bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of an artificial intelligence-based smartphone app for guided reading of SARS-CoV-2 lateral-flow immunoassays
Authors: Bermejo-Peláez David , Marcos-Mencía Daniel , Álamo Elisa , Pérez-Panizo Nuria , Mousa Adriana , Dacal Elena , Lin Lin , Vladimirov Alexander , Cuadrado Daniel , Mateos-Nozal Jesús , Galán Juan Carlos , Romero-Hernández Beatriz , Cantón Rafael , Luengo-Oroz Miguel , Rodríguez-Domínguez Mario
Published: February 2022

Objectives

To evaluate an artificial intelligence-based smartphone application to automatically and objectively read rapid diagnostic test (RDT) results and assess its impact on COVID-19 pandemic management.

Methods

Overall, 252 human sera from individuals with PCR-positive SARS-CoV-2 infection were used to inoculate a total of 1165 RDTs for training and validation purposes. We then conducted two field studies to assess the performance on real-world scenarios by testing 172 antibody RDTs at two nursing homes and 92 antigen RDTs at one hospital emergency department.

Results

Field studies demonstrated high levels of sensitivity (100%) and specificity (94.4%, CI 92.8-96.1%) for reading IgG band of COVID-19 antibodies RDTs compared to visual readings from health workers. Sensitivity of detecting IgM test bands was 100% and specificity was 95.8%, CI 94.3-97.3%. All COVID-19 antigen RDTs were correctly read by the app.

Conclusions

The proposed reading system is automatic, reducing variability and uncertainty associated with RDTs interpretation and can be used to read different RDTs brands. The platform can serve as a real time epidemiological tracking tool and facilitate reporting of positive RDTs to relevant health authorities.
Resting-state EEG distinguishes depression in Parkinson’s disease
Authors: Espinoza Arturo I , May Patrick , Anjum Md Fahim , Singh Arun , Cole Rachel C , Trapp Nicholas , Dasgupta Soura , Narayanan Nandakumar S
Published: February 2022

Introduction

Depression is a non-motor symptom of Parkinson’s disease (PD). PD-related depression is hard to diagnose and the neurophysiological basis is poorly understood. Depression can markedly affect cortical function, which suggests that scalp electroencephalography (EEG) may be able to distinguish depression in PD.

Methods

We recruited 18 PD patients, 18 PD patients with depression, and 12 demographically-similar non-PD patients with clinical depression. All patients were on their usual medications. We collected resting-state EEG in all patients and compared cortical brain signal features between patients with and without depression. We used a machine-learning algorithm that harnesses the entire power spectrum (linear predictive coding of EEG Algorithm for PD: LEAPD), to distinguish between groups.

Result

We found differences between PD patients with and without depression in the alpha band (8-13 Hz) globally and in the beta (13-30 Hz) and gamma (30-80 Hz) bands in the central electrodes. From two minutes of resting-state EEG we found that LEAPD-based machine learning could robustly distinguish between PD patients with and without depression with 97% accuracy, and between PD patients with depression and non-PD patients with depression with 100% accuracy. We verified the robustness of our finding by confirming that the classification accuracy declines gracefully as data are truncated.

Conclusions

We demonstrated the efficacy of the LEAPD algorithm in identifying PD patients with depression from PD patients without depression and controls with depression. Our data provide insight into cortical mechanisms of depression and could lead to novel neurophysiologically-based biomarkers for non-motor symptoms of PD.

HIGHLIGHTS

We used EEG to analyze depression in Parkinson’s disease.

Depressed Parkinson’s patients had distinct spectral EEG features.

Machine-learning algorithms could accurately distinguish depression in Parkinson’s disease.
Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression in the VA Health Care System
Authors: Bigdeli Tim B. , Voloudakis Georgios , Barr Peter B. , Gorman Bryan , Genovese Giulio , Peterson Roseann E. , Burstein David E. , Velicu Vlad I. , Li Yuli , Gupta Rishab , Mattheisen Manuel , Tomasi Simone , Rajeevan Nallakkandi , Sayward Frederick , Radhakrishnan Krishnan , Natarajan Sundar , Malhotra Anil K. , Shi Yunling , Zhao Hongyu , Kosten Thomas R. , Concato John , O’Leary Timothy J. , Przygodzki Ronald , Gleason Theresa , Pyarajan Saiju , Brophy Mary ,   Cooperative Studies Program (CSP) #572,   Million Veteran Program (MVP), Siever Larry J. , Huang Grant D. , Muralidhar Sumitra , Gaziano J. Michael , Aslan Mihaela , Fanous Ayman H. , Harvey Philip D. , Roussos Panos
Published: February 2022

Background

Serious mental illnesses, including schizophrenia, bipolar disorder and depression are heritable, highly multifactorial disorders and major causes of disability worldwide. Polygenic risk scores (PRS) aggregate variants identified from genome-wide association studies (GWAS) into individual-level estimates of liability, and are a promising tool for clinical risk stratification.

Methods

By leveraging the VA’s extensive electronic health record (EHR) and a cohort of 9,378 individuals with confirmed diagnoses of schizophrenia or bipolar I disorder, we validated automated case-control assignments based on ICD-9/10 codes, and benchmarked the performance of current PRS for schizophrenia, bipolar disorder, and major depression in 400,000 Million Veteran Program (MVP) participants. We explored broader relationships between PRS and 1,650 disease categories via phenome-wide association studies (PheWAS). Finally, we applied genomic structural equation modeling (gSEM) to derive novel PRS indexing common and disorder-specific latent genetic factors.

Findings

Among 3,953 and 5,425 individuals with diagnoses of schizophrenia or bipolar disorder type I that were confirmed by structured clinical interviews, 95% were correctly identified using ICD-9/10 codes (2 or more). Current PRS were robustly associated with case status in European (p<10−254) and African (p<10−5) participants and were higher among more frequently hospitalized patients (p<10−4). PheWAS confirmed previous associations among higher neuropsychiatric PRS and elevated risk for psychiatric and physical health problems and extended these findings to African Americans.

Interpretation

Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRS, we demonstrated the validity of an EHR-based phenotyping approach in US veterans, highlighting the potential of PRS for disentangling biological and mediated pleiotropy.

Funding

Department of Veterans Affairs Cooperative Studies Program (CSP) #572; Million Veteran Program (MVP-000, MVP-006); Office of Research and Development, Department of Veterans Affairs.
The effects of COVID-19 on European healthcare provision for people with major depressive disorder: a scoping review protocol
Authors: Sually Dilveer , Edwin Wong Win Lee , Hidalgo-Mazzei Diego , Quoidbach Vinciane , Simon Judit , Boyer Patrice , Strawbridge Rebecca , Young Allan H.
Published: February 2022

Even before the pandemic, the treatment gaps in depression care were substantial, with issues ranging from rates of depression detection and intervention to a lack of follow-up after treatment initiation and access to secondary care services. The COVID-19 pandemic, which has had major effects on global healthcare systems, is almost certain to have impacted the MDD care pathway, though it is unclear what changes have manifested and what opportunities have arisen in response to COVID-19. The extent to which patients receive best-practice care is likely closely linked to clinical outcomes (and therefore disability burden) and as such, it is important to examine treatment gaps on the MDD care pathway during the pandemic. Here, we outline a protocol for a scoping review that investigates this broad topic, focusing on continuity of care and novel methods (e.g. digital approaches) used to mitigate care disruption. This scoping review protocol was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) standards and will culminate in a narrative synthesis of evidence.
Multiple Introductions of SARS-CoV-2 Alpha and Delta Variants into White-Tailed Deer in Pennsylvania
Authors: Marques Andrew D. , Sherrill-Mix Scott , Everett John K. , Adhikari Hriju , Reddy Shantan , Ellis Julie C. , Zeliff Haley , Greening Sabrina S. , Cannuscio Carolyn C. , Strelau Katherine M. , Collman Ronald G. , Kelly Brendan J. , Rodino Kyle G. , Bushman Frederic D. , Gagne Roderick B. , Anis Eman
Published: February 2022

Introductory paragraph

The SARS-CoV-2 pandemic likely began by viral spillover from animals to humans1-3; today multiple animal species are known to be susceptible to infection4-8. White-tailed deer, Odocoileus virginianus are infected in North America at substantial levels9-11, and genomic data suggests that a variant in deer may have spilled back to humans12,13. Here we characterize SARS-CoV-2 in deer from Pennsylvania (PA) sampled during fall and winter 2021. Of 123 nasal swab samples analyzed by RT-qPCR, 20 (16.3%) were positive for SARS-CoV-2. Seven whole-genome sequences were obtained, together with six more partial spike sequences. These annotated as alpha and delta variants, the first reported observations of these lineages in deer, documenting multiple new jumps from humans to deer. The alpha lineage persisted in deer after its displacement by delta in humans, and deer-derived alpha variants diverged significantly from those in humans, consistent with a distinctive evolutionary trajectory in deer.
Multi-cohort transcriptomic subtyping of B-cell acute lymphoblastic leukemia
Authors: Mäkinen Ville-Petteri , Rehn Jacqueline , Breen James , Yeung David , White Deborah L
Published: February 2022

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and comprises multiple genetically distinguishable subtypes. To detect subtypes, current pipelines include fusion calling, polymorphisms, candidate gene copy numbers and cytogenetics but these approaches have limitations. RNA-seq provides a functional genome-wide snapshot that enables classification of ALL subtypes, however, typical mRNA-seq clustering analyses lack the rigor of quantitative modelling. Furthermore, high-dimensional gene expression data across cohorts and countries contain biases that previous transcriptomics studies have not addressed. Our aim was to integrate easy-to-interpret reliable transcriptome-wide biomarkers into subtyping pipelines. We analyzed 2,046 samples from two continents, carefully adjusted for biases and applied a rigorous machine learning design with independent replication. Six ALL subtypes that covered 32% of patients were robustly detected by mRNA-seq (PPV ≥ 87%). Five other frequent subtypes were distinguishable in 40% of patients, although overlapping transcriptional profiles led to lower accuracy (52% ≤ PPV ≤ 73%). Based on these findings, we developed the Allspice tool that predicts ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Allspice also includes quantitative classification and safety metrics to help determine the most plausible genetic drivers for cases where other findings are inconclusive.
Clinical severity of Omicron sub-lineage BA.2 compared to BA.1 in South Africa
Authors: Wolter Nicole , Jassat Waasila ,   DATCOV-Gen author group, von Gottberg Anne , Cohen Cheryl
Published: February 2022

Early data indicated that infection with Omicron BA.1 sub-lineage was associated with a lower risk of hospitalisation and severe illness, compared to Delta infection. Recently, the BA.2 sub-lineage has increased in many areas globally. We aimed to assess the severity of BA.2 infections compared to BA.1 in South Africa. We performed data linkages for (i) national COVID-19 case data, (ii) SARS-CoV-2 laboratory test data, and (iii) COVID-19 hospitalisations data, nationally. For cases identified using TaqPath COVID-19 PCR, infections were designated as S-gene target failure (SGTF, proxy for BA.1) or S-gene positive (proxy for BA.2). Disease severity was assessed using multivariable logistic regression models comparing individuals with S-gene positive infection to SGTF-infected individuals diagnosed between 1 December 2021 to 20 January 2022. From week 49 (starting 5 December 2021) through week 4 (ending 29 January 2022), the proportion of S-gene positive infections increased from 3% (931/31,271) to 80% (2,425/3,031). The odds of being admitted to hospital did not differ between individuals with S-gene positive (BA.2 proxy) infection compared to SGTF (BA.1 proxy) infection (adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.85-1.09). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ for individuals with S-gene positive infection compared to SGTF infection (aOR 0.91, 95%CI 0.68-1.22). These data suggest that while BA.2 may have a competitive advantage over BA.1 in some settings, the clinical profile of illness remains similar.
Should COVID-specific arrangements for abortion continue? The views of women experiencing abortion in Britain during the pandemic
Authors: Lohr Patricia A. , Lewandowska Maria , Meiksin Rebecca , Scott Rachel , Reiter Jennifer , Salaria Natasha , Cameron Sharon , Palmer Melissa , French Rebecca , Wellings Kaye
Published: February 2022

Background

During the COVID-19 pandemic, the British governments issued temporary approvals enabling the use of both pills for medical abortion at home. This permitted the introduction of a fully telemedical model of abortion care with consultations taking place via phone or video call and medications delivered to women’s homes. The approvals in England and Wales will expire at the end of March 2022, while that in Scotland remains under consultation.

Methods

We interviewed 30 women who had undergone an abortion in England, Scotland or Wales between August and December 2021. We explored their views on the changes in abortion service configuration during the pandemic and whether abortion via telemedicine and use of abortion medications at home should continue.

Results

Support for continuation of the permission to use mifepristone and misoprostol at home was overwhelmingly positive. Reasons cited included convenience, comfort, reduced stigma, privacy, and respect for autonomy. A telemedical model was also highly regarded for similar reasons but for some its necessity was linked to safety measures during the pandemic and an option to have an in-person interaction with a health professional at some point in the care pathway was endorsed.

Conclusions

The approval to use abortion pills at home via telemedicine are supported by women having abortions in Great Britain. The respective governments in England, Scotland, and Wales, should be responsive to the patient voice and move to make permanent these important advances in abortion care.

What is already known on this topic

During the COVID-pandemic, specific permission to use both pills for medical abortion at home was granted in England, Scotland and Wales leading to the widespread implementation of a telemedical model with direct-to-patient delivery of medications. The safety, effectiveness, and acceptability of this model of care had been well-documented prior to and during the pandemic.

What this study adds

This study adds the voices of women undergoing abortion during the pandemic regarding the specific changes that led to the transformation of medical abortion care in Britain. Amongst 30 women interviewed, there was endorsement for the continuation of permissions to use medical abortion pills at home via telemedicine.

How this study might affect research, practice, or policy

The UK government’s vision of health provision puts patients and the public first, where “no decision about me, without me” is the norm. Our findings support law and policy makers in applying this principle to recent developments in abortion care by making the permissions permanent.
The combination of autism and exceptional cognitive ability increases risk for suicidal ideation
Authors: Casten Lucas G , Thomas Taylor R , Doobay Alissa F , Foley-Nicpon Megan , Kramer Sydney , Nickl-Jockschat Thomas , Abel Ted , Assouline Susan , Michaelson Jacob J
Published: February 2022

Autism with co-occurring exceptional cognitive ability is often accompanied by severe internalizing symptoms and feelings of inadequacy. Whether cognitive ability also translates into greater risk for suicidal ideation is unclear. To investigate this urgent question, we examined two samples of high-ability individuals with autism for factors that were predictive of suicidal ideation. In the first sample (N=1,074 individuals seen at a clinic specializing in gifted/talented youth), we observed a striking excess of parent-reported suicidal ideation in autistic individuals with IQ≥120 (OR=5.9,p= 0.0007). In separate sample of N=1,983 SPARK participants, we confirmed higher rates of suicidal thoughts compared to non-autistic children from the ABCD cohort (OR=6.8,p <2.2×10−16), and further that autistic children with suicidal thoughts had significantly higher cognitive ability (p <2.2×10−16) than those without. Elevated polygenic scores (PGS) for cognitive performance were associated with increased suicidal thoughts (Z= 2.16,p= 0.03), with PGS for educational attainment trending in the same direction (Z= 1.4,p= 0.17). Notably, similar results were found in parents of these autistic youth, where higher PGS for educational attainment was associated with increasing thoughts of suicide (Z=2.28, p=0.02). Taken together, these results suggest that on a phenotypic and genetic level, increasing cognitive ability is an unexpected risk factor for suicidal ideation in individuals diagnosed with, or at risk for autism.
Global prevalence of antidepressant utilization in the community: A protocol for a systematic review
Authors: Lunghi Carlotta , Dugas Michèle , Leclerc Jacinthe , Poluzzi Elisabetta , Martineau Cathy , Carnovale Valérie , Stéfan Théo , Blouin Patrick , Lépine Johanie , Jalbert Laura , Espinoza Suarez Nataly R. , Svyntozelska Olha , Dery Marie-Pier , Ekanmian Giraud , Nogueira Daniele Maria , Akinola Pelumi Samuel , Skidmore Becky , LeBlanc Annie
Published: February 2022

Background

Antidepressant drugs are the most frequently prescribed medication for mental disorders. They are also used off-label and for non-psychiatric indications. Prescriptions of antidepressants have increased in the last decades, but no systematic review exists on the extent of their use in the community.

Methods and analysis

We will conduct a systematic review to estimate the prevalence of antidepressant use in the community. We will search for studies published from 2010 in the Embase and MEDLINE databases. Study selection (by title/abstract and full-text screening) and data extraction for included studies will be independently conducted by pairs of reviewers. We will then synthesize the data on the prevalence of antidepressant use in individuals living in the community. If possible, we will perform a meta-analysis to generate prevalence-pooled estimates. If the data allows it, we will conduct subgroup analyses by antidepressant class, age, sex, country or other sociodemographics. We will evaluate the risk of bias for each included study through a quality assessment using the Joanna Briggs Institute Critical Appraisal tool: Checklist for Studies Reporting Prevalence Data. DistillerSR software will be used for the management of this review.

Ethics and dissemination

Ethical approval is not required for this review as it will not involve human or animal subjects. The findings of our systematic review will be disseminated through publications in peer-reviewed journals, the Qualaxia Network (https://qualaxia.org), presentations to international conferences on mental health and pharmacoepidemiology, as well as general public events.

PROSPERO registration details

CRD42021247423
AIscEA: Unsupervised Integration of Single-cell Gene Expression and Chromatin Accessibility via Their Biological Consistency
Authors: Jafari Elham , Johnson Travis , Wang Yue , Liu Yunlong , Huang Kun , Wang Yijie
Published: February 2022

Since the integrative analysis of single-cell gene expression and chromatin accessibility measurements is essential for revealing gene regulation at the single-cell resolution, integrating these two measurements becomes one of the key challenges in computational biology. Because gene expression and chromatin accessibility are measurements from different modalities, no common features can be directly used to guide their integration. Current state-of-the-art methods assume that the number of cell types across the measurements is the same. However, when cell-type heterogeneity exists, they might not generate reliable results. Furthermore, current methods do not have an effective way to select the hyper-parameter under the unsupervised setting. Therefore, applying computational methods to integrate single-cell gene expression and chromatin accessibility measurements remains difficult.

We introduce AIscEA – Alignment-based Integration of single-cell gene Expression and chromatin Accessibility – a computational method that integrates single-cell gene expression and chromatin accessibility measurements using their biological consistency. AIscEA first defines a ranked similarity score to quantify the biological consistency between cell types across measurements. AIscEA then uses the ranked similarity score and a novel permutation test to identify the cell-type alignment across measurements. For the aligned cell types, AIscEA further utilizes graph alignment to align the cells across measurements. We compared AIscEA with the competing methods on several benchmark datasets and demonstrated that AIscEA is more robust to hyper-parameters and can better handle the cell-type heterogeneity problem. Furthermore, we demonstrate that AIscEA significantly outperforms the state-of-the-art methods when integrating real-world SNARE-seq and scMultiome-seq datasets in terms of integration accuracy.
Rapid thalamocortical network switching mediated by cortical synchronization underlies propofol-induced EEG signatures: a biophysical model
Authors: Soplata Austin E. , Adam Elie , Brown Emery N. , Purdon Patrick L. , McCarthy Michelle M. , Kopell Nancy
Published: February 2022

Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brainstem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low beta and slow rhythm, as well as their interactions.

Our model suggests propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta frequency spiking in thalamus (C-state), while in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha co-localizes to the peak of the slow; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brainstem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state.

New & Noteworthy

GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We construct a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brainstem neuromodulation.
The virtual aging brain: a model-driven explanation for cognitive decline in older subjects
Authors: Lavanga Mario , Stumme Johanna , Yalcinkaya Bahar Hazal , Fousek Jan , Jockwitz Christiane , Sheheitli Hiba , Bittner Nora , Hashemi Meysam , Petkoski Spase , Caspers Svenja , Jirsa Viktor
Published: February 2022

Healthy aging is accompanied by heterogeneous decline of cognitive abilities among individuals, especially during senescence. The mechanisms of this variability are not understood, but have been associated with the reorganization of white matter fiber tracts and the functional co-activations of brain regions. Here, we built a causal inference framework to provide mechanistic insight into the link between structural connectivity and brain function, informed by brain imaging data and network modeling. By applying various degrees of interhemispheric degradation of structural connectivity, we were not only able to reproduce the age-related decline in interhemispheric functional communication and the associated dynamical flexibility, but we obtained an increase of global modulation of structural connectivity over the brain function during senescence. Notably, the increase in modulation between structural connectivity and brian function was higher in magnitude and steeper in its increase in older adults with poor cognitive performance. We independently validated the causal hypothesis of our framework via a Bayesian approach based on deep-learning. The current results might be the first mechanistic demonstration of dedifferentiation and scaffolding during aging leading to cognitive decline demonstrated in a large cohort.
The impact of familiarity on cortical taste coding
Authors: Staszko Stephanie M. , Boughter John D. , Fletcher Max L.
Published: February 2022

The role of the gustatory region of the insular cortex in mediating associative taste learning, such as conditioned taste aversion, has been well studied. However, while associative learning plays a role in some taste behaviors, such as avoidance of toxins, taste stimuli are often encountered by animals in their natural environment without explicit consequences. This type of inconsequential experience with sensory stimuli has been studied in other sensory systems, generally with the finding that neuronal responses habituate with repeated sensory exposure. The present study sought to determine the effect of taste familiarity on population taste coding in mouse gustatory cortex (GC). Using microendoscope calcium imaging, we studied the taste responses of visually identifiable neurons over five days of taste experience, during which animals could freely choose to consume taste stimuli. We found that the number of active cells in insular cortex, as well as the number of cells characterized as taste-responsive, significantly decreased as animals became familiar with taste stimuli. Moreover, the magnitude of taste-evoked excited responses increased, and inhibited responses decreased with experience. By tracking individual neurons over time, we focused on taste coding in a subpopulation of “stable” neurons that were present on all days of the taste familiarity paradigm. The population-level response across these stable cells was distinct when taste stimuli were novel but became more intercorrelated among those taste stimuli mice willingly consumed as the stimuli became familiar. Overall, these results highlight the effects of familiarity on taste responses in gustatory cortex.
Reduced sensorimotor beta dynamics could represent a “slowed movement state” in healthy individuals
Authors: Leriche Ryan B. , Jackson Nicholas , Peterson Kathryn , Aspandiar Zeeya , Hufnagel Vanessa , Swann Nicole C.
Published: February 2022

Beta oscillations (~13-30 Hz) recorded from the sensorimotor cortex have canonical amplitude changes during movement. Specifically, a movement-related beta decrease (MRBD) occurs before movement, and a post-movement beta rebound (PMBR) follows. We investigated how the MRBD and PMBR vary with movement speed. Individuals performed a task with blocks that generated longer reaction times (RTs) and shorter RTs (Slow and Fast blocks, respectively) while scalp-electroencephalography (EEG) was recorded. The timing of task events before movement was also modulated to generate blocks with certain and uncertain timing (Fixed and Varied blocks, respectively). Beta modulation was reduced in Slow blocks compared to Fast blocks (i.e., a less negative MRBD and less positive PMBR). For the movement certainty manipulation, we saw mixed behavioral and EEG results. Our primary findings align with previous work which has shown reduced movement-related beta modulation in patients with Parkinson’s disease. We propose that a “slowed movement state”, whether it is experimentally induced or a manifestation of Parkinson’s disease bradykinesia, is represented through reduced beta dynamics. Altogether, the MRBD and PMBR may represent motor speed on a continuum with Parkinson’s disease as an extreme example of slowed movement.
Host and microbiome features of secondary infections in lethal covid-19
Authors: Zacharias Martin , Kashofer Karl , Wurm Philipp , Regitnig Peter , Schütte Moritz , Neger Margit , Ehmann Sandra , Marsh Leigh M. , Kwapiszewska Grazyna , Loibner Martina , Birnhuber Anna , Leitner Eva , Thüringer Andrea , Winter Elke , Sauer Stefan , Pollheimer Marion J. , Vagena Fotini R. , Lackner Carolin , Jelusic Barbara , Ogilvie Lesley , Durdevic Marija , Timmermann Bernd , Lehrach Hans , Zatloukal Kurt , Gorkiewicz Gregor
Published: February 2022

Secondary infections contribute significantly to covid-19 mortality but host and microbial factors driving this sequel remain poorly understood. We performed an autopsy study of 20 covid-19 cases and 14 controls from the first pandemic wave. Autopsies combined with microbial cultivation and deep RNA sequencing (RNAseq) allowed us to define major organ pathologies and specify secondary infections. Lethal covid-19 segregated into two main death causes separating cases with either dominant diffuse alveolar damage (DAD) or secondary infections of lungs. Lung microbiome changes were profound in covid-19 showing a reduced biodiversity and increased presence of prototypical bacterial and fungal pathogens in cases with secondary infections. Deep RNAseq of lung tissues distinctly mirrored death causes and cellular deconvolution stratified DAD cases into subgroups with different cellular compositions. Myeloid cells, including macrophages, and complement C1q activation were found to be strong stratifying factors suggesting a pathophysiological link possibly leading to tolerance in DAD subgroups. Moreover, several signs of immune-impairment were evident in covid-19 lungs including strong induction of inhibitory immune-checkpoints. Thus, our study highlights profound alterations of the local immunity in covid-19, wherein immune-impairment leads to reduced antimicrobial defense favoring the development of secondary infections on top of SARS-CoV-2 infection.
Characterizing SARS-CoV-2 transcription of subgenomic and genomic RNAs during early human infection using multiplexed ddPCR
Authors: Hwang Hyon S. , Lo Che-Min , Murphy Michael , Grudda Tanner , Gallagher Nicholas , Luo Chun Huai , Robinson Matthew L. , Mirza Agha , Conte Madison , Conte Abigail , Zhou Ruifeng , Brooke Christopher B. , Pekosz Andrew , Mostafa Heba H. , Manabe Yukari C. , Thio Chloe L. , Balagopal Ashwin
Published: February 2022

Control of SARS-CoV-2 (SCV-2) transmission is a major priority that requires understanding SCV-2 replication dynamics. We developed and validated novel droplet digital PCR (ddPCR) assays to quantify SCV-2 subgenomic RNAs (sgRNAs), which are only produced during active viral replication, and discriminate them from full-length genomic RNAs (gRNAs) in a multiplexed format. We applied this multiplex ddPCR assay to 144 cross-sectional nasopharyngeal samples. sgRNAs were quantifiable across a range of qPCR cycle threshold (Ct) values and correlated with Ct values. The ratio of sgRNA:gRNA was remarkably stable across a wide range of Ct values, whereas adjusted amounts of N sgRNA to a human housekeeping gene declined with higher Ct values. Interestingly, adjusted sgRNA and gRNA amounts were quantifiable in culture-negative samples, although levels were significantly lower than in culture-positive samples. Longitudinal daily testing of 6 persons for up to 14 days revealed that sgRNA is concordant with culture results during the first week of infection but may be discordant with culture later in infection. Further, sgRNA:gRNA is constant during infection despite changes in viral culture. These data indicate stable viral transcription during infection. More work is needed to understand why cultures are negative despite persistence of viral RNAs.
Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores
Authors: Kappel Djenifer B. , Legge Sophie E. , Hubbard Leon , Willcocks Isabella R. , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T.R. , Pardiñas Antonio F.
Published: February 2022

BACKGROUND

Treatment-resistant schizophrenia (TRS) affects ∼30% of individuals with the disorder. Clozapine is the medication of choice in TRS but optimizing administration and dose titration are complex. The identification of predictive factors that influence clozapine prescription and response, including genetics, is of clinical interest in a precision psychiatry framework. We aimed to determine if a polygenic risk score (PRS) for schizophrenia is associated with the highest drug dose an individual received during clozapine treatment.

METHODS

We used generalized linear regression models accounting for demographic, pharmacological, and clinical covariates to determine the relationship between PRS and highest daily dose of clozapine. We used two independent multi-ancestry samples of individuals from the UK from a clozapine monitoring system, CLOZUK2 (N= 3133) and CLOZUK3 (N= 909). Schizophrenia PRS were calculated using the latest available GWAS summary statistics from the Psychiatric Genomics Consortium. In a secondary analysis of the two merged cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRS and clozapine doses classified as low, standard, or high (>600 mg/day).

RESULTS

After controlling for relevant available covariates, schizophrenia PRS were correlated with the highest clozapine dose ever prescribed, in both CLOZUK2 (β= 12.217, s.e= 3.776, P= 0.001) and CLOZUK3 (β= 12.730, s.e= 5.987, P= 0.034). In the secondary analysis, the schizophrenia PRS was specifically associated with taking a clozapine dose greater than 600 mg/day (OR= 1.279, P= 0.006).

CONCLUSIONS

Schizophrenia PRS is associated with the highest clozapine dose ever prescribed in two independent multi-ancestry samples from the UK, suggesting that the genetic liability to schizophrenia might index factors associated with therapeutic decisions in TRS cohorts.
Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring STAG2 mutations
Authors: Subramaniam Agatheeswaran , Sandén Carl , Moura-Castro Larissa , Žemaitis Kristijonas , Schmiderer Ludwig , Bäckström Alexandra , Arvidsson Elin , Hultmark Simon , Miharada Natsumi , Paulsson Kajsa , Fioretos Thoas , Larsson Jonas
Published: February 2022

Targeted therapies exploiting selective vulnerabilities of malignant cells are highly desired for clinical applications. The cohesin protein complex comprises of RAD21, SMC3, SMC1A as well as a fourth subunit that consists of either STAG1 or STAG2 and is essential for proper chromosomal segregation during mitosis. STAG2 loss-of-function mutations are recurrent driver events in acute myeloid leukemia (AML) and appear relatively early during leukemogenesis. Studies in cell lines have shown that STAG2 deficient cells are uniquely vulnerable to STAG1 perturbation, and this vulnerability could thus be exploited to selectively eliminate STAG2 null AML cells. Here we show that partial perturbation of STAG1 is well tolerated by normal human hematopoietic stem cells and does not affect their functionality. By contrast, STAG1 knockdown is lethal to STAG2 null human HSCs by inducing major mitotic defects. Moreover, STAG1 knockdown induced synthetic lethality in primary human AML cells harboring a STAG2 mutation and completely abrogated leukemia progression in xenograft models. Overall, our study provides proof-of-concept demonstration of a synthetic lethal approach to selectively target primary human cancer cells with STAG2 mutations
Controlling microbial co-culture based on substrate pulsing can lead to stability through differential fitness advantages
Authors: Martinez J.Andres , Delvenne Matheo , Henrion Lucas , Moreno Fabian , Telek Samuel , Dusny Christian , Delvigne Frank
Published: February 2022

Microbial consortia are an exciting alternative for increasing the performances of bioprocesses for the production of complex metabolic products. However, the functional properties of microbial communities remain challenging to control, considering the complex interaction mechanisms occurring between co-cultured microbial species. Indeed, microbial communities are highly dynamic and can adapt to changing environmental conditions through complex mechanisms, such as phenotypic diversification. We focused on stabilizing a co-culture ofSaccharomyces cerevisiaeandEscherichia coliin continuous cultures. Our preliminary data pointed out that transient diauxic shifts could lead to stable co-culture by providing periodic fitness advantages to the yeast. Based on a computational toolbox called MONCKS (for MONod-type Co-culture Kinetic Simulation), we were able to predict the dynamics of diauxic shift for both species based on a cybernetic approach. This toolbox was further used to predict the frequency of diauxic shift to be applied to reach co-culture stability. These simulations were successfully reproduced experimentally in continuous bioreactors with glucose pulsing. Finally, based on a bet-hedging reporter, we observed that the yeast population exhibited an increased phenotypic diversification process in co-culture compared with mono-culture, suggesting that this mechanism could be the basis of the metabolic fitness of the yeast.
Long noncoding RNA MEG3 activates neuronal necroptosis in Alzheimer’s disease
Authors: Balusu Sriram , Horré Katrien , Thrupp Nicola , Snellinx An , Serneels Lutgarde , Chrysidou Iordana , Arranz Amaia M. , Sierksma Annerieke , Simrén Joel , Karikari Thomas K. , Zetterberg Henrik , Chen Wei-Ting , Thal Dietmar Rudolf , Salta Evgenia , Fiers Mark , Strooper Bart De
Published: February 2022

Abstract/Summary

Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but it remains unclear how neurons die and how this relates to other defining characteristics of the disease1. Existing in vivo AD models only partially recapitulate the neuropathology of AD with very mild or no neuronal cell loss. Here we demonstrate that human neurons xenografted in mouse brain exposed to amyloid pathology develop sarkosyl-insoluble tau filaments, positive Gallyas silver staining, release phosphorylated tau (P-tau181) into the blood, and display considerable neuronal cell loss, providing a model for the induction of full Tau pathology by simple exposure to amyloid pathology in AD. The alterations are specific to human neurons and contrast with the mild effects exhibited in mouse neurons. A core transcriptional program in the human neurons is characterized by strong upregulation of MEG3, a neuron-specific long noncoding RNA. MEG3 is also strongly upregulated in neurons from AD patients in situ. MEG3 expression alone is sufficient to induce necroptosis in human neurons in vitro. Orally administered small molecule receptor-interacting protein (RIP) kinase -1 and -3 inhibitors rescued the neuronal cell loss in this novel AD model. Thus, xenografted human neurons are uniquely sensitive to amyloid pathology, recapitulate all the defining neuropathological features of AD, and ultimately die by necroptosis.
Network communication models narrow the gap between the modular organization of structural and functional brain networks
Authors: Seguin Caio , Mansour L Sina , Sporns Olaf , Zalesky Andrew , Calamante Fernando
Published: February 2022

Structural and functional brain networks are modular. Canonical functional systems, such as the default mode network, are well-known modules of the human brain and have been implicated in a large number of cognitive, behavioral and clinical processes. However, modules delineated in structural brain networks inferred from tractography generally do not recapitulate canonical functional systems. Neuroimaging evidence suggests that functional connectivity between regions in the same systems is not always underpinned by anatomical connections. As such, direct structural connectivity alone would be insufficient to characterize the functional modular organization of the brain. Here, we demonstrate that augmenting structural brain networks with models of indirect (polysynaptic) communication unveils a modular network architecture that more closely resembles the brain’s established functional systems. We find that diffusion models of polysynaptic connectivity, particularly communicability, narrow the gap between the modular organization of structural and functional brain networks by 20–60%, whereas routing models based on single efficient paths do not improve mesoscopic structure-function correspondence. This suggests that functional modules emerge from the constraints imposed by local network structure that facilitates diffusive neural communication. Our work establishes the importance of modeling polysynaptic communication to understand the structural basis of functional systems.
Description of Life History and Reproductive Size Thresholds in Three High ElevationPuya(Bromeliaceae)
Authors: Veldhuisen Leah , Garcia Lino Mary Carolina , Bodine Erin , Aguirre-Santoro Julián , Jabaily Rachel
Published: February 2022

Abstract

The Andes are a hotspot for biodiversity and high species endemism for both plants and animals. The genusPuya(Bromeliaceae) lives throughout the Andes, including puna and the páramo ecosystems above 3500m. Here, we studied the life history and reproductive size thresholds in three species ofPuya(P. raimondii, P. cryptanthaandP. goudotiana):P. raimondiiin the Bolivian puna, andP. cryptanthaandP. goudotianain the Colombian páramo. We collected data on threshold size at flowering and clonal reproduction. All three species were found to have a consistent minimum size at flowering, while onlyP. cryptanthademonstrated a minimum size for clonal reproduction. No such evidence was found forP. goudotiana. We also found a positive correlation between leaf length and fruit number forP. goudotianaandP. cryptantha. Our data supported thatP. raimondiiis fully semelparous and indicated thatP. goudotianaandP. cryptanthamay be semi-semelparous.
Deletion of the microglial transmembrane immune signaling adaptor TYROBP ameliorates Huntington’s disease mouse phenotype
Authors: Creus-Muncunill Jordi , Mattei Daniele , Bons Joanna , Ramirez-Jimenez Angie V. , Hamilton B. Wade , Corwin Chuhyon , Chowdhury Sarah , Schilling Birgit , Ellerby Lisa , Ehrlich Michelle E.
Published: February 2022

BACKGROUND

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene. Immune activation is abundant in the striatum of HD patients. Detection of active microglia at presymptomatic stages suggests that microgliosis is a key early driver of neuronal dysfunction and degeneration. Recent studies showed that deletion of Tyrobp, a microglial-enriched protein, ameliorates neuronal function in Alzheimer’s disease amyloid and tauopathy mouse models while decreasing components of the complement subnetwork, thus raising the possibility that Tyrobp deletion can be beneficial for HD.

METHODS

To test the hypothesis that Tyrobp deficiency would be beneficial in a HD model, we placed the Q175 HD mouse model on a Tyrobp-null background. We characterized these mice with a combination of behavioral testing, immunohistochemistry, transcriptomic and proteomic profiling. Further, we evaluated the Q175 microglia-specific gene signature, with and without Tyrobp, by purifying microglia from these mice for transcriptomics.

RESULTS

Comprehensive analysis of publicly available transcriptomic HD human data revealed that TYROBP network is overactivated in HD putamen. The Q175 mice showed morphologic microglial activation, reduced levels of post-synaptic density-95 protein and motor deficits at 6 and 9 months of age, all of which were ameliorated on the Tyrobp-null background. Gene expression analysis revealed that lack of Tyrobp in the Q175 model does not prevent the decrease in the expression of striatal neuronal genes but reduces pro-inflammatory pathways that are specifically active in HD human brain. Integration of transcriptomic and proteomic data identified that astrogliosis and complement system pathway were reduced after Tyrobp deletion. Results were further validated by immunofluorescence analysis. Microglia-specific HD gene dysregulation, characterized by overexpression of neuronal genes, was also not corrected by Tyrobp deletion.

CONCLUSIONS

Our data provide molecular and functional support demonstrating that Tyrobp deletion prevents many of the abnormalities in the Q175 HD mouse model, in the absence of correction of striatal neuronal gene expression, suggesting that the Tyrobp pathway is a potential therapeutic candidate for Huntington’s disease.