bluuebunny/crossref_metadata_2025 huggingface dataset:
GRHL2 enhances phosphorylated estrogen receptor DNA-binding and regulates ER-mediated transcriptional activation and repression
Authors: Reese Rebecca M. , Helzer Kyle T. , Allen Kaelyn O. , Zheng Christy , Solodin Natalia , Alarid Elaine T.
Published: May 2022

Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) is induced by estrogen and is the most abundant post-translational mark associated with a transcriptionally active receptor. Cistromic analysis of pS118-ER from our group found enrichment of the GRHL2 motif near pS118-ER binding sites. In this report we use cistromic and transcriptomic analyses to interrogate the relationship between GRHL2 and pS118-ER. We found that GRHL2 is bound to chromatin at pS118-ER/GRHL2 co-occupancy sites prior to ligand treatment, and GRHL2 binding is required for maximal pS118-ER recruitment. pS118-ER/GRHL2 co-occupancy sites were enriched at active enhancers marked by H3K27ac and H3K4me1, along with FOXA1 and p300. Transcriptomic analysis yielded four subsets of ER/GRHL2 co-regulated genes revealing that GRHL2 can both enhance and antagonize E2-mediated ER transcriptional activity. Gene ontology analysis identified several coregulated genes involved in cell migration. Accordingly, knockdown of GRHL2 combined with estrogen treatment resulted in increased cell migration but no change in proliferation. These results support a model in which GRHL2 binds to select enhancers and facilitates pS118-ER recruitment to chromatin which then results in differential activation and repression of genes that control ER-positive breast cancer cell migration.
Firefly-inspired vocabulary generator for communication in multi-agent systems
Authors: Nguyen Chantal , Huang Isabella , Peleg Orit
Published: May 2022

Fireflies’ dazzling light displays are courtship rituals: flying males announce their presence as suitable mates to the females on the ground. Their light signal is composed of a species-specific on/off light sequence repeated periodically. However, thousands of fireflies flashing in a swarm can create immense visual clutter that hinders the detection of potential mates. A partial solution to this visual clutter problem is to flash according to sequences that are more distinct and detectable than those of other individuals. Here, we investigate how distinguishable flash sequences can co-evolve by developing a method for simulating sequences that minimize their mutual similarity with each other while minimizing their energetic cost and predation risk. This simple set of rules produces flash sequences that are remarkably similar to those of real fireflies. In particular, we observe an emergent periodicity in the resulting sequences, despite the lack of any periodicity requirements on the sequences. In addition, we demonstrate a method of reconstructing the evolutionary pressures acting on sets of firefly species. We do so by carrying out simulations that follow known phylogenetic relationships of extant species alongside their characteristic flash patterns.
Maximuma posteriorinatural scene reconstruction from retinal ganglion cells with deep denoiser priors
Authors: Wu Eric G. , Brackbill Nora , Sher Alexander , Litke Alan M. , Simoncelli Eero P. , Chichilnisky E.J.
Published: May 2022

Visual information arriving at the retina is transmitted to the brain by signals in the optic nerve, and the brain must rely solely on these signals to make inferences about the visual world. Previous work has probed the content of these signals by directly reconstructing images from retinal activity using linear regression or nonlinear regression with neural networks. Maximuma posteriori(MAP) reconstruction using retinal encoding models and separately-trained natural image priors offers a more general and principled approach. We develop a novel method for approximate MAP reconstruction that combines a generalized linear model for retinal responses to light, including their dependence on spike history and spikes of neighboring cells, with the image prior implicitly embedded in a deep convolutional neural network trained for image denoising. We use this method to reconstruct natural images fromex vivosimultaneously-recorded spikes of hundreds of retinal ganglion cells uniformly sampling a region of the retina. The method produces reconstructions that match or exceed the state-of-the-art in perceptual similarity and exhibit additional fine detail, while using substantially fewer model parameters than previous approaches. The use of more rudimentary encoding models (a linear-nonlinear-Poisson cascade) or image priors (a 1/fspectral model) significantly reduces reconstruction performance, indicating the essential role of both components in achieving high-quality reconstructed images from the retinal signal.
A Gated Graph Transformer for Protein Complex Structure Quality Assessment and its Performance in CASP15
Authors: Chen Xiao , Morehead Alex , Liu Jian , Cheng Jianlin
Published: May 2022

Motivation

Proteins interact to form complexes to carry out essential biological functions. Computational methods such as AlphaFold-multimer have been developed to predict the quaternary structures of protein complexes. An important yet largely unsolved challenge in protein complex structure prediction is to accurately estimate the quality of predicted protein complex structures without any knowledge of the corresponding native structures. Such estimations can then be used to select high-quality predicted complex structures to facilitate biomedical research such as protein function analysis and drug discovery.

Results

In this work, we introduce a new gated neighborhood-modulating graph transformer to predict the quality of 3D protein complex structures. It incorporates node and edge gates within a graph transformer framework to control information flow during graph message passing. We trained, evaluated and tested the method (called DProQA) on newly-curated protein complex datasets before the 15th Critical Assessment of Techniques for Protein Structure Prediction (CASP15) and then blindly tested it in the 2022 CASP15 experiment. The method was ranked 3rd among the single-model quality assessment methods in CASP15 in terms of the ranking loss of TM-score on 36 complex targets. The rigorous internal and external experiments demonstrate that DProQA is effective in ranking protein complex structures.

Availability

The source code, data, and pre-trained models are available athttps://github.com/jianlin-cheng/DProQA

Contact

chengji@missouri.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
The placement of foot-mounted IMU sensors does affect the accuracy of spatial parameters during regular walking
Authors: Küderle Arne , Roth Nils , Zlatanovic Jovana , Zrenner Markus , Eskofier Bjoern , Kluge Felix
Published: May 2022

Gait analysis using foot-worn inertial measurement units has proven to be a reliable tool to diagnose and monitor many neurological and musculoskeletal indications. However, only few studies have investigated the robustness of such systems to changes in the sensor attachment and no consensus for suitable sensor positions exists in the research community. Specifically for unsupervised real-world measurements, understanding how the reliability of the monitoring system changes when the sensor is attached differently is from high importance. In these scenarios, placement variations are expected because of user error or personal preferences. In this manuscript, we present the largest study to date comparing different sensor positions and attachments. We recorded 9000 strides with motion-capture reference from 14 healthy participants with six synchronized sensors attached at each foot. Spatial gait parameters were calculated using a double-integration method and compared to the reference system. The results indicate that relevant differences in the accuracy of the stride length exists between the sensor positions. While the average error over multiple strides is comparable, single stride errors and variability parameters differ greatly. We further present a physics model and an analysis of the raw sensor data to understand the origin of the observed differences. This analysis indicates that a variety of attachment parameters can influence the systems’ performance. While this is only the starting point to understand and mitigate these types of errors, we conclude that sensor systems and algorithms must be reevaluated when the sensor position or attachment changes.
Hyperbaric Oxygen for Treatment of Long COVID Syndrome (HOT-LoCO); Protocol for a Randomised, Placebo-Controlled, Double-Blind, Phase II Clinical Trial
Authors: Kjellberg Anders , Abdel-Halim Lina , Hassler Adrian , Gharbi Sara El , Al-Ezerjawi Sarah , Boström Emil , Sundberg Carl Johan , Pernow John , Medson Koshiar , Kowalski Jan , Rodriguez-Wallberg Kenny A , Zheng Xiaowei , Catrina Sergiu-Bogdan , Runold Michael , Ståhlberg Marcus , Bruchfeld Judith , Nygren-Bonnier Malin , Lindholm Peter
Published: May 2022

Introduction

Long COVID, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, post-exertional malaise, and cognitive dysfunction. There is currently no effective treatment, and the underlying mechanisms are unknown although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in Long COVID. This randomised placebo-controlled clinical trial will explore HBOT as a potential treatment for Long COVID. The primary objective is to evaluate if HBOT improves health related quality of life (HRQoL) for patients with Long COVID compared to placebo/sham. The main secondary objectives are to evaluate whether HBOT improves endothelial function, objective physical performance, and short term HRQoL.

Methods and Analysis

A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to Long COVID, with low HRQoL. Clinical data, HRQoL- questionnaires, blood samples, objective tests and activity meter data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over six weeks. Assessments for safety and efficacy will be performed at six, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND-36) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent Data Safety Monitoring Board.

Ethics and Dissemination

The trial is approved by The Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Product Agency (5.1-2020-36673). Positive, negative, and inconclusive results will be published in peer-reviewed scientific journals with open access.

Trial Registration

NCT04842448. EudraCT: 2021-000764-30

Strengths and limitations of this trial

Strengths

Randomised placebo-controlled, double-blind, parallel groups, clinical trial in compliance with ICH-GCP

Evaluation of safety and efficacy, including objective and explanatory endpoints

Independent Data Safety Monitoring Board (DSMB)

Limitations

New syndrome with unknown mechanisms

Power calculation is based on similar syndromes

Selection bias as patients are enrolled from the same post-COVID clinic
Plant to animal protein ratio in the diet: nutrient adequacy, long-term health and environmental pressure
Authors: Fouillet Hélène , Dussiot Alison , Perraud Elie , Wang Juhui , Huneau Jean-François , Kesse-Guyot Emmanuelle , Mariotti François
Published: May 2022

Background

Animal and plant protein sources have contrasting relationships with nutrient adequacy and long-term health, and their adequate ratio is highly debated.

Objective

We aimed to explore how the percentage of plant protein in the diet (%PP) relates to nutrient adequacy and long-term health but also to environmental pressures, to determine the adequate and potentially optimal %PP values.

Methods

Observed diets were extracted from the dietary intakes of French adults (INCA3, n=1 125). Using reference values for nutrients and disease burden risks for foods, we modeled diets with graded %PP values that simultaneously ensure nutrient adequacy, minimize long-term health risks and preserve at best dietary habits. This multi-criteria diet optimization was conducted in a hierarchical manner, giving priority to long-term health over diet proximity, under the constraints of ensuring nutrient adequacy and food cultural acceptability. We explored the tensions between objectives and identified the most critical nutrients and influential constraints by sensitivity analysis. Finally, environmental pressures related to the modeled diets were estimated using the AGRIBALYSE database.

Results

We find that nutrient-adequate diets must fall within the ∼15%-80% %PP range, a slightly wider range being nevertheless identifiable by waiving the food acceptability constraints. Fully healthy diets, also achieving the minimum-risk exposure levels for both unhealthy and healthy foods, must fall within the 25%-70% %PP range. All of these healthy diets were very distant from current typical diet. Those with higher %PP had lower environmental impacts, notably on climate change and land use, while being as far from current diet.

Conclusions

There is no single optimal %PP value when considering only nutrition and health, but high %PP diets are more sustainable. For %PP>80%, nutrient fortification/supplementation and/or new foods are required.
Neurostructural associations with traumatic experiences during child- and adulthood
Authors: Siehl Sebastian , Sicorello Maurizio , Herzog Julia , Nees Frauke , Kleindienst Nikolaus , Bohus Martin , Müller-Engelmann Meike , Steil Regina , Priebe Kathlen , Schmahl Christian , Flor Herta
Published: May 2022

Background

Adverse experiences can lead to severe mental health problems such as posttraumatic stress disorder (PTSD) throughout the lifespan. In individuals with PTSD, both global and local brain volume reductions have been reported—especially in the amygdala and hippocampus—while the literature on childhood maltreatment suggests strong dependency on the timing of adverse events. In the present study, we pooled data from two studies to contrast effects of reported trauma-exposure during neurodevelopmentally sensitive periods in early life with trauma-exposure during adulthood.

Methods

A total of 155 women were allocated into one of six age-matched groups according to timing of traumatization (childhood vs adulthood) and psychopathology (PTSD vs trauma-exposed healthy vs trauma-naïve healthy). Volumes of amygdala and hippocampus were compared between these groups. Six additional exploratory regions of interest (ROI) were included based on a recent meta-analysis.

Results

Amygdala volume was strongly dependent on timing of traumatization: Smaller amygdala volumes were observed in the childhood sample, while larger volumes were observed in the adulthood sample. Hippocampal volume comparisons revealed no statistically significant differences, although the descriptive pattern was similar to that found for the amygdala. The remaining exploratory ROIs showed significant group effects, but no timing effects.

Conclusions

Timing of traumatization was associated with amygdala volumes throughout the lifespan, with opposite effects dependent on age at trauma occurrence. The relevance of potential confounders like trauma-type and multiplicity is discussed.
Improving the efficiency of scale-up and deployment of community health workers in Mali: a geospatial analysis
Authors: Oliphant Nicholas P , Sy Zeynabou , Koné Brehima , Berthé Mohamed , Beebe Madeleine , Samake Moussa , Diabaté Mamoutou , Tounkara Salimata , Diarra Borodjan , Diarra Amadou B , Diawara Cheickna H , Yakimova Tsvetana , Florisse Sonia , Jackson Debra , Ray Nicolas , Doherty Tanya
Published: May 2022

Optimising the scale and deployment of community health workers (CHWs) is important for maximizing geographical accessibility of integrated primary health care (PHC) services. Yet little is known about approaches for doing so.

We used geospatial analysis to model optimised scale-up and deployment of CHWs in Mali, to inform strategic and operational planning by the Ministry of Health and Social Development. Accessibility catchments were modelled based on travel time, accounting for barriers to movement. We compared geographic coverage of the estimated population, under-five deaths, and plasmodium falciparum (Pf) malaria cases across different hypothetical optimised CHW networks and identified surpluses and deficits of CHWs compared to the existing CHW network.

A network of 15843 CHW, if optimally deployed, would ensure that 77.3% of the population beyond 5 km of the CSCom (community health centre) and CSRef (referral health facility) network would be within a 30-minute walk of a CHW. The same network would cover an estimated 59.5% of U5 deaths and 58.5% of Pf malaria cases. As an intermediary step, an optimised network of 4500 CHW, primarily filling deficits of CHW in the regions of Kayes, Koulikoro, Sikasso, and Ségou would ensure geographic coverage for 31.3% of the estimated population. There were no important differences in geographic coverage percentage when prioritizing CHW scale-up and deployment based on the estimated population, U5 deaths, or Pf malaria cases.

Our geospatial analysis provides useful information to policymakers and planners in Mali for optimising the scale-up and deployment of CHW and, in turn, for maximizing the value-for-money of resources of investment in CHWs in the context of the country’s health sector reform. Countries with similar interests in optimising the scale and deployment of their CHW workforce may look to Mali as an exemplar model from which to learn.
DNA Methylation as a Potential Mediator of the Association Between Prenatal Tobacco and Alcohol Exposure and Child Neurodevelopment in a South African Birth Cohort
Authors: Abrishamcar Sarina , Chen Junyu , Feil Dakotah , Kilanowski Anna , Koen Nastassja , Vanker Aneesa , Wedderburn Catherine J. , Donald Kirsten A. , Zar Heather J. , Stein Dan J. , Hüls Anke
Published: May 2022

Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N=113) and 24 months (N=187) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE).

PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R2=0.006). For PTE, 31 CpG sites and 8 CpG sites were identified as significant mediators (ACME and TEP<0.05) for the cognitive and motor domains at 6 months, respectively. For PAE, 16 CpG sites and 1 CpG site were significant mediators for the motor and adaptive behavior domains at 6 months, respectively. Several genes includingMAD1L1, CAMTA1, andALDH1A2have been implicated in neurodevelopmental delay, suggesting that differential DNAm may partly explain the biological mechanisms underlying the relationship between PTE and PAE and child neurodevelopment.
The Role of HIV Partner Services in the Modern Biomedical HIV Prevention Era: A Network Modeling Study
Authors: Jenness Samuel M. , Le Guillou Adrien , Lyles Cynthia , Bernstein Kyle T. , Krupinsky Kathryn , Enns Eva A. , Sullivan Patrick S. , Delaney Kevin P.
Published: May 2022

Background

HIV partner services can accelerate the use of antiretroviral-based HIV prevention tools (ART and PrEP), but its population impact on long-term HIV incidence reduction is challenging to quantify with traditional PS metrics of partner identified or HIV-screened. Understanding the role of partner services within the portfolio of HIV prevention interventions, including using it to efficiently deliver antiretrovirals, is needed to achieve HIV prevention targets.

Methods

We used a stochastic network model of HIV/STI transmission for men who have sex with men (MSM), calibrated to surveillance-based estimates in the Atlanta area, a jurisdiction with high HIV burden and suboptimal partner services uptake. Model scenarios varied successful delivery of partner services cascade steps (newly diagnosed “index” patient and partner identification, partner HIV screening, and linkage or reengagement of partners in PrEP or ART care) individually and jointly.

Results

At current levels observed in Atlanta, removal of HIV partner services had minimal impact on 10-year cumulative HIV incidence, as did improving a single partner services step while holding the others constant. These changes did not sufficiently impact overall PrEP or ART coverage to reduce HIV transmission. If all index patients and partners were identified, maximizing partner HIV screening, partner PrEP provision, partner ART linkage, and partner ART reengagement would avert 6%, 11%, 5%, and 18% of infections, respectively. Realistic improvements in partner identification and service delivery were estimated to avert 2–8% of infections, depending on the combination of improvements.

Conclusions

Achieving optimal HIV prevention with partner services depends on pairing improvements in index patient and partner identification with maximal delivery of HIV screening, ART, and PrEP to partners if indicated. Improving the identification steps without improvement to antiretroviral service delivery steps, or vice versa, is projected to result in negligible population HIV prevention benefit.
The trends in the uninsured rates among non-elderly adult patients hospitalized with acute pancreatitis in the US during 2004-2019
Authors: Kumar Vivek , Barkoudah Ebrahim , Jin David X , Banks Peter , McNabb-Baltar Julia
Published: May 2022

Background and Aim

The impact of health reforms such as affordable care act (ACA) and Medicaid expansion program on health insurance coverage among acute pancreatitis (AP) patients in the United States (US) is unknown. We report the trends and forecasts for the uninsured rates among acute pancreatitis (AP) patients in the US.

Methods

We included non-elderly adult patients (aged 18 -64 years), hospitalized with AP in the nationwide inpatient sample database years 2004-2019. We calculated the percentage of uninsured and Medicaid patients for each year and applied joinpoint (JP) regression model to study the trends.

Results

The uninsured rates among patients hospitalized with AP were almost twice compared to the national average rates for all hospitalized patients. Uninsured rates were higher among Hispanic and African American races, rural location, lower income quartiles and in the southern US regions. A statistically significant decline was observed during 2013-2016 with an APC of - 12.23 (−20--4); p<0/01). The decline was apparent among all racial groups, locations and income groups but not in the southern region where gap in the uninsured rates worsened compared to other geographical regions. The trends reversed more recently, and the uninsured rates surged in 2018 for the first time after 2010. In 2019, 12.5% AP patients were uninsured compared to 11.6% in 2017. The forecasts after taking unemployment rates into account showed that uninsured rates would peak in 2020 followed by a gentle decline in the following years but overall uninsured rates would remain higher compared to 2017.

Conclusions

The ACA and Medicaid expansion programs resulted in overall decrease in the uninsured rates, particularly among racial minorities, rural location and in the lowest income group. However, there was a surge in uninsured rate in the most recent years (2017-2019) which will continue during the next four years
Heterologous Expression of NoxA Confers Aerotolerance in Clostridium sporogenes
Authors: Sadr Sara , Zargar Bahram , Perez Justo , Aucoin Marc , Ingalls Brian
Published: May 2022

Clostridium is a genus of Gram-positive obligate anaerobic bacteria. Some species of Clostridium, including C. sporogenes, may be of use in bacteria-mediated cancer therapy. Spores of Clostridium are inert in healthy normoxic tissue, but germinate when in the hypoxic regions of solid tumors, causing tumor regression. However, such treatments fail to completely eradicate tumors because of higher oxygen levels rise at the tumor’s outer rim. In this study, we demonstrate that a degree of aerotolerance can be introduced to C. sporogenes by transfer of the noxA gene from C. aminovalericum. NoxA is a water-forming NADH oxidase enzyme. Thus, its activity has no detrimental effect on cell viability. In addition to its potential in cancer treatment, the noxA-expressing strain described here could be used to alleviate challenges related to oxygen sensitivity of C. sporogenes in biomanufacturing.
A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8
Authors: Tarasov Kirill V. , Chakir Khalid , Riordon Daniel R. , Lyashkov Alexey E. , Ahmet Ismayil , Perino Maria Grazia , Silvester Allwin Jennifa , Zhang Jing , Wang Mingyi , Lukyanenko Yevgeniya O. , Qu Jia-Hua , Barrera Miguel Calvo-Rubio , Juhaszova Magdalena , Tarasova Yelena S , Ziman Bruce , Telljohann Richard , Kumar Vikas , Ranek Mark , Lammons John , Beshkov Rostislav , deCabo Rafael , Jun Seungho , Keceli Gizem , Gupta Ashish , Yang Dongmei , Aon Miguel A. , Adamo Luigi , Morrell Christopher H. , Otu Walter , Carroll Cameron , Chambers Shane , Paolocci Nazareno , Huynh Thanh , Pacak Karel , Weiss Robert G , Field Loren , Sollott Steven J. , Lakatta Edward G
Published: May 2022

Adult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload (∼30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here we show that despite markedly increased cardiac work, classical cardiac hypertrophy markers were absent in TGAC8, total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8was encased by thicker LV walls harboring an increased number of small cardiac myocytes and a network of small interstitial non-cardiac myocytes, manifesting increased proliferation markers and compared to WT. Protein synthesis, proteosome activity, autophagy, and Nrf-2, Hsp90α, ACC2 protein levels were increased in TGAC8, but LV ATP and phosphocreatine levels in vivo did not differ by genotype. 2,323 transcripts and 2,184 proteins identified in unbiased omics analyses, spanning a wide array of biological processes and molecular functions in numerous cellular compartments differed in TGAC8vs WT; and over 250 canonical signaling pathways characteristic of adaptive survival circuitry of cancers, including PI3K and growth factor signaling, cytokine and T cell receptor signaling, immune responses, ROS scavenging, proliferation, protection from apoptosis, and nutrient sensing, were activated in TGAC8; and compared to WT there was a shift from fatty acid oxidation to increased aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, the adaptive paradigm, that becomes activated in the LV of TGAC8in response to severe chronic, intense AC/PKA/Ca2+signaling embodies many hallmarks of cancer.
Cerebellum Directly Modulates the Substantia Nigra Dopaminergic Activity
Authors: Washburn Samantha , Oñate Maritza , Yoshida Junichi , Vera Jorge , K. B. Ramakrishnan , Khatami Leila , Nadim Farzan , Khodakhah Kamran
Published: May 2022

Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show that the Cb-SNc form monosynaptic glutamatergic synapses with both dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation Cb-SNc axons in the SNc rapidly increases SNc activity, elevates striatal dopamine levels, and increases the probability of locomotion. During ongoing behavior, Cb-SNc axons are bilaterally activated prior to ambulation and unilateral lever manipulation. The Cb-SNc axons show prominent activation to water reward, and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly, and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor, and possibly reward processing.
Bees differentiate sucrose solution from water at a distance
Authors: Kienitz Melina , Czaczkes Tomer , De Agrò Massimo
Published: May 2022

Bees are perhaps the most important model for studying complex cognition in invertebrates, showing a variety of impressive abilities. Many experiments employ a training procedure in which the animal associates a characteristic of a “flower” (neutral stimulus) to sucrose solution (positive stimulus) over multiple foraging bouts. We hypothesized that sucrose solution might appear different from water to the bee sensorium, rendering it superfluous for the animal to learn the intended experimental cues. To test this hypothesis, we presented bumblebees simultaneously with 1.6M sucrose and water on artificial flowers. We presented the solutions in three conditions, to identify the most likely recognition mechanism: in drop form, inside cotton-plugged centrifuge tubes, and soaked into raised cigarette filters. The bumblebees chose to contact the sucrose solution significantly more often in all three conditions, confirming their ability to discriminate sucrose from water at a distance, with spectral differences being the most likely mechanism for this differentiation. These results have large implications for the design of training procedures, as the presence of an alternative cue may mask the learning of challenging tasks. This may force us to re-examine much of the literature and unpublished ‘negative results’ on bee cognition: weakening some claims, but strengthening others.
SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly
Authors: Onnis Anna , Andreano Emanuele , Cassioli Chiara , Pantano Elisa , Abbiento Valentina , Marotta Giuseppe , Rappuoli Rino , Baldari Cosima T
Published: May 2022

CTL-mediated killing of virally infected or malignant cells is orchestrated at a specialized intercellular junction, the immune synapse (IS). We hypothesized that SARS-CoV-2 may target IS assembly in CTLs to escape killing. We show that primary human CD8+ T cells strongly upregulate the expression of ACE2, the Spike protein receptor, during differentiation to CTLs. CTL pre-incubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarisation to the IS, resulting in impaired target cell killing. These defects were reversed by anti-Spike antibodies that interfere with ACE2 binding and were reproduced by ACE2 engagement with Angiotensin-II or an anti-ACE2 antibody, but not by the ACE2 product Ang (1-7). These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent the elimination of infected cells.

Summary statement

We report a new mechanism of immune evasion by SARS-CoV-2 based on direct disabling CTLs to form immune synapses through Spike protein binding to ACE2. This mechanism could contribute to the failure of the immune system to control SARS-CoV-2 infection.
Graph-based algorithms for Laplace transformed coalescence time distributions
Authors: Bisschop Gertjan
Published: May 2022

Extracting information on the selective and demographic past of populations that is contained in samples of genome sequences requires a description of the distribution of the underlying genealogies. Using the Laplace transform, this distribution can be generated with a simple recursive procedure, regardless of model complexity. Assuming an infinite-sites mutation model, the probability of observing specific configurations of linked variants within small haplotype blocks can be recovered from the Laplace transform of the joint distribution of branch lengths. However, the repeated differentiation required to compute these probabilities has proven to be a serious computational bottleneck in earlier implementations.

Here, I show that the state space diagram can be turned into a computational graph, allowing efficient evaluation of the Laplace transform by means of a graph traversal algorithm. This general algorithm can, for example, be applied to tabulate the likelihoods of mutational configurations in non-recombining blocks. This work provides a crucial speed up for existing composite likelihood approaches that rely on the joint distribution of branch lengths to fit isolation with migration models and estimate the parameters of selective sweeps. The associated software is available as an open-source Python library, agemo.
Drosophila embryos spatially sort their nutrient stores to facilitate their utilization
Authors: Kilwein Marcus D. , Johnson Matthew R. , Thomalla Jonathon M. , Mahowald Anthony , Welte Michael A.
Published: May 2022

Animal embryos are provisioned by their mothers with a diverse nutrient supply critical for development. In Drosophila, the three most abundant nutrients (triglycerides, proteins, and glycogen) are sequestered in distinct storage structures, lipid droplets (LDs), yolk vesicles (YVs) and glycogen granules (GGs). Using transmission electron microscopy as well as live and fixed-sample fluorescence imaging, we find that all three storage structures are dispersed throughout the egg but are then spatially allocated to distinct tissues by gastrulation: LDs largely to the peripheral epithelium, YVs and GGs to the central yolk cell. To confound the embryo’s ability to sort its nutrients, we employ mutants in Jabba and Mauve to generate LD:GG or LD:YV compound structures. In these mutants, LDs are missorted to the yolk cell and their turnover is delayed. Our observations demonstrate dramatic spatial nutrient sorting in early embryos and provide the first evidence for its functional importance.
The Batten disease protein CLN3 is important for stress granules dynamics and translational activity
Authors: Relton Emily L. , Roth Nicolas J. , Yasa Seda , Kaleem Abuzar , Hermey Guido , Lefrancois Stephane , McCormick Peter J. , Locker Nicolas
Published: May 2022

The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganising cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions and signalling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent of aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations inCLN3are causative of juvenile neuronal ceroid lipofuscinosis (JNCL), a rare neurodegenerative disease affecting children.CLN3encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa KO model, we now show that CLN3KOis associated with an altered metabolic profile, reduced global translation, and altered stress signalling. We further demonstrate that loss of CLN3 results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.
Automated optimisation of solubility and conformational stability of antibodies and proteins
Authors: Rosace Angelo , Bennett Anja , Oeller Marc , Mortensen Mie M. , Sakhnini Laila , Lorenzen Nikolai , Poulsen Christian , Sormanni Pietro
Published: May 2022

Biologics, such as antibodies and enzymes, are crucial in research, biotechnology, diagnostics, and therapeutics. Often, biologics with suitable functionality are discovered, but their development is impeded by developability issues. Stability and solubility are key biophysical traits underpinning developability potential, as they determine aggregation, correlate with production yield and polyspecificity, and are essential to access parenteral and oral delivery. While advances for the optimisation of individual traits have been made, the co-optimization of multiple traits remains highly problematic and time-consuming, as mutations that improve one property often negatively impact others. In this work, we introduce a fully automated computational strategy for the simultaneous optimisation of conformational stability and solubility, which we experimentally validate on six antibodies, including two approved therapeutics. Our results on 42 designs demonstrate that the computational procedure is highly effective at improving developability potential, while not affecting antigen-binding.

We make the method available as a webserver atwww-cohsoftware.ch.cam.ac.uk
Statistical significance and biological relevance: The case ofNosema ceranaeand honey bee colony losses in winter
Authors: Schüler Vivian , Liu Yuk-Chien , Gisder Sebastian , Horchler Lennart , Groth Detlef , Genersch Elke
Published: May 2022

Managed and wild insect pollinators play a key role in ensuring that mankind is adequately supplied with food. Among the pollinating insects, the managed Western honey bee providing about 90% of commercial pollination is of special importance. Hence, diseases as well as disease causing pathogens and parasites that threaten honey bees, have become the focus of many research studies. The ectoparasitic miteVarroa destructortogether with deformed wing virus (DWV) vectored by the mite have been identified as the main contributors to colony losses, while the role of the microsporidiumNosema ceranaein colony losses is still controversially discussed. In an attempt to solve this controversy, we statistically analyzed a unique data set on honey bee colony health comprising data on mite infestation levels,Nosemaspp. infections and winter losses continuously collected over 15 years. We used various statistical methods to investigate the relationship between colony mortality and the two pathogens,V. destructorandN. ceranae. Our multivariate statistical analysis confirmed thatV. destructoris the major cause of colony winter losses. When using cumulative data sets, we also found a significant relationship betweenN. ceranaeinfections and colony losses. However, determining the effect size revealed that this statistical significance was of low biological relevance, because the deleterious effects ofN. ceranaeinfection are normally masked by the more severe effects ofV. destructoron colony health and therefore only detectable in the few colonies that are not infested with mites or are infested at low levels.
Quantification and statistical modeling of Chromium-based single-nucleus RNA-sequencing data
Authors: Kuo Albert , Hansen Kasper D. , Hicks Stephanie C.
Published: May 2022

In complex tissues containing cells that are difficult to dissociate, single-nucleus RNA-sequencing (snRNA-seq) has become the preferred experimental technology over single-cell RNA-sequencing (scRNA-seq) to measure gene expression. To accurately model these data in downstream analyses, previous work has shown that droplet-based scRNA-seq data are not zero-inflated, but whether droplet-based snRNA-seq data follow the same probability distributions has not been systematically evaluated. Using pseudo-negative control data from nuclei in mouse cortex sequenced with the 10x Genomics Chromium system, we found that snRNA-seq data follow a negative binomial distribution, suggesting that parametric statistical models applied to scRNA-seq are transferable to snRNA-seq. Furthermore, we found that the quantification choices in adapting quantification mapping strategies from scRNA-seq to snRNA-seq can play a significant role in downstream analyses and biological interpretation. In particular, reference transcriptomes that do not include intronic regions result in significantly smaller library sizes and incongruous cell type classifications. We also confirmed the presence of a gene length bias in snRNA-seq data, which we show is present in both exonic and intronic reads, and investigate potential causes for the bias.
Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption
Authors: Ingram Robbie J. , Leverton Leanna K. , Daniels Victoria C. , Li Jiang , Christian-Hinman Catherine A.
Published: May 2022

Patients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice.

HIGHLIGHTS

Increased GABA transmission to GnRH neurons in IHKA mouse model of epilepsy

Increased GABA transmission is dependent on upstream glutamate signaling

Increased GABA transmission only seen in females with disrupted estrous cycles

Potential sex-specific mechanism for reproductive endocrine dysfunction in epilepsy
Quadrangular Space Syndrome: A Systematic Review of Surgical and Medical Therapeutic advances
Authors: Charmode Sundip , Sharma Shelja , Kushwaha Sudhir , Mehra Simmi , Philip Shalom , Janagal Ranjna , Amrutiya Pratik
Published: May 2022

The Axillary Nerve (AXN) and Posterior Circumflex Humeral Artery (PCHA) are compressed in quadrangular space syndrome (QSS), which can be treated with conservative approaches or surgical decompression in recalcitrant instances. There are no clear guidelines for determining which surgical method is optimal for treating QSS and other disorders that mirror QSS. The goal of this study is to grade and review past, current, and planned medicinal and surgical care modalities for QSS. PROSPERO was used to submit the review protocol (ID: 332766). To identify recent advances in the methods/techniques of medical and surgical management of QSS, PubMed and Medline databases were searched until March 2022 for publications, including case studies, case reports, and review articles, using Medical Subject Headings (MeSH) terms like quadrilateral space syndrome, surgical management, and medical management. Throughout the study, all the authors scrupulously followed a well-developed registered review process and the risk of bias in systematic reviews (ROBIS) guidance tool. Data on proposed medical and surgical management methods/techniques was compiled, and each was analyzed based on the underlying neuro-vascular systems. There were 88 items found in the first search. Following applying the inclusion and exclusion criteria, 16 papers were chosen for synthesis in the review study after a thorough assessment. Three studies (conservative and advanced) focused on medical care of QSS, while 12 articles (prior, current, and newer) focused on surgical management of QSS. Only four of the 15 studies reviewed proposed different surgical approaches/techniques for surgical decompression in QSS. There were two regularly used surgical procedures discovered, one anterior/delto-pectoral and the other posterior/scapular. The anterior route is more technically straightforward and can be employed for surgical QSS decompression.
Improved antibody-specific epitope prediction using AlphaFold and AbAdapt
Authors: Xu Zichang , Davila Ana , Wiamowski Jan , Teraguchi Shunsuke , Standley Daron M.
Published: May 2022

Antibodies recognize their cognate antigens with high affinity and specificity, but the prediction of binding sites on the antigen (epitope) corresponding to a specific antibody remains a challenging problem. To address this problem, we developed AbAdapt, a pipeline that integrates antibody and antigen structural modeling with rigid docking in order to derive antibody-antigen specific features for epitope prediction. In this study, we assess the impact of integrating the state-of-the-art protein modeling method AlphaFold with the AbAdapt pipeline and demonstrate significant improvement in the prediction of antibody-specific epitope residues.