bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Resolution Diffusion-Weighted Imaging for Evaluation of Extramural Tumor Invasion in Primary Rectal Cancer
Authors: Park Eun Joo , Kim Seung Ho , Jo Sung Jae , Nam Kyung Han , Lim Yun-jung , Jung Hyun Kyung
Published: May 2021

Objective

The aim of this study was to determine the added value of high-resolution diffusion-weighted imaging (DWI) to T2-weighted imaging (T2WI) for evaluation of extramural tumor invasion (EMTI) in patients with primary rectal cancer.

Methods

Seventy-eight patients who had undergone 3.0-T magnetic resonance imaging including DWI (b = 0, 1000 s/mm2, 2 mm iso-voxel) and subsequent surgery were included. Two blinded radiologists independently read the T2WI first and then the combined DWI set. They recorded their confidence level using a 5-point scale. The diagnostic accuracy was calculated by receiver operating characteristic curve analysis based on the histopathological results as the reference.

Results

The study population consisted of EMTI positive (n = 44) and negative (n = 34). The area under the curve was not significantly increased after adding DWI to T2WI (reader 1, 0.868–0.856, P = 0.5618; reader 2, 0.848–0.865, P = 0.4539).

Conclusion

Adding DWI to T2WI showed no additional diagnostic value for the evaluation of EMTI in patients with primary rectal cancer.
Simulation Training Improves Trainee Technical Skill and Procedural Attitudes in Endoscopic Gastrostomy Tube Placement
Authors: Wright Andrew P. , Patel Anish H. , Farida Jeremy P. , Suresh Suraj , Rizk Rafat S. , Prabhu Anoop
Published: May 2021

Introduction

Percutaneous endoscopic gastrostomy (PEG) tube placement remains a core competency of gastroenterology fellowship, although this procedure is performed infrequently. Some training programs lack sufficient procedural volume for trainees to develop confidence and competence in this procedure. We aimed to determine the impact of a simulation-based educational intervention on trainee technical skill and procedural attitudes in simulated PEG tube placement.

Methods

Gastroenterology fellows were invited to participate in the study. Baseline procedural attitudes toward PEG tube placement (self-confidence, perceived skill level, perceived level of required supervision) were assessed before simulation training using a Likert scale. Baseline technical skills were assessed by video recording–simulated PEG tube placement on a PEG tube simulator with scoring using a procedural checklist. Fellows next underwent individualized simulation training and repeated simulated PEG tube placement until greater than 90% of checklist items were achieved. Procedural attitudes were reassessed directly after the simulation. Technical skill and procedural attitudes were then reassessed 6 to 12 weeks later (delayed posttraining).

Results

Twelve fellows completed the study. Simulation training led to significant improvement in technical skill at delayed reassessment (52.9 ± 14.3% vs. 78.0 ± 8.9% correct, P = 0.0002). Simulation training also led to significant immediate improvements in self-confidence (2.1 ± 0.7 vs. 3.1 ± 0.3, P = 0.001), perceived skill level (2.2 ± 1.0 vs. 4 ± 1.1, P < 0.001), and perceived level of required supervision (2.2 ± 0.9 vs. 3.2 ± 0.6, P = 0.003).

Conclusions

Simulation training led to sustained improvements in gastroenterology fellows' technical skill and procedural attitudes in PEG tube placement. Incorporation of simulation curricula in gastroenterology fellowships for this infrequently performed procedure should be considered.
The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory Death
Authors: Villanueva Jeanette E. , Chew Hong C. , Gao Ling , Doyle Aoife , Scheuer Sarah E. , Hicks Mark , Jabbour Andrew , Dhital Kumud K. , Macdonald Peter S.
Published: May 2021

Background.

Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation.

Methods.

Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity.

Results.

Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage.

Conclusions.

Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.
Iain Donald Campbell. 24 April 1941—5 March 2014
Authors: Naismith James H.
Published: May 2021

Iain Campbell defined the study of proteins by nuclear magnetic resonance spectroscopy (NMR) in the UK, and was a towering international figure in biophysics and structural cell biology. His scientific career spanned nearly 50 years, almost entirely spent at the University of Oxford. As a PhD student he recorded electron spin resonance spectra, then later became a pioneer in the application of NMR methodology to whole cells, determining the world's second and UK's first protein structure by NMR. He ended his career as one of the leading scientific lights in integrin adhesion and focal cell assembly. His scientific contributions are characterized by intellectual rigour and a desire to solve the problem by applying the most appropriate tools. All who knew Iain noted his incredible work ethic, his precision and in particular his wry humour. The co-workers trained by Iain form the backbone of protein NMR internationally today, a tribute to his mentorship. His loss was deeply felt by colleagues across the world and of course most of all by his loving family.
Jennifer A. Clack. 3 November 1947—26 March 2020
Authors: Ahlberg P. E. , Smithson T. R.
Published: May 2021

Jennifer Clack (née Agnew) dedicated her entire research career of more than 40 years to the fish-tetrapod transition, the evolutionary process during the Devonian and Carboniferous periods that transformed a lineage of lobe-finned fishes into the earliest land vertebrates. She was widely regarded as the world leader in this field. During an expedition in the summer of 1987 to the Late Devonian vertebrate localities of East Greenland, Clack collected numerous fossils of two of the earliest tetrapods,
Acanthostega
and
Ichthyostega
, which revolutionized the understanding of these animals and created a surge of renewed interest in what had previously been a small and somnolent research area. However, much of her work focused on the Carboniferous, the time when the group underwent its first major diversification and the amphibian and amniote lineages first appeared. Here too she produced a stream of ground-breaking discoveries. She published close to 100 primary research papers, many in flagship journals, as well as numerous popular articles and the influential textbook
Gaining Ground
. Modest and unassuming in person, and unfailingly supportive towards young scientists, Jennifer Clack was enormously respected and helped to make the entire research field into a more open, collaborative, and welcoming environment.
COVID-19 Serology in New York State Using a Multiplex Microsphere Immunoassay
Authors: Hunt Danielle T. , Yates Jennifer L. , Kulas Karen E. , Carson Kyle , Lamson Theresa , Demarest Valerie , Furuya Andrea , Howard Kelly , Marchewka Mary , Stone Randy , Tucker Heidi , Warszycki Casey , Yee Jim , Yang He S. , Racine-Brzostek Sabrina , Zhao Zhen , Ejemel Monir , Li Qi , Wang Yang , Fernando Sebastian , La Carpia Francesca , Hod Eldad A. , McDonough Kathleen A. , Lee William T.
Published: May 2021

The emergence of SARS-CoV-2, leading to COVID-19, necessitated the development of new molecular and serological tests. Here, we describe a multiplexed serological assay developed as the global pandemic moved into New York State in the spring of 2020. The original microsphere immunoassay used a target antigen from the SARS-CoV-1 virus responsible for the 2003 SARS outbreak, but evolved to incorporate multiple SARS-CoV-2 protein antigens (nucleocapsid, spike and spike domains, spike and nucleocapsid proteins from seasonal human coronaviruses). Besides being highly versatile due to multiplex capabilities, the assay was highly specific and sensitive and adaptable to measuring both total antibodies and antibody isotypes. While determining the assay performance characteristics, we were able to identify antibody production patterns (e.g., kinetics of isotypes, individual variations) for total antibodies and individual antibody classes. Overall, the results provide insights into the laboratory response to new serology needs, and how the evolution and fine-tuning of a serology assay helped contribute to a better understanding of the antibody response to SARS-CoV-2.
Early mineralocorticoid receptor antagonism in diabetic nephropathy limits albuminuria by preserving the glomerular endothelial glycocalyx
Authors: Crompton Michael , Ferguson Joanne K. , Ramnath Raina D. , Onions Karen L. , Ogier Anna S. , Down Colin J. , Skinner Laura , Dixon Lauren K. , Sutak Judit , Harper Steven J. , Pontrelli Paola , Gesualdo Loreto , Welsh Gavin I. , Foster Rebecca R. , Satchell Simon C. , Butler Matthew J.
Published: May 2021

The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier (GFB). We have previously shown that excess mineralocorticoid receptor (MR) activation causes GEnGlx damage and albuminuria. Damage to the GEnGlx occurs early in the pathogenesis of diabetic nephropathy (DN). Here we sought to determine whether MR antagonism with spironolactone could prevent the development of albuminuria in diabetes, by preserving the GEnGlx to maintain the GFB. Streptozotocin-induced diabetic Wistar rats developed increased glomerular albumin permeability (Ps’alb) and albuminuria, with associated GEnGlx loss and increases in plasma and urine active matrix metalloproteinase 2 (MMP2). MR antagonism reduced urine active MMP2, preserved the GEnGlx, restored Ps’alb to control values and prevented diabetes-induced albuminuria progression. Enzymatic degradation of the GEnGlx, with hyaluronidase, reversed the effect of MR antagonism in diabetic rats, confirming the importance of GEnGlx preservation in this model. Using this model we validated a novel fluorescent profile peak-to-peak confocal imaging technique and applied it to assess GEnGlx damage on renal biopsies from patients with DN and compared them to healthy controls. We confirmed that GEnGlx loss occurs in human DN and may contribute to the disease phenotype. Taken together our work suggests GEnGlx preservation as an important novel mechanism for reno-protection by MR inhibitors in diabetes.

Translational Statement

Mineralocorticoid receptor (MR) antagonists reduce albuminuria in diabetic nephropathy (DN), but side effects limit their clinical utility, and the mechanism is unknown. This paper demonstrates that MR antagonism prevented the development of glomerular endothelial glycocalyx (GEnGlx) dysfunction and albuminuria. Highly specific, enzyme mediated, removal of the GEnGlx abolished this effect, confirming the importance of EnGlx preservation in this model. Our data also confirm that GEnGlx damage occurs in human DN and may contribute to the clinical phenotype. This work suggests directly targeting glycocalyx preservation in DN could reproduce the protective effects seen with MR inhibition, whilst avoiding side effects.
Evolutionary assembly of cooperating cell types in an animal chemical defense system
Authors: Brückner Adrian , Badroos Jean M. , Learsch Robert W. , Yousefelahiyeh Mina , Kitchen Sheila A. , Parker Joseph
Published: May 2021

A long-standing challenge in biology is explaining how the functions of multicellular organs emerge from the underlying evolution of cell types. We deconstructed evolution of an organ novelty: a rove beetle gland that secretes a defensive cocktail. We show that gland function was pieced together via assembly of two cell types that manufacture distinct compounds. One cell type forms a chemical reservoir in the beetle’s abdomen and produces alkane and ester compounds. We demonstrate that this cell type is a hybrid of cuticle cells and ancient pheromone and adipocyte-like cells, and executes its function via a mosaic of enzymes sourced from each parental cell type. The second cell type synthesizes noxious benzoquinones using a chimeric pathway derived from conserved cellular energy and cuticle formation pathways. We present evidence that evolution of each cell type was shaped by coevolution between the two cell types: the benzoquinones produced by the second cell type dissolve in solvents produced by the first, yielding a potent secretion that confers adaptive value onto the gland as a whole. Our findings illustrate how cooperation between cell types can arise, generating new, organ-level behaviors.
Effects of Slow Oscillatory Transcranial Alternating Current Stimulation on Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation
Authors: Geffen Asher , Bland Nicholas , Sale Martin V
Published: May 2021

Converging evidence suggests that transcranial alternating current stimulation (tACS) may entrain endogenous neural oscillations to match the frequency and phase of the exogenously applied current and this entrainment may outlast the stimulation (although only for a few oscillatory cycles following the cessation of stimulation). However, observing entrainment in the electroencephalograph (EEG) during stimulation is extremely difficult due to the presence of complex tACS artefacts. The present study assessed entrainment to slow oscillatory (SO) tACS by measuring motor cortical excitability across different oscillatory phases during (i.e., online) and outlasting (i.e., offline) stimulation. 30 healthy participants received 60 trials of intermittent SO tACS (0.75 Hz; 16s on / off interleaved) at an intensity of 2mA peak-to-peak. Motor cortical excitability was assessed using transcranial magnetic stimulation (TMS) of the hand region of the primary motor cortex (M1HAND) to induce motor evoked potentials (MEPs) in the contralateral thumb. MEPs were acquired at four time-points within each trial – early online, late online, early offline, and late offline – as well as at the start and end of the overall stimulation period (to probe longer-lasting aftereffects of tACS). A significant increase in MEP amplitude was observed from pre-to post-tACS (P = 0.013) and from the first to the last tACS block (P = 0.008). However, no phase-dependent modulation of excitability was observed. Therefore, although SO tACS had a facilitatory effect on motor cortical excitability that outlasted stimulation, there was no evidence supporting entrainment of endogenous oscillations as the underlying mechanism.
A Trifector of New Insights into Ovine Footrot for Infection Drivers, Immune Response and Host Pathogen Interactions
Authors: Blanchard Adam M. , Staley Ceri E. , Shaw Laurence , Wattegedera Sean R , Baumbach Christina-Marie , Michler Jule K. , Rutland Catrin , Back Charlotte , Newbold Nerissa , Entrican Gary , Tötemeyer Sabine
Published: May 2021

Footrot is a polymicrobial infectious disease in sheep causing severe lameness, leading to one of the industry’s biggest welfare problems. The complex aetiology of footrot makes in-situ or in-vitro investigations difficult. Computational methods offer a solution to understanding the bacteria involved, how they may interact with the host and ultimately providing a way to identify targets for future hypotheses driven investigative work. Here we present the first combined global analysis of the bacterial community transcripts together with the host immune response in healthy and diseased ovine feet during a natural polymicrobial infection state using metatranscriptomics. The intra tissue and surface bacterial populations and the most abundant bacterial transcriptome were analysed, demonstrating footrot affected skin has a reduced diversity and increased abundances of, not only the causative bacteria Dichelobacter nodosus, but other species such as Mycoplasma fermentans and Porphyromonas asaccharolytica. Host transcriptomics reveals a suppression of biological processes relating to skin barrier function, vascular functions, and immunosurveillance in unhealthy interdigital skin, supported by histological findings that type I collagen (associated with scar tissue formation) is significantly increased in footrot affected interdigital skin comparted to outwardly healthy skin. Finally, we provide some interesting indications of host and pathogen interactions associated with virulence genes and the host spliceosome which could lead to the identification of future therapeutic targets.

Impact Statement

Lameness in sheep is a global welfare and economic concern and footrot is the leading cause of lameness, affecting up to 70% of flocks in the U.K. Current methods for control of this disease are labour intensive and account for approximately 65% of antibiotic use in sheep farming, whilst preventative vaccines suffer from poor efficacy due to antigen competition. Our limited understanding of cofounders, such as strain variation and polymicrobial nature of infection mean new efficacious, affordable and scalable control measures are not receiving much attention. Here we examine the surface and intracellular bacterial populations and propose potential interactions with the host. Identification of these key bacterial species involved in the initiation and progression of disease and the host immune mechanisms could help form the basis of new therapies.
Histone acetyltransferases and deacetylases are required for virulence, conidiation, DNA damage repair, and multiple stresses resistance of Alternaria alternata
Authors: Ma Haijie , Li Lei , Gai Yunpeng , Zhang Xiaoyan , Chen Yanan , Zhuo Xiaokang , Cao Yingzi , Jiao Chen , Gmitter Fred G. , Li Hongye
Published: May 2021

Histone acetylation, which is critical for transcriptional regulation and various biological processes in eukaryotes, is a reversible dynamic process regulated by HATs and HDACs. This study determined the function of 6 histone acetyltransferases (HATs) (Gcn5, RTT109, Elp3, Sas3, Sas2, Nat3) and 6 histone deacetylases (HDACs) (Hos2, Rpd3, Hda1, Hos3, Hst2, Sir2) in the phytopathogenic fungus Alternaria alternata by analyzing targeted gene deletion mutants. Our data provide evidence that HATs and HDACs are both required for mycelium growth, cell development and pathogenicity as many gene deletion mutants (ΔGcn5, ΔRTT109, ΔElp3, ΔSas3, ΔNat3, ΔHos2, and ΔRpd3) displayed reduced growth, conidiation or virulence at varying degrees. In addition, HATs and HDACs are involved in the resistance to multiple stresses such as oxidative stress (Sas3, Gcn5, Elp3, RTT109, Hos2), osmotic stress (Sas3, Gcn5, RTT109, Hos2), cell wall-targeting agents (Sas3, Gcn5, Hos2), and fungicide (Gcn5, Hos2). ΔGcn5, ΔSas3 and ΔHos2 displayed severe growth defects on sole carbon source medium suggesting a vital role of HATs and HDACs in carbon source utilization. More SNPs were generated in ΔGcn5 in comparison to wild-type when they were exposed to ultraviolet ray. Moreover, ΔRTT109, ΔGcn5 and ΔHos2 showed severe defects in resistance to DNA-damaging agents, indicating the critical role of HATs and HDACs in DNA damage repair. These phenotypes correlated well with the differentially expressed genes in ΔGcn5 and ΔHos2 that are essential for carbon sources metabolism, DNA damage repair, ROS detoxification, and asexual development. Furthermore, Gcn5 is required for the acetylation of H3K4. Overall, our study provides genetic evidence to define the central role of HATs and HDACs in the pathological and biological functions of A. alternata.

Importance

In filamentous fungi, HATs and HDACs have been found to be involved in growth, development, virulence, synthesis of secondary metabolites and multi-stress resistance. However, the role of all HATs and HDACs in the same fungal pathogen has not been systematically explored. Our study revealed that HATs and HDACs are required for the vegetative growth, conidiation, pathogenicity, multiple stresses resistance, DNA damage repair, and carbon source utilization in A. alternata. Moreover, HATs and HDACs identified in A. alternata are highly conserved in many notorious pathogenic fungi, such as Magnaporthe grisea and Candida albicans. Therefore, this study not only systematically reveals the biological functions of twelve histone acetylation-required enzymes for the first time, but also provides a foundation for future investigations in A. alternata or other pathogenic fungi.
Hypervirulent extensively-drug resistant (XDR) Klebsiella pneumoniae associated with complicated urinary tract infection in Northern India
Authors: Kaza Parinitha , Britto Xavier Basil , Mahindroo Jaspreet , Baker Stephen , Nguyen To Nguyen Thi , Mavuduru Ravimohan Suryanarayana , Mohan Balvinder , Taneja Neelam
Published: May 2021

Klebsiella pneumoniae associated with hospital acquired infections in South Asia are frequently extensively-drug resistant (XDR), making treatment and control problematic. It is important to understand the epidemiology and genetic structure of XDR K. pneumoniae and to determine their potential to be hypervirulent (hv) through the presence of siderophores. Here, we characterized the genomes of 20 colistin-resistant XDR K. pneumoniae isolated from 16 patients with complicated UTI over a six-month period in a healthcare facility in northern India. The 16 organisms comprised five STs: ST14 (10/20), ST147 (5/20), ST231 (3/20), ST2096 (1/20), and ST25 (1/20). Notably, several patients admitted to a single ward were infected with the same ST, potentially indicating a common infection source. Additionally, some patients had recurrent infections with multiple STs that were circulating concurrently in a particular ward, providing further evidence for hospital transmission. Beta lactamase genes (blaCTX-M-1, blaSHV, blaLEN, and blaAMP-H) were present in all isolates and the blaNDM,blaOXA1-90, and blaOXA48 carbapenemases were present in 17, 18, and 3 isolates, respectively. Disruption of mgrB with various IS elements was identified in six organisms and was the most common mechanism of colistin resistance. The most frequent K type was K2 (11/20), followed by K10, K51, and K64. Notably, we identified one XDR convergent hypervirulent K. pneumoniae (hvKp) associated with prolonged hospitalisation (iuc+ybt+ESBL+OXA-1, OXA-48), belonging to ST2096. Our data suggest that convergent XDR-hvKp is circulating in our healthcare facility. We speculate that such organisms may have outbreak potential, warranting more effective antimicrobial stewardship and better infection control strategies.
Pregnancy and birth outcomes after SARS-CoV-2 vaccination in pregnancy
Authors: Theiler Regan N. , Wick Myra , Mehta Ramila , Weaver Amy , Virk Abinash , Swift Melanie
Published: May 2021

Background

SARS-CoV-2 infection during pregnancy is associated with significant maternal morbidity and increased rates of preterm birth. For this reason, COVID-19 vaccine administration in pregnancy has been endorsed by multiple professional societies including ACOG and SMFM despite exclusion of pregnant women from initial clinical trials of vaccine safety and efficacy. However, to date little data exists regarding outcomes after COVID-19 vaccination of pregnant patients.

Study Design

A comprehensive vaccine registry was combined with a delivery database for an integrated healthcare system to create a delivery cohort including vaccinated patients. Maternal sociodemographic data were examined univariately for factors associated with COVID-19 vaccination. Pregnancy and birth outcomes were analyzed, including a composite measure of maternal and neonatal pregnancy complications, the Adverse Outcome Index.

Results

Of 2002 patients in the delivery cohort, 140 (7.0%) received a COVID-19 vaccination during pregnancy and 212 (10.6%) experienced a COVID-19 infection during pregnancy. The median gestational age at first vaccination was 32 weeks (range 13 6/7-40 4/7), and patients vaccinated during pregnancy were less likely than unvaccinated patients to experience COVID-19 infection prior to delivery (1.4% (2/140) vs. 11.3% (210/1862)) P<0.001No maternal COVID-19 infections occurred after vaccination during pregnancy.

Factors significantly associated with increased likelihood of vaccination included older age, higher level of maternal education, lower pre-pregnancy BMI, and use of infertility treatment for the current pregnancy. Tobacco or other substance use, Hispanic ethnicity, and higher gravidity were associated with a lower likelihood of vaccination. No significant difference in the composite adverse outcome (5.0% (7/140) vs. 4.9% (91/1862) P=0.95) or other maternal or neonatal complications, including thromboembolic events and preterm birth, was observed in vaccinated mothers compared to unvaccinated patients.

Conclusions

Vaccinated pregnant women in this birth cohort were less likely to experience COVID-19 infection compared to unvaccinated pregnant patients, and COVID-19 vaccination during pregnancy was not associated with increased pregnancy or delivery complications. Significant sociodemographic disparities in vaccine uptake and/or access were observed among pregnant patients, and future efforts should focus on outreach to low-uptake populations.
Delta-9-tetrahydrocannabinol and cannabidiol in psychosis: A balancing act of the principal phyto-cannabinoids on human brain and behavior?
Authors: Ganesh Suhas , Cortes-Briones Jose , Martin Ashley M. Schnakenberg , Skosnik Patrick D , D’Souza Deepak C , Ranganathan Mohini
Published: May 2021

Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations. In this double-blind randomized placebo-controlled counterbalanced human laboratory experiment, we examined the effects of three different dose ratios of CBD: THC (1:1, 2:1 and 3:1) on ‘neural noise’, an electrophysiological biomarker of psychosis known to be sensitive to cannabinoids as well as subjective and psychotomimetic effects. Interestingly, the lowest CBD:THC ratio (1:1) resulted in maximal attenuation of both THC induced psychotomimetic effects (PANSS positive - ATS = 7.83, df = 1, pcorr = 0.015) and neural noise (ATS = 8.83, df = 1, pcorr = 0.009) with an inverse-linear dose response relationship. Further, in line with previous studies, addition of CBD did not reduce the subjective experience of THC induced “high” (p > 0.05 for all CBD doses).

These novel results demonstrate that CBD attenuates THC induced subjective and objective effects relevant to psychosis- but in a dose/ratio dependent manner. Given the increasing global trend of cannabis liberalization and application for medical indications, these results assume considerable significance given the potential dose related interactions of these key phyto-cannabinoids.
SARS-like coronaviruses in horseshoe bats (Rhinolophus spp.) in Russia, 2020
Authors: Alkhovsky Sergey V. , Lenshin Sergey V. , Romashin Alexey V. , Vishnevskaya Tatyana V. , Vyshemirsky Oleg I. , Bulycheva Yulia I. , Lvov Dmitry K. , Gitelman Asya K.
Published: May 2021

We found and genetically described two novel SARS-like coronaviruses in feces and oral swabs of the great (R. ferrumequinum) and the lesser (R. hipposideros) horseshoe bats in southern region of Russia. The viruses, named Khosta-1 and Khosta-2, together with related viruses from Bulgaria and Kenya, form a separate phylogenetic lineage. We found an evidence of recombination events in evolutionary history of Khosta-1, which involved the acquisition of structural proteins S, E, and M as well as nonstructural genes ORF3, ORF6, ORF7a, and ORF7b from a virus that is closely related to Kenyan isolate BtKY72. Examination of bats by RT-PCR revealed that 62,5% of great horseshoe bats in one of the caves were positive for Khosta-1 virus while its overall prevalence was 14%. The prevalence of Khosta-2 was 1,75%. Our results show that SARS-like coronaviruses circulate in horseshoe bats in the region and provide a new data on their genetic diversity.
Platelet expression and reactivity after BNT162b2 vaccine administration
Authors: Klug Melissa , Lazareva Olga , Kirmes Kilian , Rosenbaum Marc , Lukas Marina , Weidlich Simon , Spinner Christoph D. , von Scheidt Moritz , Gosetti Rosanna , Baumbach Jan , Ruland Jürgen , Condorelli Gianluigi , Laugwitz Karl-Ludwig , List Markus , Bernlochner Isabell , Bongiovanni Dario
Published: May 2021

SARS-CoV-2 infection induces a coagulopathy characterized by platelet activation and a hypercoagulable state with an increased incidence of cardiovascular events. The viral spike protein S has been reported to enhance thrombosis formation, stimulate platelets to release pro-coagulant factors and promote the formation of platelet-leukocyte aggregates even in absence of the virus. Although SARS-CoV-2 vaccines induce spike protein overexpression to trigger SARS-CoV-2-specific immune protection, thrombocyte activity has not been investigated in this context. Here, we provide the first phenotypic platelet characterization of healthy human subjects undergoing BNT162b2 vaccination.

Using mass cytometry, we analyzed the expression of constitutive transmembrane receptors, adhesion proteins and platelet activation markers in 12 healthy donors before and at five different timepoints within four weeks after the first BNT162b2 administration. We measured platelet reactivity by stimulating thrombocyte activation with thrombin receptor-activating peptide (TRAP). Activation marker expression (P-Selectin, LAMP-3, LAMP-1, CD40L and PAC-1) did not change after vaccination. All investigated constitutive transmembrane proteins showed similar expressions over time. Platelet reactivity was not altered after BNT162b2 administration. Activation marker expression was significantly lower compared to an independent cohort of mild symptomatic COVID-19 patients analyzed with the same platform.

This study reveals that BNT162b2 administration does not alter platelet protein expression and reactivity.
The New Therapeutics in Alzheimer’s Disease Longitudinal Cohort study (NTAD): study protocol
Authors: Lanskey Juliette H , Kocagoncu Ece , Quin Andrew J , Cheng Yun-Ju , Karadag Melek , Pitt Jemma , Isaac John , Lowe Stephen , Perkinton Michael , Raymont Vanessa , Singh Krish D , Woolrich Mark , Nobre Anna C , Henson Richard N , Rowe James B
Published: May 2021

Introduction

With the pressing need to develop treatments that slow or stop the progression of Alzheimer’s disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease.

Methods and Analysis

The New Therapeutics in Alzheimer’s disease study (NTAD) aims to identify a biomarker set from magneto/electro-encephalographic that is sensitive to disease and progression over one year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimer’s disease and 30 healthy controls aged between 50 and 85 years. Repeat measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and magnetic resonance imaging) of participants with Alzheimer’s disease or mild cognitive impairment will be taken at baseline and at one year. To assess reliability of magneto/electro-encephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimer’s disease will undergo repeat magneto/electro-encephalographic two weeks after baseline. Clinical and cognitive assessment will be repeated at 2 years. Linear mixed models of baseline and longitudinal change in neurophysiology are the primary analyses of interest, supported by Bayesian inference. Additional outputs will include relative effect sizes for physiological markers, atrophy and cognitive change and the respective numbers needed to treat each arm of simulated clinical trials of a future disease modifying therapy.

Ethics and dissemination

The study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.

STRENGTHS AND LIMITATIONS OF THIS STUDY

Strengths

NTAD is a longitudinal, multicentre study of magneto/electro-encephalographic measures of Alzheimer’s disease progression

NTAD assesses the test-retest reliability of magneto/electro-encephalographic parameters

All participants with early-stage Alzheimer’s disease or mild cognitive impairment will be amyloid-positive

Limitations

Attrition during follow up may limit inferences

Recruitment is from volunteer panels and clinical services that may not reflect national diversity of people affected by Alzheimer’s disease
Incorporating structural knowledge into unsupervised deep learning for two-photon imaging data
Authors: Eichin Florian , Hackenberg Maren , Broichhagen Caroline , Kilias Antje , Schmoranzer Jan , Bartos Marlene , Binder Harald
Published: May 2021

Live imaging techniques, such as two-photon imaging, promise novel insights into cellular activity patterns at a high spatio-temporal resolution. While current deep learning approaches typically focus on specific supervised tasks in the analysis of such data, we investigate how structural knowledge can be incorporated into an unsupervised generative deep learning model directly at the level of the video frames. We exemplify the proposed approach with two-photon imaging data from hippocampal CA1 neurons in mice, where we account for spatial structure with convolutional neural network components, disentangle the neural activity of interest from the neuropil background signal with separate foreground and background encoders and model gradual temporal changes by imposing smoothness constraints. Taken together, our results illustrate how such architecture choices facilitate a modeling approach that combines the flexibility of deep learning with the benefits of domain knowledge, providing an interpretable, purely image-based model of activity signals from live imaging data.

Teaser sentence

Using a neural network architecture that reflects domain knowledge provides an interpretable model of live cell imaging data.
A combined lifestyle intervention induces a sensitization of the blood transcriptomic response to a nutrient challenge
Authors: Gehrmann Thies , Beekman Marian , Deelen Joris , Partridge Linda , van de Rest Ondine , Mei Leon , Raz Yotam , de Groot Lisette , van der Breggen Ruud , Reinders Marcel J. T. , van den Akker Erik B. , Slagboom P. Eline
Published: May 2021

The global population is growing older. As age is a primary risk factor of (multi)morbidity, there is a need for novel indicators to predict, track, treat and prevent the development of disease. Lifestyle interventions have shown promising results in improving the health of participants and reducing the risk for disease, but in the elderly population, such interventions often show less reliable or subtle effects on health outcomes. This is further complicated by a poor understanding of the homeodynamics and the molecular effects of lifestyle interventions, by which their effects of a lifestyle intervention remain obscured. In the Growing Old Together (GOTO) study, we examined the responses of 164 healthy, elderly men and women to a 13-week combined physical and dietary lifestyle intervention. In addition to collecting blood samples at a fasted state, we sampled blood also 30 minutes following a standardized meal. This allows us to investigate an intervention response not only in the traditional fasted state, but also in the blood metabolic and cellular responses to a nutrient challenge. We investigated the transcriptomic and metabolomic responses to this nutrient challenge, how these responses relate to each other, and how this response is affected by the lifestyle intervention.

We find that the intervention has very little effect on the fasted blood transcriptome, but that the nutrient challenge induces a large translational inhibition, and an innate immune activation, which together comprise a cellular stress response that is stimulated by the intervention. A sex-specific analysis reveals that although the same set of genes respond in the same direction in both males and females, the magnitude of these effects differ, and are modulated differently by the intervention. On the other hand, the metabolomic response to the nutrient challenge is largely unaffected by the intervention, and the correlation between the metabolomic nutrient response and transcriptomic modules indicates that the change in transcriptomic response to the nutrient challenge is independent from a change in cellular metabolomic environment.

This work constitutes a glance at the acute transcriptomic stress response to nutrient intake in blood, and how a lifestyle intervention affects this response in healthy elderly, and may lead to the development of novel biomarkers to capture the phenotypic flexibility of health.
Y recombination arrest and degeneration in the absence of sexual dimorphism
Authors: Lenormand Thomas , Roze Denis
Published: May 2021

Current theory proposes degenerated sex chromosomes evolve via three successive steps: recombination arrest, which links male-beneficial alleles to the Y chromosome; degeneration of these regions due to the inefficacy of natural selection in the absence of recombination; and lastly, the evolution of dosage compensation to correct the resulting low expression of X-linked genes in males. Here we investigate new models of sex chromosome evolution incorporating the coevolution of cis- and trans-regulators of gene expression. We show that the early emergence of dosage compensation favors the maintenance of Y-linked inversions by creating sex-antagonistic regulatory effects. This is followed by inversion degeneration caused by regulatory divergence between the X and Y chromosomes. In stark contrast to the current theory, the whole process occurs without any selective pressure related to sexual dimorphism.

One Sentence Summary

Turning sex chromosome theory on its head: early evolution of dosage compensation can maintain successively forming Y chromosome strata that undergo genetic degeneration.
The processing of semantic complexity and co-speech gestures in schizophrenia: a naturalistic, multimodal fMRI study
Authors: Cuevas Paulina , He Yifei , Steines Miriam , Straube Benjamin
Published: May 2021

Schizophrenia is marked by aberrant processing of complex speech and gesture, which may contribute functionally to its impaired social communication. To date, extant neuroscientific studies of schizophrenia have largely investigated dysfunctional speech and gesture in isolation, and no prior research has examined how the two communicative channels may interact in more natural contexts. Here, we tested if patients with schizophrenia show aberrant neural processing of semantically complex story segments, and if speech-associated gestures (co-speech gestures) might modulate this effect. In a functional MRI study, we presented to 34 participants (16 patients and 18 matched-controls) an ecologically-valid retelling of a continuous story, performed via speech and spontaneous gestures. We split the entire story into ten-word segments, and measured the semantic complexity for each segment with idea density, a linguistic measure that is commonly used clinically to evaluate aberrant language dysfunction at semantic level. Per segment, the presence of numbers of gestures varied (n = 0, 1, +2). Our results suggest that, in comparison to controls, patients showed reduced activation for more complex segments in the bilateral middle frontal and inferior parietal regions. Importantly, this neural aberrance was reduced in segments presented with gestures. Thus, for the first time with a naturalistic multimodal stimulation paradigm, we show that gestures reduced group differences when processing a natural story, probably by facilitating the processing of semantically complex segments of the story in schizophrenia.
Highly basic clusters in the HSV-1 nuclear egress complex drive membrane budding by inducing lipid ordering
Authors: Thorsen Michael K. , Lai Alex , Lee Michelle W. , Hoogerheide David P. , Wong Gerard C. L. , Freed Jack H. , Heldwein Ekaterina E.
Published: May 2021

During replication of herpesviruses, capsids escape from the nucleus into the cytoplasm by budding at the inner nuclear membrane. This unusual process is mediated by the viral nuclear egress complex (NEC) that deforms the membrane around the capsid by oligomerizing into a hexagonal, membrane-bound scaffold. Here, we found that highly basic membrane-proximal regions (MPRs) of the NEC alter lipid order by inserting into the lipid headgroups and also promote negative Gaussian curvature. We also find that the electrostatic interactions between the MPRs and the membranes are essential for membrane deformation. One of the MPRs is phosphorylated by a viral kinase during infection, and the corresponding phosphomimicking mutations block capsid nuclear egress. We show that the same phosphomimicking mutations disrupt the NEC/membrane interactions and inhibit NEC-mediated buddingin vitro, providing a biophysical explanation for thein-vivophenomenon. Our data suggest that the NEC generates negative membrane curvature by both lipid ordering and protein scaffolding and that phosphorylation acts as an “off” switch that inhibits the membrane-budding activity of the NEC to prevent capsid-less budding.
Fusion of single-cell transcriptome and DNA-binding data, for genomic network inference in cortical development
Authors: Bartlett Thomas
Published: May 2021

Background

Network models are well-established as very useful computational-statistical tools in cell biology. However, a genomic network model based only on gene expression data can, by definition, only infer gene co-expression networks. Hence, in order to infer gene regulatory patterns, it is necessary to also include data related to binding of regulatory factors to DNA.

Results

We propose a new dynamic genomic network model, for inferring patterns of genomic regulatory influence in dynamic processes such as development. Our model fuses experiment-specific gene expression data with publicly available DNA-binding data. The method we propose is computationally efficient, and can be applied to genome-wide data with tens of thousands of transcripts. Thus, our method is well suited for use as an exploratory tool for genome-wide data. We apply our method to data from human fetal cortical development, and our findings confirm genomic regulatory patterns which are recognised as being fundamental to neuronal development.

Conclusions

Our method provides a mathematical/computational toolbox which, when coupled with targeted experiments, will reveal and confirm important new functional genomic regulatory processes in mammalian development.
ModEst - Precise estimation of genome size from NGS data
Authors: Pfenninger Markus , Schönnenbeck Philipp , Schell Tilman
Published: May 2021

Precise estimates of genome sizes are important parameters for both theoretical and practical biodiversity genomics. We present here a fast, easy-to-implement and precise method to estimate genome size from the number of bases sequenced and the mean sequence coverage. To estimate the latter, we take advantage of the fact that a precise estimation of the Poisson distribution parameter lambda is possible from truncated data, restricted to the part of the coverage distribution representing the true underlying distribution. With simulations we could show that reasonable genome size estimates can be gained even from low-coverage (10X), highly discontinuous genome drafts. Comparison of estimates from a wide range of taxa and sequencing strategies with flow-cytometry estimates of the same individuals showed a very good fit and suggested that both methods yield comparable, interchangeable results.
Structure induces computational function in networks with diverse types of spiking neurons
Authors: Stoeckl Christoph , Lang Dominik , Maass Wolfgang
Published: May 2021

Nature endows networks of spiking neurons in the brain with innate computing capabilities. But it has remained an open problem how the genome achieves that. Experimental data imply that the genome encodes synaptic connection probabilities between neurons depending on their genetic types and spatial distance. We show that this low dimensional parameterization suffices for programming fundamental computing capabilities into networks of spiking neurons. However, this method is only effective if the network employs a substantial number of different neuron types. This provides an intriguing answer to the open question why the brain employs so many neuron types, many more than were used so far in neural network models. Neural networks whose computational function is induced through their connectivity structure, rather than through synaptic plasticity, are distinguished by short wire length and robustness to weight perturbations. These neural networks features are not only essential for the brain, but also for energy-efficient neuromorphic hardware.
Presence of a SARS-COV-2 protein enhances Amyloid Formation of Serum Amyloid A
Authors: Jana Asis K. , Greenwood Augustus B. , Hansmann Ulrich H. E.
Published: May 2021

A marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. In order to understand whether SAA amyloidosis could also be a long-term risk of SARS-COV-2 infections we have used long all-atom molecular dynamic simulations to study the effect of a SARS-COV-2 protein segment on SAA amyloid formation. Sampling over 40 µs we find that presence of the nine-residue segment SK9, located at the C-terminus of the Envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis and related pathologies may be a long-term risk of SARS-COV-2 infections.