bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic performance of biomarkers for ovarian cancer
Authors: Hua Jinyong , Liu Jing , Hua Mengge , Cai Runjin , Li Muyang , Wang Jing , Wang Jiancheng
Published: May 2019

Background:

Ovarian cancer is one of the deadliest gynecological diseases and the annual mortality of ovarian cancer continues to rise. The prognosis of ovarian cancer is poor because it is prone to early metastasis during progression. Therefore, early diagnosis of ovarian cancer is very important. Some systematic reviews have evaluated the diagnostic value of different biomarkers for ovarian cancer. However, there is no consensus in the conclusions, and some are even contradictory. This study aims to assess the methodological and reporting quality of available systematic reviews and to find an optimal biomarker for diagnosing ovarian cancer.

Methods:

The PubMed, Embase.com, the Cochrane Library of Systematic Reviews, and Web of Science were searched to identify relevant systematic reviews from inception to February 2019. We included systematic reviews that include randomized controlled trials, cross-sectional studies, case-control studies, or cohort studies as long as the systematic reviews evaluated the diagnostic performance of biomarkers for ovarian cancer. The methodological quality will be assessed using assessment of multiple systematic reviews-2 checklist, and the reporting quality will be assessed using preferred reporting items for systematic reviews and meta-analysis diagnostic test accuracy (PRISMA-DTA) checklist. The pairwise meta-analysis and indirect comparisons will be performed using STATA (13.0; Stata Corporation, College Station, TX).

Results:

The results of this overview will be submitted to a peer-reviewed journal for publication.

Conclusion:

This overview will provide comprehensive evidence of different biomarkers for diagnosing ovarian cancer.

PROSPERO registration number:

CRD42019125880.
The level of Krüppel-like factor 8 expression predicts prognosis and metastasis in various carcinomas
Authors: Liu Jun , Zheng Huimin , Ding Yangyang , Li Manman , Li Jingrong , Guo Jiaojiao , Hu Linhui , Pu Lianfang , Xiong Shudao
Published: May 2019

Background and objective:

Krüppel-like factor 8 (KLF8), a transcription factor, belongs to the KLF8 family. Currently, studies have shown that KLF8 is highly expressed in some tumors. However, the prognostic value and metastasis of KLF8 in cancers remain unclear. For the first time, we conducted meta-analysis to explore the relationship between KLF8 expression with prognosis and metastasis in various carcinomas patients.

Methods:

Web of Science, PubMed, Embase, and Cochrane Library were systematically searched for eligible articles. Pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated to evaluate the prognostic value and metastasis of KLF8 expression in human cancer patients.

Results:

The result revealed that highly expression level of KLF8 was significantly associated with poor overall survival (OS) (HR = 1.56, 95% CI: 1.26–1.87). Meanwhile, this significant correlation was also observed in subgroup analysis stratified by cancer types, source of HR, sample size, follow-up (months). In addition, highly expression of KLF8 was also closely associated with metastasis (HR = 1.37, 95% CI: 0.57–2.17) and tumor node metastasis stage (HR = 1.58, 95% CI: 0.90–2.25) in carcinomas.

Conclusion:

In summary, our meta-analysis indicates that overexpression of KLF8 may be associated with poor prognosis and higher incidence of metastasis in various carcinomas, and KLF8 may be used as a prognostic and metastatic indicator in human cancers.
Mitochondrial metabolism and the maintenance of hematopoietic stem cell quiescence
Authors: Hu Mengjia , Wang Junping
Published: May 2019

Purpose of review

Hematopoietic stem cells (HSCs) are characterized by a potent multilineage regenerative capability that is dependent on their quiescence property. In the past few decades, researchers have found many intrinsic and niche-derived factors that can regulate HSCs, whereas how to precisely control HSC behaviors remains elusive. Recently, mitochondrial metabolism has been shown to be involved in the regulation of HSC biology. The purpose of this review is to overview recent advances in the relationship between mitochondrial metabolism and maintenance of HSC quiescence.

Recent findings

On the basis of fact that HSCs are heterogeneous populations that have their unique metabolic characteristics, increasing studies have demonstrated that the quiescence and function of HSCs are closely correlated with the mitochondrial mass and activity, as well as the levels of mitochondria-derived reactive oxygen species and metabolites. Apart from that, mitochondria have been reported to undergo internal protective programs, including mitochondrial unfolded protein response, autophagy and mitochondrial dynamics, which are beneficial to maintaining HSC homeostasis.

The maintenance of HSC quiescence needs a metabolic balance in mitochondria, and unraveling the metabolic complexity may provide deep understanding of the functional heterogeneity of HSCs.
Palliative Care in Botswana
Authors: Matula Samuel T.
Published: May 2019

Palliative care is an essential aspect of care for patients with serious illness and their families, but a large proportion of the world’s population, particularly in developing countries like Botswana, do not have access to it. In Botswana and other developing countries, palliative care is often sporadic and lacks comprehensive delivery owing to a lag between policies and practice and a lack of knowledge about palliative care among health care professionals and communities. In this article, the progress of palliative care in Botswana is discussed by first evaluating at the relevance of palliative care in Botswana given the burden of diseases and resources available for disease management. Second, the palliative care delivery models and their successes and shortcomings in Botswana context are discussed. Third, the Botswana palliative care services are viewed on a global scale to illuminate progress and areas that need improvement. Thereafter, using a case as a reference, this article highlights the challenges faced by Botswana palliative care services. Finally, some areas that can be targeted to improve palliative care services in Botswana and possible solutions are discussed. Overall, palliative care is at infancy stage in Botswana and many opportunities exist in education, research, and resource support to transform it into a full-fledged service.
Feasibility of e-Pain Reporter
Authors: Mayahara Masako , Wilbur Joellen , Fogg Louis , Breitenstein Susan M. , Miller Arlene Michaels
Published: May 2019

Informal hospice caregivers often have difficulty managing patient pain at home. We developed a digital application, e-Pain Reporter, for informal caregivers to record and providers to monitor patient pain and pain management. The purpose of this study was (1) to assess the feasibility of informal caregivers using the e-Pain Reporter for 9 days in home hospice by investigating recruitment and retention and caregiver satisfaction with and frequency of use of the e-Pain Reporter and (2) describe patient pain characteristics and caregiver’s barriers to pain management and self-efficacy in providing patient care in the home. One-group pre-post design was used. Patient-caregiver dyads were recruited from 1 hospice agency. Caregivers were asked to report all patient pain and pain management using the e-Pain Reporter. Feasibility of the e-Pain Reporter was assessed by the average number of times caregivers recorded breakthrough and daily pain and caregiver satisfaction with the app. The 27-item Barriers Questionnaire II and 21-item Caregiver Self-efficacy Scale were administered at baseline. Fourteen dyads enrolled, 2 patients died, and 12 dyads completed the study. Mean number of pain reports over 9 days was 10.5. Caregivers reported high overall satisfaction with the e-Pain Reporter. Barriers scores were moderately high, suggesting erroneous beliefs and misconceptions about pain reporting and use of analgesics, but self-efficacy in managing pain was also high (93% confidence). Findings suggest that the e-Pain Reporter is a feasible method to report and monitor caregiver management of pain at home. Caregiver high barriers and high overconfidence suggest the need for an educational component to the e-Pain Reporter to address misconceptions about pain and pain management.
Addressing Health Disparities in America: Analysis of Community Health Improvement Plans
Authors: Inderstrodt Jill , Perrault Evan K. , Hintz Elizabeth A. , Hildenbrand Grace M.
Published: May 2019

Background

Healthy People 2020 has made achieving health equity one of its overarching goals; another goal is increasing the number of accredited local agencies that have Community Health Improvement Plans (CHIPs). Community Health Improvement Plans are meant to serve agencies as guiding documents for multiple years.

Objectives

This study investigates the prevalence with which health disparities are addressed within CHIPs and the specific health disparities targeted by these objectives.

Methods

Researchers analyzed 4,094 objectives from CHIPs of 280 local Public Health Accreditation Board (PHAB)-accredited and nonaccredited public health agencies in the United States.

Results

Despite the PHAB's focus on addressing health equity, not all PHAB-accredited agencies addressed health disparities (85.4% of CHIPs analyzed). However, more accredited than nonaccredited agencies (73.9%) contained at least one objective focused on health disparities.

Discussion

Findings indicate that if health equity is truly a goal of national initiatives, agencies' planning documents (e.g., CHIPs) can do a better job addressing commonly ignored populations.
Late-onset Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Presenting With Auditory Agnosia
Authors: Smith Kelsey , Chiu Shannon , Hunt Christopher , Chandregowda Adithya , Babovic-Vuksanovic Dusica , Keegan B. Mark
Published: May 2019

Introduction:

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder that usually presents in childhood. Patients can have a wide array of neurological symptoms when presenting with stroke-like episodes, and imaging characteristics during the episodes can overlap with different neurological disorders.

Case Report:

A 61-year-old woman presented with communication difficulties consistent with auditory agnosia and was found to have bitemporal abnormalities on imaging that first raised the concern for herpes simplex virus encephalitis. Further work-up, in conjunction with the patient’s past medical and family history, suggested a mitochondrial disorder. Mitochondrial full genome analysis revealed m.3243A>G variant in the MT-TL1 gene, with 6% heteroplasmy in blood leading to a diagnosis of MELAS.

Conclusions:

MELAS is a disorder with clinical variability. Neuroimaging studies during stroke-like episodes in MELAS can provide significant clues to the underlying disorder. Although patients typically present in childhood, the first stroke-like episode can occur later in life in some patients, potentially related to a lower heteroplasmy level.
Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors
Authors: Xu Min , Nie Yan , Yang Ying , Lu, MD Yang-Tian , Su Qiang
Published: May 2019

Objectives:

The objective of this study was to assess risk of neurological toxicities following the use of different immune checkpoint inhibitor (ICI) regimens in solid tumors.

Methods:

Pubmed, Embase, and ClinicalTrials.gov databases were searched for publications, and data were analyzed using Review Manager 5.3 software to compare the risk of immune-related and nonspecific neurological complications potentially triggered by ICIs to controls.

Results:

In total 23 randomized clinical trials comprising 11,687 patients were included in this meta-analysis. Patients with PD-L1 (OR, 0.29; 95% confidence interval [CI], 0.18-0.48; P<0.01) or programmed cell-death protein 1 (PD-1) inhibitor (OR, 0.21; 95% CI, 0.14-0.31; P<0.01) were less likely to develop any-grade peripheral neuropathy than chemotherapy, while the risk of grade 3-5 was also smaller for PD-1 inhibitor (OR, 0.16; 95% CI, 0.05-0.54; P=0.003). Combination therapy with CTLA4 and PD-1 inhibitor did not significantly increase the risk of any-grade (OR, 0.83; 95% CI, 0.21-3.32; P>0.05) or grade 3-5 (OR, 1.4; 95% CI, 0.2-9.61; P>0.05) peripheral neuropathy compared to monotherapy with CTLA4 or PD-1 inhibitor. However, difference in risk of immune-related adverse events (irAEs) involving central nervous system did not reach statistical significance in patients with different ICI regimens compared those under chemotherapy. Additionally, risk of experiencing paresthesia was in line with that of peripheral neuropathy (OR, 0.42; 95% CI, 0.28-0.62; P<0.01).

Conclusions:

This meta-analysis shows that PD-L1/PD-1 and CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy, while combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.
Case Report: Optical Coherence Tomography Can Find Typical Features in Pregnancy-induced Hypertension with Retinopathy
Authors: Zhang Zhenzhen , Lu Jianmin , Qin Xiuhong
Published: May 2019

SIGNIFICANCE

Pregnancy-induced hypertension is a unique yet common complication in pregnant women and may cause retinopathy. Optical coherence tomography (OCT) may help find the features of retinopathy that are difficult to observe through fundus examination. Not all patients can fully recover from retinopathy.

PURPOSE

This report describes a case of pregnancy-induced hypertension with retinopathy and represents the features of retinopathy in OCT and fundus fluorescein angiography.

CASE REPORT

A 29-year-old pregnant woman presented with bilateral blurred vision and xanthopsia 2 days before her induced labor; she was also diagnosed as pre-eclamptic in the obstetrics department. The vision in her right eye was 20/33, and that in her left eye was 20/20. Fundus fluorescein angiography showed scattered-dot hypofluorescence around the disc at an early stage, and needle-like hyperfluorescence gradually appeared near the disc with late-stage fluorescein leakage in both eyes. Optical coherence tomography revealed multiple shallow retinal detachments with hyperreflective bright spots in the outer retina and clumped hyperreflective materials on the retinal pigment epithelium (RPE).

CONCLUSIONS

Typical findings and some tiny changes in the outer retina and RPE can be observed through spectral-domain OCT. The clumped hyperreflective deposits in the outer retina may be by-products of RPE swelling and necrosis that lead to barrier dysfunctions and fluid leakage. These described features may help diagnose retinopathy from pregnancy-induced hypertension. Although it is a self-limited disease, the disruptions in the ellipsoid and interdigitation zones may not fully recover and result in reduced visual dysfunction. Therefore, control of hypertension is indicated.
Bifocal & Atropine in Myopia Study: Baseline Data and Methods
Authors: Huang Juan , Mutti Donald O. , Jones-Jordan Lisa A. , Walline Jeffrey J.
Published: May 2019

SIGNIFICANCE

The Bifocal & Atropine in Myopia (BAM) study aims to determine whether combining 0.01% atropine and +2.50-diopter add center-distance soft bifocal contact lenses (SBCL) slows myopia progression more than SBCL alone. The results could provide significant information on the myopia control effect of combining optical and pharmacological treatments.

PURPOSE

This article describes the subject characteristics at baseline, the study methods, and the short-term effects of this combination treatment on visual acuity (VA) and vision-related outcomes.

METHODS

Subjects from the BAM study who met the baseline eligibility criteria were dispensed the combination treatment for 2 weeks to determine final eligibility. Outcome measures included VA at near and distance (Bailey-Lovie logMAR charts), near phoria (modified Thorington), accommodative lag (Grand Seiko WAM-5500), and pupil size (NeurOptics VIP-200 Pupillometer). Compliance was monitored using surveys. Two subgroups in the Bifocal Lenses In Nearsighted Kids study, single-vision contact lens wearers and those who wore +2.50-diopter add SBCL, will serve as the age-matched historical controls for BAM study.

RESULTS

Forty-nine BAM subjects (9.6 ± 1.4 years) were enrolled; mean spherical equivalent cycloplegic autorefraction was −2.33 ± 1.03 diopters. After 2 weeks of treatment, the best-corrected low-contrast (10% Michelson) distance VA was reduced (pre-treatment, +0.09 ± 0.07; post-treatment, +0.16 ± 0.08; P < .0001), but the high-contrast VA at near or distance was unaffected. Near phoria increased by approximately 2△ in the exo direction (P = .01), but the accommodative lag was unchanged. The pupil size was not significantly different between pre-treatment and post-treatment of either the photopic or mesopic condition. Surveys indicated that the subjects wore SBCL 77 ± 22% of waking hours and used atropine 6.4 ± 0.7 days per week.

CONCLUSIONS

Two weeks of combination treatment reduced low-contrast distance VA and increased near exophoria slightly, but the subjects were compliant and tolerated the treatment well.
Monophosphoryl Lipid a Attenuates Multiorgan Dysfunction During Post-Burn Pseudomonas Aeruginosa Pneumonia in Sheep
Authors: Fukuda Satoshi , Ihara Koji , Bohannon Julia K. , Hernandez Antonio , Patil Naeem K. , Luan Liming , Stothers Cody , Stark Ryan , Prough Donald S. , Herndon David N. , Sherwood Edward R. , Enkhbaatar Perenlei
Published: May 2019

Background:

Monophosphoryl lipid A (MPLA) is a TLR4 agonist that has potent immunomodulatory properties and modulates innate immune function to improve host resistance to infection with common nosocomial pathogens in mice. The goal of this study was to assess the safety and efficacy of MPLA in a sheep model of burn injury and Pseudomonas aeruginosa pneumonia. The sheep provides a favorable model for preclinical testing as their response to TLR4 agonists closely mimics that of humans.

Methods:

Twelve chronically instrumented adult female Merino sheep received 20% total body surface area, third-degree cutaneous burn under anesthesia and analgesia. At 24 h after burn, sheep were randomly allocated to receive: MPLA (2.5 μg/kg i.v., n = 6), or vehicle (i.v., n = 6). At 24 h after MPLA or vehicle treatment, Pseudomonas aeruginosa pneumonia was induced. Sheep were mechanically ventilated, fluid resuscitated and cardiopulmonary variables were monitored for 24 h after induction of pneumonia. Cytokine production, vascular barrier function, and lung bacterial burden were also measured.

Results:

MPLA infusion induced small and transient alterations in core body temperature, heart rate, pulmonary artery pressure, and pulmonary vascular resistance. Pulmonary mechanics were not altered. Vehicle-treated sheep developed severe acute lung injury during Pseudomonas aeruginosa pneumonia, which was attenuated by MPLA as indicated by improved PaO2/FiO2 ratio, oxygenation index, and shunt fraction. Sheep treated with MPLA also exhibited less vascular leak, lower blood lactate levels, and lower modified organ injury score. MPLA treatment attenuated systemic cytokine production and decreased lung bacterial burden.

Conclusions:

MPLA was well tolerated in burned sheep and attenuated development of acute lung injury, lactatemia, cytokinemia, vascular leak, and hemodynamic changes caused by Pseudomonas aeruginosa pneumonia.
Long-Term Selegiline Monotherapy for the Treatment of Early Parkinson Disease
Authors: Mizuno Yoshikuni , Hattori Nobutaka , Kondo Tomoyoshi , Nomoto Masahiro , Origasa Hideki , Takahashi Ryosuke , Yamamoto Mitsutoshi , Yanagisawa Nobuo
Published: May 2019

Objectives

The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD).

Methods

We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated.

Results

Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, −2.62 ± 3.83; P < 0.0001) to week 56 (−3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (−5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration.

Conclusions

Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.
Spurious inference when comparing networks
Authors: Farine Damien R. , Aplin Lucy M.
Published: May 2019

Comparing networks is challenging. Social networks can be shaped by many factors. Failing to adequately consider non-social processes, including sampling artefacts, can lead to spurious conclusions about differences in social networks among groups. Here we demonstrate that incorrect application of statistical testing methods when comparing networks can generate very high rates of false positives. We then show that null models, specifically pre-network permutation tests, can control for non-social differences in networks and substantially reduce rates of false positives.
A neuromimetic approach to the serial acquisition, long-term storage, and selective utilization of overlapping memory engrams
Authors: Quintanar-Zilinskas Victor
Published: May 2019

Biological organisms that sequentially experience multiple environments develop self-organized representations of the stimuli unique to each; moreover, these representations are retained long-term, and sometimes utilize overlapping sets of neurons. This functionality is difficult to replicate in silico for several reasons, such as the tradeoff between stability, which enables retention, and plasticity, which enables ongoing learning. Here, by using a network that leverages an ensemble of neuromimetic mechanisms, I successfully simulate multi-environment learning; additionally, from measurements of synapse states and stimulus recognition performance taken at multiple time points, the following network features emerge as particularly important to its operation. First, while reinforcement-driven stabilization preserves the synapses most important to the representation of each stimulus, pruning eliminates many of the rest, thereby resulting in low-noise representations. Second, in familiar environments, a low baseline rate of exploratory synapse generation balances with pruning to confer plasticity without introducing significant noise; meanwhile, in novel environments, new synapses are reinforced, reinforcement-driven spine generation promotes further exploration, and learning is hastened. Thus, reinforcement-driven spine generation allows the network to temporally separate its pursuit of pruning and plasticity objectives. Third, the permanent synapses interfere with the learning of new environments; but, stimulus competition and long-term depression mitigate this effect; and, even when weakened, the permanent synapses enable the rapid relearning of the representations to which they correspond. This exhibition of memory suppression and rapid recovery is notable because of its biological analogs, and because this biologically-viable strategy for reducing interference would not be favored by artificial objective functions unaccommodating of brief performance lapses. Together, these modeling results advance understanding of intelligent systems by demonstrating the emergence of system-level operations and naturalistic learning outcomes from component-level features, and by showcasing strategies for finessing system design tradeoffs.
Comparative phosphorylation map of Dishevelled3 (DVL3)
Authors: Hanáková Kateřina , Bernatík Ondřej , Ovesná Petra , Kravec Marek , Micka Miroslav , Rádsetoulal Matěj , Potěšil David , Čajánek Lukáš , Zdráhal Zbyněk , Bryja Vítězslav
Published: May 2019

In the presented study we analyze phosphorylation of human Dishevelled 3 (DVL3) induced by its previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and the newly identified (TTBK2, Aurora A) kinases. DVL3 contains 131 Ser/Thr whose phosphorylation generates complex barcodes underlying diverse DVL3 functions in Wnt pathways and other processes. We use quantitative mass spectrometry and via several complementary pipelines calculate site occupancies and quantify phosphorylation of >80 phosphorylated residues. In order to visualize the complex phosphorylation patterns, we design a novel visualization diagram, phosphoplot. Finally, we compare the individual sample and data processing approaches, identify their strengths and weaknesses. Subsequently, we verified a set of anti-phospho-DVL antibodies and were able to successfully confirm induction for several of the phosphorylation sites. From the biological point of view, our data represent an important reference point and a toolbox for further analysis of DVL functions and phosphorylation events that control them.

One sentence summary

The study provides a comprehensive comparison of the phosphorylation of DVL3 induced by eight Ser/Thr kinases and identifies phosphorylation signatures associated with individual kinases.
Deceptive combined effects of short allele dominance and stuttering: an example withIxodes scapularis, the main vector of Lyme disease in the U.S.A.
Authors: De Meeûs Thierry , Chan Cynthia T. , Ludwig John M. , Tsao Jean I. , Patel Jaymin , Bhagatwala Jigar , Beati Lorenza
Published: May 2019

Null alleles, short allele dominance (SAD), and stuttering increase the perceived relative inbreeding of individuals and subpopulations as measured by Wright’sFISandFST. Ascertainment bias, due to such amplifying problems are usually caused by inaccurate primer design (if developed from a different species or a distant population), poor DNA quality, low DNA concentration, or a combination of some or all these sources of inaccuracy. When combined, these issues can increase the correlation between polymorphism at concerned loci and, consequently, of linkage disequilibrium (LD) between those. In this note, we studied an original microsatellite data set generated by analyzing nine loci inIxodes scapularisticks from the eastern U.S.A. To detect null alleles and SAD we used correlation methods and variation measures. To detect stuttering, we evaluated heterozygote deficit between alleles displaying a single repeat difference. We demonstrated that an important proportion of loci affected by amplification problems (one with null alleles, two with SAD and three with stuttering) lead to highly significant heterozygote deficits (FIS=0.1,p-value<0.0001). This occurred together with an important proportion (22%) of pairs of loci in significant LD, two of which were still significant after a false discovery rate (FDR) correction, and some variation in the measurement of population subdivision across loci (Wright’sFST). This suggested a strong Wahlund effect and/or selection at several loci. By finding small peaks corresponding to previously disregarded larger alleles in some homozygous profiles for loci with SAD and by pooling alleles close in size for loci with stuttering, we generated an amended dataset. Except for one locus with null alleles and another still displaying a modest SAD, the analyses of the corrected dataset revealed a significant excess of heterozygotes (FIS=-0.07 as expected in dioecious and strongly subdivided populations, with a more reasonable proportion (19%) of pairs of loci characterized by significant LD, none of which stayed significant after the FDR procedure. Strong subdivision was also confirmed by the standardizedFST’ corrected for null alleles (FST’=0.19) and small effective subpopulation sizes (Ne=7).
Structural abnormalities in thalamo-prefrontal tracks revealed by high angular resolution diffusion imaging predict working memory scores in concussed children
Authors: Guberman Guido I. , Houde Jean-Christophe , Ptito Alain , Gagnon Isabelle , Descoteaux Maxime
Published: May 2019

Because of their massive prevalence, wide-ranging sequelae, and insidious nature, concussions are a potentially devastating neurological condition, especially in children. Shearing forces transmitted across the brain during concussions often result in white matter damage. The neuropathological impact of concussions has been discerned from animal studies and includes inflammation, demyelination, and axonal loss. These pathologies can overlap during the subacute stage of recovery. However, due to the challenges of accurately modelling complex white matter structure, these neuropathologies have not yet been differentiated in children in vivo. In the present study, we leveraged recent advances in diffusion imaging modelling, tractography, and tractometry to better understand the neuropathology underlying working memory problems in concussion. Studying a sample of 16 concussed and 46 healthy youths, we used novel tractography methods to isolate 11 working memory tracks. Along these tracks, we measured fractional anisotropy, diffusivities, track volume, apparent fiber density, and free water fraction. In three tracks connecting the right thalamus to the right dorsolateral prefrontal cortex (DLPFC), we found microstructural differences suggestive of myelin alterations. In another track connecting the left anterior-cingulate cortex with the left DLPFC, we found microstructural changes suggestive of axonal loss. Structural differences and tractography reconstructions were reproduced using test-retest analyses. White matter structure in the three thalamo-prefrontal tracks, but not the cingulo-prefrontal track, appeared to play a key role in working memory function. The present results improve understanding of working memory neuropathology in concussions, which constitutes an important first step towards developing neuropathologically-informed biomarkers of concussion in children.
Analysis of distance-based protein structure prediction by deep learning in CASP13
Authors: Xu Jinbo , Wang Sheng
Published: May 2019

This paper reports the CASP13 results of distance-based contact prediction, threading and folding methods implemented in three RaptorX servers, which are built upon the powerful deep convolutional residual neural network (ResNet) method initiated by us for contact prediction in CASP12. On the 32 CASP13 FM (free-modeling) targets with a median MSA (multiple sequence alignment) depth of 36, RaptorX yielded the best contact prediction among 46 groups and almost the best 3D structure modeling among all server groups without time-consuming conformation sampling. In particular, RaptorX achieved top L/5, L/2 and L long-range contact precision of 70%, 58% and 45%, respectively, and predicted correct folds (TMscore>0.5) for 18 of 32 targets. Although on average underperforming AlphaFold in 3D modeling, RaptorX predicted correct folds for all FM targets with >300 residues (T0950-D1, T0969-D1 and T1000-D2) and generated the best 3D models for T0950-D1 and T0969-D1 among all groups. This CASP13 test confirms our previous findings: (1) predicted distance is more useful than contacts for both template-based and free modeling; and (2) structure modeling may be improved by integrating alignment and co-evolutionary information via deep learning. This paper will discuss progress we have made since CASP12, the strength and weakness of our methods, and why deep learning performed much better in CASP13.
ML277 specifically enhances pore opening of KCNQ1 with VSD at the activated state by modulating VSD-pore coupling
Authors: Hou Panpan , Shi Jingyi , White Kelli McFarland , Gao Yuan , Cui Jianmin
Published: May 2019

In response to membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states that correspond to the stepwise activation of the voltage sensing domain (VSD) to the intermediate (I) and activated (A) states. In the heart, KCNQ1 associates with the auxiliary subunit KCNE1 to form the IKs channel that regulates heart rhythm. More than 300 of loss-of-function KCNQ1 mutations cause long QT syndrome (LQTS). KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Thus, enhancing AO state presents a potential therapy for anti-LQTS. Here, we systematically tested modulations of KCNQ1 channels by a KCNQ1 activator, ML277. It enhances the current amplitude, slows down activation, deactivation and inactivation kinetics, shifts the voltage dependence of activation to more positive voltages, decreases the Rb+/K+ permeability ratio, and selectively increases currents of mutant KCNQ1 channels that open only to the AO state. All these observations are consistent with the mechanism that ML277 specifically potentiates the AO state. On the other hand, ML277 does not affect the VSD activation, suggesting that it potentiates the AO state by enhancing the electromechanical (E-M) coupling when the VSD moves to the activated state. Our results suggest that ML277 provides a unique tool to investigate the gating mechanism of KCNQ1 and IKs channels. The specificity of ML277 to increase the AO state of native IKs currents also suggests a new strategy for anti-LQTS therapy.
Transcriptional Regulation and Mechanism of SigN (ZpdN), a pBS32 encoded Sigma Factor
Authors: Burton Aisha T. , DeLoughery Aaron , Li Gene-Wei , Kearns Daniel B.
Published: May 2019

Laboratory strains ofBacillus subtilisencodes as many as 16 alternative sigma factors, each dedicated to expressing a unique regulon such as those involved in stress resistance, sporulation, and motility. The ancestral strain ofB. subtilisalso encodes an additional sigma factor homolog, ZpdN, not found in lab strains due to it being encoded on the large, low copy number plasmid pBS32 that was lost during domestication. DNA damage triggers pBS32 hyper-replication and cell death in a manner that depends on ZpdN but how ZpdN mediates these effects was unknown. Here we show that ZpdN is a bona fide sigma factor that can direct RNA polymerase to transcribe ZpdN-dependent genes and we rename ZpdN to SigN accordingly. Rend-seq analysis was used to determine the SigN regulon on pBS32, and the 5’ ends of transcripts were used to predict the SigN consensus sequence. Finally, we characterize the regulation of SigN itself, and show that it is transcribed by at least three promoters:PsigN1, a strong SigA-dependent LexA-repressed promoter,PsigN2, a weak SigA-dependent constitutive promoter, andPsigN3, a SigN-dependent promoter. Thus, in response to DNA damage LexA is derepressed, SigN is expressed and then experiences positive feedback. How cells die in a pBS32-dependent manner remains unknown, but we predict that death is the product of expressing one or more genes in the SigN regulon.

IMPORTANCE

Sigma factors are utilized by bacteria to control and regulate gene expression. Extra cytoplasmic function sigma factors are activated during times of stress to ensure the survival of the bacterium. Here, we report the presence of a sigma factor that is encoded on a plasmid that leads to cellular death after DNA damage.
The effect of pupil size and peripheral brightness on detection and discrimination performance
Authors: Mathôt Sebastiaan , Ivanov Yavor
Published: May 2019

It is easier to read dark text on a bright background (positive polarity) than to read bright text on a dark background (negative polarity). This positive-polarity advantage is often linked to pupil size: A bright background induces small pupils, which in turn increases visual acuity. Here we report that pupil size, when manipulated through peripheral brightness, has qualitatively different effects on discrimination of fine stimuli in central vision and detection of faint stimuli in peripheral vision. Small pupils lead to improved discrimination performance, consistent with the positive-polarity advantage, but only for very small stimuli that are at the threshold of visual acuity. In contrast, large pupils lead to improved detection performance. These results are likely due to two pupil-size related factors: Small pupils increase visual acuity, which improves discrimination of fine stimuli; and large pupils increase light influx, which improves detection of faint stimuli. Light scatter is likely also a contributing factor: When a display is bright, light scatter creates a diffuse veil of retinal illumination that reduces image contrast, thus impairing detection performance. We further found that pupil size was larger during the detection task than during the discrimination task, even though both tasks were equally difficult and similar in visual input; this suggests that the pupil may automatically assume an optimal size for the current task. Our results may explain why pupils dilate in response to arousal: This may reflect an increased emphasis on detection of unpredictable danger, which is crucially important in many situations that are characterized by high levels of arousal. Finally, we discuss the implications of our results for the ergonomics of display design.
Single-molecule observation of ligand binding and conformational changes in FeuA
Authors: de Boer Marijn , Gouridis Giorgos , Abdillah Muthahari Yusran , Cordes Thorben
Published: May 2019

The specific binding of ligands by proteins and the coupling of this process to conformational changes are fundamental to protein function. We designed a fluorescence-based single-molecule assay and data analysis procedure that allows the simultaneous real-time observation of ligand binding and conformational changes in FeuA. The substrate-binding protein FeuA binds the ligand ferri-bacillibactin and delivers it to the ABC importer FeuBC, which is involved in iron uptake in bacteria. The conformational dynamics of FeuA was assessed via Förster resonance energy transfer (FRET), whereas the presence of the ligand was probed by fluorophore quenching. We reveal that ligand binding shifts the conformational equilibrium of FeuA from an open to a closed conformation. Ligand binding occurs via an induced-fit mechanism, i.e., the ligand binds to the open state and subsequently triggers a rapid closing of the protein. However, FeuA also rarely samples the closed conformation without the involvement of the ligand. This shows that ligand interactions are not required for conformational changes in FeuA. However, ligand interactions accelerate the conformational change 10000-fold and temporally stabilize the formed conformation 250-fold.

SIGNIFICANCE STATEMENT

Ligand binding and the coupling of this process to conformational changes in proteins are fundamental to their function. We developed a single-molecule approach that allows the simultaneous observation of ligand binding and conformational changes in the substrate-binding protein FeuA. This allows to directly observe the ligand binding process, ligand-driven conformational changes as well as rare short-lived conformational transitions that are uncoupled from the ligand. These findings provide insight into the fundamental relation between ligand-protein interactions and conformational changes. Our findings are, however, not only of interest to understand protein function, but the developed data analysis procedure allows the determination of (relative) distance changes in single-molecule FRET experiments, for situations in which donor and acceptor fluorophore are influenced by quenching processes.
Red blood cell-derived extracellular vesicles mediate intercellular communication in ischemic heart failure
Authors: Das Avash , Valkov Nedyalka , Salvador Ane M. , Kur Ivan , Ziegler Olivia , Yeri Ashish , Garcia Fernando Camacho , Lu Shulin , Khamesra Aushee , Xiao Chunyang , Rodosthenous Rodosthenis , Li Guoping , Srinivasan Srimeenakshi , Toxavidis Vasilis , Tigges John , Laurent Louise C. , Momma Stefan , Ghiran Ionita , Das Saumya
Published: May 2019

Extracellular vesicles (EV) mediate intercellular signaling by transferring their cargo to recipient cells. Red blood cell (RBC)-derived EVs constitute a significant proportion of circulating EVs and have been implicated in regulating immune responses. Here, we describe a transgenic mouse model for fluorescent-based mapping of RBC-EV target cells based on the functional transfer of EV-contained Cre-recombinase to target cells. In a murine model of ischemic heart failure, we detect an increase in RBC-EV-targeted cardiomyocytes in the hearts and microglial cells in the brains. Cells targeted by RBC-EVs present an enrichment of genes implicated in cell proliferation and metabolism pathways compared to non-recombined (non-targeted) cells. Cardiomyocytes targeted by RBC-EVs are more likely to demonstrate cellular markers of DNA synthesis and proliferation, suggesting functional significance of EV-mediated signaling. In conclusion, we leverage our mouse model for mapping of RBC-EV targets in murine ischemic heart failure to demonstrate quantitative and qualitative changes in RBC-EV recipients.
Efficient and robust NK-Cell transduction with Baboon Envelope pseudotyped lentivector: a major tool for immunotherapy
Authors: Colamartino Aurelien B.L. , Lemieux William , Bifsha Panojot , Nicoletti Simon , Chakravarti Nitin , Remon Joaquin Sanz , Roméro Hugo , Selleri Silvia , Béland Kathie , Guiot Mélanie , Tremblay-Laganière Camille , Dicaire Renée , Barreiro Luis , Lee Dean A. , Verhoeyen Els , Haddad Elie
Published: May 2019

NK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a transduction rate of 23.0±6.6% in freshly-isolated NK-cells (FI-NK) and 83.4±10.1% in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), even at low MOI, with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114-and Measles Virus (MV)-pseudotyped LVs (p<0.001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with much higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 44.2%±14.2% of NKAES cells, which allowed the specific killing of the NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector, encoding a dual CD19/CD22-CAR separated by T2A, we were able to transduce and re-expand dual-CAR-expressing NKAES, even with low viral titer. These dual-CAR-NK efficiently and specifically killed both CD19KO-and CD22KO-RS4;11 cells, which may overcome antigen-loss escape in the clinical setting. Our results suggest that BaEV-LVs may efficiently enable NK-cell biological studies and translation of NK-cell-based immunotherapy to the clinic.
Linker dependence of avidity in multivalent interactions between disordered proteins
Authors: Sørensen Charlotte S. , Jendroszek Agnieszka , Kjaergaard Magnus
Published: May 2019

Multidomain proteins often interact through several independent binding sites connected by disordered linkers. The architecture of such linkers affect avidity by modulating the effective concentration of intra-molecular binding. The linker dependence of avidity has been estimated theoretically using simple physical models, but such models have not been tested experimentally since the effective concentrations could not be measured directly. We have developed a model system for bivalent protein interactions connected by disordered linkers, where the effective concentration can be measured using a competition experiment. We characterized the bivalent protein interactions kinetically and thermodynamically for a variety of linker lengths and interaction strengths. In total, this allowed us to critically assess the existing theoretical models of avidity in disordered, multivalent interactions. As expected, the onset of avidity occurs when the effective concentration reached the dissociation constant of the weakest interaction. Avidity decreased monotonously with linker length, but only by a third of what is predicted by theoretical models. We suggest that the length dependence of avidity is attenuated by compensating mechanisms such as linker interactions or entanglement. The direct role of linkers in avidity suggest they provide a generic mechanism for allosteric regulation of disordered, multivalent proteins.
All-FIT: Allele-Frequency-based Imputation of Tumor Purity from High-Depth Sequencing Data
Authors: Loh Jui Wan , Guccione Caitlin , Di Clemente Frances , Riedlinger Gregory , Ganesan Shridar , Khiabanian Hossein
Published: May 2019

Motivation

Clinical sequencing aims to identify somatic mutations in cancer cells for accurate diagnosis and treatment. However, most widely used clinical assays lack patient-matched control DNA and additional analysis is needed to distinguish somatic and unfiltered germline variants. Such computational analyses require accurate assessment of tumor cell content in individual specimens. Histological estimates often do not corroborate with results from computational methods that are primarily designed for normal-tumor matched data and can be confounded by genomic heterogeneity and presence of sub-clonal mutations.

Methods

All-FIT is an iterative weighted least square method to estimate specimen tumor purity based on the allele frequencies of variants detected in high-depth, targeted, clinical sequencing data.

Results

Using simulated and clinical data, we demonstrate All-FIT’s accuracy and improved performance against leading computational approaches, highlighting the importance of interpreting purity estimates based on expected biology of tumors.

Availability and Implementation

Freely available at http://software.khiabanian-lab.org.
Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice
Authors: Sell Gabrielle L. , Xin Wendy , Cook Emily K. , Zbinden Mark A. , Schaffer Thomas B. , O’Meally Robert N. , Cole Robert N. , Bonci Antonello , Margolis Seth S.
Published: May 2019

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in >1-2% of patients with autism spectrum disorders – a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 is a direct substrate of UBE3A ubiquitin ligase activity. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.