bluuebunny/crossref_metadata_2025 huggingface dataset:
Air pollution, lung function and mortality: survival and mediation analyses in UK Biobank
Authors: Guyatt Anna L , Cai Yutong Samuel , Doiron Dany , Tobin Martin D , Hansell Anna L
Published: June 2023

Background

Air pollution is associated with lower lung function, and both are associated with premature mortality and cardiovascular disease (CVD). Evidence remains scarce on the potential mediating effect of impaired lung function on the association between air pollution and mortality or CVD.

Methods

We used data from the UK Biobank cohort (∼200,000 individuals) with 8-year follow-up to mortality and incident CVD. Exposures to PM10, PM2.5, and NO2at baseline were assessed by land-use regression modelling. Lung function [forced expiratory volume in 1 second (FEV1), Forced Vital Capacity (FVC)] was measured by spirometry and transformed to Global Lung Function Initiative z-scores. Adjusted Cox proportional hazards and causal proportional hazards mediation analysis models were fitted, stratified by smoking status.

Results

Lower FEV1and FVC were associated with all-cause and CVD mortality, and incident CVD. Point estimates for the mortality outcomes were larger in ever-smokers than never-smokers (all-cause mortality Hazard Ratio (HR) per decrease FEV1GLI z-score, ever smokers: 1.29 [95%CI:1.24-1.34], versus never-smokers: HR 1.16 [95%CI:1.12-1.21]). Long-term exposure to PM2.5or NO2was associated with incident CVD, with similar effect sizes for ever and never smokers. Mediated proportions of the air pollution—all-cause mortality estimates driven by FEV1were 18% [95%CI: 2%-33%] for PM2.5, and 27% [95%CI: 3%-51%] for NO2. The estimated mediated proportions for air pollution—incident CVD were 9% [95%CI: 4%-13%] for PM2.5and 16% [95%CI: 6%-25%] for NO2.

Conclusions

Lower FEV1may mediate some associations between air pollution on mortality and CVD outcomes, with more pronounced effect sizes for NO2than for PM2.5.

Take-home message

Adverse effects of air pollution on lower lung function (FEV1) potentially mediate 10-30% of the effects of PM2.5or NO2on mortality and incident cardiovascular disease.
Impact of the Covid-19 Pandemic on Audiology Service Delivery: Observational Study of the Role of Social Media in Patient Communication
Authors: Hussain Adeel , Hussain Zain , Gogate Mandar , Dashtipour Kia , Goman Adele , Sheikh Aziz , Hussain Amir
Published: June 2023

The Covid-19 pandemic has highlighted an era in hearing health care that necessitates a comprehensive rethinking of audiology service delivery. There has been a significant increase in the number of individuals with hearing loss who seek information online. An estimated 430 million individuals worldwide suffer from hearing loss, including 11 million in the United Kingdom. The objective of this study was to identify NHS audiology service social media posts and understand how they were used to communicate service changes within audiology departments at the onset of the Covid-19 pandemic.Facebook and Twitter posts relating to audiology were extracted over a six week period (March 23 to April 30 2020) from the United Kingdom. We manually filtered the posts to remove those not directly linked to NHS audiology service communication. The extracted data was then geospatially mapped, and themes of interest were identified via a manual review. We also calculated interactions (likes, shares, comments) per post to determine the posts’ efficacy. A total of 981 Facebook and 291 Twitter posts were initially mined using our keywords, and following filtration, 174 posts related to NHS audiology change of service were included for analysis. The results were then analysed geographically, along with an assessment of the interactions within the included posts. NHS Trusts and Boards should consider incorporating and promoting social media to communicate service changes. Users would be notified of service modifications in real-time, and different modalities could be used (e.g. videos), resulting in a more efficient service.
Identifying Optimal Parameters for Neuroscience-Informed Interventions for Misophonia
Authors: Neacsiu Andrada D. , Beynel Lysianne , Gerlus Nimesha , Szymkiewicz Victoria , LaBar Kevin S. , Bukhari-Parlakturk Noreen , Rosenthal M. Zachary
Published: June 2023

Background

Misophonia is the inability to tolerate certain aversive, repetitive common sounds.

Methods

Using a within-subjects experimental design, twenty-nine participants with misophonia and thirty clinical controls with high emotion dysregulation received inhibitory neurostimulation (1Hz) over a personalized medial prefrontal cortex (mPFC) target functionally connected to the left insula; excitatory neurostimulation (10Hz) over a personalized dorsolateral PFC (dlPFC) target; and sham stimulation over either target. Stimulations were applied while participants were either listening or cognitively downregulating emotions associated with personalized aversive, misophonic, or neutral sounds. Subjective units of distress (SUDS) and psychophysiological measurements (skin conductance response[SCR] and level [SCL], and high-frequency heart rate variability [HF-HRV]) were collected.

Results

Compared to controls, participants with misophonia reported higher distress (ΔSUDS= 1.91-1.93,ps<.001) when listening to and when downregulating misophonic distress, although no psychophysiological differences were found. Both types of neurostimulation reduced distress significantly more than sham, with excitatory rTMS providing the most benefit (Cohen’sdSUDS=0.53;dSCL= 0.14). Excitatory rTMS also enhanced the regulation of emotions associated with misophonic sounds in both groups when measured by SUDS (dcontrol= 1.28;dMisophonia=0.94), and in the misophonia group alone when measured with SCL (d= 0.20). Both types of neurostimulation were well tolerated and feasible to administer.

Discussion

Clinical controls and misophonic participants were different in their self-report but not in psychophysiological measures of distress and regulations. Participants reported the lowest misophonic distress when engaging in cognitive restructuring enhanced with high-frequency neurostimulation, a finding that offers insight into the best path forward for misophonia interventions.
Real-World Effectiveness and Safety of Evolocumab in Very High-risk Atherosclerotic Cardiovascular Disease Patients with Acute Ischemic Stroke
Authors: Zhang Ting , Zhang Yajing , Yang Yun , Liao Haibing , Li Xun , Liu Ran , Liu Xueqing , Yang Liqin , Yue Wei
Published: June 2023

Background

We investigated evolocumab’s real-world effectiveness and safety on a background of statin therapy in the acute phase of ischemic stroke (IS) patients with a very high-risk of atherosclerotic cardiovascular disease (ASCVD).

Methods

A real-world, single-center, retrospective study was conducted in the neurology department at Tianjin Huanhu Hospital in China. Patients were divided into two groups: evolocumab treatment (140 mg every two weeks) or the standard of care (SOC) group. The primary efficacy outcome of the study was the achievement of a targeted lipid control rate and the incidence of major adverse cardiovascular events (MACE) by the end of the follow-up. Propensity score matching (PSM) analysis was utilized to account for confounding factors between groups. Survival analysises were performed using the Kaplan-Meier method.

Results

1080 AIS patients with very high-risk ASCVD were recruited. After PSM, there were 528 individuals, with 206 in the evolocumab group and 322 in the standard of care (SOC) group. At 12 months of follow-up, the proportion of LDL-C < 1.4mmol/L and ≥50% reduction was 44.9% in the evolocumab group, compared with only 3.1% of SOC-treated patients (p= 0.000). The median follow-up time for clinical events was 15 months. The evolocumab group was associated with a lower risk of cerebrovascular events compared to the SOC group (HR, 0.45; 95% CI, 0.23-0.89;p= 0.022) but did not significantly reduce the incidence of cardiovascular events (HR, 0.51; 95% CI, 0.17-1.51;p= 0.224), event-related deaths (HR, 0.71; 95% CI, 0.34-1.46;p= 0.349), or MACE (HR, 0.71; 95% CI, 0.44-1.06;p= 0.089).

Conclusions

This real-world study suggested that evolocumab on a background of statin reduced the LDL-C levels significantly with a well-tolerated profile and lowered the incidence of recurrent cerebrovascular events in the very high-risk ASCVD patients with AIS in China.
Targeting hepatitis B vaccine escape using immunogenetics in Bangladeshi infants
Authors: Butler-Laporte Guillaume , Auckland Kathryn , Noor Zannatun , Kabir Mamun , Alam Masud , Carstensen Tommy , Wojcik Genevieve L , Chong Amanda Y , Pomilla Cristina , Noble Janelle A , McDevitt Shana L. , Smits Gaby , Wareing Susan , van der Klis Fiona RM , Jeffery Katie , Kirkpatrick Beth D , Sirima Sodiomon , Madhi Shabir , Elliott Alison , Richards J Brent , Hill Adrian VS , Duggal Priya ,   PROVIDE authors,   Cryptosporidiosis Birth Cohort authors, Sandhu Manjinder S , Haque Rashidul , Petri William A , Mentzer Alexander J
Published: June 2023

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individualsDPB1*04:01was associated with higher HBV antibody responses (p=4.5×10−30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen ‘a-determinant’ segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.

One-Sentence Summary

Host genetics underlying hepatitis B vaccine response in Bangladeshi infants identifies mechanisms of viral vaccine escape, and how to prevent it.
Application of Coincidence Index in the Discovery of Co-Expressed Metabolic Pathways
Authors: dos Santos João Paulo Cassucci , Bruno Odemir Martinez
Published: June 2023

Analyzing transcription data requires intensive statistical analysis in order to obtain useful biological information and knowledge. A significant portion of this data is affected by random noise or even noise intrinsic to the modeling of the experiment. Without a robust treatment, the data might not be very thoroughly explored and even incorrect conclusions could be drawn. Examining the correlation between gene expression profiles is one of the ways bioinformaticians extract information from transcriptomic experiments. However, the correlation measurements traditionally used have worrisome shortcomings that need to be addressed. This paper compares the two most common correlation measurements, Pearson’s r and Spearman’s r, to the newly developed coincidence index, a similarity measurement that combines Jaccard and interiority indexes and generalizes them to be applied to vectors containing real values. We used experimental data from a microarray experiment from the archaeonHalobacterium salinarumthat evaluates the effects on the organism when exposed to light in an anaerobic environment. The utilized method explores the co-expressed metabolic pathways by measuring the correlations between enzymes that share metabolites and searches for local maxima using a simulated annealing algorithm. We demonstrate that the coincidence index extracts larger, more comprehensive, and more statistically significant pathways than the traditional Pearson’s and Spearman’s measurements.
Scalable Integration of Multiomic Single Cell Data Using Generative Adversarial Networks
Authors: Giansanti Valentina , Giannese Francesca , Botrugno Oronza A. , Gandolfi Giorgia , Balestrieri Chiara , Antoniotti Marco , Tonon Giovanni , Cittaro Davide
Published: June 2023

Single cell profiling has become a common practice to investigate the complexity of tissues, organs and organisms. Recent technological advances are expanding our capabilities to profile various molecular layers beyond the transcriptome such as, but not limited to, the genome, the epigenome and the proteome. Depending on the experimental procedure, these data can be obtained from separate assays or from the very same cells. Despite development of computational methods for data integration is an active research field, most of the available strategies have been devised for the joint analysis of two modalities and cannot accommodate a high number of them.

To solve this problem, we here propose a multiomic data integration framework based on Wasserstein Generative Adversarial Networks (MOWGAN) suitable for the analysis of paired or unpaired data with high number of modalities (>2). At the core of our strategy is a single network trained on all modalities together, limiting the computational burden when many molecular layers are evaluated. Source code of our framework is available athttps://github.com/vgiansanti/MOWGAN.
GEMspa: a Napari plugin for analysis of single particle tracking data
Authors: Keegan Sarah , Fenyö David , Holt Liam J.
Published: June 2023

The cellular environment is crowded with macromolecules and far from thermodynamic equilibrium. This active, crowded environment influences biochemical reactions and the formation of cellular structures such as membraneless organelles. These physical properties can change during normal physiology and in disease states such as neurodegenerative diseases and cancer, impacting cell behavior and function. Therefore, it is crucial to develop methods to characterize these properties. Microrheology is the inference of physical properties from the motion of tracer particles embedded within a material. This technique requires single particle tracking (SPT) and analysis of these tracks through the framework of soft-condensed matter physics. Analysis of SPT data can be challenging due to the lack of comprehensive user-friendly software tools. To address this, we introduce GEMspa, a software package implemented as a plugin for the open source image analysis platform, napari. GEMspa provides a GUI for a commonly used localization/tracking algorithm (via Trackpy), and a suite of methods to extract basic parameters describing particle motion. This platform aims to streamline the workflow of data analysis steps and allow researchers to visualize and optimize parameters for high-quality results, thereby making microrheology accessible to non-expert scientists.
The circadian molecular clock in the suprachiasmatic nucleus is necessary but not sufficient for fear entrainment in the mouse
Authors: Bussi Ivana L. , Ben-Hamo Miriam , Leon Luis E. Salazar , Casiraghi Leandro P. , Zhang Victor Y. , Neitz Alexandra F. , Lee Jeffrey , Takahashi Joseph S. , Kim Jeansok J. , de la Iglesia Horacio O.
Published: June 2023

Nocturnal aversive stimuli presented to mice during eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our results support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders may represent the output of a fear-entrained clock.

One-Sentence Summary

Cyclic fearful stimuli can entrain circadian rhythms in mice, and the molecular clock within the central circadian pacemaker is necessary but not sufficient for fear-entrainment.
Porous membrane electrical cell-substrate impedance spectroscopy for versatile assessment of biological barriers in vitro
Authors: Chebotarev Oleg , Ugodnikov Alisa , Simmons Craig A.
Published: June 2023

Cell culture models of endothelial and epithelial barriers typically use porous membrane inserts (e.g., Transwell inserts) as a permeable substrate on which barrier cells are grown, often in co-culture with other cell types on the opposite side of the membrane. Current methods to characterize barrier function in porous membrane inserts can disrupt the barrier or provide bulk measurements that cannot isolate barrier cell resistance alone. Electrical cell-substrate impedance sensing (ECIS) addresses these limitations but its implementation on porous membrane inserts has been limited by costly manufacturing and low sensitivity. Here we present porous membrane ECIS (PM-ECIS), a cost-effective method to adapt ECIS technology to porous substrate-basedin vitromodels. We demonstrate high fidelity patterning of electrodes on porous membranes that can be incorporated into well plates of a variety of sizes with excellent cell biocompatibility with mono- and co-culture set ups. PM-ECIS provided sensitive, real-time measurement of isolated changes in endothelial cell barrier impedance with cell growth and barrier disruption. Barrier function characterized by PM-ECIS resistance correlated well with permeability coefficients obtained from molecular tracer permeability assays performed on the same cultures, validating the device. Integration of ECIS into conventional porous cell culture inserts provides a versatile, sensitive, and automated alternative to current methods to measure barrier function in vitro, including molecular tracer assays and transepithelial/endothelial electrical resistance (TEER).
Rural Public Health Landscape: Funding, Personnel, Expertise, Community Resources, and Barriers in Rural Settings
Authors: Ellison Olivia , Silenzio Vincent
Published: June 2023

Objectives

To describe and understand the funding, personnel, expertise, community resources, and issues in rural settings by local public health departments post COVID-19.

Methods

Rural county health departments in ten states were sent a survey via web link in the Spring of 2021. 552 responses were collected with a 63% completion rate for all counties surveyed.

Results

Most counties utilized public health nurses, administrators, or community health professionals. Of these, 25% had formal education in public health and 10% had public health experience. 65% of respondents disagreed with having adequate funding, staff, and resources. 83% of counties reported working with nonprofits and 43% utilized volunteers. The top two issues in rural public health identified were mental health and substance use.

Conclusions

Rural county public health departments do not have the support needed to sustain or advance public health in their specific population.

Policy implications

This report gives insight into the needs of rural health in 2021 that can be used to guide policy and funding to support rural health’s specific needs.
PharmGScore scores of compound genetic variant burden for psychiatric treatment optimization
Authors: Borczyk Malgorzata , Hajto Jacek , Piechota Marcin , Korostynski Michal
Published: June 2023

The acceptability of antidepressant drugs partly depends on genetic factors. The list of genes involved in antidepressant response, including Adverse Drug Reactions (ADRs) is broad and contains both drug-metabolizing enzymes (pharmacogenes) and genes involved in pharmacodynamics. Variants in pharmacogenes are traditionally reported in the form of star alleles and are partially annotated with known phenotypic consequences. As it is unfeasible to analyze all genotype-phenotype pairs, computational approaches remain the practical solution. A pharmacogenetic framework to predict responses to antidepressant drug treatment would provide great benefit to patients. In this study, we present a scoring system (PharmGScore) to assess both rare and common genetic variant burden across multiple genes. The PharmGScore is constructed by normalizing and aggregating existing, well-established computational variant predictors (CADD, Fathmm-xf, PROVEAN, Mutation Assessor). We show that this score effectively distinguishes no and decreased function from normal and increased function pharmacogenetic variants reported in PharmVar (PharmGScore AUC = 0.86). PharmGScore has improved performance when compared to its component scores (AUCs: CADD = 0.79; FATHMM-XF = 0.81; PROVEAN = 0.81; Mutation Assessor = 0.75). We then apply the PharmGScore to the 200k exome sequences of the UK Biobank (UKB). We report the overrepresentation of UKB participants with high (>50) gene PharmGScore forCYP2C19andCYP2C9and with high (>100) compound PharmGScore from nine pharmacogenes within a group with an antidepressant toxicity diagnostic code (T43.2). We then analyze all UKB participants that received any antidepressant toxicity or ADR diagnosis (n = 602). We indicate genes for which a higher burden may be associated with antidepressant toxicity or ADRs and confirm the known roles ofCYP2C19andCYP2D6in this process. Finally, we show that patients who experienced ADRs to antidepressants in the therapeutic process or accidental poisoning with antidepressants have a higher PharmGScore composed of nine cytochrome P450 genes. Our study proposes a novel paradigm to assess the compound genetic variant burden associated with antidepressant response from exome sequencing data. This approach can be further applied to a user-defined set of genes to investigate other pharmacological traits.
Epidemiology of Atrial Fibrillation in Colombia 2010-2015
Authors: Miranda-Machado Pablo Andrés , Guzman-Saenz Roberto Carlos
Published: June 2023

Atrial Fibrillation (AF) is a common cardiac arrhythmia. Its prevalence worldwide has doubled in the last decade due to increased capacity for diagnosis and management of heart disease and chronic non-cardiac. The purpose of this study was to estimate the prevalence, incidence and demand for treatment of AF in Colombia during the period 2010 to 2015.
EPIDEMIOLOGY OF ANAPHYLAXIS IN COLOMBIA 2010-2015
Authors: Miranda-Machado Pablo Andrés
Published: June 2023

Background

The lifetime prevalence of anaphylaxis from all triggers is estimated to range from 0.05 % to 2.6 %. Data on anaphylaxis in the Latin American region and Colombia are scant.

Objective

Estimate the prevalence, incidence and mortality for anaphylaxis in Colombia.

Methods

Records with diagnosis of anaphylaxis (ICD-10 code T78.0-T78.2) of Information System of Social Protection (SISPRO) between 2010 and 2015 were included. To determine the prevalence, incidence and mortality for anaphylaxis, population estimates from the National Statistics Department of Colombia (DANE) were used.

Results

The average estimated annual prevalence of anaphylaxis were 25.1 cases per million. The average estimated annual incidence of anaphylaxis were 3.2 cases per million. Most cases range between 45 and 49 years age. On average 8.4 cases of anaphylaxis deaths per year were estimated. The average estimated annual mortality of anaphylaxis were 0.16 cases per million.

Conclusions

Both under-diagnosis and under-report of anaphylaxis are common in the world. Population studies in Colombia, with diagnoses of based primarily on clinical history and clinical criteria for accurate and early identification of anaphylaxis recently established are required.
Understanding consumers to inform market interventions for Singapore’s shark fin trade
Authors: Choy Christina , Booth Hollie , Veríssimo Diogo
Published: June 2023

Sharks, rays and their cartilaginous relatives (Class Chondricthyes, herein ‘sharks’) are amongst the world’s most threatened species groups, primarily due to overfishing, which in turn is driven by complex market forces including demand for fins. Understanding the high-value shark fin market is a global priority for conserving shark and rays, yet the preferences of shark fin consumers are not well understood. This gap hinders the design of evidence-based consumer-focused conservation interventions.

Using an online discrete choice experiment, we explored preferences for price, quality, size, menu types (as a proxy for exclusivity) and source of fins (with varying degrees of sustainability) among 300 shark fin consumers in Singapore: a global entrepot for shark fin trade.

Overall, consumers preferred lower-priced fins sourced from responsible fisheries or produced using novel lab-cultured techniques. We also identified four consumer segments, each with distinct psychographic characteristics and consumption behaviors.

These preferences and profiles could be leveraged to inform new regulatory and market-based interventions regarding the sale and consumption of shark fins, and incentivize responsible fisheries and lab-cultured innovation for delivering conservation and sustainability goals.

In addition, message framing around health benefits, shark endangerment and counterfeiting could reinforce existing beliefs amongst consumers in Singapore and drive behavioral shifts to ensure that market demand remains within the limits of sustainable supply.
Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors
Authors: Enriquez-Traba Juan , Yarur-Castillo Hector E , Flores Rodolfo J , Weil Tenley , Roy Snehashis , Usdin Ted B , LaGamma Christina T , Arenivar Miguel , Wang Huikun , Tsai Valerie S , Moritz Amy E , Sibley David R , Moratalla Rosario , Freyberg Zachary Z , Tejeda Hugo A
Published: June 2023

Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks separable features of reward such as motivation and reinforcement. However, the cellular and circuit mechanisms by which dopamine receptors transform dopamine release into distinct constructs of reward remain unclear. Here, we show that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by regulating local NAc microcircuits. Furthermore, D3Rs co-express with dopamine D1 receptors (D1Rs), which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report non-overlapping physiological actions of D3R and D1R signaling in NAc neurons. Our results establish a novel cellular framework wherein dopamine signaling within the same NAc cell type is physiologically compartmentalized via actions on distinct dopamine receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.
Sequence basis of transcription initiation in human genome
Authors: Dudnyk Kseniia , Shi Chenlai , Zhou Jian
Published: June 2023

Transcription initiation is an essential process for ensuring proper function of any gene, however, a unified understanding of sequence patterns and rules that determine transcription initiation sites in human genome remains elusive. By explaining transcription initiation at basepair resolution from sequence with a deep learning-inspired explainable modeling approach, here we show that simple rules can explain the vast majority of human promoters. We identified key sequence patterns that contribute to human promoter function, each activating transcription with a distinct position-specific effect curve that likely reflects its mechanism of promoting transcription initiation. Most of these position-specific effects have not been previously characterized, and we verified them using experimental perturbations of transcription factors and sequences. We revealed the sequence basis of bidirectional transcription at promoters and links between promoter selectivity and gene expression variation across cell types. Additionally, by analyzing 241 mammalian genomes and mouse transcription initiation site data, we showed that the sequence determinants are conserved across mammalian species. Taken together, we provide a unified model of the sequence basis of transcription initiation at the basepair level that is broadly applicable across mammalian species, and shed new light on basic questions related to promoter sequence and function.
Unidirectional expression of enhancers with cell type-dependent direction of transcription
Authors: Agrawal Saumya , Kanamaru Emi , Saito Yoriko , Ishikawa Fumihiko , de Hoon Michiel
Published: June 2023

Enhancers are genomic regulatory elements that can affect expression of genes over megabases of genomic distances. As previous evidence suggested that transcription initiation at enhancers occurs in a bidirectional pattern, balanced expression of divergently transcribed capped RNAs has been used as a hallmark for enhancer detection from transcriptome data.

By analyzing deep Cap Analysis Gene Expression (CAGE) data from FANTOM5, FANTOM6, and other studies, we show that enhancers are usually unidirectionally transcribed in a given cell type. However, since the preferred direction of transcription of an enhancer may switch between cell types, enhancers may appear to be bidirectionally expressed when using CAGE data aggregated over many cell types. By analyzing expression directionality of enhancers across cell types, we classified enhancers into bidirectionally expressed, unidirectionally expressed with a consistent direction of transcription, and unidirectionally expressed with a switching direction, which was the largest category.

We conclude that requiring bidirectional expression during enhancer prediction from transcriptome data may lead to false negatives. Also, the preference of a given cell type for a specific direction of transcription at an enhancer suggests that enhancer RNAs are not transcriptional noise, but may be functional.
Genome-wide transcriptome analysis reveals the diversity and function of long non-coding RNAs in dinoflagellates
Authors: Chen Yibi , Dougan Katherine E. , Nguyen Quan , Bhattacharya Debashish , Chan Cheong Xin
Published: June 2023

Dinoflagellates are a diverse group of phytoplankton, ranging from harmful bloom-forming microalgae to photosymbionts that are critical for sustaining coral reefs. Genome and transcriptome data from dinoflagellates are revealing extensive genomic divergence and lineage-specific innovation of gene functions. However, most studies thus far have focused on protein-coding genes; long non-coding RNAs (lncRNAs), known to regulate gene expression in eukaryotes, are largely unexplored. Here, using both genome and transcriptome data, we identified a combined total of 48,039 polyadenylated lncRNAs in the genomes of three dinoflagellate species: the coral symbionts ofCladocopium proliferumandDurusdinium trenchii, and the bloom-formingProrocentrum cordatum. These putative lncRNAs are shorter, and have fewer introns and lower G+C-content when compared to protein-coding sequences. Although 37,768 (78.6%) lncRNAs shared no significant similarity with one another, we classified all lncRNAs based on conserved sequence motifs (k-mers) into distinct clusters following properties of potential protein-binding and/or subcellular localisation. Interestingly, 3708 (7.7%) lncRNAs were differentially expressed in response to heat stress, lifestyle, and/or growth phases, and they shared co-expression patterns with protein-coding genes. Based on inferred triplex interactions between lncRNA and upstream (putative promoter) regions of protein-coding genes, we identified a combined 19,460 putative gene targets for 3,721 lncRNAs; 907 genes exhibit differential expression under heat stress. These results reveal for the first time the functional diversity of lncRNAs in dinoflagellates, and demonstrate how lncRNAs, often overlooked in transcriptome data, could regulate gene expression as a molecular response to heat stress in these ecologically important organisms.
Experimental safety testing confirms that the NSAID nimesulide is toxic toGypsvultures in India
Authors: Mathesh Karikalan , Manickam Kesavan , Mallord John W. , Mahendran K. , Asok Kumar M. , Saikia Debasish , Chandra Mohan S. , Beena V , Sree Lakshmi P. , Prakash Nikita , Shringarpure Rohan , Pawde Abhijit , Green Rhys E. , Prakash Vibhu
Published: June 2023

Population declines ofGypsvultures throughout South Asia were caused by unintentional poisoning by the NSAID diclofenac, which was subsequently banned. However, other vulture-toxic NSAIDs are available, including nimesulide, which, in experiments carried out in South Africa, was shown to be toxic toGypsvultures. We report on safety-testing of nimesulide carried out on Himalayan GriffonsG. himalayensis. We gave two vultures a dose of nimesulide by oral gavage at the maximum level of exposure, with two controls dosed with benzyl alcohol. In the two tested birds, plasma nimesulide concentrations peaked after six hours, while serum uric acid concentrations increased steadily up until 24 hours post-treatment, after which both birds died, displaying severe visceral gout. The control birds showed no adverse clinical or biochemical signs. We confirm that nimesulide is toxic toGypsvultures. Veterinary use of nimesulide should be banned in allGypsvulture range countries in the region.
Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Authors: Hu Jinjian , Xia Wencheng , Zeng Shuyi , Lim Yeh-Jun , Tao Youqi , Sun Yunpeng , Zhao Lang , Wang Haosen , Li Dan , Liu Cong , Li Yan-Mei
Published: June 2023

α-Synuclein (α-syn) forms amyloid fibrils that are critical in the progression of Parkinson’s disease (PD) and serves as the pathological hallmark of PD. Different posttranslational modifications (PTMs) have been identified at multiple sites of α-syn, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-syn site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-syn monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM analysis revealed that pS87 and gS87 α-syn form two novel but distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. While, phosphorylation at the same site prevents a lengthy C-terminal region including residues 73-140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half (1-72) shapes a novel arch-like fibril structure. We further show that both pS87 and gS87 α-syn fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-syn fibril. Our findings demonstrate that different PTMs at the same site can produce distinct fibril structures, which emphasizes the precise regulation of PTMs to amyloid fibril formation and pathology.
Visual features are processed before navigational affordances in the human brain
Authors: Dwivedi Kshitij , Sadiya Sari , Balode Marta P. , Roig Gemma , Cichy Radoslaw M.
Published: June 2023

To navigate through their immediate environment humans process scene information rapidly. How does the cascade of neural processing elicited by scene viewing to facilitate navigational planning unfold over time? To investigate, we recorded human brain responses to visual scenes with electroencephalography (EEG) and related those to computational models that operationalize three aspects of scene processing (2D, 3D, and semantic information), as well as to a behavioral model capturing navigational affordances. We found a temporal processing hierarchy: navigational affordance is processed later than the other scene features (2D, 3D, and semantic) investigated. This reveals the temporal order with which the human brain computes complex scene information and suggests that the brain leverages these pieces of information to plan navigation.
The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes
Authors: Matsumoto Collin , O’Dwyer Samantha C. , Manning Declan , Hernandez-Hernandez Gonzalo , Rhana Paula , Fong Zhihui , Sato Daisuke , Clancy Colleen E. , Vierra Nicholas C. , Trimmer James S. , Santana L. Fernando
Published: June 2023

In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.
Implementing a framework of carbon and nitrogen feedback responses into a plant resource allocation model
Authors: Holland Bethany L , Monk Nicholas A M , Clayton Richard H , Osborne Colin P
Published: June 2023

The allocation of resources to roots and shoots can greatly alter total plant mass. Allocation is thought to be the consequence of growth processes (i.e uptake rates, transport rates, growth rates) and the communication between them via signalling mechanisms. Feedbacks that alter growth processes are induced in nature by changes in the internal pools of carbon and nitrogen, but how these function together to define allocation remains unclear.

We introduce a framework model of internal feedback responses to changes in plant carbon and nitrogen concentrations. We evaluate how well the model responds to changes in carbon and nitrogen availability by simulating external environmental perturbations that influence the uptake of resources.

The model reflects experimental results when looking at the effect of atmosphericCO2and soil nitrogen concentrations on total plant mass and replicates observed responses to leaf defoliation events. Overall this shows that a combination of known signalling mechanisms are sufficient to reproduce experimentally observed responses to external resource availability.

Model simulations highlight key areas of uncertainty where more empirical data is needed. In particular, quantitative data is needed to establish the strengths and rates at which feedback responses to carbon and nitrogen substrate concentrations alter growth and uptake rates.
Evaluating Study Design Rigor in Preclinical Cardiovascular Research: A Replication Study
Authors: Jimenez Isaiah C. , Montenegro Gabrielle C. , Zahiri Keyana , Patel Damini , Mueller Adrienne
Published: June 2023

Background

Methodological rigor remains a priority in preclinical cardiovascular research to ensure experimental reproducibility and high-quality research. Limited reproducibility diminishes the translation of preclinical discoveries into medical practice. In addition, lack of reproducibility fosters uncertainty in the public’s acceptance of reported research results.

Methods

We evaluated the reporting of methodological practices in preclinical cardiovascular research studies published in leading scientific journals by screening articles for the inclusion of the following study design elements (SDEs): considering sex as a biological variable, randomization, blinding, and sample size power estimation. We screened for these SDEs across articles regarding preclinical cardiovascular research studies published between 2011 and 2021. We replicated and extended a study published in 2017 by Ramirez et al. We hypothesized a higher SDE inclusion across preclinical studies over time, that preclinical studies that include human and animal substudies within the same study will exhibit greater SDE inclusion than animal-only preclinical studies, and that a difference exists in SDE usage between large and small animal models.

Results

SDE inclusion was low; with 15.2% of animal-only studies including both sexes as a biological variable, 30.4% including randomization, 32.1% including blinding, and 8.2% including sample size estimation. The incorporation of SDEs did not significantly increase over the ten-year timeframe in the screened articles. Randomization and sample size estimation differed significantly between animal and human substudies (corrected p=1.85e-05 and corrected p=3.81e-07, respectively.)

Conclusions

Evidence of methodological rigor varies depending on the study type and model organisms used. From 2011-2021, SDE reporting within preclinical studies has not increased, suggesting more work is needed to foster the inclusion of rigorous study design elements in cardiovascular research.
Genomic insights into southern white rhinoceros (Ceratotherium simum simum) reproduction: revealing granulosa cell gene expression
Authors: Ruggeri Elena , Klohonatz Kristin , Sirard Marc-André , Durrant Barbara , Coleman Stephen
Published: June 2023

In vivo-collected granulosa cells (GC) from the southern white rhinoceros (SWR) provide a non-invasive assessment of the developmental status of oocytes prior toin vitroculture, which could aid in the development of assisted reproductive technologies (ART). Our study aimed to investigate gene expression in SWR granulosa cells, collectedin vivoand gain preliminary insight into the transcriptional activity occurring within the cells during various stages of oocyte development. It was hypothesized there would be similarities between the SWR GC transcriptome and cattle and humans, two species for which well-annotated genomes are available and ART are commonly used. GC were collected from SWR following ovum pickup (OPU) and pooled from all aspirated follicles. Total RNA was isolated, libraries prepared, and sequencing performed using an Illumina NextSeq 500. Reads were aligned and annotated to CerSimCot1.0. Databases for cattle and human were acquired for comparison. This study identified 37,407 transcripts present in GC of SWR. It was determined that cattle and human transcriptomes are valuable resources with a homology of 45% with the SWR. In conclusion, these data provide preliminary, novel insights into the transcriptional activity of GC in the SWR that can be used to enhance ART in this species.
Dying of thirst: Osmoregulation by a hawkmoth pollinator in response to variability in ambient humidity and nectar availability
Authors: Dahake Ajinkya , Persaud Steven , Jones Marnesha N. , Goyret Joaquin , Davidowitz Goggy , Raguso Robert A.
Published: June 2023

Climate-induced alterations in flowering phenology can lead to a temporal mismatch between pollinators and the availability of floral resources. Such asynchrony may be especially impactful in desert ecosystems, where flowering time and pollinator emergence are particularly sensitive to rainfall. To investigate the osmoregulation of a desert-living hawkmoth pollinatorManduca sexta, we sampled hemolymph osmolality of over 1000 lab-grown moths held at 20%, 50%, and 80% ambient humidity. Under starvation, the hemolymph osmolality of moths remained within a healthy range from days 1-3, regardless of ambient humidity. However, osmolality levels increase steeply from a baseline of 360-370 mmol/kg to 550 mmol/kg after 4-5 days in low and intermediate humidity and after 5 days in high humidity. Starved moths exposed to low humidity conditions died within 5 days, whereas those in high humidity conditions lived twice as long. Moths fed either syntheticDatura wrightiinectar, syntheticAgave palmerinectar, or water, maintained osmolality within a healthy baseline range of 350-400 mmol/kg. The same was true for moths that fed on authentic floral nectars. However, moths consumed higher amounts of synthetic nectar, likely due to the non-sugar nectar constituents in the authentic nectar. Finally, simulating a 4-day mismatch between pollinator emergence and nectar availability, we found that a single nectar meal can osmotically rescue moths in dry ambient conditions. Our findings indicate that hemolymph osmolality provides a rapid and accurate biomarker for assessing both the health and relative hydration state of insect pollinators.
Phylogenetic placement ofCeratophyllum submersumbased on a complete plastome sequence derived from nanopore long read sequencing data
Authors: Meckoni Samuel Nestor , Nass Benneth , Pucker Boas
Published: June 2023

Objective

Eutrophication poses a mounting concern in today’s world.Ceratophyllum submersumL. is one of many plants capable of living in eutrophic conditions, therefore it could play a critical role in addressing the problem of eutrophication. This study aimed to take a first genomic look atC. submersum.

Results

Sequencing of gDNA fromC. submersumyielded enough reads to assemble a plastome. Subsequent annotation and phylogenetic analysis validated existing information regarding angiosperm relationships and the positioning of Ceratophylalles in a wider phylogenetic context.
Pixel-wise programmability enables dynamic high-SNR cameras for high-speed microscopy
Authors: Zhang Jie , Newman Jonathan , Wang Zeguan , Qian Yong , Feliciano-Ramos Pedro , Guo Wei , Honda Takato , Chen Zhe Sage , Linghu Changyang , Etienne-Cummings Ralph , Fossum Eric , Boyden Edward , Wilson Matthew
Published: June 2023

High-speed wide-field fluorescence microscopy has the potential to capture biological processes with exceptional spatiotemporal resolution. However, conventional cameras suffer from low signal-to-noise ratio at high frame rates, limiting their ability to detect faint fluorescent events. Here, we introduce an image sensor where each pixel has individually programmable sampling speed and phase, so that pixels can be arranged to simultaneously sample at high speed with a high signal-to-noise ratio. In high-speed voltage imaging experiments, our image sensor significantly increases the output signal-to-noise ratio compared to a low-noise scientific CMOS camera (∼2-3 folds). This signal-to-noise ratio gain enables the detection of weak neuronal action potentials and subthreshold activities missed by the standard scientific CMOS cameras. Our camera with flexible pixel exposure configurations offers versatile sampling strategies to improve signal quality in various experimental conditions.
Competitive specific anchorage of molecules onto surfaces: quantitative control of grafting densities and contamination by free anchors
Authors: Kirichuk Oksana , Srimasorn Sumitra , Zhang Xiaoli , Roberts Abigail R. E. , Coche-Guerente Liliane , Kwok Jessica C. F. , Bureau Lionel , Débarre Delphine , Richter Ralf P.
Published: June 2023

The formation of surfaces decorated with biomacromolecules such as proteins, glycans or nucleic acids with well-controlled orientations and densities is of critical importance for the design ofin vitromodels,e.g., synthetic cell membranes, and interaction assays. To this effect, ligand molecules are often functionalized with an anchor that specifically binds to a surface with a high density of binding sites, providing control over the presentation of the molecules. Here, we present a method to robustly and quantitatively control the surface density of one or several types of anchor-bearing molecules by tuning the relative concentrations of target molecules and free anchors in the incubation solution. We provide a theoretical background that relates incubation concentrations to the final surface density of the molecules of interest, and present effective guidelines towards optimizing incubation conditions for the quantitative control of surface densities. Focussing on the biotin anchor, a commonly used anchor for interaction studies, as a salient example, we experimentally demonstrate surface density control over a wide range of densities and target molecule sizes. Conversely, we show how the method can be adapted to quality control the purity of end-grafted biopolymers such as biotinylated glycosaminoglycans by quantifying the amount of residual free biotin reactant in the sample solution.