In Situ GIWAXS Analysis of Solvent and Additive Effects on PTB7 Thin Film Microstructure Evolution during Spin Coating

Abstract

The influence of solvent and processing additives on the pathways and rates of crystalline morphology formation for spin-coated semiconducting PTB7 (poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)-carbonyl]-thieno[3,4-b]thiophenediyl]]) thin films is investigated by in situ grazing incidence wide-angle X-ray scattering (GIWAXS) and optical reflectance, to better understand polymer solar cell (PSC) optimization approaches. In situ characterization of PTB7 film formation from chloroform (CF), chlorobenzene (CB), and 1,2-dichlorobenzene (DCB) solutions, as well as CB solutions with 1% and 3% v/v of the processing additives 1-chloronapthalene (CN), diphenylether (DPE), and 1,8-diiodooctane (DIO), reveals multiple crystallization pathways with: (i) single-solvent systems exhibiting rapid (<3 s) crystallization after a solvent boiling point-dependent film thinning transition, (ii) solvent + additive systems exhibiting different crystallization pathways and crystallite formation times from minutes (CN, DPE) to 1.5 h (DIO). Identifying crystalline intermediates has implications for bulk-heterojunction PSC morphology optimization via optimized spin-casting processes.

An in situ GIWAXS study of the crystalline evolution of PTB7 thin films during spin coating is performed. A divergence in intermediate aggregation states and film formation times determined by solvent additive choice is observed. This work shows how additive effects go beyond simply boiling point and the importance of the additive molecular structure on morphological evolution.

http://ift.tt/2fVf7sP

Re Doping in 2D Transition Metal Dichalcogenides as a New Route to Tailor Structural Phases and Induced Magnetism

Abstract

Alloying in 2D results in the development of new, diverse, and versatile systems with prospects in bandgap engineering, catalysis, and energy storage. Tailoring structural phase transitions using alloying is a novel idea with implications in designing all 2D device architecture as the structural phases in 2D materials such as transition metal dichalcogenides are correlated with electronic phases. Here, this study develops a new growth strategy employing chemical vapor deposition to grow monolayer 2D alloys of Re-doped MoSe₂ with show composition tunable structural phase variations. The compositions where the phase transition is observed agree well with the theoretical predictions for these 2D systems. It is also shown that in addition to the predicted new electronic phases, these systems also provide opportunities to study novel phenomena such as magnetism which broadens the range of their applications.

Re doping is demonstrated to be a controllable way to tailor crystal structure and magnetic properties in chemical vapor deposition (CVD)-synthesized 2D transition metal dichalcogenides. Extra electrons from Re atoms induce a 2H–1T′ phase transformation in monolayer Mo_1–xRe_xSe₂ alloys. These results show that chemical doping is a promising pathway to tune structural and magnetic properties of other CVD-grown MX₂ (M = Mo, W; X = S, Se).

http://ift.tt/2y2xmYj

Treatment decisions and employment of breast cancer patients: Results of a population-based survey

BACKGROUND

Many patients with breast cancer work for pay at the time of their diagnosis, and the treatment plan may threaten their livelihood. Understanding work experiences in a contemporary population-based sample is necessary to inform initiatives to reduce the burden of cancer care.

METHODS

Women who were 20 to 79 years old and had been diagnosed with stage 0 to II breast cancer, as reported to the Georgia and Los Angeles Surveillance, Epidemiology, and End Results registries in 2014-2015, were surveyed. Of the 3672 eligible women, 2502 responded (68%); 1006 who reported working before their diagnosis were analyzed. Multivariate models evaluated correlates of missing work for >1 month and stopping work altogether versus missing work for ≤1 month.

RESULTS

In this diverse sample, most patients (62%) underwent lumpectomy; 16% underwent unilateral mastectomy (8% with reconstruction); and 23% underwent bilateral mastectomy (19% with reconstruction). One-third (33%) received chemotherapy. Most (84%) worked full-time before their diagnosis; however, only 50% had paid sick leave, 39% had disability benefits, and 38% had flexible work schedules. Surgical treatment was strongly correlated with missing >1 month of work (odds ratio [OR] for bilateral mastectomy with reconstruction vs lumpectomy, 7.8) and with stopping work altogether (OR for bilateral mastectomy with reconstruction vs lumpectomy, 3.1). Chemotherapy receipt (OR for missing >1 month, 1.3; OR for stopping work altogether, 3.9) and race (OR for missing >1 month for blacks vs whites, 2.0; OR for stopping work altogether for blacks vs whites, 1.7) also correlated. Those with paid sick leave were less likely to stop working (OR, 0.5), as were those with flexible schedules (OR, 0.3).

CONCLUSIONS

Working patients who received more aggressive treatments were more likely to experience substantial employment disruptions. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2g5SDcp

Patterns of axillary evaluation in older patients with breast cancer and associations with adjuvant therapy receipt

Abstract

Purpose

Although axillary lymph node status has traditionally been a key factor in informing adjuvant breast cancer therapy recommendations, this information may be less relevant as our focus shifts more towards tumor biology, particularly in older patients where comorbidity influences treatment decisions and nodal staging and/or surgery may not improve outcomes. We examined patterns of axillary surgery and associations between axillary surgery and receipt of adjuvant treatment in older breast cancer patients.

Methods

Women aged ≥ 65 years with clinically node-negative, stage I–II breast cancer treated between 2012 and 2013 were identified using the National Cancer Data Base. Using multivariable logistic regression, we examined associations between axillary surgery and age, adjusting for patient, clinical, and facility factors. We also examined receipt of adjuvant treatment by nodal surgery.

Results

Among 68,205 women, 40.1% were aged 65–70, 24.5% were 71–75, 17.4% were 76–80, and 18.0% were > 80. Overall, 91.2% had axillary surgery (67.8% sentinel lymph node biopsy, 11.7% axillary lymph node dissection, 11.7% unspecified/unknown axillary surgery); 88.0% of those aged ≥ 70 with lower risk, hormone receptor-positive tumors underwent axillary surgery. In adjusted analyses, compared to patients aged 65–70, increasing age was associated with lower odds of any axillary surgery (ages 71–75: OR 0.64, 95% CI 0.57–0.71; ages 76–80: OR 0.33, 95% CI 0.30–0.37; age > 80: OR 0.08, 95% CI 0.07–0.08). Axillary surgery was associated with higher odds of receipt of radiation after breast conservation and receipt of chemotherapy in human epidermal growth factor 2-positive disease.

Conclusions

In a large nationwide dataset, the vast majority of older women with clinically node-negative breast cancer underwent axillary staging despite uncertainty about its impact on survival, particularly for those with lower-risk disease. Further study on how to tailor node assessment in older patients is warranted.

http://ift.tt/2fUV5ib

Influence of atrial contraction dynamics on cardiac function

Summary

In recent years, there has been a move from mono- or biventricular models of the heart, to more complex models that incorporate the electromechanical function in all four chambers. However, the biophysical foundation is still under-developed, with most work in atrial cellular models having focused on electrophysiological properties. Here we present a biophysical model of human atrial contraction at body temperature, and use it to study the effects of atrial contraction on whole organ function, and a study of the effects of remodelling due to atrial fibrillation on atrial and ventricular function. This article is protected by copyright. All rights reserved.

http://ift.tt/2xswQ6p

Bacterial strategies along nutrient and time gradients, revealed by metagenomic analysis of laboratory microcosms

Abstract

There is considerable interest in the functional basis of ecological strategies amongst bacteria. We used laboratory microcosms based on culturing of elutant from soil to study the effects of varying initial nutrient concentration, and time succession, on the community metagenome. We found a distinct set of nutrient-related or time-related changes in the functional metagenome. For example, a high nutrient (copiotrophic) strategy was associated with greater abundance of genes related to cell division and cell cycle, while a low nutrient (oligotrophic) strategy had greater abundance of genes related to carbohydrate metabolism and virulence, disease and defense. We also found time-related changes in the functional metagenome, revealing a distinct 'r'-related strategy with greater abundance of genes related to regulation and cell signaling, and a 'K' strategy rich in motility and chemotaxis-related genes. These different gene-based strategies may help to explain how so many bacterial OTUs coexist in nature, and the functional principles dominating natural communities. In terms of diversity, both the OTU richness and the richness of species assignment of functional genes showed linear correlations with functional gene richness, supporting the hypothesis that greater taxonomic diversity is associated with greater functional diversity, with possible implications for ecosystem stability.

http://ift.tt/2h9cIuV

Cyanobacterial bloom significantly boosts hypolimnelic anammox bacterial abundance in a subtropical stratified reservoir

Abstract

The degradation of freshwater quality induced by cyanobacterial blooms is a major global environmental concern. Microbially driven nitrogen removal could alleviate eutrophication to some degree in freshwater ecosystems. However, the response of anaerobic ammonium oxidizing (anammox) bacterial communities to cyanobacterial blooms remains poorly understood, especially in reservoir ecosystems. Here we compared the dynamics of anammox bacterial communities during and after a cyanobacterial bloom in a subtropical reservoir. Our data showed that a cyanobacterial bloom triggered a significant increase in bottom anammox bacterial abundance. During the bloom period, anammox bacterial abundance in bottom waters was 9-fold and 52-fold higher compared with non-bloom stratification and mixing periods, respectively. The community composition of anammox bacteria in surface waters changed substantially accompanied by the disappearance of the cyanobacterial bloom, and a shift of dominance from unidentified anammox genera to Ca. Brocadia was observed. Although Ca. Brocadia was always predominant in both middle and bottom waters, the non-bloom period had more unique taxa than the bloom period. Cyanobacterial bloom-related changes in environmental conditions (e.g. NH₄-N and total organic carbon) and water stratification together influenced the distribution and dynamics of anammox bacteria. Altogether, our study lays the basis for a better understanding of the breakdown of cyanobacterial blooms in a stratified reservoir.

http://ift.tt/2gWyjKC

Climate controls prokaryotic community composition in desert soils of the southwestern United States

Abstract

Aridisols are the dominant soil type in drylands, which occupy one-third of Earth's terrestrial surface. We examined controls on biogeographical patterns of Aridisol prokaryotic (bacterial and archaeal) communities at a regional scale by comparing communities from 100 Aridisols throughout the southwestern United States using high-throughput sequencing of the 16S rRNA gene. We found that microbial communities differed among global biomes and deserts of the Southwest. Differences among biomes were driven by differences in taxonomic identities, whereas differences among deserts of the Southwest were driven by differences in relative sequence abundance. Desert communities were dominated by Actinobacteria, Proteobacteria and Crenarchaeota, supporting the notion of a core set of abundant taxa in desert soils. Our findings contrast with studies showing little taxonomic overlap at the OTU level (97% sequence similarity) across large spatial scales, as we found ∼90% of taxa in at least two of the three deserts. Geographic distance structured prokaryotic communities indirectly through the influence of climate and soil properties. Structural equation modeling suggests that climate exerts a stronger influence than soil properties in shaping the composition of Aridisol microbial communities, with annual heat moisture index (an aridity metric) being the strongest climate driver. Annual heat moisture index was associated with decreased microbial diversity and richness. If the Desert Southwest becomes hotter and drier as predicted, these findings suggest that prokaryotic diversity and richness in Aridisols will decline.

http://ift.tt/2vPCXgc

Diagnosis and Management of Cognitive and Behavioral Changes in Dementia With Lewy Bodies

Opinion statement

Proper diagnosis of dementia with Lewy bodies (DLB) in clinical practice remains suboptimal as many cases are misdiagnosed, usually as Alzheimer disease (AD) or Parkinson's disease (PD) and, in rare cases, psychosis. Therefore, it is important for patients with dementia to be thoroughly evaluated by a specialist who is familiar with current diagnostic tests and treatment options. New diagnostic criteria from the Dementia with Lewy Bodies Consortium have been developed to increase diagnostic sensitivity for DLB (Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium; McKeith et al.; Neurology, 89(1): 88–100). REM sleep behavior disorder (RBD) has been studied more thoroughly in correlation with DLB and is now considered a core feature. D2 receptor blocking antipsychotics, which can cause severe antipsychotic sensitivity, are now rarely prescribed for treatment. Therefore, severe antipsychotic sensitivity, which was a suggestive criterion for DLB diagnosis, is now listed as a supportive feature. Reduced DAT uptake in basal ganglia demonstrated by SPECT or PET imaging has high specificity (90%) for distinguishing DLB from AD. Reduced uptake on metaiodobenzylguanidine myocardial scintigraphy correlates with reduced postganglionic sympathetic cardiac innervation in Lewy body diseases, which can increase specificity for discriminating probable DLB from probable AD in milder cases of dementia. However, the latter is more commonly used in Japan and is not used in the USA. The evidence supporting the benefit of other therapeutic modalities is limited in DLB due to lack of extensive studies. There are no FDA-approved medications for the treatment of DLB, although some effective drugs have been used off label to treat various symptoms.

http://ift.tt/2yycloM

A Comparison of the Device-Related Complications of Intramedullary Lengthening Nails Using a New Classification System

The purpose of this study was to understand the pros and cons of the lengthening nails which have their own mechanical mechanism; we propose a classification for "device-related complications" arising from mechanical properties of the nail itself. From March 2010 to March 2014, 115 segments of lower limb lengthening were performed using intramedullary lengthening nails (35 ISKD, 34 PRECICE1, and 46 PRECICE2). Device-related complications were sorted into three categories according to a new classification: distraction control-related (type I), stability related (type II), and other device-related (type III); these were subdivided using Paley's concept of problems (a), obstacles (b), and sequel (c). Most common complications were distraction mechanism issues (type I) in ISKD and mechanical strength related ones (type II) in PRECICE1 and PRECICE2. Sixty percent (21/35) of ISKD had device-related problems. In PRECICE1 group, 8.8% (3/34) had device-related problems, and 8.8% (3/34) showed device-related obstacle. In PRECICE2, forty-four percent (20/46) had device-related problems. In conclusion, a new classification showed more clearly the differences of mechanical characteristics of different nails. The most essential thing of future lengthening nail development is minimizing the types I and II complications. Further study is necessary to compare the mechanical strength and stability of lengthening nails.

http://ift.tt/2g31AU7

In Vivo Tracking of Human Adipose-derived Mesenchymal Stem Cells in a Rat Knee Osteoarthritis Model with Fluorescent Lipophilic Membrane Dye

This protocol describes an efficient way to monitor the cell persistence and biodistribution of human adipose-derived mesenchymal stem cells (haMSCs) by far-red fluorescence labeling in a rat knee osteoarthritis (KOA) model via intra-articular (IA) injection.

http://ift.tt/2y1bOLs

Pattern-based Search of Epigenomic Data Using GeNemo

Unlike DNA sequence data, epigenomic data are not readily subjected to text-based searches. Presented here are the procedures to use an upgraded version of GeNemo, a web-based bioinformatics tool, to conduct pattern-based searches for similarities in epigenomic data comparing available online databases including Encyclopedia of DNA Elements with user's data.

http://ift.tt/2y14dMW

The Utility of MRI in the Diagnosis of Takayasu Arteritis

Takayasu Arteritis (TA) is an inflammatory disorder involving the thoracoabdominal aorta and its branches and the pulmonary arteries, with eventual vascular stenosis, occlusion, or aneurysm formation. Conventional angiography has been the reference imaging standard for diagnosis of TA. The purpose of this case report is to demonstrate the utility of MR imaging and MR angiography in the diagnosis of Takayasu Arteritis in a pediatric patient. The patient is a 15-year-old female patient presenting with anemia, hypertension, and acute kidney injury. Initial chest CT demonstrated ectasia of the ascending and focal stenosis of the descending thoracic aorta, prompting further evaluation with MRI and MRA. MRI/MRA demonstrated mural thickening with luminal stenosis of the aorta and aortic branch vessels. These imaging findings were suggestive of a large vessel arteritis and along with the clinical presentation and laboratory abnormalities the diagnosis of Takayasu Arteritis was suggested. Several case series in adults have described the cross-sectional findings of TA. However, this case report demonstrates the utility of MRI/MRA in the evaluation of TA in children and in the course of follow-up, as it provides a noninvasive method for evaluating a child without ionizing radiation or iodinated contrast.

http://ift.tt/2xrsyY5

Cytomegalovirus Associated Duodenal Ulcer and Duodenitis in a Malnourished Pediatric Patient

Cytomegalovirus (CMV) duodenitis is a rare occurrence, especially in pediatric patients. A thirteen-month-old female presented to the Emergency Department for a febrile seizure. She was incidentally admitted for severe malnutrition with an initial workup remarkable for only a slight elevation in her ALT at 48. The patient was found to have an oral aversion requiring nasogastric tube feeds for adequate caloric intake. She continued to fail to gain weight and underwent an EGD that demonstrated a duodenal ulcer. She was consequently started on sucralfate and omeprazole. Post-EGD lab work demonstrated a pronounced increase in AST and ALT. Pathology from the EGD biopsies later demonstrated viral inclusion bodies consistent with CMV duodenitis. Apart from malnutrition, other causes of immune deficiency were eliminated from the differential diagnosis due to negative HIV PCR and normal immunoglobulins. While on antiviral treatment, her viral load of 1080 IU/mL trended to resolution and her liver enzymes normalized. The patient was ultimately discharged home demonstrating adequate weight gain via gastrostomy tube feeds. This case advocates for pediatricians to include immunodeficiency and infectious etiologies in their differential for malnourished patients in order to lead to earlier diagnosis and management of this treatable condition.

http://ift.tt/2xpbBCx

iSepsis – Death by Fluids, Part 1.5 – Moronic Protocols

A Blog by Dr Wong (professor of Surgery) highlighting the stupidity of the mindless adoption of Surviving Sepsis Campaign Guidelines

EMCrit by Paul Marik.

http://ift.tt/2y2orWF

A Randomized Controlled Trial Evaluating the Effects of Diosmin in the Treatment of Radicular Pain

Diosmin has been widely used to treat patients with vascular pain for its potent anti-inflammatory and analgesic effects. To evaluate the therapeutic effects of Diosmin in the treatment of radicular pain, we conducted an investigator-initiated, randomized, active-controlled noninferiority trial between January 1, 2009, and December 1, 2010. Diosmin (50 mg/kg/day) was orally administered to treat the radicular pain in 150 patients for one month. Another 150 patients with the same symptom were given 20% 250 ml mannitol (1 g/kg/day) for 7 days and dexamethasone (10 mg/day) for 3 days intravenously guttae. Short-term relief and long-term relief were measured. Secondary outcomes include improvement in functional and psychological status, return to work, and reduction in anti-inflammatory analgesic drugs intake. Patients treated with oral Diosmin achieved reduction in radicular pain. The total satisfaction rate of Diosmin group was 84.7% [95% confidence interval (CI): 77.9%, 90.0%], and the complete satisfaction rate was 50.7% (95% CI: 42.4%, 58.9%). No statistically significant difference was found between the Diosmin group and the active-control group regarding patient satisfaction. No adverse effects were found during the study period. Our study suggests that clinical application of Diosmin with a dose of 50 mg/kg/day might reduce the radicular pain. This trial is registered with ISRCTN97157037.

http://ift.tt/2z6kOMV

Pediatric Pulmonary Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Case Report and Review of the Literature

Non-Hodgkin's lymphoma (NHL) is a common malignancy of childhood; however, a lung primary presentation is an uncommon finding, as is finding an association with the Epstein-Barr virus (EBV). We report the case of a 23-month-old female who developed EBV-associated diffuse large B-cell lymphoma (DLBCL) that was initially thought to be pneumonia. Extensive tissue necrosis, focal angioinvasion, and angiodestruction were observed. She was refractory to various therapy regimens, subsequently developed DLBCL in the central nervous system, and eventually expired. Although EBV+ DLBCL was initially considered to occur predominantly in elderly patients over 50 years of age, it is now increasingly recognized to occur in younger patients with primarily nodal involvement who have overall better prognoses. To our knowledge, this case is the first reported EBV+ DLBCL occurring in a patient below two years of age with lung involvement as the initial clinical presentation.

http://ift.tt/2yQ84cz

Expression and Immunogenicity of Two Recombinant Fusion Proteins Comprising Foot-and-Mouth Disease Virus Structural Protein VP1 and DC-SIGN-Binding Glycoproteins

Improving vaccine immunogenicity by targeting antigens to dendritic cells has recently emerged as a new design strategy in vaccine development. In this study, the VP1 gene of foot-and-mouth disease virus (FMDV) serotype A was fused with the gene encoding human immunodeficiency virus (HIV) membrane glycoprotein gp120 or C2-V3 domain of hepatitis C virus (HCV) envelope glycoprotein E2, both of which are DC-SIGN-binding glycoproteins. After codon optimization, the VP1 protein and the two recombinant VP1-gp120 and VP1-E2 fusion proteins were expressed in Sf9 insect cells using the insect cell-baculovirus expression system. Western blotting showed that the VP1 protein and two recombinant VP1-gp120 and VP1-E2 fusion proteins were correctly expressed in the Sf9 insect cells and had good reactogenicity. Guinea pigs were then immunized with the purified proteins, and the resulting humoral and cellular immune responses were analyzed. The VP1-gp120 and VP1-E2 fusion proteins induced significantly higher specific anti-FMDV antibody levels than the VP1 protein and stronger cell-mediated immune responses. This study provides a new perspective for the development of novel FMDV subunit vaccines.

http://ift.tt/2y8tc0b

Homozygous indel mutation in CDH11 as the probable cause of Elsahy–Waters syndrome

Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy–Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell–cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).

http://ift.tt/2wFSEqM

A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q)), segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating) domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147) with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported), highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.

http://ift.tt/2glb5ea

All-Atom Four-Body Knowledge-Based Statistical Potentials to Distinguish Native Protein Structures from Nonnative Folds

Recent advances in understanding protein folding have benefitted from coarse-grained representations of protein structures. Empirical energy functions derived from these techniques occasionally succeed in distinguishing native structures from their corresponding ensembles of nonnative folds or decoys which display varying degrees of structural dissimilarity to the native proteins. Here we utilized atomic coordinates of single protein chains, comprising a large diverse training set, to develop and evaluate twelve all-atom four-body statistical potentials obtained by exploring alternative values for a pair of inherent parameters. Delaunay tessellation was performed on the atomic coordinates of each protein to objectively identify all quadruplets of interacting atoms, and atomic potentials were generated via statistical analysis of the data and implementation of the inverted Boltzmann principle. Our potentials were evaluated using benchmarking datasets from Decoys-'R'-Us, and comparisons were made with twelve other physics- and knowledge-based potentials. Ranking 3rd, our best potential tied CHARMM19 and surpassed AMBER force field potentials. We illustrate how a generalized version of our potential can be used to empirically calculate binding energies for target-ligand complexes, using HIV-1 protease-inhibitor complexes for a practical application. The combined results suggest an accurate and efficient atomic four-body statistical potential for protein structure prediction and assessment.

http://ift.tt/2y8CoSH

Optimization of the Time Window of Interest in Ovariectomized Imprinting Control Region Mice for Antiosteoporosis Research

This study was performed to determine the optimal window of time during which the properties of osteoporosis are obvious and to explore the best region of interest for microstructural evaluation in antiosteoporosis research in an ovariectomized mouse model by examining changes in micro-computed tomography parameters and serum indices. Ovariectomized mice and sham-operated mice were randomly divided into five groups. At the end of the 4th, 8th, 12th, 16th, and 20th weeks after ovariectomy, the microstructure of the proximal tibia and distal femur was scanned by micro-computed tomography and blood samples were collected to detect serum biochemical indicators including alkaline phosphatase, osteocalcin, N-terminal propeptide of type I procollagen (P1NP), and C-terminal telopeptide fragment of type I collagen (CTX1). The trabecular number and connectivity density decreased while the trabecular thickness and trabecular separation increased, indicating substantial changes in the trabecular microstructure of both the tibia and femur and significant changes in bone turnover after ovariectomy, as indicated by lower levels of serum alkaline phosphatase, osteocalcin, and P1NP and higher level of CTX1 in the ovariectomy than sham group. The proximal tibia from weeks 8 to 16 after ovariectomy was optimal for osteoporosis research in this model.

http://ift.tt/2xrodEa

Increased EGFR Phosphorylation Correlates with Higher Programmed Death Ligand-1 Expression: Analysis of TKI-Resistant Lung Cancer Cell Lines

Despite the recent development of immunotherapies that target programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) treatment, these therapies are less effective in NSCLC patients with epidermal growth factor receptor (EGFR) mutations. However, the molecular mechanisms underlying this lower efficacy of immunotherapies in EGFR mutant lung cancers are still unclear. In this study, we analyzed PD-L1 protein expression in lung cancer cell lines with EGFR mutations prior to and after acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs). We found that parental lung cancer cell lines harboring EGFR mutations showed negative (PC9 and H3255 cells) and positive (HCC827 cells) staining for PD-L1 by immunohistochemistry. Comparing PD-L1 expression between EGFR-TKI resistant cell lines and their parental cells, we found that increased phosphorylation of EGFR was related to increased expression of PD-L1. Increased phosphorylation of EGFR was accompanied by the T790M secondary mutation. Acquired resistance cells with MET amplification or EGFR loss both showed decreased phosphorylation of EGFR and decreased PD-L1 expression. Our results indicate that lung cancer cell lines with EGFR mutations (parental cells) do not harbor high PD-L1 protein expression. In addition, EGFR phosphorylation affects PD-L1 expression after acquisition of resistance to EGFR-TKIs.

http://ift.tt/2y8Y8h1

Surgical Management of Gallbladder Cancer: Simple Versus Extended Cholecystectomy and the Role of Adjuvant Therapy

Objective: To assess if simple cholecystectomy with adjuvant therapy could provide outcomes comparable to extended cholecystectomy. Background: Current guidelines recommend extended/radical cholecystectomy for T2/T3 gallbladder cancer; however, many tumors are discovered incidentally at laparoscopic cholecystectomy. Methods: The national Cancer Data Base 2004 to 2014 was queried for patients with pT2/T3 gallbladder adenocarcinoma who underwent resection. Adjuvant therapy was defined as chemotherapy, with or without radiotherapy, within 90 days of surgery. Baseline characteristics and overall survival were compared by χ2 and Kaplan-Meier method, respectively. One-to-one propensity score matching for receipt of adjuvant therapy was used to account for potential selection bias. Results: A total of 6825 patients were identified. Diagnosis was made predominantly (78.9%) at the time of surgery or on pathology; 31.8% (2168) received adjuvant therapy. The majority, 88.8% (6060), had a simple cholecystectomy. Patients who received adjuvant therapy versus surgery alone were more likely to: be younger, privately insured, have no comorbidities, pT3 disease, positive lymph nodes, positive resection margins, and extended cholecystectomy. After matching, median survival was significantly longer for extended cholecystectomy with adjuvant therapy (23.3 months) than cholecystectomy with adjuvant therapy (16.4 months), which was significantly longer than either simple (12.4 months) or extended (10.7 months) cholecystectomy alone (all log-rank P

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Use of Limiting Dilution Method for Isolation of Nucleus Pulposus Mesenchymal Stem/Progenitor Cells and Effects of Plating Density on Biological Characteristics and Plasticity

Objectives. To evaluate the effects of the limiting dilution method and plating density in rat nucleus pulposus mesenchymal stem/progenitor cells (NPMSCs). Materials and Methods. Nucleus pulposus tissues were isolated from 12-week-old male Sprague-Dawley rats and NPMSCs were isolated using limiting dilution method. Cells were then classified into 3 groups according to plating density. Cell morphologies were observed, and colony-forming units, migration abilities, proliferative capacities, cell cycle percentages, multilineage differentiation capacities, stem cell biomarker expression levels, and immunophenotyping were also examined in each group. Results. Low density group (LD) had higher morphological homogeneity, stronger colony-forming ability, higher cell proliferation capacity, and enhanced cell migration ability relative to the other two groups (). Moreover, LD had more cells entering S phase, with fewer cells arrested in G0/G1 phase (). While all three density groups showed a multilineage differentiation potential, LD showed a higher degree of observed and semiquantified lineage specific staining (). Furthermore, LD displayed higher expression levels of stem cell biomarkers (Nanog, Oct4, and Sox2) and showed higher percentages of CD29+, CD44+, and CD90+ cells () following flow cytometry analysis. Conclusions. Limiting dilution method is suggested when isolating NPMSCs as a means of improving cell activity and plasticity.

http://ift.tt/2glAWlY

Predictive Role of F2-Isoprostanes as Biomarkers for Brain Damage after Neonatal Surgery

Objective. Neonates have a high risk of oxidative stress during anesthetic procedures. The predictive role of oxidative stress biomarkers on the occurrence of brain injury in the perioperative period has not been reported before. Methods. A prospective cohort study of patients requiring major surgery in the neonatal period was conducted. Biomarker levels of nonprotein-bound iron (NPBI) in plasma and F2-isoprostane in plasma and urine before and after surgical intervention were determined. Brain injury was assessed using postoperative MRI. Results. In total, 61 neonates were included, median gestational age at 39 weeks (range 31–42) and weight at 3000 grams (1400–4400). Mild to moderate brain lesions were found in 66%. Logistic regression analysis showed a significant difference between plasma NPBI in patients with nonparenchymal injury versus no brain injury: 1.34 umol/L was identified as correlation threshold for nonparenchymal injury (sensitivity 67%, specificity 91%). In the multivariable analysis, correcting for GA, no other significant relation was found with the oxidative stress biomarkers and risk factors. Conclusion. Oxidative stress seems to occur during anaesthesia in this cohort of neonates. Plasma nonprotein-bound iron showed to be associated with nonparenchymal injury after surgery, with values of 1.34 umol/L or higher. Risk factors should be elucidated in a more homogeneous patient group.

http://ift.tt/2yxs8UV