bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
Authors: Hong Hyejeong , Dill-McFarland Kimberly A. , Simmons Jason D. , Peterson Glenna J. , Benchek Penelope , Mayanja-Kizza Harriet , Boom W. Henry , Stein Catherine M. , Hawn Thomas R.
Published: August 2023

The heterogeneity of outcomes afterMycobacterium tuberculosis(Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in media condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression ofBMP6, an Mtb-dependent eQTL gene, was associated withIFNB1induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.
Changing Faces of Authorship: A Study of Gender, Race, Regional Disparities in Gastroenterology/Hepatology-related RCTs. A Two Decade Analysis (2000-2022)
Authors: Kumari Roopa , Sadarat FNU , Luhana Sindhu , Parkash Om , Chander Subhash
Published: August 2023

Objective

To investigate gender, racial, ethnic, and regional disparities in first and senior authorship positions in gastroenterology/hepatology-related randomised controlled trials (RCT).

Design

Retrospective bibliometric analysis of PubMed-indexed RCTs published between January 2000 to December 2022 in leading journals with an impact factor of at least five.

Results

943 RCTs met our inclusion criteria, providing a participant pool of 301 female (15.96%) and 1,585 male (84.04%) authors from 37 countries (70% high-income countries). Despite a significant increase in the proportion of female authors in first and senior authorship positions between 2000 and 2022 (p<0.001), females were grossly underrepresented in both authorship positions, with a male-to-female ratio of 4.45 and 6.37, respectively. The male-to-female ratio was highest among Asian authors (7.79) than among White (4.22), Hispanic (1.44), and Black (1) authors in the first authorship position. In contrast, the male-to-female ratio was similar for Asian (6.2) and White (6.67) authors in the senior authorship position, with a low underlying frequency of Hispanic and Black female authors. There were statistically significant differences in gender distribution for first authorship at the country level (p=0.0018). Binary logistic regression analysis showed significant positive effects of the senior author being a female (β=1.124, p<0.001) and the senior author having PhD qualification (β=0.753, p=0.021) on female first authorship.

Conclusion

Despite significant improvements in gender, racial and ethnic representation in first and senior authorship of gastroenterology/hepatology-related RCTs published in high-impact journals, progress toward parity remains slow. Targeted interventions to improve author diversity are warranted.
Axons of cortical basket cells originating from dendrites develop higher local complexity than axons emerging from basket cell somata
Authors: Gonda Steffen , Riedel Christian , Reiner Andreas , Köhler Ina , Wahle Petra
Published: August 2023

Neuronal differentiation is regulated by neuronal activity. Here, we analyzed dendritic and axonal growth of Basket cells and non-Basket cells using sparse transfection of channelrhodopsin-YFP and repetitive optogenetic stimulation in slice cultures of rat visual cortex. Neocortical interneurons often display axon-carrying dendrites (AcDs). We found that the AcDs of Basket cells and non-Basket cells were on average their most complex dendrite. Further, the AcD configuration had an influence on Basket cell axonal development. Axons originating from an AcD formed denser arborizations with more terminal endings within the dendritic field of the parent cell. Intriguingly, this occurred already in unstimulated Basket cells, and complexity was not increased further by optogenetic stimulation. However, optogenetic stimulation exerted a growth-promoting effect on axons emerging from Basket cell somata. The axons of non-Basket cells neither responded to the AcD configuration nor to the optogenetic stimulation. The results suggest that the formation of locally dense Basket cell plexuses is regulated by spontaneous activity. Moreover, in the AcD configuration, the AcD and the axon it carries mutually support each others growth.

Teaser

Textbooks usually draw cortical neurons with axons emerging from the cell body. Axons emerging from dendrites have been considered a caprice of nature until recent work demonstrated that axon-carrying dendrites are neither a rare nor a random phenomenon. Rather, this morphological configuration awards specific functional properties. Here, we discovered a morphogenetic role of the AcD configuration in developing Basket neurons which deliver axo-somatic inhibition to pyramidal neurons. Driven by spontaneous activity, AcD and the axon mutually promote each others growth such that the axon rapidly forms a denser presynaptic terminal field. Basket cells with axons from the cell body achieve the same complexity with technical assistance via an optogenetic stimulation. This way, a dendritic origin accelerates Basket cell axonal development.
Nociceptor to macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth
Authors: Fattori Victor , Zaninelli Tiago H. , Rasquel-Oliveira Fernanda S. , Heintz Olivia K. , Jain Ashish , Sun Liang , Seshan Maya L. , Peterse Daniëlle , Lindholm Anne E. , Anchan Raymond M. , Veri Waldiceu A. , Rogers Michael S.
Published: August 2023

Endometriosis is a debilitating and painful gynecological inflammatory disease affecting approximately 15% of women. Current treatments are ineffective for a significant fraction of patients, underscoring the need for new medical therapies with long-term benefits. Given the genetic correlation between migraines and endometriosis, we sought evidence for the role of CGRP-mediated neuroimmune communication in endometriosis. We found that mouse and human endometriosis lesions contained CGRP and RAMP1. In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptors support endometriosis lesions.In vitro,CGRP-treated macrophages showed impaired efferocytosis and supported endometrial cell growth in a RAMP1-dependent manner. Treatment with FDA-approved drugs that block CGRP-RAMP1 signaling reduced evoked and spontaneous pain, and lesion size. Since the lack of drug efficacy at reducing ongoing pain drives most endometriosis therapy failure, our data demonstrating effectiveness of non-hormonal and non-opioid CGRP/RAMP1 blocking therapies may lead to clinical benefit for endometriosis patients.
The geometry of photopolymerized topography influences neurite pathfinding by directing growth cone morphology and migration
Authors: Vecchi Joseph T. , Rhomberg Madeline , Guymon C. Allan , Hansen Marlan R.
Published: August 2023

Cochlear implants (CIs) provide auditory perception to those with profound sensorineural hearing loss: however, the quality of sound perceived by a CI user does not approximate natural hearing. This limitation is due in part to the large physical gap between the stimulating electrodes and their target neurons. Therefore, directing the controlled outgrowth of processes from spiral ganglion neurons (SGNs) into close proximity to the electrode array could provide significantly increased hearing function. For this objective to be properly designed and implemented, the ability and limits of SGN neurites to be guided must first be determined. In this work, we engineered precise topographical microfeatures with angle turn challenges of various geometries to study SGN pathfinding. Additionally, we analyze sensory neurite growth in response to topographically patterned substrates and use live imaging to better understand how neurite growth is guided by these cues. In assessing the ability of neurites to sense and turn in response to topographical cues, we find that the geometry of the angled microfeatures determines the ability of neurites to navigate the angled microfeature turns. SGN neurite pathfinding fidelity can be increased by 20-70% through minor increases in microfeature amplitude (depth) and by 25% if the angle of the patterned turn is made more obtuse. Further, by using engineered topographies and live imaging of dorsal root ganglion neurons (DRGNs), we see that DRGN growth cones change their morphology and migration to become more elongated within microfeatures. However, our observations also indicate complexities in studying neurite turning. First, as the growth cone pathfinds in response to the various cues, the associated neurite often reorients across the angle topographical microfeatures. This reorientation is likely related to the tension the neurite shaft experiences when the growth cone elongates in the microfeature around a turn. Additionally, neurite branching is observed in response to topographical guidance cues, most frequently when turning decisions are most uncertain. Overall, the multi-angle channel micropatterned substrate is a versatile and efficient system to assess SGN neurite turning and pathfinding in response to topographical cues. These findings represent fundamental principles of neurite pathfinding that will be essential to consider for the design of 3D systems aiming to guide neurite growthin vivo.
Age-Associated Weaker Immunity to Coronaviruses is Characteristic of Children that Develop Multisystem Inflammatory Syndrome following SARS-CoV-2 Infection
Authors: Camerini David , Arrieta Antonio , Randall Arlo Z. , Gach Johannes S. , Maecker Holden , Hoang Janet , Imfeld Karen , Osborne Stephanie , Enriquez Claudia , Hung Christopher , Edgar Joshua , Shandling Adam , Huynh Vu , Teng Andy A. , Pablo Jozelyn V. , Forthal Donald N. , Campo Joseph J. , Nugent Diane
Published: August 2023

We analyzed the antibody and cytokine responses of twenty-three patients with multisystem inflammatory syndrome of children (MIS-C) that appeared with a three-to-six-week delay following a mild or asymptomatic SARS-CoV-2 infection. These responses were compared to healthy convalescent pediatric COVID-19 patients approximately twenty-eight days after the onset of symptoms. Both groups had strong IgG responses to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, but the MIS-C patients had weaker antibody responses to certain epitopes in the SARS-CoV-2 S and N proteins and to the S and N proteins of endemic human coronaviruses (HCoV) compared to pediatric convalescent COVID patients. HCoV antibody reactivity was correlated with age. In contrast, MIS-C patients had elevated serum levels of several proinflammatory cytokines compared to convalescent COVID patients, including interleukins IL-6, IL-8, IL-18 and chemokines CCL2, CCL8, CXCL5, CXCL9 and CXCL10 as well as tumor necrosis factor alpha and interferon gamma. Moreover, many cytokine responses of MIS-C patients were positively correlated with antibody responses to the SARS-CoV-2 S, N, membrane and ORF3a proteins while pediatric convalescent COVID patient cytokine responses were more often negatively correlated with antibody responses to the S, N and ORF3a proteins of SARS-CoV-2.
3D kinematics of leaf-cutter ant mandibles: not all dicondylic joints are simple hinges
Authors: Kang Victor , Püffel Frederik , Labonte David
Published: August 2023

Insects use their mandibles for a variety of tasks, including cutting and material transport, defence, building nests, caring for brood, and competing for mates. Despite this functional diversity, mandible motion is thought to be constrained to rotation about a single fixed axis in the majority of extant species. Here, we conduct a direct quantitative test of this ‘hinge joint hypothesis’ in a species that uses its mandibles for a wide range of tasks:Atta vollenweiderileaf-cutter ants. Mandible movements from live restrained ants were reconstructed in 3D using a multi-camera rig. Rigid body kinematic analyses revealed strong evidence that mandible movement occupies a kinematic space which requires more than one rotational degree of freedom: at large opening angles, mandible motion is dominated by yaw. But at small opening angles, mandibles yaw and pitch. The combination of yaw and pitch allows mandibles to ‘criss-cross’: either mandible can be on top when mandibles are closed. We observed criss-crossing in freely cutting ants, suggesting that it is functionally important. Combined with recent reports on diversity of joint articulations in other insects, our results show that insect mandible kinematics are more diverse than traditionally assumed, and thus worthy of further detailed investigation.
A subclass of evening cells promotes the switch from arousal to sleep at dusk
Authors: Brown Matthew P. , Verma Shubha , Palmer Isabelle , Zuniga Adler Guerrero , Rosensweig Clark , Keles Mehmet F. , Wu Mark N.
Published: August 2023

Animals exhibit rhythmic patterns of behavior that are shaped by an internal circadian clock and the external environment. While light intensity varies across the day, there are particularly robust differences at twilight (dawn/dusk). These periods are also associated with major changes in behavioral states, such as the transition from arousal to sleep. However, the neural mechanisms by which time and environmental conditions promote these behavioral transitions are poorly defined. Here, we show that the E1 subclass ofDrosophilaevening clock neurons promotes the transition from arousal to sleep at dusk. We first demonstrate that the cell-autonomous clocks of E2 neurons alone are required to drive and adjust the phase of evening anticipation, the canonical behavior associated with “evening” clock neurons. We next show that conditionally silencing E1 neurons causes a significant delay in sleep onset after dusk. However, rather than simply promoting sleep, activating E1 neurons produces time- and light- dependent effects on behavior. Activation of E1 neurons has no effect early in the day, but then triggers arousal before dusk and induces sleep after dusk. Strikingly, these phenotypes critically depend on the presence of light during the day. Despite their influence on behavior around dusk,in vivovoltage imaging of E1 neurons reveals that their spiking rate does not vary between dawn and dusk. Moreover, E1-specific clock ablation has no effect on arousal or sleep. Thus, we suggest that, rather than specifying “evening” time, E1 neurons act, in concert with other rhythmic neurons, to promote behavioral transitions at dusk.
Mapping caudolenticular gray matter bridges in the human brain striatum through diffusion magnetic resonance imaging and tractography
Authors: Little Graham , Poirier Charles , Parent Martin , Petit Laurent , Descoteaux Maxime
Published: August 2023

In primates, the putamen and the caudate nucleus are connected by ∼1mm-thick caudolenticular gray matter bridges (CLGBs) interspersed between the white matter bundles of the internal capsule. Little is understood about the functional or microstructural properties of the CLGBs. In studies proposing high resolution diffusion magnetic resolution imaging (dMRI) techniques, CLGBs have been qualitatively identified as an example of superior imaging quality, however, the microstructural properties of these structures have yet to be examined. In this study, it is demonstrated for the first time that dMRI is sensitive to an organized anisotropic signal oriented in the direction parallel to the CLGBs, suggesting that dMRI could be a useful imaging method for probing the microstructure of the CLGBs. To demonstrate the anisotropic diffusion signal is coherently organized along the extent of the CLGBs and to enable a subsequent CLGB microstructural measurement, a novel tractography algorithm is proposed that utilizes the shape of the human striatum (putamen + caudate nucleus) to reconstruct the CLGBs in 3D. The method is applied to two publicly available and one locally acquired diffusion imaging datasets varying in resolution and imaging quality, thereafter demonstrating that the reconstructed CLGBs directly overlap expected gray matter regions in the human brain. In addition, the method is shown to accurately reconstruct CLGBs repeatedly across multiple test-retest cohorts. The novel tractography CLGB reconstructions are then used to extract a quantitative measurement of microstructure from a local model of the diffusion signal along the CLGBs themselves. This is the first work to comprehensively study the CLGBs in-vivo using dMRI and presents techniques suitable for future human neuroscience studies targeting these structures.
Small RNA Analysis of Virus-virus Interaction between Two Orthotospoviruses
Authors: Zhao Kaixi , Islam Md Tariqul , Johnson Nathan R. , Axtell Michael J. , Rosa Cristina
Published: August 2023

Mixed infections of plant viruses are commonly found in natural patho-systems and present a valuable opportunity to understand how multiple viruses can co-infect the same host. Tomato spotted wilt orthotospovirus (TSWV) and impatiens necrotic spot orthotospovirus (INSV) are present in the same geographic areas and are closely related. More mixed infections of TSWV and INSV have been reported in recent years, and the INSV host range has been reported to be increasing. In a previous study, we have isolated one strain of INSV and one of TSWV and showed that they have an antagonistic relationship in their vectors, but we were unable to determine, the underlying mechanisms governing their antagonismin plantaand the contribution of the host to this. Here, we used small RNA sequencing to study TSWV-INSV antagonistic interaction and showed that INSV alters plant responses and the processing of TSWV.
A defined diet for pre-adultDrosophila melanogaster
Authors: Martelli Felipe , Quig Annelise , Mele Sarah , Lin Jiayi , Fulton Tahlia L. , Wansbrough Mia , Barlow Christopher K. , Schittenhelm Ralf B. , Johnson Travis K. , Piper Matthew D.W.
Published: August 2023

Drosophilamelanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that improves larval growth, development rate, and rescues survival. We demonstrate its use for exploring pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder.
Protein Coronas on Functionalized Nanoparticles Enable Quantitative and Precise Large-Scale Deep Plasma Proteomics
Authors: Huang Ting , Wang Jian , Stukalov Alexey , Donovan Margaret K. R. , Ferdosi Shadi , Williamson Lucy , Just Seth , Castro Gabriel , Cantrell Lee S. , Elgierari Eltaher , Benz Ryan W. , Huang Yingxiang , Motamedchaboki Khatereh , Hakimi Amirmansoor , Arrey Tabiwang , Damoc Eugen , Kreimer Simion , Farokhzad Omid C. , Batzoglou Serafim , Siddiqui Asim , Van Eyk Jennifer E. , Hornburg Daniel
Published: August 2023

Background

The wide dynamic range of circulating proteins coupled with the diversity of proteoforms present in plasma has historically impeded comprehensive and quantitative characterization of the plasma proteome at scale. Automated nanoparticle (NP) protein corona-based proteomics workflows can efficiently compress the dynamic range of protein abundances into a mass spectrometry (MS)-accessible detection range. This enhances the depth and scalability of quantitative MS-based methods, which can elucidate the molecular mechanisms of biological processes, discover new protein biomarkers, and improve comprehensiveness of MS-based diagnostics.

Methods

Investigating multi-species spike-in experiments and a cohort, we investigated fold-change accuracy, linearity, precision, and statistical power for the using the Proteograph™ Product Suite, a deep plasma proteomics workflow, in conjunction with multiple MS instruments.

Results

We show that NP-based workflows enable accurate identification (false discovery rate of 1%) of more than 6,000 proteins from plasma (Orbitrap Astral) and, compared to a gold standard neat plasma workflow that is limited to the detection of hundreds of plasma proteins, facilitate quantification of more proteins with accurate fold-changes, high linearity, and precision. Furthermore, we demonstrate high statistical power for the discovery of biomarkers in small- and large-scale cohorts.

Conclusions

The automated NP workflow enables high-throughput, deep, and quantitative plasma proteomics investigation with sufficient power to discover new biomarker signatures with a peptide level resolution.
Disruptive mutations in the serotonin transporter associate serotonin dysfunction with treatment-resistant affective disorder
Authors: Støier Jonatan Fullerton , Jørgensen Trine Nygaard , Sparsø Thomas , Rasmussen Henrik Berg , Kumar Vivek , Newman Amy Hauck , Blakely Randy D. , Werge Thomas , Gether Ulrik , Herborg Freja
Published: August 2023

Affective or mood disorders are a leading cause of disability worldwide. The serotonergic system has been heavily implicated in the complex etiology and serves as a therapeutic target. The serotonin transporter (SERT) is a major regulator of serotonin neurotransmission, yet the disease-relevance of impaired SERT function remains unknown. Here, we present the first identification and functional characterization of disruptive coding SERT variants found in patients with psychiatric diseases. In a unique cohort of 144 patients characterized by treatment-resistant chronic affective disorders with a lifetime history of electroconvulsive therapy, we identified two previously uncharacterized coding SERT variants: SERT-N217S and SERT-A500T. Both variants were significantly enriched in the patient cohort compared to GnomAD (SERT-N217S: OR = 151,P= 0.0001 and SERT-A500T: OR = 1348,P= 0.0022) and ethnicity-matched healthy controls (SERT-N217S: OR ≥ 17.7,P≤ 0.013 and SERT-A500T: OR = ∞,P= 0.029). Functional investigations revealed that the mutations exert distinct perturbations to SERT function, but their overall effects converge on a partial loss-of-function molecular phenotype. Thus, the SERT-A500T variant compromises the catalytic activity, while SERT-N217S disrupts proper glycosylation of SERT with a resulting dominant-negative trafficking deficiency. Moreover, we demonstrate that the trafficking deficiency of SERT-N217S is amenable to pharmacochaperoning by noribogaine. Collectively, our findings describe the first disease-associated loss-of-function SERT variants and implicate serotonergic disturbances arising from SERT dysfunction as a risk factor for chronic affective disorders.
A genome-wide association study of adults with community-acquired pneumonia
Authors: Suarez-Pajes Eva , Marcelino-Rodriguez Itahisa , Brito Elisa Hernández , Gonzalez-Barbuzano Silvia , Ramirez-Falcon Melody , Tosco-Herrera Eva , Rubio-Rodríguez Luis A. , Briones María Luisa , Rajas Olga , Borderías Luis , Ferreres Jose , Payeras Antoni , Lorente Leonardo , Aspa Javier , Lorenzo Salazar Jose M. , Valencia-Gallardo José Manuel , Carbonell Edurne , Freixinet Jordi , de Castro Felipe Rodríguez , Violán Jordi Solé , Flores Carlos , Rodríguez-Gallego Carlos
Published: August 2023

Introduction

Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of entry.

Objective

To identify genetic risk loci for CAP using a one-stage genome-wide association study (GWAS).

Methods

We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. Genotyping and imputation allowed testing the association of 7,6 million variants using logistic regressions. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association testing of the classic HLA alleles and amino acids was also conducted.

Results

We revealed six independent sentinel variants that were genome-wide significant (p<5×10−8), three located on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Our analyses prioritizedC4orf33on 4q28.2,TAPBPon 6p21.32, andZNF341on 20q11.22. Interestingly, genetic defects ofTAPBPandZNF341are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus andHaemophyilus influenzae. Associations were all non-significant for the classic HLA alleles.

Conclusions

We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.
Mood instability may be causally associated with the high risk of cardiovascular disease: evidence from a mendelian randomization analysis
Authors: Liu Zirui , Wang Haocheng , Yang Zhengkai , Lu Yu , Wang Jikai , Zou Cao
Published: August 2023

Background

Mental illness was identified associated with high risk of cardiovascular diseases (CVDs). However, few studies focused on the effect of personality traits, the causal relationships remain unknown. Here, we use mendelian randomization (MR) analyses to evaluate the causal association between mood instability (mood swings) and 5 common CVDs.

Methods

Large genome-wide association studies (GWAS) of mood swings (n= 373733) and 5 CVDs from two independent cohorts respectively including coronary artery disease (CAD) (n= 766053), myocardial infarction (MI) (n= 596436), heart failure (HF) (n= 1185501), atrial fibrillation (AF) (n= 2169833) and stroke (n = 627558). We performed a range of bidirectional two-sample MR and related sensitive analysis including MR-Egger regression, MR-PRESSO global test and “Leave-one-out” method. A Bonferroni-corrected significance level of p < 0.01 (0.05/5) was identified to be statistically significant, while p < 0.05 was considered to indicate suggestive evidence. Moreover, multivariable MR (MVMR) and mediation analyses were also conducted to adjust confounding factors as well as found potential mediators.

Results

This MR analyses revealed the significant causal effects of mood swings on CAD (OR = 1.45, 95% CI 1.24–1.71; P = 5.52e-6), MI (OR = 1.60, 95% CI 1.32–1.95; P = 1.77e-6), HF (OR = 1.42, 95% CI 1.12–1.71; P = 2.32e-6) and stroke (OR = 1.48, 95% CI 1.19–1.83; P = 3.46e-4). However, no causal effects of mood swings on AF (P=0.16) were found. In the reverse MR, no causal relationships were observed. Additionally, hypertension may mediate the causal pathway from mood swings to CAD (proportion of mediation effect in total effect: 39.60%, 95% CI: 19.31%–59.89%), MI (35.37%, 95% CI: 17.10%–53.65%), HF (43.19%, 95% CI: 20.68%–65.69%) and stroke (55.47%, 95% CI: 27.00%–83.95%).

Conclusion

Mood instability (mood swings) causally resulted in CAD, MI, HF and stroke, and these causal effects may be partly mediated by hypertension.
The predictive capacity of polygenic risk scores for disease risk is only moderately influenced by imputation panels tailored to the target population
Authors: Levi Hagai , Elkon Ran , Shamir Ron
Published: August 2023

Polygenic risk scores (PRS) predict individuals’ genetic risk of developing complex diseases. They summarize the effect of many genetic variants discovered in genome-wide association studies (GWASs). However, to date, large GWASs exist primarily for the European population and the quality of PRS prediction declines when applied to target sets of other ethnicities. A key step in using a PRS is imputation, which is the inference of un-typed SNPs using a set of fully-sequenced individuals, called the imputation panel. The SNP genotypes called by the imputation process depend on the ethnic composition of the imputation panel. Several studies have shown that imputing genotypes using a panel that contains individuals of the same ethnicity as the genotyped individuals improves imputation accuracy. However, until now, there has been no systematic investigation into the influence of the ethnic composition of imputation panels on the accuracy of PRS predictions when applied to ethnic groups that differ from the population used in the GWAS.

In this study we estimated the effect of imputation of the target set on prediction accuracy of PRS when the discovery (GWAS) and the target sets come from different ethnic groups. We analyzed twelve binary phenotypes and three populations from the UK Biobank (Europeans, South-Asians, and Africans). We generated imputation panels from several ethnic groups, imputed the target set using each panel, and generated PRS to compute individuals’ risk scores. Then, we assessed the prediction accuracy obtained from each imputation panel. Our analysis indicates that using an imputation panel matched to the ethnic group of the target population yields only a marginal improvement and only under specific conditions. Hence, while a target-matched imputation panel can potentially improve prediction accuracy of European PRSs in non-EUR populations, the improvement is limited.
High-efficiency gene editing inAnopheles sinensisusing ReMOT control
Authors: Yang Xiao-lin , Ling Xia , Sun Quan , Qiu Pin-pin , Xiang Kai , Hong Jun-feng , He Shu-lin , Chen Jie , Ding Xin , Hu Hai , He Zheng-bo , Zhou Cao , Chen Bin , Qiao Liang
Published: August 2023

CRISPR/Cas9-mediated gene editing provides an effective method for deciphering the molecular mechanisms underlying mosquito development and mosquito-borne disease transmission, as well as for exploring genetic control strategies. However, delivering the Cas9 ribonucleoprotein complex by embryo injection to produce genetic modifications is challenging, is mostly confined to model mosquitoes and specialized laboratories, and has low editing efficiency. Here, we established an effective Receptor-Mediated Ovary Transduction of Cargo (ReMOT) control method, enabling the introduction of heritable mutations intoAnopheles sinensis, the major malaria vector in China and Southeast Asia, via the injection of female adult mosquitoes. Injection of a mixture of P2C-DsRed and saponin resulted in red fluorescence in the ovaries, with a 100% success rate. Using this system, we knocked-out the pigment synthesis genes,AswhiteandAsyellow, using injected wild-type (WT) females mated with WT males, resulting in the highest efficiency of gene editing among mosquitoes under the same mating conditions. Furthermore, the gene-editing efficiency was increased by at least 2.1-fold using injected WT females mated with mutant males. This improved ReMOT control method exhibits high editing efficiency, with important benefits in terms of functional genomics research and genetic control strategies inAn. sinensis. Moreover, this represents a convenient method for gene manipulation in laboratories that are unable to perform embryo injection or that lack embryo-injection equipment.
RdDM mutants reduce histone methylation rather than DNA methylation at the paramutated maizeb1enhancer
Authors: Hövel Iris , Bader Rechien , Louwers Marieke , Haring Max , Peek Kevin , Gent Jonathan I. , Stam Maike
Published: August 2023

Paramutation is the transfer of mitotically and meiotically heritable silencing information between two alleles. With paramutation at the maizebooster1(b1) locus, the low expressedB’epiallele heritably changes the high expressedB-Iepiallele intoB’with 100% frequency. This requires specific tandem repeats and multiple components of the RNA-directed DNA methylation (RdDM) pathway, including the RNA-dependent RNA polymerase (RdRP,mediator of paramutation1, MOP1), the second-largest subunit of RNA polymerase IV and V (NRP(D/E)2a,mediator of paramutation2,MOP2), and the largest subunit of RNA Polymerase IV (NRPD1,mediator of paramutation3, MOP3). Mutations inmopgenes prevent paramutation and release silencing at theB’epiallele. In this study we investigated the effect of mutations inmop1,mop2andmop3on chromatin structure and DNA methylation at theB’epiallele, and especially the regulatory hepta-repeat 100 kb upstream of theb1gene.

We show that mutations inmop1andmop3result in decreased repressive histone modifications H3K9me2 and H3K27me2 at the hepta-repeat. Associated with this decrease are partial activation of the hepta-repeat enhancer function, formation of a multi-loop structure, and elevatedb1expression. Inmop2mutants, which do not show elevatedb1expression, H3K9me2 and H3K27me2 and a single-loop structure like in wild typeB’are retained. Surprisingly, high DNA methylation levels at theB’hepta-repeat remains in all three mutants. Our results raise the possibility of MOP factors mediating RNA-directed histone methylation rather than RNA-directed DNA methylation at theb1locus.
KRASallelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancerin vivo
Authors: Najumudeen Arafath K. , Fey Sigrid K. , Millett Laura M. , Ford Catriona , Gilroy Kathryn , Gunduz Nuray , Ridgway Rachel A. , Anderson Eve , Strathdee Douglas , Clark William , Nixon Colin , Morton Jennifer P. , Campbell Andrew D. , Sansom Owen J.
Published: August 2023

OncogenicKRASmutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence ofKRASallelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele inKRASmutant cancers. However, there is still much debate over the function of wild-typeKRASin tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy ofKrasin the context of an intact oncogenicKrasin colorectal cancer. We observe that in the presence of oncogenicKras, wild-typeKrasacts to restrain tumour growth. Mechanistically, deletion of wild-typeKrasexacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-typeKraspotentiates the oncogenic effect of KRASG12D, while presence of wild-typeKrasis associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-typeKrasin oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-typeKrasduring colon tumour initiation and highlights the critical impact of wild-typeKrasupon therapeutic response to MAPK and tumour progression inKrasmutant cancers.

Highlights

Wild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer modelsin vivo

Concomitant loss of wild-type KRAS and activation of WNT signalling promotes mutant KRAS-driven tumour initiation.

Wild-type KRAS promotes resistance to MAPK inhibition in KRAS mutant tumours

Loss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models.
An amphipathic helix facilitates direct membrane binding of Mycoplasma FtsZ
Authors: Dutta Soumyajit , Poddar Sakshi , Chakraborty Joyeeta , Srinivasan Ramanujam , Gayathri Pananghat
Published: August 2023

Cell division in bacteria is initiated by constriction of the Z-ring comprising two essential proteins FtsZ and FtsA. Despite our knowledge about the crucial function of the Z-ring in bacterial division, the precise roles and mechanism of how FtsZ and FtsA drive cell constriction remain elusive. FtsZ/FtsA in wall-less bacteria like mycoplasmas is an ideal model system for obtaining mechanistic insights into Z-ring constriction in the absence of cell wall machinery. In this study, we have analyzed FtsZ and FtsA sequences of 113 mycoplasma species and compared with the corresponding protein sequences in cell-walled bacteria. We report a phylogenetically distinct group of 12 species that possess FtsZs without the canonical FtsA interacting conserved C-terminal peptide (CCTP) motif. Interestingly, these FtsZs contain a putative membrane-binding amphipathic helix as an N-terminal or C-terminal extension to the globular FtsZ domain. As a proof-of-concept, we experimentally show that the proposed C-terminal amphipathic helix inM. genitaliumFtsZ binds liposomesin vitroas well as localizes toE. colimembranein vivo. Additionally, we identify a putative cholesterol recognition motif within the C-terminal amphipathic helix region ofM. genitaliumFtsZ. Our study catalogues the functional variations of membrane attachment by the FtsZ and FtsA system in cell wall-less mycoplasmas and provides a new perspective to study novel functions of FtsZ/A system in cell division.

Importance

Z-ring and peptidoglycan synthesis machinery both play crucial roles in bacterial cell division. Currently, our knowledge about how FtsZ and FtsA, the two primary components of the Z-ring, function, is limited to cell-walled bacteria where ring constriction is coupled to peptidoglycan synthesis. Cell wall-less bacterial FtsZ/A system is an excellent model to study the mechanism of Z-ring constriction in the absence of cell wall synthesis machinery. Here, we analysed FtsZ protein sequences across mycoplasma species and identified their characteristic sequence features. Our study reveals a novel group of FtsZs from mycoplasma with an inherent membrane binding and probable cholesterol sensing amphipathic motif, which serves as a new paradigm to explore fundamental roles of FtsZ and FtsA in Z-ring constriction during bacterial division.
Modelling the impact of rainfall events on increasingVibrio vulnificusconcentrations in Pacific oysters (Crassostrea gigas)
Authors: Fletcher Graham C. , Taylor Roland , Hedderley Duncan
Published: August 2023

Vibrio vulnificusoccurs naturally in seawater and causes debilitating, often fatal illnesses, particularly in people with underlying health issues such as liver disease. The illness can occur when raw molluscan shellfish that have bio-accumulated the organism are consumed. New Zealand seafood is not known to have caused any illnesses, although there have been wound infections. This study sought to better understand the effect of environmental conditions on concentrations ofV. vulnificusin Pacific oysters in three harbours over the summer months of 2016–19. Fortnightly sampling at two harbours only once gave a most probable number (MPN) of >10 per g of oyster meat, while the third harbour regularly produced much higher counts (up to 220,000 per g). From 2017–19, weekly samples from three sites in this harbour (four in 2018) were tested. Eleven peaks in concentration were observed, all when seawater temperatures exceeded 20°C and after heavy rainfall had reduced the seawater salinity, usually to <25‰ from the average of 32‰. A fitted structural equation model with temperature and salinity terms accounted for 60% of the variance in concentrations and rates of decline after concentration peaks averaged 1.05 log10MPN per week.

The rate of decline was highly variable so microbiological testing would be required to confirm this rate for use in food safety management. However, the results of the study will enable better risk management.

Importance

Vibrio vulnificusis a deadly bacterium that naturally occurs in some seawater and can be concentrated in shellfish such as oysters. Consumers with underlying health issues who eat contaminated shellfish may suffer serious illnesses. New Zealand shellfish have never been known to cause such illnesses although the species is present in our seawater. The strains present may not be able to cause foodborne illness. We found thatV. vulnificuscould be present in high concentrations in farmed Pacific oysters in one of three studied harbours. This happened when seawater temperatures were warm and heavy rainfall reduced salinity. We developed a model based on seawater temperature and salinity that would be able to predict concentrations in shellfish, at least in this harbour. This will help industry and regulators manage the food safety risk should this organism become a public health issue.

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We modelled concentrations ofVibrio vulnificusin Pacific oysters after flood events and showed that seawater salinity and temperatures in previous 168 h affected them.
Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue
Authors: Chen Hong , Sun Lijun , Feng Lu , Han Xue , Zhang Yunhua , Zhai Wenbo , Zhang Zehe , Mulholland Michael , Zhang Weizhen , Yin Yue
Published: August 2023

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by ILC3s and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell‒cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.
FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
Authors: Tan Can , Kurup Shreya , Dyakiv Yaryna , Kume Tsutomu
Published: August 2023

Background

Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates mutations of the transcription factorFOXC1are associated with MV defects, including mitral valve regurgitation. In this study, we sought to determine whether murineFoxc1and its closely related factor,Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar extracellular matrix (ECM).

Methods

Adult mice carrying tamoxifen-inducible, endothelial cell (EC)-specific, compoundFoxc1;Foxc2mutations (i.e., EC-Foxc-DKO mice) were used to study the function ofFoxc1andFoxc2in the maintenance of mitral valves. The EC-mutations ofFoxc1/c2were induced at 7 – 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of EC-Foxc-DKO mice were assessed via whole-mount immunostaining, immunohistochemistry, and Movat pentachrome/Masson’s Trichrome staining.

Results

EC-deletions ofFoxc1andFoxc2in mice resulted in abnormally extended and thicker mitral valves by causing defects in regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-Foxc1/c2mutant mice. PROX1, a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-Foxc1/c2mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded in EC-Foxc1/c2mutant mitral valves.

Conclusions

Our results indicate thatFoxc1andFoxc2are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessels to prevent myxomatous mitral valve degeneration.
Waiting for the punch(line): the circuit of culture and internal public relations at Netflix
Authors: Kazmi Saima , Heisten Mark , St John III Burton
Published: August 2023

Purpose

This study is concerned with the dynamics of the internal communications at Netflix following the release of The Closer and the public debate that followed, testing Netflix's long-standing reputation for promoting diverse content and supporting a progressive organizational culture.

Design/methodology/approach

Using the circuit of culture (CoC) as a theoretical framework, this study applies a case study approach to analyze internal communication and strategic public relations in addressing this crisis.

Findings

This study's findings illustrate that by failing to interpret two of the five moments of the CoC, production and identity, Netflix negated the very values that constitute its brand. These findings have implications for how public relations' long-standing focus on two-way symmetrical communication is problematic, especially in the workplace.

Originality/value

The findings situate how the exertion of power within an organization, particularly in moments of identity and production, problematize the role of two-way symmetrical communication within an organization in crisis.
Mining safely: examining the moderating role of safety climate on mineworkers' mental health and safety behavior nexus
Authors: Amoako Emmanuel Kodwo , Nubuor Saviour Ayertey , Suleman Abdul-Razak , Abdul Bawa Amin , Akwetey-Siaw Bridget
Published: August 2023

Purpose

The study aims to investigate the impact of anxiety and depression (dimensions of mental health) on mineworkers' safety behaviors (safety compliance and safety participation) while examining the moderating role of safety climate on these relationships.

Design/methodology/approach

A quantitative research approach with an explanatory cross-sectional survey research design was adopted. A total of 274 purposively selected mineworkers participated in the study. Responses were obtained from participants through a structured questionnaire which was analyzed using the partial least square structural equation modeling.

Findings

Anxiety had a significant negative effect on safety compliance but not participation. However, depression was found to have a significant negative effect on both mineworkers' safety compliance and participation behaviors. The findings of the study also show that safety climate moderates the relationships between the dimensions of mental health and mineworkers' safety behavior except for the relationship between anxiety and mineworkers' safety participation behavior.

Originality/value

The study offers an account of the negative effect of mental health on mineworkers' safety behavior whiles highlighting that safety climate is an important construct to mitigate the negative effects of mental illness on the safety behaviors of mineworkers.