƒ_H for estimating V̇o₂ in the field. The mean algebraic estimate errors varied between 10% and 35%, with the ƒ_H associated errors being larger than those derived from accelerometry. The mean algebraic errors were all underestimates of field V̇o₂, by around 10% for f_H and varying between 0% and 15% for accelerometry. Researchers should question and consider how accurately a treadmill-derived proxy calibration of V̇o₂ will estimate V̇o₂ during terrestrial locomotion in free-living animals.

http://ift.tt/2wlBuBy

Introduction to the Symposium: Integrative Life-History of Whole-Organism Performance

Synopsis

A strong case can be made for whole-organism performance traits (i.e., dynamic, ecologically relevant traits whose expression is shaped by underlying morphological factors) as being the ultimate integrative traits. This is not only because they capture the output of multiple lower levels of biological organization, but also because they are directly relevant to individual fitness in multiple ecological contexts, and are in many cases important proximate determinants of survival and/or reproductive success. But although many ecological and evolutionary phenomena can be examined through the lens of performance (and vice-versa), performance research has been surprisingly slow to incorporate concepts from the large and important field of life-history evolution. Such a synthesis is necessary, because shifts in resource allocation strategies can have implications for these highly ecologically relevant, functional traits, whose expression may trade-off against fecundity, immune function, or longevity, among other key life-history traits. The papers in this symposium showcase many of the ways in which life-history strategies can have direct consequences for the expression, maintenance, and evolution of whole-organism performance (and at least one case where they may not). By approaching the issue of life-history trade-offs from a number of diverse perspectives, this symposium reveals the scope for future explicit integration of life-history techniques with those of whole-organism performance studies for a more complete understanding of multivariate phenotypic evolution.

http://ift.tt/2w0XY8x

The Ecology of Exercise: Mechanisms Underlying Individual Variation in Behavior, Activity, and Performance: An Introduction to Symposium

Synopsis

Wild animals often engage in intense physical activity while performing tasks vital for their survival and reproduction associated with foraging, avoiding predators, fighting, providing parental care, and migrating. In this theme issue we consider how viewing these tasks as "exercise"—analogous to that performed by human athletes—may help provide insight into the mechanisms underlying individual variation in these types of behaviors and the importance of physical activity in an ecological context. In this article and throughout this issue, we focus on four key questions relevant to the study of behavioral ecology that may be addressed by studying wild animal behavior from the perspective of exercise physiology: (1) How hard do individual animals work in response to ecological (or evolutionary) demands?; (2) Do lab-based studies of activity provide good models for understanding activity in free-living animals and individual variation in traits?; (3) Can animals work too hard during "routine" activities?; and (4) Can paradigms of "exercise" and "training" be applied to free-living animals? Attempts to address these issues are currently being facilitated by rapid technological developments associated with physiological measurements and the remote tracking of wild animals, to provide mechanistic insights into the behavior of free-ranging animals at spatial and temporal scales that were previously impossible. We further suggest that viewing the behaviors of non-human animals in terms of the physical exercise performed will allow us to fully take advantage of these technological advances, draw from knowledge and conceptual frameworks already in use by human exercise physiologists, and identify key traits that constrain performance and generate variation in performance among individuals. It is our hope that, by highlighting mechanisms of behavior and performance, the articles in this issue will spur on further synergies between physiologists and ecologists, to take advantage of emerging cross-disciplinary perspectives and technologies.

http://ift.tt/2wlCOED

Fuel Use in Mammals: Conserved Patterns and Evolved Strategies for Aerobic Locomotion and Thermogenesis

Synopsis

Effective aerobic locomotion depends on adequate delivery of oxygen and an appropriate allocation of metabolic substrates. The use of metabolic substrates during exercise follows a predictive pattern of lipid and carbohydrate oxidation that is similar in lowland native cursorial mammals. We have found that in two highland lineages of mice (Phyllotis and Peromyscus) the fuel use pattern is shifted to a greater reliance on carbohydrates compared to their lowland conspecifics and congenerics. However, there is variation between lineages in the importance of phenotypic plasticity in the expression of this metabolic phenotype. Moreover, this metabolic phenotype is independent of running aerobic capacity and can also be independent of thermogenic capacity. For example, wild-caught mice from a highland population of deer mice (Peromyscus maniculatus) housed in warm normoxic laboratory conditions maintain higher maximum cold-induced oxygen consumption in acute hypoxia than lowland congenerics, but shivering and non-shivering thermogenesis is supported by high rates of lipid oxidation. This is reflected in the consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius of highland deer mice compared to lowlanders, which are resistant to hypoxia acclimation. While a fixed trait in muscle aerobic capacity may reflect the pervasive and unremitting low PO₂ at high altitudes, muscle capacities for substrate oxidation may be more flexible to match appropriate substrate use with changing energetic demands. How shivering thermogenesis and locomotion potentially interact in the matching of muscle metabolic capacities to appropriate substrate use is unclear. Perhaps it is possible that shivering serves as "training" to ensure muscles have the capacity to support locomotion or visa-versa.

http://ift.tt/2w1IwsQ

Systems Biology of Phenotypic Robustness and Plasticity

Synopsis

Gene regulatory networks, cellular biochemistry, tissue function, and whole body physiology are imbued with myriad overlapping and interacting homeostatic mechanisms that ensure that many phenotypes are robust to genetic and environmental variation. Animals also often have plastic responses to environmental variables, which means that many different phenotypes can correspond to a single genotype. Since natural selection acts on phenotypes, this raises the question of how selection can act on the genome if genotypes are decoupled from phenotypes by robustness and plasticity mechanisms. The answer can be found in the systems biology of the homeostatic mechanisms themselves. First, all such mechanisms operate over a limited range and outside that range the controlled variable changes rapidly allowing natural selection to act. Second, mutations and environmental stressors can disrupt homeostatic mechanisms, exposing cryptic genetic variation and allowing natural selection to act. We illustrate these ideas by examining the systems biology of four specific examples. We show how it is possible to analyze and visualize the roles of specific genes and specific polymorphisms in robustness in the context of large and realistic nonlinear systems. We also describe a new method, system population models, that allows one to connect causal dynamics to the variable outcomes that one sees in biological populations with large variation.

http://ift.tt/2wlBtgY

Of Uberfleas and Krakens: Detecting Trade-offs Using Mixed Models

Synopsis

All animals experience performance trade-offs as they complete tasks such as capturing prey, defending territories, acquiring mates, and escaping predators. Why then, is it so hard to detect performance trade-offs at the whole-organismal level? Why do we sometimes even obtain positive correlations between two performance traits that are predicted to be negatively associated? Here we explore two plausible explanations. First, most analyses are based on individual maximal values (i.e., personal best), which could introduce a bias in the correlation estimates. Second, phenotypic correlations alone may be poor indicators of a trade-off when contrasting processes occur at the among- versus within-individual levels. One such scenario is the "big houses big cars" model developed in life-history theory to explain the existence of "uberfleas" that are superior in all regards (because they acquire more resources than others). We highlight that the exact opposite scenario might occur for performance trade-offs, where among-individual trade-offs may be masked by within-individual changes in physical condition. One of the best ways to test among these alternative scenarios is to collect repeated pairs of performance traits and analyze them using multivariate mixed models (MMMs). MMMs allow straightforward and simultaneous examination of trait correlations at the among- and within-individual levels. We use a simple simulation tool (SQuID package in R) to create a population of Krakens, a mythical giant squid-like sea creature whose morphology generates a performance trade-off between swimming speed and strength or ability to sink ships. The simulations showed that using individual maximum values introduces a bias that is particularly severe when individuals differ in the number of repeated samples (n_trial). Finally, we show how MMMs can help detect performance (or any other type of) trade-offs and offer additional insights (e.g., help detect plasticity integration). We hope researchers will adopt MMMs when exploring trade-offs in whole-animal performances.

http://ift.tt/2w19XmE

Parasites and Host Performance: Incorporating Infection into Our Understanding of Animal Movement

Synopsis

Studies of animal locomotion and movement largely assume that individuals are healthy and performing to the best of their abilities in ways which are adapted to their survival. However, wild animals face numerous ecological challenges that can compromise their health, reduce their performance capacity, impair their movement abilities and, ultimately, lower their fitness. By diverting resources and increasing host energetic demands, parasites, bacteria, and viruses (hereafter parasites) can dramatically influence the ways in which their hosts allocate energy to movement. Yet, the role of parasites in influencing animal locomotor performance and movement remains relatively unexplored, perhaps because animals often hide outward signs of sickness, and parasites tend to be small and inconspicuous to researchers. Here, we review how parasite infection can alter host locomotor performance via impacts on host morphology and physiology. We also give examples of behavioral strategies that some hosts employ to help overcome the disadvantages imposed by infection. Finally, we discuss how parasites can lead to both increased and decreased host movement patterns, either as an adaptive strategy for the host or due to manipulation by the parasite. The dynamic interplay between host movement (such as migration and dispersal) and infection has profound consequences for population and ecosystem-level processes that are influenced by movement. Acknowledging the important functional role played by parasites in driving the evolution of host locomotor performance and behavior is a critical step toward developing a comprehensive understanding of the causes and consequences of animal movement.

http://ift.tt/2wlBcKZ

Ecology of Exercise in Wild Fish: Integrating Concepts of Individual Physiological Capacity, Behavior, and Fitness Through Diverse Case Studies

Synopsis

Wild animals maximize fitness through certain behaviors (e.g., foraging, mating, predator avoidance) that incur metabolic costs and often require high levels of locomotor activity. Consequently, the ability of animals to achieve high fitness often relies on their physiological capacity for exercise (aerobic scope) and/or their ability to acquire and utilize energy judiciously. Here, we explore how environmental factors and physiological limitations influence exercise and metabolism in fish while foraging, migrating to spawning grounds, and providing parental care. We do so with three case studies that use a number of approaches to studying exercise in wild fish using biologging and biotelemetry platforms. Bonefish (Albula vulpes) selectively use shallow water tropical marine environments to forage when temperatures are near optimal for aerobic scope and exercise capacity. Bonefish energy expenditure at upper thermal extremes is maximal while activity levels diminish, likely caused by reduced aerobic scope. Pacific salmon (Oncorhynchus spp.) reproductive migrations frequently involve passage through hydraulically challenging areas, and their ability to successfully pass these regions is constrained by their physiological capacity for exercise. Aerobic scope and swim performance are correlated with migration difficulty among sockeye salmon (O. nerka) populations; however, depletion of endogenous energy stores can also limit migration success. In another example, male smallmouth bass (Micropterus dolomieu) allocate a significant amount of energy to nest-guarding behaviors to protect their developing brood. Smallmouth bass body size, endogenous energy reserves, and physiological state influence nest-guarding behaviors and reproductive success. We suggest that in some scenarios (e.g., bonefish foraging, Pacific salmon dam passage) metabolic capacity for exercise may be the strongest determinant of biological fitness, while in others (e.g., long distance salmon migration, smallmouth bass parental care) energy stores may be more important. Interactions among environmental and ecological factors, fish behavior, and fish physiology offer important avenues of mechanistic inquiry to explain ecological dynamics and demonstrate how exercise is fundamental to the ecology of fish.

http://ift.tt/2w1d2Ty

Plasmodium Infections in Natural Populations of Anolis sagrei Reflect Tolerance Rather Than Susceptibility

Synopsis

Parasites can represent formidable selection pressures for hosts, but the cost of infection is sometimes difficult to demonstrate in natural populations. While parasite exploitation strategies may, in some instances, actually inflict low costs on their hosts, the response of hosts to infection is also likely to determine whether or not these costs can be detected. Indeed, costs of infection may be obscured if infected individuals in the wild are those that are the most tolerant, rather than the most susceptible, to infection. Here we test this hypothesis in two natural populations of Anolis sagrei, one of the most common anole lizard of the Bahamas. Plasmodium parasites were detected in > 7% of individuals and belonged to two distinct clades: P. mexicanum and P. floriensis. Infected individuals displayed greater body condition than non-infected ones and we found no association between infection status, stamina, and survival to the end of the breeding season. Furthermore, we found no significant difference in the immuno-competence (measured as a response to phytohemagglutinin challenge) of infected versus non-infected individuals. Taken together, our results suggest that the infected individuals that are caught in the wild are those most able to withstand the cost of the infection and that susceptible, infected individuals have been removed from the population (i.e., through disease-induced mortality). This study highlights the need for caution when interpreting estimates of infection costs in natural populations, as costs may appear low either when parasites exploitation strategies truly inflict low costs on their hosts or when those costs are so high that susceptible hosts are removed from the population.

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How Do We Measure the Cost of Whole-Organism Performance Traits?

Synopsis

Whole-organism performance traits, such as maximal speed and endurance capacity are undoubtedly costly, but we know little about how or when all of the costs associated with performance are paid to individuals or how to measure them. To understand how performance traits might be involved in trade-offs with other life-history traits it is critical to determine the development, production, and maintenance costs of performance traits, as well as how each of these changes with increased or decreased use of the performance trait. We discuss the advantages and disadvantages of several potential phenotypic measures of dynamic whole-organism performance that may be used in life-history studies, including direct performance measures; metabolic rates; ecological cost of transport; and changes in metabolic rate after training. We use the first approach, direct performance measures, to show trade-offs between endurance capacity and several traditional life history variables in phrynosomatid lizards. The largest problem currently in determining the costs of performance traits and how those costs might lead to life-history trade-offs is that there are estimates of performance costs in very few taxa, and when there are, those species typically are not studied with respect to "traditional" life-history traits.

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Do Bar-Headed Geese Train for High Altitude Flights?

Synopsis

Exercise at high altitude is extremely challenging, largely due to hypobaric hypoxia (low oxygen levels brought about by low air pressure). In humans, the maximal rate of oxygen consumption decreases with increasing altitude, supporting progressively poorer performance. Bar-headed geese (Anser indicus) are renowned high altitude migrants and, although they appear to minimize altitude during migration where possible, they must fly over the Tibetan Plateau (mean altitude 4800 m) for much of their annual migration. This requires considerable cardiovascular effort, but no study has assessed the extent to which bar-headed geese may train prior to migration for long distances, or for high altitudes. Using implanted loggers that recorded heart rate, acceleration, pressure, and temperature, we found no evidence of training for migration in bar-headed geese. Geese showed no significant change in summed activity per day or maximal activity per day. There was also no significant change in maximum heart rate per day or minimum resting heart rate, which may be evidence of an increase in cardiac stroke volume if all other variables were to remain the same. We discuss the strategies used by bar-headed geese in the context of training undertaken by human mountaineers when preparing for high altitude, noting the differences between their respective cardiovascular physiology.

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Omega-3 fatty acid levels in red blood cell membranes and physical decline over 3 years: longitudinal data from the MAPT study

Abstract

Studies have shown that omega-3 polyunsaturated fatty acids (PUFAs) are associated with brain, cardiovascular, and immune function, as well as physical performance and bone health in older adults. So far, few studies have investigated the associations between PUFA status and performance-based tests of physical function. The objective of this study was to investigate the associations between the omega-3 PUFA levels (eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)) in red blood cell (RBC) membranes and physical performance, in a sample of community-dwelling older adults. This is a longitudinal observational study using data from the Multidomain Alzheimer's Disease Trial (MAPT), a randomized, placebo-controlled trial. Four hundred participants from MAPT placebo group with available PUFA data were included. Omega-3 PUFA levels in RBC membranes were measured at baseline, and their percentage of total RBC membrane fatty acid content was calculated. We dichotomized the standardized omega-3 PUFA levels in RBC membranes as low (lowest quartile) vs. high (three upper quartiles). Gait speed (in m/s) and short physical performance battery (SPPB) score (range from 0 to 12, higher is better) were used to assess physical performance at baseline and after 6, 12, 24, and 36 months. Participants were 75.2 (± 4.3) years old and 68% were female. Bivariate analyses found that the characteristic of the participants in the lowest quartile of omega-3 PUFA levels (Q1) and those in the three upper quartiles (Q2–Q4) was not different at baseline; only those in Q1 were slightly older. In an unadjusted model, the difference in gait speed after 3 years of follow-up was significant (− 0.09 ± 0.03 m/s; p = 0.008) between participants in Q1 and those in Q2–Q4. In a model adjusted for age, gender, educational level, cognitive function, depressive status, body mass index, physical activity, grip strength, and their time interaction, this difference remained clinically relevant (− 0.07 ± 0.04 m/s; p = 0.075). No difference between the two groups was found for the SPPB score development over 3 years. Older adults with subjective memory complaints and in the lower quartile of omega-3 have a faster decline on gait speed compared to people in the three upper quartiles. Other longitudinal studies are needed to explore this association and to examine mechanisms.

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On Faculty Development of STEM Inclusive Teaching practices

Abstract

Faculty development of inclusive teaching practices has become more common in response to significant differences in STEM student retention between underrepresented minorities in the United States and students from other ethnic groups. Approaches to solve this have shifted from focusing on student deficits, to changing campus culture, including the mindsets of instructors who teach STEM courses. In this manuscript I argue that based on the literature informing the conceptual frameworks used for faculty development in inclusive teaching, faculty developers should reframe the message of their workshops to focus participants more on the scope of the journey, and shift the direction of overall efforts some to redevelop pedagogical training at the graduate and postdoc levels. Informed by historical as well as recent theories on the role of higher education to society, I highlight the areas of the literature that can effectively inform our current approaches to inclusion. I also briefly review the reasons why this approach is needed, and include suggestions for new faculty development approaches for long-term sustainable change in STEM inclusive education at the postsecondary level.

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Ring Chromosome in Myeloid Neoplasms is Associated with Complex Karyotype and Disease Progression

Ring chromosome (RC) is a poorly understood genetic anomaly seen in myeloid neoplasms. This study aims to shed light on the clinical significance of this finding. We identified 96 cases of myeloid neoplasms with RC from 3 academic hospitals. Clinicopathologic features and overall- (OS) and leukemia-free survival were reviewed and compared to cases of myeloid neoplasms lacking RC. We identified 59 acute myeloid leukemias (AML-RC) and 37 myelodysplastic syndromes (MDS-RC) with RC identified on routine karyotyping.

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Hospital quality factors influencing the mobility of patients for radical prostate cancer radiotherapy: a national population based study

Using geographic information systems and econometric modelling we present the first national study evaluating the hospital quality factors that attract patients for radiotherapy treatment in health-care markets. We found that one in five men bypassed their nearest radiotherapy centre for treatment, especially those who were younger, and more affluent. In the absence of indicators reflecting treatment quality, centres that were early adopters of intensity modulated radiotherapy or that offered shorter hypofractionated treatment schedules were more attractive to patients.

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Does modality matter? Palliative care units associated with more cost-avoidance than consultations

Inpatient palliative care is associated with reduced costs, but the optimal model for providing inpatient palliative care is unknown.

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Spiritual Needs and Perception of Quality of Care and Satisfaction with Care in Oncology Patients: a Multi-cultural Assessment

Assessment and response to patients' spiritual concerns are crucial components of high quality supportive care. Better measures of spiritual needs across the cultural spectrum may help direct necessary interventions.

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Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma

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Knowledge or noise? Making sense of General Practitioners’ and Consultant use of 2-week-wait referrals for suspected cancer

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Long-term outcomes of patients with 10 or more colorectal liver metastases

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Leukocyte telomere length and renal cell carcinoma survival in two studies

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Correlation between circulating mutant DNA and metabolic tumour burden in advanced non-small cell lung cancer patients

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The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

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Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium

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Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

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The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer

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HMGA1 expression levels are elevated in pancreatic intraepithelial neoplasia cells in the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer

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Platelet releasate promotes breast cancer growth and angiogenesis via VEGF–integrin cooperative signalling

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A comparative study of germline BRCA1 and BRCA2 mutation screening methods in use in 20 European clinical diagnostic laboratories

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TCTP as a therapeutic target in melanoma treatment

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Disseminated tumour cells with highly aberrant genomes are linked to poor prognosis in operable oesophageal adenocarcinoma

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A combined biomarker panel shows improved sensitivity for the early detection of ovarian cancer allowing the identification of the most aggressive type II tumours

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Lung cancer prognostic index: a risk score to predict overall survival after the diagnosis of non-small-cell lung cancer

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RBM38 is involved in TGF-β-induced epithelial-to-mesenchymal transition by stabilising zonula occludens-1 mRNA in breast cancer

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Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

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Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer

Objective

Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.

Design

To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets.

Results

By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G₁ cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer.

Conclusions

BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453).

Trial registration number

NCT02884453; Pre-results

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Adherence to the Mediterranean Dietary Pattern and Incidence of Nephrolithiasis in the Seguimiento Universidad de Navarra Follow-up (SUN) Cohort

Diet plays an important role in the pathogenesis of nephrolithiasis. Limited data are available to investigate the association between a Mediterranean dietary pattern and risk for nephrolithiasis.

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Concentrations of Trace Elements in Hemodialysis Patients: A Prospective Cohort Study

Low concentrations and excessive concentrations of trace elements have been commonly reported in hemodialysis patients, but available studies have several important limitations.

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Prenatal Growth and CKD in Older Adults: Longitudinal Findings From the Helsinki Birth Cohort Study, 1924-1944

According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, several noncommunicable diseases, including hypertension, type 2 diabetes, and coronary heart disease, have their origins in early life. Chronic kidney disease (CKD) has traditionally been assumed to develop as the result of an interaction between genetic and environmental factors, although more recently, the importance of factors present early in life has been recognized.

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C4 Nephritic Factors in C3 Glomerulopathy: A Case Series

C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases.

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DOA-informed source extraction in the presence of competing talkers and background noise

A desired speech signal in hands-free communication systems is often degraded by noise and interfering speech. Even though the number and locations of the interferers are often unknown in practice, it is justi...

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Efficient reversible data hiding in encrypted image with public key cryptosystem

This paper proposes a new reversible data hiding scheme for encrypted images by using homomorphic and probabilistic properties of Paillier cryptosystem. The proposed method can embed additional data directly i...

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Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities

Abstract

Background

Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.

Methods

We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.

Results

TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.

Conclusions

Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.

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S198 Different region-specific networks sustain focal seizures with a fast-activity onset: Evidence from patients and animal models

Focal seizure patterns generated by different cortical networks are not well characterized. I will provide evidence that different seizure patterns are generated by specific brain regions explored with stereo-EEG in patients with drug-resistant focal epilepsy candidate for surgery. Two main patterns typical of temporo-mesial involvement and neocortical involvement are identified. These two patterns were reproduced in an in vitro isolated brain preparation to characterize the network and cellular determinants.

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S200 Paroxyzmal depolarization shift – Is it an interictal phenomenon is humans?

Paroxysmal depolarization shift (PDS) was extensively studied in animal models of acute and subacut epilepsy. Based on the observation that PDS occurred between behavioral seizures it had been complemented by interictal discharges, that can be recorded in humans in the seizure onset zone (SOZ) and around. PDS is characterized by excessive discharge of large number of neurons within a certain area of the cortex. Studying human SOZ with microelectrodes revealed that selective or no neuronal firing increase happen during IIDs.

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P382 Neural mechanisms of attentional switching during distraction analgesia: A single-trial laser evoked potential study

Noxious stimuli capture attention and at the same time, pain is attenuated by a concurrent cognitive task. The present study aimed to elucidate the cortical mechanisms underlying diminution of pain during attentional distraction using single-trial electrocortical and subjective responses.

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P381 Event-related potentials and personality type in patients with multiple sclerosis

The clinical course of multiple sclerosis (MS) can vary significantly among patients and is affected by many factors. Among these, psychoaffective aspects, including the type of personality, have been recently gaining attention. The aim of our study was to investigate the parameters of event-related potentials (ERP) with regards to personality type in MS patients.

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Then and now: EMS practices through the years

By Will Wyatt, EMS1 Contributor When you have engaged in an endeavor for a long time, invariably, noticeable changes occur. The longer you participate in a hobby, activity or career, the more changes time brings. I was reminded of this evolution the other night as I was assisting an old friend teaching a CPR class to a church group. The students were nice people, eager to learn. They of course had the ...

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Rho-GTPase activating-protein 18: a biomarker associated with good prognosis in invasive breast cancer

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RNA helicase DHX15 acts as a tumour suppressor in glioma

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A cluster randomised feasibility study of an adolescent incentive intervention to increase uptake of HPV vaccination

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Did the addition of concurrent chemotherapy to conventional radiotherapy improve survival for patients with HPV+ve and HPV−ve Oropharynx cancer? A population-based study

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Circulating resistin levels and risk of multiple myeloma in three prospective cohorts

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RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

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Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

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Measurements of Long-range Electronic Correlations During Femtosecond Diffraction Experiments Performed on Nanocrystals of Buckminsterfullerene

We describe an experiment designed to probe the electronic damage induced in nanocrystals of Buckminsterfullerene (C60) by intense, femtosecond pulses of X-rays. The experiment found that, surprisingly, rather than being stochastic, the X-ray induced electron dynamics in C60 are highly correlated, extending over hundreds of unit cells within the crystals1.

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Like Adults, Children Show Bias in Attributing Mental States to Others

Young children are more likely to attribute mental states to characters that belong to the same group as them relative to characters that belong to an outside group, according to findings published in Psychological Science, a journal of the Association for Psychological Science. The study shows that 5- and 6-year-olds were more likely to describe interactions between two characters in terms of what they were thinking and feeling when the characters had the same gender or geographic origin as them.

"We found that young children were selective in the way they attribute mental states – they were less likely to spontaneously refer to the mind of individuals belonging to a different group," says researcher Niamh McLoughlin of the University of York. "Our research suggests that, at least from the age of 5, children demonstrate a bias that might be similar to dehumanization – ascribing fewer mental abilities and uniquely human traits to others. In addition, this work illustrates that there are situations in which children are more or less motivated to reason about the minds of other people."

Previous research has shown that adults tend to dehumanize people who belong to social groups or categories – for example, race, gender, socioeconomic status – that are different from their own. These "outsiders" are seen as having less intelligence, rationality, and emotional depth relative to those who belong to the in-group. McLoughlin and University of York co-author Harriet Over were interested in investigating the developmental origins of this phenomenon.

"Our aim was to examine whether young children also exhibited this bias with relation to mental state attribution," says McLoughlin.

Adapting an established technique, the researchers showed a total of 128 5- and 6-year-olds animations of a big triangle and a small triangle that seemed to interact, with one triangle seemingly coaxing or surprising the other.

Each child saw two videos. In one, the triangles were described as having the same gender or coming from the same town as the participant; in the other, the triangles were described as having a different gender or coming from a far-away country. The researchers chose to examine gender because it's a category that children are particularly sensitive to, while they decided to look at geographic origin because of its relevance to current social and political debates.

The researchers asked the participants to describe what happened and to rate how much they liked the group discussed in each video.

Using a predetermined coding scheme, the researchers counted any words that described a character's thoughts, desires, emotions, intentions, or current states as mental-state terms.

The data showed that 6 year-olds used more mental-state words overall and a more diverse range of these words compared with children who were one year younger, a finding that highlights the ongoing development of theory-of-mind processes in early childhood.

More importantly, both 5- and 6-year-olds used more mental-state terms when they believed the characters had the same gender or home town as opposed to when they had a different one. Six-year-olds also used more diverse mental-state words in describing characters from the same group relative to those from a different group.

This group-based bias extended to direct ratings: Participants also preferred individuals who belonged to their own gender and geographic group.

These findings hint at early origins for social phenomena including bias between social groups and dehumanization, the researchers argue.

"We plan to use this research as the base for future work examining the social consequences of biased mental-state attribution, such as the extent to which children help members of an outgroup," says McLoughlin. "We hope that this work can ultimately inform research-led interventions that aim to foster positive intergroup relations."

This research was funded by Economic and Social Research Council Grant ES/K006702/1 (to H. Over).

All data have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Data.

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Quantification of the Abundance and Charging Levels of Transfer RNAs in Escherichia coli

Here we present a method for directly measuring transfer RNA charging levels from purified Escherichia coli RNA as well as a way to compare relative levels of transfer RNA, or any other short RNA, across different samples based on the addition of spike-in cells expressing a reference gene.

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A20 deletion in T cells modulates acute graft-versus-host disease in mice

The NF-κB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4⁺ and CD8⁺ donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-γ and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20^+/+ T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20^+/+ T cells, highlighting that A20 balances both, T cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T cell mediated inflammatory diseases like GVHD.

This article is protected by copyright. All rights reserved

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