bluuebunny/crossref_metadata_2025 huggingface dataset:
Increase in Alcoholic Hepatitis as an Etiology for Liver Transplantation in the United States: A 2004–2018 Analysis
Authors: Noureddin Nabil , Yang Ju Dong , Alkhouri Naim , Noreen Samantha M. , Toll Alice E. , Todo Tsuyoshi , Ayoub Walid , Kuo Alexander , Voidonikolas Georgios , Kotler Honore G. , Pelphrey Michalyn D. , Durand Brenda J. , Kosari Kambiz , Brennan Todd V. , Kim Irene , Klein Andrew S. , Seki Ekihiro , Nissen Nicholas N. , Lu Shelly C. , Sundaram Vinay , Noureddin Mazen
Published: January 2021

Background.

Changing opinions on the alcohol abstinence requirement have led to increased liver transplantation (LT) for alcoholic hepatitis (AH). We aimed to determine the trend in LT for AH in the United States and overall and graft survival rates.

Methods.

Adult liver-alone and liver-kidney registrations added to the Organ Procurement and Transplantation Network waiting list between 2004 and 2018 were divided into 3 periods (2004–2009, 2010–2013, 2014–2018). Kaplan-Meier survival models illustrated patient and graft survival.

Results.

Between 2004 and 2018, 529 AH patients were registered for and 254 received LT. By periods, 116, 73, and 340 patients were registered for and 49, 17, and 188 patients received LT, respectively, indicating a increase in LT for AH from 2014 to 2018. Yearly registrants from 2014 to 2018 were 32, 47, 51, 70, and 140, and recipients were 16, 24, 24, 38, and 88, respectively, indicating increases of 338% and 450% in registrants and recipients, respectively, since 2014. AH patients had the highest 1- and 3-year posttransplant survival (93.2% and 87.3%, respectively) and graft survival (90.4% and 84.8%, respectively) comparing to other LT recipients.

Conclusions.

LT for AH in the United States is at an all-time high with an increased overall patient and graft survival.
Prevascularization-free Primary Subcutaneous Transplantation of Xenogeneic Islets Coencapsulated With Hepatocyte Growth Factor
Authors: Yang Sin-Yu , Yang Kai-Chiang , Sumi Shoichiro
Published: January 2021

Background.

Subcutaneous pouch is a potential site for islet transplantation. However, insufficient oxygen supply remains challenging. Pretreatment of neovascularization using basic fibroblast growth factor can solve this, but it needs 2× operations. We developed a device that contains rat islets in chitosan gel packed in a bag made of highly biocompatible ethylene vinyl alcohol copolymer porous membrane. This study investigated whether coencapsulation of hepatocyte growth factor (HGF) with islets in the device enables novel method of prevascularization-free primary subcutaneous transplantation.

Methods.

In vitro experiments examined slow release of HGF from the chitosan gel and islet-protection effect of HGF against hypoxia. In the latter, rat islets with/without HGF (200 ng/mL) was cultured in 1% oxygen. In in vivo experiment, fabricated device with/without HGF (10 μg/device) containing rat islets was primarily transplanted to streptozotocin-induced diabetic mice subcutaneously.

Results.

In vitro experiments showed sustained release of HGF for 28 d and alleviating effect of HGF on cell death and glucose-responsive insulin release after hypoxic culture. Islet + HGF mice, but not islet-alone mice, showed decreased nonfasting blood glucose and regained body weight after transplantation. In intraperitoneal glucose tolerance test, islet + HGF mice exhibited decreased fasting blood glucose (200 ± 55 mg/dL) and good blood glucose disappearance rate (K value) (0.817 ± 0.101) comparing to normal mice (123 ± 28 mg/dL and 1.074 ± 0.374, respectively). However, in islet-alone mice, fasting blood glucose was high (365 ± 172 mg/dL) and K value was indeterminable. Serum insulin in islet + HGF mice (1.58 ± 0.94 μg/L) was close to normal mice (1.66 ± 0.55 μg/L), whereas those in islet-alone mice (0.279 ± 0.076 μg/L) and diabetic mice (0.165 ± 0.079 μg/L) were low. Immunohistochemical examination showed intact insulin- and glucagon-positive islets in retrieved devices with HGF, but no intact islet was found in the device without HGF.

Conclusions.

HGF could enhance islet survival in hypoxia and enhance in vivo function of encapsulated islets after primary subcutaneous transplantation.
Early administration of aripiprazole long-acting injectable in acute inpatients with schizophrenia: a clinical report
Authors: Palomar-Ciria Nora , Migoya-Borja Marta , Cegla-Schvartzman Fanny , Ovejero Santiago , Alvarez-Garcia Raquel , Bello Hugo J. , Baca-García Enrique
Published: January 2021

Fifty-one patients suffering an acute episode of schizophrenia and treated with aripiprazole long-acting injectable (ALAI) were chosen to elaborate an observational study in two in-patient units in Spain, in order to examine the effects of early administration during a hospital admission. When treatment with ALAI is administered in the first week of admission (in 31 patients, 60.78%), hospitalization time is significantly reduced, 12.1 days on average. It can be concluded that ALAI is an effective treatment for these patients. Analysis in economic terms and comparison with other LAI antipsychotics are interesting lines for further research.
Benefit of long-acting paliperidone in Huntington’s disease: a case report
Authors: Javelot Hervé , Meyer Mylène , Frismand Solène , Hingray Coraline
Published: January 2021

Through this brief report, we described our clinical considerations about the treatment of motor fluctuations and psychiatric comorbidities in Huntington’s disease, for example, aggressiveness and obsessive-compulsive disorders. Indeed, as classical treatment, for example, olanzapine and risperidone, were inefficient to improve motor disorders in our patient, we postulated that motor fluctuations could be influenced by the pharmacokinetic profile of oral risperidone. So, in line with recent practice in schizophrenia, we proposed empirically paliperidone 1-month long-acting injections hypothesized to improve motor fluctuations, treatment so far reserved to Huntington’s disease patients who are noncompliant to oral risperidone. Improvement was soon observed concerning motor fluctuations, but also aggressiveness, supporting our initial hypothesis.
Consultagene: Pre- and Post-Pandemic Experience with a Web-based Platform and Remote Delivery of Genetic Services
Authors: Worley Kim C. , Riconda Daniel Lee , Wallis Amy M. , Shaw Chad A. , Holder Chris M. , Nassef Salma A. , Darilek Sandra , Lalani Seema R. , Magoulas Pilar L. , Huguenard Sarah M. , Lee Brendan H. L.
Published: January 2021

Changes in genetics and genomics sequencing in recent years have created increased demand for genetics professionals, including clinical geneticists and genetic counselors. A significant workforce shortage of these professionals has become widely recognized. This shortage is driven by several factors, including the increased role of genetics in healthcare due to precision medicine initiatives and demand outside of medical practices in clinical and direct-to-consumer genetic testing companies that require genetics professionals for education and counseling.

We developed the Consultagene virtual platform for delivery of genetic care, counseling, and education to address some of these issues that have become global challenges in the field of clinical genetics and to bridge existing gaps at the point of care. The platform provides access to specific content based upon the referral indication including educational videos and resource links, allows document sharing, health and history information gathering and appointment scheduling with persistent access to the materials via secure data infrastructure. Having the platform coupled with access to our tele- and video consultation service allows clients convenient on-demand access to genetic education and services as needed.

This report describes the Consultagene platform development and use prior to and during the COVID-19 pandemic, some of the identified strengths and weaknesses of such a platform, and the current applications in the new environment where telemedicine practice has rapidly expanded.

Topic Summary

Consultagene is the first academic virtual platform to integrate a comprehensive range of genetics services including genetics education, genetics consultation, and genetic counseling. Consultagene addresses the increasing demands and unmet, evolving needs for genetic services due to widely available genomic sequencing and the platform seamlessly adapted to the pandemic-induced adjustments to clinical practice.
Interpretable machine learning prediction of all-cause mortality
Authors: Qiu Wei , Chen Hugh , Dincer Ayse Berceste , Lundberg Scott , Kaeberlein Matt , Lee Su-In
Published: January 2021

Prior studies on all-cause mortality traditionally use linear models; however, growing field of explainable artificial intelligence (XAI) can improve prediction accuracy over traditional linear models using complex machine learning (ML) models while still revealing novel insights. We propose the IMPACT (Interpretable Machine learning Prediction of All-Cause morTality) framework that implements and explains complex, non-linear ML models by combining a tree ensemble mortality prediction model and a principled XAI technique. We apply IMPACT to the NHANES (1999-2014) dataset, which enables us to understand different subpopulations according to shorter or longer term mortality and younger and older individuals. Our IMPACT models have higher predictive accuracy than popular pre-existing mortality risk scores and biological ages. Using individualized feature importance scores, we discover novel risk predictors (e.g., arm circumference) and interactions between risk predictors (e.g., serum chloride with age and/or gender). Furthermore, IMPACT provides a novel perspective of reference intervals and may suggest that the widely accepted reference intervals for serum albumin, mean cell volume and platelet count may in fact be sub-optimal for health. Finally, in order to ensure that our models are useful to as broad of a community as possible, we develop and publish a variety of explainable risk scores usable by individuals with and without medical expertise. The predictive accuracy of IMPACT combined with the capability of discovering mortality risk predictors and complex relationships demonstrates the value and utility of XAI in epidemiologic study design.
ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically Ill COVID-19 Patients
Authors: Karakike Eleni , Dalekos George N. , Koutsodimitropoulos Ioannis , Saridaki Maria , Pourzitaki Chryssa , Papathanakos Georgios , Kotsaki Antigone , Chalvatzis Stamatios , Dimakopoulou Vasiliki , Vechlidis Nikolaos , Paramythiotou Elisabeth , Avgoustou Christina , Ioakeimidou Aikaterini , Kouriannidi Elli , Komnos Apostolos , Neou Evangelia , Rovina Nikoletta , Stefanatou Eleni , Milionis Haralampos , Nikolaidis George , Koutsoukou Antonia , Damoraki Georgia , Dimopoulos George , Zoumpos Vassileios , Eugen-Olsen Jesper , Akinosoglou Karolina , Gatselis Nikolaos K. , Koulouras Vasilios , Gkeka Eleni , Markou Nikolaos , Netea Mihai G. , Giamarellos-Bourboulis Evangelos J.
Published: January 2021

Rationale

Macrophage activation syndrome (MAS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19.

Objective

To investigate the outcome of personalized immunotherapy in critical COVID-19.

Methods

In this open-label prospective trial, 102 patients with SOFA (sequential organ failure assessment) score ≥2 or ARDS by SARS-CoV-2 were screened for MAS (ferritin more than 4420 ng/ml) and CID (ferritin ≤4420 ng/ml and low expression of HLA-DR on CD14-monocytes). Patients with MAS and CID with increased aminotransferases were assigned to intravenous anakinra; those with CID and normal aminotransferases to tocilizumab. The primary outcome was at least 25% decrease of SOFA score and/or 50% increase of respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28; serum biomarkers and cytokine production by mononuclear cells were secondary endpoints.

Measurements and Main Results

The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (odds ratio 3.11; 95% CIs 1.29-7.73; P: 0.011). No differences were found in mortality and in SOFA score changes. By day 4, ferritin was decreased among anakinra-treated patients; interleukin (IL)-6, soluble urokinase plasminogen activator receptor (suPAR) and the expression of HLA-DR were increased among tocilizumab-treated patients. Anakinra increased capacity of mononuclear cells to produce IL-6. Survivors by day 28 who received anakinra were distributed to scales of the WHO clinical progression of lower severity. Greater incidence of secondary infections was found with tocilizumab treatment.

Conclusions

Biomarkers may guide favourable anakinra responses in critically ill patients with COVID-19.

Trial Registration

ClinicalTrials.gov, NCT04339712
Reduction of brooding and more general depressive symptoms after fMRI neurofeedback targeting a melancholic functional-connectivity biomarker
Authors: Taylor Jessica Elizabeth , Yamada Takashi , Kawashima Takahiko , Kobayashi Yuko , Yoshihara Yujiro , Miyata Jun , Murai Toshiya , Kawato Mitsuo , Motegi Tomokazu
Published: January 2021

Depressive disorders contribute heavily to global disease burden; This is possibly because patients are usually treated homogeneously, despite having heterogeneous symptoms with differing underlying neural mechanisms. On the contrary, treatment that directly influences the neural circuit relevant to an individual patient’s subset of symptoms might more precisely and thus effectively aid in the alleviation of their specific symptoms. We tested this hypothesis, using fMRI functional connectivity neurofeedback to target a neural biomarker that objectively relates to a specific subset (melancholic) of depressive symptoms and that is generalizable across independent cohorts of patients. The targeted biomarker was the functional connectivity between the left dorsolateral prefrontal cortex and left precuneus, which has been shown in a data-driven manner to be less anticorrelated in patients with melancholic depression than in healthy controls. We found that the more a participant normalized this biomarker, the more related (brooding and more general depressive), but not unrelated (trait anxiety), symptoms were reduced. Thus, one-to-one correspondence between a normalized neural network and decreased depressive symptoms was demonstrated. These results were found in two experiments that took place several years apart by different experimenters, indicating their reproducibility. Indicative of their potential clinical utility, effects remained one-two months later.
Management of conductive deafness from Otitis Media with Effusion (known as ‘glue ear’) in children using bone conduction headsets when grommet operations were unavailable during COVID-19
Authors: Brown T Holland , O’Connor Isobel Fitzgerlad , Bewick Jessica , Morley Colin
Published: January 2021

Background

Otitis Media with Effusion (OME) causing hearing impairments affects ∼1 in 10 children starting school in UK/ Europe. 80% have at least one episode with most having conductive hearing loss. Studies showed children with OME hear better with bone conducting headsets. During COVID-19 we investigated whether children with deafness secondary OME, without access to audiology or grommet surgery, could be aided with bone conduction kits and the HearGlueEar app.

Methods

Starting July 2020, during COVID-19, children aged 3-11 years with OME and on a grommet waiting list were invited to a single arm, prospective study. They received the kit, instructions and HearGlueEar app by post. By 3 weeks parents were asked to charge and pair the devices, attend a remote consultation and complete an OMQ-14 questionnaire. Remote follow-up lasted 3 months. Outcomes: ability to use the equipment, complete the questionnaire about child’s hearing and behaviour before and with the equipment, declining grommet surgery or where deafness resolved, and give opinion about the intervention.

Findings

26 children enrolled. Families used the kit at home and school. Most found remote consultations positive and convenient. OMQ-14 responses were 90% positive. Comments were: “Other people have said, wow his speech is clearer.”, “It is making a real difference at home.”, “He said over and over again, “I can hear everybody, wow, wow, wow.”, “It is no exaggeration to say this has made an astronomical improvement to his quality of life”. One child reported “I can hear my best friend again”. “She is getting on really well with the headphones - pairing them with the iPad at home is simply brilliant.” Three families continued with the headset to avoid grommets.

Interpretation

Posting a bone conduction kit, HearGlueEar app and remote consultation is effective support for children with deafness secondary to OME.

Funding

None
Data Resource Profile: thousands of circulating RNA profiles of pre-clinical samples from the Janus Serum Bank Cohort
Authors: Langseth Hilde , Umu Sinan Ugur , Bucher-Johannessen Cecilie , Babigumira Ronnie , Leithaug Magnus , Lauritzen Marianne , Vineis Paolo , Ursin Giske , Lyle Robert , Rounge Trine B
Published: January 2021

There is justified optimism regarding the use of miRNAs as early detection biomarkers of cancer. They are well characterized and are involved in all the hallmarks of cancer. Less is known about the role of most other non-coding RNA (ncRNAs) classes in normal physiology and tumorigenesis. The JanusRNA dataset consist of circulating RNA profiles of pre-clinical samples from 1631 cancer patients and 673 cancer-free controls. We studied eight cancer types including cancer of the: lung, colon, rectum, prostate, breast, testis, ovaries and gallbladder. JanusRNA has its origin from the large population-based Janus Serum Bank Cohort which consists of 318 628 Norwegians. The dataset combines information from the complete nationwide cancer registry, RNA sequencing profiles from 1631 cancer patients and 673 cancer-free controls, as well as data on lifestyle, anthropometry and biochemical measurements from national health surveys. The Janus Serum Bank is specifically suited for studies of early detection and risk biomarkers of cancer, since samples are collected nationwide over a large time span, pre-clinically and cancer occurs at different points in time after blood draw. We used a nested case-control design, selecting both cases and controls among the Janus cohort members. We restricted our selection to cases with at least one sample collected within 10 years prior to cancer diagnosis. We selected 673 cancer-free Janus participants for comparison of RNA levels with the cancer cases. The controls were frequency matched to the case group on sex, age at blood donation and date of blood donation. The JanusRNA dataset has been used to investigate the natural variation of circulating RNAs in cancer-free individuals. This data resource was also used in a study of variation in RNA expression associated with common traits like age, sex, smoking, BMI and physical activity in cancer-free individuals. RNA dynamics in lung and testicular carcinogenesis throughout a 10-year follow-up has also been studied.
Role of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 in severity of COVID-19 infection
Authors: Smieszek Sandra P. , Przychodzen Bartlomiej , Polymeropoulos Christos , Polymeropoulos Vasilios , Polymeropoulos Mihael H.
Published: January 2021

Coronaviruses remodel intracellular membranes to form specialized viral replication compartments, such as double-membrane vesicles where viral RNA genome replication takes place. Understanding the factors affecting host response is instrumental to design of therapeutics to prevent or ameliorate the course of infection.

As part of explorative tests in hospitalized patients with confirmed COVID-19 infection participating in ODYSSEY trial, we obtained samples for whole genome sequencing analysis as well as for viral genome sequencing. Based on our data, we confirm one of the strongest severity susceptibility locus thus far reported in association with severe COVID-19: 3p21.31 locus with lead variant rs73064425. We further examine the associated region. Interestingly based on LD analysis we report 3 coding mutations within one gene in the region of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1). We specifically focus on the role of FYCO1 modifiers and gain-of-function variants. We report the associations between the region and clinical characteristics in this severe set of COVID-19 patients.

We next analyzed expression profiles of FYCO1 across all 466 compounds tested. We selected only those results that showed a significant reduction of expression of FYCO1. The most significant candidate was indomethacin – an anti-inflammatory that could potentially downregulate FYCO1. We hypothesize that via its direct effects on efficiency of viral egress, it may serve as a potent therapeutic decreasing the replication and infectivity of the virus. Clinical studies will be needed to examine the therapeutic utility of indomethacin and other compounds downregulating FYCO1 in COVID-19 infection and other strains of betacoronaviruses.
Assessing the lockdown effect from excess mortalities
Authors: Weber Alexej
Published: January 2021

Background and Aims

The reported case numbers of COVID-19 are often used to estimate the growth rate of infections. We use the excess mortality instead to show the effect of most restrictive non-pharmaceutical interventions (mrNPIs) as compared to less restrictive NPIs (lrNPIs) concerning growth rate and death counts.

Methods

We estimate the COVID-19 growth rate for Austria, France, Germany, Italy, Netherlands, South Korea, Spain, Sweden, UK and USA from the excess mortality. We use the average growth rate obtained for Sweden and South Korea, the only countries with lrNPIs only, to estimate additional death numbers in the other countries, had mrNPIs not been applied.

Results

The growth rate estimated from excess mortality decreased faster for countries with mrNPIs than for Sweden and South Korea, suggesting that the mrNPIs do have a non-negligible effect. Implementing lrNPIs instead of mrNPIs results in up to 3 times higher death numbers. This is not visible when the growth rate is calculated using the reported case numbers of COVID-19 instead of the excess mortality.

Conclusion

The conclusion for the spreading of COVID-19 obtained from reported COVID-19 cases in previous studies are most likely biased. Using our method, a more realistic estimate of the growth rate is obtained. Conclusions made for the reproduction number derived from the reported case numbers, such as the apparent insignificance of mrNPIs (lockdowns), might therefore be wrong and will have to be reevaluated using the growth rates obtained with our method.
Exploring domains, clinical implications and environmental associations of a deep learning marker of biological ageing
Authors: Gialluisi Alessandro , Di Castelnuovo Augusto , Costanzo Simona , Bonaccio Marialaura , Persichillo Mariarosaria , Magnacca Sara , De Curtis Amalia , Cerletti Chiara , Donati Maria Benedetta , de Gaetano Giovanni , Capobianco Enrico , Iacoviello Licia
Published: January 2021

Deep Neural Networks (DNN) have been recently developed for the estimation of Biological Age (BA), the hypothetical underlying age of an organism, which can differ from its chronological age (CA). Although promising, these population-specific algorithms warrant further characterization and validation, since their biological, clinical and environmental correlates remain largely unexplored.

Here, an accurate DNN was trained to compute BA based on 36 circulating biomarkers in an Italian population (N=23,858; age≥35 years; 51.7% women). This estimate was heavily influenced by markers of metabolic, heart, kidney and liver function. The resulting Δage (BA-CA) significantly predicted mortality and hospitalization risk for all and specific causes. Slowed biological aging (Δage<0) was associated with higher physical and mental wellbeing, healthy lifestyles (e.g. adherence to Mediterranean diet) and higher socioeconomic status (educational attainment, household income and occupational status), while accelerated aging (Δage>0) was associated with smoking and obesity. Together, lifestyles and socioeconomic variables explained □48% of the total variance in Δage, potentially suggesting the existence of a genetic basis.

These findings validate blood-based biological aging as a marker of public health in adult Italians and provide a robust body of knowledge on its biological architecture, clinical implications and potential environmental influences.
FILER: large-scale, harmonized FunctIonaL gEnomics Repository
Authors: Kuksa Pavel P. , Gangadharan Prabhakaran , Katanic Zivadin , Kleidermacher Lauren , Amlie-Wolf Alexandre , Lee Chien-Yueh , Qu Liming , Greenfest-Allen Emily , Valladares Otto , Leung Yuk Yee , Wang Li-San
Published: January 2021

Motivation

Querying massive collections of functional genomic and annotation data, linking and summarizing the query results across data sources and data types are important steps in high-throughput genomic and genetic analytical workflows. However, accomplishing these steps is difficult because of the heterogeneity and breadth of data sources, experimental assays, biological conditions (e.g., tissues, cell types), data types, and file formats.

Results

FunctIonaL gEnomics Repository (FILER) is a large-scale, harmonized functional genomics data catalog uniquely providing: 1) streamlined access to >50,000 harmonized, annotated functional genomic and annotation datasets across >20 integrated data sources, >1,100 biological conditions/tissues/cell types, and >20 experimental assays; 2) a scalable, indexing-based genomic querying interface; 3) ability for users to analyze and annotate their own experimental data against reference datasets. This rich resource spans >17 Billion genomic records for both GRCh37/hg19 and GRCh38/hg38 genome builds. FILER scales well with the experimental (query) data size and the number of reference datasets and data sources. When evaluated on large-scale analysis tasks, FILER demonstrated great efficiency as the observed running time for querying 1000x more genomic intervals (106vs. 103) against all 7×109hg19 FILER records increased sub-linearly by only a factor of 15x. Together, these features facilitate reproducible research and streamline querying, integrating, and utilizing large-scale functional genomics and annotation data.

Availability and implementation

FILER can be 1) freely accessed athttps://lisanwanglab.org/FILER, 2) deployed on cloud or local servers (https://bitbucket.org/wanglab-upenn/FILER), and 3) integrated with other pipelines using provided scripts.

Contact

lswang@pennmedicine.upenn.edu
Effects of Task Demands on Neural Correlates of Acoustic and Semantic Processing in Challenging Listening Conditions
Authors: Devaraju Dhatri S. , Kemp Amy , Eddins David A. , Shrivastav Rahul , Chandrasekaran Bharath , Wray Amanda Hampton
Published: January 2021

Purpose

Listeners shift their listening strategies to prioritize lower-level acoustic information and higher-level semantic information in challenging listening conditions. However, the neural mechanisms underlying different strategies are unclear. The current study examined the extent to which encoding of lower-level acoustic cues is modulated by task demand and relationships with the higher-level semantic processing.

Method

Electroencephalography (EEG) was acquired while participants listened to sentences in noise that contained either higher or lower probability final words. Task difficulty was modulated by time available to process responses. Cortical tracking of speech - neural correlates of acoustic temporal envelope processing - were estimated using temporal response functions (TRFs).

Results

Task difficulty did not affect cortical tracking of temporal envelope of speech under challenging listening conditions. No correlations were observed between the cortical tracking of temporal envelope of speech and semantic processes, even after controlling for the effect of individualized signal-to-noise ratios.

Conclusions

Cortical tracking of temporal envelope of speech and semantic processing are differentially influenced by task difficulty. While increased task demands modulated higher-level semantic processing, cortical tracking of temporal envelope of speech may be influenced by task difficulty primarily when the demand is manipulated in terms of acoustic properties of the stimulus, consistent with an emerging perspective in speech perception.
Proteins observed in scalp hair from preschool children
Authors: Singhal Kratika , Leib Ryan D. , Rovnaghi Cynthia R. , Xenochristou Maria , Aghaeepour Nima , Chien Allis S. , Tam Grace K-Y. , Ruiz Monica O. , Dinakarpandian Deendayal , Anand Kanwaljeet J. S.
Published: January 2021

Early childhood experiences have long-lasting effects on subsequent mental and physical health, education, and employment. Measurement of these effects relies on insensitive behavioral signs, subjective assessments by adult observers, neuroimaging and neurophysiological studies, or remote epidemiologic outcomes. Despite intensive search, no biomarkers for developmental changes in the brain have been identified. We analyzed scalp hair from healthy children and their mothers using an unbiased proteomics platform to reveal 1368 hair proteins commonly observed in children, 1438 proteins commonly observed in mothers, and 1288 proteins observed sporadically in individual subjects. Mothers showed higher numbers of peptide spectral matches and hair proteins compared to children, with important age-related differences between mothers and children. Age-related differences were also observed in children, with differential protein expression patterns between younger (2 years and below) and older children (3-5 years). Boolean analyses showed greater conservation of hair protein patterns between mothers and their biological children as compared to mothers and unrelated children. The top 5% proteins driving population variability represent biological pathways associated with brain development, immune signaling, and stress response regulation. Non-structural proteins observed in scalp hair may include promising biomarkers to investigate the developmental changes associated with early childhood experiences.

One Sentence Summary

The non-structural proteins observed in scalp hair from preschool children show evidence for heritability, reflect biological functions such as brain development, or immune function and regulation of stress responses, and exhibit age- and sex-related differences across periods of early childhood development.
Achieving natural behavior in a robot using neurally inspired hierarchical control
Authors: Barter Joseph W. , Yin Henry H.
Published: January 2021

Terrestrial locomotion presents tremendous computational challenges on account of the enormous degrees of freedom in legged animals, and the complex and unpredictable properties of the natural environment and the effectors. Yet the nervous system can achieve locomotion with ease. Here we introduce a quadrupedal robot capable of goal-directed posture control and locomotion over rough terrain. The underlying control architecture is a hierarchical network of simple negative feedback control systems inspired by the organization of the vertebrate nervous system. Without using an internal model or feedforward planning, and without any training, our robot shows robust posture control and locomotor behavior in novel environments with unpredictable disturbances.
Analysis of the number of deaths in Brazil between 2003 and 2020 and possible inferences about the COVID-19 pandemic and history of other diseases
Authors: Sosman Lilian P. , Papa Andrés R. R.
Published: January 2021

This work explores data on the number of deaths in Brazil since the beginning of the historical series of IBGE, 2003, together with data for the period 2015-2020 of the Transparency Portal. The graphs for total deaths, deaths from violence and deaths in hospitals are discussed. The relationship between them leads to conclusions about the real dimension of the effect of COVID-19 in Brazilian society during the year 2020 and its relative importance to other diseases that had a lesser impact. Hypotheses are also made about the number of deaths in future years.
Tumor Microenvironment Alters Chemoresistance of Hepatocellular Carcinoma Through CYP3A4 Metabolic Activity
Authors: Özkan Alican , Stolley Danielle L. , Cressman Erik N. K. , McMillin Matthew , DeMorrow Sharon , Yankeelov Thomas E. , Rylander Marissa Nichole
Published: January 2021

Variations in tumor biology from patient to patient combined with the low overall survival rate of hepatocellular carcinoma (HCC) present significant clinical challenges. During the progression of chronic liver diseases from inflammation to the development of HCC, microenvironmental properties, including tissue stiffness and oxygen concentration, change over time. This can potentially impact drug metabolism and subsequent therapy response to commonly utilized therapeutics, such as doxorubicin, multi-kinase inhibitors (e.g., sorafenib), and other drugs, including immunotherapies. In this study, we utilized four common HCC cell lines embedded in 3D collagen type-I gels of varying stiffnesses to mimic normal and cirrhotic livers with environmental oxygen regulation to quantify the impact of these microenvironmental factors on HCC chemoresistance. In general, we found that HCC cells with higher baseline levels of cytochrome p450-3A4 (CYP3A4) enzyme expression, HepG2 and C3Asub28, exhibited a cirrhosis-dependent increase in doxorubicin chemoresistance. Under the same conditions, HCC cell lines with lower CYP3A4 expression, HuH-7 and Hep3B2, showed a decrease in doxorubicin chemoresistance in response to an increase in microenvironmental stiffness. This differential therapeutic response was correlated with the regulation of CYP3A4 expression levels under the influence of stiffness and oxygen variation. In all tested HCC cell lines, the addition of sorafenib lowered the required doxorubicin dose to induce significant levels of cell death, demonstrating its potential to help reduce systemic doxorubicin toxicity when used in combination. These results suggest that patient-specific tumor microenvironmental factors, including tissue stiffness, hypoxia, and CYP3A4 activity levels, may need to be considered for more effective use of chemotherapeutics in HCC patients.
Tapping into the aging brain:In vivomicrodialysis reveals mirroring pathology between preclinical models and patients with Alzheimer’s disease
Authors: Bjorkli C. , Louet C. , Flo T.H. , Hemler M. , Sandvig A. , Sandvig I.
Published: January 2021

Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal monitoring of CSF akin to methods employed in AD patients. An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Our novel push-pull microdialysis method in AD mice permitsin vivolongitudinal monitoring of dynamic changes of Aβ and tau in CSF and allows for better translational understanding of CSF biomarkers. Specifically, we demonstrate that CSF concentrations of Aβ and tau along disease progression in transgenic mice mirror what is observed in patients, with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to lumbar puncture CSF collection in patients. We furthermore provide specific recommendations for optimal application of our novel microdialysis method, such as achieving optimal recovery of analytes, which depends heavily on the flow rate of perfusion, probe properties and perfusate composition. Our approach can further advance AD research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal, and can additionally be used to administer pharmaceutical compounds and assess their efficacy in treating AD.
Dynamics of sex-biased gene expression during development in the stick insectTimema californicum
Authors: Jelisaveta Djordjevic , Zoé Dumas , Marc Robinson-Rechavi , Tanja Schwander , James Parker Darren
Published: January 2021

Abstract

Sexually dimorphic phenotypes are thought to arise primarily from sex-biased gene expression during development. Major changes in developmental strategies, such as the shift from hemimetabolous to holometabolous development, are therefore expected to have profound consequences for the dynamics of sex-biased gene expression. However, no studies have previously examined sex-biased gene expression during development in hemimetabolous insects, precluding comparisons between developmental strategies. Here we characterized sex-biased gene expression at three developmental stages in a hemimetabolous stick insect (Timema californicum): hatchlings, juveniles, and adults. As expected, the proportion of sex-biased genes gradually increased during development, mirroring the gradual increase of phenotypic sexual dimorphism. Sex-biased genes identified at early developmental stages were generally consistently male- or female-biased at later stages, suggesting their importance in sexual differentiation. Additionally, we compared the dynamics of sex-biased gene expression during development inT. californicumto those of the holometabolous flyDrosophila melanogasterby reanalyzing publicly available RNA-seq data from third instar larval, pupal and adult stages. InD. melanogaster, 84% of genes were sex-biased at the adult stage (compared to only 20% inT. californicum), and sex-biased gene expression increased abruptly at the adult stage when morphological sexual dimorphism is manifested. Our findings are consistent with the prediction that the dynamics of sex-biased gene expression during development differ extensively between holometabolous and hemimetabolous insect species.
SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
Authors: Yang Kan , Shi Yuhan , Du Xiujuan , Wang Jincheng , Zhang Yuefang , Shan Shifang , Yuan Yiting , Wang Ruoqing , Zhou Chenhuan , Liu Yuting , Cai Zilin , Wang Yanzhi , Fan Liu , Xu Huatai , Yu Juehua , Cheng Jinke , Li Fei , Qiu Zilong
Published: January 2021

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, in which core symptoms are defects of social interaction and evidently repetitive behaviors. Although around 50-70 % of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), there are some ASD patients who exhibit only core symptoms but without ID/DD, raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified ade novoheterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found thatSenp1haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex ofSenp1haploinsufficient mice. Lack ofSenp1led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by theFMR1gene, also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms ofSenp1haploinsufficient mice. Together, these results demonstrated that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which provide a candidate brain region of ASD for potential therapeutic intervene by neural modulation approaches.
The brain clock portal system: SCN-OVLT
Authors: Yao Yifan , Taub Alana , LeSauter Joseph , Silver Rae
Published: January 2021

Vascular portal systems are key structures, necessary for transporting products directly from the capillary bed of one region to the capillary bed of another region in high concentrations, without first returning to the heart. The only known portal systems in the brain is the hypophyseal-pituitary portal system, a structure necessary for survival and reproduction. Secretions from specific populations of hypothalamic neurons travel into fenestrated capillaries of the median eminence (ME) and thence drain into portal veins which break up into the secondary capillary plexus of the anterior pituitary. Neurons of the hypothalamic suprachiasmatic nucleus (SCN), locus of the brain’s master clock, also produces secretions deeply implicated in health and survival (Karatsoreos, 2019; Musiek & Holtzman, 2016). Here we describe a portal system connecting the SCN and organum vasculosum of the lamina terminalis (OVLT) - a circumventricular organ (CVO). CVOs lie around ventricles and lack a blood-brain barrier, enabling communication between the blood, brain, and cerebrospinal fluid. This “clock portal system” points to entirely new routes and targets for secreted signals, restructuring our understanding of brain communication pathways. Whether any of the remaining six CVOs in the mammalian brain bear portal systems is yet to be determined.
Sea of Electrodes Array (SEA): Extremely Dense and High-Count Silicon-Based Electrode Array Technology for High-Resolution High-Bandwidth Interfacing with 3D Neural Structures
Authors: Zardini Amin Sandoughsaz , Rostami Behnoush , Najafi Khalil , Hetrick Vaughn L. , Ahmed Omar J.
Published: January 2021

In this work, we propose a new silicon-based micro-fabrication technology to fabricate 3D high-density high-electrode-count neural micro-probe arrays scalable to thousands and even millions of individual electrodes with user-defined length, width, shape, and tip profile. This unique technology utilizes DRIE of ultra-high aspect-ratio holes in silicon and refilling them with multiple films to form thousands of individual needles with metal tips making up the “sea-of-electrodes” array (SEA). World-record density of 400 electrodes/mm2in a 5184-needle array is achieved. The needles are ~0.5-1.2mm long, <20μm wide at the base, and <1μm at the tip. The silicon-based structure of these 3D array probes with sharp tips, makes them stiff enough and easily implantable in the brain to reach a targeted region without failing. Moreover, the high aspect ratio of these extremely fine needles reduces the tissue damage and improves the chronic stability. Functionality of the electrodes is investigated using acutein vivorecording in a rat barrel field cortex under isoflurane anesthesia.
Profile hidden Markov model sequence analysis can help remove putative pseudogenes from DNA barcoding and metabarcoding datasets
Authors: Porter T. M. , Hajibabaei M.
Published: January 2021

Background

Pseudogenes are non-functional copies of protein coding genes that typically follow a different molecular evolutionary path as compared to functional genes. The inclusion of pseudogene sequences in DNA barcoding and metabarcoding analysis can lead to misleading results. None of the most widely used bioinformatic pipelines used to process marker gene (metabarcode) high throughput sequencing data specifically accounts for the presence of pseudogenes in protein-coding marker genes. The purpose of this study is to develop a method to screen for obvious pseudogenes in large COI metabarcode datasets. We do this by: 1) describing gene and pseudogene characteristics from a simulated DNA barcode dataset, 2) show the impact of two different pseudogene removal methods on mock metabarcode datasets with simulated pseudogenes, and 3) incorporate a pseudogene filtering step in a bioinformatic pipeline that can be used to process Illumina paired-end COI metabarcode sequences. Open reading frame length and sequence bit scores from hidden Markov model (HMM) profile were used to detect pseudogenes.

Results

Our simulations showed that it was more difficult to identify pseudogenes from shorter amplicon sequences such as those typically used in metabarcoding (∼300 bp) compared with full length DNA barcodes that are used in construction of barcode libraries (∼ 650 bp). It was also more difficult to identify pseudogenes in datasets where there is a high percentage of pseudogene sequences. We show that existing bioinformatic pipelines used to process metabarcode sequences already remove some apparent pseudogenes, especially in the rare sequence removal step, but the addition of a pseudogene filtering step can remove more.

Conclusions

The combination of open reading frame length and hidden Markov model profile analysis can be used to effectively screen out obvious pseudogenes from large datasets. There is more to learn from COI pseudogenes such as their frequency in DNA barcode and metabarcoding studies, their taxonomic distribution, and evolution. Thus, we encourage the submission of verified COI pseudogenes to public databases to facilitate future studies.
Large-scale analysis of interindividual variability in single and paired-pulse TMS data: results from the ‘Big TMS Data Collaboration’
Authors: Corp Daniel T. , Bereznicki Hannah G. K. , Clark Gillian M. , Youssef George J. , Fried Peter J. , Jannati Ali , Davies Charlotte B. , Gomes-Osman Joyce , Kirkovski Melissa , Albein-Urios Natalia , Fitzgerald Paul B. , Koch Giacomo , Lazzaro Vincenzo Di , Pascual-Leone Alvaro , Enticott Peter G. ,   the Big TMS Data Collaboration
Published: January 2021

Objective

Interindividual variability of single and paired-pulse TMS data has limited the clinical and experimental applicability of these methods. This study brought together over 60 TMS researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability.

Methods

118 corresponding authors provided deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and pp TMS data.

Results

687 healthy participant’s TMS data was pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual’s single pulse TMS amplitude. Baseline MEP amplitude, M1 hemisphere, and biphasic AMT significantly predicted SICI response. Baseline MEP amplitude, test stimulus intensity, interstimulus interval, monophasic RMT, monophasic AMT, and biphasic RMT significantly predicted ICF response. Age, M1 hemisphere, and TMS machine significantly predicted motor threshold.

Conclusions

This large-scale analysis has identified a number of factors influencing participants’ responses to single and paired pulse TMS. We provide specific recommendations to increase the standardisation of TMS methods within and across laboratories, thereby minimising interindividual variability in single and pp TMS data.

Highlights

687 healthy participant’s TMS data was pooled across 35 studies

Significant relationships between age and resting motor threshold

Significant relationships between baseline MEP amplitude and SICI/ICF