bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alteration in Gut Microbiome and Intestinal Barrier Function caused by Efavirenz versus Dolutegravir Treatments in Mice
Authors: Tang Qin , Pan Hai-en , Liu Zhe , Deng Zhou , Zhong Qing-Yang , Cao Huan-huan , Ye Jun-yan , Li Jin , Li Xue-ying , Zhu Hai-peng , Chen Song 
Published: November 2023

AbstractDolutegravir (DTG) is replacing efavirenz (EFV) as first-line antiretroviral therapy because of its better tolerance. However, DTG cause similar, but milder, gastrointestinal and neurological side effects as EFV does. We speculated that impaired gut barrier function contributes to their side effects. For this purpose, the mice were intragastrically administered EFV, DTG, or vehicle for 60 consecutive days. The plasma levels of FITC-dextran were determined to evaluate gut barrier integrity. Colonic contents were collected for 16S rRNA sequencing. Adipose, liver, ileum, and colon tissues were collected for pathological examination, and intestinal zona occludens-1 (ZO-1) immunofluorescence staining and goblet cell staining were performed. We found that EFV significantly retarded body weight gain, decreased glucose uptake, and caused lipodystrophy and hepatocyte necrosis. EFV also decreased species richness of gut microbiota, increased Verrucomicrobia and Proteobacteria, and decreased Patescibacteria and Cyanobacteria. Moreover, it caused crypt damage, goblet cell loss, reduced ZO-1 expression, impaired gut barrier function, and suppressed expressions of Pdha1 and Ndufv1. Interestingly, DTG impaired barrier function similar to EFV, but the impairment was milder. DTC also inhibited MPC1, MPC2, and Pdha1 expression. Our results suggest a link between abnormal energy metabolism, impaired gut barrier integrity and side effects of EFV and DTG.
Insights intoKIF11pathogenesis in Microcephaly-Lymphedema-Chorioretinopathy syndrome: a lymphatic perspective
Authors: Ogmen Kazim , Dobbins Sara , Martinez-Corral Ines , Behncke Rose Yinghan , Brown Ryan C.S. , Ulferts Sascha , Hansmeier Nils Rouven , Sackey Ege , Alqahtani Ahlam , Karapouliou Christina , Grigoriadis Dionysios , Oberlin Michael , Williams Denise , Ekici Arzu , Karaer Kadri , Jeffery Steve , Mortimer Peter , Gordon Kristiana , Hogan Benjamin M. , Mäkinen Taija , Hägerling René , Mansour Sahar , Martin-Almedina Silvia , Ostergaard Pia 
Published: November 2023

AbstractPathogenic variants in kinesinKIF11underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association ofKIF11(encoding EG5) with development of the lymphatic system, and howKIF11pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown.Using patient-derived lymphoblastoid cells, we demonstrate that MLC patients carrying pathogenic stop-gain variants inKIF11have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused byKIF11haploinsufficiency.We reveal thatKIF11is expressed in early human and mouse development with the lymphatic markers VEGFR3, Podoplanin and PROX1. In zebrafish, scRNA-seq identifiedKIF11specifically expressed in endothelial precursors. In human lymphatic endothelial cells (LECs), EG5 inhibition with Ispinesib, reduces VEGFC-driven AKT phosphorylation, migration and spheroid sprouting.KIF11knockdown reducesPROX1andVEGFR3expression, providing for the first time a link betweenKIF11and drivers of lymphangiogenesis and lymphatic identity.
Sex-stratified phenotyping of comorbidities associated with an inpatient delirium diagnosis using real world data
Authors: Kodama Lay , Woldemariam Sarah , Tang Alice , Li Yaqiao , Oskotsky Tomiko , Raphael Eva , Sirota Marina 
Published: November 2023

AbstractDelirium is a heterogeneous and detrimental mental condition often seen in older, hospitalized patients and is currently hard to predict. In this study, we leverage large-scale, real- world data using the electronic health records (EHR) to identify two cohorts comprised of 7,492 UCSF patients and 19,417 UC health system patients (excluding UCSF patients) with an inpatient delirium diagnosis and the same number of propensity score-matched control patients without delirium. We found significant associations between comorbidities or laboratory test values and an inpatient delirium diagnosis which were validated independently. Most of these associations were those previously-identified as risk factors for delirium, including metabolic abnormalities, mental health diagnoses, and infections. Some of the associations were sex- specific, including those related to dementia subtypes and infections. We further explored the diagnostic associations with anemia and bipolar disorder by conducting longitudinal analyses from the time of first diagnosis of the risk factor to development of delirium demonstrating a significant relationship across time. Finally, we show that an inpatient delirium diagnosis leads to dramatic increases in mortality outcome across both cohorts. These results demonstrate the powerful application of leveraging EHR data to shed insights into prior diagnoses and laboratory test values that could help predict development of inpatient delirium and emphasize the importance of considering patient demographic characteristics including documented sex when making these assessments.One Sentence SummaryLongitudinal analysis of electronic health record data reveals associations between inpatient delirium, comorbidities, and mortality.
Genomic fingerprints of the world’s soil ecosystems
Authors: Graham Emily B. , Garayburu-Caruso Vanessa A. , Wu Ruonan , Zheng Jianqiu , McClure Ryan , Jones Gerrad 
Published: November 2023

AbstractDespite the explosion of soil metagenomic data, we lack a synthesized understanding of patterns in the distribution and functions of soil microorganisms. These patterns are critical to predictions of soil microbiome responses to climate change and resulting feedbacks that regulate greenhouse gas release from soils. To address this gap, we assay 1512 manually-curated soil metagenomes using complementary annotation databases, read-based taxonomy, and machine learning to extract multidimensional genomic fingerprints of global soil microbiomes. Our objective is to uncover novel biogeographical patterns of soil microbiomes across environmental factors and ecological biomes with high molecular resolution. We reveal shifts in the potential for (1) microbial nutrient acquisition across pH gradients; (2) stress, transport, and redox-based processes across changes in soil bulk density; and (3) greenhouse gas emissions across biomes. We also use an unsupervised approach to reveal a collection of soils with distinct genomic signatures, characterized by coordinated changes in soil organic carbon, nitrogen, and cation exchange capacity and in bulk density and clay content that may ultimately reflect soil environments with high microbial activity. Genomic fingerprints for these soils highlight the importance of resource scavenging, plant-microbe interactions, fungi, and heterotrophic metabolisms. Across all analyses, we observed phylogenetic coherence in soil microbiomes –– more closely related microorganisms tended to move congruently in response to soil factors. Collectively, the genomic fingerprints uncovered here present a basis for global patterns in the microbial mechanisms underlying soil biogeochemistry and help beget tractable microbial reaction networks for incorporation into process-based models of soil carbon and nutrient cycling.ImportanceWe address a critical gap in our understanding of soil microorganisms and their functions, which have a profound impact on our environment. We analyzed 1512 global soils with advanced analytics to create detailed genetic profiles (fingerprints) of soil microbiomes. This reveals novel patterns in how microorganisms are distributed across different soil environments. For instance, we discovered shifts in microbial potential to acquire nutrients in relation to soil acidity, as well as changes in stress responses and potential greenhouse gas emissions linked to soil structure. We also identified soils with putative high activity that had unique genomic characteristics surrounding resource acquisition, plant-microbe interactions, and fungal activity. Finally, we observed that closely related microorganisms tend to respond in similar ways to changes in their surroundings. Our work is a significant step towards comprehending the intricate world of soil microorganisms and its role in the global climate.
Orsay virus infection increasesCaenorhabditis elegansresistance to heat-shock
Authors: Castiglioni Victoria G. , Elena Santiago F. 
Published: November 2023

ABSTRACTThe heat shock response plays a role in the immune defense against viruses across various organisms. Studies on model organisms show that inducing this response prior to viral exposure enhances host resistance to infections, while deficient responses make individuals more vulnerable. Moreover, viruses rely on components of the heat shock response for their own stability and viral infections improve thermal tolerance in plants, giving infected individuals an advantage in extreme conditions, which aids the virus in replication and transmission. Here, we examine the interaction between the nematodeCaenorhabditis elegansand its natural pathogen the Orsay virus (OrV) under heat stress. We found that OrV infection leads to differential gene expression related to heat stress, and infected populations showed increased resistance to heat shock. This resistance was associated with increased expression of argonautesalg-1andalg-2, which are crucial for survival after heat shock and for OrV replication. Overall, our study suggests an environmental-dependent mutualistic relationship between the worm and OrV, potentially expanding the worm’s ecological niche and providing the virus with extra opportunities for replication and adaptation to extreme conditions.IMPORTANCEViruses have traditionally been viewed as self-serving pathogens that harm their hosts to ensure their own survival. However, recent studies are painting a different picture, revealing that viruses are ubiquitous and not always linked to diseases. In the realm of plant pathology, it has been long noted that the outcome of an infection hinges on environmental factors. Here, we show that the interaction between an animal virus and its natural host can be mutualistic under harsh temperature conditions. Our research highlights that this shift towards mutualism hinges on the expression of argonaute proteins.
The evolution of multiply substituted isotopologues of methane during microbial aerobic oxidation
Authors: Li Jiawen , Chiu Beverly K. , Piasecki Alison M. , Feng Xiahong , Landis Joshua D. , Marcum Sarah , Young Edward D. , Leavitt William D. 
Published: November 2023

AbstractAerobic methane oxidation (AeOM) is an important biological sink of methane on Earth. Stable isotopes are critical tools in tracking the sources and sinks of Earth’s surface methane budget. However, the major factors that influence the two multiply-substituted (clumped) isotope signatures of AeOM, Δ13CH3D and Δ12CH2D2, are not well known. Here we quantify the influence of kinetics as a function of temperature, and different methane monooxygenase (MMO) enzymes as a function of copper, on the isotopologue concentrations of residual methane by the obligate aerobic methanotroph,Methylococcus capsulatus(Bath). We observe deviations from traditional closed-system distillation (Rayleigh) fractionation during exponential growth at high oxidation rates. We model this as a reservoir effect controlled by the ratio of oxidation rate in the cells to transport rate of methane into the cells, where environmental temperature affects both rates. We also test whether clumped isotope fractionation values vary for the particulate versus soluble MMOs, but the results show minimal differences. We further determine that the back reaction (re-equilibration) of methane with medium water is unlikely. Together, the observations and model demonstrate that at low oxidation-to-transport ratios, the clumped isotope signatures follow canonical Rayleigh fractionation, whereas at high ratios, more positive Δ12CH2D2values result, deviating from simple Rayleigh-like trajectories. This study shows that the methane oxidation-to-transport ratio is a critical influence on clumped isotope signatures of AeOM that should be considered when interpreting the isotopic data of natural methane samples in both open and closed systems.
A review on human gut microbial diversity in 21 tribal populations from India
Authors: Chakraborty Sayak , Mollick Sahid Afrid , Roy Bidyut 
Published: November 2023

AbstractFrom the earlier to modern times, the human populations passed through stages of subsistence such as foraging, rural farming and industrialized urban life. Till date various tribal people are living in geographically isolated areas depending on their traditional (gathering/rural farming) food sources. The long term cultural practices and food habits shaped the gut microbiome composition in these populations and contributed to health. However, the population-level study of the gut microbiota in Indian tribes with representative sampling across its geography and subsistence are limited. So, it is important to understand the complexity and diversity of the gut microbiome in healthy tribal populations, studied so far, to explore relationship among food, gut microbiome and health. Here, we reviewed gut microbiome studies which included 21 Indian tribal populations from different geographical regions to understand the role of food, ecology and cultural habits on variation of gut microbiota.
Educational Impact of a Research and Mentoring Symposium Emphasizing Formative Feedback for Medical Students and Early Career Doctors in Africa
Authors: Nowbuth Avis A , Muwowo Mwiza , Makashinyi Mwitupa , Kumwenda Andrew , Mwanamwampula Sheila J , Kaluba Tamara , Mazimba Sula , Bloom Seth M , Asombang Akwi W 
Published: November 2023

SummaryResearch training is a core component of medical education, but many African medical schools lack resources to support student research, impeding global health progress. Conferences offer alternate venues to learn about research, network, and receive scientific feedback, but conference access for African trainees is limited. We hypothesized that a research and mentorship symposium for African medical trainees could promote research knowledge and interest among attendees.MethodsWe co-organized a symposium attended by medical students and early career doctors from African institutions in-person (Lusaka, Zambia) and virtually. The program featured trainee abstract presentations, keynote lectures, and networking. Abstracts received written reviews and judges provided live formative feedback on presentations. Participants completed a post-symposium survey on demographics, institutional research support, and benefits of symposium participation.ResultsRespondents included 87 trainees from 7 African countries, including 28 presenters from 11 schools. Most had never attended or presented at a conference, interacted with peers in a research forum, or received formal research training. The majority reported key unmet needs in research training and resources at their institutions. Trainees praised the symposium’s judging format and said attendance inspired them, increased their interest in research, improved quality of their projects, and motivated them to initiate new studies.InterpretationA volunteer-organized research and mentorship symposium emphasizing formative feedback enhanced research knowledge and interest among African medical trainees, many of whom had limited access to institutional research training and support. Such initiatives can inspire and nurture new generations of African scientists to advance global health.FundingNone
A Comprehensive Study of GPT-4V’s Multimodal Capabilities in Medical Imaging
Authors: Li Yingshu , Liu Yunyi , Wang Zhanyu , Liang Xinyu , Liu Lingqiao , Wang Lei , Cui Leyang , Tu Zhaopeng , Wang Longyue , Zhou Luping 
Published: November 2023

AbstractThis paper presents a comprehensive evaluation of GPT-4V’s capabilities across diverse medical imaging tasks, including Radiology Report Generation, Medical Visual Question Answering (VQA), and Visual Grounding. While prior efforts have explored GPT-4V’s performance in medical imaging, to the best of our knowledge, our study represents the first quantitative evaluation on publicly available benchmarks. Our findings highlight GPT-4V’s potential in generating descriptive reports for chest X-ray images, particularly when guided by well-structured prompts. However, its performance on the MIMIC-CXR dataset benchmark reveals areas for improvement in certain evaluation metrics, such as CIDEr. In the domain of Medical VQA, GPT-4V demonstrates proficiency in distinguishing between question types but falls short of prevailing benchmarks in terms of accuracy. Furthermore, our analysis finds the limitations of conventional evaluation metrics like the BLEU score, advocating for the development of more semantically robust assessment methods. In the field of Visual Grounding, GPT-4V exhibits preliminary promise in recognizing bounding boxes, but its precision is lacking, especially in identifying specific medical organs and signs. Our evaluation underscores the significant potential of GPT-4V in the medical imaging domain, while also emphasizing the need for targeted refinements to fully unlock its capabilities.
A chemically-induced attenuated strain ofCandida albicansgenerates robust protective immune responses and prevents systemic candidiasis development
Authors: Bose Swagata , Sahu Satya Ranjan , Dutta Abinash , Acharya Narottam 
Published: November 2023

AbstractDespite current antifungal therapy, invasive candidiasis causes >40% mortality in immunocompromised individuals. Therefore, developing an antifungal vaccine is a priority. Here, we could for the first time successfully attenuate the virulence ofCandida albicansby treating it with a fungistatic dosage of EDTA and demonstrate it to be a potential live whole cell vaccine by using murine models of systemic candidiasis. EDTA inhibited the growth and biofilm formation ofC. albicans. RNA-seq analyses of EDTA-treated cells (CAET) revealed that genes mostly involved in metal homeostasis and ribosome biogenesis were up- and down-regulated, respectively. Consequently, a bulky cell wall with elevated levels of mannan and β-glucan, and reduced levels of total monosomes and polysomes were observed. CAET was eliminated faster than the untreated strain (Ca) as found by differential fungal burden in the vital organs of the mice. Higher monocytes, granulocytes, and platelet counts were detected inCa-vsCAET-challenged mice. While hyper-inflammation and immunosuppression caused the killing ofCa-challenged mice, a critical balance of pro- and anti-inflammatory cytokines-mediated immune responses are the likely reasons for the protective immunity in CAET-infected mice.
Modulation of hepatic transcription factor EB activity during cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids byPla2g15
Authors: Davidson Jessica W. , Jain Raghav , Kizzar Thomas , Geoghegan Gisela , Nesbitt Daniel J , Cavanagh Amy , Abe Akira , Nyame Kwamina , Hunger Andrea , Chao Xiaojuan , James Isabella , Von Bank Helaina , Baldwin Dominique A. , Wade Gina , Michorowska Sylwia , Verma Rakesh , Scheuler Kathryn , Hinkovska-Galcheva Vania , Shishkova Evgenia , Ding Wen-Xing , Coon Joshua J , Shayman James A. , Abu-Remaileh Monther , Simcox Judith A. 
Published: November 2023

SummaryCold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of TFEB in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB binding sites of lysosomal genes and determined that the phospholipase Pla2g15 regulates BMP lipid catabolism. Knockdown of Pla2g15 in mice increased BMP lipid levels, ablated the cold-induced rise, and improved cold tolerance. Knockout of Pla2g15 in mice and hepatocytes led to increased BMP lipid levels, that were decreased with re-expression of Pla2g15. Mutation of the catalytic site of Pla2g15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through Pla2g15 catabolism.
A novel stabilization mechanism accommodating genome length variation in evolutionarily related viral capsids
Authors: Podgorski Jennifer M. , Podgorski Joshua , Abad Lawrence , Jacobs-Sera Deborah , Freeman Krista G. , Brown Colin , Hatfull Graham , Luque Antoni , White Simon J. 
Published: November 2023

AbstractTailed bacteriophages are one of the most numerous and diverse group of viruses. They store their genome at quasi-crystalline densities in capsids built from multiple copies of proteins adopting the HK97-fold. The high density of the genome exerts an internal pressure, requiring a maturation process that reinforces their capsids. However, it is unclear how capsid stabilization strategies have adapted to accommodate the evolution of larger genomes in this virus group. Here we characterized a novel capsid reinforcement mechanism in two evolutionary-related actinobacteriophages that modifies the length of a stabilization protein to accommodate a larger genome while maintaining the same capsid size. We used cryo-EM to reveal that capsids contained split hexamers of HK97-fold proteins with a stabilization protein in the chasm. The observation of split hexamers in mature capsids was unprecedented, so we rationalized this result mathematically, discovering that icosahedral capsids can be formed by all split or skewed hexamers as long as their T-number is not a multiple of three. Our results suggest that analogous stabilization mechanisms can be present in other icosahedral capsids, and they provide a strategy for engineering capsids accommodating larger DNA cargoes as gene delivery systems.Significance StatementHow capsids are stabilized and change size is an important part of understanding how to design protein containers and understand viral evolution. We describe a novel capsid stability mechanism that allows the capsid to package a larger genome without changing the capsid architecture and have predicted other capsids using this mechanism. Beyond the evolutionary implications, our findings provide a mechanism to increase the amount of DNA packaged in a capsid, offering a solution to engineer gene delivery systems with larger DNA content, a pressing challenge in gene therapy.