bluuebunny/crossref_metadata_2025 huggingface dataset:
Polygenic risk scores lack prognostic value for adults with severe mental illness
Authors: Landi Isotta , Kaji Deepak , Cotter Liam , Vleck Tielman Van , Belbin Gillian , Preuss Michael , Loos Ruth , Kenny Eimear , Glicksberg Benjamin S , Beckmann Noam , O’Reilly Paul , Schadt Eric E. , Achtyes Eric D. , Buckley Peter F. , Lehrer Douglas , Malaspina Dolores P. , McCarroll Steven A. , Rapaport Mark H. , Fanous Ayman H. , Pato Michele T. , Pato Carlos N. ,   Genomic Psychiatry Cohort (GPC) Investigators, Bigdeli Tim B. , Nadkarni Girish N , Charney Alexander W.
Published: March 2021

Schizophrenia (SCZ) is the archetypal severe mental illness and one of the most deeply characterized human genetic traits. Like most common diseases SCZ is highly polygenic, and as such its genetic liability can be summarized at the individual level by a polygenic risk score (PRS). Polygenic risk scores are a cornerstone of the precision medicine vision, as it is widely anticipated they will come to serve as biomarkers of disease and poor outcomes in real-world clinical practice. However, to date, few studies have assessed their actual prognostic value relative to current standards-of-care. SCZ is an ideal test case towards this end because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, assessing whether the SCZ PRS improves poor outcome prediction relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case definitions and ancestral backgrounds of study participants. These findings demonstrate the limited potential of even the most powerful contemporary polygenic risk scores as a tool for individualized outcome prediction.
Developing Machine Learning Models for Predicting Intensive Care Unit Resource Use During the COVID-19 Pandemic
Authors: Lorenzen Stephan Sloth , Nielsen Mads , Jimenez-Solem Espen , Petersen Tonny Studsgaard , Perner Anders , Thorsen-Meyer Hans-Christian , Igel Christian , Sillesen Martin
Published: March 2021

Importance

The COVID-19 pandemic has put massive strains on hospitals, and tools to guide hospital planners in resource allocation during the ebbs and flows of the pandemic are urgently needed.

Objective

We investigate whether Machine Learning (ML) can be used for predictions of intensive care requirements 5 and 10 days into the future.

Design

Retrospective design where health Records from 34,012 SARS-CoV-2 positive patients was extracted. Random Forest (RF) models were trained to predict risk of ICU admission and use of mechanical ventilation after n days (n = 5, 10).

Setting

Two Danish regions, encompassing approx. 2.5 million citizens.

Participants

All patients from the bi-regional area with a registered positive SARS-CoV-2 test from March 2020 to January 2021.

Main outcomes

Prediction of future 5- and 10-day requirements of ICU admission and ventilator use. Mortality was also predicted.

Results

Models predicted 5-day risk of ICU admission with an area under the receiver operator characteristic curve (ROC-AUC) of 0.986 and 5-day risk of use of ventilation with an ROC-AUC of 0.995. The corresponding 5-day forecasting models predicted the needed ICU capacity with a coefficient of determination (R2) of 0.930 and use of ventilation with an R2 of 0.934. Performance was comparable but slightly reduced for 10-day forecasting models.

Conclusions

Random Forest-based modelling can be used for accurate 5- and 10-day forecasting predictions of ICU resource requirements.

Funding

The study was funded by grants from the Novo Nordisk Foundation to MS (#NNF20SA0062879 and #NNF19OC0055183) and MN (#NNF20SA0062879).

The foundation took no part in project design, data handling and manuscript preparation.

KEY POINTS

Question

Can machine learning models (ML) be used for predicting hospital and intensive care unit (ICU) resource requirements, and thus assist in logistics crisis management during the COVID-19 pandemic?

Findings

Retrospective study of the resource use of 34.012 COVID-19 patients during the first and second COVID-19 wave in Denmark. ML models were trained for the purpose of predicting the number of patients needing ICU admission and ventilators 5 and 10 day after their first positive SARS-CoV-2 test. The study demonstrates that ML models can accurately predict intensive care admission requirements with 5-day area under the receiver operator characteristic curve (ROC-AUC) of 0.986 and need for ventilator support with a ROC-AUC of 0.995. 10-day predictions were comparable.

Meaning

The study demonstrates that ML modelled could be a useful tool for hospital planners during crisis management, including the current COVID-19 pandemic.
Job stress among workers who telecommute during the coronavirus disease (COVID-19) pandemic in Japan: a cross-sectional study
Authors: Ikegami Kazunori , Baba Hiroka , Ando Hajime , Hino Ayako , Tsuji Mayumi , Tateishi Seiichiro , Nagata Tomohisa , Matsuda Shinya , Fujino Yoshihisa
Published: March 2021

Objectives

The work system reform and the COVID-19 pandemic in Japan have prompted efforts toward telecommuting in Japan, and there has been little research regarding the stress and health effects of telecommuting. This study aimed to clarify the relationship between telecommuting and job stress among Japanese workers.

Study Design

This was a cross-sectional study.

Methods

In December 2020, during the ‘third wave’ of the COVID-19 pandemic, an Internet-based nationwide health survey of 33,087 Japanese workers (CORoNaWork study) was conducted. Data for 27,036 individuals was included as 6,051 individuals provided invalid responses. We analysed a sample of 13,468 office workers from this database. We classified participants into four groups according to telecommuting frequency and compared the subscale of the Job Content Questionnaire and subjective job stress among these groups: high-frequency, medium-frequency, and low-frequency telecommuters group and non-telecommuters group. We used a linear mixed model and ordinal logistic regression analysis.

Results

There was a significant difference in the score of job control of the JCQ among the four groups after adjusting for multiple confounding factors. The high-frequency telecommuters group had the highest job control score. Regarding the fluctuation score of subjective job stress, the high- and medium-frequency telecommuters groups were significantly lower than those of the non-telecommuters group after adjusting for multiple confounding factors.

Conclusion

We found that high-frequency telecommuting was associated with high job control. This study suggests that the widespread adoption of telecommuting as a countermeasure to the public health challenges associated with the COVID-19 pandemic may also have a positive impact on job stress.
Primary care clinical management following self-harm during the first wave of COVID-19 in the UK
Authors: Steeg Sarah , Carr Matthew J , Trefan Laszlo , Ashcroft Darren M , Kapur Nav , Nielsen Emma , McMillan Brian , Webb Roger T
Published: March 2021

Background

A substantial reduction in GP-recorded self-harm occurred during the first wave of COVID-19 but effects on primary care management of self-harm are unknown.

Aim

To examine the impact of COVID-19 on clinical management within three months of an episode of self-harm.

Design and setting

Prospective cohort study using data from the UK Clinical Practice Research Datalink.

Method

We compared cohorts of patients with an index self-harm episode recorded during a pre-pandemic period (10th March-10th June, 2010-2019) versus the COVID-19 first-wave period (10th March-10th June 2020). Patients were followed up for three months to capture psychotropic medication prescribing, GP/practice nurse consultation and referral to mental health services.

Results

48,739 episodes of self-harm were recorded during the pre-pandemic period and 4,238 during the first-wave COVID-19 period. Similar proportions were prescribed psychotropic medication within 3 months in the pre-pandemic (54.0%) and COVID-19 first-wave (54.9%) cohorts. Likelihood of having at least one GP/practice nurse consultation was broadly similar (83.2% vs. 80.3% in the COVID-19 cohort). The proportion of patients referred to mental health services in the COVID-19 cohort (3.4%) was around half of that in the pre-pandemic cohort (6.5%).

Conclusion

Despite the challenges experienced by primary healthcare teams during the initial COVID-19 wave, prescribing and consultation patterns following self-harm were broadly similar to pre-pandemic levels. However, the reduced likelihood of referral to mental health services warrants attention. Accessible outpatient and community services for people who have self-harmed are required as the COVID-19 crisis recedes and the population faces new challenges to mental health.
Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors
Authors: Kunze Katie L. , Johnson Patrick W. , van Helmond Noud , Senefeld Jonathon W. , Petersen Molly M. , Klassen Stephen A. , Wiggins Chad C. , Klompas Allan M. , Bruno Katelyn A. , Mills John R. , Theel Elitza S. , Buras Matthew R. , Golafshar Michael A. , Sexton Matthew A. , Soto Juan C. Diaz , Baker Sarah E. , Shepherd John R.A. , Verdun Nicole C. , Marks Peter , Paneth Nigel S. , Fairweather DeLisa , Wright R. Scott , Casadevall Arturo , Carter Rickey E. , Joyner Michael J. ,   the US EAP COVID-19 Plasma Consortium, van Buskirk Camille M. , Winters Jeffrey L. , Stubbs James R. , Senese Katherine A. , Pletsch Michaela C. , Buchholtz Zachary A. , Rea Robert F. , Herasevich Vitaly , Whelan Emily R. , Clayburn Andrew J. , Larson Kathryn F. , Ripoll Juan G. , Andersen Kylie J. , Lesser Elizabeth R. , Vogt Matthew N.P. , Dennis Joshua J. , Regimbal Riley J. , Bauer Philippe R. , Blair Janis E.
Published: March 2021

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma is likely to reflect the antigenic composition of local viral strains, we hypothesized that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to a national registry of hospitalized COVID-19 patients supported this hypothesis. These findings have implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.
Gene-level germline contributions to clinical risk of recurrence scores in Black and White breast cancer patients
Authors: Patel Achal , García-Closas Montserrat , Olshan Andrew F. , Perou Charles M. , Troester Melissa A. , Love Michael I. , Bhattacharya Arjun
Published: March 2021

Continuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer (BC). Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to BC disparities, evidence for biological and germline contributions is emerging. We investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N=1,043 WW, 1083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; Proliferation Score; ROR-P: ROR-S plus Proliferation Score) on imputed Genetically-Regulated tumor eXpression (GReX). Using Bayesian multivariate regression and adaptive shrinkage, we tested GReX-prioritized genes for associations with PAM50 tumor expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjustedP< 0.10, we detected 7 and 1 GReX-prioritized genes among WW and BW. Among WW, CRS were positively associated withMCM10, FAM64A, CCNB2, andMMP1GReX and negatively associated withVAV3, PCSK6, andGNG11GReX. Among BW, higherMMP1GReX predicted lower Proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among BC patients, we find differential germline associations with CRS by race, underscoring the need for larger, diverse datasets in molecular studies of BC. Our findings also suggest possible germlinetrans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings.

SIGNIFICANCE

We find race-specific genetic associations with breast cancer risk-of-recurrence scores (CRS). Follow-up analyses suggest mediation of these associations by PAM50 molecular subtype and gene expression, with implications for clinical interpretation of CRS.
Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against SARS-CoV-2 Variants of Concern
Authors: Lien Chia-En , Kuo Tsun-Yung , Lin Yi-Jiun , Lian Wei-Cheng , Lin Meei-Yun , Liu Luke Tzu-Chi , Chou Yu-Chi , Chen Charles
Published: March 2021

Vaccination is currently the best weapon to control the COVID-19 pandemic. However, an alarming number of novel variants termed Variants of Concern (VoC) were found to harbor mutations that diminished the neutralizing capacity of antibodies elicited by the vaccines. We have investigated the neutralizing titers of antibodies from sera of humans and rats immunized with the MVC-COV1901 vaccine against pseudoviruses coated with the wildtype, D614G, B.1.1.7, or B.1.351 spike proteins. Rats vaccinated with two doses of adjuvanted S-2P retained neutralization activities against the B.1.351 variant, albeit with a slight reduction compared to wildtype. Phase 1 vaccinated subjects showed more reduced neutralization abilities against the B.1.351 variant. The study is among the first, to our knowledge, to demonstrate dose-dependent neutralizing responses against VoCs, particularly against B.1.351, from different doses of antigen in a clinical trial for a subunit protein COVID-19 vaccine. The appearance of vaccine escape variants is a growing concern facing many current COVID-19 vaccines and therapeutics. Strategies should be adopted against the ever-changing nature of these variants. The observations of this study grant us valuable insight into preemptive strikes against current and future variants.
From atoms to cells: bridging the gap between potency, efficacy, and safety of small molecules directed at a membrane protein
Authors: Aguayo-Ortiz Rodrigo , Creech Jeffery , Jiménez-Vázquez Eric N. , Guerrero-Serna Guadalupe , Wang Nulang , da Rocha Andre Monteiro , Herron Todd J. , Espinoza-Fonseca L. Michel
Published: March 2021

Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand–membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca2+pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.
High rates of plasmid cotransformation inE. colioverturn the clonality myth and reveal colony development
Authors: Tomoiaga Delia , Bubnell Jaclyn , Herndon Liam , Feinstein Paul
Published: March 2021

The concept of DNA transfer between bacteria was put forth by Griffith in 1928. During the dawn of molecular cloning of DNA in the 1980s, Hanahan described how the transformation of DNA plasmids into bacteria would allow for cloning of DNA fragments. Through this foundational work, it is widely taught that a typical transformation produces clonal bacterial colonies. Using low concentrations of several plasmids that encode different fluorescent proteins, under the same selective antibiotic, we show thatE. colibacteria readily accept multiple plasmids, resulting in widespread aclonality and reveal a complex pattern of colony development. Cotransformation of plasmids occurs by either CaCl2or by electroporation methods. A bacterium rod transformed with three plasmids - each expressing a high level of a unique fluorescent protein - and replated on agar, appears to reassign a random number of the three fluorescent plasmids to its daughter cell during cell division. The potential to simultaneously follow multiple lineages of clonally related bacteria in a bacteria colony would allow for mosaic analysis of gene function. We show that clonally related bacterium rods self-organize in a fractal growth pattern and can remain linked during colony development revealing a potential target against microbiota growth.
The impact of brain lesions on tDCS-induced electric field magnitude
Authors: Johnstone Ainslie , Zich Catharina , Evans Carys , Lee Jenny , Ward Nick , Bestmann Sven
Published: March 2021

Background

Transcranial direct current stimulation (tDCS) has been used to enhance motor and language rehabilitation following a stroke. However, improving the effectiveness of clinical tDCS protocols depends on understanding how lesions may influence tDCS-induced current flow through the brain.

Objective

We systematically investigated the effect of brain lesions on the magnitude of electric fields (e-mag) induced by tDCS, and how to overcome lesion-induced inter-individual variability in e-mag.

Methods

We simulated the effect of 630 different lesions - by varying lesion location, distance from the target region of interest (ROI), size and conductivity - on tDCS-induced e-mag in the brains of two participants. Current flow modelling was conducted for two tDCS montages commonly used in clinical applications, which target either primary motor cortex (M1) or Broca’s area (BA44), respectively. We further explored how the inherent variability in e-mag that is introduced by inter-lesion differences can be overcome by individualising tDCS protocols.

Results

The effect onabsolutee-mag was highly dependent on lesion size, conductance and the distance from the target ROI. Larger lesions, with high conductivity, closer to the ROI caused e-mag changes of more than 30%. Thesignof this change was determined by the location of the lesion. Specifically, lesions located in-line with the predominant direction of current flow increased e-mag in the ROI, whereas lesions located in the opposite direction caused a decrease. Lesions had a large impact on the optimal electrode configuration if attempting to maximise for the total e-mag in the ROI, but little impact if only the component of e-mag flowing radially inward to the cortex was maximised. Knowing the effect of a given lesion on e-mag also allows for individualising tDCS intensity to reduce variability.

Conclusions

These results demonstrate that tDCS-induced electric fields are profoundly influenced by lesion characteristics, and further exacerbate the known variability in e-mag across individuals. Additionally, the dependence of these results on the assigned conductance of the lesion underlines the need for improved estimates of lesion conductivity for current flow models. Our results highlight the need for individualised dose control of tDCS in the lesioned brain to overcome the substantial inter-individual variability in electric fields delivered to a cortical target region.

Highlights

-

Lesions can alter tDCS-induced electric field magnitude (e-mag) in a target by 30%

-

Lesions can cause increases or decreases to e-mag

-

Direction of change depends on the position of the lesion relative to current flow

-

Lesion conductivity - the true value for which is unknown - also impacts change

-

E-mag variability can be reduced by individualising montage and stimulation intensity
Non-REM sleep in major depressive disorder
Authors: Bovy Leonore , Weber Frederik D. , Tendolkar Indira , Fernández Guillén , Czisch Michael , Steiger Axel , Zeising Marcel , Dresler Martin
Published: March 2021

Disturbed sleep is a key symptom in major depressive disorder (MDD). REM sleep alterations are well described in the current fliterature, but little is known about non-REM sleep alterations. Additionally, sleep disturbances relate to a variety of cognitive symptoms in MDD, but which features of non-REM sleep EEG contribute to this, remains unknown. We comprehensively analyzed non-REM sleep EEG features in three independently collected datasets (N=284). These included MDD patients with a broad age range, varying duration and severity of depression, unmedicated or medicated, age- and gender-matched to healthy controls. We explored changes in sleep architecture including sleep stages and cycles, spectral power, sleep spindles, slow waves (SW), and SW-spindle coupling. Next, we analyzed the association of these sleep features with acute measures of depression severity and overnight consolidation of procedural memory. Overall, no major systematic alterations in non-REM sleep architecture were found in patients compared to controls. For the microstructure of non-REM sleep, we observed a higher spindle amplitude in unmedicated patients compared to controls, and after the start of antidepressant medication longer SWs with lower amplitude and a more dispersed SW-spindle coupling. In addition, long-term, but not short-term medication seemed to lower spindle density. Overnight procedural memory consolidation was impaired in medicated patients and associated with lower sleep spindle density. Our results suggest that alterations in non-REM sleep EEG might be more subtle than previously reported. We discuss these findings in the context of antidepressant medication intake and age.

Statement of Significance

Depression affects large and diverse populations worldwide, including their sleep. Most sleep is non-REM sleep, which is vital to cognitive function, including memory. How non-REM is affected during a depression or medical treatment remains poorly investigated. We classified non-REM sleep of depressive patients against healthy controls in unprecedented analysis detail and confidence using the largest dataset published so far while also test sleep alterations associations with impaired memory. Surprisingly, severe depression alone did not alter sleep. We observed severe non-REM sleep alterations only worsening under patient medication, which ultimately coincided with 24-hour memory impairments. Though causal influences of medication on sleep in depressive patients remains to be investigated, this cautions common clinical practice in long-term treatment with antidepressants.
Catchet-MS identifies IKZF1-targeting Thalidomide analogues as novel HIV-1 latency reversal agents
Authors: Ne Enrico , Crespo Raquel , Izquierdo-Lara Ray , Rao Shringar , Koçer Selin , Górska Alicja , van Staveren Thomas , Kan Tsung Wai , Dekkers Dick , Rokx Casper , Moulos Panagiotis , Hatzis Pantelis , Palstra Robert-Jan , Demmers Jeroen , Mahmoudi Tokameh
Published: March 2021

A major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular determinants of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has not been possible. Here we use a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to describe the protein composition of the latent and activated HIV-1 5’LTR. Catchet-MS identified known and novel latent 5’LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the clinically advanced thalidomide analogue iberdomide, and the FDA approved analogues lenalidomide and pomalidomide, to be novel LRAs that, by targeting IKZF1 for degradation, reverse HIV-1 latency in CD4+T-cells isolated from virally suppressed people living with HIV-1.

One Sentence Summary

dCas9 targeted chromatin and histone enrichment for mass spectrometry (Catchet-MS) led to the identification of IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents
Bacterial-type plant ferroxidases tune local phosphate sensing in root development
Authors: Naumann Christin , Heisters Marcus , Brandt Wolfgang , Janitza Philipp , Alfs Carolin , Tang Nancy , Nienguesso Alicia Toto , Ziegler Joerg , Imre Richard , Mechtler Karl , Dagdas Yasin , Hoehenwarter Wolfgang , Sawers Gary , Quint Marcel , Abel Steffen
Published: March 2021

Fluctuating bioavailability of inorganic phosphate (Pi), often caused by complex Pi-metal interactions, guide root tip growth and root system architecture for maximizing the foraged soil volume. Two interacting genes inArabidopsis thaliana,PDR2(P5-type ATPase) andLPR1(multicopper oxidase), are central to external Pi monitoring by root tips, which is modified by iron (Fe) co-occurrence. Upon Pi deficiency, thePDR2-LPR1module facilitates cell type-specific Fe accumulation and cell wall modifications in root meristems, inhibiting intercellular communication and thus root growth. LPR1 executes local Pi sensing, whereas PDR2 restricts LPR1 function. We show that native LPR1 displays specific ferroxidase activity and requires a conserved acidic triad motif for high-affinity Fe2+binding and root growth inhibition under limiting Pi. Our data indicate that substrate availability tunes LPR1 function and implicate PDR2 in maintaining Fe homeostasis. LPR1 represents the prototype of an ancient ferroxidase family, which evolved very early upon bacterial colonization of land. During plant terrestrialization, horizontal gene transfer transmitted LPR1-type ferroxidase from soil bacteria to the common ancestor of Zygnematophyceae algae and embryophytes, a hypothesis supported by homology modeling, phylogenomics, and activity assays of bacterial LPR1-type multicopper oxidases.
Explicit and implicit depth-cue integration: evidence of systematic biases with real objects
Authors: Campagnoli Carlo , Hung Bethany , Domini Fulvio
Published: March 2021

In a previous series of experiments using virtual stimuli, we found evidence that 3D shape estimation agrees to a superadditivity rule of depth-cue combination. According to this rule, adding depth cues leads to greater perceived depth magnitudes and, in principle, to depth overestimation. The mechanism underlying the superadditivity effect can be fully accounted for by a normative theory of cue integration, through the adaptation of a model of cue integration termed the Intrinsic Constraint (IC) model. As for its nature, it remains unclear whether superadditivity is a byproduct of the artificial nature of virtual environments, causing explicit reasoning to infiltrate behavior and inflate the depth judgments when a scene is richer in depth cues, or the genuine output of the process of depth-cue integration. In the present study, we addressed this question by testing whether the IC model’s prediction of superadditivity generalizes beyond VR environments to real world situations. We asked participants to judge the perceived 3D shape of cardboard prisms through a matching task. To assay the potential influence of explicit control over those perceptual estimates, we also asked participants to reach and hold the same objects with their fingertips and we analyzed the in-flight grip size during the reaching. Using physical objects ensured that all visual information was fully consistent with the stimuli’s 3D structure without computer-generated artifacts. We designed a novel technique to carefully control binocular and monocular 3D cues independently from one another, allowing to add or remove depth information from the scene seamlessly. Even with real objects, participants exhibited a clear superadditivity effect in both explicit and implicit tasks. Furthermore, the magnitude of this effect was accurately predicted by the IC model. These results confirm that superadditivity is an inherent feature of depth estimation.
Prediction errors for aversive events shape long-term memory formation through a distinct neural mechanism
Authors: Kalbe Felix , Schwabe Lars
Published: March 2021

Prediction errors (PEs) have been known for decades to guide associative learning, but their role in episodic memory formation has been discovered only recently. Using an encoding task in which participants learned to predict which stimuli are followed by aversive shocks, combined with univariate, multivoxel, and large-scale network analyses of fMRI data, we show that enhanced memory for events associated with negative PEs was linked to reduced hippocampal responses to PEs and increased crosstalk between the ‘salience network’ and a frontoparietal network commonly implicated in memory formation for events that are in line with prior expectation. These PE-related effects could not be explained by mere changes in physiological arousal or the prediction itself. Our results suggest that superior memory for events associated with high PEs is driven by a distinct neural mechanism that might serve to set memories of high PE events apart from those with expected outcomes.
Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication
Authors: Theruvath Johanna , Menard Marie , Smith Benjamin A.H. , Linde Miles H. , Coles Garry L. , Wu Wei , Kiru Louise , Delaidelli Alberto , Silberstein John L. , Banuelos Allison , Dhingra Shaurya , Sotillo Elena , Heitzeneder Sabine , Tousley Aidan , Lattin John , Xu Peng , Huang Jing , Nasholm Nicole , Dalton Guillermo Nicolas , He Andy , Kuo Tracy C. , Sangalang Emma R.B. , Pons Jaume , Barkal Amira , Brewer Rachel , Marjon Kristopher D. , Marshall Payton L. , Fernandes Ricardo , Cochran Jennifer R. , Sorensen Poul H. , Daldrup-Link Heike E. , Weissman Irving L. , Sage Julien , Majeti Ravindra , Bertozzi Carolyn R. , Weiss William A. , Mackall Crystal L. , Majzner Robbie G.
Published: March 2021

The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.
Non-Alcoholic Fatty Liver Disease (NAFLD) in Children and Adolescents taking Atypical Antipsychotic Medications: A Protocol for Systematic Review and Meta-Analysis
Authors: Hatem Reem , Nawaz Faisal A. , Al-Sharif Ghadah A. , Almoosa Mohammad , Kattan Wid , Tzivinikos Christos , Amirali Lila , Albanna Ammar
Published: March 2021

Atypical Antipsychotic medications are commonly prescribed to children and adolescents and are associated with important adverse effects including weight gain and metabolic syndrome. Non-Alcoholic Fatty Liver Disease (NAFLD) is not only the most common pediatric liver disease, but can also be associated with serious complications including liver cirrhosis. Given that both NAFLD and Atypical Antipsychotics (AAP) are associated with metabolic syndrome, we aimed to comprehensively examine the association between AAP and NAFLD in children and adolescents. We will conduct a systematic review following the PRISMA guidelines, of English-language literature published between 1950 and 2020, exploring NAFLD in subjects younger than 18 years on AAP.
Automated long-term two-photon imaging in head-fixed walkingDrosophila
Authors: Valle Andres Flores , Honnef Rolf , Seelig Johannes D.
Published: March 2021

The brain ofDrosophilashows dynamics at multiple timescales, from the millisecond range of fast voltage or calcium transients to functional and structural changes occurring over multiple days. To relate such dynamics to behavior requires monitoring neural circuits across these multiple timescales in behaving animals.

Here, we develop a technique for automated long-term two-photon imaging in fruit flies, during wakefulness and sleep, navigating in virtual reality over up to seven days. The method is enabled by laser surgery, a microrobotic arm for controlling forceps for dissection assistance, an automated feeding robot, as well as volumetric, simultaneous multiplane imaging. The approach is validated in the fly’s head direction system.

Imaging in behaving flies over multiple timescales will be useful for understanding circadian activity, learning and long-term memory, or sleep.
Why humans are stronger but not faster after isometric strength training: specific neural, not muscular, motor unit adaptations
Authors: Del Vecchio A. , Casolo A. , Dideriksen J. , Aagaard P. , Felici F. , Falla D. , Farina D.
Published: March 2021

While maximal force increases following short-term isometric strength training, the rate of force development (RFD) may remain relatively unaffected. The underlying neural and muscular mechanisms during rapid contractions after strength training are largely unknown. Since strength training increases the neural drive to muscles, it may be hypothesized that there are distinct neural or muscular adaptations determining the change in RFD independently of an increase in maximal force. Therefore, we examined motor unit population data during the rapid generation of force before and after four weeks of strength training. We observed that strength training did not change the RFD because it did not influence the number of motor units recruited per second or their initial discharge rate during rapid contractions. While strength training did not change motoneuron behaviour in the force increase phase of rapid contractions, it increased the discharge rate of motoneurons (by ∼4 spikes/s) when reaching the plateau phase (∼150 ms) of the rapid contractions, determining an increase in maximal force production. Computer simulations with a motor unit model that included neural and muscular properties, closely matched the experimental observations and demonstrated that the lack of change in RFD following training is primarily mediated by an unchanged maximal recruitment speed of motoneurons. These results demonstrate that maximal force and contraction speed are determined by different adaptations in motoneuron behaviour following strength training and indicate that increases in the recruitment speed of motoneurons are required to evoke training-induced increases in RFD.
Constructing phylogenetic relationship based on the independent selection law of genome sequences
Authors: Xiaolong Li , Hong Li , Zhenhua Yang , Zefeng Zhang
Published: March 2021

Exploring the composition and evolution regularity of genome sequences and constructing phylogenetic relationship by alignment-free method in genome level are high-profile topics. Our previous researches discovered the CG and TA independent selection law s existed in genome sequences by analysis on the spectral features of 8-mer subsets of 920 eukaryote and prokaryote genomes. We found that the evolution state of genomes is determined by the intensity of the two independent selections and the degree of the mutual inhibition between them. In this study, the two independent selection patterns of 22 primate and 28 insect genome sequences were analyzed further. The two complete 8-mer motif sets containing CG or TA dinucleotide and their feature of relative frequency are proposed. We found that the two 8-mer sets and their feature are related directly to sequence evolution of genomes. According to the relative frequency of two 8-mer sets, phylogenetic trees were constructed respectively for the given primate and insect genomes. Through analysis and comparison, we found that our phylogenetic trees are more consistent with the known conclusions. The two kinds of phylogenetic relationships constructed by CG 8-mer set and TA 8-mer set are similar in insect genomes, but the phylogenetic relationship constructed by CG 8-mer set reflect the evolution state of genomes in current age and phylogenetic relationship constructed by TA 8-mer set reflect the evolution state of genomes in a slight earlier period. We thought it is the result that the TA independent selection is repressed by the CG independent selection in the process of genome evolution. Our study provides a theoretical approach to construct more objective evolution relationships in genome level.
Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in aC. eleganssensory circuit
Authors: Choi Jung-Hwan , Horowitz Lauren Bayer , Ringstad Niels
Published: March 2021

At chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in aC. eleganschemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate thatin vivothe strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.
Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses
Authors: Napolitano Valeria , Dabrowska Agnieszka , Schorpp Kenji , Mourão André , Barreto-Duran Emilia , Benedyk Malgorzata , Botwina Pawel , Brandner Stefanie , Bostock Mark , Chykunova Yuliya , Czarna Anna , Dubin Grzegorz , Fröhlich Tony , Hoelscher Michael , Jedrysik Malwina , Matsuda Alex , Owczarek Katarzyna , Pachota Magdalena , Plettenburg Oliver , Potempa Jan , Rothenaigner Ina , Schlauderer Florian , Szczepanski Artur , Mohn Kristin Greve-Isdahl , Blomberg Bjorn , Sattler Michael , Hadian Kamyar , Popowicz Grzegorz Maria , Pyrc Krzysztof
Published: March 2021

Summary

The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLprocatalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models,in vivoin mice andex vivoin human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.
Extracellular vesicles produced by the human commensal gut bacteriumBacteroides thetaiotaomicronaffect host immune pathways in a cell-type specific manner that are altered in inflammatory bowel disease
Authors: Gul Lejla , Modos Dezso , Fonseca Sonia , Madgwick Matthew , Thomas John P. , Sudhakar Padhmanand , Stentz Régis , Carding Simon R. , Korcsmaros Tamas
Published: March 2021

The gastrointestinal (GI) tract is inhabited by a complex microbial community, which contributes to its homeostasis. Disrupted microbiome can cause GI-related diseases, including inflammatory bowel disease, therefore identifying host-microbe interactions is crucial for better understanding gut health. Bacterial extracellular vesicles (BEVs), released into the gut lumen, can cross the mucus layer and access underlying immune cells. To study cross-kingdom communication between BEVs and host, we focused on the influence of BEVs, generated byBacteroides thetaiotaomicron(VPI-5482), on host immune cells. Using single-cell RNA sequencing data and host-microbe protein-protein interaction networks, we examined the potential effect of BEVs on dendritic cells, macrophages and monocytes with particular focus on the Toll-like receptor (TLR) pathway. We identified biological processes affected in each immune cell type, and also cell-type specific processes (e.g myeloid cell differentiation). The TLR pathway analysis highlighted that BEV targets differ among cells and even between the same cells in healthy versus disease (ulcerative colitis) conditions. Ourin silicofindings were validated in BEV-monocyte co-cultures demonstrating the requirement for TLR4 in BEV-elicited NF-κ B activation. This study demonstrates that both cell-type and health condition influence BEV-host communication. The results and the pipeline can facilitate BEV-based therapy development for the treatment of IBD.
Persistent cell migration emerges from a coupling between protrusion dynamics and polarized trafficking
Authors: Vaidžiulytė Kotryna , Macé Anne-Sophie , Battistella Aude , Beng William , Schauer Kristine , Coppey Mathieu
Published: March 2021

Migrating cells present a variety of paths, from random to highly directional ones. While random movement can be explained by basal intrinsic activity, persistent movement requires stable polarization. Here, we quantitatively address emergence of persistent migration in RPE1 cells over long timescales. By live-cell imaging and dynamic micropatterning, we demonstrate that the Nucleus-Golgi axis aligns with direction of migration leading to efficient cell movement. We show that polarized trafficking is directed towards protrusions with a 20 min delay, and that migration becomes random after disrupting internal cell organization. Eventually, we prove that localized optogenetic Cdc42 activation orients the Nucleus-Golgi axis. Our work suggests that polarized trafficking stabilizes the protrusive activity of the cell, while protrusive activity orients this polarity axis, leading to persistent cell migration. Using a minimal physical model, we show that this feedback is sufficient to recapitulate the quantitative properties of cell migration in the timescale of hours.
Avoiding attack: How dune wasps leverage colour and motion to detect their cryptic spider predators
Authors: Rodríguez-Morales Dulce , Tapia-McClung Horacio , Robledo-Ospina Luis , Rao Dinesh
Published: March 2021

Ambush predators depend on cryptic body colouration, stillness and a suitable hunting location to optimise the probability of prey capture. Detection of cryptic predators, such as crab spiders, by flower seeking wasps may also be hindered by wind induced movement of the flowers themselves. In a beach dune habitat,Microbembex nigrifronswasps approaching flowerheads of thePalafoxia lindeniiplant need to evaluate the flowers to avoid spider attack. Wasps may detect spiders through colour and movement cues. We tracked the flight trajectories of dune wasps as they approached occupied and unoccupied flowers under two movement conditions; when the flowers were still or moving. We simulated the appearance of the spider and the flower using psychophysical visual modelling techniques and related it to the decisions made by the wasp to land or avoid the flower. Wasps could discriminate spiders only at a very close range, and this was reflected in the shape of their trajectories. Wasps were more prone to making errors in threat assessment when the flowers are moving. Our results suggest that dune wasp predation risk is augmented by abiotic conditions such as wind and compromises their early detection capabilities.