bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotion regulation therapy for cancer caregivers—an open trial of a mechanism-targeted approach to addressing caregiver distress
Authors: Applebaum Allison J , Panjwani Aliza A , Buda Kara , O’Toole Mia S , Hoyt Michael A , Garcia Adam , Fresco David M , Mennin Douglas S
Published: November 2018

Informal caregivers (ICs) are integral to care provided to patients facing life-threatening or incurable illnesses. This responsibility causes considerable burden, as approximately one half of ICs report clinically significant symptoms of depression and/or anxiety that persist when left untreated. Psychosocial interventions containing efficacious treatment principles (e.g., cognitive behavior therapy [CBT]) show disappointing results in reducing anxiety and depression in ICs. This may reflect failure of these interventions to specifically target crucial mechanisms underlying the central feature of distress caused by the patient’s illness—notably, perseverative negative thinking (PNT). Emotion Regulation Therapy (ERT) is an efficacious CBT developed to explicitly target mechanisms underlying PNT and the emotional concomitants that arise in response to stressful situations. This open trial was conducted to evaluate the acceptability and initial efficacy of ERT adapted to the experience of cancer ICs (ERT-C). Thirty-one ICs provided informed consent and completed eight weekly individual sessions of ERT-C. Participants completed self-report measures of depression and anxiety symptoms, PNT, emotion regulation deficits, and caregiver burden before and after treatment. ERT-C was well tolerated as indicated by 22 treatment completers and feedback provided in exit interviews. ICs demonstrated reduced depression and anxiety symptoms, PNT, and emotion regulation deficits with moderate to large effect sizes (Hedge’s g range: 0.36–0.92). Notably, caregiver burden was not reduced but ICs expressed more ability to confront caregiving-related challenges. Findings offer promising but preliminary support for ERT-C as a conceptual model and treatment modality for distressed cancer ICs.
Biomarkers of Systemic Inflammation and Risk of Incident Hearing Loss
Authors: Gupta Shruti , Curhan Sharon G. , Curhan Gary C.
Published: November 2018

Background:

Chronic inflammation may lead to cochlear damage, and the only longitudinal study that examined biomarkers of systemic inflammation and risk of hearing loss found an association with a single biomarker in individuals <60 years of age. The purpose of our study was to determine whether plasma inflammatory markers are associated with incident hearing loss in two large prospective cohorts, Nurses’ Health Studies (NHS) I and II.

Methods:

We examined the independent associations between plasma levels of markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and soluble tumor necrosis factor receptor 2 [TNFR-2]) and self-reported hearing loss. The participants in NHS I (n = 6194 women) were 42 to 69 years of age at the start of the analysis in 1990, while the participants in NHS II (n = 2885 women) were 32 to 53 years in 1995. After excluding women with self-reported hearing loss before the time of blood-draw, incident cases of hearing loss were defined as those women who reported hearing loss on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. The primary outcome was hearing loss that was reported as moderate or worse in severity, pooled across the NHS I and NHS II cohorts. We also examined the pooled multivariable-adjusted hazard ratios for mild or worse hearing loss. Cox proportional hazards regression was used to adjust for potential confounders.

Results:

At baseline, women ranged from 42 to 69 years of age in NHS I and 32 to 53 years of age in NHS II. Among the NHS I and II women with measured plasma CRP, there were 628 incident cases of moderate or worse hearing loss during 100,277 person-years of follow-up. There was no significant association between the plasma levels of any of the three inflammatory markers and incident moderate or worse hearing loss (multivariable-adjusted pooled p trend for CRP = 0.33; p trend IL-6 = 0.54; p trend TNFR-2 = 0.70). There was also no significant relation between inflammatory marker levels and mild or worse hearing loss. While there was no significant effect modification by age for CRP or IL-6 in NHS I, there was a statistically significant higher risk of moderate or worse hearing loss (p interaction = 0.02) as well as mild or worse hearing loss (p interaction = 0.004) in women ≥60 years of age who had higher plasma TNFR-2 levels.

Conclusions:

Overall, there was no significant association between plasma markers of inflammation and risk of hearing loss.
The association between birth order and childhood brain tumors: a systematic review and meta-analysis
Authors: Nguyen Mai V. , Tran Mo T. , Tran Chi TDu , Tran Quang H. , Tuonga Thuy TV , Phung Lam N. , Vu Huyen X. , Le Linh C. , Boffetta Paolo , Luu Hung N.
Published: November 2018

The incidence of childhood brain tumors (CBT) has increased worldwide, likely resulting from the improvements of early diagnostics. We conducted a systematic review and meta-analysis to clarify the association between birth order and CBT. We followed established guidelines to systematically search Ovid Medline, PubMed, and the Cochrane Library for English language studies, published before March 2018. Quality assessment was performed using the Newcastle–Ottawa Scale. Meta-analysis provided pooled risk estimates and their 95% confidence intervals (CIs) for birth order and CBT. We identified 16 case–control studies with a total sample of 32 439 cases and 166 144 controls and three prospective cohort studies (i.e. 4515 incident cases of CBTs among 5 281 558 participants). Compared with first birth order, the meta-odds ratio for second birth order in case–control studies was 1.04 (95% CI: 1.01–1.07), that for third birth order was 0.98 (95% CI: 0.90–1.06), and that for fourth order was 0.85 (95% CI: 0.78–0.92). The meta-hazard ratio for second or higher birth order compared with first birth order in cohort studies was 1.00 (95% CI: 0.96–1.05). We found no association between birth order and CBT in both case–control and cohort study designs; the small association observed for fourth birth order deserves further consideration.
Monoaminergic modulation of decision-making under risk of punishment in a rat model
Authors: Blaes Shelby L. , Orsini Caitlin A. , Mitchell Marci R. , Spurrell Megan S. , Betzhold Sara M. , Vera Kenneth , Bizon Jennifer L. , Setlow Barry
Published: November 2018

The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision-making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision-making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision-making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between a small, ‘safe’ food reward and a large food reward associated with variable risks of punishment. Preference for the large, risky reward (risk-taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities but did not affect risk-taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision-making, decision-making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.
Resveratrol Mitigates High-Fat Diet–Induced Vascular Dysfunction by Activating the Akt/eNOS/NO and Sirt1/ER Pathway
Authors: Huang Jiung-Pang , Hsu Sheng-Chieh , Li Dai-Er , Chen Kuan-Hsing , Kuo Chao-Yu , Hung Li-Man
Published: November 2018

We investigated whether resveratrol (RSV) can attenuate obesity and diabetes progression and improve diabetes-induced vascular dysfunction, and we attempted to delineate its underlying mechanisms. Male C57Bl/6 mice were administered a high-fat diet (HFD) for 17 weeks. Mice developed type 2 diabetes with increased body weight, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Oral gavage with RSV significantly reversed the symptoms induced by the HFD. Insulin sensitivity likewise improved after the RSV intervention in these mice. Phenylephrine-induced cremaster arteriolar constriction was impaired, whereas RSV treatment significantly mitigated the vessel responsiveness to phenylephrine. The obese diabetic mice exhibited increased leukocyte rolling, adhesion, and transmigration in the postcapillary venules of the cremaster muscle. By contrast, RSV treatment significantly attenuated HFD-induced extravasation. RSV significantly recovered phosphorylated Akt and eNOS expression in the thoracic aorta. In addition, activated adenosine monophosphate-activated protein kinase in the thoracic aorta was involved in the improvement of epithelial function after RSV intervention. RSV considerably upregulated the plasma NO level in HFD mice. Moreover, RSV-enhanced human umbilical vein endothelial cells healing through Sirt1/ER pathway may be involved in the prevention of leukocyte extravasation. Collectively, RSV attenuates diabetes-induced vascular dysfunction by activating Akt/eNOS/NO and Sirt1/ER pathway. Our mechanistic study provides a potential RSV-based therapeutic strategy against cardiovascular disease.
Understanding Quality of Care and Satisfaction With Sexual and Reproductive Healthcare Among Young Men
Authors: Pilgrim Nanlesta A. , Jennings Jacky M. , Sanders Renata , Page Kathleen R. , Loosier Penny S. , Dittus Patricia J. , Marcell Arik V.
Published: November 2018

Introduction:

Sexual and reproductive healthcare (SRHC) guidelines recommend the delivery of quality preventive SRHC to males beginning in adolescence. A quality of care (QOC) framework was used to examine factors associated with young male's perceptions of QOC and satisfaction with care, which can influence their use of SRHC.

Methods:

Cross-sectional surveys were conducted from August 2014 to September 2016 with 385 male patients aged 15–24 years, recruited from primary care and sexually transmitted disease (STD) clinics. Surveys measured QOC received, satisfaction with care, and domains of a QOC framework. Poisson regression analyses examined associations between the framework domains and perceived QOC as well as satisfaction with care.

Results:

Over half of males reported QOC as excellent (59%) and were very satisfied with services (56.7%). Excellent QOC and high satisfaction with services were associated with timely care, higher Clinician-Client Centeredness, and being a bisexual male. Excellent QOC was also associated with greater comfort in the clinic, being tested for human immunodeficiency virus/STDs, attending primary care settings, and receipt of higher number of SRHC services.

Conclusions:

Using a QOC framework as part of providing SRHC to young males is important to improving their perceptions of QOC and satisfaction with services.
Impacting Delirium in the Trauma ICU Utilizing the ICU Liberation Collaborative Benchmark Report
Authors: Sweeney Jennifer
Published: November 2018

Delirium is a frequent complication of intensive care unit (ICU) admissions, manifesting as acute confusion with inattention and disordered thinking. Patients in the ICU who develop acute delirium are more likely to experience long-term disability and mortality. The Society of Critical Care Medicine published guidelines for the management of pain, agitation, and delirium (PAD) in the ICU in 2013. Based on these PAD guidelines, the ABCDEF bundle was created. Research is lacking on how adherence to the ABCDEF bundle elements impacts specific populations such as trauma patients. This represents a significant gap for patients whose multisystem injuries and comorbidities add a higher level of complexity to their care and outcomes. The medical ICU at a large community hospital participated in a 2-year quality improvement project as part of the Society of Critical Care Medicine's ICU Liberation Collaborative. However the organization's trauma ICU (TICU) was excluded from the study. The purpose of this study was to conduct a baseline assessment of trauma patient records to determine which bundle elements were already being applied in the TICU, and if the resources required for implementing the full ABCDEF bundle would be beneficial to the TICU patient outcomes. Benchmark data from the organization's participation in the ICU Liberation Collaborative quality improvement project served as the primary source of evidence. Analysis revealed strengths and opportunities for improvement. Incidence of delirium remained unchanged and far below national averages, indicating the need for further investigation into practices to verify this finding. An opportunity was identified to expand implementation of certain elements of the ABCDEF bundle in the trauma ICU. There is an opportunity for nurses to take the lead in improving patient outcomes. With improved education, evidence-based assessment tools, and best practice guidelines, nurses can help decrease the incidence of delirium by as much as 30%.
Short article: Association between liver fibrosis and hepatitis E seroprevalence among HIV-positive individuals in Nepal
Authors: Shah Shemal M. , Baniya Jagat B. , Gupta Birendra Prasad , Shrestha Ananta , Rodin Holly , Boonstra Andre , Debes Jose D.
Published: November 2018

Objective

Hepatitis E virus (HEV) seropositivity may confer an increased risk of liver fibrosis in immunosuppressed individuals. We studied this effect in HIV-infected individuals in Nepal, a country hyperendemic for HEV.

Participants and methods

We prospectively evaluated 200 HIV-positive individuals. Serum samples were tested for components of fibrosis scores and cytokeratin-18.

Results

Of 200 patients, 43% were HEV-immunoglobulin G+. The mean fibrosis-4 score was 8.02 in the HEV-positive and 1.17 in the HEV-negative group (P<0.001). The mean nonalcoholic fatty liver disease score was 2.12 in the HEV-positive and −2.53 in the HEV-negative group (P=0.02). The mean aminotransferase-platelet ratio index score was 0.37 in the HEV-positive and 0.38 in the HEV-negative group (P=0.9). The mean cytokeratin-18 levels were 119.9 in the HEV-positive group and 158.6 in the HEV-negative group (P=0.08).

Conclusion

We found higher fibrosis-4 and nonalcoholic fatty liver disease scores in HEV-HIV-positive individuals, suggesting an increased liver fibrosis profile in this group. Further studies using liver stiffness measurements should be carried out.
Optimum Chest Compression Point for Cardiopulmonary Resuscitation in Children Revisited Using a 3D Coordinate System Imposed on CT: A Retrospective, Cross-Sectional Study
Authors: Park Myoungjae , Oh Won Sup , Chon Sung-Bin , Cho Sunho
Published: November 2018

Objectives:

The optimum chest compression site (P_optimum) in children is debated: European Resuscitation Council recommends one finger breadth above the xiphisternal joint, whereas American Heart Association proposes the lower sternal half. Using a coordinate system imposed on CT, we aimed to determine the pediatric P_optimum to maximize stroke volume, the key point for successful cardiopulmonary resuscitation, while minimizing hepatic injury.

Design:

Retrospective, cross-sectional study.

Setting:

University hospital.

Patients:

Children 1–15 years old who underwent chest CT.

Interventions:

None.

Measurements and Main Results:

We defined zero point (0, 0) as the center of the xiphisternal joint designating leftward and upward directions of the patients as positive on each axis. P_optimum (x_max. left ventricle, y_max. left ventricle) was defined as the center of the maximum diameter of the left ventricle, whereas P_aorta (x_aorta, y_aorta) as that of the aortic annulus. To compress the left ventricle exclusively, y_max. left ventricle should range above the y coordinate of hepatic dome (y_liver_dome) and below y_aorta. Data were presented as median (interquartile range) and compared among age groups 1.0–5.0, 5.1–10.0, and 10.1–15.0 years using Kruskal-Wallis test. For universal application regardless of age, y coordinates were converted into relative ones with unit of sternal top: 1 unit of sternal top was the y coordinate of the sternal top. A total of 163 patients were enrolled, median age 8.8 year (4.2–14.3 yr). Among age groups, no significant difference was observed in y_max. left ventricle, relative y_max. left ventricle, y_aorta, and y_liver_dome: 1.0 cm (0.1–1.9 cm), 0.10 unit of sternal top (0.01–0.18 unit of sternal top), 0.39 unit of sternal top (0.30–0.47 unit of sternal top), and –0.14 unit of sternal top (–0.25 to –0.03 unit of sternal top), respectively. The probability to compress the left ventricle exclusively was greater than or equal to 96% when placing hand at 0.05–0.20 unit of sternal top. Subgroup analysis demonstrated the following regression equation: x_max. left ventricle (mm) = 0.173 × (height in cm) + 13 (n = 106; p < 0.001; R
2 = 0.278).

Conclusions:

Theoretically, pediatric P_optimum is located 1 cm (or 0.1 unit of sternal top) above the xiphisternal joint.
Monocyte-to-Lymphocyte Ratio Is Associated With Tuberculosis Disease and Declines With Anti-TB Treatment in HIV-Infected Children
Authors: Choudhary Rewa K , Wall Kristin M. , Njuguna Irene , Pavlinac Patricia B. , LaCourse Sylvia M. , Otieno Vincent , Gatimu John , Stern Joshua , Maleche-Obimbo Elizabeth , Wamalwa Dalton , John-Stewart Grace , Cranmer Lisa M.
Published: November 2018

Background:

The blood monocyte-to-lymphocyte ratio (MLR) is associated with active tuberculosis (TB) in adults but has not been evaluated as a TB diagnostic biomarker in HIV-infected children in whom respiratory sampling is difficult.

Setting:

In a cohort of HIV-infected hospitalized Kenyan children initiating antiretroviral therapy, absolute monocyte and lymphocyte counts were determined at enrollment and 4, 12, and 24 weeks thereafter.

Methods:

Children were classified as confirmed, unconfirmed, or unlikely pulmonary TB. Receiver operating characteristic curves of MLR cutoff values were generated to distinguish children with confirmed TB from those with unconfirmed and unlikely TB. General estimating equations were used to estimate change in the MLR over time by TB status.

Results:

Of 160 children with median age 23 months, 13 (8.1%) had confirmed TB and 67 (41.9%) had unconfirmed TB. The median MLR among children with confirmed TB {0.407 [interquartile range (IQR) 0.378–0.675]} was higher than the MLR in children with unconfirmed [0.207 (IQR 0.148–0.348), P < 0.01] or unlikely [0.212 (IQR 0.138–0.391), P = 0.01] TB. The MLR above 0.378 identified children with confirmed TB with 77% sensitivity, 78% specificity, 24% positive predictive value, and 97% negative predictive value. After TB treatment, the median MLR declined in children with confirmed TB and levels were similar to children with unlikely TB after 12 weeks.

Conclusions:

The blood MLR distinguished HIV-infected children with confirmed TB from those with unlikely TB and declined with TB treatment. The MLR may be a useful diagnostic tool for TB in settings where respiratory-based microbiologic confirmation is inaccessible.
HIV-Related Stigma Affects Cognition in Older Men Living With HIV
Authors: Lam Austin , Mayo Nancy E. , Scott Susan , Brouillette Marie-Josée , Fellows Lesley K.
Published: November 2018

Background:

Stigma remains a reality for many people living with HIV. Stigma bears on mental health, but we hypothesized that it might also affect cognition, in turn affecting function.

Methods:

We estimated the impact of HIV-related stigma on brain health and everyday functioning among 512 older white men living with HIV in Canada, using the International Classification of Functioning, Disability and Health as a comprehensive framework to integrate biopsychosocial perspectives. Experience of HIV-related stigma, as indicated by a single self-report item, was related to cognitive test performance, cognitive symptoms, and mood. Structural equation modeling was used to estimate the relationships between these variables.

Findings:

A comprehensive structural equation model was built including personal, environmental, and biological factors, measures of mental and cognitive health, activity limitations, and participation restrictions. HIV-related stigma contributed to lower cognitive test performance and worse mental health. These in turn affected real-world function. The paths from stigma to cognition and mood had distinct downstream effects on physical, cognitive, and meaningful activities.

Interpretation:

This provides evidence that HIV-related stigma is a threat to cognitive as well as mental health, with a negative impact on everyday function in men aging with HIV. This argues for direct links between the psychosocial and biological impacts of HIV at the level of the brain. Stigma reduction may be a novel route to addressing cognitive impairment in this population.

Funding:

Operating support was provided by the Canadian Institutes of Health Research (TCO-125272) and by the CIHR HIV Clinical Trials Network (CTN-273).
T2 Mapping in Prostate Cancer
Authors: Mai Julia , Abubrig Mohamed , Lehmann Thomas , Hilbert Tom , Weiland Elisabeth , Grimm Marc O. , Teichgräber Ulf , Franiel Tobias
Published: November 2018

Objectives

The aim of the study was to determine the quantitative T2 values in prostate tissue and evaluate them for detection and grading of prostate cancer.

Materials and Methods

After approval from the local ethics committee, morphological T2-weighted (T2w) images, apparent diffusion coefficient (ADC) maps from diffusion-weighted images, quantitative T2 maps, and calculated T2w images from 75 men (median age, 66.3 years; median PSA, 8.2 ng/mL) were acquired at 3 T magnetic resonance imaging (MRI). Data were retrospectively evaluated for their distinction between prostate pathologies.

Eight hundred fifty-seven areas of normal gland (n = 378), prostate cancer (54x Gleason score 6, 98x Gleason score 7, 25x Gleason score 8), benign prostatic hyperplasia (BPH) nodes (n = 150), prostatitis (n = 119), and precancerous lesions (n = 33) were determined on calculated and morphological T2w images. Histological criterion standards were whole gland sections (16 patients), MRI-guided in-bore biopsies (32 patients), MRI/transrectal ultrasound-fusion biopsies (15 patients), and systematic 12-core transrectal ultrasound-guided biopsies (12 patients). Significance was assumed to be P < 0.05.

Results

The quantitative T2 values vary significantly between prostate cancer and normal gland tissue (area under the curve [AUC], 0.871), cancer and BPH nodes (AUC = 0.827), and Gleason score 6 and 7 or higher (AUC, 0.742). The quantitative T2 values decrease with increasing Gleason scores and correlate significantly with the ADC values (r = 0.806).

The detection accuracy of prostate cancer on calculated (AUC = 0.682) and morphological T2w images (AUC = 0.658) is not significantly different.

Conclusions

Quantitative T2 values seem to be suitable for distinguishing between prostate cancer and normal gland tissue or BPH nodes. Similar to the ADC values, they offer an indication of the aggressiveness of the prostate cancer.
Prognostic Value of Vascular Calcifications and Regional Fat Depots Derived From Conventional Chest Computed Tomography
Authors: Rodríguez-Granillo Gastón A. , Reynoso Exequiel , Capuñay Carlos , Antoniades Charalambos , Shaw Leslee J. , Carrascosa Patricia
Published: November 2018

Purpose:

The prognostic value of vascular calcifications as well as of regional fat depots has been reported separately, in population-based studies, and using gated-computed tomography (CT) examinations. We, therefore, explored the interplay and prognostic value of vascular calcifications and adipose tissue depots assessed during conventional nongated chest CT.

Materials and Methods:

We enrolled a consecutive series of 1250 patients aged between 35 and 74 years who underwent clinically indicated chest CT scans. We measured the extent of coronary artery calcification (CAC) using the segment-involvement score (CACSIS), and aortic and valve calcification. Pericardial fat volume (PFV), hepatic fat, and abdominal subcutaneous adipose tissue were also calculated. Patients were followed-up for all-cause mortality.

Results:

A total of 577 (46%) patients had presence of CAC in the coronary tree. Over a mean follow-up of 3.7 years, 51 (4%) deaths occurred, 23 (4.1%) in male patients and 28 (4.1%) in female patients. Patients with higher PFV were older (P<0.0001), more frequently male (P<0.0001), had higher abdominal subcutaneous adipose tissue (P<0.0001), hepatic fat (P<0.0001), as well as a larger extent of CAC (P<0.0001), aortic calcium (P<0.0001), and valve calcium (P<0.0001). From a multivariable Cox regression model, age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03-1.11), P=0.001, PFV upper tertile (HR, 4.07; 95% CI, 2.09-7.92), P<0.0001, and CACSIS>5 (HR, 2.19; 95% CI, 1.14-4.23; P<0.0001) were independent predictors of all-cause death.

Conclusions:

In this relatively large patient cohort undergoing clinically indicated conventional chest CT scans, PFV and coronary calcification were high-risk markers associated with worsening survival.
Terminal nucleotidyl transferases (TENTs) in mammalian RNA metabolism
Authors: Warkocki Zbigniew , Liudkovska Vladyslava , Gewartowska Olga , Mroczek Seweryn , Dziembowski Andrzej
Published: November 2018

In eukaryotes, almost all RNA species are processed at their 3′ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases. In recent years, several terminal nucleotidyl transferases (TENTs) including non-canonical poly(A) polymerases (ncPAPs) and terminal uridyl transferases (TUTases) have been discovered. In contrast to canonical polymerases, TENTs' functions are more diverse; some, especially TUTases, induce RNA decay while others, such as cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. The mammalian genome encodes 11 different TENTs. This review summarizes the current knowledge about the functions and mechanisms of action of these enzymes.

This article is part of the theme issue ‘5′ and 3′ modifications controlling RNA degradation’.
HIV-1 subtype C with PYxE insertion has enhanced binding of Gag-p6 to host cell protein ALIX and increased replication fitness
Authors: Domselaar Robert van , Njenda Duncan T. , Rao Rohit , Sönnerborg Anders , Singh Kamalendra , Neogi Ujjwal
Published: November 2018

Human immunodeficiency virus type 1 subtype C (HIV-1C) has a natural deletion of a YPxL motif in its Gag-p6 late domain. This domain mediates the binding of Gag to host cell protein ALIX and subsequently facilitates viral budding. In a subset of HIV-1C infected individuals, the tetrapeptide insertion PYxE has been identified at the deleted YPxL motif site. Here, we report the consequences of PYxE insertion on the interaction with ALIX and the relevance regarding replication fitness and drug sensitivity. In our three HIV-1C cohorts, PYKE and PYQE were most prevalent among PYxE variants. Throughin silicopredictions andin vitroexperiments, we showed that HIV-1C Gag has an increased binding to ALIX when PYxE motif is present. To go more into the clinical relevance of the PYxE insertion, we obtained patient-derived gag-pol sequences from HIV-1CPYxEiviruses and inserted them in a reference HIV-1. Viral growth was increased, and the sensitivity to protease inhibitor (PI) lopinavir (LPV) and nucleoside reverse transcriptase inhibitor tenofovir alafenamide (TAF) was decreased for some of the HIV-1C PYxE variants compared to wild-type variants. Our data suggest that PYxE insertion in Gag restores the ability of Gag to bind ALIX and correlates with enhanced viral fitness in the absence or presence of LPV and TAF. The high prevalence and increased replication fitness of the HIV-1C virus with PYxE insertion could indicate the clinical importance of these viral variants.

Importance

Genomic differences within HIV-1 subtypes is associated with a varying degree of viral spread, disease progression, and clinical outcome. Viral budding is essential in the HIV-1 life cycle and mainly mediated through the interaction of Gag with host proteins. Two motifs within Gag-p6 mediate binding of host cell proteins and facilitate budding. HIV-1 subtype C (HIV-1C) has a natural deletion of one of these two motifs resulting in an inability to bind to host cell protein ALIX. Previously, we have identified a tetrapeptide (PYxE) insertion at this deleted motif site in a subset of HIV-1C patients. Here, we report the incidence of PYxE insertions in three different HIV-1C cohorts, and the insertion restores the binding of Gag to ALIX. It also increases viral growth even in the presence of antiretroviral drugs lopinavir and tenofovir alafenamide. Hence, PYxE insertion in HIV-1C might be biologically relevant for viruses and clinically significant among patients.
The Prevalence and Impact of Model Violations in Phylogenetics Analysis
Authors: Naser-Khdour Suha , Minh Bui Quang , Zhang Wenqi , Stone Eric , Lanfear Robert
Published: November 2018

In phylogenetic inference we commonly use models of substitution which assume that sequence evolution is stationary, reversible and homogeneous (SRH). Although the use of such models is often criticized, the extent of SRH violations and their effects on phylogenetic inference of tree topologies and edge lengths are not well understood. Here, we introduce and apply the maximal matched-pairs tests of homogeneity to assess the scale and impact of SRH model violations on 3,572 partitions from 35 published phylogenetic datasets. We show that many partitions (39.5%) reject the SRH assumptions, and that for most datasets, the topologies of trees inferred from all partitions differ significantly from those inferred using the subset of partitions that do not reject the SRH assumptions. These results suggest that the extent and effects of model violation in phylogenetics may be substantial. They highlight the importance of testing for model violations and possibly excluding partitions that violate models prior to tree reconstruction. They also suggest that further effort in developing models that do not require SRH assumptions could lead to large improvements in the accuracy of phylogenomic inference. The scripts necessary to perform the analysis are available inhttps://github.com/roblanf/SRHtests, and the new tests we describe are available as a new option in IQ-TREE (http://www.iqtree.org).
Pre-implantation genetic diagnosis for a family with Usher syndrome through targeted sequencing and haplotype analysis
Authors: Luo Haining , Chen Chao , Yang Yun , Yuan Yuan , Wang Wanyang , Wu Renhua , Zhang Yinfeng , Peng Zhiyu , Han Ying , Jiang Lu , Yao Ruqiang , An Xiaoying , Zhang Weiwei , Le Yanqun , Xiang Jiale , Yi Na , Huang Hui , Li Wei , Zhang Yunshan , Sun Jun
Published: November 2018

Objective

Our objective was to investigate the applicability of targeted capture massively parallel sequencing in developing personalized pre-implantation genetic diagnosis (PGD) assay.

Methods

One couple at risk of transmitting Usher Syndrome to their offspring was recruited to this study. The genomics DNA (gDNA) was extracted from the peripheral blood and underwent in vitro fertilization (IVF)-PGD. Prenatal molecular diagnosis was performed in the 20th week of gestation and the chromosomal anomaly was analyzed.

Results

Customized capture probe targeted at USH2A gene and 350kb flanking region were designed for PGD. Eleven blastocysts were biopsied and amplified by using multiple displacement amplification (MDA) and capture sequencing. A HMM-based haplotype analysis was performed to deduce embryo’s genotype by using SNPs identified in each sample. Four embryos were diagnosed as free of father’s rare mutation, two were transferred and one achieved a successful pregnancy. The fetal genotype was confirmed by Sanger sequencing of fetal genomic DNA obtained by amniocentesis. The PGD and prenatal diagnosis results were further confirmed by the molecular diagnosis of the baby’s genomic DNA sample. The auditory test showed that the hearing was normal.

Conclusion

Targeted capture massively parallel sequencing (MPS) is an effective and convenient strategy to develop customized PGD assay.

Key points

Genetic counseling session was conducted with a family having Usher patient who was molecularly diagnosed, and a healthy baby was born with the help of successful PGD assay. This is of vast importance in management plans since it is the first report of PGD in Usher syndrome based on targeted capture MPS.
Statistical Mechanical Prediction of Ligand Perturbation to RNA Secondary Structure and Application to the SAM-I Riboswitch
Authors: Alaidi Osama , Aboul-ela Fareed
Published: November 2018

The realization that non protein-coding RNA (ncRNA) is implicated in an increasing number of cellular processes, many related to human disease, makes it imperative to understand and predict RNA folding. RNA secondary structure prediction is more tractable than tertiary structure or protein structure. Yet insights into RNA structure-function relationships are complicated by coupling between RNA folding and ligand binding. Here, we introduce a simple statistical mechanical formalism to calculate perturbations to equilibrium secondary structure conformational distributions for RNA, in the presence of bound cognate ligands. For the first time, this formalism incorporates a key factor in coupling ligand binding to RNA conformation: the differential affinity of the ligand for a range of RNA-folding intermediates. We apply the approach to the SAM-I riboswitch, for which binding data is available for analogs of intermediate secondary structure conformers. Calculations of equilibrium secondary structure distributions during the transcriptional “decision window” predict subtle shifts due to the ligand, rather than an on/off switch. The results suggest how ligand perturbation can release a kinetic block to the formation of a terminator hairpin in the full-length riboswitch. Such predictions identify aspects of folding that are most affected by ligand binding, and can readily be compared with experiment.
Impact of genetic variations on the human brain: when and where?
Authors: Vervier Kevin , Brueggeman Leo , Michaelson Jacob
Published: November 2018

Genetic studies have found candidates in most of neurological and psychiatric conditions. However, it remains challenging to assess, in which brain region, and when in the brain development, a mutation is more likely to have an impact, especially for intergenic loci. Here we present, BRAVA, a publicly available resource for estimating genetic mutations spatio-temporal context on the human brain. Different contexts were observed for schizophrenia associated loci, suggesting both neurodevelopmental and late onset components.
Introducing double bouquet cells into a modular cortical associative memory model
Authors: Chrysanthidis Nikolaos , Fiebig Florian , Lansner Anders
Published: November 2018

We present an electrophysiological model of double bouquet cells and integrate them into an established cortical columnar microcircuit model that has previously been used as a spiking attractor model for memory. Learning in that model relies on a Bayesian-Hebbian learning rule to condition recurrent connectivity between pyramidal cells. We here demonstrate that the inclusion of a biophysically plausible double bouquet cell model can solve earlier concerns about learning rules that simultaneously learn excitation and inhibition and might thus violate Dale’s Principle.

We show that learning ability and resulting effective connectivity between functional columns of previous network models is preserved when pyramidal synapses onto double-bouquet cells are plastic under the same Hebbian-Bayesian learning rule. The proposed architecture draws on experimental evidence on double bouquet cells and effectively solves the problem of duplexed learning of inhibition and excitation by replacing recurrent inhibition between pyramidal cells in functional columns of different stimulus selectivity with a plastic disynaptic pathway. We thus show that the resulting change to the microcircuit architecture improves the model’s biological plausibility without otherwise impacting the models spiking activity, basic operation, and learning abilities.
mtDNA recombination indicative of hybridization suggests a role of the mitogenome in the adaptation of reef-building corals to extreme environments
Authors: Banguera-Hinestroza Eulalia , Sawall Yvonne , Al-Sofyani Abdulmohsin , Mardulyn Patrick , Fuertes-Aguilar Javier , Cárdenas-Henao Heiber , Cárdenas-Henao Heiber , Jimenez-Infante Francy , Voolstra Christian R. , Flot Jean-François
Published: November 2018

mtDNA recombination following hybridization is rarely found in animals and was never until now reported in reef-building corals. Here we report unexpected topological incongruence among mitochondrial markers as evidence of mitochondrial introgression in the phylogenetic history of Stylophora species distributed along broad geographic ranges. Our analyses include specimens from the Indo-Pacific, the Indian Ocean and the full latitudinal (2000 km) and environmental gradient (21°C-33°C) of the Red Sea (N=827). The analysis of Stylophora lineages in the framework of the mitogenome phylogenies of the family Pocilloporidae, coupled with analyses of recombination, shows the first evidence of asymmetric patterns of introgressive hybridization associated to mitochondrial recombination in this genus. Hybridization likely occurred between an ancestral lineage restricted to the Red Sea/Gulf of Aden basins and migrants from the Indo-Pacific/Indian Ocean that reached the Gulf of Aden. The resulting hybrid lives in sympatry with the descendants of the parental Red Sea lineage, from which it inherited most of its mtDNA (except a highly variable recombinant region that includes the nd6, atp6, and mtORF genes) and expanded its range into the hottest region of the Arabian Gulf, where it is scarcely found. Noticeably, across the Red Sea both lineages exhibit striking differences in terms of phylogeographic patterns, clades-morphospecies association, and zooxanthellae composition. Our data suggest that the early colonization of the Red Sea by the ancestral lineage, which involved overcoming multiple habitat changes and extreme temperatures, resulted in changes in mitochondrial proteins, which led to its successful adaptation to the novel environmental conditions.
Retinoic acid and androgens interact to regulate spermatogenesis in a non-mammalian vertebrate lackingstra8
Authors: Crespo Diego , Assis Luiz H.C. , van de Kant Henk J.G. , Waard Sjors de , Safian Diego , Lemos Moline S. , Bogerd Jan , Schulz Rüdiger W.
Published: November 2018

In mammals, retinoic acid (RA) signaling is critical for spermatogonial differentiation and for entering meiosis, the latter depending on RA-inducedStra8gene expression. Many fish species, including zebrafish, do not contain astra8gene, but RA signaling nevertheless is important for sperm production. However, it is not known which stages of spermatogenesis respond to RA. Here, we show in zebrafish that RA promotes spermatogonial differentiation and reduces the apoptotic loss of spermatids, but is not required for meiosis. Some of the RA effects are mediated by other genes, in particularrec8a. Surprisingly, androgens can partially compensate for the loss of RA signaling, and we identify a link between the endocrine system and RA signaling: follicle-stimulating hormone (Fsh) stimulates testicular RA production. While RA signaling is relevant at the basis of the vertebrates, it also targets processes and mechanisms that are different from those known in mammals so far.
Refolding activity of bacterial Hsp90in vivoreveals ancient chaperoning function
Authors: Luengo Tania Morán , Ahlnäs Toveann , Hoekstra Anna T. , Berkers Celia R. , Mayer Matthias P. , Rüdiger Stefan G. D.
Published: November 2018

The conserved molecular chaperones Hsp70 and Hsp90 play a key role in protein folding. Mechanistically, Hsp90 acts downstream from Hsp70 solving an Hsp70-inflicted folding block. It is unclear, though, when and to which extend the concerted action of this cascade becomes crucial in living organisms. Here we show that, in E. coli cells, Hsp90 dramatically improves protein refolding after heat stress while it is dispensable for de novo folding. We found that Hsp90 inhibition effectively reduced the refolding yields in vivo, leading to strongly reduced enzymatic activity of the paradigmatic chaperone client luciferase and broadly increased aggregation of the E. coli proteome. Additionally, the presence of Hsp90 during refolding reduces the net ATP consumption presumably by sparing the substrate binding-and-release cycles on Hsp70. This mechanism explains how the cooperation of Hsp90 with the Hsp70 chaperone system creates robust folding machinery in a sustainable manner. Together, we describe a general function for bacterial Hsp90 as a key factor of the folding cascade, which may be the ancient activity of this evolutionary conserved machine.
eIF2B activator prevents neurological defects caused by a chronic Integrated Stress Response
Authors: Wong Yao Liang , LeBon Lauren , Basso Ana M. , Kohlhaas Kathy L. , Nikkel Arthur L. , Robb Holly M. , Donnelly-Roberts Diana L. , Prakash Janani , Swensen Andrew M. , Rubinstein Nimrod D. , Krishnan Swathi , McAllister Fiona E. , Haste Nicole V. , O’Brien Jonathon J. , Frost Jennifer M. , Shi Lei , Riedmaier Stephan , Martin Kathleen , Dart Michael J. , Sidrauski Carmela
Published: November 2018

The Integrated Stress Response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a novel eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complexin vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of other disease contexts.
Factors influencing knowledge and practice on helping babies breathe among Skilled Birth Attendants in rural areas in Lake Zone in Tanzania
Authors: Mzurikwao Cecilia B , Ng’weshemi Kapalata Secilia K , Ernest Alex Ibolinga
Published: November 2018

Background

It is estimated that 1 million babies die each year due to birth asphyxia. Globally, it is approximated that 10 million babies cannot do it by themselves and need assistance. Helping babies breathe is a key component in reducing neonatal mortality due to birth asphyxia.

Methods

A cross-sectional design was used, A total of 330 respondents included in the study. Simple random sampling by lottery was used to select the 2 regions and health facilities. The participants were selected through convenient. Data were collected using standard semi-structured questionnaire. Chi-square and Binary logistic regression were used to analyse the data.

Results

Out of 330 participants, Those who working in hospital and were more likely to have adequate knowledge (AOR= 3.227, P< 0.001) and practice (AOR= 43.807, P<0.001) than those working in Health Centers; Enlored nurses were more likely to have adequate knowledge (AOR= 3.118,P<0.05) than AMO/MD;Those with 1 year and above of experience in labor ward were more likely to have adequate practice(AOR=15.418,P<0.001) than those with less than 1 year of experience in labor ward; those who attended once on neonatal resuscitation training were adequate knowledge (AOR=1.778,P<0.05) than those who had never attended. Those with Enough equipment of neonatal resuscitation had adequate practice (AOR=4.355, P<0.001) than with no enough equipment.

Conclusion

Regarding the findings of the current study, it was revealed that working facility, Professional/ qualification, and training was significant predictor of knowledge while working facility, experience, and equipment was significant predictor of practice. There is a need to find effective measures on how to reduce those factors which affect knowledge and practice on helping babies breathe.
Quantitative mapping of triacylglycerol chain length and saturation using broadband CARS microscopy
Authors: Paul A. , Wang Y.J. , Brännmark C. , Kumar S. , Bonn M. , Parekh S. H.
Published: November 2018

Lipid droplets (LDs) are highly dynamic organelles that store neutral lipids, primarily triacylglycerols (TAGs), and are found in many cell types. While their primary function is to store excess energy, LDs are also modified in different disease states and during developmental processes. In many cases, not only the presence, but also the composition, of LDs can be equally important. In humans, LD composition has been linked to diseases such as type 2 diabetes; in plants and yeast, LD composition is relevant for engineering these organisms into biological factories in,e.g., algal bioenergy or food oil production. Therefore, lipid analysis of biological LDs with high speed and accuracyin situis a very active area of research. Here we present an approach forin situ, quantitative TAG analysis using label-free, coherent Raman microscopy to decipher LD TAG composition in different biochemically complex samples. Our method allows direct visualization of inter-LD compositional heterogeneity of physiological quantities – TAG chain length and number of C=C bonds – with sub-micrometer spatial resolution within 5-100 milliseconds. Combined with virtually no sample preparation, this approach should enable rapid and accurate TAG LD analysis for a variety of applications.
Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
Authors: Halbrook Christopher J. , Pontious Corbin , Lee Ho-Joon , Kovalenko Ilya , Zhang Yaqing , Lapienyte Laura , Dreyer Stephan , Kremer Daniel M. , Sajjakulnukit Peter , Zhang Li , Nelson Barbara , Hong Hanna S. , Kemp Samantha , Chang David , Biankin Andrew , Crawford Howard C. , Morton Jennifer P. , di Magliano Marina Pasca , Lyssiotis Costas A.
Published: November 2018

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.