bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of combined tobacco use and type 2 diabetes mellitus on prevalent fibrosis in patients with MASLD
Authors: Balogun Oluwafemi , Wang Jeffrey Y. , Shaikh Emad S. , Liu Karine , Stoyanova Stefania , Memel Zoe N. , Schultz Hayley , Mun Lisa , Bertman Jack , Rogen Cheryl A. , Ibrahim Maryam K. , Berschback Madeline , Uche-Anya Eugenia , Wilechansky Robert , Simon Tracey G. , Corey Kathleen E.
Published: October 2023

Background:

Several studies have investigated the independent effect of cigarette smoking or type 2 diabetes mellitus (T2DM) on MASLD. However, the interaction effect between tobacco consumption and T2DM on MASLD severity remains underexplored. In this study, we assessed the combined effect of tobacco use and T2DM on hepatic fibrosis in MASLD.

Methods:

We conducted a single-center retrospective cross-sectional analysis of eligible participants from the Mass General Brigham Fibroscan© database. The participants were divided into 3 groups: those with T2DM and a history of tobacco use (primary exposure group), those with T2DM but no history of tobacco use (secondary exposure group), and those without T2DM and no history of tobacco use (reference group). An additional model was developed, which included a fourth group, participants with a history of tobacco use but no T2DM. The likelihood of fibrosis was determined using a defined fibrosis-4 index cutoff value of 1.3. In addition, we computed the estimated marginal means for liver stiffness measurement and compared the values among the exposure groups. Bivariable and multivariable logistic regression models were used to explore the associations between the exposure groups and the risk for hepatic fibrosis.

Results:

Overall, 598 individuals were enrolled in the study. The bivariable logistic regression model revealed a significant independent association between T2DM, combined smoking and T2DM, and the outcome of interest, fibrosis. Age, sex, metabolic syndrome, aspirin use, statin use, hemoglobin A1C (A1C), and total bilirubin level were also significantly associated with fibrosis. In the adjusted fibrosis-4 multivariable model (comparing exposure groups to controls), cigarette smoking and T2DM interaction had higher odds of prevalent fibrosis (aOR, 3.04; 95% CI, 1.62–5.76), compared to those with T2DM alone (aOR 2.28; 95% CI, 1.37–3.85). The continuous liver stiffness measurement comparison across the exposure group showed an estimated marginal means of 6.26 (95% CL: 5.58–6.94), 7.54 (95% CL: 6.78–8.30), and 7.88 (6.78–8.99) for the reference group, T2DM only group, and tobacco-T2DM group, respectively. The diabetes-only group and the combined tobacco-T2DM group had statistically significant associations with liver stiffness measurement (p values: 0.013 and 0.014, respectively).

Conclusion:

Although diabetes is independently associated with hepatic fibrosis in patients with MASLD, the combination of tobacco consumption and diabetes is associated with a higher prevalence of fibrosis. Therefore, lifestyle change through tobacco use cessation in patients with diabetes could be beneficial in reducing the incidence of liver fibrosis among individuals with MASLD.
It Is All About the Angle: A Clinical and Optical Coherence Tomography Comparison of Corneal Ocular Surface Squamous Neoplasia and Corneal Pannus
Authors: Huang Jaxon J. , Locatelli Elyana V. T. , Huang Jordan J. , De Arrigunaga Sofia , Rao Pragnya , Dubovy Sander , Karp Carol L. , Galor Anat
Published: October 2023

Purpose:

The aim of this study was to compare clinical characteristics and high-resolution optical coherence tomography (HR-OCT) findings between corneal ocular surface squamous neoplasia (OSSN) and corneal pannus.

Methods:

Retrospective study of 9 individuals, 3 with lesions histologically confirmed to be OSSN, 3 with lesions histologically confirmed to be pannus, 1 with lesions histologically confirmed to be OSSN followed by pannus, and 2 with long-standing, nonchanging lesions clinically diagnosed as pannus. All individuals presented to the Miami Veterans Affairs Medical Center eye clinic or Bascom Palmer Eye Institute between 2015 and 2023. Clinical characteristics and HR-OCT findings were evaluated and compared.

Results:

Mean age of the population was 72.8 ± 5.1 years, 100% self-identified as male, 100% as White, and 11.1% as Hispanic. Clinically, all lesions appeared as whitish, opalescent, variably vascularized opacities extending from the limbus. None of the OSSN cases had vessels that extended to the border, whereas 4 cases of pannus (67%) had at least 1 vessel that reached the border. On HR-OCT, epithelial hyperreflectivity was observed in all cases of OSSN and pannus. Epithelial thickening was observed in all cases of OSSN, but in none of the cases of pannus. An important distinction between the 2 groups was the transition between normal and abnormal epithelium. All cases of OSSN had a vertical transition, whereas all cases of pannus had an angled transition.

Conclusions:

Corneal OSSN and corneal pannus can both present with clinical findings of an opalescent lesion and may have overlapping findings on HR-OCT. Although both entities may show epithelial hyperreflectivity on HR-OCT, OSSN demonstrates an abrupt transition at a vertical, 90 degrees angle perpendicular to the Bowman layer, whereas pannus appears as an angled transition around 45 degrees. Therefore, the angle of transition between normal and abnormal epithelium can be useful in distinguishing between the 2 entities.
Comparison of direct intra-arterial pressure and ClearSight finger cuff arterial pressure measurements in elderly patients undergoing transcatheter aortic valve replacement
Authors: Yahagi Musashi , Sasaki Momoko
Published: October 2023

Objective:

This study aimed to assess the agreement between direct intra-arterial pressure and ClearSight finger cuff arterial pressure measurements in elderly patients undergoing transcatheter aortic valve replacement (TAVR).

Methods:

A prospective observational study was conducted at Hitachi General Hospital, Japan, involving 30 patients aged 65 years and older who underwent TAVR under general anesthesia. Intra-arterial pressure and finger cuff arterial pressure measurements were recorded for 30 min after valve deployment. Bland–Altman analysis, four-quadrant plot analysis, and error grid analysis were used to assess the concordance between the two methods. Multiple regression analysis was performed to explore potential confounding factors affecting the agreement.

Results:

The bias and precision of ClearSight measurements were −4.88 ± 15.46 (mmHg) for SBP, 4.73 ± 8.95 (mmHg) for mean, and 9.53 ± 9.01 (mmHg) for DBP. The Bland–Altman analysis demonstrated acceptable agreement between intra-arterial pressure and finger cuff arterial pressure measurements. The four-quadrant plot analysis showed good trend-tracking ability, and the error grid analysis revealed that most of the observed values fell into the no-risk category. The mean BP match ratio and SBP match ratio were influenced by several factors such as age, BSA, ejection fraction, valve size, and gender.

Conclusion:

The ClearSight finger cuff arterial pressure measurement showed good agreement with direct intra-arterial pressure in elderly patients undergoing TAVR. However, factors such as age, BSA, ejection fraction, valve size, and gender may influence the agreement between the two methods.
Real-world use of antiretroviral therapy and risk of cancer among people with HIV in Texas
Authors: Horner Marie-Josephe , Shiels Meredith S. , McNeel Timothy S. , Monterosso Analise , Miller Paige , Pfeiffer Ruth M. , Engels Eric A.
Published: October 2023

Background:

Combination antiretroviral therapy (cART) may reduce cancer risk among people with HIV (PWH), but cancer-specific associations are incompletely understood.

Methods:

We linked HIV and cancer registries in Texas to a national prescription claims database. cART use was quantified as the proportion of days covered (PDC). Cox proportional hazards models assessed associations of cancer risk with cART usage, adjusting for demographic characteristics, AIDS status, and time since HIV report.

Results:

We evaluated 63 694 PWH followed for 276 804 person-years. The median cART PDC was 21.4% (interquartile range: 0.0–59.8%). cART use was associated with reduced risk of Kaposi sarcoma [adjusted hazard ratio (aHR) 0.48, 95% confidence interval (CI) 0.34–0.68 relative to unexposed status] and non-Hodgkin lymphoma (aHR 0.41, 95% CI 0.31–0.53), liver cancer (aHR 0.61, 95% CI 0.39–0.96), anal cancer (aHR 0.65, 95% CI 0.46–0.92), and a miscellaneous group of ‘other’ cancers (aHR 0.80, 95% CI 0.66–0.98). In contrast, cART-exposed status was not associated with risk for cervical, lung, colorectal, prostate or breast cancers.

Conclusion:

In a large HIV cohort incorporating data from prescription claims, cART was associated with greatly reduced risks of Kaposi sarcoma and non-Hodgkin lymphoma, and to a lesser degree, reduced risks of liver and anal cancers. These associations likely reflect the beneficial effects of HIV suppression and improved immune control of oncogenic viruses. Efforts to increase cART use and adherence may further decrease cancer incidence among PWH.
Aurantibacillus circumpalustris gen. nov., sp. nov., the first characterized representative of the Bacteroidota candidate family env.OPS 17 and proposal of Aurantibacillaceae fam. nov.
Authors: Vieira Selma , Riedel Thomas , Geppert Alicia , Rohde Manfred , Wolf Jacqueline , Neumann-Schaal Meina , Overmann Jörg
Published: October 2023

16S rRNA sequence types associated with the candidate family env.OPS 17 have been reported from various environments, but no representatives have been characterized and validly named. Bacteria of env.OPS 17 are affiliated with the order

Sphingobacteriales

and were first detected more than two decades ago in the vicinity of a thermal spring in Yellowstone National Park. Strain Swamp196T, isolated from the soil surrounding a swamp in Northern Germany, is the first characterized representative of candidate family env.OPS 17. Cells of strain Swamp196T are rod-shaped, non-motile, non-spore-forming, non-capsulated and stain Gram-negative. Colonies are small and orange-coloured. The strain is mesophilic and grows under aerobic or microaerophilic conditions. It grows chemo-organotrophically over a narrow range of pH and exclusively on proteinaceous substrates. The major cellular fatty acids are iso-C15 : 0, iso-C15 : 1
 ω10c, C18 : 1
 ω9c and C16 : 1
 ω7c and the major polar lipids are two unidentified aminophospholipids, one unidentified aminolipid and one unidentified lipid. The predominant respiratory quinone is MK-7. The DNA G+C content of genomic DNA is 35.5 mol%. Strain Swamp196T is related to

Pedobacter cryophilus

AR-3-17T,

Arcticibacter pallidicorallinus

Hh36T and

Pedobacter daechungensis

Dae 13T with 16S rRNA gene sequence similarity of 84.1, 83.8 and 83.5 %, respectively. Based on our phenotypic, genomic and phylogenetic analysis, we propose the novel species Aurantibacillus circumpalustris sp. nov (type strain Swamp196T=DSM 105849T=CECT 30420T) of the novel genus Aurantibacillus gen. nov. and the novel family Aurantibacillaceae fam. nov.
AlphaMissense is better correlated with functional assays of missense impact than earlier prediction algorithms
Authors: Ljungdahl Alicia , Kohani Sayeh , Page Nicholas F. , Wells Eloise S. , Wigdor Emilie M. , Dong Shan , Sanders Stephan J.
Published: October 2023

Missense variants that alter a single amino acid in the encoded protein contribute to many human disorders but pose a substantial challenge in interpretation. Though these variants can be reliably identified through sequencing, distinguishing the clinically significant ones remains difficult, such that “Variants of Unknown Significance” outnumber those classified as “Pathogenic” or “Likely Pathogenic.” Numerousin silicoapproaches have been developed to predict the functional impact of missense variants to inform clinical interpretation, the latest being AlphaMissense, which uses artificial intelligence methods trained on predicted protein structure. To independently assess the performance of AlphaMissense and 38 other predictors of missense severity, we compared predictions to data from multiplexed assays of variant effect (MAVE). MAVE experiments generate almost every possible individual amino acid change in a gene and measure their functional impact using a high-throughput assay. Assessing 17,696 variants across five genes (DDX3X, MSH2, PTEN, KCNQ4, andBRCA1), we find that AlphaMissense is consistently one of the top five algorithms based on correlation with functional impact and is the best-correlated algorithm for two genes. We conclude that AlphaMissense represents the current best-in-class predictor by this metric; however, the improvement over other algorithms is modest. We note that multiple missense predictors, including AlphaMissense, appear to overcall variants as pathogenic despite minimal functional impact and that substantially more high-quality training data, including consistently analyzed patient cohorts and MAVE analyses, are required to improve accuracy.
Developing small Cas9 hybrids using molecular modeling
Authors: Mangin Antoine , Dion Vincent , Menzies Georgina
Published: October 2023

The RNA-guided CRISPR-Cas9 fromStreptococcus pyogenesis the best characterized enzyme for gene editing. Its large size, however, precludes it from being packaged together with its single guide (sg)RNA into a single adeno-associated virus, limitingin vivoapplications. Here, we developed smaller Cas9 hybrids, made of the PAM interacting domain (PID) ofS. pyogenesand the catalytic domains of the smaller Cas9 orthologues, as well as sgRNA cognate hybrids. Molecular modeling revealed that the presence of a sgRNA stabilizes Cas9. Making the D10A mutation to turn Cas9 into a nickase dramatically alters its binding energy to the sgRNA, showing that the approach can identify functionally relevant changes. However, we found that the four Cas9/sgRNA hybrid pairs tested in human cells failed to edit target sequences. We conclude thatin silicoapproaches can identify functional changes caused by point mutations but are not sufficient for designing Cas9/sgRNA hybrids.
Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas
Authors: Miller Tyler E. , Farran Chadi A. El , Couturier Charles P. , Chen Zeyu , D’Antonio Joshua P. , Verga Julia , Villanueva Martin A. , Castro L. Nicolas Gonzalez , Tong Yuzhou Evelyn , Saadi Tariq Al , Chiocca Andrew N. , Fischer David S. , Heiland Dieter Henrik , Guerriero Jennifer L. , Petrecca Kevin , Suva Mario L. , Shalek Alex K. , Bernstein Bradley E.
Published: October 2023

Gliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.
A Foundational Large Language Model for Edible Plant Genomes
Authors: Mendoza-Revilla Javier , Trop Evan , Gonzalez Liam , Roller Masa , Dalla-Torre Hugo , de Almeida Bernardo P , Richard Guillaume , Caton Jonathan , Lopez Carranza Nicolas , Skwark Marcin , Laterre Alex , Beguir Karim , Pierrot Thomas , Lopez Marie
Published: October 2023

Significant progress has been made in the field of plant genomics, as demonstrated by the increased use of high-throughput methodologies that enable the characterization of multiple genome-wide molecular phenotypes. These findings have provided valuable insights into plant traits and their underlying genetic mechanisms, particularly in model plant species. Nonetheless, effectively leveraging them to make accurate predictions represents a critical step in crop genomic improvement. We present AgroNT, a foundational large language model trained on genomes from 48 plant species with a predominant focus on crop species. We show that AgroNT can obtain state-of-the-art predictions for regulatory annotations, promoter/terminator strength, tissue-specific gene expression, and prioritize functional variants. We conduct a large-scale in silico saturation mutagenesis analysis on cassava to evaluate the regulatory impact of over 10 million mutations and provide their predicted effects as a resource for variant characterization. Finally, we propose the use of the diverse datasets compiled here as the Plants Genomic Benchmark (PGB), providing a comprehensive benchmark for deep learning-based methods in plant genomic research. The pre-trained AgroNT model is publicly available on HuggingFace at https://huggingface.co/InstaDeepAI/agro-nucleotide-transformer-1b for future research purposes.
Angular leaf spot inAcmella oleraceacaused by a foliar nematode
Authors: de Freitas Silva Marcela , Faccioli Felipe Castro , Honório Amanda Pereira , Fonseca Andressa Rodrigues , de Jesus Boari Alessandra , Buonicontro Dalila Sêni
Published: October 2023

Jambu plants (Acmella oleracea) exhibiting necrotic angular leaf spots were collected in Belém - Pará, Brazil. After previous analysis, the presence of nematodes fromAphelenchoidesgenus was observed. These nematodes were cultured onFusariumsp. and subsequently morphologically and molecularly characterized for species-level identification.Aphelenchoidessp. associated with jambu exhibited morphological and morphometric characteristics very similar to those of species within theA. besseyicomplex (A. besseyi,A. oryzaeandA. pseudobesseyi), but these characteristics were not sufficient to separate them into a unique species. The Bayesian inference analysis, utilizing the expansion segment of the large subunit (D2-D3 LSU) of nuclear ribosomal DNA, yielded results with a high posterior probability, indicating that theAphelenchoidessp. associated with jambu belongs to theA. pseudobesseyispecies. Under controlled conditions, the reproduction of the nematode in the leaf tissues (FR > 1) was observed, resulting in disease symptoms. The highest reproduction rate ofA. pseudobesseyi(FR = 2.6) was observed from inoculation with 100 nematodes per leaf. It is concluded thatA. pseudobesseyiis the etiological agent of jambu angular leaf spot. For future research, like evaluating the resistance of jambu to this nematode, it is recommended to inoculate a maximum of 100 nematodes per leaf.
PhysiCell Studio: a graphical tool to make agent-based modeling more accessible
Authors: Heiland Randy , Bergman Daniel , Lyons Blair , Cass Julie , Rocha Heber L. , Ruscone Marco , Noël Vincent , Macklin Paul
Published: October 2023

Defining a multicellular model can be challenging. There may be hundreds of parameters that specify the attributes and behaviors of objects. Hopefully the model will be defined using some format specification, e.g., a markup language, that will provide easy model sharing (and a minimal step toward reproducibility). PhysiCell is an open source, physics-based multicellular simulation framework with an active and growing user community. It uses XML to define a model and, traditionally, users needed to manually edit the XML to modify the model. PhysiCell Studio is a tool to make this task easier. It provides a graphical user interface that allows editing the XML model definition, including the creation and deletion of fundamental objects, e.g., cell types and substrates in the microenvironment. It also lets users build their model by defining initial conditions and biological rules, run simulations, and view results interactively. PhysiCell Studio has evolved over multiple workshops and academic courses in recent years which has led to many improvements. Its design and development has benefited from an active undergraduate and graduate research program. Like PhysiCell, the Studio is open source software and contributions from the community are encouraged.
Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB
Authors: Chan Jonathan K. , Sun Yan , Bhushan Anand , Willard Belinda , Tam Connie
Published: October 2023

The corneal epithelium at the ocular surface is constantly exposed to the environment and represents the first line of defense against infection, mechanical injury or chemical irritation. Through TLR-mediated recognition of pathogen- and damage-associated molecular patterns, it engages in direct antimicrobial responses and alerts the immune system on intruder and tissue damage by secreting pro-inflammatory and chemotactic cytokines that promote immune cell infiltration. How the corneal epithelium downregulates TLR signaling is unclear, yet it highly expresses keratin 6a (K6a), a cytoskeletal protein that has emerged to play essential regulatory roles in corneal innate immune response. Here we report that mice harboring genetic deletion of K6a are more susceptible to developing bacterial keratitis with unresolved corneal opacification and higher bacterial load. Such disease phenotype is caused by the increased pro-inflammatory cytokine and chemokine secretions from the K6a-null corneal epithelium, which further promotes the infiltration of immune cells and their associated pro-inflammatory response. Using human corneal epithelial cells immortalized by telomerase reverse transcriptase (hTCEpi cells), we demonstrated that knocking down K6a enhances NF-κB/ RelA-dependent cytokine and chemokine expression. Moreover, proteomic screen reveals that K6a interacts with ELKS, a critical NEMO-binding scaffold that links between canonical IKKα/β and the principal cytoplasmic inhibitor of RelA, i.e. IκBα., to promote its phosphorylation and degradation. Surprisingly, K6a does not antagonize any of these canonical NF-κB signaling events. Instead, we found that ELKS in addition to canonical IKKs interacts with the atypical IKK member IKKε. Furthermore, knockdown of K6a in hTCEpi cells promotes ELKS-dependent phosphoactivation of IKKε, which in turn phosphorylates and activates RelA. Our study thus demonstrated an unexpected role of cytosolic K6a as a novel negative regulator of TLR/NF-κB signaling in preventing excess proinflammatory cytokine and chemokine expressions. It further highlighted the functional importance of ELKS as a common signaling scaffold for both canonical and atypical IKK-dependent activation of NF-κB in corneal epithelial cells. Using both IKK classes other than only canonical IKKs for TLR/NF-κB induction as in other cell types including myeloid immune cells suggest that the cornea epithelium is more flexible in modulating its inflammatory response, which could greatly minimize corneal damage while preserving its essential functions for barrier protection and light refraction.
Reduced Monocyte Proportions and Responsiveness in Convalescent COVID-19 Patients
Authors: Ravkov Eugene V. , Williams Elizabeth S.C.P. , Elgort Mark , Barker Adam P. , Planelles Vicente , Spivak Adam M. , Delgado Julio C. , Lin Leo , Hanley Timothy M.
Published: October 2023

The clinical manifestations of acute severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and COVID-19 suggest a dysregulation of the host immune response that leads to inflammation, thrombosis, and organ dysfunction. It is less clear whether these dysregulated processes persist during the convalescent phase of disease or during long COVID. We investigated the effects of SARS-CoV-2 infection on the proportions of classical, intermediate, and non-classical monocytes, their activation status, and their functional properties in convalescent COVID-19 patients and uninfected control subjects. We found that the percentage of total monocytes was decreased in convalescent COVID-19 patients compared to uninfected controls. This was due to decreased intermediate and non-classical monocytes. Classical monocytes from convalescent COVID-19 patients demonstrated a decrease in activation markers, such as CD56, in response to stimulation with bacterial lipopolysaccharide (LPS). In addition, classical monocytes from convalescent COVID-19 patients showed decreased expression of CD142 (tissue factor), which can initiate the extrinsic coagulation cascade, in response to LPS stimulation. Finally, we found that monocytes from convalescent COVID-19 patients produced less TNF-α and IL-6 in response to LPS stimulation, than those from uninfected controls. In conclusion, SARS-CoV-2 infection exhibits a clear effect on the relative proportions of monocyte subsets, the activation status of classical monocytes, and proinflammatory cytokine production that persists during the convalescent phase of disease.
Vagus nerve stimulation limits the germinal center B cell response via CD4+ T cell-derived acetylcholine
Authors: Kurata-Sato Izumi , Mughrabi Ibrahim T , Rana Minakshi , Gerber Michael , Al-Abed Yousef , Sherry Barbara , Zanos Stavros , Diamond Betty
Published: October 2023

Neural signals are known to contribute to immune regulation and modulation of the innate immune response downstream of the vagus nerve has been well studied. The effects of vagus nerve activity on antibody production, however, have been largely unexplored. Here we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of vagal activation on T-dependent B cell responses. We observed lower titers of high-affinity serum IgG and fewer antigen-specific germinal center (GC) B cells in the spleen. GC B cells from chronic VNS mice expressed more active caspase-3 and exhibited an altered gene expression profile suggesting increased susceptibility to apoptosis and impaired maturation. Follicular dendritic cell (FDC) cluster dispersal and altered FDC gene expression suggested poor FDC function. These alterations were diminished in the absence of a subset of acetylcholine-producing CD4+ T cells. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. Engagement of the α4 nAChR subunit on B cells impaired Akt phosphorylation, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed, at least in part, to the effect of acetylcholine on B cell intrinsic pathways, resulting in hindered B cell survival and maturation and leading to an alteration in FDC function. Our findings identify a potential therapeutic target to prevent immunosuppression in conditions associated with increased vagal activity.
Multi-omics Quality Assessment in Personalized Medicine through EATRIS
Authors:   EATRIS Plus Multi-omics working group and stakeholders (in alphabetical order by last name), Alonso-Andrés Patricia , Baldazzi Davide , Chen Qiaochu , Conde Moreno Elisa , Crespo-Toro Lorena , Donner Kati , Džubák Petr , Ekberg Sara , Garcia-Bermejo Maria Laura , Gasparotto Daniela , Ghimire Bishwa , Gloerich Jolein , Habier Janine , Hajdúch Marián , Halder Rashi , Hannula Sari , Lindgren Hanna , Liu Yaqing , Maestro Roberta , Martin Tom , Mattila Pirkko , Najdekr Lukáš , Nazir Kenneth , Niehues Anna , Nieminen Anni I , Nordlund Jessica , Oldoni Emanuela , Övernäs Elin , Palva Aino , Puhka Maija , Quintero Ileana , Ramos-Muñoz Miren Edurne , Rodríguez-Serrano Esperanza Macarena , Saracino Sabrina , Scherer Andreas , Shi Leming , Stanková Jarmila , ’t Hoen Peter-Bram , Tunstall Tanushree , Valenti Beatrice , van Gool Alain , Weiss Marjan , Yadav Bhagwan , Zheng Yuanting , Žižkovičová Patricia
Published: October 2023

Molecular characterization of a biological sample, e.g., with omics approaches, is fundamental for the development and implementation of personalized and precision medicine approaches. In this context, quality assessment is one of the most critical aspects. Accurate performance and interpretation of omics techniques is based on consensus, harmonization, and standardization of protocols, procedures, data analysis and reference values and materials. EATRIS, the European Infrastructure for Translational Medicine (www.EATRIS.eu), brings together resources and services to support researchers in developing their biomedical discoveries into novel translational tools and interventions for better health outcomes. Here we describe activities of member facilities of EATRIS towards quality assessment of pre-clinical sample processing, clinical omics data generation, multi-omics data integration, and dissemination of the resources in a Multi-Omics Toolbox, the principal deliverable of the EATRIS Plus project for the consolidation of EATRIS towards translational Medicine.
MatK impacts Differential Chloroplast Translation of Ribosomal and Photosynthetic genes by limiting spliced tRNA-K(UUU) abundance
Authors: Muino Jose M. , Qu Yujiao , Ruwe Hannes , Maschmann Sascha , Chen Wei , Zoschke Reimo , Ohler Uwe , Kaufmann Kerstin , Schmitz-Linneweber Christian
Published: October 2023

The protein levels of chloroplast photosynthetic genes and genes related to the chloroplast genetic apparatus vary to adapt to different conditions. However, the underlying mechanisms governing these variations remain unclear. The chloroplast intron Maturase K is encoded within thetrnKintron and has been suggested to be required for splicing several group IIA introns, including thetrnKintron. In this study, we employed RNA immunoprecipitation followed by high-throughput sequencing (RIP-Seq) to identify MatK’s preference for binding to group IIA intron domains I and VI within target transcripts. Importantly, these domains are crucial for branch point selection, and we discovered alternative branch points in three MatK target introns, the first observed instances of alternative splicing in chloroplasts. The alternativetrnKlariat structure showed increased accumulation during heat acclimation. The cognate codon of tRNA-K(UUU) is highly enriched in mRNAs encoding ribosomal proteins and ribosome profiling in atrnK-matKover-expressor exhibited elevated levels of the spliced tRNA-K(UUU). Our analysis revealed a significant up-shift in the translation of ribosomal proteins compared to photosynthetic genes. Our findings suggest the existence of a novel regulatory mechanism linked to the abundance of tRNA-K(UUU), enabling the differential expression of functional chloroplast gene groups.
Non-modular Fatty Acid Synthases Yield Unique Acylation in Ribosomal Peptides
Authors: Ren Hengqian , Huang Chunshuai , Pan Yuwei , Cui Haiyang , Dommaraju Shravan R. , Mitchell Douglas A. , Zhao Huimin
Published: October 2023

Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries1, 2. However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machineries from other natural product families3–8. Here, we report lipoavitides, a class of RiPP/fatty acid hybrid lipopeptides that display a unique, membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modifiedN-terminus. The HMP is formed via condensation of isobutyryl-CoA and methylmalonyl-CoA catalyzed by a 3-ketoacyl-ACP synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering.
Medical tourism’s vulnerability to COVID-19 and its path to recovery: a 10-year data analysis of international patient visits
Authors: Myung Gihyun , Lim Juwon
Published: October 2023

Background

This study seeks to assess the trends in international patient intake over the past decade, with a specific focus on the impact of the COVID-19 pandemic.

Methods

This is a retrospective study on the data obtained from SUPREME (CDW Research Search System) of Information Center from a single university hospital. Patient demographics on the gender, age, nationality, and diagnosis visiting International Healthcare Center from January 2013 to June 2023 were collected, and the impact and recovery rates from COVID-19 were calculated in terms of the number of foreign patients. The patient number was further analyzed based on gender, age, nationality, and diagnosis.

Results

The impact and recovery rates of COVID-19 on the number of foreign patients was 57% and 71%, respectively. The patients from USA, the old adult group (age 40-64), and patients with cancer were least affected by COVID-19, whereas the patients from the UAE, the young adult group (age 19-39), and patients for medical screening were most affected by COVID-19.

Conclusions

The number of international patients steadily was steadily rising since 2013 with a drop in number more than half with the advent of COVID-19 in 2019. However, recent data suggests a revival of this trend, signaling a gradual return to pre-pandemic levels. Despite the overall recovery, future trends are not entirely predictable due to potential factors. Future pandemics, international conflicts, or economic instability could potentially affect the influx of foreign patients. To revive medical tourism, a joint effort from the government and hospital is necessary.
Adapting a Data to Care Approach for HIV to Promote HCV Cure for Persons with HIV/HCV Co-infection
Authors: Wegener Maximilian , Gosselin Deborah , Brooks Ralph , Speers Suzanne , Villanueva Merceditas
Published: October 2023

With Direct Acting Antivirals for Hepatitis C virus (HCV), cure is possible in >95% including those with HIV/HCV co-infection. Achieving strategic targets for cure requires addressing barriers including suboptimal care engagement. We adapted Data to Care (D2C), a public health strategy designed to identify and link persons out of care (OOC) for HIV, for persons with HIV/HCV co-infection untreated for HCV. In partnership with Connecticut Department of Public Health (DPH), persons OOC for HIV (defined as no HIV surveillance laboratory tests from 10/1/2018-10/1/2019) were matched to a list of persons co-infected with HIV/HCV (through 12/31/2019). We used a three-phase follow-up approach (pre-work, case conferencing, and Disease Intervention Specialist (DIS) follow-up) to track outreach outcomes and re-engagement/HCV cure success. There were 90 HIV/HCV co-infected persons who were OOC for HIV. The pre-work and case conferencing phases determined that 33 (36.7%) had previous HCV cure or were in treatment. There were 41 eligible for DIS-follow-up of which 21 (51%) were successfully contacted and 7 (33%) successfully re-engaged (kept appointment with HCV provider). No new HCV treatment initiations were recorded. Using a D2C approach, we identified and conducted outreach to persons who were OOC for HIV to promote HCV treatment. This approach resulted in intensive data clean-up and outreach efforts which produced modest re-engagement and no HCV treatment initiations. Future studies should develop alternative and complementary interventions to promote effective re-engagement and HCV treatment.
Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders
Authors: Arbabi Keon , Newton Dwight F. , Oh Hyunjung , Davie Melanie C. , Lewis David A. , Wainberg Michael , Tripathy Shreejoy J. , Sibille Etienne
Published: October 2023

Background

Psychiatric disorders like major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are characterized by altered cognition and mood, brain functions that depend on information processing by cortical microcircuits. We hypothesized that psychiatric disorders would display cell type-specific transcriptional alterations in neuronal subpopulations that make up cortical microcircuits: excitatory pyramidal (PYR) neurons and vasoactive intestinal peptide- (VIP), somatostatin- (SST), and parvalbumin- (PVALB) expressing inhibitory interneurons.

Methods

We performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control, using laser capture microdissection followed by RNA sequencing (LCM-seq). We sequenced libraries from 130 whole cells pooled per neuronal subtype (VIP, SST, PVALB, superficial and deep PYR) in 76 subjects from the University of Pittsburgh Brain Tissue Donation Program, evenly split between MDD, BD, and SCZ subjects and healthy controls.

Results

We identified hundreds of differentially expressed (DE) genes and biological pathways across disorders and neuronal subtypes, with the vast majority in inhibitory neuron types, primarily PVALB. DE genes were distinct across cell types, but partially shared across disorders, with nearly all shared genes involved in the formation and maintenance of neuronal circuits. Coordinated alterations in biological pathways were observed between select pairs of microcircuit cell types and partially shared across disorders. Finally, DE genes coincided with known risk variants from psychiatric genome-wide association studies, indicating cell type-specific convergence between genetic and transcriptomic risk for psychiatric disorders.

Conclusions

We present the first cell type-specific dataset of cortical microcircuit gene expression across multiple psychiatric disorders. Each neuronal subtype displayed unique dysregulation signatures, some shared across cell types and disorders. Inhibitory interneurons showed more dysregulation than excitatory pyramidal neurons. Our study suggests transdiagnostic cortical microcircuit pathology in SCZ, BD, and MDD and sets the stage for larger-scale studies investigating how cell circuit-based changes contribute to shared psychiatric risk.
Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS-CARES Study
Authors: Blake Jason A. , Long D. Leann , Knight Amy J. , Goodin Burel R. , Crowe Michael , Judd Suzanne E. , Rhodes J. David , Roth David L. , Clay Olivio J.
Published: October 2023

Objective

Cognitive impairment after stroke is common, present up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of two stroke severity ratings and a caregiver-report of post-stroke functioning with longitudinal cognitive outcomes.

Methods

The analysis was conducted on 157 caregivers and stroke survivor dyads who participated in the Caring for Adults Recovering from the Effects of Stroke (CARES) project, an ancillary study of the REasons for Geographic and Racial Differences in Stroke (REGARDS) national cohort study. Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) collected at hospitalization discharge were included as two primary predictors of cognitive impairment. The number of caregiver-reported problems and impairments at nine months following stroke were included as a third predictor. Cognition was assessed using a biennial telephone battery, incorporating multiple cognitive assessments to assess learning, memory, and executive functioning. Longitudinal cognitive scores were analyzed up to five years post-stroke, controlling for baseline (pre-stroke) cognitive scores and demographic variables of each stroke survivor collected at CARES baseline.

Results

Separate mixed models showed significant main effects of GOS (b=0.3280, p=0.0009), mRS (b=-0.2119, p=0.0002), and caregiver-reported impairments (b=-0.0671, p<0.0001) on longitudinal cognitive scores. In a combined model including all three predictors, only caregiver-reported problems significantly predicted cognitive outcomes (b=-0.0480, p<0.0001).

Impact

These findings underscore the importance of incorporating caregivers feedback in understanding cognitive consequences of stroke.
Drab and distant birds are studied less than their fancy-feathered friends
Authors: Fischer Silas E. , Otten Joshua G. , Lindsay Andrea M. , Miles Donald B. , Streby Henry M.
Published: October 2023

Human decisions are influenced by implicit biases, and scientists do not exist in an objectivity vacuum. Subconscious biases in scientists’ choices about which species to study may beget distorted knowledge bases and stagnant paradigms. Disparities in biological knowledge can result from bias in study species selection within a cycle of policymaking, funding, and publication, all subject to implicit biases. Here, we show that ornithological research in the USA and Canada is biased toward birds with greater aesthetic salience and those with larger breeding ranges and ranges that encompass more universities. We quantified components of aesthetic salience (e.g., color, pattern/contrast, body size) of 293 passerines and near-passerines based on empirically documented human visual preferences and investigated whether these components were associated with research effort. We also quantified each species’ breeding range size and the number of universities within that range. Accounting for phylogenetic relatedness, we found that these metrics of aesthetics, familiarity, and accessibility combined to explain 45% of the variation in the number of published papers about each species from 1965–2020. On average, birds in the top 10% of aesthetic salience were studied 3.0X more than birds in the bottom 10%, and publication numbers were predicted most strongly by color and pattern components of aesthetic salience. Birds in the top 10% of breeding range size and university abundance were studied 3.8X and 3.5X more often than species in the bottom 10% of those categories, respectively. Species listed as Endangered and those featured on journal covers have greater aesthetic salience scores than other species. We discuss how these biases may influence perceived relative value of species with respect to culture and conservation. The disparities in empirical knowledge we describe here perpetuate a positive feedback loop, thus widening the gap between the avian “haves” and “have-nots”, with some questions answered repeatedly while potentially critical discoveries are left undiscovered.

“All animals are equal, but some animals are more equal than others.” —George Orwell,Animal Farm(1945)
Single nuclei sequencing reveals C4photosynthesis is based on rewiring of ancestral cell identity networks
Authors: Swift Joseph , Luginbuehl Leonie H. , Schreier Tina B. , Donald Ruth M. , Lee Travis A. , Nery Joseph R. , Ecker Joseph R. , Hibberd Julian M.
Published: October 2023

In multicellular systems changes to the patterning of gene expression drive modifications in cell function and trait evolution. One striking example is found in more than sixty plant lineages where compartmentation of photosynthesis between cell types allowed the evolution of the efficient C4pathway from the ancestral C3state. The molecular events enabling this transition are unclear. We used single nuclei sequencing to generate atlases for C3rice and C4sorghum during photomorphogenesis. Our analysis revealed that initiation of photosynthesis gene expression is conditioned by cell identity. In both species a conserved cistrome defines each cell type, and photosynthesis genes switching expression from mesophyll in rice to bundle sheath in sorghum acquire hallmarks of bundle sheath identity. The sorghum bundle sheath has also acquired gene networks associated with C3guard cells. We conclude C4photosynthesis is based on rewiring incisthat exapts cell identity networks of C3plants.
The mycobacterial glycoside hydrolase LamH enables capsular arabinomannan release and stimulates growth
Authors: Franklin Aaron , Layton Abigail J. , Mize Todd , Salgueiro Vivian C. , Sullivan Rudi , Benedict Samuel T. , Gurcha Sudagar S. , Anso Itxaso , Besra Gurdyal S. , Banzhaf Manuel , Lovering Andrew L. , Williams Spencer J. , Guerin Marcelo E. , Scott Nichollas E. , Prados-Rosales Rafael , Lowe Elisabeth C. , Moynihan Patrick J.
Published: October 2023

Mycobacterial glycolipids are important cell envelope structures that drive host-pathogen interactions. Arguably, the most important amongst these are lipoarabinomannan (LAM) and its precursor, lipomannan (LM), which are both trafficked out of the bacterium to the host via unknown mechanisms. An important class of exported LM/LAM is the capsular derivative of these molecules which is devoid of its lipid anchor. Here, we describe the identification of a glycoside hydrolase family 76 enzyme that we term LamH which specifically cleaves α-1,6-mannoside linkages within LM and LAM, driving its export to the capsule releasing its phosphatidyl-myo-inositol mannoside lipid anchor. Unexpectedly, we found that the catalytic activity of this enzyme is important for efficient exit from stationary phase cultures where arabinomannan acts as a signal for growth phase transition. Finally, we demonstrate that LamH is important forMycobacterium tuberculosissurvival in macrophages. These data provide a new framework for understanding the biological role of LAM in mycobacteria.
Bayesian Fluorescence Framework for integrative modeling of biomolecules
Authors: Peulen Thomas-Otavio , Sali Andrej
Published: October 2023

Fluorescence spectroscopic and imaging techniques, such as fluorescence-correlation spectroscopy, image correlation spectroscopy, time-resolved fluorescence spectroscopy, and intensity-based spectroscopy, can provide sparse time-dependent positional and inter-fluorophore distance information for macromolecules and their complexesin vitroand in living cells. Here, we formulated a Bayesian framework for processing and using the fluorescence data for interpreting by static and dynamic models of biomolecules. We introduceBayesian Fluorescence Framework(BFF) as part of the open-sourceIntegrative Modeling Platform(IMP) software environment, facilitating the development of modeling protocols based in part on fluorescence data. BFF improves the accuracy, precision, and completeness of the resulting models by formulating the modeling problem as a sampling problem dependent on general and flexible libraries of (i) atomic and coarse-grained molecular representations of single-state models, multi-state models, and dynamic processes, (ii) Bayesian data likelihoods and priors, as well as (iii) sampling schemes. To illustrate the framework, we apply it to a sample synthetic single-molecule FRET dataset of the human transglutaminase 2. We show how to integrate time-resolved fluorescence intensities, fluorescence correlation spectroscopy curves, and fluorescence anisotropies to simultaneously resolve dynamic structures, state populations, and molecular kinetics. As BFF is part of IMP, fluorescence data can be easily integrated with other data types to solve challenging modeling problems.

Statement of Significance

Bayesian Framework for Fluorescence(BFF) is software that implements a probabilistic framework for processing experimental fluorescence data to provide input information for Bayesian integrative structure modeling. BFF facilitates constructing integrative modeling protocols based in part on fluorescence data by reducing the required fluorescence spectroscopy and microscopy domain knowledge. In addition, it improves the precision and accuracy of the resulting models.