bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive Value of International Classification of Diseases Codes for Idiopathic Intracranial Hypertension in a University Health System
Authors: Khushzad Fareshta , Kumar Riya , Muminovic Irma , Moss Heather E.
Published: February 2022

Background:

Misclassification bias is introduced into medical claims–based research because of reliance on diagnostic coding rather than full medical record review. We sought to characterize this bias for idiopathic intracranial hypertension (IIH) and evaluate strategies to reduce it.

Methods:

A retrospective review of medical records was conducted using a clinical data warehouse containing medical records and administrative data from an academic medical center. Patients with 1 or more instances of International Classification of Diseases (ICD)-9 or -10 codes for IIH (348.2 or G93.2) between 1989 and 2017 and original results of neuroimaging (head CT or MRI), lumbar puncture, and optic nerve examination were included in the study. Diagnosis of IIH was classified as definite, probable, possible, or inaccurate based on review of medical records. The positive predictive value (PPV) for IIH ICD codes was calculated for all subjects, subjects with an IIH code after all testing was completed, subjects with high numbers of IIH ICD codes and codes spanning longer periods, subjects with IIH ICD codes associated with expert encounters (ophthalmology, neurology, or neurosurgery), and subjects with acetazolamide treatment.

Results:

Of 1,005 patients with ICD codes for IIH, 103 patients had complete testing results and were included in the study. PPV of ICD-9/-10 codes for IIH was 0.63. PPV in restricted samples was 0.82 (code by an ophthalmologist n = 57), 0.70 (acetazolamide treatment n = 87), and 0.72 (code after all testing, n = 78). High numbers of code instances and longer duration between the first and last code instance also increased the PPV.

Conclusions:

An ICD-9 or -10 code for IIH had a PPV of 63% for probable or definite IIH in patients with necessary diagnostic testing performed at a single institution. Coding accuracy was improved in patients with an IIH ICD code assigned by an ophthalmologist. Use of coding algorithms considering treatment providers, number of codes, and treatment is a potential strategy to reduce misclassification bias in medical claims–based research on IIH. However, these are associated with a reduced sample size.
Thermus brevis sp. nov., a moderately thermophilic bacterium isolated from a hot spring microbial mat
Authors: Hu Chao-Jian , Xian Wen-Dong , Luo Xiao-Qing , Liu Lan , Li Meng-Meng , Jiao Jian-Yu , Tan Sha , Zhou En-Min , Li Wen-Jun
Published: February 2022

Three closely related, facultative anaerobic, Gram-stain-negative, twitching motile, short rod-shaped, non-endospore-forming, moderately thermophilic bacteria, designated strains SYSU G05001T, SYSU G05003 and SYSU G05004, were isolated from a hot spring microbial mat, collected from Rehai National Park, Tengchong, Yunnan Province, south-western China. The results of phylogenetic analysis based on the 16S rRNA gene sequences indicated that these three strains were closely related to

Thermus scotoductus

SE-1T (97.97, 98.18, 97.90 % sequence similarity). Whole genome sequencing and polyphasic taxonomic approach were used to determine the genomic profile and taxonomic status of the novel strain SYSU G05001T. Cell growth occurred at 37–80 °C (optimum, 55 °C), pH 6.0–8.0 (optimum, pH 7.0) and with 0–3.0 % (w/v) NaCl (optimum, 1%). Thiosulfate enhanced cell growth. MK-8 was the predominant menaquinone. The major cellular fatty acids included iso-C15 : 0, iso-C17 : 0 and anteiso-C15 : 0. The major polar lipids were consisted of aminophospholipid, glycolipid and phospholipids. The whole genome of strain SYSU G05001T consisted of 2.55 Mbp and the DNA G+C content was 64.94 mol%. The average nucleotide identity (≤94.95 %) and digital DNA–DNA hybridization (≤62.3 %) values between strain SYSU G05001T and other members of the genus

Thermus

were all lower than the threshold values recommended for distinguishing novel prokaryotic species. On the basis of the presented polyphasic evidence and genotypic data, it is proposed that strain SYSU G05001T (=KCTC 82627T=MCCC 1K06118T) represents a novel species of the genus

Thermus

, for which the name Thermus brevis sp. nov. is proposed.
The impact of working during the Covid-19 pandemic on health care workers and first responders: mental health, function, and professional retention
Authors: Hendrickson Rebecca C. , Slevín Roisin A. , Chang Bernard P. , Sano Ellen , McCall Catherine , Raskind Murray A.
Published: February 2022

Background

The COVID-19 pandemic has greatly affected front line health care workers (HCW) and first responders (FR). The infection risk from SARS CoV-2, the high mortality of hospitalized COVID-19 patients and the duration of the pandemic have created sustained and often traumatic stressors affecting HCW and FR.

Objectives

To assess the relationship of COVID-19 stressor frequency scores to psychiatric rating scale scores amongst HCW and FR. To determine if psychiatric rating scale scores mediate stressor effects on perceived work function and likelihood of remaining in current occupation.

Design

Observational, self-report in a convenience sample.

Participants

118 HCW and FR caring for COVID-19 patients in the United States.

Main Measure

COVID-19 related stressor frequencies were assessed using a 17-item questionnaire. Psychiatric symptoms were assessed with the PTSD Checklist 5 (PCL5), the Patient Health Questionnaire 9 (for depression) (PHQ9), the Insomnia Severity Index (ISI), and the General Anxiety Disorder 7 (GAD7).

Key Results

Stressor frequency scores correlated significantly with PCL5 scores (R=.57, p<1e-8), PHQ scores (R=.35, P<.001), ISI scores (R=.38, p<1e-4), and GAD7 scores (R=.39, p<.001), likelihood of staying in current occupation (R=-.39,p<1e-4), and trouble doing usual work (R=.33,p<.001). 51% of HCW and 44% of FR indicated decreased likelihood of staying in their current occupation. PCL5 scores substantially mediated the association between stress frequency scores and work function impairment.

Conclusions

These results direct attention to recognizing potentially treatable psychiatric symptoms, particularly those of PTSD, in HCW and FR experiencing COVID-19 related stressors. They also suggest that mitigating COVID-19 related stressors when possible, such as by providing adequate personal protective equipment, can improve HCW and FR mental health, work function and retention in the health care work force.

Strengths and Limitations of this Study

Detailed assessments of participants’ exposure to covid-19 related occupational stressors, current psychiatric symptoms, and self-reported occupational functioning and likelihood of remaining in their current field (functional outcomes).

Assessment of the dose-response relationship between exposure to covid-19 related occupational stressors and current psychiatric symptoms and functional outcomes.

Mediation analysis quantifying the potential for current psychiatric symptoms to mediate the relationship between exposure to covid-19 related occupational stressors and functional outcomes.

Limitations: convenience sample, limited numbers of first responder participants
Pooling for SARS-CoV2 Surveillance: Validation and Strategy for Implementation in K-12 Schools
Authors: Simas Alexandra M. , Crott Jimmy W. , Sedore Chris , Rohrbach Augusta , Monaco Anthony P. , Gabriel Stacey B. , Lennon Niall , Blumenstiel Brendan , Genco Caroline A.
Published: February 2022

Repeated testing of a population is critical for limiting the spread of the SARS-CoV-2 virus and for the safe reopening of educational institutions such as K-12 schools and colleges. Many screening efforts utilize the CDC RT-PCR based assay which targets two regions of the novel Coronavirus nucleocapsid gene. The standard approach of testing each person individually, however, poses a financial burden to these institutions and is therefore a barrier to using testing for re-opening. Pooling samples from multiple individuals into a single test is an attractive alternate approach that promises significant cost savings - however the of specificity and sensitivity of such approaches needs to be assessed prior to deployment. To this end, we conducted a pilot study to evaluate the feasibility of analyzing samples in pools of eight by the established RT-PCR assay. Participants (1,576) were recruited from amongst the Tufts University community undergoing regular screening. Each volunteer provided two swabs, one analyzed separately and the other in a pool of eight. Because the positivity rate was very low, we spiked approximately half of the pools with laboratory-generated swabs produced from known positive cases outside the Tufts testing program. The results of pooled tests had 100% correspondence with those of their respective individual tests. We conclude that pooling eight samples does not negatively impact the specificity or sensitivity of the RT-PCR assay and suggest that his approach can be utilized by institutions seeking to reduce surveillance costs.
Prevalence Of Multi Drug Resistant Bacteria On Environmental And Medical Device Surfaces Of Korea Nepal Friendship Hospital
Authors: Paudel Nisha , Awasthi Nagendra Prasad , Lekhak Binod , Acharya Amrit
Published: February 2022

The microbial monitoring of environmental and medical-devices’ surface is used to evaluate efficacy of routine cleaning and disinfection practises and to detect the presence of specific Nosocomial Pathogens. The prevalence of Multidrug Resistance organisms in hospital premises projects serious problems in transmitting to susceptible hosts which is difficult to treat. A cross sectional descriptive research was conducted from December 2016 to June 2017 at the pathology laboratory of Korea Nepal Friendship Hospital (KNFH). A total 140 samples were considered, encompassing the medical devices of the hospital (100), housekeeping surfaces (15) and air (25). Susceptibility test for bacterial isolates was done by disk diffusion assay. Of the total 140 samples taken and analysed, 100% showed growth positivity. In most of the swabs taken, Coagulase Negative Staphylococci was dominant, followed by Staphylococcus aureus, Streptococcus spp. Micrococcus spp., E coli, Pseudomonas spp., Bacillus spp., Acinetobacter spp., Klebsiella spp., Fungi, and least Proteus spp. The dry surfaces were dominantly contaminated by gram positive bacteria whereas moistened surfaces like wash basin were contaminated by gram negative as well as gram positive bacteria. Total 277 strains were exposed to various class of antibiotics, among the gram positive environmental isolates, Coagulase Negative Staphylococci 16 (34.78%) had highest MDR prevalence followed by Staphylococcus aureus 8 (29.62%), Streptococcus spp. 4 (12.90%), Micrococcus spp. 4 (9.30%) and no MDR was shown by any Bacillus spp isolates. Whereas, in case of gram negative, Klebsiella spp. 6 (35.29%) had highest MDR prevalence

followed by Acinetobacter spp. 6 (31.57%), E. coli 8 (27.58%), Pseudomonas spp. 4 (18.18%), and lastly Proteus spp. with no MDR at all. The thick dirt covering the cotton swabs and heavy microbial load on them has displayed not only disinfecting practice but also cleaning practice is missing. Heavy contamination shows possible NIs breakout, it’s important to have routine microbial assessment with standard protocol and find ways to decrease its load.
Exploring facilitators for a transition from alternative and complementary therapies to evidence-based treatments in Ugandan first-episode psychosis patients
Authors: Mwesiga Emmanuel K. , Ssemata Andrew S. , Nakitende Ann Jacquelline , Ongeri Linnet , Semeere Aggrey , Loewy Rachel , Meffert Susan , Nakasujja Noeline
Published: February 2022

Introduction

Most patients with psychotic disorders in Africa initially use alternative and complementary therapies leading to delays accessing evidence-based treatments. This delay, known as the duration of untreated psychosis (DUP), is associated with suboptimal response and reduced efficacy in short-term and long-term outcomes. In this study, we explore facilitators for transitioning from alternative and complementary therapies to evidence-based treatments for psychotic disorders, comparing these facilitators between patients and their caregivers.

Methods

The study was conducted at Butabika hospital in Kampala, Uganda. Participants included patients with first-episode psychosis who had used alternative and complementary therapies and their caregivers. An exploratory qualitative design using in-depth interviews was performed with thematic analysis used to analyze the data.

Results

We interviewed eight patients and eight caregivers. The key themes that led to a switch were the high cost of alternative therapies, a desire to know the cause of the illness, seeking better care and the influence of friends and community members. Themes were similar among the participants and their caregivers except for stigma, which was only found among the caregivers.

Conclusions

The reasons for transitioning from alternative and complementary therapies to evidence-based treatments are similar between patients and caregivers, except for stigma that is a more important factor for transition among caregivers. Since this was an exploratory study, additional research with a larger sample and more diverse population would enable a deeper understanding of these factors and guide the development of interventions to reduce DUP and improve outcomes for psychotic disorders.
SARS-CoV-2 RNA wastewater settled solids surveillance frequency and impact on predicted COVID-19 incidence using a distributed lag model
Authors: Schoen Mary E. , Wolfe Marlene K. , Li Linlin , Duong Dorothea , White Bradley J. , Hughes Bridgette , Boehm Alexandria B.
Published: February 2022

SARS-CoV-2 RNA concentrations in wastewater settled solids correlate well with COVID-19 incidence rates (IRs). Here, we develop distributed lag models (DLMs) to estimate IRs using concentrations of SARS-CoV-2 RNA from wastewater solids and investigate the impact of sampling frequency on model performance. SARS-CoV-2 N gene and PMMoV RNA concentrations were measured daily at four wastewater treatment plants in California. Artificially reduced datasets were produced for each plant with sampling frequencies of once every 2, 3, 4, and 7 days. Sewershed-specific models that related daily N/PMMoV to IR were fit for each sampling frequency with data from mid-Nov 2020 through mid-July 2021, which included the period of time during which Delta emerged. Models were used to predict IRs during a subsequent out-of-sample time period. When sampling occurred at least once every 4 days, the in- and out-of-sample root mean square error (RMSE) changed less than 7 cases/100,000 compared to daily sampling across sewersheds. This work illustrates that real-time, daily predictions of IR are possible with small error, despite changes in circulating variants, when sampling frequency is once every 4 days or more. However, reduced sampling frequency may not serve other important wastewater surveillance use cases.
Discovery and functional interrogation of SARS-CoV-2 protein-RNA interactions
Authors: Xiang Joy S. , Mueller Jasmine R. , Luo En-Ching , Yee Brian A. , Schafer Danielle , Schmok Jonathan C. , Tan Frederick E. , Rothamel Katherine , McVicar Rachael N. , Kwong Elizabeth M. , Jones Krysten L. , Her Hsuan-Lin , Chen Chun-Yuan , Vu Anthony Q. , Jin Wenhao , Park Samuel S. , Le Phuong , Brannan Kristopher W. , Kofman Eric R. , Li Yanhua , Tankka Alexandra T. , Dong Kevin D. , Song Yan , Carlin Aaron F. , Van Nostrand Eric L. , Leibel Sandra L. , Yeo Gene W.
Published: February 2022

The COVID-19 pandemic is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The betacoronvirus has a positive sense RNA genome which encodes for several RNA binding proteins. Here, we use enhanced crosslinking and immunoprecipitation to investigate SARS-CoV-2 protein interactions with viral and host RNAs in authentic virus-infected cells. SARS-CoV-2 proteins, NSP8, NSP12, and nucleocapsid display distinct preferences to specific regions in the RNA viral genome, providing evidence for their shared and separate roles in replication, transcription, and viral packaging. SARS-CoV-2 proteins expressed in human lung epithelial cells bind to 4773 unique host coding RNAs. Nine SARS-CoV-2 proteins upregulate target gene expression, including NSP12 and ORF9c, whose RNA substrates are associated with pathways in protein N-linked glycosylation ER processing and mitochondrial processes. Furthermore, siRNA knockdown of host genes targeted by viral proteins in human lung organoid cells identify potential antiviral host targets across different SARS-CoV-2 variants. Conversely, NSP9 inhibits host gene expression by blocking mRNA export and dampens cytokine productions, including interleukin-1α/β. Our viral protein-RNA interactome provides a catalog of potential therapeutic targets and offers insight into the etiology of COVID-19 as a safeguard against future pandemics.
An in-silico study of the mutation-associated effects on the spike protein of SARS-CoV-2, Omicron variant
Authors: Shishir Tushar Ahmed , Jannat Taslimun , Naser Iftekhar Bin
Published: February 2022

The emergence of Omicron (B.1.1.529), a new Variant of Concern in the COVID-19 outbreak, while accompanied by the ongoing Delta variant infection, has once again fueled fears of a new infection wave and global health concern. In the Omicron variant, the receptor-binding domain (RBD) of its spike glycoprotein is heavily mutated, a feature critical for the transmission rate of the virus by interacting with hACE2. In this study, we used a combination of conventional and advanced neural network-based in silico approaches to predict how these mutations would affect the spike protein. The results demonstrated a decrease in the electrostatic potentials of residues corresponding to receptor recognition sites, an increase in the alkalinity of the protein, a change in hydrophobicity, variations in functional residues, and an increase in the percentage of alpha-helix structure. Our next step was to predict the structural changes of the spike protein using the AI-based tool Alphafold2 and dock it with hACE2. The results revealed that the RBD of the Omicron variant had a higher affinity than the reference. Moreover, all-atom molecular dynamics simulations concluded that the RBD of the Omicron variant exhibits a more dispersed interaction network since mutations resulted in an increased number of hydrophobic interactions and hydrogen bonds with hACE2 compared to the reference RBD. In summary, our current study highlighted the potential structural basis for the enhanced transmissibility and pathogenicity of the Omicron variant, although further research is needed to investigate its epidemiological and biological implications.
Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population
Authors: Humphries Elizabeth M. , Ahn Kwangmi , Kember Rachel L. , Lopes Fabiana L. , Mocci Evelina , Peralta Juan M. ,   Bipolar Sequencing Consortium, Blangero John , Glahn David C. , Goes Fernando S. , Zandi Peter P. , Kochunov Peter , Van Hout Cristopher , Shuldiner Alan R. , Pollin Toni I. , Mitchell Braxton D. , Bucan Maja , Hong L. Elliot , McMahon Francis J. , Ament Seth A.
Published: February 2022

Background

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants.

Methods

We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n=1,672).

Results

Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n=314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors,CUX1andCNOT1.

Conclusions

Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.
Impact of key meteorological parameters on the spread of COVID-19 in Mumbai: Correlation and Regression Analysis
Authors: Shetty Sushant , Gawade Amit , Deolekar Subodh , Patil Vaishali , Pandharkar Rohit , Salunkhe Uday
Published: February 2022

Purpose

To understand key meteorological parameters that influence the spread of COVID-19 in Mumbai, India (based on data from April 2020 – April 2021).

Methods

The meteorological parameters chosen were Temperature, Dew Temperature, Humidity, Pressure, Wind Speed. The underlying basic relationships between meteorological parameters and COVID-19 information for Mumbai was understood using Spearman’s rank correlation coefficients. After establishing basic relationships, Linear analysis and Generalized Additive Model’s (GAM) were used to figure out statistically significant weather parameters and model them to explain the best possible variance in the pandemic data.

Results

A model of temperature and windspeed could explain 17.3% and 8.3% of variance in Daily new cases and Daily recoveries respectively. As for deaths occurring due to the virus, a model comprising of only pressure best explains a variance of 17.3% in the data. Non-Linear modelling based on GAM confirms the findings of linear analysis and establishes certain non-linear relationships as well.

Conclusion

SARS-CoV-2 belongs to the class of Human Coronaviruses (HCoV) which show seasonality depending on weather conditions. The above article focuses on understanding the underlying relationships between SARS-CoV-2 and meteorological parameters that would help progress basic research and formulation of policies around the disease for each weather/season.

Competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Patterns of connectome variability in autism across five functional activation tasks. Findings from the LEAP project
Authors: Looden Tristan , Floris Dorothea L. , Llera Alberto , Chauvin Roselyne J. , Charman Tony , Banaschewski Tobias , Murphy Declan , Marquand Andre. F. , Buitelaar Jan K. , Beckmann Christian F. ,   the AIMS-2-TRIALS group
Published: February 2022

Background

Autism spectrum disorder (autism) is a complex neurodevelopmental condition with pronounced behavioural, cognitive, and neural heterogeneities across individuals. Here, our goal was to characterise heterogeneity in autism by identifying patterns of neural diversity as reflected in BOLD fMRI in the way individuals with autism engage with a varied array of cognitive tasks.

Methods

All analyses were based on the EU-AIMS/AIMS-2-TRIALS multisite Longitudinal European Autism Project (LEAP) with participants with autism and typically developing controls (TD) between 6 and 30 years of age. We employed a novel task-potency approach which combines the unique aspects of both resting-state fMRI and task-fMRI to quantify task-induced variations in the functional connectome. Normative modelling was used to map atypicality of features on an individual basis with respect to their distribution in neurotypical control participants. We applied robust out-of-sample canonical correlation analysis (CCA) to relate connectome data to behavioural data.

Results

Deviation from the normative ranges of global functional connectivity was greater for individuals with autism compared to TD in each fMRI task paradigm (all tasks p<0.001). The similarity across individuals of the deviation pattern was significantly increased in autistic relative to TD individuals (p<0.002). The CCA identified significant and robust brainbehavior covariation between functional connectivity atypicality and autism-related behavioral features.

Conclusions

Individuals with autism engage with tasks in a globally atypical way, but the particular spatial pattern of this atypicality is nevertheless similar across tasks. Atypicalities in the tasks originate mostly from prefrontal cortex and default mode network regions, but also speech and auditory networks. We show, moving forward, sophisticated modeling methods such as task-potency and normative modeling will prove key to unravelling complex heterogeneous conditions like autism.
Deep learning-based system for real-time behavior recognition and closed-loop control of behavioral mazes using depth sensing
Authors: Gerós Ana , Cruz Ricardo , de Chaumont Fabrice , Cardoso Jaime S. , Aguiar Paulo
Published: February 2022

Robust quantification of animal behavior is fundamental in experimental neuroscience research. Systems providing automated behavioral assessment are an important alternative to manual measurements avoiding problems such as human bias, low reproducibility and high cost. Integrating these tools with closed-loop control systems creates conditions to correlate environment and behavioral expressions effectively, and ultimately explain the neural foundations of behavior. We present an integrated solution for automated behavioral analysis of rodents using deep learning networks on video streams acquired from a depth-sensing camera. The use of depth sensors has notable advantages: tracking/classification performance is improved and independent of animals’ coat color, and videos can be recorded in dark conditions without affecting animals’ natural behavior. Convolutional and recurrent layers were combined in deep network architectures, and both spatial and temporal representations were successfully learned for a 4- classes behavior classification task (standstill, walking, rearing and grooming). Integration with Arduino microcontrollers creates an easy-to-use control platform providing low-latency feedback signals based on the deep learning automatic classification of animal behavior. The complete system, combining depth-sensor camera, computer, and Arduino microcontroller, allows simple mapping of input-output control signals using the animal’s current behavior and position. For example, a feeder can be controlled not by pressing a lever but by the animal behavior itself. An integrated graphical user interface completes a user-friendly and cost-effective solution for animal tracking and behavior classification. This open-software/open-hardware platform can boost the development of customized protocols for automated behavioral research, and support ever more sophisticated, reliable and reproducible behavioral neuroscience experiments.
A model of colour appearance based on efficient coding of natural images
Authors: Troscianko Jolyon , Osorio Daniel
Published: February 2022

An object’s colour, brightness and pattern are all influenced by its surroundings, and a number of visual phenomena and “illusions” have been discovered that highlight these often dramatic effects. Explanations for these phenomena range from low-level neural mechanisms to high-level processes that incorporate contextual information or prior knowledge. Importantly, few of these phenomena can currently be accounted for when measuring an object’s perceived colour. Here we ask to what extent colour appearance is predicted by a model based on the principle of coding efficiency. The model assumes that the image is encoded by noisy spatio-chromatic filters at one octave separations, which are either circularly symmetrical or oriented. Each spatial band’s lower threshold is set by the contrast sensitivity function, and the dynamic range of the band is a fixed multiple of this threshold, above which the response saturates. Filter outputs are then reweighted to give equal power in each channel for natural images. We demonstrate that the model fits human behavioural performance in psychophysics experiments, and also primate retinal ganglion responses. Next we systematically test the model’s ability to qualitatively predict over 35 brightness and colour phenomena, with almost complete success. This implies that contrary to high-level processing explanations, much of colour appearance is potentially attributable to simple mechanisms evolved for efficient coding of natural images, and is a basis for modelling the vision of humans and other animals.
Anatomy of the heart of the leatherback turtle
Authors: Jensen Bjarke , Lauridsen Henrik , Webb Grahame , Wang Tobias
Published: February 2022

Non-crocodylian reptiles have hearts with a single ventricle, which is partially separated by a muscular ridge that provide some separation of blood flows. An exceptional situation exists in monitor lizards and pythons, where the ventricular left side generates a much higher systolic blood pressure than the right side, thus resembling mammals and birds. This functional division of the ventricle depends on a large muscular ridge and may relate to high metabolic demand. The large leatherback turtle (<1000 kg), with its active ocean-going lifestyle and elevated body temperatures, may have similar adaptations. Here, we report on the anatomy the hearts of two leatherback turtles. One stranded in Ballum, Denmark in 2020, and was examined in detail, supplemented by observations and photos of an additional stranding specimen from Canada. The external morphology of the leatherback heart resembles that of other turtles, but it is large. We made morphometric measurements of the Ballum heart and created an interactive 3D model using high resolution MRI. The volume of the ventricle was 950 ml, from a turtle of 300 kg, which is almost twice as large as in other reptiles. The Ballum heart was compared to MRI scans of the hearts of a tortoise, a python, and a monitor lizard. Internally, the leatherback heart is typical of non-crocodylian reptiles, and did not contain the well-developed septation found in pythons and monitor lizards. We conclude that if leatherback turtles have exceptional circulation needs, they are sustained with a relatively large but otherwise typical non-crocodylian reptile heart.
Characterization of various remdesivir-resistant mutations of SARS-CoV-2 by mathematical modeling and molecular dynamics simulation
Authors: Torii Shiho , Kim Kwang Su , Koseki Jun , Suzuki Rigel , Iwanami Shoya , Fujita Yasuhisa , Jeong Yong Dam , Matsuura Yoshiharu , Shimamura Teppei , Iwami Shingo , Fukuhara Takasuke
Published: February 2022

Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.

Significance Statement

Considering the emerging Omicron strain, quick characterization of SARS-CoV-2 mutations is important. However, owing to the difficulties in genetically modifying SARS-CoV-2, limited groups have produced multiple mutant viruses. Our cutting-edge reverse genetics technique enabled construction of eight reporter-carrying mutant SARS-CoV-2 in this study. We developed a mathematical model taking into account sequential changes and identified antiviral effects against mutant viruses with differing propagation capacities and lethal effects on cells. In addition to identifying the positions of mutations, we analyzed the structural changes in SARS-CoV-2 NSP12 by computer simulation to understand the mechanism of resistance. This multidisciplinary approach promotes the evaluation of future resistance mutations.
Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis
Authors: Sun Mengyi , Zhang Jianzhi
Published: February 2022

A commonly stated cause of the widespread phenomenon of unequal uses of synonymous codons is their differential translational accuracies. However, this long-standing translational accuracy hypothesis (TAH) of codon usage bias has had no direct evidence beyond anecdotes. Analyzing proteomic data from Escherichia coli, we observe higher translational accuracies of more frequently used synonymous codons, offering direct, global evidence for the TAH. The experimentally measured codon-specific translational accuracies validate a sequence-based proxy; this proxy provides support for the TAH from the vast majority of over 1000 taxa surveyed in all domains of life. We find that the relative translational accuracies of synonymous codons vary substantially among taxa and are strongly correlated with the amounts of cognate tRNAs relative to those of near-cognate tRNAs. These and other observations suggest a model in which selections for translational efficiency and accuracy drive codon usage bias and its coevolution with the tRNA pool.
MetaboListem and TABoLiSTM: Two Deep Learning Algorithms for Metabolite Named Entity Recognition
Authors: Yeung Cheng S. , Beck Tim , Posma Joram M.
Published: February 2022

Reviewing the metabolomics literature is becoming increasingly difficult because of the rapid expansion of relevant journal literature. Text-mining technologies are therefore needed to facilitate more efficient literature review. Here we contribute a standardised corpus of full-text publications from metabolomics studies and describe the development of two new metabolite named entity recognition (NER) methods. We introduce two deep learning methods for metabolite NER based on Bidirectional Long Short-Term Memory (BiLSTM) networks incorporating different transfer learning techniques. Our first model (MetaboListem) follows prior methodology using GloVe word embeddings. Our second model exploits BERT and BioBERT for embedding and is named TABoLiSTM (Transformer-Affixed BiLSTM). The methods are trained on a novel corpus annotated using rule-based methods, and evaluated on manually annotated metabolomics articles. MetaboListem (F1 score 0.890, precision 0.892, recall 0.888) and TABoLiSTM (BioBERT version: F1 score 0.909, precision 0.926, recall 0.893) have achieved state-of-the-art performance on metabolite NER. A corpus with >1,200 full-text Open Access metabolomics publications and >116,000 annotated metabolites was created. This work demonstrates that deep learning algorithms are capable of identifying metabolite names accurately and efficiently in text. The proposed corpus and NER algorithms can be used for metabolomics text-mining tasks such as information retrieval, document classification and literature-based discovery.

Availability

The corpus and NER algorithms are freely available with detailed instructions from Github at https://github.com/omicsNLP/MetaboliteNER.
Wide-field Calcium Imaging Reveals Widespread Changes in Cortical Connectivity Following Repetitive, Mild Traumatic Brain Injury in the Mouse
Authors: Cramer Samuel W. , Haley Samuel P. , Popa Laurentiu S. , Carter Russell E. , Scott Earl , Flaherty Evelyn B. , Dominguez Judith , Aronson Justin D. , Sabal Lukas , Surinach Daniel , Chen Clark C. , Kodandaramaiah Suhasa B. , Ebner Timothy J.
Published: February 2022

The physiologic basis underlying the long-term consequences of repetitive, mild traumatic brain injury (mTBI) remains poorly understood. Mild traumatic brain injury often results in brief loss of consciousness, impaired attention and concentration, memory problems, impulsivity, and headache, without objective findings on clinical imaging or examination. The effects of mTBI can persist and become cumulative with repetitive injury, suggesting global alterations in cortical networks. Using transparent polymer skulls, we performed mesoscopic Ca2+ imaging in mice to evaluate how repetitive mTBI alters patterns of neuronal interactions across the dorsal cerebral cortex. Spatial Independent Component Analysis (sICA) and Localized semi-Nonnegative Matrix Factorization (LocaNMF) were used to quantify changes in cerebral functional connectivity (FC). Repetitive, mild, controlled cortical impacts induce temporary neuroinflammatory responses, characterized by increased density of microglia exhibiting de-ramified morphology. These temporary neuro-inflammatory changes were not associated with compromised cognitive performance in the Barnes maze or motor function as assessed by rotarod. However, long-term alterations in functional connectivity were observed. Widespread, bilateral changes in FC occurred immediately following impact and persisted for up to 7 weeks, the duration of the experiment. Network alterations include decreases in global efficiency, clustering coefficient, and nodal strength, thereby disrupting functional interactions and information flow throughout the dorsal cerebral cortex. A subnetwork analysis shows the largest disruptions in FC were concentrated near the impact site. Therefore, repetitive mTBI induces a transient neuroinflammation, without alterations in cognitive or motor behavior, and a reorganized cortical network evidenced by the widespread, chronic alterations in cortical FC.

Significance Statement

More than 2.5 million individuals in the United States suffer minor traumatic brain injuries annually. Because these injuries are typically not associated with visible anatomic injuries or objective clinical findings, they were thought benign and fully recoverable. However, there is increasing awareness of the long-term deleterious consequences, particularly in patients who suffer repeated mTBI. Using long-term, mesoscopic neuronal Ca2+ imaging to characterize the dorsal cerebral cortical connectome following repetitive mTBI, we show extensive, persistent changes in functional connectivity, not only at the site of injury but throughout the cortex. These findings provide new insights into the pathophysiology of mTBI.
First passage time analysis of spatial mutation patterns reveals evolutionary dynamics of pre-existing resistance in colorectal cancer
Authors: Haughey Magnus J. , Bassolas Aleix , Sousa Sandro , Baker Ann-Marie , Graham Trevor A. , Nicosia Vincenzo , Huang Weini
Published: February 2022

The footprint left by early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how therapy resistant sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dynamics to the resulting spatial architecture of the tumour. Here, we propose a framework using first passage times of random walks to quantify the complex spatial patterns of tumour cell population mixing. First, using a toy model of cell mixing we demonstrate how first passage time statistics can distinguish between different pattern structures. We then apply our method to simulated patterns of wild-type and mutated tumour cell population mixing, generated using an agent-based model of expanding tumours, to explore how first passage times reflect mutant cell replicative advantage, time of emergence and strength of cell pushing. Finally, we analyse experimentally measured patterns of genetic point mutations in human colorectal cancer, and estimate parameters of early sub-clonal dynamics using our spatial computational model. We uncover a wide range of mutant cell replicative advantages and timings, with the majority of sampled tumours consistent with boundary driven growth or short-range cell pushing. By analysing multiple sub-sampled regions in a small number of samples, we explore how the distribution of inferred dynamics could inform about the initial mutational event. Our results demonstrate the efficacy of first passage time analysis as a new methodology for quantifying cell mixing patterns in vivo, and suggest that patterns of sub-clonal mixing can provide insights into early cancer dynamics.
Recombination smooths the time-signal disrupted by latency in within-host HIV phylogenies
Authors: Castro Lauren A. , Leitner Thomas , Romero-Severson Ethan
Published: February 2022

Within-host HIV evolution involves latency and re-activation of integrated provirus that has the potential to disrupt the temporal signal induced by the evolutionary race between host immune responses and viral evolution. Yet, within-host HIV phylogenies tend to show clear, ladder-like trees structured by the time of sampling. Recombination complicates this dynamic by allowing latent HIV viruses to re-integrate as fragments in the genomes of contemporary virus populations. That is, recombination violates the fundamental assumption made by the phylogenetic methods typically used to study within-host HIV sequence data that evolutionary history can be represented by a single bifurcating tree. In this paper we develop a coalescent-based simulator of within-host HIV evolution that includes, latency, recombination, and population dynamics that allows us to study the relationship between the true, complex genealogy of within-host HIV, encoded as an Ancestral Recombination Graph (ARG), and the observed phylogenetic tree. We show how recombination recovers the disruption of the temporal signal of within-host HIV evolution caused by latency by mixing fragments of ancestral, latent genomes into the contemporary population through recombination. In effect, recombination averages over extant heterogeneity, whether it stems from mixed time-signals or population bottlenecks. Further, we establish that the signals of latency and recombination can be observed in phylogenetic trees despite being an incorrect representation of the true evolutionary history. Using an Approximate Bayesian Computation method, we develop a set of statistical probes to tune our simulation model to nine longitudinally-sampled within-host HIV phylogenies, finding evidence for recombination rates at the lower end of published estimates and relatively small latent pool sizes ranging from about 1000 to 2500 cells.
Myopia alters the structural organization of the retinal astrocyte template, associated vasculature and ganglion layer thickness
Authors: Lin Carol , Toychiev Abduqodir , Slavi Nefeli , Ablordeppey Reynolds , Srinivas Miduturu , Benavente-Perez Alexandra
Published: February 2022

Purpose

To describe the effect of myopic eye growth on the structure and distribution of astrocytes, vasculature and ganglion cell thickness, critical for inner retinal tissue homeostasis and survival.

Methods

Astrocyte and capillary distribution, retinal nerve fiber (RNFL) and ganglion cell layer (GCL) thicknesses were assessed using immunochemistry and spectral domain optical coherence tomography on eleven retinas of juvenile common marmosets (Callithrix Jacchus), six of which were induced with lens-induced myopia (refraction, Rx: −7.01±1.8D). Five untreated age-matched juvenile marmoset retinas were used as controls (Rx: −0.74±0.4D).

Results

As control marmoset eyes grew normally, there was an age-related increase in astrocyte numbers associated with RNFL thickening. Marmosets with induced myopia did not show this trend and, on the contrary, had reduced astrocyte numbers, increased positive GFAP immunopositive staining, thinner RNFL, lower peripheral capillary branching, and increased numbers of string vessels.

Conclusion

The myopic changes in retinal astrocytes, vasculature, and ganglion cell layer thickness suggest a reorganization of the astrocyte and vascular templates during myopia development and progression. Whether these adaptations are beneficial or harmful to the retina remains to be investigated.

Summary Statement

This article provides new information on how progressive myopia affects key elements of the retinal neurovascular unit.
PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
Authors: Lakhia Ronak , Ramalingam Harini , Chang Chun-Mien , Cobo-Stark Patricia , Biggers Laurence , Flaten Andrea , Alvarez Jesus , Valencia Tania , Wallace Darren P. , Lee Edmund , Patel Vishal
Published: February 2022

Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation ensues when the PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are cis-repressed via their 3’-UTR miR-17 binding element. Eliminating this motif (Pkd1Δ17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also autoinhibited via its 3’-UTR miR-17 motif, and Pkd2Δ17-induced Polycystin-2 derepression partly compensates and retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, PKD1Δ17 or PKD2Δ17 alleles revert cyst-pathogenic sequala in patient-derived primary ADPKD cultures. Thus, evading 3’-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.
Long read mitochondrial genome sequencing using Cas9-guided adaptor ligation
Authors: Vandiver Amy R. , Pielstick Brittany , Gilpatrick Timothy , Hoang Austin N. , Vernon Hillary J. , Wanagat Jonathan , Timp Winston
Published: February 2022

The mitochondrial genome (mtDNA) is an important source of disease-causing genetic variability, but existing sequencing methods limit understanding, precluding phased measurement of mutations and clear detection of large sporadic deletions. We adapted a method for amplification-free sequence enrichment using Cas9 cleavage to obtain full length nanopore reads of mtDNA. We then utilized the long reads to phase mutations in a patient with an mtDNA-linked syndrome and demonstrated that this method can map age-induced mtDNA deletions. We believe this method will offer deeper insight into our understanding of mtDNA variation.