tbuckley/cabot-search huggingface dataset:
Transcriptomic evaluation of skin tape‐strips in children with allergic asthma uncovers epidermal barrier dysfunction and asthma‐associated biomarkers abnormalities
Authors: Ester Del Duca, Dante Dahabreh, Madeline Kim, Jonathan Bar, Joel Correa Da Rosa, Grace Rabinowitz, Paola Facheris, Pedro Jesús Gómez‐Arias, Annie Chang, Vivian Utti, Amira Chowdhury, Ying Liu, Yeriel D. Estrada, Alexandru Laculiceanu, Ioana Agache, Emma Guttman‐Yassky
Journal: Allergy (2024)

Abstract Introduction Tape‐strips, a minimally invasive method validated for the evaluation of several skin diseases, may help identify asthma‐specific biomarkers in the skin of children with allergic asthma. Methods Skin tape‐strips were obtained and analyzed with RNA‐Seq from children with moderate allergic asthma (MAA) ( n = 11, mean age 7.00; SD = 1.67), severe allergic asthma (SAA) ( n = 9, mean age 9.11; SD = 2.37), and healthy controls (HCs) ( n = 12, mean age 7.36; SD = 2.03). Differentially expressed genes (DEGs) were identified by fold change ≥2 with a false discovery rate &lt;0.05. Transcriptomic biomarkers were analyzed for their accuracy in distinguishing asthma from HCs, their relationships with asthma‐related outcomes (exacerbation rate, lung function‐FEV1, IOS‐R5‐20, and lung inflammation‐FeNO), and their links to skin (barrier and immune response) and lung (remodeling, metabolism, aging) pathogenetic pathways. Results RNA‐Seq captured 1113 in MAA and 2117 DEGs in SAA. Epidermal transcriptomic biomarkers for terminal differentiation (FLG/filaggrin), cell adhesion (CDH19, JAM2), lipid biosynthesis/metabolism (ACOT2, LOXL2) were significantly downregulated. Gene set variation analysis revealed enrichment of Th1/IFNγ pathways ( p &lt; .01). MAA and SAA shared downregulation of G‐protein‐coupled receptor (OR4A16, TAS1R3), upregulation of TGF‐β/ErbB signaling‐related (ACVR1B, EGFR, ID1/2), and upregulation of mitochondrial‐related (HIGD2A, VDAC3, NDUFB9) genes. Skin transcriptomic biomarkers correlated with the annualized exacerbation rate and with lung function parameters. A two‐gene classifier (TSSC4‐FAM212B) was able to differentiate asthma from HCs with 100% accuracy. Conclusion Tape‐strips detected epithelial barrier and asthma‐associated signatures in normal‐appearing skin from children with allergic asthma and may serve as an alternative to invasive approaches for evaluating asthma endotypes.
Dietary resistant starch supplementation increases gut luminal deoxycholic acid abundance in mice
Authors: Melanie A. Reuter, Madelynn Tucker, Zara Marfori, Rahaf Shishani, Jessica Miranda Bustamante, Rosalinda Moreno, Michael L. Goodson, Allison Ehrlich, Ameer Y. Taha, Pamela J. Lein, Nikhil Joshi, Ilana Brito, Blythe Durbin-Johnson, Renu Nandakumar, Bethany P. Cummings
Journal: Gut Microbes (2024)

Bile acids (BA) are among the most abundant metabolites produced by the gut microbiome. Primary BAs produced in the liver are converted by gut bacterial 7-α-dehydroxylation into secondary BAs, which can differentially regulate host health via signaling based on their varying affinity for BA receptors. Despite the importance of secondary BAs in host health, the regulation of 7-α-dehydroxylation and the role of diet in modulating this process is incompletely defined. Understanding this process could lead to dietary guidelines that beneficially shift BA metabolism. Dietary fiber regulates gut microbial composition and metabolite production. We tested the hypothesis that feeding mice a diet rich in a fermentable dietary fiber, resistant starch (RS), would alter gut bacterial BA metabolism. Male and female wild-type mice were fed a diet supplemented with RS or an isocaloric control diet (IC). Metabolic parameters were similar between groups. RS supplementation increased gut luminal deoxycholic acid (DCA) abundance. However, gut luminal cholic acid (CA) abundance, the substrate for 7-α-dehydroxylation in DCA production, was unaltered by RS. Further, RS supplementation did not change the mRNA expression of hepatic BA producing enzymes or ileal BA transporters. Metagenomic assessment of gut bacterial composition revealed no change in the relative abundance of bacteria known to perform 7-α-dehydroxylation. P. ginsenosidimutans and P. multiformis were positively correlated with gut luminal DCA abundance and increased in response to RS supplementation. These data demonstrate that RS supplementation enriches gut luminal DCA abundance without increasing the relative abundance of bacteria known to perform 7-α-dehydroxylation.
Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism
Authors: Alain J. De Solis, Almudena Del Río-Martín, Jan Radermacher, Weiyi Chen, Lukas Steuernagel, Corinna A. Bauder, Fynn R. Eggersmann, Donald A. Morgan, Anna-Lena Cremer, Michael Sué, Maximilian Germer, Christian Kukat, Stefan Vollmar, Heiko Backes, Kamal Rahmouni, Peter Kloppenburg, Jens C. Brüning
Journal: Nature Metabolism (2024)

Abstract Agouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons for comparing metabolic responses in male and female mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. We show that food intake is regulated by the additive effect of AgRP neuron activation and POMC neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated-versus-simultaneous regulation of AgRP and POMC neurons. We identify a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus, where activated AgRP neurons and inhibited POMC neurons cooperate to promote food consumption and activate Th + neurons in the nucleus tractus solitarii. Collectively, these results unveil how food intake is precisely regulated by the simultaneous bidirectional interplay between AgRP and POMC neurocircuits.
A phenotypic screening platform for identifying chemical modulators of astrocyte reactivity
Authors: Benjamin L. L. Clayton, James D. Kristell, Kevin C. Allan, Erin F. Cohn, Molly Karl, Andrew D. Jerome, Eric Garrison, Yuka Maeno-Hikichi, Annalise M. Sturno, Alexis Kerr, H. Elizabeth Shick, Jesse A. Sepeda, Eric C. Freundt, Andrew R. Sas, Benjamin M. Segal, Robert H. Miller, Paul J. Tesar
Journal: Nature Neuroscience (2024)
Clinical surveillance systems obscure the true cholera infection burden in an endemic region
Authors: Sonia T Hegde, Ashraful Islam Khan, Javier Perez-Saez, Ishtiakul Islam Khan, Juan Dent Hulse, Md Taufiqul Islam, Zahid Hasan Khan, Shakeel Ahmed, Taner Bertuna, Mamunur Rashid, Rumana Rashid, Md Zakir Hossain, Tahmina Shirin, Kirsten E Wiens, Emily S Gurley, Taufiqur Rahman Bhuiyan, Firdausi Qadri, Andrew S Azman
Journal: Nature Medicine (2024)

Abstract Our understanding of cholera transmission and burden largely relies on clinic-based surveillance, which can obscure trends, bias burden estimates and limit the impact of targeted cholera-prevention measures. Serological surveillance provides a complementary approach to monitoring infections, although the link between serologically derived infections and medically attended disease incidence—shaped by immunological, behavioral and clinical factors—remains poorly understood. We unravel this cascade in a cholera-endemic Bangladeshi community by integrating clinic-based surveillance, healthcare-seeking and longitudinal serological data through statistical modeling. Combining the serological trajectories with a reconstructed incidence timeline of symptomatic cholera, we estimated an annual Vibrio cholerae O1 infection incidence rate of 535 per 1,000 population (95% credible interval 514–556), with incidence increasing by age group. Clinic-based surveillance alone underestimated the number of infections and reported cases were not consistently correlated with infection timing. Of the infections, 4 in 3,280 resulted in symptoms, only 1 of which was reported through the surveillance system. These results impart insights into cholera transmission dynamics and burden in the epicenter of the seventh cholera pandemic, where &gt;50% of our study population had an annual V. cholerae O1 infection, and emphasize the potential for a biased view of disease burden and infection risk when depending solely on clinical surveillance data.
Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease
Authors: Feng Xiao, Xiaoran Zhang, Sarah U. Morton, Seong Won Kim, Youfei Fan, Joshua M. Gorham, Huan Zhang, Paul J. Berkson, Neil Mazumdar, Yangpo Cao, Jian Chen, Jacob Hagen, Xujie Liu, Pingzhu Zhou, Felix Richter, Yufeng Shen, Tarsha Ward, Bruce D. Gelb, Jonathan G. Seidman, Christine E. Seidman, William T. Pu
Journal: Nature Genetics (2024)
Undetectable off-target effects induced by FokI catalytic domain in mouse embryos
Authors: Long Xie, Hu Feng, Zhifang Li, Di Li, Xiali Yang, Tanglong Yuan, Nana Yan, Chenfei He, Jitan Zheng, Zhenrui Zuo, Yaxuan Zheng, Yaqi Cao, Yangqing Lu, Xing Yao Xiong, Erwei Zuo
Journal: Genome biology (2024)

Abstract The FokI catalytic domain can be fused to various DNA binding architectures to improve the precision of genome editing tools. However, evaluation of off-target effects is essential for developing these tools. We use Genome-wide Off-target analysis by Two-cell embryo Injection (GOTI) to detect low-frequency off-target editing events in mouse embryos injected with FokI-based architectures. Specifically, we test FokI-heterodimers fused with TALENs, FokI homodimers fused with RYdCas9, or FokI catalytic domains alone resulting in no significant off-target effects. These FokI genome editing systems exhibit undetectable off-target effects in mouse embryos, supporting the further development of these systems for clinical applications.
Small-molecule-mediated control of the anti-tumour activity and off-tumour toxicity of a supramolecular bispecific T cell engager
Authors: Ningqiang Gong, Xuexiang Han, Lulu Xue, Margaret M. Billingsley, Xisha Huang, Rakan El-Mayta, Jingya Qin, Neil C. Sheppard, Carl H. June, Michael J. Mitchell
Journal: Nature Biomedical Engineering (2024)
Screening oral drugs for their interactions with the intestinal transportome via porcine tissue explants and machine learning
Authors: Yunhua Shi, Daniel Reker, James D. Byrne, Ameya R. Kirtane, Kaitlyn Hess, Zhuyi Wang, Natsuda Navamajiti, Cameron C. Young, Zachary Fralish, Zilu Zhang, Aaron Lopes, Vance Soares, Jacob Wainer, Thomas von Erlach, Lei Miao, Robert Langer, Giovanni Traverso
Journal: Nature Biomedical Engineering (2024)
Prediction, screening and characterization of novel bioactive tetrapeptide matrikines for skin rejuvenation
Authors: Nathan Jariwala, Matiss Ozols, Alexander Eckersley, Bezaleel Mambwe, Rachel E B Watson, Leo Zeef, Andrew Gilmore, Laurent Debelle, Mike Bell, Eleanor J Bradley, Yegor Doush, Amy Keenan, Carole Courage, Richard Leroux, Olivier Peschard, Philippe Mondon, Caroline Ringenbach, Laure Bernard, Aurelien Pitois, Michael J Sherratt
Journal: British Journal of Dermatology (2024)

Abstract Background Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In skin, loss of dermal collagens and disorganization of elastic fibre components are key features of photoageing. Although the application of some small matrix-derived peptides to aged skin has been shown to beneficially affect in vitro cell behaviour and, in vivo, molecular architecture and clinical appearance, the discovery of new peptides has lacked a guiding hypothesis. Objectives To identify, using protease cleavage site prediction, novel putative matrikines with beneficial activities for skin composition and structure. Methods Here, we present an in silico (peptide cleavage prediction) to in vitro (proteomic and transcriptomic activity testing in cultured human dermal fibroblasts) to in vivo (short-term patch test and longer-term split-face clinical study) discovery pipeline, which enables the identification and characterization of peptides with differential activities. Results Using this pipeline we showed that cultured fibroblasts were responsive to all applied peptides, but their associated bioactivity was sequence-dependent. Based on bioactivity, toxicity and protein source, we further characterized a combination of two novel peptides, GPKG (glycine–proline–lysine–glycine) and LSVD (leucine–serine–valine–aspartate), that acted in vitro to enhance the transcription of matrix ­organization and cell proliferation genes and in vivo (in a short-term patch test) to promote processes associated with epithelial and dermal maintenance and remodelling. Prolonged use of a formulation containing these peptides in a split-face clinical study led to significantly improved measures of crow’s feet and firmness in a mixed population. Conclusions This approach to peptide discovery and testing can identify new synthetic matrikines, providing insights into biological mechanisms of tissue homeostasis and repair and new pathways to clinical intervention.
‘Considering the reality, I am very lucky’: how professional players and staff perceive injury prevention and performance protection in women’s football
Authors: Caroline Bolling, Rita Tomás, Evert Verhagen
Journal: British Journal of Sports Medicine (2024)

Objective To explore the beliefs and perceptions of professional female footballers and staff regarding injury prevention and performance protection in professional women’s football. Methods This qualitative study applied semistructured interviews with 18 participants from 3 top-tier teams from 2 countries (Portugal and England) and 4 nationalities, including 2 physiotherapists, 5 players, 3 team doctors, 2 head coaches, 3 strength and conditioning coaches, 2 managers, and 1 head of performance. Data analysis applied constant comparison analysis, using principles of grounded theory. There were no major differences in the perspectives of players and staff, and the findings are presented together. Results Identifying and reporting injuries and recognising potential injury risk factors were mentioned to influence the prevention of injury. Participants stated that the growth and evolution of women’s football could influence injury risk. Before reaching the professional level, exposure to potential risk factors, such as lack of recovery, limited awareness and opportunities for prevention (eg, preventive exercises and load management strategies), was believed to impact players’ injury risk. Players further described their experiences and the ‘bumpy road’ to becoming a professional player, their current context and potential future improvements for women’s football regarding injury prevention and performance protection. Conclusion Professional female football players face different injury risks during different moments of their careers. According to elite players and staff, amateur and semiprofessionals have limited resources and lack injury prevention strategies. Professional players and staff perceived the current preventive measures as good and relied on the value of individualised care and a multidisciplinary approach. In the future, more resources and structured injury prevention strategies are needed in youth and non-professional levels of women’s football to reduce injury risk and allow more players to reach their maximal performance.
Reshaping the tumor microenvironment of cold soft-tissue sarcomas with oncolytic viral therapy: a phase 2 trial of intratumoral JX-594 combined with avelumab and low-dose cyclophosphamide
Authors: Maud Toulmonde, Jean-Philippe Guegan, Mariella Spalato-Ceruso, Florent Peyraud, Michèle Kind, Lucile Vanhersecke, François Le Loarer, Raul Perret, Coralie Cantarel, Carine Bellera, Alban Bessede, Antoine Italiano
Journal: Molecular Cancer (2024)

Abstract Most soft-tissue sarcomas (STS) exhibit an immunosuppressive tumor microenvironment (TME), leading to resistance against immune checkpoint inhibitors (ICIs) and limited therapeutic response. Preclinical data suggest that oncolytic viral therapy can remodel the TME, facilitating T cell accumulation and enhancing the immunogenicity of these tumors. We conducted the METROMAJX, a phase II clinical trial, to investigate the combination of JX-594, an oncolytic vaccinia virus engineered for selective tumor cell replication, with metronomic cyclophosphamide and the PD-L1 inhibitor avelumab in patients with advanced, ‘cold’ STS, characterized by an absence of tertiary lymphoid structures. The trial employed a two-stage Simon design. JX-594 was administered intratumorally at a dose of 1.10 9 pfu every 2 weeks for up to 4 intra-tumoral administrations. Cyclophosphamide was given orally at 50 mg twice daily in a week-on, week-off schedule, and avelumab was administered at 10 mg/kg biweekly. The primary endpoint was the 6-month non-progression rate. Fifteen patients were enrolled, with the most frequent toxicities being grade 1 fatigue and fever. Fourteen patients were assessable for efficacy analysis. At 6 months, only one patient remained progression-free, indicating that the trial did not meet the first stage endpoint of Simon’s design. Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10. Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.
Glioblastoma patients’ survival and its relevant risk factors during the pre- and post-COVID-19 pandemic: Real-world cohort study in the USA and China
Authors: Ling Qin, Haoyi Li, Dao Zheng, Song Lin, Xiaohui Ren
Journal: International Journal of Surgery (2024)

Background: Although the coronavirus disease 2019 (COVID-19) pandemic has exerted potential impact on patients with glioblastomas (GBMs), it remains unclear whether the survival and its related risk factors of GBM patients would be altered or not during the period spanning from pre- to post- COVID-19 pandemic era. This study aimed to clarify the important issues above. Methods: Two observational cohorts were utilized, including the nationwide American cohort from the Surveillance, Epidemiology, and End-Results (SEER) and the Chinese glioblastoma cohort (CGC) at our institution during 2018-2020. Demographics, tumor features, treatment regimens and clinical outcomes were collected. Cox regression model, competing risk model, and subgroup and sensitivity analysis were used to dynamically estimate the survival and its relevant risk factors over different diagnosis years from the pre- (2018 and 2019) to post-COVID-19 (2020) pandemic. Causal mediation analysis was further adopted to explore the potential relationship between risk factors and mortality. Results: This study included 11321 GBM cases in SEER and 226 GBM patients in CGC, respectively. Instead of the diagnostic years of 2018-2020, the prognostic risk factors, such as advanced age, bilateral tumor and absence of comprehensive therapy (surgery combined with chemoradiotherapy), were identified to persistently affect GBM survival independently during the period from 2018 to 2020 in the SEER cohort (all P &lt; 0.05). In CGC, lack of comprehensive therapy for GBM patients were restated as survival risk factors during the same timeframe. Causal mediation analysis showed that the effect of comprehensive therapy on all-cause mortality played a determinant role (direct effect value -0.227, 95% confidence interval -0.248 to -0.207), which was partially mediated by age (9.11%) rather than tumor laterality. Conclusions: As the timeframe shifted from pre- to post-COVID-19 pandemic, survival of GBM patients remained stable, yet advanced age, bilateral tumors, and passive treatment continuingly impacted GBM survival. It is necessary to optimize the comprehensive treatment for GBM patients even in the post-pandemic era.
Degeneration of the Olfactory System in a Murid Rodent that Evolved Diurnalism
Authors: Ben-Yang Liao, Meng-Pin Weng, Ting-Yan Chang, Andrew Ying-Fei Chang, Yung-Hao Ching, Chia-Hwa Wu
Journal: Molecular Biology and Evolution (2024)

Abstract In mammalian research, it has been debated what can initiate an evolutionary tradeoff between different senses, and the phenomenon of sensory tradeoff in rodents, the most abundant mammalian clade, is not evident. The Nile rat (Arvicanthis niloticus), a murid rodent, recently adapted to a diurnal niche through an evolutionary acquisition of daylight vision with enhanced visual acuity. As such, this model provides an opportunity for a cross-species investigation where comparative morphological and multi-omic analyses of the Nile rat are made with its closely related nocturnal species, e.g. the mouse (Mus musculus) and the rat (Rattus norvegicus). Thus, morphological examinations were performed, and evolutionary reductions in relative sizes of turbinal bone surfaces, the cribriform plate, and the olfactory bulb were discovered in Nile rats. Subsequently, we compared multiple murid genomes, and profiled olfactory epithelium transcriptomes of mice and Nile rats at various ages with RNA sequencing. The results further demonstrate that, in comparison with mouse olfactory receptor (OR) genes, Nile rat OR genes have experienced less frequent gain, more frequent loss, and more frequent expression reduction during their evolution. Furthermore, functional degeneration of coding sequences in the Nile rat lineage was found in OR genes, yet not in other genes. Taken together, these results suggest that acquisition of improved vision in the Nile rat has been accompanied by degeneration of both olfaction-related anatomical structures and OR gene repertoires, consistent with the hypothesis of an olfaction-vision tradeoff initiated by the switch from a nocturnal to a diurnal lifestyle in mammals.
Early Metformin Treatment for Gestational Diabetes
Authors: Yeojin Park, Na Eun Kim, Soo-Jeong Lee
Journal: JAMA (2024)

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