bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of social vulnerability on cardiac arrest mortality in the United States, 2016-2020
Authors: Gonuguntla Karthik , Chobufo Muchi Ditah , Shaik Ayesha , Patel Neel , Penmetsa Mouna , Sattar Yasar , Thyagaturu Harshith , Chan Paul S. , Balla Sudarshan
Published: August 2023

Importance

Cardiac arrest is one of the leading causes of morbidity and mortality, with an estimated 340,000 out-of-hospital and 292,000 in-hospital cardiac arrest events per year in the U.S. Survival rates are lower in certain racial and socioeconomic groups.

Objective

To examine the impact of social determinants on cardiac arrest mortality among adults stratified by age, race, and sex in the U.S.

Design

A county-level cross-sectional longitudinal study using death data between 2016 and 2020 from the Centers for Disease Control and Prevention’s (CDC) Wide-Ranging Online Data for Epidemiologic Research (WONDER) database.

Setting

Using the multiple causes of death dataset from the CDC’s WONDER database, cardiac arrests were identified using the International Classification of Diseases (ICD), tenth revision, clinical modification codes.

Participants

Individuals aged 15 years or more whose death was attributed to cardiac arrest.

Exposures

Social vulnerability index (SVI), reported by the CDC, is a composite measure that includes socioeconomic vulnerability, household composition, disability, minority status and language, and housing and transportation domains.

Main outcomes and measures

Cardiac arrest mortality per 100,000 adults.

Results

Overall age-adjusted cardiac arrest mortality (AAMR) during the study period was 95.6 per 100,000 persons. The AAMR was higher for men as compared with women (119.6 vs. 89.9 per 100,000) and for Black, as compared with White, adults (150.4 vs. 92.3 per 100,000). The AAMR increased from 64.8 per 100,000 persons in counties in Quintile 1 (Q1) of SVI to 141 per 100,000 persons in Quintile 5, with an average increase of 13% (95% CI: 9.8-16.9) in AAMR per quintile increase.

Conclusion and relevance

Mortality from cardiac arrest varies widely, with a more than 2-fold difference between the counties with the highest and lowest social vulnerability, highlighting the differential burden of cardiac arrest deaths throughout the U.S. based on social determinants of health.

Key Points

Question

What is the impact of social determinants of health on cardiac arrest mortality in the United States (U.S.)?

Findings

In this national cross-sectional study spanning 5 years, we found that counties in higher quintiles of the social vulnerability index had higher rates of mortality from cardiac arrest, which was consistent across all subgroups.

Meaning

Our data suggests that sizable disparities in cardiac arrest remain in the U.S. A multi- dimensional approach to address gaps, with emphasis on social determinants of health, is needed for vulnerable populations to impact outcomes.
Methylprednisolone as Adjunctive Therapy for Large Vessel Occlusion (MARVEL): a Randomized Double-blind, Placebo-controlled Trial in Patients undergoing Endovascular therapy: Study Rationale and Design
Authors: Yang Qing-Wu , Guo Changwei , Yue Chengsong , Yang Jie , Li Linyu , Peng Zhouzhou , Hu Jinrong , Huang Jiandi , Song Jiaxing , Huang Jiacheng , Kong Weilin , Yu Nizhen , Yang Dahong , Liu Xiang , Wang Duolao , Nogueira Raul G. , Li Fengli , Nguyen Thanh N. , Zi Wenjie
Published: August 2023

Background

Steroids have pleiotropic neuroprotective actions including the regulation of inflammation and apoptosis which may influence the effects of ischemia on neurons, glial cells, and blood vessels. The effect of low-dose methylprednisolone in acute ischemic stroke (AIS) patients in the endovascular treatment (EVT) era remains unknown.

Objective

This trial investigates the efficacy and safety of low-dose methylprednisolone (2 mg/kg intravenous for 3 days) as adjunctive therapy for AIS patients undergoing mechanical thrombectomy (MT) within 24 hours from symptom onset.

Methods and design

Methylprednisolone as Adjunctive Therapy for Acute Large Vessel Occlusion (MARVEL) Trial is an investigator-initiated, prospective, randomized, double-blind, placebo-controlled multicenter clinical trial. Up to 1672 eligible patients with anterior circulation large vessel occlusion (LVO) stroke presenting within 24 hours from symptom onset are planned to be consecutively randomized to receive methylprednisolone or placebo in a 1:1 ratio across 82 stroke centers in China.

Outcomes

The primary outcome is the ordinal shift in the modified Rankin scale (mRS) score at 90 days. Secondary outcomes include 90-day functional independence (mRS 0-2). The primary safety endpoints include mortality at 90 days and symptomatic intracerebral hemorrhage within 48 hours of MT.

Conclusion

The MARVEL trial will provide evidence of the efficacy and safety of low-dose methylprednisolone as adjunctive therapy to anterior circulation LVO stroke patients undergoing endovascular treatment.

Trial registry number

ChiCTR2100051729 (www.chictr.org.cn).
A fibroblast-dependent TGFβ1/sFRP2 noncanonical Wnt signaling axis underlies epithelial metaplasia in idiopathic pulmonary fibrosis
Authors: Cohen Max L. , Brumwell Alexis N. , Ho Tsung Che , Montas Genevieve , Golden Jeffrey A. , Jones Kirk D. , Wolters Paul J. , Wei Ying , Chapman Harold A. , Le Saux Claude J.
Published: August 2023

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate this, we administered the fibroblast-selective TGFβ1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Unexposed biopsy samples showed higher fibroblast TGFβ1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG significantly downregulated TGFβ1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted Frizzle-like Receptor Protein 2 (sFRP2), an unrecognized TGFβ1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s). In human AEC2-fibroblast coculture organoids, sFRP2 was essential for AEC2 trans-differentiation to basal cells. Precision cut lung slices (PCLS) from normal donors demonstrated that TGFβ1 promoted KRT17 expression and AEC2 morphological change, while sFRP2 was necessary for KRT5 expression in AEC2-derived basaloid cells. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin-related signaling in AEC2s were required for sFRP2-induced KRT5 expression. These findings highlight stage-specific TGFβ1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify the TGFβ1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.
Integrated multiplexed assays of variant effect revealcis-regulatory determinants of catechol-O-methyltransferase gene expression
Authors: Hoskins Ian , Rao Shilpa , Tante Charisma , Cenik Can
Published: August 2023

Multiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase and decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped thecis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alterCOMTexpression. Finally, we trained machine learning models to map signatures of variant effects onCOMTgene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants inCOMTand highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression.
Direct photoreception of a pituitary endocrine cell, melanotroph, induces a hormone release
Authors: Fukuda Ayaka , Sato Keita , Fujimori Chika , Yamashita Takahiro , Takeuchi Atsuko , Ohuchi Hideyo , Umatani Chie , Kanda Shinji
Published: August 2023

In addition to canonical photoreception by the eye, many other organs express non-visual photoreceptors although their biological significance is mostly unknown. Here, we discovered a novel phenomenon in which the pituitary of medaka directly receives light, which induces hormone release. Ca2+imaging analysis revealed that a melanotroph, a pituitary endocrine cell secreting melanocyte-stimulating hormone (MSH), robustly increases [Ca2+]iduring short-wavelength light irradiation. Moreover, we identified Opn5m as the key molecule of this mechanism. The significance of this phenomenon was suggested to be involved in UV protection because knockout ofopn5msignificantly reduced the expression oftyrosinase, the rate-limiting enzyme for melanogenesis, in the skin. These results suggest a novel mechanism in which direct reception of short-wavelength light by pituitary endocrine cells triggers the pathway to enhance UV protection.

One-Sentence Summary

An endocrine cell of the pituitary was proven to be a photoreceptive cell that enables autonomous hormone release.
Radiation-induced rescue effect on human breast carcinoma cells is regulated by macrophages
Authors: Pathikonda Spoorthy , Tian Li , Cheng Shuk Han , Lam Yun Wah
Published: August 2023

The susceptibility of cancer cells to DNA damages is influenced by their microenvironment. For example, unirradiated neighbors of irradiated cells can produce signals that reduce DNA damages. This phenomenon, known as Radiation-Induced Rescue Effect (RIRE), has profound implications on the efficacy of radiotherapy. Using bystander cells cocultured with mock-irradiated cells as a control, we demonstrated, for the first time, two types of RIRE. Conditioned medium from naïve bystander cells, i.e., cells not exposed to irradiated cells, could mitigate UV-induced DNA damages in human breast carcinoma MCF7 cells, as judged by phospho-H2AX and 53BP1 immunostaining. This protective effect could be further enhanced by the prior treatment of bystander cells with factors from UV-irradiated cells. We named the former effect “basal RIRE” and the latter “active RIRE” which were cell type-dependent. As bystanders, MCF7 showed a significant active RIRE, whereas THP1-derived macrophages showed a strong basal RIRE but no active RIRE. Interestingly, RIRE of macrophages could further be modulated by polarisation. The basal RIRE of macrophages was abolished by M1 polarisation, while M2 and Tumour Associated Macrophages (TAM) demonstrated pronounced basal and active RIRE. When mixtures of MCF7 cells and polarised macrophages were used as bystanders, the overall RIRE was dictated by macrophage phenotypes: RIRE was suppressed by M1 macrophages but significantly enhanced by M2 and TAM. This study shows a previously unappreciated role of the innate immune system in RIRE. Depending on polarised phenotypes, macrophages in the tumour microenvironment can interfere with the effectiveness of radiotherapy by adjusting the RIRE magnitudes.
The effect of information content distributions on word recollection and familiarity
Authors: Wallenberg Joel C. , Fadhilah Salsabila Nadhif , Hinton Taylor D. , Smulders Tom V. , Read Jenny C.A. , Cuskley Christine
Published: August 2023

This study builds on work on language processing and information theory which suggests that informationally uniform, or smoother, sequences are easier to process than ones in which information arrives in clumps. Because episodic memory is a form of memory in which information is encoded within its surrounding context, we predicted that episodic memory in particular would be sensitive to information distribution. We used the “dual process” theory of recognition memory to separate the episodic memory component (recollection) from the non-episodic component (familiarity) of recognition memory. Though we find a weak effect in the predicted direction, this does not reach statistical significance and so the study does not support the hypothesis. The study does replicate a known effect from the literature where low frequency words are more easily recognized than high frequency ones when participants employ recollection-type memory. We suggest our results may be explained by linguistic processing being particularly adapted to processing linear sequences of information in a way that episodic memory is not. Episodic memory likely evolved to deal with unpredictable, sometimes clumped, information streams.
Multi-representation DeepInsight: an improvement on tabular data analysis
Authors: Sharma Alok , López Yosvany , Jia Shangru , Lysenko Artem , Boroevich Keith A. , Tsunoda Tatsuhiko
Published: August 2023

Tabular data analysis is a critical task in various domains, enabling us to uncover valuable insights from structured datasets. While traditional machine learning methods have been employed for feature engineering and dimensionality reduction, they often struggle to capture the intricate relationships and dependencies within real-world datasets. In this paper, we present Multi-representation DeepInsight (abbreviated as MRep-DeepInsight), an innovative extension of the DeepInsight method, specifically designed to enhance the analysis of tabular data. By generating multiple representations of samples using diverse feature extraction techniques, our approach aims to capture a broader range of features and reveal deeper insights. We demonstrate the effectiveness of MRep-DeepInsight on single-cell datasets, Alzheimer’s data, and artificial data, showcasing an improved accuracy over the original DeepInsight approach and machine learning methods like random forest and L2-regularized logistic regression. Our results highlight the value of incorporating multiple representations for robust and accurate tabular data analysis. By embracing the power of diverse representations, MRep-DeepInsight offers a promising avenue for advancing decision-making and scientific discovery across a wide range of fields.
A major endogenous glycosidase mediating quercetin uptake inBombyx mori
Authors: Waizumi Ryusei , Hirayama Chikara , Tomita Shuichiro , Iizuka Tetsuya , Kuwazaki Seigou , Jouraku Akiya , Tsubota Takuya , Yokoi Kakeru , Yamamoto Kimiko , Sezutsu Hideki
Published: August 2023

Quercetin is a common plant flavonoid that is involved in herbivore–plant interactions. Mulberry silkworms (domestic silkworm,Bombyx mori, and wild silkworm,Bombyx mandarina) uptake quercetin from mulberry leaves and accumulate the metabolites in the cocoon, thereby improving its protective properties. Here we identified and characterized a glycosidase, named LPH-like quercetin glycoside hydrolase 1 (LQGH1), that initiates quercetin metabolism in the domestic silkworm. LQGH1 is expressed in the midgut where it mediates quercetin uptake by deglycosylating the three most common quercetin glycosides present in mulberry leaf: rutin, quercetin-3-O-malonyl-glucoside, quercetin-3-O-glucoside. Despite being located in an unequal crossing-over hotspot,LQGH1is conserved in some species in clade Macroheterocera, including the wild silkworm, indicating the adaptive significance of quercetin uptake.LQGH1is important also in breeding: defective mutations ofLQGH1, which result in discoloration of the cocoon and increased silk yield, are homozygously conserved in 27 of the 32 Japanese white-cocoon domestic silkworm strains and 12 of the 30 Chinese ones we investigated.
Efficacy of Centers of Biomedical Research Excellence (CoBRE) Grants to Build Research Capacity in Underrepresented States
Authors: Schaller Michael D.
Published: August 2023

Federal funding for research has immediate and long-term economic impact. Since federal research funding is regionally concentrated and not geographically distributed, the benefits are not fully realized in some regions of the country. The Established (previously Experimental) Program to Stimulate Competitive Research (EPSCoR) programs at several agencies, e.g. the National Science Foundation, and the Institutional Development Award (IDeA) program at the National Institutes of Health were created to increase competitiveness for funding in states with historically low levels of federal funding. The Centers of Biomedical Research Excellence (CoBRE) award program is a component of the IDeA program. The CoBRE grants support research core facilities to develop research infrastructure. These grants also support the research projects of junior investigators, under the guidance of mentoring teams of senior investigators, to develop human resources at these institutions. Few studies have assessed the effectiveness of these programs. This study examines the investment and outcomes of the CoBRE grants from 2000 through 2022. The maturation of junior investigators into independently funded principal investigators is comparable to other mentoring programs supported by NIH. The investment in research cores resulted in substantial research productivity, measured by publications. Despite the successes of individual investigators and increase research infrastructure and productivity, the geographic distribution of federal and NIH research dollars has not changed. These results will be informative in consideration of policies designed to enhance the geographic distribution of federal research dollars.
Ecological Network Resilience & Extinction Proxies - Updating Projections of Ecological Networks
Authors: Kusch Erik , Ordonez Alejandro
Published: August 2023

Forecasting biodiversity and functioning changes to ecosystem composition and functioning under climate change requires using multi-species approaches that explicitly consider ecological interactions. Here, we propose a framework with which to incorporate considerations of (1) localised extinction risk proxies, (2) resilience mechanisms of ecological networks, and (3) extinction cascade directionality as a driving force of ecological change. These three aspects are seldomly considered when establishing ecosystems responses to climate change and biodiversity loss. Using this framework, we demonstrate that current practices may severely underpredict ecological change measured as loss of biodiversity and change in connectedness. Our novel framework which explicitly explores two-dimensional resilience landscapes defined by network resilience mechanisms (i.e., link loss sensitivity and realisation of rewiring potential) represents the most complete toolbox for assessment of vulnerability of ecological networks to extinction cascades. Ultimately, we propose that using localised extinction proxies, explicitly quantifying ecological network resilience through link-loss sensitivity and realisation of rewiring potential, as well as simulation of bidirectional extinction cascades will lead to improved capabilities of estimating ecosystem trajectories throughout the Anthropocene.
High-temporal resolution functional PET/MRI reveals coupling between human metabolic and hemodynamic brain response
Authors: Hahn Andreas , Reed Murray B. , Vraka Chrysoula , Godbersen Godber M. , Klug Sebastian , Komorowski Arkadiusz , Falb Pia , Nics Lukas , Traub-Weidinger Tatjana , Hacker Marcus , Lanzenberger Rupert
Published: August 2023

Positron emission tomography (PET) provides precise molecular information on physiological processes, but its low temporal resolution is a major obstacle. Consequently, we characterized the metabolic response of the human brain to working memory performance using an optimized functional PET framework at a temporal resolution of 3 seconds. Consistent with simulated kinetic modeling, we observed a constant increase in the [18F]FDG signal during task execution, followed by a rapid return to baseline after stimulation ceased. The simultaneous acquisition of BOLD fMRI revealed that the temporal coupling between hemodynamic and metabolic signals in the primary motor cortex was related to individual behavioral performance during working memory. Furthermore, task-induced BOLD deactivations in the posteromedial default mode network were accompanied by distinct temporal patterns in glucose metabolism, which depended on the task-positive network metabolic demands. In sum, the proposed approach enables the advancement from parallel to truly synchronized investigation of metabolic and hemodynamic responses during cognitive processing.
Immunoglobulin M regulates airway hyperresponsiveness independent of T helper 2 allergic inflammation
Authors: Hadebe Sabelo , Savulescu Anca Flavia , Khumalo Jermaine , Jones Katelyn , Mangali Sandisiwe , Mthembu Nontobeko , Musaigwa Fungai , Maepa Welcome , Ndlovu Hlumani , Ngomti Amkele , Scibiorek Martyna , Okendo Javan , Brombacher Frank
Published: August 2023

Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions.

We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model.

We sensitised wild-type (WT) and IgM-deficient (IgM-/-) mice with HDM and measured AHR, and Th2 responses. We performed RNA sequencing on the whole lung of WT and IgM-/-mice sensitised to saline or HDM. We validated our AHR data on human ASM by deleting genes using CRISPR and measuring contraction by single-cell force cytometry.

We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and other genes. Deletion ofBAIAP2L1led to a differential reduction in human ASM contraction when stimulated with TNF-α and Acetylcholine, but not IL-13.

These findings have implications for future treatment of asthma beyond current therapies.
RNA splicing modulator induces peripheral neuropathy with increased neurofilament light chain levels via p53 signaling
Authors: Krach Florian , Boerstler Tom , Reischl Stephanie , Krumm Laura , Regensburger Martin , Winkler Jürgen , Winner Beate
Published: August 2023

RNA splicing modulators are a new class of small molecules with the potential to modify the expression levels of proteins. A recent clinical trial investigating the splicing modulator branaplam for Huntington’s disease to lower huntingtin levels was terminated due to the development of peripheral neuropathy. Here, we describe how branaplam leads to this adverse effect. On a cellular level, branaplam disrupts neurite integrity reflected by elevated neurofilament light chain levels in human induced pluripotent stem cell (iPSC)-derived motor neurons (iPSC-MN). Branaplam does not target neuropathy-associated genes. However, transcription factor binding site enrichment analysis indicates p53 activation. P53 activation upon branaplam treatment in iPSC-MN is linked to increased nucleolar stress, thereby enhanced expression of the neurotoxic p53-target gene BBC3. These findings illustrate that RNA splicing modulators may have clinically relevant off-target effects, implying the necessity of comprehensive pre-screening in human models prior to executing clinical trials.

Graphical abstract

One Sentence Summary

Predicting side effects of RNA splicing modulator branaplam leading to neurotoxicity via nucleolar stress, p53 activation, and axonal degeneration.
Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: August 2023

Sepsis is the leading systemic inflammatory response syndrome in worldwide, yet relatively little is known about the genes and signaling pathways involved in sepsis progression. The current investigation aimed to elucidate potential key candidate genes and pathways in sepsis and its associated complications. Next generation sequencing (NGS) dataset (GSE185263) was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 348 sepsis samples and 44 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the DESeq2 R package. Next, we made use of the g:Profiler to analyze gene ontology (GO) and REACTOME pathway. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Furthermore, we constructed miRNA-hub gene regulatory network and TF-hub gene regulatory network among hub genes utilizing miRNet and NetworkAnalyst online databases tool and Cytoscape software. Finally, we performed receiver operating characteristic (ROC) curve analysis of hub genes through the pROC package in R statistical software. In total, 958 DEGs were identified, of which 479 were up regulated and 479 were down regulated. GO and REACTOME results showed that DEGs mainly enriched in regulation of cellular process, response to stimulus, extracellular matrix organization and immune system. The hub genes of PRKN, KIT, FGFR2, GATA3, ERBB3, CDK1, PPARG, H2BC5, H4C4 and CDC20 might be associated with sepsis and its associated complications. Predicted miRNAs (e.g., hsa-mir-548ad-5p and hsa-mir-2113) and TFs (e.g., YAP1 and TBX5) were found to be significantly correlated with sepsis and its associated complications. In conclusion, the DEGs, relative pathways, hub genes, miRNA and TFs identified in the current investigation might help in understanding of the molecular mechanisms underlying sepsis and its associated complications progression and provide potential molecular targets and biomarkers for sepsis and its associated complications.
Selective elimination of CD169+macrophages in lymph nodes invaded by breast cancers
Authors: Maeshima Yurina , Kataoka Tatsuki R. , Vandenbon Alexis , Hirata Masahiro , Takeuchi Yasuhide , Suzuki Yutaka , Fukui Yukiko , Ibi Yumiko , Haga Hironori , Morita Satoshi , Toi Masakazu , Kawaoka Shinpei , Kawaguchi Kosuke
Published: August 2023

Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we report that metastasized breast cancer cells selectively eliminate CD169+lymph node sinus macrophages, an initiator of anti-cancer immunity, from the lymph nodes. The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+macrophages was reduced in metastatic lymph nodes, whereas the numbers of other major immune cell types were unaltered. We also detected the infiltration of CD169+macrophages into metastasized cancer tissues depending on sections, suggesting that CD169+macrophages were gradually eliminated after anti-cancer reactions. Furthermore, CD169+macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging. Collectively, we propose that metastasized breast cancer cells dispel CD169+macrophages from lymph nodes in a phased manner, disabling a critical step of anti-cancer immunity.
Prevalence of mango postharvest Stem-end rot disease in Cote d’Ivoire and identification of fungal pathogens associated
Authors: Yeo Yéfoungnigui S. , Kone Yassogui , Dembele Dio D. , Amari Elisee L D G , Rey Jean-Yves , Del Ponte Emerson M. , Fernandez Diana , Kone Daouda
Published: August 2023

The Stem-end rot (SER) postharvest disease of mango (Mangifera indicaL.) fruits is a significant economic threat to mango production. If suitable conditions are not maintained, it can lead to losses of up to 100 %. Despite its importance, very little information is known about this disease in Côte d’Ivoire. This research aimed determining the incidence and severity of SER in mango orchards, assess how preharvest climate parameters affect the disease and determine the pathogenic fungi associated with SER. Therefore, mango SER was evaluated on 1500 mango fruits collected from 15 orchards.in Boundiali, Ferkéssédougou, Korhogo, Odienné, and Sinématiali departments. Mango SER incidence ranged from 10 % to 30 %, while severity ranged from 5 % to 20 %. No significant differences in these parameters were observed between the different departments (P>0.05). The study also revealed a low correlation between SER disease incidence and mean air temperature (r=0.36) and minimum air temperature (r=0.26) data, indicating that preharvest weather conditions may have a marginal impact on mango SER disease intensity in the postharvest phase. Pathogenic fungi associated with SER were isolated and identified using morphological characteristics and multilocus sequence analysis of the rDNA internal transcribed spacer (ITS) region and the translation elongation factor 1-alpha (tef1-α). We identified various fungal species associated with mango SER disease, withLasiodiplodiaspecies (74%) being the most prevalent (includingLasiodiplodia theobromae, L. euphorbicola, andL. caatinguensis), followed byColletotrichum gloeosporioides,Curvularia pseudobrachyspora,Diaporthe endophyticaandFusarium mangiferae. However, onlyLasiodiplodiaspecies andDiaporthe endophyticainduced SER symptoms. This study was the first ever evaluation of mango SER disease and associated fungal pathogens identification in Côte d’Ivoire. This result will assist researchers in developing a control method for mango SER.
Declines in ice cover induce light limitation in freshwater diatoms
Authors: Zepernick Brittany N. , Chase Emily E. , Denison Elizabeth R. , Gilbert Naomi E. , Martin Robbie M. , Truchon Alexander R. , Frenken Thijs , Cody William R. , Chaffin Justin D. , Bullerjahn George S. , McKay R. Michael L. , Wilhelm Steven W.
Published: August 2023

The rediscovery of diatom blooms embedded within and beneath Lake Erie ice cover (2007-2012) ignited an intense interest in psychrophilic adaptations and winter limnology. Subsequent studies determined ice plays a vital role in winter diatom ecophysiology, as diatoms partition to the underside of ice thereby fixing their location within the photic zone. Yet, climate change has led to widespread ice decline across the Great Lakes, with Lake Erie presenting a nearly ice-free state in several recent winters. It has been hypothesized the resultant turbid, isothermal water column will induce light limitation amongst winter diatoms, serving as a detrimental competitive disadvantage. Here, we conducted a physiochemical and metatranscriptomic survey of the winter Lake Erie water column (2019-2020) that spanned spatial, temporal, and climatic gradients to investigate this hypothesis. We determined ice-free conditions decreased diatom bloom magnitude and altered diatom community composition. Diatoms increased the expression of various photosynthetic genes and iron transporters, suggesting they are attempting to increase their quantity of photosystems and light-harvesting components (a well-defined indicator of light limitation). Notably, we identified two gene families which serve to increase diatom fitness in the turbid ice-free water column: proton-pumping rhodopsins (a second means of light-driven energy acquisition) and fasciclins (a means to “raft” together to increase buoyancy and co-locate to the surface to optimize light acquisition). With large-scale climatic changes already underway, our observations provide insight into how diatoms respond to the dynamic ice conditions of today and shed light on how they will fare in a climatically altered tomorrow.
The genomes and epigenomes of aquatic plants (Lemnaceae) promote triploid hybridization and clonal reproduction
Authors: Ernst Evan , Abramson Bradley , Acosta Kenneth , Hoang Phuong T.N. , Mateo-Elizalde Cristian , Schubert Veit , Pasaribu Buntora , Hartwick Nolan , Colt Kelly , Aylward Anthony , Lee Seung Cho , Ramu Umamaheswari , Birchler James A. , Schubert Ingo , Lam Eric , Michael Todd P. , Martienssen Robert A.
Published: August 2023

The Lemnaceae (duckweeds) are the world’s smallest but fastest growing flowering plants. Prolific clonal propagation facilitates continuous micro-cropping for plant-based protein and starch production, and holds tremendous promise for sequestration of atmospheric CO2. Here, we present chromosomal assemblies, annotations, and phylogenomic analysis ofLemnagenomes that uncover candidate genes responsible for the metabolic and developmental traits of the family, such as anatomical reduction, adaxial stomata, lack of stomatal closure, and carbon sequestration via crystalline calcium oxalate. Lemnaceae have selectively lost genes required for RNA interference, including Argonaute genes required for reproductive isolation (the triploid block) and haploid gamete formation. Triploid hybrids arise commonly amongLemna, and we have found mutations in highly-conserved meiotic crossover genes that could support polyploid meiosis. Syntenic comparisons withWolffiaandSpirodelareveal that diversification of these genera coincided with the “Azolla event” in the mid-Eocene, during which aquatic macrophytes reduced high atmospheric CO2levels to those of the current ice age.

Facile regeneration of transgenic fronds from tissue culture, aided by reduced epigenetic silencing, makesLemnaa powerful biotechnological platform, as exemplified by recent engineering of high-oilLemnathat outperforms oil seed crops.
Improving rigor and reproducibility in western blot experiments with the blotRig analysis software
Authors: Omondi Cleopa , Chou Austin , Fond Kenneth A. , Morioka Kazuhito , Joseph Nadine R. , Sacramento Jeffrey A. , Iorio Emma , Torres-Espin Abel , Radabaugh Hannah L. , Davis Jacob A. , Gumbel Jason H. , Russell Huie J. , Ferguson Adam R.
Published: August 2023

Western blot is a popular biomolecular analysis method for measuring the relative quantities of independent proteins in complex biological samples. However, variability in quantitative western blot data analysis poses a challenge in designing reproducible experiments. The lack of rigorous quantitative approaches in current western blot statistical methodology may result in irreproducible inferences. Here we describe best practices for the design and analysis of western blot experiments, with examples and demonstrations of how different analytical approaches can lead to widely varying outcomes. To facilitate best practices, we have developed the blotRig tool for designing and analyzing western blot experiments to improve their rigor and reproducibility. The blotRig application includes functions for counterbalancing experimental design by lane position, batch management across gels, and analytics with covariates and random effects.
Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation
Authors: Elkholi Islam E. , Robert Amélie , Malouf Camille , Kuasne Hellen , Drapela Stanislav , Macleod Graham , Hébert Steven , Pacis Alain , Calderon Virginie , Kleinman Claudia L. , Gomes Ana P. , Aguirre-Ghiso Julio A. , Park Morag , Angers Stéphane , Côté Jean-François
Published: August 2023

Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1.

Statement of Significance

We reveal that dormancy-prone breast cancer cells depend on the class III PI3K to mediate a constant peripheral lysosomal positioning and mTORC1 hyperactivity. Targeting this pathway might blunt breast cancer metastasis.
PxBLAT: An efficient python binding library for BLAT
Authors: Li Yangyang , Yang Rendong
Published: August 2023

We introduce PxBLAT, a Python library designed to enhance usability and efficiency in interacting with the BLAST-like alignment tool (BLAT). PxBLAT provides an intuitive Application Programming Interface (API) design, allowing the incorporation of its functionality directly into Python-based bioinformatics workflows. Moreover, PxBLAT’s design philosophy emphasizes ease of use, memory efficiency, and the elimination of intermediary files and unnecessary system calls, thereby enhancing computational speed and user experience. Benchmark tests reveal its superior performance across various datasets, illustrating its capacity to maintain correctness. PxBLAT supports Python (version 3.9+), and pre-compiled packages are released via PyPI (https://pypi.org/project/pxblat/) and Bioconda (https://anaconda.org/bioconda/pxblat). The source code and executable are freely available for academic, nonprofit, and personal use. Its documentation is available on ReadTheDocs (https://pxblat.readthedocs.io/en/latest/).
Single-cell analysis characterizes PLK1 as a catalyst of an immunosuppressive tumor microenvironment in LUAD
Authors: Kong Yifan , Li Chaohao , Liu Jinpeng , Zhang Min , Allison Derek B. , Hassan Faisal , He Daheng , Wang Xinyi , Mao Fengyi , Zhang Qiongsi , Zhang Yanquan , Li Zhiguo , Wu Sai , Wang Chi , Liu Xiaoqi
Published: August 2023

PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immunotherapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single-cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coincides with increased secretion of CXCL2 cytokine, which promotes M2 polarization of TAM and diminishes expression of class II major histocompatibility complex (MHC-II) in professional antigen-presenting cells. Furthermore, PLK1 negatively regulates MHC-II expression in cancer cells, which has been shown to be associated with compromised tumor immunity and unfavorable patient outcomes. Taken together, our results reveal PLK1 as a novel modulator of TME in LUAD and provide possible therapeutic interventions.
Phylogeny and divergence time estimation of Io moths and relatives (Lepidoptera: Saturniidae:Automeris)
Authors: Skojec Chelsea , Earl Chandra , Couch Christian D. , Masonick Paul , Kawahara Akito Y.
Published: August 2023

The saturniid moth genusAutomerisincludes 145 described species. Their geographic distribution ranges from the eastern half of North America to as far south as Peru.Automeris moths are cryptically colored, with forewings that resemble dead leaves, and conspicuously colored, elaborate eyespots hidden on their hindwings. Despite their charismatic nature, the evolutionary history and relationships withinAutomerisand between closely related genera, remain poorly understood. In this study, we present the most comprehensive phylogeny ofAutomeristo date, including 80 of the 145 described species. We also incorporate two morphologically similar hemileucine genera,PseudautomerisandLeucanella, as well as a morphologically distinct genus,Molippa. We obtained DNA data from both dry-pinned and ethanol-stored museum specimens and conducted Anchored Hybrid Enrichment (AHE) sequencing to reconstruct a high-quality dataset for phylogenetic analysis. The resulting phylogeny supportsAutomerisas a paraphyletic genus, withLeucanellaandPseudautomerisnested within, with the most recent common ancestor dating back to 21 mya. This study lays the foundation for future research on various aspects ofAutomerisbiology, including anti-predator defense mechanisms, ecological adaptations, geographical distribution patterns, and potential drivers of speciation.
Quantitative Receptor Model for Responses That Are Left- or Right-Shifted Versus Occupancy (Are More or Less Concentration Sensitive): The SABRE Approach
Authors: Buchwald Peter
Published: August 2023

Abstract

Simple one-to three-parameter models routinely used to fit typical dose-response curves and calculate EC50values using the Hill or Clark equation cannot provide the full picture connecting measured response to receptor occupancy, which can be quite complex due to the interplay between partial agonism and (pathway-dependent) signal amplification. The recently introduced SABRE quantitative receptor model is the first one that explicitly includes a parameter for signal amplification (γ) in addition to those for binding affinity (Kd), receptor-activation efficacy (ε), constitutive activity (εR0), and steepness of response (Hill slope,n). It can provide a unified framework to fit complex cases, where fractional response and occupancy do not match, as well as simple ones, where parameters constrained to specific values can be used (e.g.,εR0=0,γ=1, orn=1). Here, it is shown that SABRE can fit not only typical cases where response curves are left-shifted compared to occupancy (κ=Kd/EC50>1) due to signal amplification (γ>1), but also less common ones where they are right-shifted (i.e., less concentration-sensitive;κ=Kd/EC50<1) by modeling them as apparent signal attenuation/loss (γ<1). Illustrations are provided withμ-opioid receptor (MOPr) data from three different experiments with one left- and one right-shifted response (G protein activation andβ-arrestin2 recruitment, respectively; EC50,Gprt<Kd<EC50,βArr). For such cases of diverging pathways with differently shifted responses, partial agonists can cause very weak responses in the less concentration-sensitive pathway without having to be biased ligands due to the combination of low ligand efficacy and signal attenuation/loss – an illustration with SABRE-fitted oliceridine data is included.
Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons
Authors: Perez Claudia I. , Luis-Islas Jorge , Lopez Axel , Diaz Xarenny , Molina Omar , Arroyo Benjamin , Moreno Mario G. , Lievana Elvi Gil , Fonseca Esmeralda , Castañeda-Hernández Gilberto , Gutierrez Ranier
Published: August 2023

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. We investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats using various techniques. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induced greater weight loss in obese than lean rats, which was associated with changes in LH ensemble activity. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine’s food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine’s appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.
Social flocking increases in harsh and challenging environments
Authors: Bellefeuille Jessica J. , Ratnayake Ruchitha C. B. , Cornthwaite Emily , Dakin Roslyn
Published: August 2023

Grouping with others can provide enhanced information about resources and threats. A key hypothesis in social evolution proposes that individuals can benefit from social information in environments where it is challenging to meet energetic needs. Here, we test this hypothesis by examining the environmental drivers of conspecific flocking behaviour in a large archive of citizen science observations of two common North American birds, the dark-eyed junco (Junco hyemalis) and black-capped chickadee (Poecile atricapillus). To quantify flocking behaviour, we apply the index of dispersion,D, as a metric of clumpiness in each species’ spatiotemporal distribution. We show that juncos in winter are nearly always more clustered than a random expectation, whereas chickadees span a range from uniform to socially clustered distributions. In both species, the degree of social clustering strongly increases with abundance. We identify several key environmental variables that explain the extent of conspecific flocking in both species. Flocks are more socially clustered at higher latitudes, higher elevations, closer to midwinter, and at temperatures that are colder than average given the location and time of year. Together, these findings support the hypothesis that sociality is a key strategy for coping with harsh environments.

HIGHLIGHTS

Grouping with others can be an important source of information about resources

We analyzed how flocking behaviour changes throughout winter in two bird species

We used the index of dispersion to quantify social clustering at a broad scale

In both species, social clustering increases in response to climate challenges