bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jagged-1+ Skin Tregs Modulate the Innate Immune Response to Wound Healing
Authors: Lui Prudence PokWai , Xu Jessie Z. , Aziz Hafsah , Sen Monica , Ali Niwa 
Published: June 2024

ABSTRACTSkin-resident regulatory T cells (Tregs) play an irreplaceable role in orchestrating cutaneous immune homeostasis and repair, including the promotion of hair regeneration via the Notch signaling ligand Jagged-1 (Jag1). While skin Tregs are indispensable for facilitating tissue repair post-wounding, it remains unknown if Jag1-expressing skin Tregs impact wound healing. Using a tamoxifen inducible Foxp3creERT2Jag1fl/flmodel, we show that loss of functional Jag1 in Tregs significantly delays the rate of full-thickness wound closure. Unlike in hair regeneration, skin Tregs do not utilize Jag1 to impact epithelial stem cells during wound healing. Instead, mice with Treg-specific Jag1 ablation exhibit a significant reduction in Ly6G+ neutrophil accumulation at the wound site. However, during both homeostasis and wound healing, the loss of Jag1 in Tregs does not impact the overall abundance or activation profile of immune cell targets in the skin, such as CD4+ and CD8+ T cells, or pro-inflammatory macrophages. This collectively suggests that skin Tregs may utilize Jag1-Notch signalling to co-ordinate innate cell recruitment under conditions of injury but not homeostasis. Overall, our study demonstrates the importance of Jag1 expression in Tregs to facilitate adequate wound repair in the skin.
Novel genomic features in entomopathogenic fungusBeauveria bassiana: supernumerary chromosomes and putative virulence genes involved in the infection process of soybean pestPiezodorus guildinii
Authors: Oberti H. , Sessa L. , Oliveira-Rizzo C. , Di Paolo A. , Sanchez-Vallet A. , Seidl M.F. , Abreo E. 
Published: June 2024

AbstractBiological control methods involving entomopathogenic fungi likeBeauveria bassianahave shown to be a valuable approach in integrated pest management as an environmentally friendly alternative to control pests and pathogens. Identifying genetic determinants of pathogenicity inB. bassianais instrumental for enhancing its virulence against insects like the resistant soybean pestPiezodorus guildinii. This study focused on comparative genomics of differentB. bassianastrains and gene expression analyses to identify virulence genes in the hypervirulent strain ILB308, especially in response to infection ofP. guildniiiand growth on hydrocarbon HC15, a known virulence enhancer. Strain ILB308 showed the highest number of virulence-related features, such as candidate virulence proteins, effectors, small secreted proteins, and biosynthetic gene clusters. ILB308 also had a high percentage of unique DNA sequences, including six putative supernumerary scaffolds. Gene expression analysis at 4 days post-inoculation revealed upregulation of known virulence factors, including Tudor domain proteins, LysM motif-containing proteins, and subtilisin-like proteases, and novel genes like secreted effectors and heat-labile enterotoxins. Growth on HC15 led to the upregulation of genes associated with oxidoreductase activity related to cuticular alkane degradation and fermentation metabolism/antioxidant responses in the hemolymph. The presence of supernumerary chromosomes and unique virulence genes in ILB308 may contribute to its higher virulence and could be considered as potential targets for enhancing fungal virulence through genetic manipulation.Author SummaryUnderstanding mechanisms of virulence and virulence enhancement inBeauveria bassianacan lay the basis for the development of improved biocontrol agents. Here we used genomic and transcriptomic approaches to study the infection process of ILB308 -an hypervirulent strain- against insect pestPiezodorus guildinii. We found that this strain has putative supernumerary chromosomes and an enriched set of presumed virulence proteins like secreted effectors. We infer that the particular assortment of strain specific genes and supernumerary chromosome/s play a role in the degree of virulence exhibited by ILB308 and could be used for future strain improvement strategies.
Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children
Authors: Lindell Robert B. , Sayed Samir , Campos Jose S. , Knight Montana , Mauracher Andrea A. , Hay Ceire A. , Conrey Peyton E. , Fitzgerald Julie C. , Yehya Nadir , Famularo Stephen T. , Arroyo Teresa , Tustin Richard , Fazelinia Hossein , Behrens Edward M. , Teachey David T. , Freeman Alexandra F. , Bergerson Jenna R. E. , Holland Steven M. , Leiding Jennifer W. , Weiss Scott L. , Hall Mark W. , Zuppa Athena F. , Taylor Deanne M. , Feng Rui , Wherry E. John , Meyer Nuala J. , Henrickson Sarah E. 
Published: June 2024

ABSTRACTSepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.
Effects of temperature settings on information quality of ChatGPT-3.5 responses: A prospective, single-blind, observational cohort study
Authors: Akamine Akihiko , Hayashi Daisuke , Tomizawa Atsushi , Nagasaki Yuya , Akamine Chikae , Fukawa Takahiro , Hirosawa Iori , Saigo Orie , Hayashi Misa , Nanaoya Mitsuru , Odate Yuka 
Published: June 2024

AbstractObjectiveThe effect of temperature settings on the quality of ChatGPT version 3.5 (OpenAI) responses related to drug information remains unclear. We investigated ChatGPT-3.5’s response quality on apixaban information with and without the temperature being set to 0.MethodsOn 6 September 2023, 37 questions regarding apixaban, derived from the frequently asked questions on the Bristol–Myers Squibb’s website, were entered into ChatGPT in Japanese. The primary endpoint was the effect of temperature settings on ChatGPT-3.5’s responses to apixaban-related questions. The response accuracy, clarity, detail, and adequacy were rated on a 5-point Likert scale by 10 pharmacists, with higher scores indicating higher response quality. Cumulative score means were analyzed using the Mann–Whitney U test. In the subgroup analysis, evaluators were limited to pharmacists at university hospitals. Welch’s t-test was employed in sensitivity analysis to validate primary endpoint findings.ResultsThe mean scores for ChatGPT-3.5’s apixaban-related responses with (13.08) and without (14.40) the temperature being set to 0 were not significantly different (p = 0.064). Accuracy differed significantly (3.15 vs. 3.54, p = 0.045), whereas clarity, detail, and appropriateness were similar. Subgroup analysis (13.30 vs. 14.21, p = 0.394) and sensitivity analysis confirmed similar results (13.45 vs. 14.52, p = 0.105).ConclusionsChatGPT-3.5 temperature setting does not significantly affect overall responses to apixaban-related inquiries. However, the variance in accuracy suggests that ChatGPT-3.5 is unable to consistently provide precise responses. Hence, it is more suitable as a supplementary tool rather than a primary medical resource.
Estimation of Sexual and Gender Minorities in the adult population of Japan: Descriptive Epidemiological Study utilizing a Nationwide Cross-Sectional Internet Survey
Authors: Minami Tetsuji , Inoue Manami , Matsushima Midori , Yoshioka Takashi , Tabuchi Takahiro 
Published: June 2024

AbstractBackgroundDescriptive study of Japanese sexual and gender minority (SGM) population with national representativeness have not been conducted. We sought to estimate the proportion of the Japanese SGM, and to describe those demographic, socioeconomic, and health-related variables.MethodsUtilizing data on a nationwide cross-sectional internet survey from September 12th to October 19th, 2022, we conducted a comprehensive descriptive study by applying inverse probable weighting method for national representativeness. Participants self-reported as heterosexual, homosexual, bisexual, or gender minority (GM) and responded to questions on various demographic, socioeconomic, and health-related concerns.FindingsAmong Japanese adults, 4.8% identified as homosexuals, 1.3% as bisexuals, and 3.8% as GMs. SGMs were less likely to be married/partnered compared to heterosexuals, though a certain proportion were in opposite-sex marriages/partnerships. SGMs had lower household equivalent income, insurance coverage, home ownership, current smoking rates, good self-rated health, and full COVID-19 vaccination rates. They also exhibited higher rates of substance use, severe psychological distress, feelings of loneliness, and fear of COVID-19 compared to heterosexuals. When divided by assigned sex at birth, SGM males had poorer employment status, lower academic attainment, and higher body mass index compared to their heterosexual counterparts, while SGM females showed opposite trends.InterpretationDifferences in demographic, socioeconomic, and health status between heterosexuals and SGMs underscore the need for targeted health policies and interventions to address health disparities among Japanese SGMs. Additionally, these results suggest that directly applying Western health policies to the Japanese context may not always be appropriate.FundingFunded by the Japan Society for the Promotion of Science, the Research Support Program to Apply the Wisdom of the University to tackle COVID-19 Related Emergency Problems, University of Tsukuba, and Health Labour Sciences Research Grantand the Japan Agency for Medical Research and Development.
Structures of Native Doublet Microtubules fromTrichomonas vaginalisReveal Parasite-Specific Proteins as Potential Drug Targets
Authors: Stevens Alexander , Kashyap Saarang , Crofut Ethan H. , Wang Shuqi E. , Muratore Katherine A. , Johnson Patricia J. , Zhou Z. Hong 
Published: June 2024

AbstractDoublet microtubules (DMTs) are flagellar components required for the protistTrichomonas vaginalis(Tv) to swim through the human genitourinary tract to cause trichomoniasis, the most common non-viral sexually transmitted disease. Lack of DMT structures has prevented structure-guided drug design to manageTvinfection. Here, we determined the cryo-EM structure of nativeTv-DMTs, identifying 29 unique proteins, including 18 microtubule inner proteins and 9 microtubule outer proteins. While the A-tubule is simplistic compared to DMTs of other organisms, the B-tubule features specialized, parasite-specific proteins, likeTvFAP40 andTvFAP35 that form filaments near the inner and outer junctions, respectively, to stabilize DMTs and enableTvlocomotion. Notably, a small molecule, assigned as IP6, is coordinated within a pocket ofTvFAP40 and has characteristics of a drug molecule. This first atomic model of theTv-DMT highlights the diversity of eukaryotic motility machinery and provides a structural framework to inform the rational design of therapeutics.
A stargate mechanism ofMicroviridaegenome delivery unveiled by cryogenic electron tomography
Authors: Bardy Pavol , MacDonald Conor I.W. , Kirchberger Paul C. , Jenkins Huw T. , Botka Tibor , Byrom Lewis , Alim Nawshin T.B. , Traore Daouda A.K. , König Hannah C. , Nicholas Tristan R. , Chechik Maria , Hart Samuel J. , Turkenburg Johan P. , Blaza James N. , Beatty J. Thomas , Fogg Paul C.M. , Antson Alfred A. 
Published: June 2024

AbstractSingle-stranded DNA bacteriophages of theMicroviridaefamily are major components of the global virosphere. Microviruses are highly abundant in aquatic ecosystems and are prominent members of the mammalian gut microbiome, where their diversity has been linked to various chronic health disorders. Despite the clear importance of microviruses, little is known about the molecular mechanism of host infection. Here, we have characterized an exceptionally large microvirus, Ebor, and provide crucial insights into long-standing mechanistic questions. Cryogenic electron microscopy of Ebor revealed a capsid with trimeric protrusions that recognise lipopolysaccharides on the host surface. Cryogenic electron tomography of the host cell colonized with virus particles demonstrated that the virus initially attaches to the cell via five such protrusions, located at the corners of a single pentamer. This interaction triggers a stargate mechanism of capsid opening along the 5-fold symmetry axis, enabling delivery of the virus genome. Despite variations in specific virus-host interactions among differentMicroviridaefamily viruses, structural data indicate that the stargate mechanism of infection is universally employed by all members of the family. Startlingly, our data reveal a mechanistic link for the opening of relatively small capsids made out of a single jelly-roll fold with the structurally unrelated giant viruses.
Spatial resolution of transcriptomic plasticity states underpinning lethal morphologies in lung adenocarcinoma
Authors: Williams Hannah L , Poulain Nicolas , Powley Ian , Martinelli Silvia , Bielik Robert , Leslie Holly , Nixon Colin , Wilson Claire R , Sereno Marco , He Zhangyi , Officer-Jones Leah , Ballantyne Fiona , Pennie Rachel , Wood Colin S , Lewis David Y , Jamieson Nigel B , Le Quesne John 
Published: June 2024

AbstractAdenocarcinoma of the lung (LUAD) is a common and highly lethal disease. Clinical grading of disease strongly predicts recurrence and survival after surgery and is determined by morphological assessment of histological growth patterns in resected tumours. The molecular basis of growth pattern is poorly understood at present, as are the mechanisms linking growth pattern to recurrence and death.Interestingly, the two archetypal lethal morphologies, solid and micropapillary patterns, are characterised by their biphasic appearance. Both have an epithelial fraction which is in direct stromal contact, and a fraction which is not. This morphological variance seems likely to represent plasticity, and to be causally linked to mechanisms of virulence.To investigate the gene expression changes related to growth pattern both intra- and intertumoral, we applied spatial transcriptomics (Nanostring GeoMx DSP) to tissue microarray specimens of primary resected human lung adenocarcinoma. Using a variety of region-of-interest (ROI) selection strategies, we sampled 160 pure epithelial ROIs across 7 distinct morphological features of LUAD from 51 patients. Analyses of gene expression reveal fundamental trajectories connecting growth patterns, and crucial modes of plasticity which underly high-risk morphologies. These modes suggest mechanisms for the origins of growth pattern and mechanisms of virulence.Our work highlights dramatic divergence in gene expression programmes between highly lethal but morphologically diverse modes of tumour growth. Furthermore, it provides an explanation for how microscopically localised hypoxia in the primary tumour helps to establish and maintain survival strategies which ultimately determine morphology-specific mechanisms of tumour metastasis, suggesting new therapeutic vulnerabilities.
Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchyme
Authors: Follmer Mikaela L , Isner Trevor , Ozekin Yunus H. , Levitt Claire , Bates Emily Anne 
Published: June 2024

ABSTRACTIon channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of theKcnj2potassium channel disrupts Bone Morphogenetic Protein (BMP) signaling within the developing palate. BMP signaling is essential for the correct development of several skeletal structures, including the palate, though little is known about the mechanisms that govern BMP secretion. We introduce a tool to image the release of bone morphogenetic protein 4 (BMP4) from mammalian cells. Using this tool, we show that depolarization induces BMP4 release from mouse embryonic palate mesenchyme cells in a calcium-dependent manner. We show native transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day (E) 9.5 to 13.5 mice. Disruption ofKcnj2significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Together, these data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and changes in intracellular calcium for mammalian craniofacial morphogenesis.SUMMARYWe show that embryonic palate mesenchyme cells undergo transient changes in intracellular calcium. Depolarization of these cells induces BMP4 release suggesting that ion channels are a node in BMP4 signaling.
HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene
Authors: Roark Ryan S. , Habib Rumi , Gorman Jason , Li Hui , Connell Andrew Jesse , Bonsignori Mattia , Guo Yicheng , Hogarty Michael P. , Olia Adam S. , Sowers Kirsten , Zhang Baoshan , Bibollet-Ruche Frederic , Callaghan Sean , Carey John W. , Cerutti Gabriele , Harris Darcy R. , He Wanting , Lewis Emily , Liu Tracy , Mason Rosemarie D. , Park Younghoon , Rando Juliette M. , Singh Ajay , Wolff Jeremy , Lei Q. Paula , Louder Mark K. , Doria-Rose Nicole A. , Andrabi Raiees , Saunders Kevin O. , Seaman Michael S. , Haynes Barton F. , Kulp Daniel W. , Mascola John R. , Roederer Mario , Sheng Zizhang , Hahn Beatrice H. , Shaw George M. , Kwong Peter D. , Shapiro Lawrence 
Published: June 2024

AbstractBroadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition.HighlightsIsolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaquesCryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognitionAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame twoThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodiesStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition modePropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naïve rhesus repertoireDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity
Deciphering the Binding of 5’ Stem Loop RNA to the La Domain of Human LARP6
Authors: Gordon Blaine H. , Blackford Nolan , Silvers Robert 
Published: June 2024

AbstractLa-related protein 6 regulates the highly organized biosynthesis of type I procollagen polypeptides and affects proper assembly of procollagen peptides into heterotrimers of type I procollagen. LARP6-mediated regulation of collagen biosynthesis is mediated through interaction with the 5’ stem loop motif found in type I and III collagen mRNA. Recent studies highlight the involvement of HsLARP6 in fibroproliferative diseases and its potential as a target for therapeutic intervention. The intrinsic instability of the La domain of HsLARP6 hampers studies probing the molecular basis of biologically- and disease-relevant structure-function relationship, particularly when high concentrations are required. This work provides detailed procedures to produce milligram amounts of RNase-free and functional La domain of HsLARP6. Furthermore, we investigated the effect of the construct length as well as RNA binding on protein stability. N- and C-terminal extensions greatly impact stability based on interactions with the core domain and modulation of the pI. When in complex with its cognate 5’SL RNA, the La domain shows unprecedented stability compared to the aggregation-prone unbound state. The protein-RNA complex remains stable for at least 50x longer than the unbound state, under identical conditions, likely due to a global change in conformational plasticity upon RNA binding. These results provide a foundation for further studies of the molecular recognition of 5’SL by HsLARP6 as well as a platform for refining potential antifibrotic therapeutics.