bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomness in the choice of neighbours promotes cohesion in mobile animal groups
Authors: Jadhav Vivek , Guttal Vishwesha , Masila Danny Raj
Published: March 2022

Classic computational models of collective motion suggest that simple local averaging rules can promote many observed group-level patterns. Recent studies, however, suggest that rules simpler than local averaging may be at play in real organisms; for example, fish stochastically align towards only one randomly chosen neighbour and yet the schools are highly polarized. Here, we ask—how do organisms maintain group cohesion? Using a spatially explicit model, inspired from empirical investigations, we show that group cohesion can be achieved in finite groups even when organisms randomly choose only one neighbour to interact with. Cohesion is maintained even in the absence of local averaging that requires interactions with many neighbours. Furthermore, we show that choosing a neighbour randomly is a better way to achieve cohesion than interacting with just its closest neighbour. To understand how cohesion emerges from these random pairwise interactions, we turn to a graph-theoretic analysis of the underlying dynamic interaction networks. We find that randomness in choosing a neighbour gives rise to well-connected networks that essentially cause the groups to stay cohesive. We compare our findings with the canonical averaging models (analogous to the Vicsek model). In summary, we argue that randomness in the choice of interacting neighbours plays a crucial role in achieving cohesion.
Size is relative: use of relational concepts by wild hummingbirds
Authors: Brown Theo , Hurly T. Andrew , Healy Susan D. , Tello-Ramos Maria C.
Published: March 2022

Rufous hummingbirds (
Selasphorus rufus
) will readily learn the location and the colour of rewarded flowers within their territory. But if these birds could apply a relational concept such as ‘the larger flowers have more nectar’, they could forego learning the locations of hundreds of individual flowers. Here, we investigated whether wild male territorial rufous hummingbirds might use ‘larger than’ and ‘smaller than’ relational rules and apply them to flowers of different sizes. Subjects were trained to feed consistently from one of two flowers. Although the flowers differed only in size, the reward was always contained in the same-size flower. The birds were then tested on a choice of two empty flowers: one of the familiar size and the other a novel size. Hummingbirds applied relational rules by choosing the flower that was of the correct relational size rather than visiting the flower of the size rewarded during training. The choices made by the hummingbirds were not consistent with alternative mechanisms such as peak shift or associative learning. We suggest that while hummingbirds are very good at remembering the spatial locations of rewarding flowers, they would be able to use relative rules when foraging in new and changing environments.
Support needs of people living with obesity during transition from tertiary obesity treatment to community care
Authors: Alsultany Ghada , El-Masri Aymen , MacMillan Freya , Williams Kath , McBride Kate A
Published: March 2022

Background: As the number of people living with obesity increases, the maintenance of
treatment outcomes is especially pertinent. Treatment at tertiary obesity services have
proven to be successful, but patients need to be transitioned out of these services to
community-based care to accommodate the influx of new patients. Little is known
about the support needs of patients after transition from acute tertiary obesity services.
It is important to establish the supports needed by these patients, especially in the
context of maintaining treatment outcomes and ensuring continuity of care.
Methods: A qualitative study was conducted to identify the support needs of people
with obesity as they transition to community care. Patients and clinicians recruited from
a tertiary obesity clinic participated in semi-structured interviews and focus groups to
explore factors influencing transition and supports needed in the community. Data was
collected through audio recordings, transcribed verbatim and analysed thematically.
Results: A total of 16 patients and 7 clinicians involved in the care of these patients
participated between July 2020 and July 2021. Themes identified included the
influence of clinic and individual factors on transition, the benefits of phased transition,
patient-centred communication, and the role of social support. It was found that
dependency and lack of self-efficacy, as well as low social support, hindered transition
efforts. It was also identified that patients required substantial integrated professional
and social support structures in the community to adequately address their care needs
both during and following transition.
Conclusion: Interventions are needed to provide social community services following
transition to ensure adequate community care that can support the maintenance of
treatment outcomes. Such services should be integrated and address the social needs
of people living with obesity.
Immunogenic superiority and safety of Biological E CORBEVAX vaccine compared to COVISHIELD (ChAdOx1 nCoV-19) vaccine studied in a phase III, single blind, multicenter, randomized clinical trial
Authors: Thuluva Subhash , Paradkar Vikram , Turaga Kishore , Gunneri Subbareddy , Yerroju Vijay , Mogulla Rammohan Reddy , Pothakamuri Venkata Suneetha , Kyasani Mahesh , Manoharan Senthilkumar , Adabala Srikanth , Javvadi Aditya Sri , Medigeshi Guruprasad R , Singh Janmejay , Shaman Heena , Binayke Akshay , Zaheer Aymaan , Awasrhi Amit , Singh Chandramani , A Venkateshwar Rao , Basu Indranil , Khobragade Akash Ashok Kumar , Pandey Anil Kumar
Published: March 2022

Background: Optimum formulation of Biological Es CORBEVAX vaccine that contains protein sub unit of Receptor Binding Domain (RBD) from the spike protein of SARS-COV-2 formulated with aluminum hydroxide (Al3+) and CpG1018 as adjuvants was selected in phase-1 and 2 studies and proven to be safe, well tolerated and immunogenic in healthy adult population. In the current study, additional data was generated to determine immunogenic superiority of CORBEVAX vaccine over COVISHIELD vaccine and safety in larger and older population.
Methods: This is a phase III prospective, single blinded, randomized, active controlled study (CTRI/2021/08/036074) conducted at 18 sites across India in healthy adults aged between 18-80 years. This study has two arms; immunogenicity arm and safety arm. Participants in immunogenicity arm were randomized equally to either CORBEVAX or COVISHIELD vaccination groups to determine the immunogenic superiority. Healthy adults without a history of Covid-19 vaccination or SARS-CoV-2 infection, were enrolled.
Findings: The safety profile of CORBEVAX vaccine was comparable to the comparator vaccine COVISHIELD in terms of overall AE rates, related AE rates and medically attended AEs. Majority of reported AEs were mild in nature, and overall CORBEVAX appeared to cause fewer local and systemic adverse reactions/events. Overall, two grade-3 serious AEs (Dengue fever and femur fracture) were reported and they are unrelated to study vaccine. Neutralizing Antibody titers, against both Ancestral and Delta strain, induced post two-dose vaccination regimen were higher in the CORBEVAX arm as compared to COVISHIELD and the analysis of GMT ratios demonstrated immunogenic superiority of CORBEVAX in comparison with COVISHIELD. Both CORBEVAX and COVISHIELD vaccines showed comparable seroconversion post vaccination when assessed against anti-RBD IgG response. The subjects in CORBEVAX cohort also exhibited higher Interferon-gamma secreting PBMCs post stimulation with SARS-COV-2 RBD peptides than the subjects in COVISHIELD cohort.
Interpretations: Neutralizing antibody titers induced by CORBEVAX vaccine against Delta and Ancestral strains were protective, indicative of vaccine effectiveness of >90% for prevention of symptomatic infections based on the Correlates of Protection assessment performed during Moderna and Astra-Zeneca vaccine Phase III studies. Safety findings revealed that CORBEVAX vaccine has excellent safety profile when tested in larger and older population.
A Standardised Protocol for Neuro-endoscopic Lavage for Post-haemorrhagic Ventricular Dilatation: A Delphi Consensus Approach
Authors:   DOLPHIN-UK Collaborators, Mediratta Saniya
Published: March 2022

Purpose
Neuro-endoscopic lavage (NEL) has shown promise as an emerging procedure for intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation (PHVD). However, there is considerable variation with regards to the indications, objectives, and surgical technique in NEL. There is currently no randomised trial evidence that supports the use of NEL in the context of PHVD. This study aims to form a consensus on technical variations in the indications and procedural steps of NEL.

Methods
A mixed methods modified Delphi consensus process was conducted between consultant paediatric neurosurgeons across the United Kingdom. Stages involved literature review, survey, focused online consultation and iterative revisions until > 80% consensus was achieved.

Results
Twelve consultant paediatric neurosurgeons from 10 centres participated. A standardised protocol including indications, a 3-phase operative workflow (pre-ventricular, intraventricular, post-ventricular) and post-operative care was agreed upon by 100% of participants. Case- and surgeon-specific variation was considered and included through delineation of mandatory, optional, and not recommended steps.

Conclusion
Expert consensus on a standardised protocol for NEL was achieved, delineating the surgical workflow into three phases: pre-ventricular, intraventricular, and post-ventricular, each consisting of mandatory, optional, and not recommended steps. The work provides a platform for future trials, training, and implementation of NEL.
Acceptance of COVID-19 vaccine among healthcare workers in Katsina state, Northwest Nigeria
Authors: Abubakar Ahmed Tijani , Suleiman Kabir , Ahmad Suleiman Idris , Suleiman Shamsuddeen Yahaya , Ibrahim Umar Bello , Suleiman Bello Abdullahi , Haladu Suleiman Ahmed , Al-Mustapha Ahmad Ibrahim , Abubakar Musa Imam
Published: March 2022

High acceptance of COVID-19 vaccines is crucial to ending the COVID-19 pandemic. Healthcare workers (HCWs) are frontline responders in the fight against COVID-19, they were prioritized to receive the COVID-19 vaccine in Nigeria. This study assessed the acceptance of the COVID-19 vaccine among HCWs in Katsina State using an online structured questionnaire and predicted variables that could increase the acceptance of the vaccine among HCWs using logistic regression analysis.
A total of 793 HCWs were included in this study. Of these, 65.4% (n=519) of them were male and 36.2% (n=287) were aged between 30-39 years. Eighty percent (80%, n=638) of the HCWs have been tested for the SARS-CoV-2 out of which 10.8% (n=65) of them tested positive. The majority of the HCWs (97.3%, n=765) believed that the COVID-19 vaccine was safe and 90% (n=714) of the HCWs have received the first dose of the COVID-19 vaccine. Our findings showed that the age of the HCW, their COVID-19 testing status, and the type of health facility they work (either public or private) were the main predictors for the acceptance of the COVID-19 vaccine among HCWs in Katsina state. HCWs between the age of 30-39 years were more likely (OR:7.06; 95% CI: 2.36, 21.07; p < 0.001) to accept the vaccine than others. In the same vein, HCWs that have been tested for COVID-19 were more likely (OR:7.64; 95% CI: 3.62, 16.16; p < 0.001) to accept the vaccine than those that have not been tested. In addition, HCWs in public health facilities were more likely (OR: 2.91; 95% CI: 1.17, 6.11; p = 0.094) to accept the COVID-19 vaccine than their counterparts in private health facilities.
There was a high acceptance of the COVID-19 vaccines among HCWs in Katsina State. More emphasis should be paid on adherence to non-pharmaceutical interventions and the availability of vaccines for HCWs in private hospitals.
Mitochondrial DAMPs as mechanistic biomarkers of mucosal inflammation in Crohn’s disease: Study protocol for prospective longitudinal cohort study in Scotland
Authors: Chuah Shaun , Hall Rebecca , Ward Emma , Drury Broc , Ho Gwo-tzer
Published: March 2022

The MUSIC study is a multi-centre, longitudinal study set in the real world IBD clinical setting to investigate and develop a new biomarker approach utilising mitochondrial DAMP and circulating DNA in assessing mucosal healing in Crohn’s disease. We present the study protocol (approved by East of Scotland Research Ethics Service, Scotland, United Kingdom - Reference No. 19/ES/0087) on 17th September 2019 and registered in ClinicalTrials.gov as NCT04760964 for this on-going project based in Scotland, UK.
Development and Validation of the Michigan Chronic Disease Simulation Model (MICROSIM)
Authors: Burke James F. , Copeland Luciana L. , Sussman Jeremy B. , Hayward Rodney A. , Gross Alden L. , Briceño Emily M. , Whitney Rachael , Giordani Bruno J. , Elkind Mitchell S. V. , Manly Jennifer J. , Gottesman Rebecca F. , Gaskin Darrell J. , Sidney Stephen , Yaffe Kristine , Sacco Ralph L. , Heckbert Susan R. , Hughes Timothy M. , Galecki Andrzej T. , Levine Deborah A.
Published: March 2022

Strategies to prevent or delay Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) are urgently needed. Blood pressure (BP) management is a promising strategy for AD/ADRD prevention and the key element in the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), yet the effects of different population level BP control strategies across the life course on AD/ADRD are not known.

Large-scale randomized controlled trials are the least biased approach to identifying the effect of BP control on AD/ADRD, yet trials may be infeasible due to the need for prolonged follow-up and very large sample sizes. Thus, simulation analyses leveraging the best available observational data may be the best and most practical approach to answering these questions.

In this manuscript, we describe the design principles, implementation details, and population-level validation of a novel population health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP COG) study of the effect of BP levels over the life course on cognitive decline and dementia.

MICROSIM was designed by applying computer programming best practices to create a novel simulation model. The initial purpose of this extensible, open-source framework is to explore a series of questions related to the impact of different blood pressure management strategies on late-life cognition and all-cause dementia, as well as the effects on race differences in all-cause dementia incidence. Ultimately, though, the framework is designed to be extensible such that a variety of different clinical conditions could be added to the framework.
Prevalence of neutralizing antibody to human coronavirus 229E in Taiwan
Authors: Chen Hao-Huan , Chen Wei-Fan , Hsieh Yhu-Chia , Chen Chih-Jung
Published: March 2022

Background Four members in the Coronaviruses family including 229E circulating in the community were known to cause mild respiratory tract infections in humans. The epidemiologic information of the seasonal human coronavirus (HCoV) may help gain insight into the development of the ongoing pandemic of coronavirus disease since 2019 (COVID-19).
Methods Plasma collection containing 1558 samples was obtained in 2010 for an estimate of the prevalence and severity of 2009 pandemic influenza A H1N1 in Taiwan. Of 1558 samples, 200 were randomly selected from those aged < 1 year to > 60 years. The neutralizing antibody titers to HCoV-229E were determined in the serums using live virus ATCC VR_740TM cultivating in the Huh_
7 cell line.
Results Seroconversion of HCoV-229E (titer ≥ 1:2) was identified as early as less than 5 years of age. Among 140 subjects aged younger than or equal to 40 years, all of them had uniformly low titers (< 1:10) and the geometric mean titers (GMTs) were not significantly different for those aged 0-5, 6-12, 13-18 and 19-40 years (P > 0.1). For 60 subjects greater than 40 years old, a majority (39, 65%) of them had high titers ≥ 1:10 and the GMTs were significantly increased with advanced age (P < 0.0001). Age was the most significant factor predicting seropositivity in the multivariate analysis, with an adjusted odds ratio of 1.107 and a 95% adjusted confidence interval of 1.061-1.155 (P < 0.0001).
Conclusion
HCoV-229E infection occurred as early as younger than 5 years old in Taiwanese and the magnitudes of neutralizing titers against HCoV-229E increased with advanced age beyond 40 years.
Usefulness of the pancreas as a prime target for histopathological diagnosis of Tilapia parvovirus (TiPV) infection in Nile tilapia, Oreochromis niloticus
Authors: Dong Ha Thanh , Sangpo Pattiya , Le Dien Thanh , Mai Thao Thu , Nguyen Vu Linh , Jorge del-Pozo Jorge , Salin Krishna R , Senapin Saengchan
Published: March 2022

Tilapia parvovirus (TiPV) is an emerging virus reportedly associated with disease and mortality in farmed tilapia. Although previous descriptions of histopathological changes are available, the lesions reported in these are not pathognomonic. Here, we report Cowdry type A inclusion bodies (CAIB) in the pancreas as a diagnostic histopathological feature found in adult Nile tilapia naturally infected with TiPV. This type of inclusion body has been well-known as a histopathological landmark for the diagnosis of other parvoviral infections in shrimp and terrestrial species. Interestingly, this lesion could be exclusively observed in pancreatic acinar cells, both in the hepatopancreas and pancreatic tissue along the intestine. In situ hybridization (ISH) using a TiPV-specific probe revealed the intranuclear presence of TiPV DNA in multiple tissues, including the liver, pancreas, kidney, spleen, gills, and the membrane of oocytes in the ovary. These findings suggest that although TiPV can replicate in several tissue types, CAIB manifest exclusively in pancreatic tissues. In addition to TiPV, most diseased fish were co-infected with Streptococcus agalactiae, and presented with multifocal granulomas secondary to this bacterial infection. Partial genome amplification of TiPV was successful and revealed high nucleotide identity (> 99%) to previously reported isolates. In summary, this study highlights the usefulness of pancreatic tissue as a prime target for histopathological diagnosis of TiPV in diseased Nile tilapia. This pattern may be critical when determining the presence of TiPV infection in new geographic areas, where ancillary testing may not be available. TiPV pathogenesis in this landmark organ warrants further investigation.
Three-dimensional multilayer concentric bipolar electrodes enhance the selectivity of optic nerve stimulation
Authors: Borda Eleonora , Gaillet Vivien , Airaghi Leccardi Marta JI , Zollinger Elodie G , Moreira Ricardo C. , Ghezzi Diego
Published: March 2022

Objective: Intraneural nerve interfaces often operate in a monopolar configuration with a common and distant ground electrode. This configuration leads to a wide spreading of the electric field. Therefore, this approach is suboptimal for intraneural nerve interfaces when selective stimulation is required. Approach: We designed a multilayer electrode array embedding three-dimensional concentric bipolar electrodes. First, we validated the higher stimulation selectivity of this new electrode array compared to classical monopolar stimulation using simulations. Next, we compared them in-vivo by intraneural stimulation of the rabbit optic nerve and recording evoked potentials in the primary visual cortex. Main results: Simulations showed that three-dimensional concentric bipolar electrodes provide a high localisation of the electric field in the tissue so that electrodes are electrically independent even for high electrode density. Experiments in-vivo highlighted that this configuration leads to evoked responses with lower amplitude and more localised cortical patterns due to the fewer fibres activated by the electric stimulus in the nerve. Significance: Highly focused electric stimulation is crucial to achieving high selectivity in fibre activation. The multilayer array embedding three-dimensional concentric bipolar electrodes improves selectivity in optic nerve stimulation. This approach is suitable for other neural applications, including bioelectronic medicine.
The generation of HepG2 transmitochondrial cybrids to reveal the role of mitochondrial genotype in idiosyncratic drug-induced liver injury: a translational in vitro study
Authors: Ball Amy Louise , Jolly Carol Elizabeth , Lyon Jonathan , Alfirevic Ana , Chadwick Amy
Published: March 2022

Background: Evidence supports an important link between mitochondrial DNA (mtDNA) variation and adverse drug reactions such as idiosyncratic drug-induced liver injury (iDILI). Here we describe the generation of HepG2-derived transmitochondrial cybrids in order to investigate the impact of mtDNA variation upon mitochondrial (dys)function and susceptibility to iDILI against a constant nuclear background. In this study, cybrids were created to contain mitochondrial genotypes of haplogroup H and haplogroup J for comparison. Methods: Briefly, HepG2 cells were depleted of mtDNA to make rho zero cells before the introduction of known mitochondrial genotypes using platelets from healthy volunteers (n=10), thus generating 10 distinct transmitochondrial cybrid cell lines. The mitochondrial function of each was assessed at basal state and following treatment with compounds associated with iDILI; flutamide, 2-hydroxyflutamide and tolcapone, by ATP assays and extracellular flux analysis Findings: Overall, baseline mitochondrial function was similar between haplogroups H and J. However, haplogroup specific responses to mitotoxic drugs were observed; haplogroup J was more susceptible to the inhibition of respiratory complexes I and II, and also to the effects of tolcapone, an uncoupler of mitochondrial respiration. Conclusions: This study demonstrates that HepG2 transmitochondrial cybrids can be created to contain the mitochondrial genotype of any individual of interest, thus providing a practical and reproducible system to investigate the cellular consequences of variation in mitochondrial genome against a constant nuclear background. Additionally the results support that that inter-individual variation in mitochondrial genotype and haplogroup may be a factor in determining sensitivity to mitochondrial toxicants. Funding: This work was supported by the Centre for Drug Safety Science supported by the Medical Research Council, United Kingdom (Grant Number G0700654); and GlaxoSmithKline as part of an MRC-CASE studentship (grant number MR/L006758/1).
Dietary fibre deprivation and bacterial curli exposure shift gut microbiome and exacerbate Parkinson's disease-like pathologies in an alpha-synuclein-overexpressing mouse
Authors: Schmit Kristopher J , Sciortino Alessia , Aho Velma TE , Garcia Pierre , Pardo Rodriguez Beatriz , Thomas Melanie H , Gerardy Jean-Jacques , Halder Rashi , Cialini Camille , Heurtaux Tony , Bastero Acha Irati , Ostahi Irina , Martens Eric C , Mittelbronn Michel , Buttini Manuel , Wilmes Paul
Published: March 2022

The microbiome-gut-brain axis has been proposed as a pathogenic path in Parkinson's disease (PD). Dietary driven dysbiosis and reduced gut barrier function could facilitate the interaction of toxic external or internal factors with the enteric nervous system, where PD could start. Amyloid bacterial protein such as curli can act as seed to corrupt enteric alpha-synuclein and lead to its aggregation. Misfolded alpha-synuclein can propagate to and throughout the brain. Here, we aimed at understanding if fibre deprivation and amyloidogenic protein curli could, individually or together, exacerbate the phenotype in both enteric and central nervous systems of a transgenic mouse overexpressing wild-type human alpha-synuclein. We analysed the gut microbiome, motor behaviour, gastrointestinal and brain pathologies in these mice. Our findings show that external interventions, akin to unhealthy life habits in humans, can exacerbate PD-like pathologies in mice. We believe that our results shed light on how lifestyle affects PD progression.
Optimized transcriptional signature for evaluation of MEK/ERK pathway baseline activity and long-term modulations in ovarian cancer
Authors: Chesnokov Mikhail S. , Yadav Anil , Chefetz Ilana
Published: March 2022

Ovarian cancer is the most aggressive and lethal of all gynecologic malignancies. High activity of the MEK/ERK signaling pathway is tightly associated with tumor growth, high recurrence rate, and treatment resistance. Several transcriptional signatures were proposed recently for evaluation of MEK/ERK activity in tumor tissue. In the present study, we validated the performance of a robust multi-cancer MPAS 10-gene signature in various experimental models and publicly available sets of ovarian cancer samples. Expression of four MPAS genes (PHLDA1, DUSP4, EPHA2, andSPRY4) displayed reproducible responses to MEK/ERK activity modulations across several experimental modelsin vitroandin vivo. Levels ofPHLDA1, DUSP4, andEPHA2expression were also significantly associated with baseline levels of MEK/ERK pathway activity in multiple human ovarian cancer cell lines and ovarian cancer patient samples available from the TCGA database. HighEPHA2expression, platinum therapy resistance, and advanced age at diagnosis were associated with poor overall patient survival. Taken together, our results demonstrate that performance of transcriptional signatures is significantly affected by tissue specificity and aspects of particular experimental models. We therefore propose that gene expression signatures derived from comprehensive multi-cancer studies should be always validated for each cancer type.
Multicellular PI control for gene regulation in microbial consortia
Authors: Martinelli Vittoria , Salzano Davide , Fiore Davide , di Bernardo Mario
Published: March 2022

We describe two multicellular implementations of the classical P and PI feedback controllers for the regulation of gene expression in a target cell population. Specifically, we propose to distribute the proportional and integral actions over two different cellular populations in a microbial consortium comprising a third target population whose output needs to be regulated. By engineering communication among the different cellular populations via appropriate orthogonal quorum sensing molecules, we are able to close the feedback loop across the consortium. We derive analytical conditions on the biological parameters guaranteeing the regulation of the output of the target population and we validate the robustness and modularity of proposed control schemes via in silico experiments in BSim, a realistic agent-based simulator of bacterial populations.
Single cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis
Authors: O’Sullivan Eoin D , Mylonas Katie J , Bell Rachel , Carvalho Cyril , Baird David P , Cairns Carolynn , Gallagher Kevin M , Campbell Ross , Docherty Marie , Laird Alexander , Henderson Neil C , Chandra Tamir , Kirschner Kristina , Conway Bryan , Dihazi Gry H. , Zeisberg Michael , Hughes Jeremy , Denby Laura , Dihazi Hassan , Ferenbach David A
Published: March 2022

Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with ageing and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using two murine models of injury and repair we show that obstructive injury generates senescent epithelia which persist after resolution of the original injury, promote ongoing fibrosis and impede adaptive repair. Depletion of senescent cells with ABT263 reduces fibrosis in reversed ureteric obstruction and after renal ischaemia-reperfusion injury. We validate these findings in humans, showing that senescence and fibrosis persist after relieved renal obstruction. We next characterise senescent epithelia in murine renal injury using single cell RNA-Seq. We extend our classification to human kidney and liver disease and identify conserved pro-fibrotic proteins which we validate in vitro and in human disease. We demonstrate that one such molecule, Protein Disulfide Isomerase Family A Member 3 (PDIA3), is essential for TGF-beta mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduces kidney fibrosis during ongoing renal injury and as such represents a new potential therapeutic pathway. Analysis of the signalling pathways of senescent epithelia connects senescence to organ fibrosis, permitting rational design of anti-fibrotic therapies.
A mRNA vaccine encoding for a RBD 60-mer nanoparticle elicits neutralizing antibodies and protective immunity against the SARS-CoV-2 delta variant in transgenic K18-hACE2 mice
Authors: Brandys Pascal , Montagutelli Xavier , Merenkova Irena , Barut Güliz T , Thiel Volker , Schork Nicholas J , Trüeb Bettina , Conquet Laurine , Deng Aihua , Antanasijevic Aleksandar , Lee Hyun-Ku , Valière Martine , Sindhu Anoop , Singh Gita , Herold Jens
Published: March 2022

Two years into the COVID-19 pandemic there is still a need for vaccines to effectively control the spread of novel SARS-CoV-2 variants and associated cases of severe disease. Here we report a messenger RNA vaccine directly encoding for a nanoparticle displaying 60 receptor binding domains (RBDs) of SARS-CoV-2 that acts as a highly effective antigen. A construct encoding the RBD of the delta variant elicits robust neutralizing antibody response with neutralizing titers an order of magnitude above currently approved mRNA vaccines. The construct also provides protective immunity against the delta variant in a widely used transgenic mouse model. We ultimately find that the proposed mRNA RBD nanoparticle-based vaccine provides a flexible platform for rapid development and will likely be of great value in combatting current and future SARS-CoV-2 variants of concern.
Genetic Diversity of Candidatus Liberibacter asiaticus Based on Four Hypervariable Genomic Regions in China
Authors: zhang muqing , Gao Fanglan , Wu Bo , Zou Chengwu , Bao Yixue , Li Dean , Yao Wei , Powell Charles A
Published: March 2022

Huanglongbing (HLB; greening disease), caused by Candidatus Liberibacter asiaticus (CLas), is the most damaging citrus disease worldwide. The disease has spread throughout the citrus-producing regions of Guangxi, Guangdong, Fujian, and others in China. A total of 1,789 HLB-like symptomatic or asymptomatic samples were collected from the Guangxi and Fujian provinces of China to decipher the genetic diversity of CLas and its correlation with pathogenicity and host range. The disease was the most severe in orange and the least in pomelo. CLas bacteria associated with the specific geographical and citrus variety infected more than 50% of the HLB-like symptomatic samples. We identified a total of 6,286 minor variations by comparing 35 published CLas genomes and observed a highly heterogeneous variation distribution across the genome. Highly diverse regions, including two prophages, were generally more unstable and prone to lose. In the collected CLas strains, four highly diverse non-prophage segments and three prophage segments in the prophage region were chosen for PCR amplification and genotyping. Four hypervariable regions were used to decipher CLas diversity. A total of 100 strains were divided into four groups, of which 90 strains were clustered into two clades with 15 reported reference genomes, while 10 were grouped in two clades separately from the reported genomes. This study provides insight into the molecular characteristics and genetic variations of different CLas strains in China and might help develop HLB prevention and control strategies.
Evaluation of different diffusion-weighted image techniques for head and neck radiation treatment: phantom and volunteer studies
Authors: Ding Yao , Meheissen Mohamed A. M. , Zhou Kun , Mohamed Abdallah S. R. , Wen Zhifei , Ng Sweet Ping , Elhalawani Hesham M. , Elgohari Baher A. , Hutcheson Katherine A. , Chung Caroline , Lai Stephen Y , Fuller Clifton D. , Wang Jihong
Published: March 2022

Purpose

To quantitatively compare and assess the geometric distortion and apparent diffusion coefficient (ADC) accuracy of conventional single-shot EPI (SSEPI)-DWI, readout segmentation of long variable echo-trains (RESOLVE)-DWI, and BLADE-DWI techniques in both phantom and volunteer imaging studies.

Methods

Phantom measurements were obtained using the QIBA DWI phantom at 0° and at ambient temperature (~17°). DW images were acquired using SSEPI-DWI, RESOLVE-DWI, and BLADE-DWI. Image geometric distortion factors (compression and dilation, shear distortion), and image shift factors were measured and compared with computed tomography images. ADC and signal-to-noise ratio (SNR) values were measured for the various DWI techniques. Images were also obtained from three healthy volunteers and three oropharynx cancer patients. Geometric distortion parameters and ADC values were analyzed in the following head and neck regions of interest (ROI): salivary glands, tonsils, and primary tumors (patient only). The metric evaluation included Dice similarity coefficient and Hausdorff distance mean. T2-weighted images were used as a reference to evaluate geometric distortion.

Results

In the phantom experiment, the vials were prominently distorted on the SSEPI-DWI and RESOLVE-DWI images but were less distorted on the BLADE-DWI image, as determined by the overall effects of Image geometric distortion factors. The paired t-test showed no significant difference (0.15 < p < 0.88) in ADC values among the three DWI techniques; however, BLADE-DWI led to a lower SNR in vials. In the volunteer and patient studies, an ROI-based overlap metrics analysis of the salivary glands and gross tumor volumes were less distorted for BLADE-DWI than for EPI-based DWI, as determined by Wilcoxon paired signed-rank test.

Conclusion

BLADE-DWI demonstrated excellent geometric accuracy, with similar quantitative ADC values to those of EPI-based DW-MRI, thus potentially making this technique suitable for target volume delineation and functional assessment for head and neck radiation treatment in the future.
Predicting Adverse Drug Effects: A Heterogeneous Graph Convolution Network with a Multi-layer Perceptron Approach
Authors: Chen Y.-H. , Shih Y.-T. , Chien C.-S. , Tsai C.-S.
Published: March 2022

The GCNMLP is implemented on three different datasets of side effects, namely, the SIDER, OFFSIDERS, and FAERS. Our results show that the performance of the GCNMLP on these three datasets is superior to the non-negative matrix factorization method (NMF) and some well-known machine learning methods with respect to various evaluation scales. Moreover, new side effects of drugs can be obtained using the GCNMLP.

Author summary

The GCNMLP enables us to get better drug side effect prediction, which improves personalized medicine prescriptions.
Endothelial-derived sphingolipids are required for vascular development and systemic lipid homeostasis
Authors: Kuo Andrew , Checa Antonio , Niaudet Colin , Jung Bongnam , Fu Zhongjie , Wheelock Craig E. , Singh Sasha A. , Aikawa Masanori , Smith Lois E. , Proia Richard L. , Hla Timothy
Published: March 2022

Serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL), is needed for embryonic development, physiological homeostasis, and response to stress. The functions of de novo SL synthesis in vascular endothelial cells (EC), which line the entire circulatory system, are not well understood. Here we show that the EC de novo synthesis not only impacts vascular development but also maintains normal SL metabolic homeostasis in the circulatory system and peripheral organs. Mice with an endothelial-specific gene knockout of SPTLC1 (Sptlc1 ECKO), an essential subunit of the SPT complex, exhibited EC-intrinsic effects including reduced EC proliferation and tip/stalk cell differentiation, resulting in delayed retinal vascular development. In addition, Sptlc1 ECKO mice had reduced pathological retinal neovascularization in the oxygen-induced retinopathy model, suggesting that EC SL produced from the de novo pathway are needed for efficient VEGF signaling within the vascular system. Post-natal deletion of the EC Sptlc1also showed cell-extrinsic effects, including rapid reduction of several SL metabolites in plasma, red blood cells and peripheral organs (lung and liver) but not in the retina, part of the central nervous system (CNS). In the liver, EC de novo SL synthesis was required for acetaminophen-induced ceramide elevation and hepatotoxicity. These results suggest that EC-derived SL metabolites are in constant flux between the vasculature, circulatory elements, and parenchymal cells of non-CNS organs. Taken together, our data point to the central role of the endothelial SL biosynthesis in maintaining vascular development and neovascular proliferation, non-CNS tissue metabolic homeostasis and hepatocyte response to stress.
Small Molecule Modulation of the Archetypal UbiB protein COQ8
Authors: Murray Nathan H. , Lewis Adam , Asquith Christopher R. M. , Rincon Pabon Juan P. , Fang Zixiang , Ptak Naomi , Smith Robert W. , Vasta James D. , Zimprich Chad A. , Corona Cesear R. , Robers Matthew B. , Bingman Craig A. , Gross Michael L. , Henzler-Wildman Katherine , Pagliarini David J.
Published: March 2022

Small molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize inhibitor and activator molecules for the archetypal UbiB member, COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays, and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Second, using 1H-13C HMQC NMR and hydrogen-deuterium exchange mass spectrometry, we reveal that the CoQ precursor mimetic, 2-propylphenol (2-PP), modulates the quintessential UbiB KxGQ domain to increase COQ8A nucleotide affinity and ATPase activity. Our newfound chemical tools promise to lend new mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction.
Live-cell RNA imaging with metabolically incorporated fluorescent nucleosides
Authors: Wang Danyang , Shalamberidze Ana , Arguello A Emilia , Purse Byron , Kleiner Ralph E
Published: March 2022

Fluorescence imaging is a powerful method for probing macromolecular dynamics in biological systems, however approaches for cellular RNA imaging are limited to the investigation of individual RNA constructs or bulk RNA labeling methods compatible primarily with fixed samples. Here, we develop a platform for fluorescence imaging of bulk RNA dynamics in living cells. We show that fluorescent bicyclic and tricyclic cytidine analogues can be metabolically incorporated into cellular RNA by overexpression of uridine-cytidine kinase 2 (UCK2). In particular, metabolic feeding with the tricyclic cytidine-derived nucleoside tC combined with quantitative confocal imaging enables the investigation of RNA synthesis, degradation, and trafficking at single-cell resolution. We apply our imaging modality to study RNA metabolism and localization during the oxidative stress response and find that bulk RNA turnover is greatly accelerated upon NaAsO2 treatment. Further, we identify cytoplasmic RNA granules containing RNA transcripts generated during oxidative stress that are distinct from canonical stress granules and P-bodies and co-localize with the RNA helicase DDX6. Taken together, our work provides a powerful approach for live-cell RNA imaging and reveals how cells reshape RNA transcriptome dynamics in response to oxidative stress.
Acetaldehyde makes a distinct mutation signature in single-stranded DNA
Authors: Vijayraghavan Sriram , Porcher Latarsha , Mieczkowski Piotr A , Saini Natalie
Published: March 2022

Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the genotoxic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA is highly mutagenic and makes strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption.
Cellulosic copper nanoparticles and a hydrogen peroxide-based disinfectant protect Vero E6 cells against infection by viral pseudotyped particles expressing SARS-CoV-2, SARS-CoV or MERS-CoV Spike protein
Authors: Brault Ariane , Néré Raphael , Prados Jérôme , Boudreault Simon , Bisaillon Martin , Marchand Patrick , Couture Patrick , Labbé Simon
Published: March 2022

Severe acute respiratory syndrome (SARS) is a viral respiratory infection caused by human coronaviruses (HuCoV) that include SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). Although their primary mode of transmission is through contaminated respiratory droplets from infected carriers, the deposition of expelled virus particles onto surface and fomites could contribute to viral transmission. Here, we use replication-deficient murine leukemia virus (MLV) pseudoviral particles expressing SARS-CoV-2, SARS-CoV, or MERS-CoV Spike (S) protein on their surface. These surrogates of native coronavirus counterparts serve as a model to analyze the S-mediated entry into target cells. Carboxymethyl cellulose (CMC) nanofibers that are combined with copper (Cu) exhibit strong antimicrobial properties. S-pseudovirions that are exposed to CMC-Cu nanoparticles (30 s) display a dramatic reduction in their ability to infect target Vero E6 cells, with ∼97% less infectivity as compared to untreated pseudovirions. In contrast, addition of the Cu chelator tetrathiomolybdate protects S- pseudovirions from CMC-Cu-mediated inactivation. When S-pseudovirions were treated with a hydrogen peroxide-based disinfectant (denoted SaberTM) used at 1:16 dilution, their infectivity was dramatically reduced by ∼98%. However, the combined use of SaberTM and CMC-Cu is the most effective approach to restrict infectivity of SARS-CoV-2-S, SARS-CoV-S, and MERS-CoV-S pseudovirions in Vero E6 cell assays. Together, these results show that cellulosic Cu nanoparticles enhance the effectiveness of diluted SaberTM sanitizer, setting up an improved strategy to lower the risk of surface- and fomite-mediated transmission of enveloped respiratory viruses.
Hand cold pressor test induces thermogenesis in upper thoracic regions as measured by skin surface infrared thermography
Authors: Levtova Natalie , Benoit Emilie-Anne , Jhajj Aneet K. , Narayana Thivaedee , Purkayastha Dipannita , Salimi Ali , Kakon Gabriel , Maurice-Ventouris Meagane E. I. , Kaffash Mohamadi Amir Arshiya , Kizhner Tomas , Khayargoli Pranamika , Darlington Peter J.
Published: March 2022

Background
Cold exposure may cause health problems and impaired productivity in outdoor or cold-temperature workers. The cold pressor test (CPT) is a laboratory procedure that measures cardiovascular and thermoregulatory responses to acute cold exposure such as metabolic activity in brown adipose tissue. How the body responds to acute cold exposure of a hand is not completely understood. We tested the hypothesis that the upper thorax produces heat during a single hand-CPT, which restores warmth to the cold-expose appendage.
Objectives
The objective was to measure skin temperature changes in the upper thoracic regions and the cold-exposed appendage during a CPT. The secondary objective was to determine if cardiovascular or psychological responses during CPT accounted for skin temperature changes.
Methods
50 healthy participants immersed their right hand up to wrist level in 4 °C water for three minutes. Surface skin temperatures were imaged by infrared thermography at baseline, during CPT, and in the recovery phase. Sublingual oral temperature and water bath temperature were recorded throughout the test. Cardiovascular responses were monitored by continuous finger pulse-wave plethysmography. Peak pain and peak stress were reported by the participants on a Likert scale.
Results
CPT increased the systolic blood pressure (+22 mmHg, p <  0.001), diastolic blood pressure (+15 mmHg, p <  0.001) and heart rate (+7 beats per minute, p =  0.024). During CPT, skin temperature increased on thoracic regions including mediastinal (+0.5°C, p <  0.021), sternal (+0.5°C, p <  0.002), right supraclavicular (+0.3°C, p <  0.042) and left supraclavicular (+0.3°C, p <  0.016) regions. During CPT, the hand was cooler on ventral (-14.6°C  p <  0.001) and dorsal (-15.2°C  p <  0.001) sides, and warmed up during recovery. The ventral forearm, dorsal forearm, antecubital fossa, and adjacent medial epicondyle region were significantly cooler throughout the recovery time. The oral temperature did not change during CPT. There were no correlations between the change in mediastinal skin temperature and the sex of the participant, or changes in cardiovascular parameters, peak pain, or peak stress values.
Conclusions
Localized hand cooling caused a rapid warming of the thorax, dissipation of cold in the forearm, and rewarming of the hand during recovery. Thermoregulation was not dependant on pain, stress, sex, or cardiovascular changes between participants. By understanding thermoregulation, better approaches can be developed to mitigate the negative impacts of cold exposure.
A Single Cell Cloning Platform for Gene Edited Functional Murine Hematopoietic Stem Cells
Authors: Becker Hans Jiro , Ishida Reiko , Wilkinson Adam C. , Kimura Takaharu , Jann Lee Michelle Sue , Coban Cevayir , Ota Yasunori , Tojo Arinobu , Kent David , Yamazaki Satoshi
Published: March 2022

Gene editing using engineered nucleases frequently produces on- and off-target indels in hematopoietic stem cells (HSCs). Gene-edited HSC cultures thus contain genetically heterogenous populations, the majority of which either do not carry the desired edit or harbor unwanted mutations. In consequence, transplanting edited HSCs carries the risks of suboptimal efficiency and of unwanted mutations in the graft. Here, we present an approach for expanding gene-edited HSCs at clonal density, allowing for genetic profiling of individual clones before transplantation. We achieved this by developing a defined, polymer-based expansion system and identifying long-term expanding clones within the CD201+CD150+CD48-c-Kit+Sca-1+Lin- population of pre-cultured HSCs. Using the Prkdcscid immunodeficiency model, we demonstrate that we can expand and profile edited HSC clones to check for desired and unintended modifications. Transplantation of Prkdc-corrected HSCs rescued the immunodeficient phenotype. Our ex vivo-manipulation platform establishes a novel paradigm to control genetic heterogeneity in HSC gene editing and therapy.