bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Methods for Pairing Electrodes Across Ears With Cochlear Implants
Authors: Staisloff Hannah E. , Aronoff Justin M.
Published: February 2021

Objectives:

Currently, bilateral cochlear implants (CIs) are independently programmed in clinics using frequency allocations based on the relative location of a given electrode from the end of each electrode array. By pairing electrodes based on this method, bilateral CI recipients may have decreased sensitivity to interaural time differences (ITD) and/or interaural level differences (ILD), two cues critical for binaural tasks. There are multiple different binaural measures that can potentially be used to determine the optimal way to pair electrodes across the ears. Previous studies suggest that the optimal electrode pairing between the left and right ears may vary depending on the binaural task used. These studies, however, have only used one reference location or a single bilateral CI user. In both instances, it is difficult to determine if the results that were obtained reflect a measurement error or a systematic difference across binaural tasks. It is also difficult to determine from these studies if the differences between the three cues vary across electrode regions, which could result from differences in the availability of binaural cues across frequency regions. The purpose of this study was to determine if, after experience-dependent adaptation, there are systematic differences in the optimal pairing of electrodes at different points along the array for the optimal perception of ITD, ILD, and pitch.

Design:

Data from seven bilateral Nucleus users was collected and analyzed. Participants were tested with ITD, ILD, and pitch-matching tasks using five different reference electrodes in one ear, spaced across the array. Comparisons were conducted to determine if the optimal bilateral electrode pairs systematically differed in different regions depending on whether they were measured based on ITD sensitivity, ILD sensitivity, or pitch matching, and how those pairs differed from the pairing in the participants’ clinical programs.

Results:

Results indicate that there was a significant difference in the optimal pairing depending on the cue measured, but only at the basal end of the array.

Conclusion:

The results suggest that optimal electrode pairings differ depending on the cue measured to determine optimal pairing, at least for the basal end of the array. This also suggests that the improvements seen when using optimally paired electrodes may be tied to the particular percept being measured both to determine electrode pairing and to assess performance, at least for the basal end of the array.
Prognosis of Symptomatic Pseudarthrosis Observed at 1 Year After Lateral Lumbar Interbody Fusion
Authors: Jung Jong-myung , Chung Chun Kee , Kim Chi Heon , Yang Seung Heon , Ko Young San
Published: February 2021

Study Design.

Retrospective cohort study.

Objective.

The aim of this study was to investigate the prognosis of symptomatic pseudarthrosis observed at 1 year after lateral lumbar interbody fusion (LLIF) surgery and to analyze the risk factors for persistent pseudarthrosis for 2 years postoperatively.

Summary of Background Data.

Few articles have evaluated the prognosis of symptomatic pseudarthrosis following LLIF surgery.

Methods.

One hundred fifty-two patients with a minimum follow-up of 2 years were screened. Fusion status was assessed at 1 year postoperatively, and unfused segments were reevaluated at 2 years postoperatively. Dynamic x-rays and computed tomography images were acquired to evaluate the fusion status. Demographic data were evaluated to identify the risk factors associated with persistent pseudarthrosis. Clinical outcomes, including the visual analog scale (VAS) for back/leg pain and the Oswestry disability index (ODI), were evaluated preoperatively and at 1 and 2 years postoperatively.

Results.

Symptomatic pseudarthrosis was detected in 42 patients at 1 year postoperatively. Among them, 23 patients (54.8%) exhibited solid bony fusion 2 years postoperatively without further intervention. Fourteen patients (33.3%) showed asymptomatic pseudarthrosis, and the remaining five patients (11.9%) showed symptomatic pseudarthrosis. Multivariable analysis showed that diabetes (adjusted odds ratio [OR]: 2.817, P = 0.007), smoking (adjusted OR: 6.497, P = 0.008), and fusion at more than three levels (adjusted OR: 2.525, P = 0.031) were risk factors for persistent pseudarthrosis. Improvements in the VAS scores for back pain and ODI scores were significantly lower in the persistent pseudarthrosis group than in the final solid fusion group at 2 years postoperatively.

Conclusion.

It is not necessary to intervene for all patients in whom symptomatic pseudarthrosis is detected at 1 year postoperatively because only 11.9% of them will show persistent symptomatic pseudarthrosis. However, early revision surgery should be considered when severe symptomatic pseudarthrosis associated with diabetes, smoking, and fusion at more than three levels is present.

Level of Evidence: 4
Vascularized Toe Joint Transfer for Hypoplastic Thumb Type IV
Authors: Luangjarmekorn Pobe , Pongernnak Nontich , Kitidumrongsook Pravit
Published: February 2021

Vascularized toe joint transfer can be an alternative treatment for children who have hypoplastic thumb with unstable carpometacarpal joint and refuse thumb ablation with index pollicization. This procedure can reconstruct a 5-digit hand with stable thumb for opposition. As the viable epiphyseal plate is included in this transfer, the potential for future growth can be expected from this type of reconstruction. This article describes details of the surgical procedures. The outcomes of this reconstruction are shown in a 7-year-old girl who presented with hypoplastic thumb type IV. Initially, her thumb was unstable, nonmobile, and had no function. The skin pedicle of this thumb had a diameter of about 3 mm. Preoperative radiography showed floating thumb without first metacarpal bone. The vascularized metatarsophalangeal joint from the opposite second toe was used for her hypoplastic thumb reconstruction. During the procedure, the flail thumb was preserved. The intraoperative bone gap that was needed for reconstruction was 3.5 cm. The artery was anastomosed with common digital artery from the third web space. Two dorsal veins were joined with the subcutaneous vein at the dorsum of the hand. Total operative time was 6 hours. At the 9-month follow-up, this girl achieved a 5-digit hand with stable thumb that had opposition to the tip of her little finger. She can use this hand to perform all activities of daily living without any pain. Both patient and parents were very satisfied with the functional and cosmetic appearance.
Rapid and exceptional response to Sonidegib in a patient with multiple locally advanced basal cell carcinomas
Authors: Tarantino Vanessa , Zavattaro Elisa , Veronese Federica , Gironi Laura C. , Savoia Paola
Published: February 2021

Locally advanced basal cell carcinoma (laBCC) represents a rare but possible occurrence in the vast scenario of dermatological diseases. It is well known that most BCC has a pathological activation of the hedgehog pathway, making them susceptible to targeted therapy with selective inhibitors. Sonidegib, approved for the treatment of laBCC on the basis of the results of the basal cell carcinoma outcomes with LDE225 treatment study, demonstrated rapid efficacy and a manageable safety profile. Here, we describe the case of a patient affected by multiple laBCC treated with Sonidegib. The patient experienced an important regression of tumors after only 2 months of therapy, with few side effects. This result confirms the role of Sonidegib as a valid and well-tolerated therapeutic option for laBCC.
The need for polygenic score reporting standards in evidence-based practice: lipid genetics use case
Authors: Wand Hannah , Knowles Joshua W. , Clarke Shoa L.
Published: February 2021

Purpose of review

Polygenic scores (PGS) are used to quantify the genetic predisposition for heritable traits, with hypothesized utility for personalized risk assessments. Lipid PGS are primed for clinical translation, but evidence-based practice changes will require rigorous PGS standards to ensure reproducibility and generalizability. Here we review applicable reporting and technical standards for dyslipidemia PGS translation along phases of the ACCE (Analytical validity, Clinical validity, Clinical utility, Ethical considerations) framework for evaluating genetic tests.

Recent findings

New guidance suggests existing standards for study designs incorporating the ACCE framework are applicable to PGS and should be adopted. One recent example is the Clinical Genomics Resource (ClinGen) and Polygenic Score Catalog's PRS reporting standards, which define minimal requirements for describing rationale for score development, study population definitions and data parameters, risk model development and application, risk model evaluation, and translational considerations, such as generalizability beyond the target population studied.

Lipid PGS are likely to be integrated into clinical practice in the future. Clinicians will need to be prepared to determine if and when lipid PGS is useful and valid. This decision-making will depend on the quality of evidence for the clinical use of PGS. Establishing reporting standards for PGS will help facilitate data sharing and transparency for critical evaluation, ultimately benefiting the efficiency of evidence-based practice.
Reduction techniques for intramedullary nailing of tibial shaft fractures: a comparative study
Authors: Behlmer Richard J. , Whiting Paul S. , Kliethermes Stephanie A. , Wendt Linder , Simske Natasha M. , Sato Eleanor H. , Doro Christopher J. , Goodspeed David C. , Lang Gerald J.
Published: February 2021

Objectives:

To assess the impact of various reduction techniques on postoperative alignment following intramedullary nail (IMN) fixation of tibial shaft fractures.

Design:

Retrospective comparative study.

Setting:

Level I trauma center.

Patients:

Four hundred twenty-eight adult patients who underwent IMN fixation of a tibial shaft fracture between 2008 and 2017.

Intervention:

IMN fixation with use of one or more of the following reduction techniques: manual reduction, traveling traction, percutaneous clamps, provisional plating, or blocking screws.

Main outcome measures:

Immediate postoperative coronal and sagittal plane alignment, measured as deviation from anatomic axis (DFAA); coronal and sagittal plane malalignment (defined as DFAA >5° in either plane).

Results:

Four hundred twenty-eight patients met inclusion criteria. Manual reduction (MR) alone was used in 11% of fractures, and adjunctive reduction aids were used for the remaining 89%. After controlling for age, BMI, and fracture location, the use of traveling traction (TT) with or without percutaneous clamping (PC) resulted in significantly improved coronal plane alignment compared to MR alone (TT: 3.4°, TT+PC: 3.2°, MR: 4.5°, P = .007 and P = .01, respectively). Using TT+PC resulted in the lowest rate of coronal plane malalignment (13% vs 39% with MR alone, P = .01), and using any adjunctive reduction technique resulted in decreased malalignment rates compared to MR (24% vs 39%, P = .02). No difference was observed in sagittal plane alignment between reduction techniques. Intraclass correlation coefficient (ICC) results indicated excellent intraobserver reliability on both planes (both ICC>0.85), good inter-observer reliability in the coronal plane (ICC = 0.7), and poor inter-observer reliability in the sagittal plane (ICC = 0.05).

Conclusions:

The use of adjunctive reduction techniques during IMN fixation of tibia fractures is associated with a lower incidence of coronal plane malalignment when compared to manual reduction alone.

Level of evidence:

Therapeutic Level III.
Toward Computer-Assisted Triaging of Magnetic Resonance Imaging‐Guided Biopsy in Preoperative Breast Cancer Patients
Authors: Wang Hui , van der Velden Bas H.M. , Ragusi Max A.A. , Veldhuis Wouter B. , Viergever Max A. , Verburg Erik , Gilhuijs Kenneth G.A.
Published: February 2021

Objectives

Incidental MR-detected breast lesions (ie, additional lesions to the index cancer) pose challenges in the preoperative workup of patients with early breast cancer. We pursue computer-assisted triaging of magnetic resonance imaging (MRI)‐guided breast biopsy of additional lesions at high specificity.

Materials and Methods

We investigated 316 consecutive female patients (aged 26 to 76 years; mean, 54 years) with early breast cancer who received preoperative multiparametric breast MRI between 2013 and 2016. In total, 82 (26%) of 316 patients had additional breast lesions on MRI. These 82 patients had 101 additional lesions in total, 51 were benign and 50 were malignant. We collected 4 clinical features and 46 MRI radiomic features from T1-weighted dynamic contrast-enhanced imaging, high-temporal-resolution dynamic contrast-enhanced imaging, T2-weighted imaging, and diffusion-weighted imaging. A multiparametric computer-aided diagnosis (CAD) model using 10-fold cross-validated ridge regression was constructed. The sensitivities were calculated at operating points corresponding to 98%, 95%, and 90% specificity. The model calibration performance was evaluated by calibration plot analysis and goodness-of-fit tests. The model was tested in an independent testing cohort of 187 consecutive patients from 2017 and 2018 (aged 35 to 76 years; mean, 59 years). In this testing cohort, 45 (24%) of 187 patients had 55 additional breast lesions in total, 23 were benign and 32 were malignant.

Results

The multiparametric CAD model correctly identified 48% of the malignant additional lesions with a specificity of 98%. At specificity 95% and 90%, the sensitivity was 62% and 72%, respectively. Calibration plot analysis and goodness-of-fit tests indicated that the model was well fitted.

In the independent testing cohort, the specificity was 96% and the sensitivity 44% at the 98% specificity operating point of the training set. At operating points 95% and 90%, the specificity was 83% at 69% sensitivity and the specificity was 78% at 81% sensitivity, respectively.

Conclusions

The multiparametric CAD model showed potential to identify malignant disease extension with near-perfect specificity in approximately half the population of preoperative patients originally indicated for a breast biopsy. In the other half, patients would still proceed to MRI-guided biopsy to confirm absence of malignant disease. These findings demonstrate the potential to triage MRI-guided breast biopsy.
SARS-CoV-2 Seroprevalence in Tamil Nadu in October-November 2020
Authors: Malani Anup , Ramachandran Sabareesh , Tandel Vaidehi , Parasa Rajeswari , Imad Sofia , Sudharshini S. , Prakash V. , Yogananth Y. , Raju S. , Selvavinayagam T.S.
Published: February 2021

A population-representative serological study was conducted in all districts of the state of Tamil Nadu (population 72 million), India, in October-November 2020. State-level seroprevalence was 31.6%. However, this masks substantial variation across the state. Seroprevalence ranged from just 11.1% in The Nilgris to 51.0% in Perambalur district. Seroprevalence in urban areas (36.9%) was higher than in rural areas (26.9%). Females (30.8%) had similar seroprevalence to males (30.3%). However, working age populations (age 40-49: 31.6%) have significantly higher seroprevalence than the youth (age 18-29: 30.7%) or elderly (age 70+: 25.8%). Estimated seroprevalence implies that at least 22.6 million persons were infected by the end of November, roughly 36 times the number of confirmed cases. Estimated seroprevalence implies an infection fatality rate of 0.052%.
Modeling Influenza Seasonality in the Tropics and Subtropics
Authors: Yuan Haokun , Kramer Sarah C. , Lau Eric H. Y. , Cowling Benjamin J. , Yang Wan
Published: February 2021

Climate drivers such as humidity and temperature may play a key role in influenza seasonal transmission dynamics. Such a relationship has been well defined for temperate regions. However, to date no models capable of capturing the diverse seasonal pattern in tropical and subtropical climates exist. In addition, multiple influenza viruses could cocirculate and shape epidemic dynamics. Here we construct seven mechanistic epidemic models to test the effect of two major climate drivers (humidity and temperature) and multi-strain co-circulation on influenza transmission in Hong Kong, an influenza epidemic center located in the subtropics. Based on model fit to long-term influenza surveillance data from 1998 to 2018, we found that a simple model incorporating the effect of both humidity and temperature best recreated the influenza epidemic patterns observed in Hong Kong. The model quantifies a bimodal effect of absolute humidity on influenza transmission where both low and very high humidity levels facilitate transmission quadratically; the model also quantifies the monotonic but nonlinear relationship with temperature. In addition, model results suggest that, at the population level, a shorter immunity period can approximate the co-circulation of influenza virus (sub)types. The basic reproductive number R0 estimated by the best-fit model is also consistent with laboratory influenza survival and transmission studies under various combinations of humidity and temperature levels. Overall, our study has developed a simple mechanistic model capable of quantifying the impact of climate drivers on influenza transmission in (sub)tropical regions. This model can be applied to improve influenza forecasting in the (sub)tropics in the future.
Prediction Model for Severe Community-acquired Pneumonia Development among Patients with Diabetes Mellitus
Authors: Tan Ruoming , Pan Tingting , Qiu Yuzhen , Wang Jiahui , Qi Xiaoling , Chen Erzhen , Zhou Min , Liu Jialin , Qu Hongping
Published: February 2021

Introduction: Diabetes is an independent risk factor for the development of severe community-acquired pneumonia (CAP) and associated with pneumonia-related hospitalization as well as mortality. Here, we assessed several selected biomarkers to determine their predictive value for progression to severe CAP among diabetic patients.
Research design and methods: A retrospective cohort study of diabetic patients with CAP was conducted at a tertiary teaching hospital. The prediction model group (N=100) comprised patients registered between January 2015 to December 2016. Multivariate analysis was performed to identify predictive biomarkers from this cohort. The validation group (N=108) comprised the patients between January 2017 to February 2019. Predictive performance was assessed in the validation group.
Results: A total of 208 diabetic inpatients with CAP were recruited. Further multivariate analysis showed that C-reactive protein (CRP), absolute lymphocyte count (ALC), immunoglobulin (IgM), and HbA1C at admission were independently associated with progression to severe CAP in diabetic patients during hospitalization. The prediction model =0.0179555*CRP+1.975918* HbA1C-2.879364* ALC -0.026255* IgM -8.220555. The area under ROC (AUROC) curve in the validation group was 0.851 (0.781-0.921) with statistical significance (P<.05).
Conclusions: In diabetic patients with CAP, a combination of CRP, ALC, IgM, and HbA1C at admission could be used to predict the progression to severe CAP.
NeuroSCORE: A Genome-wide Omics-Based Model to Identify Candidate Disease Genes of the Central Nervous System
Authors: Davis Kyle W. , Bilancia Colleen G. , Martin Megan , Vanzo Rena , Rimmasch Megan , Hom Yolanda , Uddin Mohammed , Serrano Moises
Published: February 2021

To identify and prioritize candidate disease genes of the central nervous system (CNS) we created the Neurogenetic Systematic Correlation of Omics-Related Evidence (NeuroSCORE). We used five genome-wide metrics highly associated with neurological phenotypes to score 19,598 protein-coding genes. Genes scored one point per metric, resulting in a range of scores from 0-5. Approximately 13,000 genes were then paired with phenotype data from the Online Mendelian Inheritance in Man (OMIM) database. We used logistic regression to determine the odds ratio of each metric and compared genes scoring 1+ to cause a known CNS-related phenotype compared to genes that scored zero. We tested NeuroSCORE using microarray copy number variants (CNVs) in case-control cohorts, mouse model phenotype data, and gene ontology (GO) and pathway analyses. NeuroSCORE identified 8,296 genes scored ≥1, of which 1,580 are “high scoring” genes (scores ≥3). High scoring genes are significantly associated with CNS phenotypes (OR=5.5,p<2×10−16), enriched in case CNVs, and enriched in mouse ortholog genes associated with behavioral and nervous system abnormalities. GO and pathway analyses showed high scoring genes were enriched in chromatin remodeling, mRNA splicing, dendrite development, and neuron projection. OMIM has no phenotype for 1,062 high scoring genes (67%). Top scoring genes includeANKRD17, CCAR1, CLASP1, DOCK9, EIF4G2, G3BP2, GRIA1, MAP4K4, MARK2, PCBP2, RNF145, SF1, SYNCRIP, TNPO2, andZSWIM8. NeuroSCORE identifies and prioritizes CNS-disease candidate genes, many not yet associated with any phenotype in OMIM. These findings can help direct future research and improve molecular diagnostics for individuals with neurological conditions.
Interpreting machine learning models to investigate circadian regulation and facilitate exploration of clock function
Authors: Gardiner Laura-Jayne , Rusholme-Pilcher Rachel , Colmer Josh , Rees Hannah , Crescente Juan Manuel , Carrieri Anna Paola , Duncan Susan , Pyzer-Knapp Edward O. , Krishna Ritesh , Hall Anthony
Published: February 2021

The circadian clock is an important adaptation to life on earth. Here, we use machine learning to predict complex temporal circadian gene expression patterns inArabidopsis. Most significantly, we classify circadian genes using DNA sequence features generated from public genomic resources, with no experimental work or prior knowledge needed. We use model explanation to rank DNA sequence features, observing transcript-specific combinations of potential circadian regulatory elements that discriminate temporal phase of expression. Model interpretation/explanation provides the backbone of our methodological advances, giving insight into biological processes and experimental design. Next, we use model interpretation to optimize sampling strategies when we predict circadian transcripts using reduced numbers of transcriptomic timepoints, saving both time and money. Finally, we predict the circadian time from a single transcriptomic timepoint, deriving novel marker transcripts that are most impactful for accurate prediction, this could facilitate the identification of altered clock function from existing datasets.
FINDER: An automated software package to annotate eukaryotic genes from RNA-Seq data and associated protein sequences
Authors: Banerjee Sagnik , Bhandary Priyanka , Woodhouse Margaret , Sen Taner Z. , Wise Roger P. , Andorf Carson M.
Published: February 2021

Background

Gene annotation in eukaryotes is a non-trivial task that requires meticulous analysis of accumulated transcript data. Challenges include transcriptionally active regions of the genome that contain overlapping genes, genes that produce numerous transcripts, transposable elements and numerous diverse sequence repeats. Currently available gene annotation software applications depend on pre-constructed full-length gene sequence assemblies which are not guaranteed to be error-free. The origins of these sequences are often uncertain, making it difficult to identify and rectify errors in them. This hinders the creation of an accurate and holistic representation of the transcriptomic landscape across multiple tissue types and experimental conditions. Therefore, to gauge the extent of diversity in gene structures, a comprehensive analysis of genome-wide expression data is imperative.

Results

We present FINDER, a fully automated computational tool that optimizes the entire process of annotating genes and transcript structures. Unlike current state-of-the-art pipelines, FINDER automates the RNA-Seq pre-processing step by working directly with raw sequence reads and optimizes gene prediction from BRAKER2 by supplementing these reads with associated proteins. The FINDER pipeline (1) reports transcripts and recognizes genes that are expressed under specific conditions, (2) generates all possible alternatively spliced transcripts from expressed RNA-Seq data, (3) analyzes read coverage patterns to modify existing transcript models and create new ones, and (4) scores genes as high- or low-confidence based on the available evidence across multiple datasets. We demonstrate the ability of FINDER to automatically annotate a diverse pool of genomes from eight species.

Conclusions

FINDER takes a completely automated approach to annotate genes directly from raw expression data. It is capable of processing eukaryotic genomes of all sizes and requires no manual supervision – ideal for bench researchers with limited experience in handling computational tools.
Depth Dataset Using Microsoft Kinect-v2
Authors: Heravi Hamed , Delgarmi Masumeh , Jounghani Ali Rahimpour , shahrezaie Abdollah , Ebrahimi Afshin , Shamsi Mousa
Published: February 2021

In biomedical imaging studies, numerous methods have been used to capture human data, mostly by using magnetic resonance imaging (MRI) and computed tomography (CT). However, due to being inexpensive and accessibility of Microsoft Kinect, its usage has been significantly increased in recent years. In this study, we aimed to represent the procedure of data acquisition, which includes a set of depth images from individuals’ back surfaces. The goal of image acquisition is to investigate spinal deformities and landmark detection of the back surface. Traditional imaging systems are challenging, most notably because of ionized beams in the data acquisition process, which has not been solved yet. Indeed, noninvasiveness is the most crucial advantage of our study. Our imaging system was set in a dim laboratory, and the University approved the ethical letter of Medical Sciences before data acquisition. After that, the subjects (total 105; 50 women and 55 men) were recruited, and data images were captured from the back surface. Then, we increased the imaging data size by using the augmentation method to use deep learning methods in future works. Finally, this Dataset leads us to the desired output in our study procedure.
High-resolution portability of 245 polygenic scores when derived and applied in the same cohort
Authors: Privé Florian , Aschard Hugues , Carmi Shai , Folkersen Lasse , Hoggart Clive , O’Reilly Paul F. , Vilhjálmsson Bjarni J.
Published: February 2021

The low portability of polygenic scores (PGS) across global populations is a major concern that must be addressed before PGS can be used for everyone in the clinic. Indeed, prediction accuracy has been shown to decay as a function of the genetic distance between the training and test cohorts. However, such cohorts differ not only in their genetic distance but also in their geographical distance and their data collection and assaying, conflating multiple factors. In this study, we examine the extent to which PGS are transferable between ancestries by deriving polygenic scores for 245 curated traits from the UK Biobank data and applying them in nine ancestry groups from the same cohort. By restricting both training and testing to the UK Biobank data, we reduce the risk of environmental and genotyping confounding from using different cohorts. We define the nine ancestry groups at a high-resolution, country-specific level, based on a simple, robust and effective method that we introduce here. We then apply two different predictive methods to derive polygenic scores for all 245 phenotypes, and show a systematic and dramatic reduction in portability of PGS trained in the inferred ancestral UK population and applied to the inferred ancestral Polish - Italian - Iranian - Indian - Chinese - Caribbean - Nigerian - Ashkenazi populations, respectively. These analyses, performed at a finer scale than the usual continental scale, demonstrate that prediction already drops off within European ancestries and reduces globally in proportion to PC distance, even when all individuals reside in the same country and are genotyped and phenotyped as part of the same cohort. Our study provides high-resolution and robust insights into the PGS portability problem.
Endometrial microbiota composition is associated with reproductive outcome in infertile patients
Authors: Moreno Inmaculada , Garcia-Grau Iolanda , Perez-Villaroya David , Gonzalez-Monfort Marta , Bahçeci Mustafa , Barrionuevo Marcelo J. , Taguchi Sagiri , Puente Elena , Dimattina Michael , Lim Mei Wei , Meneghini Georgina , Aubuchon Mira , Leondires Mark , Izquierdo Alexandra , Perez-Olgiati Martina , Chavez Alejandro , Seethram Ken , Bau Davide , Gomez Carlos , Valbuena Diana , Vilella Felipe , Simon Carlos
Published: February 2021

Background

Previous evidence indicates associations between the female reproductive tract microbiome composition and reproductive outcome in infertile patients undergoing assisted reproduction. We aimed to determine whether the endometrial microbiota composition is associated with reproductive outcomes of live birth, biochemical pregnancy, clinical miscarriage, or no pregnancy.

Methods

Here we present a multicentre prospective observational study using 16S rRNA gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive treatments.

Results

A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes.

Conclusions

Our findings indicate that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to further improve diagnosis and treatment strategies.
UK and other SARS-CoV-2-Covariants - Simulation Modeling 70% Increase
Authors: Chang Ernie , Moselle Kenneth A.
Published: February 2021

CovidSIMVL, an agent-based contagion-based viral transmission simulation tool, was employed to simulate the effects of viral agents of differing levels of infectivity. The constructs “Velocity” and “Increase in Velocity” were operationalized in terms of rates of transmission events over successive iterations (generations) in a set of CovidSIMVL trials. Treating 40-70% increase in velocity as a target, based on reports in the literature for the UK variant (VUI 202012/01), the series of trials reported in the paper demonstrate the calibration of CovidSIMVL parameters to produce increases in transmission rates of 40-70% above a baseline value. A series of follow-up studies is proposed to evaluate three different possible explanations for reported increases in SARS-Cov2-2 infections that are being attributed to spread of the UK and other variants: (a) simulations where the inherent characteristics of the virus (infectivity) are varied (genomic studies); (b) simulations where the behaviour of agents is varied (e.g., movement within and between spaces) while inherent characteristics of the virus are held constant (behavioural studies); and (c) simulations where both inherent properties of the virus and the behaviour of agents are varying to “tease out” the interaction between biologically-based contributions to increased case counts, and contextual/behavioural contributions (epigenetic studies).
Design and Estimation for the Population Prevalence of Infectious Diseases
Authors: Oh Eric J. , Mikytuck Alyssa , Lancaster Vicki , Goldstein Joshua , Keller Sallie
Published: February 2021

Understanding the prevalence of infections in the population of interest is critical for making data-driven public health responses to infectious disease outbreaks. Accurate prevalence estimates, however, can be difficult to calculate due to a combination of low population prevalence, imperfect diagnostic tests, and limited testing resources. In addition, strategies based on convenience samples that target only symptomatic or high-risk individuals will yield biased estimates of the population prevalence. We present Bayesian multilevel regression and poststratification models that incorporate probability sampling designs, the sensitivity and specificity of a diagnostic test, and specimen pooling to obtain unbiased prevalence estimates. These models easily incorporate all available prior information and can yield reasonable inferences even with very low base rates and limited testing resources. We examine the performance of these models with an extensive numerical study that varies the sampling design, sample size, true prevalence, and pool size. We also demonstrate the relative robustness of the models to key prior distribution assumptions via sensitivity analyses.
Genetic Analysis of Right Heart Structure and Function in 40,000 People
Authors: Pirruccello James P. , Achille Paolo Di , Nauffal Victor , Nekoui Mahan , Friedman Samuel N. , Klarqvist Marcus D. R. , Chaffin Mark D. , Khurshid Shaan , Roselli Carolina , Batra Puneet , Ng Kenney , Lubitz Steven A. , Ho Jennifer E. , Lindsay Mark E. , Philippakis Anthony A. , Ellinor Patrick T.
Published: February 2021

The heart evolved hundreds of millions of years ago. During mammalian evolution, the cardiovascular system developed with complete separation between pulmonary and systemic circulations incorporated into a single pump with chambers dedicated to each circulation. A lower pressure right heart chamber supplies deoxygenated blood to the lungs, while a high pressure left heart chamber supplies oxygenated blood to the rest of the body. Due to the complexity of morphogenic cardiac looping and septation required to form these two chambers, congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. Additionally, some diseases predominantly affect structures of the right heart, including arrhythmogenic right ventricular cardiomyopathy (ARVC) and pulmonary hypertension. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, the right ventricle, and the pulmonary artery, and then used those models to measure right heart structures in over 40,000 individuals from the UK Biobank with magnetic resonance imaging. We found associations between these measurements and clinical disease including pulmonary hypertension and dilated cardiomyopathy. We then conducted genome-wide association studies, identifying 104 distinct loci associated with at least one right heart measurement. Several of these loci were found near genes previously linked with congenital heart disease, such asNKX2-5, TBX3, WNT9B, andGATA4. We also observed interesting commonalities and differences in association patterns at genetic loci linked with both right and left ventricular measurements. Finally, we found that a polygenic predictor of right ventricular end systolic volume was associated with incident dilated cardiomyopathy (HR 1.28 per standard deviation; P = 2.4E-10), and remained a significant predictor of disease even after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic and clinical determinants of right heart structure and function.
Loss of HMCES is synthetic lethal with APOBEC activity in cancer cells
Authors: Biayna Josep , Garcia-Cao Isabel , Álvarez Miguel M. , Salvadores Marina , Espinosa-Carrasco Jose , McCullough Marcel , Supek Fran , Stracker Travis H.
Published: February 2021

Analysis of cancer mutagenic signatures provides information about the origin of mutations and can inform the use of clinical therapies, including immunotherapy. In particular, APOBEC3A (A3A) has emerged as a major driver of mutagenesis in cancer cells and its expression results in DNA damage and susceptibility to treatment with inhibitors of the ATR and CHK1 checkpoint kinases. Here we report the implementation of CRISPR/Cas9 genetic screening to identify susceptibilities of multiple A3A-expressing lung adenocarcinoma cell lines. We identify HMCES, a protein recently linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression specifically in a TP53-mutant background. Analysis of previous screening data reveals a strong association between A3A mutational signatures and sensitivity to HMCES loss and indicates that HMCES is specialized in protecting against a narrow spectrum of DNA damaging agents in addition to A3A. We experimentally show that both HMCES disruption and A3A expression increase susceptibility of cancer cells to ionizing radiation, oxidative stress and ATR inhibition; strategies that are often applied in tumor therapies. Overall, our results suggest that HMCES is an attractive target for selective treatment of A3A expressing tumors.
Neuronal Switching Between Single- and Dual-Network Activity via Modulation of Intrinsic Membrane Properties
Authors: Fahoum Savanna-Rae H. , Blitz Dawn M.
Published: February 2021

Oscillatory networks underlie rhythmic behaviors (e.g. walking, chewing), and complex behaviors (e.g. memory formation, decision making). Flexibility of oscillatory networks includes neurons switching between single- and dual-network participation, even generating oscillations at two distinct frequencies. Modulation of synaptic strength can underlie this neuronal switching. Here we ask whether switching into dual-frequency oscillations can also result from modulation of intrinsic neuronal properties. The isolated stomatogastric nervous system of male Cancer borealis crabs contains two well-characterized rhythmic feeding-related networks (pyloric, ∼1 Hz; gastric mill, ∼0.1 Hz). The identified modulatory projection neuron MCN5 causes the pyloric-only LPG neuron to switch to dual pyloric/gastric mill bursting. Bath applying the MCN5 neuropeptide transmitter Gly1-SIFamide only partly mimics the LPG switch to dual activity, due to continued LP neuron inhibition of LPG. Here, we find that MCN5 uses a co-transmitter, glutamate, to inhibit LP, unlike Gly1-SIFamide excitation of LP. Thus, we modeled the MCN5-elicited LPG switching with Gly1-SIFamide application and LP photoinactivation. Using hyperpolarization of pyloric pacemaker neurons and gastric mill network neurons, we found that LPG pyloric-timed oscillations require rhythmic electrical synaptic input. However, LPG gastric mill-timed oscillations do not require any pyloric/gastric mill synaptic input and are voltage dependent. Thus, we identify modulation of intrinsic properties as an additional mechanism for switching a neuron into dual-frequency activity. Instead of synaptic modulation switching a neuron into a second network as a passive follower, modulation of intrinsic properties could enable a switching neuron to become an active contributor to rhythm generation in the second network.

Significance Statement

Neuromodulation of oscillatory networks can enable network neurons to switch from sing<bacle- to dual-network participation, even when two networks oscillate at distinct frequencies. We used small, well-characterized networks to determine whether modulation of synaptic strength, an identified mechanism for switching, is necessary for dual-network recruitment. We demonstrate that rhythmic electrical synaptic input is required for continued linkage with a “home” network, but that modulation of intrinsic properties is sufficient to switch a neuron into dual-frequency oscillations, linking it to a second network. Neuromodulator-induced switches in neuronal participation between networks occurs in motor, cognitive, and sensory networks. Our study highlights the importance of considering intrinsic properties as a pivotal target for enabling parallel participation of a neuron in two oscillatory networks.
Computational exploration of dynamic mechanisms of steady state visual evoked potentials at the whole brain level
Authors: Zhang Ge , Cui Yan , Zhang Yangsong , Cao Hefei , Zhou Guanyu , Shu Haifeng , Yao Dezhong , Xia Yang , Chen Ke , Guo Daqing
Published: February 2021

Periodic visual stimulation can induce stable steady-state visual evoked potentials (SSVEPs) distributed in multiple brain regions and has potential applications in both neural engineering and cognitive neuroscience. However, the underlying dynamic mechanisms of SSVEPs at the whole-brain level are still not completely understood. Here, we addressed this issue by simulating the rich dynamics of SSVEPs with a large-scale brain model designed with constraints of neuroimaging data acquired from the human brain. By eliciting activity of the occipital areas using an external periodic stimulus, our model was capable of replicating both the spatial distributions and response features of SSVEPs that were observed in experiments. In particular, we confirmed that alpha-band (8-12 Hz) stimulation could evoke stronger SSVEP responses; this frequency sensitivity was due to nonlinear entrainment and resonance, and could be modulated by endogenous factors in the brain. Interestingly, the stimulus-evoked brain networks also exhibited significant superiority in topological properties near this frequency-sensitivity range, and stronger SSVEP responses were demonstrated to be supported by more efficient functional connectivity at the neural activity level. These findings not only provide insights into the mechanistic understanding of SSVEPs at the whole-brain level but also indicate a bright future for large-scale brain modeling in characterizing the complicated dynamics and functions of the brain.
A Mathematical Model which Examines Age-Related Stochastic Fluctuations in DNA Maintenance Methylation
Authors: Zagkos Loukas , Roberts Jason , Auley Mark Mc
Published: February 2021

Due to its complexity and its ubiquitous nature the ageing process remains an enduring biological puzzle. Many molecular mechanisms and biochemical process have become synonymous with ageing. However, recent findings have pinpointed epigenetics as having a key role in ageing and healthspan. In particular age related changes to DNA methylation offer the possibility of monitoring the trajectory of biological ageing and could even be used to predict the onset of diseases such as cancer, Alzheimer’s disease and cardiovascular disease. At the molecular level emerging evidence strongly suggests the regulatory processes which govern DNA methylation are subject to intracellular stochasticity. It is challenging to fully understand the impact of stochasticity on DNA methylation levels at the molecular level experimentally. An ideal solution is to use mathematical models to capture the essence of the stochasticity and its outcomes. In this paper we present a novel stochastic model which accounts for specific methylation levels within a gene promoter. We quantify the uncertainty of the eventual cite-specific methylation levels for different values of methylation age, depending on the initial methylation levels. Our model predicts the observed bistable levels in CpG islands. In addition, simulations with various levels of noise indicate that uncertainty predominantly spreads through the hypermethylated region of stability, especially for large values of input noise. A key outcome of the model is that CpG islands with intermediate methylation levels tend to be more susceptible to dramatic DNA methylation changes towards both hypomethylation and hypermethylation, due to increasing methylation age.
Quantitative assessment of constitutive G protein-coupled receptor activity with BRET-based G protein biosensors
Authors: Schihada Hannes , Shekhani Rawan , Schulte Gunnar
Published: February 2021

Heterotrimeric G proteins constitute the primary transducers of G protein-coupled receptor (GPCR) signaling. Besides mediating ligand-induced GPCR activation, G proteins transduce basal levels of activity in various physiological and pathophysiological settings evoked by constitutively active, native GPCRs or disease-related receptor mutants. Several generations of optical biosensors were developed and optimized to monitor GPCR ligand-induced G protein activation, however, quantitative approaches to detect constitutively active GPCRs are not available. Here, we designed and validated a set of eight bioluminescence-resonance-energy-transfer (BRET)-based G protein sensors, covering all four major families of G proteins, and established a protocol to identify constitutive GPCR/G protein signaling in living cells. These sensors rely on the encoding of all three G protein subunits on a single plasmid, enabling their cellular expression at desired relative levels and resulting in reduced signal variability in mammalian cells. Based on this sensor platform, we further present here an experimental protocol to quantify constitutive signaling of native and mutated GPCRs through these heterotrimeric transducers. This approach will aid in the characterization of constitutively active GPCRs and the exploration of their role in health and disease.

One Sentence Summary

This Resource article describes the validation of a biophysical approach to directly assess the constitutive signaling activity of G protein-coupled receptors through heterotrimeric G proteins in living cells using optical biosensors.
Active microrheology using pulsed optical tweezers to probe viscoelasticity of Lamin A towards diagnosis of laminopathies
Authors: Mukherjee C. , Kundu A. , Dey R. , Banerjee A. , Sengupta K.
Published: February 2021

Lamins are nucleoskeletal proteins of mammalian cells that stabilize the structure and maintain the rigidity of the nucleus. These type V intermediate filament proteins which are predominantly of A and B types provide necessary tensile strength to the nucleus. Single amino acid missense mutations occurring all over the lamin A protein form a cluster of human diseases termed as laminopathies, a few of which principally affect the muscle and cardiac tissues responsible for load bearing functionalities of the body. One such mutation is lamin A350P which causes dilated cardiomyopathy in patients. It is likely that a change from alanine to proline in the α-helical 2B rod domain of the protein might severely disrupt the propensity of the filaments to polymerise into functional higher order structures required to form a fully functional lamina with its characteristic elasticity. In this study, we validate for the very first time, the application of active microrheology employing oscillating optical tweezers to investigate any alterations in the visco-elastic parameters of the mutant protein meshworkin vitro, which might translate into possible changes in nuclear plasticity. We confirm our findings from this robust yet fast method by imaging both the wild type and mutant lamins using a super resolution microscope, and observe changes in the mesh size which explain our measured changes in the viscoelastic parameters of the lamins. This method could naturally be extended to conduct microrheological measurements on any intermediate filament protein or any protein endowed with elastic behavior, with minor schematic modifications, thus bearing significant implications in laminopathies and other diseases which are associated with changes in structural rigidity of any cellular organelle.

Significance

Lamin A mutations produce an array of diseases termed as laminopathies which are primarily characterized by alteration of elastic behavior of the nucleus which in turn leads to defects in mechanotransduction. This is the first report in the lamin arena which shows a fast, accurate and direct quantification of elastic moduli of lamin A using optical tweezers-based microrheology. This has very significant implications and can be registered to be a robust and universal method that could also be suitably used for probing changes in elastic properties of any proteins or surfactants in a disease scenario such as SARS-Cov2 (Covid-19), which is pandemic at this time.