bluuebunny/crossref_metadata_2025 huggingface dataset:
LB-11. Comparison of Viral Loads in Individuals With or Without Symptoms At Time of COVID-19 Testing Among 32,480 Residents and Staff of Nursing Homes and Assisted Living Facilities in Massachusetts
Authors: Lennon Niall J , Mina Michael , Rehm Heidi L , Hung Deborah T , Smole Sandra , Woolley Ann E , Lander Eric , Gabriel Stacey
Published: January 2021

Background

Transmission of COVID-19 from people without symptoms confounds public health containment strategies. Comprehensive cross-sectional screening enables assessment of viral load independent of symptoms, informing transmission risks. We quantified SARS-CoV-2 burden by RT-qPCR from comprehensive screening of nursing homes and assisted living facilities in Massachusetts to inform our ability to detect SARS-CoV-2 in individuals with or without symptoms.

Methods

From 4/9/20 to 6/9/20, we tested nasopharyngeal (NP) swabs from 32,480 unique individuals comprising staff and residents of the majority of nursing homes and assisted living facilities in Massachusetts. Symptomatology at the time of sampling and demographic information were provided by each facility. NP swabs were collected, RNA extracted, and SARS-CoV-2 testing performed by RT-qPCR. We compared cycle thresholds (Ct) with a standard curve to quantify viral loads.

Results

The nursing home and assisted living facilities resident cohort (N = 16,966) was 65% female with mean age 82. The staff cohort (N = 15,514) was 76% female with mean age 45. In all, 2654 residents (15.5%) and 624 staff (4.1%) tested positive for SARS-CoV-2, including 12.7% of residents and 3.7% of staff without symptoms, compared to 53.1% of residents and 18.2% of staff with symptoms. The Ct distributions for viral probes were very similar between populations with and without symptoms (Fig 1), with a statistically but not meaningfully different mean (ΔCt 0.71 cycles, p = 0.006) and a similar range (12–38 cycles). This similarity persisted across all sub-categories examined (age, race, ethnicity, sex, resident/staff).

Figure 1

Conclusion

In a large cohort of individuals screened for SARS-CoV-2 by RT-qPCR, we found strikingly similar viral load distributions in patients with or without symptoms at the time of testing. The size of the study population, including both staff and residents spanning a wide range of ages, provides a comprehensive cross-sectional point prevalence measurement of viral burden. Because the distributions of viral loads are very similar regardless of symptoms, existing testing modalities validated for detection of SARS-CoV-2 RNA in symptomatic patients should perform similarly well in individuals without symptoms at the time of testing.

Disclosures

All Authors: No reported disclosures
LB-12. SARS-CoV-2 RNA and Antibodies among People Experiencing Homelessness and Staying in Shelters or Outdoor Encampments in Denver, Colorado, May-July 2020
Authors: McCormick David , Scott Tracy , Chavez Jesse , Wilcox Kay , Marx Grace E , Stella Sarah A , Wendel Karen , Burman William
Published: January 2021

Background

The COVID-19 pandemic has disproportionately affected people experiencing homelessness (PEH) residing in shelters. Initial and regular testing of PEH in communities with moderate or substantial SARS-CoV-2 transmission may limit spread in shelters. We analyzed factors associated with positive SARS-CoV-2 RNA and antibody tests for PEH staying in shelters or encampments in Denver, Colorado.

Methods

In May 2020, Denver Public Health collaborated with local leaders to identify 4 homeless shelters and 3 outdoor encampments for voluntary, universal SARS-CoV-2 testing. At each testing event, a short questionnaire including sociodemographic factors and symptoms was administered to PEH who consented to testing. SARS-CoV-2 RNA testing by reverse transcription polymerase chain reaction (RT-PCR) was performed on nasopharyngeal swabs; antibody testing was performed on venous blood samples. PEH reporting a prior positive RT-PCR test were not retested but were eligible for antibody testing. Statistical calculations were performed with an α of 0.05; all tests were two-sided.

Results

From June 2–July 28, 2020, 931 PEH were approached. A total of 863 RT-PCR tests were performed at 14 testing events, and 334 antibody tests were performed at 5 testing events. Overall, 604 and 259 RT-PCR tests were conducted in 4 shelters and 3 encampments, respectively; 189 and 145 antibody tests were conducted in 3 shelters and 2 encampments, respectively. PEH tested in shelters were older, more often men, less often Native American, and less likely to report COVID-19 symptoms than those tested at encampments (Table 1). Overall, 9% of PEH tested in shelters tested positive for SARS-CoV-2 compared to 3% of PEH tested in encampments (p=0.002); 8% of men had positive RT-PCR results compared to 2% of women (p=0.03) (Table 2). PEH tested at shelters had a higher percentage of detectable SARS-CoV-2 antibodies than those tested in encampments (24% vs 8%, p=0.0002; Table 3). Neither RT-PCR nor antibody test results differed significantly by race or ethnicity.

Table 1. Demographics of participants residing in encampments compared with shelters in Denver, Colorado, May-July 2020 (n=931)

Table 2. Comparison of participants testing positive or negative for SARS-CoV-2 RT-PCR* by location and demographics, in Denver, Colorado, May-July 2020

Table 3. Comparison of participants testing positive or negative for antibodies against SARS-CoV-2 by location and demographics in Denver, Colorado, May-July 2020

Conclusion

A greater percentage of PEH tested positive for both SARS-CoV-2 RNA and antibodies at shelters than encampments, suggesting that continued assessment of mitigation strategies in shelters should be a priority.

Disclosures

All Authors: No reported disclosures
LB-15. A Trans-Governmental Collaborative Effort to Independently Evaluate SARS-CoV-2 Serology Assays Using Well-Characterized Sample Panels
Authors: Shawar Ribhi , O’Leary Brendan , Kemp Troy , Cherry James , Owen S Michele , Gallagher Pamela , Thornburg Natalie , Kondratovich Marina , Satheshkumar Panayampalli Subbian , Schuh Amy , Lester Sandra , Cassetti Cristina , Cassetti Cristina , Lowy Douglas , Gitterman Steve R
Published: January 2021

Background

The emergence of the novel coronavirus, SARS-CoV-2, created a crucial need for accurate tests for diagnosis, assessment of prior infection, and understanding its natural history. Serology assays play an important role in the assessment of anti-viral immune responses and previous infections. Evaluation of serology assays with well-characterized serum and/or plasma samples is critical to determine assay performance. CDC, FDA and NCI’s Frederick National Laboratory for Cancer Research (NCI-FNLCR) have established a collaborative network to independently evaluate commercial antibody tests prior to their authorization.

Methods

Positive (n=30) serum samples with a range of anti-SARS-CoV-2 antibody titers (Table) and negative (n=80) serum and/or plasma samples were selected to establish performance evaluation panels (PEVs). Three PEVs with similar overall antibody titer distribution have been created. Negative samples were collected prior to 2020, before the SARS-CoV-2 pandemic. Positive samples were from patients previously confirmed to have SARS-CoV-2 using a nucleic acid amplification test. Each sample was characterized at CDC and NCI-FNLCR for presence/absence of SARS-CoV-2 IgM and IgG antibodies using a SARS-CoV-2 spike enzyme linked immunosorbent assay (ELISA). NCI-FNLCR also performed a SARS-CoV-2 spike Receptor Binding Domain (RBD) IgG ELISA. Positive samples were assessed at multiple dilutions. Manufacturers submitted their serology assays for evaluation by this program. The sensitivity of each test was assessed for each antibody class (IgG and IgM) and in a combined manner, where a positive result for either antibody was considered as a positive result. For combined specificity, a negative result meant a sample was negative for both antibodies (IgG and IgM).

Number of positive samples with anti-SARS-CoV-2 spike antibodies for each panel (n=30)

Results

To date, 53 serology assays have been evaluated. Sensitivity ranged from 30.0% to 100% for IgG, from 10.0% to 100% for IgM, and the combined specificity ranged from 57.5% to 100%. For 2 assays that measure total Ig, sensitivity was 96.7% and 100%.

Conclusion

This program completed over 50 performance evaluations with well-characterized PEVs. Results have been used to inform FDA regulatory decisions and are publicly available on FDA’s website.

Disclosures

Cristina Cassetti, PhD, Nothing to disclose
Reproductive phasiRNA loci and DICER-LIKE5, but not microRNA loci, diversified in monocotyledonous plants
Authors: Patel Parth , Mathioni Sandra M , Hammond Reza , Harkess Alex E , Kakrana Atul , Arikit Siwaret , Dusia Ayush , Meyers Blake C
Published: January 2021

In monocots other than maize (Zea mays) and rice (Oryza sativa), the repertoire and diversity of microRNAs (miRNAs) and the populations of phased, secondary, small interfering RNAs (phasiRNAs) are poorly characterized. To remedy this, we sequenced small RNAs (sRNA) from vegetative and dissected inflorescence tissue in 28 phylogenetically diverse monocots and from several early-diverging angiosperm lineages, as well as publicly available data from 10 additional monocot species. We annotated miRNAs, small interfering RNAs (siRNAs) and phasiRNAs across the monocot phylogeny, identifying miRNAs apparently lost or gained in the grasses relative to other monocot families, as well as a number of transfer RNA fragments misannotated as miRNAs. Using our miRNA database cleaned of these misannotations, we identified conservation at the 8th, 9th, 19th, and 3′-end positions that we hypothesize are signatures of selection for processing, targeting, or Argonaute sorting. We show that 21-nucleotide (nt) reproductive phasiRNAs are far more numerous in grass genomes than other monocots. Based on sequenced monocot genomes and transcriptomes, DICER-LIKE5, important to 24-nt phasiRNA biogenesis, likely originated via gene duplication before the diversification of the grasses. This curated database of phylogenetically diverse monocot miRNAs, siRNAs, and phasiRNAs represents a large collection of data that should facilitate continued exploration of sRNA diversification in flowering plants.
Distressing healthcare workers during the COVID-19 pandemic: the challenges of holiday season in the Philippines
Authors: Lagman James Darwin N , Vergara Raymond John D , Sarmiento Philip Joseph D
Published: January 2021

The holiday season, Christmas to New Year, is the most festive period of each year in the Philippines. However, the beginning of the festive holiday season in the Philippines seems to be a predicament to healthcare workers and professionals especially during this coronavirus disease 2019 (COVID-19) pandemic. The holiday season is considered a health risk in the Philippines because of the change of lifestyle leading to the increased number of health consultancies and hospitalization. Thus, the expected surge of people in the hospitals and clinics pose an added stress to healthcare workers and professionals. Pre-Holiday policies and programs are therefore essentials especially during the course of battling COVID-19.
Wordsworth, Fox, and a Poet’s Public Spirit
Authors: Bowers Will
Published: January 2021

Wordsworth’s major poetry—Lyrical Ballads (1798, 1800, 1802), The Prelude [1805], and Poems, in Two Volumes (1807)—has a rich critical heritage of political readings. This essay concerns itself with a similar but different theme: Wordsworth’s attitude towards a politician, and politicians generally, during his writing prime. From 1801 to 1806 Wordsworth corresponded with, met, and wrote poetry about the Whig statesman Charles James Fox, and in the same period he developed a civic sense of his own vocation. I argue that this engagement with Fox is an underappreciated source of what T. S. Eliot calls Wordsworth’s ‘public spirit’, a spirit which grew in conflict with the tendency of politicians in Britain and France to judge ‘men in bodies, and in classes, and accordingly to contemplate them in that relation’. The essay begins with an analysis of Wordsworth’s 1801 letter to Fox, before moving to consider Fox’s lukewarm reply and its basis in unpublished correspondence. It then explores the confident Miltonic poet who emerges in Wordsworth’s ‘Sonnets Dedicated to Liberty’, before finally considering accounts of the two men meeting in 1806, and the elegy Wordsworth wrote on Fox’s death in the same year. Attention to Wordsworth’s relationship with Fox allows focus to move away from how and why the poet’s politics changed in these five years, and on to his consistently held, revolutionary, and influential notion that poetry could provide an alternative means of animating politics.
Integrating Sequence Capture and Restriction Site-Associated DNA Sequencing to Resolve Recent Radiations of Pelagic Seabirds
Authors: Ferrer Obiol Joan , James Helen F , Chesser R Terry , Bretagnolle Vincent , González-Solís Jacob , Rozas Julio , Riutort Marta , Welch Andreanna J
Published: January 2021

The diversification of modern birds has been shaped by a number of radiations. Rapid diversification events make reconstructing the evolutionary relationships among taxa challenging due to the convoluted effects of incomplete lineage sorting (ILS) and introgression. Phylogenomic data sets have the potential to detect patterns of phylogenetic incongruence, and to address their causes. However, the footprints of ILS and introgression on sequence data can vary between different phylogenomic markers at different phylogenetic scales depending on factors such as their evolutionary rates or their selection pressures. We show that combining phylogenomic markers that evolve at different rates, such as paired-end double-digest restriction site-associated DNA (PE-ddRAD) and ultraconserved elements (UCEs), allows a comprehensive exploration of the causes of phylogenetic discordance associated with short internodes at different timescales. We used thousands of UCE and PE-ddRAD markers to produce the first well-resolved phylogeny of shearwaters, a group of medium-sized pelagic seabirds that are among the most phylogenetically controversial and endangered bird groups. We found that phylogenomic conflict was mainly derived from high levels of ILS due to rapid speciation events. We also documented a case of introgression, despite the high philopatry of shearwaters to their breeding sites, which typically limits gene flow. We integrated state-of-the-art concatenated and coalescent-based approaches to expand on previous comparisons of UCE and RAD-Seq data sets for phylogenetics, divergence time estimation, and inference of introgression, and we propose a strategy to optimize RAD-Seq data for phylogenetic analyses. Our results highlight the usefulness of combining phylogenomic markers evolving at different rates to understand the causes of phylogenetic discordance at different timescales. [Aves; incomplete lineage sorting; introgression; PE-ddRAD-Seq; phylogenomics; radiations; shearwaters; UCEs.]
Collaboration Between Infection Prevention and Clinical Education in Response to COVID-19
Authors: Edwards Pamela B. , Green Katrina , Sturdivant Margaret H. , Lobaugh-Jin Erica , Oden Mary , Reynolds Staci S.
Published: January 2021

With the rapid escalation of COVID-19 educational needs within hospitals, it was imperative for content experts of the infection prevention departments to lean on the expertise of nursing professional development specialists. This article provides a brief overview of how a clinical education and professional development department was deployed to assist and support the COVID-19 response efforts.
Probiotics treatment improves cognitive impairment in patients and animals: a systematic review and meta-analysis
Authors: Lv Tingting , Ye Mengfei , Luo Fangyi , Hu Baiqi , Wang Anzhe , Chen Jiaqi , Yan Junwei , He Ziyi , Chen Feng , Qian Chao , Gao Hui , Zhang Jian , Liu Zheng , Ding Zhinan
Published: January 2021

The gut–brain axis has received considerable attention in recent years, and the “psychobiotics” concept indicates that probiotics have a potential positive effect on cognitive function. Therefore, the aim of this study was to quantitatively evaluate the influence of probiotics on cognitive function. We conducted a random-e?ects meta-analysis of 7 controlled clinical trials and 11 animals studies to evaluate the e?ects of probiotics on cognitive function. Probiotics supplementation enhanced cognitive function in both human (0.24 [0.05–0.42]; I2 = 0%) and animal studies (0.90 [0.47–1.34]; I2 = 74%). Subgroup analyses indicated that the effects of probiotics on cognitively impaired individuals (0.25 [0.05–0.45]; I2 = 0%) were greater than those on healthy ones (0.15 [−0.30 to 0.60]; I2 = 0%). Furthermore, compared with a multiple-probiotic supplement, one strain of probiotic was more effective in humans. The meta-analysis provided some suggestions for probiotics intervention and tended to support a customized approach for different individuals to ameliorate cognitive disorders. Future additional clinical trials are necessary to evaluate therapeutic effect and influencing factors.
Predictors of CPAP outcome in hospitalised COVID-19 patients
Authors: Noeman-Ahmed Y , Gokaraju S , Powrie DJ , Amran DA , El Sayed I , Roshdy Ashraf
Published: January 2021

Introduction

Throughout March – April 2020, many patients with COVID-19 presented to Southend University Hospital with Acute Hypoxaemic Respiratory Failure (AHRF). Patients were managed in a Specialist Respiratory High Dependency Unit. We present our experience on the usage of continuous positive airway pressure (CPAP) therapy and possible indicators of its success in this patient group.

Methods

Data from patients (n=89) requiring mechanical ventilation during the months of March-April 2020, were retrospectively collected and analysed. 37 patients received IMV (Invasive Mechanical Ventilation) without a CPAP trial beforehand. 52 patients underwent a CPAP trial, of which 21 patients successfully avoided intubation and ITU admission.

Results

The 52 patients, prior to receiving CPAP had significant respiratory failure as evidenced by a low PaO2: FiO2 (PFR) (mean± SD 123 ± 60 mmHg) and mean SpO2:FiO2 (SFR) (mean ± SD: 140 ± 50). The main indicators of CPAP success were: higher SFR before and after CPAP, lower respiratory rate (RR), lower Neutrophil to Lymphocyte ratio (NLR) and higher PFR prior to CPAP.

Discussion

CPAP proved successful in 40% of COVID-19 patients presenting with AHRF. SFR, PFR, RR and NLR are predictors of such success. SFR can be used for effective real time monitoring of patients before and after CPAP to identify likelihood of success. Based on our results, we have suggested a modified CPAP management protocol in COVID-19. These findings can guide future studies and will allow improved triage of patients to either CPAP or IMV, in the event of a future COVID peak.
A persistent invasive phenotype in post-hypoxic tumor cells is revealed by novel fate-mapping and computational modeling
Authors: Rocha Heber L. , Godet Inês , Kurtoglu Furkan , Metzcar John , Konstantinopoulos Kali , Bhoyar Soumitra , Gilkes Daniele M. , Macklin Paul
Published: January 2021

Hypoxia is a critical factor in solid tumors that has been associated with cancer progression and aggressiveness. We recently developed a hypoxia-fate mapping system that allowed the tracing of post-hypoxic cells within a tumor for the first time. This novel approach, based on an oxygen-dependent fluorescent switch, made the investigation of the post-hypoxic phenotype possible. The system allowed us to measure key biological features such as oxygen distribution, cell proliferation and migration. Using this data, we developed a computational model to investigate the motility and phenotypic persistence of hypoxic and post-hypoxic cells during tumor progression. The behavior of hypoxic and post-hypoxic cells was defined by phenotypic persistence time, cell movement bias and the fraction of cells that respond to an enhanced migratory stimulus. Our studies revealed that post-hypoxic cells have an enhanced persistent migratory phenotype that promotes the formation of invasive structures (“plumes”) expanding towards the oxygenated tumor regions. This work combined advanced cell tracking and imaging techniques with mathematical modeling, and revealed for the first time that a persistent invasive migratory phenotype that develops under hypoxic conditions enhances their escape into non-hypoxic tumor regions to invade the surrounding tissue.
Single neuron activity predicts behavioral performance of individual animals during memory retention
Authors: Strube-Bloss Martin Fritz , D’Albis Tiziano , Menzel Randolf , Nawrot Martin Paul
Published: January 2021

In 1972 Rescorla and Wagner formulated their model of classical Pavlovian conditioning postulating that the associative strength of a stimulus is expressed directly in the behavior it elicits1. Many biologists and psychologists were inspired by this model, and numerous experiments thereafter were interpreted assuming that the magnitude of the conditioned response (CR) reflects an associative effect at the physiological level. However, a correlation between neural activity and the expression of the CR in individual animals has not yet been reported. Here we show that, following differential odor conditioning, the change in activity of single mushroom body output neurons (MBON) of the honeybee predicts the behavioral performance of the individual during memory retention. The encoding of the stimulus-reward association at the mushroom body output occurs about 600 ms before the initiation of the CR. We conclude that the MB provides a stable representation of the stimulus-reward associative strength, and that this representation is required for behavioral decision-making during memory retention.
Increased theta/alpha synchrony in the habenula-prefrontal network with negative emotional stimuli in human patients
Authors: Huang Yongzhi , Sun Bomin , Debarros Jean , Zhang Chao , Zhan Shikun , Li Dianyou , Zhang Chencheng , Wang Tao , Huang Peng , Lai Yijie , Brown Peter , Cao Chunyan , Tan Huiling
Published: January 2021

Lateral habenula is believed to encode negative motivational stimuli and plays key roles in the pathophysiology of psychiatric disorders. However, how habenula activities are modulated during the perception and processing of emotional information is still poorly understood. We recorded local field potentials from bilateral habenula areas with simultaneous cortical magnetoencephalography in nine patients with psychiatric disorders during an emotional picture viewing task. Oscillatory activity in the theta/alpha band (5-10 Hz) within the habenula and prefrontal cortical regions, as well as the coupling between these structures, are increased during the perception and processing of negative emotional stimuli compared to positive emotional stimuli. The evoked increase in theta/alpha band synchronization in the frontal cortex-habenula network correlated with the emotional valence not the arousal score of the stimuli. These results provide direct evidence for increased theta/alpha synchrony within the habenula area and prefrontal cortex-habenula network in the perception of negative emotion in human participants.
Fatty acid metabolic reprogramming promotesC. elegansdevelopment
Authors: Cao Xuwen , Xie Yusu , Xue Beining , Yang Hanwen , Garcia L. Rene , Zhang Liusuo
Published: January 2021

Acetylcholine signaling has been reported to play essential roles in animal metabolic regulation and disease affected by diets. However, the underlying mechanisms that how diets regulate animal physiology and health are not well understood. Here we found that the acetylcholine receptor geneeat-2was expressed in most of the pharyngeal muscles, which is in accordance to our previous report that EAT-2 received synaptic signals not only from pharyngeal MC neurons. The expression of fatty acid synthesis genes was significantly increased in botheat-2andtmc-1fast-growth mutants on CeMM food environment, compared to the wild-type. Excitingly, dietary fatty acids such as 15-methyl-hexadecanoic acid (C17ISO), palmitic acid (PA, C16:0) and stearic acid (SA, C18:0) supplementation, significantly accelerated wild-type worm development on CeMM, indicating that the fatty acid synthesis reprogramming is an essential strategy forC. elegansto regulate its development and growth on CeMM diet. Furthermore, we found that fatty acid elongase geneelo-6knock-out significantly attenuatedeat-2mutant’ fast growth, while overexpression ofelo-6could rescue theeat-2; elo-6double mutant’ slow development, which suggested thatelo-6played a major role in the above metabolic remodeling. Taken together, our report indicates that diets regulate neuromuscular circuit and modulateC. elegansdevelopment via fatty acid metabolic reprogramming. As most of the key genes and metabolites found in this study are conserved in both invertebrate and vertebrate animals, we believed that our results might provide essential clues to the molecular mechanisms underlying interactions among animal nutrition sensation, metabolism reprogramming and developmental regulation.

Significance Statement

Diets and nutritional composition affect animal development and human health, however the underlying mechanisms remain elusive. We demonstrate that the acetylcholine receptor geneeat-2is expressed in most of pharyngeal muscles, and the expression of fatty acid synthesis genes is significantly increased in botheat-2andtmc-1fast-growth mutants on the synthetic chemical defined CeMM food environment. Dietary supplementation of several fatty acids significantly speed up animal development. Furthermore, we demonstrate that the fatty acid elongase geneelo-6knock-out attenuateseat-2mutant’ fast growth, and overexpression of wild-typeelo-6promotes theeat-2; elo-6double mutant’ slow development. Our findings describe that acetylcholine signaling coordinate nutrition sensation and developmental regulation through fatty acid metabolic remodeling.
Drosophilafunctional screening ofde novovariants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases
Authors: Marcogliese Paul C , Deal Samantha L , Andrews Jonathan , Harnish J Michael , Bhavana V Hemanjani , Graves Hillary K , Jangam Sharayu , Luo Xi , Liu Ning , Bei Danqing , Chao Yu-Hsin , Hull Brooke , Lee Pei-Tseng , Pan Hongling , Longley Colleen M , Chao Hsiao-Tuan , Chung Hyunglok , Haelterman Nele A , Kanca Oguz , Manivannan Sathiya N , Rossetti Linda Z , Gerard Amanda , Schwaibold Eva Maria Christina , Guerrini Renzo , Vetro Annalisa , England Eleina , Murali Chaya N , Barakat Tahsin Stefan , van Dooren Marieke F , Wilke Martina , van Slegtenhorst Marjon , Lesca Gaetan , Sabatier Isabelle , Chatron Nicolas , Brownstein Catherine A , Madden Jill A , Agrawal Pankaj B , Keller Roberto , Pavinato Lisa , Brusco Alfredo , Rosenfeld Jill A , Marom Ronit , Wangler Michael F , Yamamoto Shinya
Published: January 2021

Individuals with autism spectrum disorders (ASD) exhibit an increased burden ofde novovariants in a broadening range of genes. We functionally tested the effects of ASD missense variants usingDrosophilathrough ‘humanization’ rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identifiedGLRA2as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.
Apomixis and genetic background affect distinct traits inHieracium pilosellaL. grown under competition
Authors: Sailer Christian , Tiberi Simone , Schmid Bernhard , Stöcklin Jürg , Grossniklaus Ueli
Published: January 2021

Background

Apomixis, the asexual reproduction through seeds, occurs in over 40 plant families and avoids the hidden cost of sex. Apomictic plants are thought to have an advantage in sparse populations and when colonizing new areas but may have a disadvantage in changing environments because they propagate via fixed genotypes.

In this study, we separated the influences of different genetic backgrounds (potentially reflecting local adaptation) from those of the mode of reproduction, i.e., sexual vs. apomictic, on nine fitness-related traits inHieracium pilosellaL. We aimed to test whether apomixisper semay provide a fitness advantage in different competition environments in a common garden setting.

Results

To separate the effects of genetic background from those of reproductive mode, we generated five families of apomictic and sexual full siblings by crossing two paternal with four maternal parents. Under competition, apomictic plants showed reproductive assurance (probability of seeding, fertility), while offspring of sexual plants with the same genetic background had a higher germination rate. Sexual plants grew better (biomass) than apomictic plants in the presence of grass as a competitor but apomictic plants spread further vegetatively (maximum stolon length) when their competitors were sexual plants of the same species. Furthermore, genetic background as represented by the five full-sibling families influenced maximum stolon length, the number of seeds, and total fitness. Under competition with grass, genetic background influenced fecundity, the number of seeds, and germination rate.

Conclusions

Our results suggest that both the mode of reproduction as well as the genetic background affect the success ofH. pilosellain competitive environments. Total fitness, the most relevant trait for adaptation, was only affected by the genetic background. However, we also show for the first time that apomixisper sehas effects on fitness-related traits that are not confounded by — and thus independent of — the genetic background.
Spatial computing for the control of working memory
Authors: Lundqvist Mikael , Brincat Scott L , Rose Jonas , Warden Melissa R. , Buschman Tim , Miller Earl K. , Herman Pawel
Published: January 2021

Working memory (WM) allows us to selectively remember and flexibly control a limited amount of information. Earlier work has suggested WM control is achieved by interactions between bursts of beta and gamma oscillations. The emerging question is how beta and gamma bursting, reflecting coherent activity of hundreds of thousands of neurons, can underlie selective control of individual items held in WM? Here, we propose a principle for how such selective control might be achieved on the neural network level. It relies on spatial computing, which suggests that beta and gamma interactions cause item-specific activity to flow spatially across the network over the course of a task. This way, control-related information about, for instance, item order can be retrieved from the spatial activity independent of the detailed recurrent connectivity that gives rise to the item-specific activity itself. The spatial flow should in turn be reflected in low-dimensional activity shared by many neurons. We test predictions of the proposed spatial computing paradigm by analysing control-related as well as item-specific activity in local field potentials and neuronal spiking from prefrontal cortex of rhesus macaques performing four WM tasks. As predicted, we find that the low-dimensional activity has a spatial component from which we can read out control-related information. These spatial components were stable over multiple sessions and did not depend on the specific WM items being used. We hypothesize that spatial computing can facilitate generalization and zero-shot learning by utilizing spatial component as an additional information encoding dimension. This offers a new perspective on the functional role of low-dimensional activity that tends to dominate cortical activity.
Coordinated poleward flux of sister kinetochore fibers drives chromosome alignment
Authors: Risteski Patrik , Božan Domagoj , Jagrić Mihaela , Bosilj Agneza , Pavin Nenad , Tolić Iva M.
Published: January 2021

Chromosome alignment at the spindle equator promotes proper chromosome segregation and depends on pulling forces exerted at kinetochore fiber tips together with polar ejection forces. However, kinetochore fibers are also subjected to forces driving their poleward flux. Here we introduce a flux-driven centering model that relies on flux generated by forces within the overlaps of bridging and kinetochore fibers. This centering mechanism works so that the longer kinetochore fiber fluxes faster than the shorter one, moving the kinetochores towards the center. We developed speckle microscopy in human spindles and confirmed the key prediction that kinetochore fiber flux is length-dependent. Kinetochores are better centered when overlaps are shorter and the kinetochore fiber flux markedly slower than the bridging fiber flux. We identify Kif18A and Kif4A as overlap and flux regulators and NuMA as a fiber coupler. Thus, length-dependent sliding forces exerted by the bridging fiber onto kinetochore fibers promote chromosome alignment.
Muscle coordination retraining inspired by musculoskeletal simulations: a study on reducing knee loading
Authors: Uhlrich Scott D , Jackson Rachel W , Seth Ajay , Kolesar Julie A , Delp Scott L
Published: January 2021

Humans typically coordinate their muscles to meet movement objectives like minimizing energy expenditure. In the presence of pathology, new objectives gain importance, like reducing loading in an osteoarthritic joint, but people often do not change their muscle coordination patterns to meet these new objectives. Here we use musculoskeletal simulations to identify simple changes in coordination that can be taught by providing feedback of electromyographic activity to achieve a therapeutic goal—reducing joint loading. Our simulations predicted that changing the relative activation of the redundant ankle plantarflexors could reduce knee contact force during walking, but it was unclear whether humans could re-coordinate redundant muscles during a complex task like walking. With simple biofeedback of electromyographic activity, healthy individuals reduced the ratio of gastrocnemius to soleus muscle activation by 25±15% (p=0.004). The resulting “gastrocnemius avoidance” gait pattern reduced the late-stance peak of simulation-estimated knee contact force by 12±12% (p=0.029). Simulation-informed muscle coordination retraining could be a promising treatment for knee osteoarthritis and a powerful tool for optimizing coordination for a variety of rehabilitation and performance applications.
Mirror Neurons are Modulated by Grip Force and Reward Expectation in the Sensorimotor Cortices (S1, M1, PMd, PMv)
Authors: Atique Md Moin Uddin , Francis Joseph Thachil
Published: January 2021

Mirror Neurons (MNs) respond similarly when primates make, or observe, grasping movements. Recent work indicates that reward expectation influences rostral M1 (rM1) during manual, observational, and Brain Machine Interface (BMI) reaching movements. Previous work showed MNs are modulated by subjective value. Here we expand on the above work utilizing two non-human primates (NHPs), one maleMacacaRadiata (NHP S) and one femaleMacacaMulatta (NHP P), that were trained to perform a cued reward level isometric grip-force task, where the NHPs had to apply visually cued grip-force to move and transport a virtual object. We found a population of (S1 area 1-2, rM1, PMd, PMv) units that significantly represented grip-force during manual and observational trials. We found the neural representation of visually cued force was similar during observational trials and manual trials for the same units, however, the representation was weaker during observational trials. Comparing changes in neural time lags between manual and observational tasks indicated that a subpopulation fit the standard MN definition of observational neural activity lagging the visual information. Neural activity in (S1 areas 1-2, rM1, PMd, PMv) significantly represented force and reward expectation. In summary, we present results indicating that sensorimotor cortices have MNs for visually cued force and value.
Analysis of Scholarly Discourse in Biosecurity from 1986-2020
Authors: Li Ye Henry , Trounce Milana Boukhman
Published: January 2021

Scholarly discourse in Biosecurity is complex and interdisciplinary. The term ‘Biosecurity’ has different meanings depending on the discipline. This term most often strives to capture efforts to prepare for and respond to threats posed by infectious organisms1. Increasing complexity of discourse in this interdisciplinary field and lack of common definitions can pose communication challenges. We use text mining of scholarly articles to characterize the interdisciplinary field of Biosecurity and the uses of this term over the past 35 years; a context evolution model is built to describe major changes in this field, and it shows a progression toward health security in recent years. Understanding the shifts in discourse predominance helps to illuminate the major challenges facing biosecurity research and academic community, and contributes to enhancing communication across disciplines within the Biosecurity field.
RNA editing controls meiotic drive by a Neurospora Spore killer
Authors: Rhoades Nicholas A. , Hammond Thomas M.
Published: January 2021

NeurosporaSk-2is a complex meiotic drive element that is transmitted to offspring through sexual reproduction in a biased manner.Sk-2’s biased transmission mechanism involves spore killing, and recent evidence has demonstrated that spore killing is triggered by a gene calledrfk-1. However, a second gene,rsk, is also critically important for meiotic drive by spore killing because it allows offspring with anSk-2genotype to survive the toxic effects ofrfk-1. Here, we present evidence demonstrating thatrfk-1encodes two protein variants: a 102 amino acid RFK-1Aand a 130 amino acid RFK-1B, but only RFK-1Bis toxic. We also show that expression of RFK-1Brequires an early stop codon inrfk-1mRNA to undergo adenosine-to-inosine (A-to-I) mRNA editing. Finally, we demonstrate that RFK-1Bis toxic when expressed within vegetative tissue of Spore killer sensitive (SkS) strains, and that this vegetative toxicity can be overcome by co-expressingSk-2’s version of RSK. Overall, our results demonstrate thatSk-2uses RNA editing to control when its spore killer is produced, and that the primary killing and resistance functions ofSk-2can be conferred upon anSkSstrain by the transfer of only two genes.
All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity
Authors: Severin Daniel , Hong Su Z. , Roh Seung-Eon , Huang Shiyong , Zhou Jiechao , Bridi Michelle C. D. , Hong Ingie , Murase Sachiko , Robertson Sarah , Haberman Rebecca , Huganir Richard , Gallagher Michela , Quinlan Elizabeth M. , Worley Paul , Kirkwood Alfredo
Published: January 2021

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected novel form of experience-dependent circuit plasticity. In layer 2/3 of mouse visual cortex monocular deprivation triggers a complete, “all-or-none”, elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr➔PV). This circuit plasticity is unique as it is transient, local and discrete. It lasts only one day, and it does not manifest as widespread changes in synaptic strength, rather, only about half of local connections are lost and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr➔PV is contingent on a reduction of the protein neuropentraxin2 (NPTX2). Functionally, the loss of Pyr➔PV is absolutely necessary for ODP. We surmise, therefore, that this “all-or-none” loss of local Pyr➔PV circuitry gates experience-dependent cortical plasticity.
Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques
Authors: Wood Matthew P. , Jones Chloe I. , Lippy Adriana , Oliver Brian G. , Walund Brynn , Fancher Katherine A. , Fisher Bridget S. , Wright Piper J. , Fuller James T. , Murapa Patience , Habib Jakob , Mavigner Maud , Chahroudi Ann , Sather D. Noah , Fuller Deborah H. , Sodora Donald L.
Published: January 2021

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody levels and SIV plasma viral load (with RP infants having low SIV-specific antibodies and high viral loads). Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype, with 5 of these succumbing to AIDS-related infections. Interestingly, the TypP and RP infants were similar in their CD4 depletion and activation of CD8 T cells as measured by the levels of HLA-DR on the cell surface. However, differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.
Neuron tracing and quantitative analyses of dendritic architecture reveal symmetrical three-way-junctions and phenotypes ofgit-1inC. elegans
Authors: Yuval Omer , Iosilevskii Yael , Meledin Anna , Podbilewicz Benjamin , Shemesh Tom
Published: January 2021

Complex dendritic trees are a distinctive feature of neurons. Alterations to dendritic morphology are associated with developmental, behavioral and neurodegenerative changes. The highly-arborized PVD neuron ofC. elegansserves as a model to study dendritic patterning; however, quantitative, objective and automated analyses of PVD morphology are missing. Here, we present a method for neuronal feature extraction, based on deep-learning and fitting algorithms. The extracted neuronal architecture is represented by a database of structural elements for abstracted analysis. We obtain excellent automatic tracing of PVD trees and uncover that dendritic junctions are unevenly distributed. Surprisingly, these junctions are three-way-symmetrical on average, while dendritic processes are arranged orthogonally. We quantify the effect of mutation ingit-1, a regulator of dendritic spine formation, on PVD morphology and discover a localized reduction in junctions. Our findings shed new light on PVD architecture, demonstrating the effectiveness of our objective analyses of dendritic morphology and suggest molecular control mechanisms.

Author Summary

Nerve cells (neurons) collect input signals via branched cellular projections called dendrites. A major aspect of the study of neurons, dating back over a century, involves the characterization of neuronal shapes and of their dendritic processes.

Here, we present an algorithmic approach for detection and classification of the tree-like dendrites of the PVD neuron inC. elegansworms. A key feature of our approach is to represent dendritic trees by a set of fundamental shapes, such as junctions and linear elements. By analyzing this dataset, we discovered several novel structural features. We have found that the junctions connecting branched dendrites have a three-way-symmetry, although the dendrites are arranged in a crosshatch pattern; and that the distribution of junctions varies across distinct sub-classes of the PVD’s dendritic tree. We further quantified subtle morphological effects due to mutation in thegit-1gene, a known regulator of dendritic spines. Our findings suggest molecular mechanisms for dendritic shape regulation and may help direct new avenues of research.
CO2signalling mediates neurovascular coupling in the cerebral cortex
Authors: Hosford Patrick S , Wells Jack A , Ruminot Iván , Christie Isabel N , Theparambil Shefeeq M , Hadjihambi Anna , Barros L Felipe , Lythgoe Mark F , Gourine Alexander V
Published: January 2021

The mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models that the neuronal activity-dependent increases in local cerebral blood flow in the somatosensory cortex are abolished by saturation of brain CO2-sensitive vasodilatory mechanism or disruption of brain HCO3-/CO2transport, independently of baseline cerebral perfusion and brain tissue pH. These results suggest that increases in metabolic CO2production and CO2signalling play an important role in the development of neurovascular coupling response.
The gastrin-releasing peptide regulates stress-enhanced fear and dopamine signaling
Authors: Morishita Yoshikazu , Fuentes Ileana , Favate John , Zushida Ko , Nishi Akinori , Hevi Charles , Goldsmith Noriko , Buyske Steve , Sillivan Stephanie E. , Miller Courtney A. , Kandel Eric R. , Uchida Shusaku , Shah Premal , Shumyatsky Gleb P.
Published: January 2021

Fear extinction is an adaptive behavioral process critical for organism’s survival, but deficiency in extinction may lead to PTSD. While the amygdala and its neural circuits are critical for fear extinction, the molecular identity and organizational logic of cell types that lie at the core of these circuits remain unclear. Here we report that mice deficient for amygdala-enrichedgastrin-releasing peptidegene (Grp-/-) exhibit enhanced neuronal activity in the basolateral amygdala (BLA) and stronger fear conditioning, as well as deficient extinction in stress-enhanced fear learning (SEFL). rAAV2-retro-based tracing combined with visualization of the GFP knocked in theGrpgene showed that BLA receives GRPergic or conditioned stimulus projections from the indirect auditory thalamus-to-auditory cortex pathway, ventral hippocampus and ventral tegmental area. Transcription of dopamine-related genes was decreased in BLA ofGrp-/-mice following SEFL extinction recall, suggesting that the GRP may mediate fear extinction regulation by dopamine.

Impact statement

Mice deficient for the amygdala-enrichedgastrin-releasing peptidegene are susceptible to stress-enhanced fear, a behavioral protocol with relevance to PTSD, and show a decrease in dopamine-related gene transcription.