Ecological and Evolutionary Benefits of Temperate Phage: What Does or Doesn't Kill You Makes You Stronger

Infection by a temperate phage can lead to death of the bacterial cell, but sometimes these phages integrate into the bacterial chromosome, offering the potential for a more long-lasting relationship to be established. Here we define three major ecological and evolutionary benefits of temperate phage for bacteria: as agents of horizontal gene transfer (HGT), as sources of genetic variation for evolutionary innovation, and as weapons of bacterial competition. We suggest that a coevolutionary perspective is required to understand the roles of temperate phages in bacterial populations.

The dual personality of temperate phages – as infectious lytic phages or prophages integrated within the bacterial genome – creates a complex interaction with bacterial hosts. Although potentially lethal, prophages confer a multitude of benefits for the host, suggesting the potential for both conflict and collaboration which must be viewed from a coevolutionary perspective that considers both host and phage fitness interests.

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Recent Progress in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia

Abstract

Purpose of Review

We reviewed recent diagnostic and therapeutic progress in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We summarized recent genetic data that may guide future efforts towards implementing risk-adapted therapy based on mutational profile and improving disease control and survival of affected patients.

Recent Findings

Recent genetic data in CNL and aCML prompted modifications to the World Health Organization (WHO) diagnostic criteria, which have improved our understanding of how CNL and aCML are different diseases despite sharing common findings of peripheral granulocytosis and marrow myeloid hyperplasia. The overlap of recurrently mutated genes between aCML and CMML support considering CSF3R-T618I mutated cases as a distinct entity, either as CNL or CNL with dysplasia. Ongoing preclinical and clinical studies will help to further inform the therapeutic approach to these diseases.

Summary

Our understanding of CNL and aCML has greatly advanced over the last few years. This will improve clarity for the diagnosis of these diseases, provide a strategy for risk stratification, and guide risk-adapted therapy.

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Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15–55 years of age

Abstract

Women remain at risk of human papillomavirus (HPV) infection for most of their lives. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. We investigated the 10-year immune response and long-term safety profile of the HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18 vaccine) in females aged between 15 and 55 years at first vaccination. Females who received primary vaccination with three doses of AS04-HPV-16/18 vaccine in the primary phase-III study (NCT00196937) were invited to attend annual evaluations for long-term immunogenicity and safety. Anti-HPV-16/18 antibodies in serum and cervico-vaginal secretions (CVS) were measured using enzyme-linked immunosorbent assay (ELISA). Serious adverse events (SAEs) were recorded throughout the follow-up period. Seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. It was found that 99.2% of 15–25-year olds remained seropositive for anti-HPV-18 compared to 93.7% and 83.8% of 26–45-year olds and 45–55-year olds, respectively. Geometric mean titers (GMT) remained above natural infection levels in all age groups. Anti-HPV-16 and anti-HPV-18 titers were at least 5.3-fold and 3.1-fold higher than titers observed after natural infection, respectively, and were predicted to persist above natural infection levels for ≥30 years in all age groups. At Year 10, anti-HPV-16/18 antibody titers in subjects aged 15–25 years remained above plateau levels observed in previous studies. Correlation coefficients for antibody titers in serum and CVS were 0.64 (anti-HPV-16) and 0.38 (anti-HPV-18). This study concluded that vaccinated females aged 15–55 years elicited sustained immunogenicity with an acceptable safety profile up to 10 years after primary vaccination, suggesting long-term protection against HPV.

The HPV-16/18 AS04-adjuvanted vaccine produced a sustained immune response in women aged 15–55 years at vaccination for up to 10 years, with an acceptable safety profile. Study results suggest that women in age groups not targeted by adolescent immunization and catch-up programs may still individually benefit from HPV vaccination.

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Inhibition of telomerase activity and induction of apoptosis by Rhodospirillum rubrum L-asparaginase in cancer Jurkat cell line and normal human CD4+ T lymphocytes

Abstract

Rhodospirillum rubrum L-asparaginase mutant _{E149R, V150P, F151T} (RrA) down-regulates telomerase activity due to its ability to inhibit the expression of telomerase catalytic subunit hTERT. The aim of this study was to define the effect of short-term and long-term RrA exposure on proliferation of cancer Jurkat cell line and normal human CD4⁺ T lymphocytes. RrA could inhibit telomerase activity in dose- and time-dependent manner in both Jurkat and normal CD4⁺ T cells. Continuous RrA exposure of these cells resulted in shortening of telomeres followed by cell cycle inhibition, replicative senescence, and development of apoptosis. Complete death of Jurkat cells was observed at the day 25 of RrA exposure while normal CD4⁺ T cells died at the day 50 due to the initial longer length of telomeres. Removal of RrA from senescent cells led to a reactivation of hTERT expression, restoration telomerase activity, re-elongation of telomeres after 48 h of cultivation, and survival of cells. These findings demonstrate that proliferation of cancer and normal telomerase-positive cells can be limited by continuous telomerase inhibition with RrA. Longer telomeres of normal CD4⁺ T lymphocytes make such cells more sustainable to RrA exposure that could give them an advantage during anti-telomerase therapy. These results should facilitate further investigations of RrA as a potent anti-telomerase therapeutic protein.

Long-term exposure to Rhodospirillum rubrum L-asparaginase (RrA) induced telomere shortening and eventual growth arrest and apoptosis in vitro. Telomerase inhibition using RrA may be considered as a promising approach for cancer treatment.

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The Use of Electronic Medical Records in Jordanian Hospitals: A Nationwide Survey

No previous nationwide study has estimated to what extent electronic health records have been implemented in Jordanian hospitals. The purpose of this descriptive, cross-sectional study was to explore the level of adoption and use of electronic health records in Jordanian hospitals across all major healthcare service providers. The standardized American Hospital Association annual survey was used. The level of use of electronic functionalities of electronic health records was determined. The association of certain hospital characteristics with the adoption of electronic health records was examined. A proportion of 10.3% of the participating hospitals had a comprehensive use of electronic health records in all units, and 15.5% had a basic system in at least one unit. Most (74.2%, n = 72) had not implemented electronic health records. The hospitals with a higher rate of adoption were found to be larger, government, urban, and teaching hospitals that had coronary care units. The level of adoption of electronic health records in Jordan is relatively low. This fact should impel policy makers to resolve the challenges and obstacles for such adoption. National strategic plans are needed to address the goals and implementation processes of electronic health record systems in all Jordanian hospitals.

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Joyce Sensmeier Honored With 2017 Virginia K. Saba Nursing Informatics Leadership Award

No abstract available

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SymptomCare@Home: Developing an Integrated Symptom Monitoring and Management System for Outpatients Receiving Chemotherapy

SymptomCare@Home, an integrated symptom monitoring and management system, was designed as part of randomized clinical trials to help patients with cancer who receive chemotherapy in ambulatory clinics and often experience significant symptoms at home. An iterative design process was informed by chronic disease management theory and features of assessment and clinical decision support systems used in other diseases. Key stakeholders participated in the design process: nurse scientists, clinical experts, bioinformatics experts, and computer programmers. Especially important was input from end users, patients, and nurse practitioners participating in a series of studies testing the system. The system includes both a patient and clinician interface and fully integrates two electronic subsystems: a telephone computer-linked interactive voice response system and a Web-based Decision Support–Symptom Management System. Key features include (1) daily symptom monitoring, (2) self-management coaching, (3) alerting, and (4) nurse practitioner follow-up. The nurse practitioner is distinctively positioned to provide assessment, education, support, and pharmacologic and nonpharmacologic interventions to intensify management of poorly controlled symptoms at home. SymptomCare@Home is a model for providing telehealth. The system facilitates using evidence-based guidelines as part of a comprehensive symptom management approach. The design process and system features can be applied to other diseases and conditions.

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Application of Clinical Intelligence to Streamline Care in Aortic Emergencies

This article discusses the lessons learned by an interdisciplinary team in a large metropolitan specialty hospital during the implementation of the Code Aorta protocol for aortic emergencies and the subsequent application of technological enhancements to improve data transfer. Aortic dissections require rapid diagnosis and surgical treatment; thus, in order to optimize patient outcomes, clinicians must be accessible, data must be readily available, and proper prompts and notifications must be made to alert and ready teams. An interdisciplinary team reviewed our hospital's processes and architecture of systems to define how we provide care during aortic emergencies. Based on this insight into patient flow, we ultimately developed a Code Aorta protocol to streamline provision of care during aortic emergencies. This process focused on protocol development, human-technology interfaces, and outcome-oriented metrics. The team also aimed to heighten awareness of the emergent process and to understand relevant outcomes data. After introduction of the Code Aorta protocol, a 78% reduction was achieved in time-to-treatment from the previous year's average time. In addition, the average length of stay was reduced by 2.4 days (18%). The team's efforts focused on clinical communication, aiming to link technology to maximize clinical efficiency. The initial results of our Code Aorta protocol show promise that continual refinement of patient care processes during aortic emergencies will improve outcomes for patients suffering aortic dissection.

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Pilot Test of a Collaborative “Helping Hands” Tele-Assistance System for the Development of Clinical Skills

No abstract available

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Using Quick Response Codes in the Classroom: Quality Outcomes

With smart device technology emerging, educators are challenged with redesigning teaching strategies using technology to allow students to participate dynamically and provide immediate answers. To facilitate integration of technology and to actively engage students, quick response codes were included in a medical surgical lecture. Quick response codes are two-dimensional square patterns that enable the coding or storage of more than 7000 characters that can be accessed via a quick response code scanning application. The aim of this quasi-experimental study was to explore quick response code use in a lecture and measure students' satisfaction (met expectations, increased interest, helped understand, and provided practice and prompt feedback) and engagement (liked most, liked least, wanted changed, and kept involved), assessed using an investigator-developed instrument. Although there was no statistically significant correlation of quick response use to examination scores, satisfaction scores were high, and there was a small yet positive association between how students perceived their learning with quick response codes and overall examination scores. Furthermore, on open-ended survey questions, students responded that they were satisfied with the use of quick response codes, appreciated the immediate feedback, and planned to use them in the clinical setting. Quick response codes offer a way to integrate technology into the classroom to provide students with instant positive feedback.

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Experience of Home Telehealth Technology in Older Patients With Diabetes

The incidence of diabetes, a common chronic disease among older adults, is increasing annually. The lack of blood glucose regulation can result in severe diabetes-related complications and substantial healthcare costs, making self-care programs specific to this population especially important. Combined with reduced numbers of healthcare professionals, the integration of healthcare and information technology and the older adults' adoption of telehealth services have become increasingly important. This study used a qualitative method to interview 18 older study participants who used a telehealth service. Subject perceptions and suggestions regarding using such a service for diabetes management were investigated. Content analysis was used to examine the interview data and determine the older patients' acceptance and perceived benefits of telehealth service. Four main themes emerged: (1) initial trial encouragement from the doctors, nurses, and financial incentives; (2) enhanced self-management capability through continuous device use for better outcomes; (3) ambivalent feelings regarding dependence on others for problem solving; and (4) consideration for continual technology use for an uncertain future. These results serve as a reference for promoting, assessing, and verifying telehealth models for older patients with diabetes.

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Increasing Health Portal Utilization in Cardiac Ambulatory Patients: A Pilot Project

Increasing health portal participation actively engages patients in their care and improves outcomes. The primary aim for this project was to increase patient health portal utilization. Nurses used a tablet-based demo to teach patients how to navigate the health portal. Assigning health videos to the portal was a tactic used to increase utilization. Each patient participant was surveyed about health portal utilization at initial nurse navigator appointment, day of procedure, and 30 days after discharge. Seventy-three percent (n = 14) of the 19 selected patients received the intervention; 36% (n = 4) of patients reported using a health portal feature; meaningful use metric preintervention increased from 12% to 16% after the intervention; 16% and 18% of patients viewed assigned videos in their health portal prior to procedure and after hospital discharge. Patients need a reason to access their health portal. Education alone is not enough to motivate patient portal use. Further research is needed to specify what tactics are required to motivate patients to use their health portals.

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Using Quick Response Codes in the Classroom: Quality Outcomes

No abstract available

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FDA Approves First Biosimilar to Treat Cancer [News in Brief]

Like the related agent bevacizumab, the drug can be used to treat multiple types of cancer.

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Deep Learning based multi-omics integration robustly predicts survival in liver cancer

Identifying robust survival subgroups of hepatocellular carcinoma (HCC) will significantly improve patient care. Currently, endeavor of integrating multi-omics data to explicitly predict HCC survival from multiple patient cohorts is lacking. To fill in this gap, we present a deep learning (DL) based model on HCC that robustly differentiates survival subpopulations of patients in six cohorts. We build the DL based, survival-sensitive model on 360 HCC patients' data using RNA-seq, miRNA-seq and methylation data from TCGA, which predicts prognosis as good as an alternative model where genomics and clinical data are both considered. This DL based model provides two optimal subgroups of patients with significant survival differences (P=7.13e-6) and good model fitness (C-index=0.68). More aggressive subtype is associated with frequent TP53 inactivation mutations, higher expression of stemness markers (KRT19, EPCAM) and tumor marker BIRC5, and activated Wnt and Akt signaling pathways. We validated this multi-omics model on five external datasets of various omics types: LIRI-JP cohort (n=230, C-index=0.75), NCI cohort (n=221, C-index=0.67), Chinese cohort (n=166, C-index=0.69), E-TABM-36 cohort (n=40, C-index=0.77), and Hawaiian cohort (n=27, C-index=0.82). This is the first study to employ deep learning to identify multi-omics features linked to the differential survival of HCC patients. Given its robustness over multiple cohorts, we expect this workflow to be useful at predicting HCC prognosis prediction.

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Therapy for Chronic Myelomonocytic Leukemia in a New Era

Abstract

Chronic myelomonocytic leukemia (CMML) is a myeloid malignancy which shares clinical and morphologic features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and is classified by the WHO as an MDS/MPN. The defining feature of CMML is clonal hematopoiesis that results in peripheral monocytosis. The benefit of early treatment is currently unclear, and treatment may be held until the disease exhibits accelerated blast counts or the patient becomes symptomatic. Optimal treatments for CMML are not well defined. Conventional treatments include hydroxyurea, cytarabine, and hypomethylating agents. However, all treatment options are limited and, with the exception of allogeneic stem cell transplantation, are considered palliative. As we continue to learn about the genomics of CMML and about arising therapeutic targets and those under active clinical investigation, the future therapy of CMML will likely improve considerably. Here, we review the data available for conventional therapies and highlight emerging therapeutic strategies.

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The association between FABP7 serum levels with survival and neurological complications in acetaminophen-induced acute liver failure: a nested case–control study

Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality due to intracranial hypertension (ICH), a result of cerebral edema (CE) and astrocyte swelling. Brain-type fatty ...

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Continuous eruption of maxillary teeth and changes in clinical crown length: A 10-year longitudinal study in adult women

Abstract

Background

Continuous physiologic eruption of teeth may become a main aesthetic issue for implants inserted in the maxillary anterior region.

Purpose

To study maxillary tooth vertical changes during a 10 years period by 3-dimensional superimposition of digital dental casts.

Material and methods

Alginate impressions were taken at both baseline and at the 10-year follow-up in a sample of 24 adult Swedish women (average age of 48 years at T0). The upper arch plaster casts were digitized with a 3-dimensional scanner and then superimposed on the palate and the palatal rugae. Occlusal and gingival anatomic structures were digitized for each upper tooth from first molar to first molar. The vertical changes of these structures gave an indication of tooth extrusion and apical or coronal displacement of the gingival margin.

Results

A trend was found for eruption in the anterior region (+0.3 mm on average) while a slight extrusion if not any was found in the first molars and premolars area. Vertical displacement of the gingival margin showed also a positive trend from first molars to incisors. Negative average values, corresponding clinically to gingival recession, were found on first molars (−0.36 mm) and premolars (−0.15 mm), while no displacement was detected in the anteriors. Clinical crown lengths increased in all teeth and it is mainly due to gingival recession for first molars and premolars, while for the incisors the eruption is coupled to a slight equivalent gingival coronal migration.

Conclusions

During a 10-year period, continuous eruption takes place in female adult subjects, especially in the upper incisors area while gingival recession occurred in first molars and premolars area leading to crown length elongation. Implant placement in the anterior area of the maxilla may have an aesthetic impact even in mature adults due to the continuous eruption of the adjacent teeth.

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Unusual presentation of long-lost inferior vena cava filter

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Anastomotic stricture: a complication of endoscopic choledochoduodenostomy

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Rare cause of colitis with calcified mesenteric veins

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Cystic pheochromocytoma masquerading as a cystic pancreatic tumour

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Unique case of a laparoscopic hand-assisted repair of an intramesosigmoid hernia causing bowel obstruction in a virgin abdomen

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Internal hernia as a rare cause of ischaemic colitis: a case report and literature review

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Emergency pancreatic resection for glucagonoma associated with severe necrolytic migratory erythema

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Cost-effective imaging for resectability of liver lesions in colorectal cancer: an economic decision model

Background

This study aimed to determine the cost-effectiveness of contrast-enhanced magnetic resonance imaging (CE-MRI) compared with multiphase CE computed tomography (CE-CT) scan to characterize suspected liver lesions in patients with known colorectal carcinoma.

Methods

A decision analytic model linking diagnostic accuracy to health outcomes in patients with colorectal carcinoma was constructed. The model assumed that CE-MRI has superior sensitivity and equivalent specificity to CE-CT, and patients with a colorectal liver metastasis could be eligible for curative surgery or chemotherapy and palliation. Delayed diagnosis or misdiagnosis was associated with worse health outcomes (disutility). Cost-effectiveness was calculated as the incremental cost relative to the incremental benefit, the benefit was estimated using quality-adjusted life years. Sensitivity analyses were conducted to test the robustness of the results.

Results

The clinical evidence supports increased sensitivity of CE-MRI compared with CE-CT (0.943 versus 0.768). CE-MRI was more effective and more costly than CE-CT. The incremental cost-effectiveness ratio was estimated to be $40 548 per quality-adjusted life year gained. The model is most sensitive to the cost of MRI, cost of palliative treatment and the disutility associated with delayed palliative care. The results were also sensitive to the assumptions made about the clinical algorithm.

Conclusion

The results provide evidence of the potential cost-effectiveness associated with CE-MRI for the diagnosis of liver metastases in patients with identified colorectal carcinoma. CE-MRI can be recommended as cost-effective provided it replaces CE-CT and that improved diagnostic accuracy results in earlier, curative, disease management.

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Comparing pathological complete response rate using oral capecitabine versus infusional 5-fluorouracil with preoperative radiotherapy in rectal cancer treatment

Background

Infusional 5-fluorouracil (5-FU) has been the standard radiation sensitizer in patients undergoing preoperative long-course chemoradiotherapy (CRT) for locally advanced rectal cancer in Australia. Capecitabine (Xeloda) is an oral 5-FU prodrug of comparable pharmacodynamic activity, currently preferred in place of 5-FU infusion, its established counterpart in neoadjuvant CRT for rectal cancer. The few studies quantifying pathological complete response (pCR) of Xeloda versus 5-FU have produced inconsistent results. We reviewed our own data to determine if the rates of pCR of oral capecitabine were non-inferior to intravenous 5-FU in patients undergoing neoadjuvant CRT for rectal cancer.

Methods

A retrospective study was performed from a prospectively kept database. Four hundred and fifty-two patients received preoperative CRT from January 2006 to January 2016. Pelvic radiotherapy was delivered concurrently with capecitabine (n = 42) or infusional 5-FU (n = 341). The remaining received different chemotherapy regimens. Surgery was performed 6–12 weeks of CRT completion. Pathological responses were assessed using Dworak regression grading score (0–4). Clinical outcomes were evaluated in terms of local control and recurrence-free survival.

Results

The proportion of patients who had a tumour regression score of 4 (pCR) after CRT was 4/42 (9.5%) in the capecitabine group and 71/341 (20%) in the infusional 5-FU group (P = 0.082). pCR was an independent predictor for survival in this group of patients (hazard ratio: 0.002, P = 0.0001, 95% confidence interval: 0.0001–0.027).

Conclusion

The use of capecitabine as neoadjuvant chemotherapy in patients with rectal cancer was associated with a reduced rate of pCR. However this difference did not achieve statistical significance.

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Pancreatoduodenectomy in a public versus private teaching hospital is comparable with some minor variations

Background

The impact of the public and private hospital systems on major abdominal operations that are demanding on clinical resources, such as pancreatic surgery, has not been explored in an Australian setting. This study examines the perioperative outcome of patients undergoing pancreatoduodenectomy (PD) at a major public and private hospital.

Methods

Patients undergoing PD between January 2004 and October 2015 were classified based on their health insurance status and location of where the surgery was performed. Clinical variables relating to perioperative outcome were retrieved and compared using univariate and multivariate analyses.

Results

Four hundred and twenty patients underwent PD of whom 232 patients (55%) were operated on in the private hospital. Overall, there was no difference in morbidity and mortality in the public versus the private hospital. However, there were variations in public versus private hospital, this included longer duration of surgery (443 min versus 372 min; P < 0.001), increased estimated blood loss (683 mL versus 506 mL; P < 0.001) and more patients requiring perioperative blood transfusion (25% versus 13%; P = 0.001). Of the 10 complications compared, post-operative bleeding was higher in the private hospital (11% versus 5%; P = 0.051) and intra-abdominal collections were more common in the public hospital (11% versus 5%; P = 0.028). Independent predictive factors for major complications were American Society of Anesthesiologists score (odds ratio (OR) = 1.91; P = 0.050), patients requiring additional visceral resection (OR = 3.36; P = 0.014) and post-operative transfusion (OR = 3.37; P < 0.001). The hospital type (public/private) was not associated with perioperative outcome.

Conclusion

Comparable perioperative outcomes were observed between patients undergoing PD in a high-volume specialized unit in both the public and private hospital systems.

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Genetic Variations of DNA Repair Genes in Breast Cancer

Abstract

Genetic variations in DNA repair genes may affect DNA repair capacity therefore increase risk for cancer. In our study, we evaluted the relation between DNA repair gene polymorphisms XRCC1 rs1799782, rs25487, rs25489; XPC rs2228000, rs2228001; XPD rs1799793, rs13181; XRCC3 rs861539; RAD51B rs10483813, rs1314913 and breast cancer risk for 202 Turkish cases in total, in which 102 patients with breast cancer and 100 controls. Genotyping of the DNA samples was carried out by multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) using Sequenom MassARRAY 4 analyzer. Genotype and allele distributions were calculated between the groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. rs25487 AA genotype and A allele was found to be increased in the control group (respectively, OR 0.16 95% CI 0.02–1.06, p = 0.058; OR 1.55, 95% CI 1.01–2.36, p = 0.043) and rs861539 T allele was found to be decreased in the patient group (OR 1.53, 95% CI 1.01–2.30, p = 0.049). No association with breast cancer was found for the remaining SNPs. Our findings suggest that XRCC1 rs25487 AA genotype and A allele, XRCC3 rs861539 T allele may have protective effects in breast cancer for Turkish population.

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Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.461

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Sesn2/AMPK/mTOR signaling mediates balance between survival and apoptosis in sensory hair cells under stress

Sesn2/AMPK/mTOR signaling mediates balance between survival and apoptosis in sensory hair cells under stress

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.457

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Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation

Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.501

http://ift.tt/2wBrtgu

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.478

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Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer

Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.460

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miRNA-223 upregulated by MYOD inhibits myoblast proliferation by repressing IGF2 and facilitates myoblast differentiation by inhibiting ZEB1

miRNA-223 upregulated by MYOD inhibits myoblast proliferation by repressing IGF2 and facilitates myoblast differentiation by inhibiting ZEB1

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.479

http://ift.tt/2gfgkvU

Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition

Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.471

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miR-23a/b promote tumor growth and suppress apoptosis by targeting PDCD4 in gastric cancer

miR-23a/b promote tumor growth and suppress apoptosis by targeting PDCD4 in gastric cancer

Cell Death & Disease, Published online: 5 October 2017; doi:10.1038/cddis.2017.447

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Contents

Amal Mattu

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Abdominal Aortic Emergencies

This article discusses abdominal aortic emergencies. There is a common thread of risk factors and causes of these diseases, including age, male gender, hypertension, dyslipidemia, and connective tissue disorders. The most common presenting symptom of these disorders is pain, usually in the chest, flank, abdomen, or back. Computed tomography scan is the gold standard for diagnosis of pathologic conditions of the aorta in the hemodynamically stable patient. Treatment consists of a combination of blood pressure and heart rate control and, in many cases, emergent surgical intervention.

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Forthcoming Issues

Trauma

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CME Accreditation Page

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Time-Critical Vascular Disasters

The body's highway for oxygen and nutrients is the vascular system, ranging from the aorta to small capillaries. This system interacts with every organ system in the body, with a myriad of pathology that must be considered.

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Mesenteric Ischemia

Mesenteric ischemia has 4 etiologies: arterial embolus, arterial thrombosis, venous thrombosis, and nonocclusive. No history or physical examination finding can definitively diagnose the condition. A wide variety of presentations occur. Pain out of proportion and gut emptying may occur early, with minimal tenderness. Once transmural infarction occurs, peritoneal findings and tenderness to palpation may occur. Physicians must be suspicious of pain out of proportion and scrutinize risk factors. Computed tomography angiography is the best imaging modality. Treatment requires surgery and interventional radiology consultation, intravenous antibiotics and fluids, and anticoagulation. The physician at the bedside is the best diagnostic tool.

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Copyright

ELSEVIER

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Vascular Disasters

EMERGENCY MEDICINE CLINICS OF NORTH AMERICA

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Vascular Emergencies

Cardiovascular disease is the number 1 cause of death in the United States and other first-world countries around the globe. It's no surprise, therefore, that a great deal of attention in emergency medicine is paid to the recognition and treatment of cardiovascular diseases. However, when the term "cardiovascular" is used in this context, most providers and laypersons only hear the first part of that word, "cardio." Emergency "cardio" seems to get the bulk of attention, and "vascular" often takes a back seat.

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In vivo Metabolic Profiles as Determined by 31 P and short TE 1 H MR-Spectroscopy

Abstract

Purpose

Previous ex vivo spectroscopic data from tissue samples revealed differences in phospholipid metabolites between isocitrate dehydrogenase mutated (IDHmut) and IDH wildtype (IDHwt) gliomas. We investigated whether these changes can be found in vivo using ¹H-decoupled ³¹P magnetic resonance spectroscopic imaging (MRSI) with 3D chemical shift imaging (CSI) at 3 T in patients with low and high-grade gliomas.

Methods

The study included 33 prospectively enrolled, mostly untreated patients who met spectral quality criteria according to the World Health Organization (WHO II n = 7, WHO III n = 17, WHO IV n = 9; 25 patients IDHmut, 8 patients IDHwt). The MRSI protocol included ¹H decoupled ³¹P MRSI with 3D CSI (3D ³¹P CSI), 2D ¹H CSI and a ¹H single voxel spectroscopy sequence (TE 30 ms) from the tumor area. For ¹H MRS, absolute metabolite concentration values were calculated (phantom replacement method). For ³¹P MRS, metabolite intensity ratios were calculated for the choline (C) and ethanolamine (E)-containing metabolites.

Results

In our patient cohort we did not find significant differences for the ratio of phosphocholine (PC) and phosphoethanolamine (PE), PC/PE, (p = 0.24) for IDHmut compared to IDHwt gliomas. Furthermore, we found no elevated ratios of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), GPC/GPE, (p = 0.68) or GPC/PE (p = 0.12) for IDHmut gliomas. Even the ratio (PC+GPC)/(PE+GPE) showed no significant differences with respect to mutation status (p = 0.16). Nonetheless, changes related to tumor grade regarding intracellular pH (pH_i) and phospholipid metabolism as well as absolute metabolite concentrations of co-registered 2D ¹H CSI data for tumor and control tissue showed the anticipated results.

Conclusion

Using 3D-CSI data acquisition, in vivo ³¹P MR spectroscopic measurement of phospholipid metabolites could not distinguish between IDHmut and IDHwt.

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Correction to: Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report

Following publication of the original article [1], the authors requested the following corrections: 1. Author 2—given name should ...  

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Intracellular superoxide level controlled by manganese superoxide dismutases affects trichothecene production in Fusarium graminearum

Abstract

The intracellular superoxide level is a clue to clarification of the regulatory mechanism for mycotoxin production in Fusarium graminearum. In this study, we focused on two manganese superoxide dismutases (SODs) of the fungus, FgSOD2 and FgSOD3, to investigate the relationship of the superoxide level to trichothecene production. Recombinant FgSOD2 and FgSOD3 showed SOD activity, and they were localized mainly in the mitochondria and cytoplasm, respectively. Trichothecene production and mRNA levels of Tri5 and Tri6, which encode a trichothecene biosynthetic enzyme and a key regulator of trichothecene production, respectively, were greatly reduced in gene-deletion mutants of FgSod2 and FgSod3 (ΔFgSod2 and ΔFgSod3). Significant increases in the cytosolic and mitochondrial superoxide levels were observed in ΔFgSod2 and ΔFgSod3, respectively. These results suggested that the cellular superoxide level affects trichothecene production in F. graminearum.

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A new cordycepin−producing caterpillar fungus Ophiocordyceps xuefengensis with artificial infection to the host, cultivation of mycelia and stromata

Abstract

Caterpillar fungi have numerous pharmacological and therapeutic applications in traditional medicine, due to a variety of active chemical constituents, such as cordycepin and adenosine. It is imperative to discover new resource for artificial cultivation and bio–metabolite production since the traditional natural species are endangered. In this study, a new strain HACM 001 was isolated and identified as Ophiocordyceps xuefengensis (O. xuefengensis) by rDNA–ITS sequencing. This strain showed the potential of artificial infection to caterpillar larvae leading to mummification, as well as fermentation mycelia in liquid culture and cultivation stromata in solid medium. Eight nucleosides and nucleobases, especially cordycepin and adenosine, were determined and analyzed with HPLC–DAD–Q–TOF–MS/MS technology. Cordycepin was detected in all forms of present O. xuefengensis strain at different contents, among which the highest content (37.1 μg/g) appeared in the stromata cultivated on solid medium. The content of adenosine in mycelia and stromata, respectively, reached 1155 μg/g and 1470 μg/g. Therefore, O. xuefengensis might be an alternative source for obtaining artificial fungus–caterpillar–larvae complex and producing cordycepin and adenosine.

http://ift.tt/2yLmfPV

MOG antibody seropositivity in a patient with encephalitis: beyond the classical syndrome

The presence of circulating anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) has been described in sera of patients with different inflammatory conditions of the central nervous system. In adults ...

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Clinical vignettes inadequate to assess impact of implicit bias: concerning limitations of a systematic review

Abstract

We are writing in response to Dehon et al's article "A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making"¹ in the August 2017 issue of Academic Emergency Medicine. As members of SAEM's Academy of Diversity and Inclusion in Emergency Medicine, we believe it is imperative to pursue research on the impact of bias and discrimination on clinical practice and healthcare outcomes. While we commend Dr. Dehon and her colleagues for their effort to assess the impact of implicit bias on clinical decision-making, we do not think that the evidence reviewed supports the breadth of their conclusions.

This article is protected by copyright. All rights reserved.

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Study Identifies Crucial Characteristic of High-Risk HPV

By comparing the genomes of women infected with a high-risk type of human papillomavirus (HPV), researchers have found that a precise DNA sequence of a viral gene is associated with cervical cancer.

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Measuring the Effect of Chemicals on the Growth and Reproduction of Caenorhabditis elegans

A basic protocol to evaluate the toxicity of chemicals in a model animal, Caenorhabditis elegans, is described. The method is convenient and useful for the development of pharmaceuticals as well as for the risk assessment of various environmental pollutants.

http://ift.tt/2fUEKO7

Simultaneous Multi-surface Anodizations and Stair-like Reverse Biases Detachment of Anodic Aluminum Oxides in Sulfuric and Oxalic Acid Electrolyte

A protocol for fabricating nanoporous anodic aluminum oxides via simultaneous multi-surfaces anodization followed by stair-like reverse biases detachments is presented. It can be applied repeatedly to the same aluminum substrate, exhibiting a facile, high-yield, and environmentally clean strategy.

http://ift.tt/2yKp83v

Disruption of Ankyrin B and Caveolin-1 Interaction Sites Alters Na,K-ATPase Membrane Diffusion

The Na+,K+-ATPase is a plasma membrane ion transporter of high physiological importance for ion homeostasis and cellular excitability in electrically active tissues. Mutations in the genes coding for Na+,K+-ATPase α-subunit isoforms lead to severe human pathologies including Familial Hemiplegic Migraine type 2, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia Parkinsonism, or epilepsy. Many of the reported mutations lead to change- or loss-of-function effects, whereas others do not alter the functional properties, but lead to, e.g., reduced protein stability, reduced protein expression, or defective plasma membrane targeting.

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Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohns disease: report of the OPERA study

Objective

This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn's disease (CD).

Design

Eligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn's Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.

Results

In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β₇+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.

Conclusions

Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β₇+ central memory T cells.

Trial registration number

NCT01276509; Results.

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Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer

Objective

Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).

Design

Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy.

Results

Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival.

Conclusion

This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.

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Abnormal intrinsic brain functional network dynamics in Parkinson’s disease

Abstract

Parkinson's disease is a neurodegenerative disorder characterized by nigrostriatal dopamine depletion. Previous studies measuring spontaneous brain activity using resting state functional magnetic resonance imaging have reported abnormal changes in broadly distributed whole-brain networks. Although resting state functional connectivity, estimating temporal correlations between brain regions, is measured with the assumption that intrinsic fluctuations throughout the scan are stable, dynamic changes of functional connectivity have recently been suggested to reflect aspects of functional capacity of neural systems, and thus may serve as biomarkers of disease. The present work is the first study to investigate the dynamic functional connectivity in patients with Parkinson's disease, with a focus on the temporal properties of functional connectivity states as well as the variability of network topological organization using resting state functional magnetic resonance imaging. Thirty-one Parkinson's disease patients and 23 healthy controls were studied using group spatial independent component analysis, a sliding windows approach, and graph-theory methods. The dynamic functional connectivity analyses suggested two discrete connectivity configurations: a more frequent, sparsely connected within-network state (State I) and a less frequent, more strongly interconnected between-network state (State II). In patients with Parkinson's disease, the occurrence of the sparsely connected State I dropped by 12.62%, while the expression of the more strongly interconnected State II increased by the same amount. This was consistent with the altered temporal properties of the dynamic functional connectivity characterized by a shortening of the dwell time of State I and by a proportional increase of the dwell time pattern in State II. These changes are suggestive of a reduction in functional segregation among networks and are correlated with the clinical severity of Parkinson's disease symptoms. Additionally, there was a higher variability in the network global efficiency, suggesting an abnormal global integration of the brain networks. The altered functional segregation and abnormal global integration in brain networks confirmed the vulnerability of functional connectivity networks in Parkinson's disease.

http://ift.tt/2y1O6xM

Sample Extraction and Simultaneous Chromatographic Quantitation of Doxorubicin and Mitomycin C Following Drug Combination Delivery in Nanoparticles to Tumor-bearing Mice

This protocol describes an efficient and convenient analytical process of sample extraction and simultaneous determination of multiple drugs, doxorubicin (DOX), mitomycin C (MMC) and a cardio-toxic DOX metabolite, doxorubicinol (DOXol), in the biological samples from a preclinical breast tumor model treated with nanoparticle formulations of synergistic drug combination.

http://ift.tt/2y3AyCm

Laboratory Protocol for Genetic Gut Content Analyses of Aquatic Macroinvertebrates Using Group-specific rDNA Primers

Most common gut content analyses of macroinvertebrates are visual. Requiring intense knowledge about morphological diversity of prey organisms, they miss soft bodied prey and, due to strong comminution of prey, are nearly impossible for some organisms, including amphipods. We provide detailed, novel genetic approaches for macroinvertebrate prey identification in the diet of amphipods.

http://ift.tt/2y3ykTo

Tumor localization may change the type of adjuvant treatment in gastric cancer

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Reply to Tumor localization may change the type of adjuvant treatment in gastric cancer

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Disruption of Ankyrin B and Caveolin-1 Interaction Sites Alters Na+,K+-ATPase Membrane Diffusion

The Na+,K+-ATPase is a plasma membrane ion transporter of high physiological importance for ion homeostasis and cellular excitability in electrically active tissues. Mutations in the genes coding for Na+,K+-ATPase α-subunit isoforms lead to severe human pathologies including Familial Hemiplegic Migraine type 2, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia Parkinsonism, or epilepsy. Many of the reported mutations lead to change- or loss-of-function effects, whereas others do not alter the functional properties, but lead to, e.g., reduced protein stability, reduced protein expression, or defective plasma membrane targeting.

http://ift.tt/2ktVJsn

Serum tau and neurological outcome in cardiac arrest

Abstract

Objective: To test serum tau as a predictor of neurological outcome after cardiac arrest.

Methods: We measured the neuronal protein tau in serum at 24, 48, and 72 h after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Category 3-5 at 6 months.

Results: Increased tau was associated with poor outcome at 6 months after cardiac arrest (median 38.5 [IQR 5.7-245] ng/L in poor versus 1.5 [0.7-2.4] ng/L in good outcome, for tau at 72 h, p<0.0001). Tau improved prediction of poor outcome compared to using clinical information (p<0.0001). Tau cut-offs had low false positive rates (FPR) for good outcome while retaining high sensitivity for poor outcome. For example, tau at 72 h had FPR 2% (95% CI 1-4%) with sensitivity 66% (95% CI 61-70%). Tau had higher accuracy than serum NSE (the area under the receiver operating characteristic curve was 0.91 for tau versus 0.86 for NSE at 72 hours, p=0.00024). During follow-up (up to 956 days), tau was significantly associated with overall survival. The accuracy to predict outcome by serum tau was equally high for patients randomized to 33°C and 36°C targeted temperature after cardiac arrest.

Interpretation: Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice in several countries to predict outcome after cardiac arrest. This article is protected by copyright. All rights reserved.

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Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson's disease

ABSTRACT

Objective: Inflammatory response plays an important role in Parkinson's disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in three population-based case-control studies from Denmark and France.

Methods: We included 2,056 cases and 2,723 controls from three PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions.

Results: Both carrying rs660895-G (AG vs. AA: OR= 0.81; GG vs. AA: OR= 0.56; p-trend=0.003) and ever smoking (OR=0.56, p<0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter=1.37, p=0.005), and dominant (interaction parameter=1.54, p=0.001) genetic models without any heterogeneity (I²=0.0%): the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR=0.64, p<0.001) disappeared among ever smokers (OR=1.00, p=0.99). Similar interactions were observed when we investigated light and heavy smokers separately.

Interpretation: Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation. This article is protected by copyright. All rights reserved.

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Gut with the Program: Direct Reprogramming toward Intestinal Epithelium Realized

Intestinal organoids offer great promise for modeling intestinal diseases; however, harvesting intestinal tissue is invasive and directed hPSC differentiation protocols are laborious and costly. In this issue of Cell Stem Cell, Miura and Suzuki (2017) describe the direct conversion of somatic cells from both mice and humans into robust intestinal epithelial tissue.

http://ift.tt/2yJSlfb

Human Embryo Editing: Opportunities and Importance of Transnational Cooperation

A recent National Academies report articulates a path forward for research, ethics, and governance of clinical applications involving genome editing. In light of recent human embryo editing developments, scientists and stakeholders from all nations should cooperate to take advantage of this historic opportunity for medicine and also basic human biology.

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Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development

Cairns and colleagues show that human spermatogonial stem cells (hSSCs) bear unique DNA methylation and open chromatin landscapes, which may enable proper development, niche responsiveness, and "poised" pluripotency. Interestingly, single-cell transcriptome and immunofluorescence analyses reveal four cellular states, spanning from quiescent hSSCs to proliferating, metabolically active, differentiating spermatogonia.

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Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia

Testing novel therapies for hematologic malignancies requires human cell models that reflect the combinatorial complexity of genetic mutations observed in patients. Ebert and colleagues use multiplex CRISPR/Cas9-based targeting of human hematopoietic stem and progenitor cells to model the genetics of clonal hematopoiesis and myeloid neoplasms in vivo.

http://ift.tt/2xWcjnw

Distinct Cell-Cycle Control in Two Different States of Mouse Pluripotency

It is widely thought that embryonic stem cells have an unusual and very rapid cell cycle, lacking normal G1 regulation. Stunnenberg and colleagues show that, in mouse ESCs, G1 regulation is, in fact, intact but abrogated in serum by ERK signaling and RB phosphorylation.

http://ift.tt/2yJSiA1

Policing Tumorigenesis within the Skin: Good Outs Bad

Recently published in Nature, Brown et al. (2017) shed new light on how the skin handles the activation of oncogenic pathways in the stem cell compartment and how wild-type cells limit the proliferation of mutant cells to maintain proper tissue homeostasis.

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E Pluribus Unum (“Out of Many, One”): CRISPR Modeling of Myeloid Expansion

In this issue of Cell Stem Cell, Tothova et al. (2017) demonstrate a promising way to model the complex genetics of clonal hematopoiesis and myeloid disorders using CRISPR-Cas9 genome editing in human hematopoietic stem and progenitor cells. Their approach opens the door to genotype-specific pharmacologic testing.

http://ift.tt/2yK5XXz

Mononuclear Diploidy at the Heart of Cardiomyocyte Proliferation

Reporting in Nature Genetics, Patterson et al. (2017) show that adult mammalian hearts possess an innate capacity to regenerate, which depends on a small population of mononuclear diploid cardiomyocytes. These cells undergo karyokinesis and cytokinesis, raising the possibility that endogenous cardiac muscle cells can be stimulated to proliferate for myocardial repair.

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The LUNGe to Model Alveolar Lung Diseases in a Dish

Obtaining alveolar epithelial type 2 cells (AEC2s) from human pluripotent stem cells (hPSCs) offers great scientific and clinical promise. In this issue of Cell Stem Cell, Jacob et al. (2017) report a method for the directed differentiation of hPSCs into mature AEC2s and demonstrate its application in modeling alveolar lung diseases.

http://ift.tt/2yJSgrT

Human Genome Editing in the Clinic: New Challenges in Regulatory Benefit-Risk Assessment

As genome editing rapidly progresses toward the realization of its clinical promise, assessing the suitability of current tools and processes used for its benefit-risk assessment is critical. Although current regulations may initially provide an adequate regulatory framework, improvements are recommended to overcome several existing technology-based safety and efficacy issues.

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CRISPR/Cas9-Based Engineering of the Epigenome

Pulecio et al. discuss opportunities that CRISPR/Cas9 technology offers for investigating and manipulating the stem cell epigenome and also provide technical considerations for CRISPR/Cas9 tool standardization and improvement.

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Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells

The mechanisms driving human germ cell specification are largely unknown. Kojima et al. define the signaling and transcriptional programs that drive human germ cell specification in vitro, which show substantial evolutionary divergence from mouse programs. These findings serve as a foundation for further reconstitution of human germ cell development.

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Spontaneous Remission of Severe Systemic Langerhans Cell Histiocytosis with Bladder Involvement: A Case Study

Background: The clinical presentation of Langerhans cell histiocytosis (LCH) is heterogeneous ranging from single-organ involvement to systemic disease causing substantial morbidity and mortality. We describe an unusual course of severe multisystem LCH with spontaneous remission. Case Presentation: We report on a 45-year-old Caucasian woman with cervical cancer, FIGO stage IVB. Five months after the end of combined radiochemotherapy and brachytherapy, the patient was readmitted because of severe dysuria. Sterile leukocyturia was seen, and cystoscopy revealed only 3 unspecific small mucosal lesions compatible with postradiation cystitis. Incidentally, a computed tomography (CT) scan of the body showed diffuse micronodular and cystic lesions in lungs and hypodense lesions in the liver. Biopsies revealed infiltrations of CD1a and Langerin (CD207)-positive histiocytes in the lung, liver, and bladder. Additionally, positron emission tomography-CT (PET-CT) was compatible with bone involvement. Retrospective analysis revealed that the increase in alkaline phosphatase might have been a surrogate of bone marrow infiltration with osseous activity. Repeated pneumothoraces occurred, and only one course of vinblastine-prednisolone could be applied. Despite ongoing tobacco consumption and without further therapy, PET-CT showed considerable remission 2 months later. However, despite stable remission, documented by serial PET and conventional CT scans, persistent infiltration of the bladder by Langerhans histiocytes could still be demonstrated 17 months later. Unfortunately, cervical cancer recurred and progressed. Conclusion: Multisystem LCH may rapidly occur, may be oligosymptomatic and, even in high-risk cases, remission without specific therapy might occur. Whether alkaline phosphatase might be a surrogate to monitor osseous disease activity has to be further explored.
Case Rep Oncol 2017;10:876–884

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Transplant-Ineligible Symptomatic but Indolent Multiple Myeloma Shows Better Prognosis with Conventional Agents

The survival of multiple myeloma patients has improved significantly over the last several decades. However, the median overall survival of these patients remains less than 5 years. In this report, we discuss 4 cases of multiple myeloma patients that showed long survival. Interestingly, these patients had severe organ damage at diagnosis, used only conventional agents, and did not always show deep response. Although current guidelines recommend novel agents to achieve deep response, the current cases suggest that some multiple myeloma patients may not need intensive treatment. Here, we discuss 4 cases of symptomatic but indolent transplant-ineligible myeloma.
Case Rep Oncol 2017;10:871–875

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Subgroup Analysis of Antibiotic Treatment for Skin Abscesses

Two large randomized trials recently demonstrated efficacy of methicillin-resistant Staphylococcus aureus (MRSA)–active antibiotics for drained skin abscesses. We determine whether outcome advantages observed in one trial exist across lesion sizes and among subgroups with and without guideline-recommended antibiotic indications.

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Three Cases of KCNT1 Mutations: Malignant Migrating Partial Seizures in Infancy with Massive Systemic to Pulmonary Collateral Arteries

KCNT1 mutations are gain-of-function mutations in potassium channels resulting in severe infantile epilepsy. Herein we describe 3 infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure.

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Prospective Evaluation of Physical Contact with Critically Ill Child on Caregiver Spiritual Wellbeing

To evaluate whether a pediatric intensive care unit initiative promoting physical contact between caregiver and patient improves caregiver spiritual wellbeing. The secondary objectives were to evaluate caregiver perceptions of care before and after the initiative and to follow unplanned extubation rate as a marker of safety of the initiative. We hypothesized that caregiver spiritual wellbeing and caregiver perceptions of care would improve with implementation of our physical contact initiative known as Project ROSE (Reach Out, Soothe, and Embrace).

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Childhood Obesity and Physical Activity-Friendly School Environments

Childhood obesity may be related to school environment, but previous studies often focused on food environment only. This study aimed to examine the relationship between school physical activity environment and childhood obesity.

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Immunomodulatory Drugs (IMiDs) in Multiple Myeloma

Background: Multiple myeloma (MM) is a hematological cancer caused by a proliferation of clonal plasma cells, leading to anemia, renal failure, hypercalcemia and destructive bone lesions resulting in significant morbidity. The overall survival has significantly improved with the incorporation of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI).

Objective: Here we provide a comprehensive review on IMiDs including molecular mechanisms, recent advances in therapeutic applications and management of toxicities in the treatment of MM.

Methods: Relevant publications in peer reviewed journals were retrieved by a selective search of PubMed. Systemic reviews, meta-analyses, randomized controlled trials, and treatment recommendations were reviewed and are summarized here.

Results: Thalidomide, a first generation IMiD, is associated with significant toxicity in older patients. Lenalidomide, a more potent second generation IMiD with fewer side effects than thalidomide, is commonly used in newly-diagnosed multiple myeloma, relapsed refractory myeloma and as maintenance therapy after autologous stem cell transplantation (ASCT). Pomalidomide, a third generation IMiD, is 10 times more potent than lenalidomide and has shown impressive results in relapsed MM patients and in those refractory to both lenalidomide and bortezomib.

Conclusion: The clinical use of IMiDs in MM has significantly improved long-term survival and quality of life. Future studies are looking into novel biomarkers predictive of outcome in MM and new combinations of lenalidomide and pomalidomde with PI, monoclonal antibodies, immune checkpoint blockers and several other chemotherapies.

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Editorial: Multiple Myeloma Immunotherapies

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Immunomodulatory Activity of MicroRNAs: Potential Implications for Multiple Myeloma Treatment

Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for about 10% of all hematologic malignancies. Recently, emerging evidence is disclosing the complexity of bone marrow interactions between MM cells and infiltrating immune cells, which have been reported to promote proliferation, survival and drug resistance of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory functions in the cell, whose expression has predictive and prognostic value in different malignancies. MiRNAs are gaining increasing interest due to their capability to polarize the immune-response through different mechanisms, which include the molecular reprogramming of immune cells. This characteristic, together with the antitumor activity of miRNA mimics or inhibitors, make the miRNA network an attractive area of investigation for novel anti-MM therapeutic approaches. In this review, we will discuss the recent advances in the understanding of the interplay between MM cells and bone marrow resident immune cells, with special focus on the molecular and functional changes induced by miRNA network modulation. We will finally indicate potential targets for therapeutic intervention.

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Stem Cell Transplantation in Multiple Myeloma

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients younger than 65 years of age with multiple myeloma (MM). However, this therapeutic approach has undergone substantial advances in this last decade, mainly due to the introduction of new drugs such as thalidomide, lenalidomide and bortezomib. These new drugs, in different combinations, have shown to significantly increase response rates after induction therapy and ASCT. Moreover, the positive results obtained with these agents in consolidation and maintenance strategies after ASCT strongly support the concept of continuous therapy, whose ultimate goal is the long-term control of the disease and the improvement of outcome. Preliminary data from studies investigating next generation proteasome inhibitors, such as carfilzomib and ixazomib, used upfront as well as at subsequent therapeutic lines, demonstrate the possibility of achieving molecular remission in most of the patients. The deeper responses obtained with new drugcombinations questioned the role of ASCT, and large, ongoing, phase 3 trials will shed light on the role and the timing of ASCT.

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Meet Our Editorial Board Member

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Targeting the Immune Niche within the Bone Marrow Microenvironment: The Rise of Immunotherapy in Multiple Myeloma

Background: Multiple Myeloma (MM) cells inhibit the development of an effective anti- MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive proinflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance. The usefulness of immunotherapies in MM patients has first been supported by the identification of the graft-versus-myeloma effect in the context of allogeneic bone marrow (BM) transplantation. Subsequently, the inclusion of thalidomide and its derivatives, the Immunomodulatory Drugs (IMiDs) as well as of (immuno) proteasome inhibitors into MM regimens dramatically improved MM patients outcome during the last 15 years. Despite these unprecedented therapeutic advances MM remains an incurable disease.

Objective: This article reviews novel immunotherapeutic approaches, which aim to restore the balance within the immunologic niche of the MM BM microenvironment.

Method: A systematic search was conducted of the Pubmed Medline, Embase, and Cochrane Library databases for primary articles, as well as of conference abstracts (e.g., of the American Society of Hematology, the American Society of Clinical Oncology, the American Association of Cancer Research, the European Hematology Association, and the Multiple Myeloma Workshop), practice guidelines, and registries of clinical trials.

Results: The inclusion of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor-engineered (CAR) T cells, genetically engineered T cells, and vaccination, dendritic cellbased cancer vaccines in particular, into existing regimens is likely to significantly improve MM patient outcome in the near future.

Conclusion: Given continuing efforts to target the immune niche within the bone marrow microenvironment we are confident that the rise of immunotherapies in MM will result in long-lasting responses in many of our patients within the next decade.

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Coinhibitory Molecule PD-1 as a Therapeutic Target in the Microenvironment of Multiple Myeloma

Background: Patients with Multiple Myeloma suffer from dysregulation of the immune system and new therapeutic options targeting the immune systems such as monoclonal antibodies or specific Cell therapy such as CAR-T cells have entered clinical practice, but the exhausted immune system hampered a more effective immunotherapy. Targeting the immunological dysfunction in the microenviroment might be a potential target for immune-mediated therapies.

Method: Here we review the current literature and knowledge about the programmed death 1 (PD-1) receptor which is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on myeloma cells and inhibits T cell-mediated apoptosis.

Results: The programmed death 1 (PD-1) receptor is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on myeloma cells and inhibits Tcell-mediated apoptosis. Inhibiting such "checkpoint" by monoclonal antibodies recently has been shown high activity in solid tumors and malignant lymphomas. In patients with multiple myelomaPD-L1 is overexpressed on myeloma cells and PD1 on T-cells suggesting an active role of PD-1/PD-L1 in the immunosuppressive microenvironment.

Conclusion: Immunotherapies using anti-PD-1/PD-L1 strategies are a promising treatment options for patients with multiple myeloma.

http://ift.tt/2gea0EK

Multiple Myeloma and the Immune Microenvironment

One of the great advances in the field of cancer therapy in recent years is the emergence of immune therapies. Immune therapies, especially immune checkpoint inhibitors, have shown promising results in pre-clinical models and clinical trials of solid tumors, such as melanoma, breast cancer and lung cancer. Therapeutic strategies targeting the immune microenvironment have also been applied to hematological malignancies such as multiple myeloma (MM), a plasma cell neoplasia characterized by clonal proliferation of malignant plasma cells mainly in the bone marrow (BM). MM is associated with both cellular and humoral immune deficiencies, indicating that the evolution of the disease from a precursor state (monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (sMM)) is associated with an immunosuppressive milieu that fosters immune escape and tumor growth. Despite significant advances in treatment, MM is mostly an incurable disease. Therefore, it is vital to develop novel therapeutic agents that not only target the MM clone itself but also the MM immune microenvironment. However, the complexity of the BM microenvironment and heterogeneity of tumor cell clones make it a difficult task for developing appropriate immune therapies of MM. In this article, we review the current knowledge of the interaction between malignant plasma cells and the bone marrow immune microenvironment during disease progression.

http://ift.tt/2xVvTTw

Acknowledgements to Reviewers

http://ift.tt/2gcre5l

Benefits of Dominance over Additive Models for the Estimation of Average Effects in the Presence of Dominance

In quantitative genetics, the average effect at a single locus can be estimated by an additive (A) model, or an additive plus dominance (AD) model. In the presence of dominance, the AD-model is expected to be more accurate, because the A-model falsely assumes that residuals are independent and identically distributed. Our objective was to investigate the accuracy of an estimated average effect ($$\widehat{\alpha }$$) in the presence of dominance, using either a single locus A-model or AD-model. Estimation was based on a finite sample from a large population in Hardy-Weinberg equilibrium (HWE), and the root mean squared error of $$\widehat{\alpha }$$ was calculated for several broad-sense heritabilities, sample sizes, and sizes of the dominance effect. Results show that with the A-model, both sampling deviations of genotype frequencies from HWE frequencies and sampling deviations of allele frequencies contributed to the error. With the AD-model, only sampling deviations of allele frequencies contributed to the error, provided that all three genotype classes were sampled. In the presence of dominance, the root mean squared error of $$\widehat{\alpha }$$ with the AD-model was always smaller than with the A-model, even when the heritability was less than one. Remarkably, in the absence of dominance, there was no disadvantage of fitting dominance. In conclusion, the AD-model yields more accurate estimates of average effects from a finite sample, because it is more robust against sampling deviations from HWE frequencies than the A-model. Genetic models that include dominance, therefore, yield higher accuracies of estimated average effects than purely additive models when dominance is present.

http://ift.tt/2y204rs

High-Quality de Novo Genome Assembly of the Dekkera bruxellensis Yeast Using Nanopore MinION Sequencing

Genetic variation in natural populations represents the raw material for phenotypic diversity. Species-wide characterization of genetic variants is crucial to have a deeper insight into the genotype-phenotype relationship. With the advent of new sequencing strategies and more recently the release of long-read sequencing platforms, it is now possible to explore the genetic diversity of any nonmodel organisms, representing a fundamental resource for biological research. In the frame of population genomic surveys, a first step is to obtain the complete sequence and high-quality assembly of a reference genome. Here, we sequenced and assembled a reference genome of the nonconventional Dekkera bruxellensis yeast. While this species is a major cause of wine spoilage, it paradoxically contributes to the specific flavor profile of some Belgium beers. In addition, an extreme karyotype variability is observed across natural isolates, highlighting that D. bruxellensis genome is very dynamic. The whole genome of the D. bruxellensis UMY321 isolate was sequenced using a combination of Nanopore long-read and Illumina short-read sequencing data. We generated the most complete and contiguous de novo assembly of D. bruxellensis to date and obtained a first glimpse into the genomic variability within this species by comparing the sequences of several isolates. This genome sequence is therefore of high value for population genomic surveys and represents a reference to study genome dynamic in this yeast species.

http://ift.tt/2z0nqMm

Genome-Wide Association Mapping of Stem Rust Resistance in Hordeum vulgare subsp. spontaneum

Stem rust was one of the most devastating diseases of barley in North America. Through the deployment of cultivars with the resistance gene Rpg1, losses to stem rust have been minimal over the past 70 yr. However, there exist both domestic (QCCJB) and foreign (TTKSK aka isolate Ug99) pathotypes with virulence for this important gene. To identify new sources of stem rust resistance for barley, we evaluated the Wild Barley Diversity Collection (WBDC) (314 ecogeographically diverse accessions of Hordeum vulgare subsp. spontaneum) for seedling resistance to four pathotypes (TTKSK, QCCJB, MCCFC, and HKHJC) of the wheat stem rust pathogen (Puccinia graminis f. sp. tritici, Pgt) and one isolate (92-MN-90) of the rye stem rust pathogen (P. graminis f. sp. secalis, Pgs). Based on a coefficient of infection, the frequency of resistance in the WBDC was low ranging from 0.6% with HKHJC to 19.4% with 92-MN-90. None of the accessions was resistant to all five cultures of P. graminis. A genome-wide association study (GWAS) was conducted to map stem rust resistance loci using 50,842 single-nucleotide polymorphic markers generated by genotype-by-sequencing and ordered using the new barley reference genome assembly. After proper accounting for genetic relatedness and structure among accessions, 45 quantitative trait loci were identified for resistance to P. graminis across all seven barley chromosomes. Three novel loci associated with resistance to TTKSK, QCCJB, MCCFC, and 92-MN-90 were identified on chromosomes 5H and 7H, and two novel loci associated with resistance to HKHJC were identified on chromosomes 1H and 3H. These novel alleles will enhance the diversity of resistance available for cultivated barley.

http://ift.tt/2y23ytN

Exploring Potential Germline-Associated Roles of the TRIM-NHL Protein NHL-2 Through RNAi Screening

TRIM-NHL proteins are highly conserved regulators of developmental pathways in vertebrates and invertebrates. The TRIM-NHL family member NHL-2 in Caenorhabditis elegans functions as a miRNA cofactor to regulate developmental timing. Similar regulatory roles have been reported in other model systems, with the mammalian ortholog in mice, TRIM32, contributing to muscle and neuronal cell proliferation via miRNA activity. Given the interest associated with TRIM-NHL family proteins, we aimed to further investigate the role of NHL-2 in C. elegans development by using a synthetic RNAi screening approach. Using the ORFeome library, we knocked down 11,942 genes in wild-type animals and nhl-2 null mutants. In total, we identified 42 genes that produced strong reproductive synthetic phenotypes when knocked down in nhl-2 null mutants, with little or no change when knocked down in wild-type animals. These included genes associated with transcriptional processes, chromosomal integrity, and key cofactors of the germline small 22G RNA pathway.

http://ift.tt/2z1iqHy

Genetic Dissection of Trabecular Bone Structure with Mouse Intersubspecific Consomic Strains

Trabecular bone structure has an important influence on bone strength, but little is known about its genetic regulation. To elucidate the genetic factor(s) regulating trabecular bone structure, we compared the trabecular bone structures of two genetically remote mouse strains, C57BL/6J and Japanese wild mouse-derived MSM/Ms. Phenotyping by X-ray micro-CT revealed that MSM/Ms has structurally more fragile trabecular bone than C57BL/6J. Toward identification of genetic determinants for the difference in fragility of trabecular bone between the two mouse strains, we employed phenotype screening of consomic mouse strains in which each C57BL/6J chromosome is substituted by its counterpart from MSM/Ms. The results showed that many chromosomes affect trabecular bone structure, and that the consomic strain B6-Chr15^MSM, carrying MSM/Ms-derived chromosome 15 (Chr15), has the lowest values for the parameters BV/TV, Tb.N, and Conn.D, and the highest values for the parameters Tb.Sp and SMI. Subsequent phenotyping of subconsomic strains for Chr15 mapped four novel trabecular bone structure-related QTL (Tbsq1-4) on mouse Chr15. These results collectively indicate that genetic regulation of trabecular bone structure is highly complex, and that even in the single Chr15, the combined action of the four Tbsqs controls the fragility of trabecular bone. Given that Tbsq4 is syntenic to human Chr 12q12-13.3, where several bone-related SNPs are assigned, further study of Tbsq4 should facilitate our understanding of the genetic regulation of bone formation in humans.

http://ift.tt/2yZ9Usx

High-Throughput Genetic Screening of 51 Pediatric Cataract Genes Identifies Causative Mutations in Inherited Pediatric Cataract in South Eastern Australia

Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP; and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for >60% of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.

http://ift.tt/2kpz0xn

Genomic Relatedness Strengthens Genetic Connectedness Across Management Units

Genetic connectedness refers to a measure of genetic relatedness across management units (e.g., herds and flocks). With the presence of high genetic connectedness in management units, best linear unbiased prediction (BLUP) is known to provide reliable comparisons between estimated genetic values. Genetic connectedness has been studied for pedigree-based BLUP; however, relatively little attention has been paid to using genomic information to measure connectedness. In this study, we assessed genome-based connectedness across management units by applying prediction error variance of difference (PEVD), coefficient of determination (CD), and prediction error correlation r to a combination of computer simulation and real data (mice and cattle). We found that genomic information ($$G$$) increased the estimate of connectedness among individuals from different management units compared to that based on pedigree ($$A$$). A disconnected design benefited the most. In both datasets, PEVD and CD statistics inferred increased connectedness across units when using $$G$$- rather than $$A$$-based relatedness, suggesting stronger connectedness. With r once using allele frequencies equal to one-half or scaling $$G$$ to values between 0 and 2, which is intrinsic to $$A,$$ connectedness also increased with genomic information. However, PEVD occasionally increased, and r decreased when obtained using the alternative form of $$G,$$ instead suggesting less connectedness. Such inconsistencies were not found with CD. We contend that genomic relatedness strengthens measures of genetic connectedness across units and has the potential to aid genomic evaluation of livestock species.

http://ift.tt/2xkb7xc

Systematic Identification of Determinants for Single-Strand Annealing-Mediated Deletion Formation in Saccharomyces cerevisiae

To ensure genomic integrity, living organisms have evolved diverse molecular processes for sensing and repairing damaged DNA. If improperly repaired, DNA damage can give rise to different types of mutations, an important class of which are genomic structural variants (SVs). In spite of their importance for phenotypic variation and genome evolution, potential contributors to SV formation in Saccharomyces cerevisiae (budding yeast), a highly tractable model organism, are not fully recognized. Here, we developed and applied a genome-wide assay to identify yeast gene knockout mutants associated with de novo deletion formation, in particular single-strand annealing (SSA)-mediated deletion formation, in a systematic manner. In addition to genes previously linked to genome instability, our approach implicates novel genes involved in chromatin remodeling and meiosis in affecting the rate of SSA-mediated deletion formation in the presence or absence of stress conditions induced by DNA-damaging agents. We closely examined two candidate genes, the chromatin remodeling gene IOC4 and the meiosis-related gene MSH4, which when knocked-out resulted in gene expression alterations affecting genes involved in cell division and chromosome organization, as well as DNA repair and recombination, respectively. Our high-throughput approach facilitates the systematic identification of processes linked to the formation of a major class of genetic variation.

http://ift.tt/2kpXFlz

High-Resolution Maps of Mouse Reference Populations

Genetic reference panels are widely used to map complex, quantitative traits in model organisms. We have generated new high-resolution genetic maps of 259 mouse inbred strains from recombinant inbred strain panels (C57BL/6J x DBA/2J, ILS/IbgTejJ x ISS/IbgTejJ, and C57BL/6J x A/J) and chromosome substitution strain panels (C57BL/6J-Chr#<A/J>, C57BL/6J-Chr#<PWD/Ph>, and C57BL/6J-Chr#<MSM/Ms>). We genotyped all samples using the Affymetrix Mouse Diversity Array with an average intermarker spacing of 4.3 kb. The new genetic maps provide increased precision in the localization of recombination breakpoints compared to the previous maps. Although the strains were presumed to be fully inbred, we found residual heterozygosity in 40% of individual mice from five of the six panels. We also identified de novo deletions and duplications, in homozygous or heterozygous state, ranging in size from 21 kb to 8.4 Mb. Almost two-thirds (46 out of 76) of these deletions overlap exons of protein coding genes and may have phenotypic consequences. Twenty-nine putative gene conversions were identified in the chromosome substitution strains. We find that gene conversions are more likely to occur in regions where the homologous chromosomes are more similar. The raw genotyping data and genetic maps of these strain panels are available at http://ift.tt/2g9Qa0a.

http://ift.tt/2kpySOp

Neo-sex Chromosomes in the Monarch Butterfly, Danaus plexippus

We report the discovery of a neo-sex chromosome in the monarch butterfly, Danaus plexippus, and several of its close relatives. Z-linked scaffolds in the D. plexippus genome assembly were identified via sex-specific differences in Illumina sequencing coverage. Additionally, a majority of the D. plexippus genome assembly was assigned to chromosomes based on counts of one-to-one orthologs relative to the butterfly Melitaea cinxia (with replication using two other lepidopteran species), in which genome scaffolds have been mapped to linkage groups. Sequencing coverage-based assessments of Z linkage combined with homology-based chromosomal assignments provided strong evidence for a Z-autosome fusion in the Danaus lineage, involving the autosome homologous to chromosome 21 in M. cinxia. Coverage analysis also identified three notable assembly errors resulting in chimeric Z-autosome scaffolds. Cytogenetic analysis further revealed a large W chromosome that is partially euchromatic, consistent with being a neo-W chromosome. The discovery of a neo-Z and the provisional assignment of chromosome linkage for >90% of D. plexippus genes lays the foundation for novel insights concerning sex chromosome evolution in this female-heterogametic model species for functional and evolutionary genomics.

http://ift.tt/2kpyKhT

Transcriptome Analysis Suggests That Chromosome Introgression Fragments from Sea Island Cotton (Gossypium barbadense) Increase Fiber Strength in Upland Cotton (Gossypium hirsutum)

As high-strength cotton fibers are critical components of high quality cotton, developing cotton cultivars with high-strength fibers as well as high yield is a top priority for cotton development. Recently, chromosome segment substitution lines (CSSLs) have been developed from high-yield Upland cotton (Gossypium hirsutum) crossed with high-quality Sea Island cotton (G. barbadense). Here, we constructed a CSSL population by crossing CCRI45, a high-yield Upland cotton cultivar, with Hai1, a Sea Island cotton cultivar with superior fiber quality. We then selected two CSSLs with significantly higher fiber strength than CCRI45 (MBI7747 and MBI7561), and one CSSL with lower fiber strength than CCRI45 (MBI7285), for further analysis. We sequenced all four transcriptomes at four different time points postanthesis, and clustered the 44,678 identified genes by function. We identified 2200 common differentially-expressed genes (DEGs): those that were found in both high quality CSSLs (MBI7747 and MBI7561), but not in the low quality CSSL (MBI7285). Many of these genes were associated with various metabolic pathways that affect fiber strength. Upregulated DEGs were associated with polysaccharide metabolic regulation, single-organism localization, cell wall organization, and biogenesis, while the downregulated DEGs were associated with microtubule regulation, the cellular response to stress, and the cell cycle. Further analyses indicated that three genes, XLOC_036333 [mannosyl-oligosaccharide-α-mannosidase (MNS1)], XLOC_029945 (FLA8), and XLOC_075372 (snakin-1), were potentially important for the regulation of cotton fiber strength. Our results suggest that these genes may be good candidates for future investigation of the molecular mechanisms of fiber strength formation and for the improvement of cotton fiber quality through molecular breeding.

http://ift.tt/2xjWyKa

Intricate and Cell Type-Specific Populations of Endogenous Circular DNA (eccDNA) in Caenorhabditis elegans and Homo sapiens

Investigations aimed at defining the 3D configuration of eukaryotic chromosomes have consistently encountered an endogenous population of chromosome-derived circular genomic DNA, referred to as extrachromosomal circular DNA (eccDNA). While the production, distribution, and activities of eccDNAs remain understudied, eccDNA formation from specific regions of the linear genome has profound consequences on the regulatory and coding capabilities for these regions. Here, we define eccDNA distributions in Caenorhabditis elegans and in three human cell types, utilizing a set of DNA topology-dependent approaches for enrichment and characterization. The use of parallel biophysical, enzymatic, and informatic approaches provides a comprehensive profiling of eccDNA robust to isolation and analysis methodology. Results in human and nematode systems provide quantitative analysis of the eccDNA loci at both unique and repetitive regions. Our studies converge on and support a consistent picture, in which endogenous genomic DNA circles are present in normal physiological states, and in which the circles come from both coding and noncoding genomic regions. Prominent among the coding regions generating DNA circles are several genes known to produce a diversity of protein isoforms, with mucin proteins and titin as specific examples.

http://ift.tt/2kpzcfX

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T in Drosophila melanogaster Indirect Flight Muscles

MicroRNAs (miRNAs) are small noncoding endogenous RNAs, typically 21–23 nucleotides long, that regulate gene expression, usually post-transcriptionally, by binding to the 3'-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure, and other cardiac myopathies. Recent studies have implicated miRNA-9 (miR-9) in myocardial hypertrophy. However, a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using a genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster. Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies overexpressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit a loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as "hypercontraction." Additionally, miR-9a overexpression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a overexpression were completely rescued by overexpression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3'-UTR of the TnT mRNA and downregulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative downregulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 overexpression.

http://ift.tt/2xjryKj

Increased LOH due to Defective Sister Chromatid Cohesion Is due Primarily to Chromosomal Aneuploidy and not Recombination

Loss of heterozygosity (LOH) is an important factor in cancer, pathogenic fungi, and adaptation to changing environments. The sister chromatid cohesion process (SCC) suppresses aneuploidy and therefore whole chromosome LOH. SCC is also important to channel recombinational repair to sister chromatids, thereby preventing LOH mediated by allelic recombination. There is, however, insufficient information about the relative roles that the SCC pathway plays in the different modes of LOH. Here, we found that the cohesin mutation mcd1-1, and other mutations in SCC, differentially affect the various types of LOH. The greatest effect, by three orders of magnitude, was on whole chromosome loss (CL). In contrast, there was little increase in recombination-mediated LOH, even for telomeric markers. Some of the LOH events that were increased by SCC mutations were complex, i.e., they were the result of several chromosome transactions. Although these events were independent of POL32, the most parsimonious way to explain the formation of at least some of them was break-induced replication through the centromere. Interestingly, the mcd1-1 pol32 double mutant showed a significant reduction in the rate of CL in comparison with the mcd1-1 single mutant. Our results show that defects in SCC allow the formation of complex LOH events that, in turn, can promote drug or pesticide resistance in diploid microbes that are pathogenic to humans or plants.

http://ift.tt/2kpXd6R

Meeting Report on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems

The fourth EMBO-sponsored conference on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems (http://ift.tt/2i8FKi0), was held at the EMBL in Heidelberg, Germany, October 19–23, 2016. The conference was organized by Judith Berman (Tel Aviv University), Maitreya Dunham (University of Washington), Jun-Yi Leu (Academia Sinica), and Lars Steinmetz (EMBL Heidelberg and Stanford University). The meeting attracted ~120 researchers from 28 countries and covered a wide range of topics in the fields of genetics, evolutionary biology, and ecology, with a unifying focus on yeast as a model system. Attendees enjoyed the Keith Haring-inspired yeast florescence microscopy artwork (Figure 1), a unique feature of the meeting since its inception, and the 1 min flash talks that catalyzed discussions at two vibrant poster sessions. The meeting coincided with the 20th anniversary of the publication describing the sequence of the first eukaryotic genome, Saccharomyces cerevisiae. Many of the conference talks focused on important questions about what is contained in the genome, how genomes evolve, and the architecture and behavior of communities of phenotypically and genotypically diverse microorganisms. Here, we summarize highlights of the research talks around these themes. Nearly all presentations focused on novel findings, and we refer the reader to relevant manuscripts that have subsequently been published.

http://ift.tt/2kpWUJf

Interchromosomal Transfer of Immune Regulation During Infection of Barley with the Powdery Mildew Pathogen

Powdery mildew pathogens colonize over 9500 plant species, causing critical yield loss. The Ascomycete fungus, Blumeria graminis f. sp. hordei (Bgh), causes powdery mildew disease in barley (Hordeum vulgare L.). Successful infection begins with penetration of host epidermal cells, culminating in haustorial feeding structures, facilitating delivery of fungal effectors to the plant and exchange of nutrients from host to pathogen. We used expression Quantitative Trait Locus (eQTL) analysis to dissect the temporal control of immunity-associated gene expression in a doubled haploid barley population challenged with Bgh. Two highly significant regions possessing trans eQTL were identified near the telomeric ends of chromosomes (Chr) 2HL and 1HS. Within these regions reside diverse resistance loci derived from barley landrace H. laevigatum (MlLa) and H. vulgare cv. Algerian (Mla1), which associate with the altered expression of 961 and 3296 genes during fungal penetration of the host and haustorial development, respectively. Regulatory control of transcript levels for 299 of the 961 genes is reprioritized from MlLa on 2HL to Mla1 on 1HS as infection progresses, with 292 of the 299 alternating the allele responsible for higher expression, including Adaptin Protein-2 subunit μ AP2M and Vesicle Associated Membrane Protein VAMP72 subfamily members VAMP721/722. AP2M mediates effector-triggered immunity (ETI) via endocytosis of plasma membrane receptor components. VAMP721/722 and SNAP33 form a Soluble N-ethylmaleimide-sensitive factor Attachment Protein REceptor (SNARE) complex with SYP121 (PEN1), which is engaged in pathogen associated molecular pattern (PAMP)-triggered immunity via exocytosis. We postulate that genes regulated by alternate chromosomal positions are repurposed as part of a conserved immune complex to respond to different pathogen attack scenarios.

http://ift.tt/2knObqO

Whole Genome Sequencing-Based Mapping and Candidate Identification of Mutations from Fixed Zebrafish Tissue

As forward genetic screens in zebrafish become more common, the number of mutants that cannot be identified by gross morphology or through transgenic approaches, such as many nervous system defects, has also increased. Screening for these difficult-to-visualize phenotypes demands techniques such as whole-mount in situ hybridization (WISH) or antibody staining, which require tissue fixation. To date, fixed tissue has not been amenable for generating libraries for whole genome sequencing (WGS). Here, we describe a method for using genomic DNA from fixed tissue and a bioinformatics suite for WGS-based mapping of zebrafish mutants. We tested our protocol using two known zebrafish mutant alleles, gpr126^st49 and egr2b^fh227, both of which cause myelin defects. As further proof of concept we mapped a novel mutation, stl64, identified in a zebrafish WISH screen for myelination defects. We linked stl64 to chromosome 1 and identified a candidate nonsense mutation in the F-box and WD repeat domain containing 7 (fbxw7) gene. Importantly, stl64 mutants phenocopy previously described fbxw7^vu56 mutants, and knockdown of fbxw7 in wild-type animals produced similar defects, demonstrating that stl64 disrupts fbxw7. Together, these data show that our mapping protocol can map and identify causative lesions in mutant screens that require tissue fixation for phenotypic analysis.

http://ift.tt/2xiGDvH