tbuckley/cabot-search huggingface dataset:
Less, but more: new insights from appendicularians on chordate <i>Fgf</i> evolution and the divergence of tunicate lifestyles
Authors: Gaspar Sánchez-Serna, Jordi Badia-Ramentol, Paula Bujosa, Alfonso Ferrández-Roldán, Nuria P Torres-Águila, Marc Fabregà-Torrus, Johannes N Wibisana, Michael J Mansfield, Charles Plessy, Nicholas M Luscombe, Ricard Albalat, Cristian Cañestro
Journal: Molecular Biology and Evolution (2024)

The impact of gene loss on the diversification of taxa and the emergence of evolutionary innovations remains poorly understood. Here, our investigation on the evolution of the Fibroblast Growth Factors (FGFs) in appendicularian tunicates as a case study reveals a scenario of "less, but more" characterized by massive losses of all Fgf gene subfamilies, except for the Fgf9/16/20 and Fgf11/12/13/14, which in turn underwent two bursts of duplications. Through phylogenetic analysis, synteny conservation, and gene and protein structure, we reconstruct the history of appendicularian Fgf genes, highlighting their paracrine and intracellular functions. An exhaustive analysis of developmental Fgf expression in Oikopleura dioica allows us to identify four associated evolutionary patterns characterizing the "less, but more" conceptual framework: conservation of ancestral functions; function shuffling between paralogs linked to gene losses; innovation of new functions after the duplication bursts; and function extinctions linked to gene losses. Our findings allow us to formulate novel hypotheses about the impact of Fgf losses and duplications on the transition from an ancestral ascidian-like biphasic lifestyle to the fully free-living appendicularians. These hypotheses include massive co-options of Fgfs for the development of the oikoblast and the tail fin; recruitment of Fgf11/12/13/14s into the evolution of a new mouth, and their role modulating neuronal excitability; the evolutionary innovation of an anterior tail FGF signaling source upon the loss of retinoic acid signaling; and the potential link between the loss of Fgf7/10/22 and Fgf8/17/18 and the loss of drastic metamorphosis and tail absorption in appendicularians, in contrast to ascidians.
Asymmetrical evolution of promoter methylation of mammalian genes after duplication
Authors: Mercedes de la Fuente, Isabel Mendizabal, Mira Han, Soojin V Yi, David Alvarez-Ponce
Journal: Molecular Biology and Evolution (2024)

Even though gene duplication is a key source of new genes and evolutionary innovation, it is unclear how duplicates survive the period immediately following gene duplication, in which both copies are functionally redundant. In the absence of epigenetic silencing, the abundance of the gene product would double after gene duplication, which would often have deleterious effects. However, recent duplicates exhibit low expression levels, which could be at least partially explained by high levels of promoter methylation. What evolutionary paths lead to duplicate hypermethylation, and does it affect both duplicates, or only one? Here, we compare levels of promoter methylation in 10 human and 16 mouse tissues, between singletons and duplicates and among human-mouse orthologs of different kinds (one-to-one, one-to-many, many-to-one, and many-to-many). Our results indicate that: (1) on average, duplicates are more methylated than singletons in mouse, but less methylated than singletons in human, (2) recently duplicated genes tend to exhibit high levels of promoter methylation, (3) genes that undergo duplication tend to be highly methylated before duplication, (4) after gene duplication, one of the copies (the daughter copy, i.e. the one that relocates to a new genomic context) tends to undergo an additional increase in promoter methylation, whereas the other (the parental copy, which remains in the original genomic location) tends to retain pre-duplication methylation levels, and (5) daughter copies tend to be lowly expressed. These observations support a model in which daughter copies are repressed via promoter hypermethylation and can thus survive the filter of purifying selection until both copies diverge functionally.
An Acellular, Self‐Healed Trilayer Cryogel for Osteochondral Regeneration in Rabbits (Adv. Healthcare Mater. 31/2024)
Authors: Tsai‐Yu Chen, Niann‐Tzyy Dai, Tsung‐Kai Wen, Shan‐hui Hsu
Journal: Advanced Healthcare Materials (2024)
Dual‐Functional Nanodroplet for Tumor Vasculature Ultrasound Imaging and Tumor Immunosuppressive Microenvironment Remodeling (Adv. Healthcare Mater. 31/2024)
Authors: Yuan Liang, Siyan Zhang, Dingyi Wang, Panpan Ji, Bin Zhang, Pengying Wu, Lantian Wang, Zhaoyou Liu, Jia Wang, Yunyou Duan, Lijun Yuan
Journal: Advanced Healthcare Materials (2024)
Extracellular Vesicle‐Inspired Minimalist Flexible Nanocapsules Assembled with Whole Active Ingredients for Highly Efficient Enhancement of DC‐Mediated Tumor Immunotherapy (Adv. Healthcare Mater. 31/2024)
Authors: Ao He, Qiang Li, Meng Dang, Wei Lu, Xiaoye Li, Zhuo Dai, Meng Ding, Yu Zhang, Heng Dong, Zhaogang Teng, Yongbin Mou
Journal: Advanced Healthcare Materials (2024)
The 2024 generation
Authors: Shruthy Suresh Aggarwal, Cristina Andreani, Zihou Deng, Julia Frede, Polina Kameneva, Marta Kovatcheva, Goran Micevic, Fay Nicolson, Jens Puschhof, Morgan Roberts, Gang Wang, Dionysios C. Watson
Journal: Nature Cancer (2024)
Project ECHO Diabetes Trial Improves Outcomes for Medically Underserved People
Authors: Ashby F. Walker, Michael J. Haller, Ananta Addala, Stephanie L. Filipp, Rayhan A. Lal, Matthew J. Gurka, Lauren E. Figg, Melanie Hechavarria, Dessi P. Zaharieva, Keilecia G. Malden, Korey K. Hood, Sarah C. Westen, Jessie J. Wong, William T. Donahoo, Marina Basina, Angelina V. Bernier, David M. Maahs
Journal: Diabetes Care (2024)

OBJECTIVE The Project Extension for Community Healthcare Outcomes (ECHO) model is used in 180 countries to address chronic disease care through a provider empowerment, tele-education approach. Few studies have rigorously evaluated the impact of the program on patient outcomes using randomized designs. RESEARCH DESIGN AND METHODS Implementation of an ECHO Diabetes program was evaluated using a stepped-wedge design with recruitment of 20 federally qualified health centers (FQHCs) across California and Florida with randomized, phased-in intervention entry. Participating FQHCs (referred to as “spokes”) provided aggregate data, including the Healthcare Effectiveness Data and Information Set (HEDIS) and diabetes technology use. Patients were recruited from spokes, and data collection involved historical and prospective HbA1c measures, HEDIS markers, and pre/post surveys. Linear mixed models were used to generate patient-level monthly HbA1c estimates and evaluate change over time; Poisson regression was used to model clinic-level technology use. RESULTS The spoke-level cohort included 32,796 people with type 1 diabetes (T1D; 3.4%) and type 2 diabetes (T2D; 96.6%), of whom 72.7% were publicly insured or uninsured. The patient-level cohort included 582 adults with diabetes (33.0% with T1D, 67.0% with T2D). Their mean age was 51.1 years, 80.7% were publicly insured or uninsured, 43.7% were non-Hispanic White, 31.6% were Hispanic, 7.9% were non-Hispanic Black, and 16.8% were in other race/ethnicity categories. At the spoke level, there were statistically significant reductions before and after the intervention in the proportion of people with HbA1c &amp;gt;9% (range 31.7% to 26.7%; P = 0.033). At the patient level, there were statistically significant increases in those using continuous glucose monitoring (range 25.1% to 36.8%; P &amp;lt; 0.0001) and pump use (range 15.3% to 18.3%; P &amp;lt; 0.001) before and after the intervention. CONCLUSIONS The ECHO model demonstrates promise for reducing health disparities in diabetes and contributes to our understanding of program benefits beyond the provider level.
Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer
Authors: Yuri Kim, Seong Won Kim, David Saul, Meraj Neyazi, Manuel Schmid, Hiroko Wakimoto, Neil Slaven, Joshua H. Lee, Olivia G. Layton, Lauren K. Wasson, Justin H. Letendre, Feng Xiao, Jourdan K. Ewoldt, Konstantinos Gkatzis, Peter Sommer, Bénédicte Gobert, Nicolas Wiest-Daesslé, Quentin McAfee, Nandita Singhal, Mingyue Lun, Joshua M. Gorham, Zoltan Arany, Arun Sharma, Christopher N. Toepfer, Gavin Y. Oudit, William T. Pu, Diane E. Dickel, Len A. Pennacchio, Axel Visel, Christopher S. Chen, J.G. Seidman, Christine E. Seidman
Journal: Journal of Clinical Investigation (2024)

Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated TTN expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted NKX2-5- and MEF2-binding sites within E1 abolished its transcriptional activity. Embryonic mice expressing E1 reporter gene constructs validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5 and MEF2 binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2 binding motif that was identified in a patient with unexplained DCM showed reduced TTN expression. Together these discoveries define an essential, functional enhancer that regulates TTN expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by TTN haploinsufficiency.
Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice
Authors: Michaela A.A. Fuchs, Alexander Grabner, Melody Shi, Susan L. Murray, Emily J. Burke, Nejla Latic, Venkataramana Thiriveedi, Jatin Roper, Shintaro Ide, Koki Abe, Hiroki Kitai, Tomokazu Souma, Myles Wolf
Journal: Journal of Clinical Investigation (2024)

Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects. Here, we describe the responses of mice with inducible global deletion, kidney-specific, and intestine-specific deletion of Cyp24a1 to dietary calcium challenge and chronic kidney disease (CKD). Global and kidney-specific Cyp24a1 deletion caused similar syndromes of systemic vitamin D intoxication: elevated circulating 1,25D, 25D and fibroblast growth factor 23 (FGF23), activation of vitamin D target genes in the kidney and intestine, hypercalcemia, and suppressed parathyroid hormone (PTH). In contrast, mice with intestine-specific Cyp24a1 deletion demonstrated activation of vitamin D target genes exclusively in the intestine despite no changes in systemic vitamin D levels. In response to a high calcium diet, PTH was suppressed despite normal serum calcium. In mice with CKD, intestinal Cyp24a1 deletion decreased PTH and FGF23 without precipitating hypercalcemia. These results implicate kidney CYP24A1 in systemic vitamin D regulation while independent local effects of intestinal CYP24A1 could be targeted to treat secondary hyperparathyroidism in CKD.
Long COVID is associated with lower percentages of mature, cytotoxic NK cell phenotypes
Authors: Tasha Tsao, Amanda M. Buck, Lilian Grimbert, Brian H. LaFranchi, Belen Altamirano Poblano, Emily A. Fehrman, Thomas Dalhuisen, Priscilla Y. Hsue, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Peter W. Hunt, Michael J. Peluso, Oscar A. Aguilar, Timothy J. Henrich
Journal: Journal of Clinical Investigation (2024)
PINK1 is a target of T cell responses in Parkinson's disease
Authors: Gregory P. Williams, Antoine Freuchet, Tanner Michaelis, April Frazier, Ngan K. Tran, João Rodrigues Lima-Junior, Elizabeth J. Phillips, Simon A. Mallal, Irene Litvan, Jennifer G. Goldman, Roy N. Alcalay, John Sidney, David Sulzer, Alessandro Sette, Cecilia S. Lindestam Arlehamn
Journal: Journal of Clinical Investigation (2024)

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. While there is no curative treatment, the immune system's involvement with autoimmune T cells that recognize the protein alpha-synuclein (α-syn) in a subset of individuals suggests new areas for therapeutic strategies. As not all patients with PD have T cells specific for α-syn, we explored additional autoantigenic targets of T cells in PD. We generated 15-mer peptides spanning several PD-related proteins implicated in PD pathology, including Glucosylceramidase Beta 1 (GBA), Superoxide dismutase 1 (SOD1), PTEN Induced Kinase 1 (PINK1), Parkin RBR E3 Ubiquitin Protein Ligase (parkin), Oxoglutarate Dehydrogenase (OGDH), and Leucine Rich Repeat Kinase 2 (LRRK2). Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. We identified PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells, as well as its unique epitopes, and their HLA restriction. The PINK1-specific T cell reactivity revealed sex-based differences as it was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.
NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis
Authors: Jingjing Liang, Ning Wang, Yihan Yao, Yingmei Wang, Xiang An, Haofei Wang, Huan Liu, Yu Jiang, Hui Li, Xiaoqing Cheng, Jiaqi Xu, Xiaojing Liang, Jun Lou, Zengfeng Xin, Ting Zhang, Xiaojian Wang, Wenlong Lin
Journal: Journal of Clinical Investigation (2024)

Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to inflammatory bowel diseases and even colorectal cancer (CRC). Loss or gain of function of many key proteins can result in dysregulated intestinal homeostasis. Our research demonstrated that neural precursor cells expressed developmentally downregulated 4-like protein (NEDD4L, or NEDD4-2), a type of HECT family E3 ubiquitin ligase, played an important role in maintaining intestinal homeostasis. NEDD4L expression was significantly inhibited in intestinal epithelial cells (IECs) of patients with Crohn's disease, ulcerative colitis, and CRC. Global KO of NEDD4L or its deficiency in IECs exacerbated colitis induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) and CRC induced by azoxymethane and DSS. Mechanistically, NEDD4L deficiency in IECs inhibited expression of the key ferroptosis regulator glutathione peroxidase 4 (GPX4) by reducing the protein expression of solute carrier family 3 member 2 (SLC3A2) without affecting its gene expression, ultimately promoting DSS-induced IEC ferroptosis. Importantly, ferroptosis inhibitors reduced the susceptibility of NEDD4L-deficient mice to colitis and colitis-associated CRC. Thus, NEDD4L is an important regulator in IEC ferroptosis, maintaining intestinal homeostasis, making it a potential clinical target for diagnosing and treating IBDs.
Drinking pattern and time lag of alcohol consumption with colorectal cancer risk in US men and women
Authors: Xinyi Li, Jinhee Hur, Yin Zhang, Mingyang Song, Stephanie A Smith-Warner, Liming Liang, Kenneth J Mukamal, Eric B Rimm, Edward L Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Association between light to moderate alcohol consumption and colorectal cancer (CRC) incidence remains understudied, especially regarding drinking pattern, beverage type and temporal aspects. Methods Hazard ratios (HRs) and 95% confidence intervals (CIs) for time to CRC diagnosis were estimated among 137,710 participants. Estimates based on remote (eg, &amp;gt;10 years before follow-up) and recent (eg, the preceding 10 years before follow-up) alcohol intake, using different cutoffs (eg, 8, 10, 12 years, etc) and mutual adjustment, enabled separating independent effects and investigating time lag of alcohol-CRC association. Results 3,599 CRC cases were documented over three decades. Light to moderate drinking was associated with an increased CRC risk only in men: HR (95% CI) for 5-14.9 and 15-29.9 vs 0 g/day of alcohol intake was 1.19 (1.01, 1.41) and 1.38 (1.13, 1.67). In women, that for 0.1-4.9 and 5-14.9 vs 0 g/day of alcohol was 1.07 (0.96, 1.20) and 1.05 (0.91, 1.20). Drinkers with both high drinking frequency and daily intake had the highest CRC risk, suggesting total alcohol intake was the critical factor. We estimated the time lag between alcohol consumption and CRC occurrence to be 8 to 12 years. Former drinkers did not experience a significant reduction in CRC risk even after 10 years of quitting or reducing consumption. Conclusions Based on two cohorts of health professionals, our findings suggest that the increased risk of CRC associated with alcohol intake is mainly driven by total quantity and remote intake. Former drinkers did not experience an immediate reduction in CRC risk after quitting or reducing consumption.
2024 ACC Expert Consensus Decision Pathway on Practical Approaches for Arrhythmia Monitoring After Stroke
Authors: Michael T. Spooner, Steven R. Messé, Seemant Chaturvedi, Monika M. Do, Ty J. Gluckman, Janet K. Han, Andrea M. Russo, Sherry J. Saxonhouse, Newton B. Wiggins
Journal: Journal of the American College of Cardiology (2024)
T-cell diversity and exclusion of blood-derived T-cells in the tumor microenvironment of classical Hodgkin Lymphoma
Authors: Nicole Seifert, Sarah Reinke, Johanna Grund, Berit Müller-Meinhard, Julia Richter, Thorsten Heilmann, Hans Schlößer, Michaela Kotrova, Monika Brüggemann, Peter Borchmann, Paul J. Bröckelmann, Michael Altenbuchinger, Wolfram Klapper
Journal: Leukemia (2024)

Abstract The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant immune cells and only few neoplastic Hodgkin and Reed-Sternberg cells (HRSC). We analyzed the T-cell receptor (TCR) repertoire to detect T-cell expansion in the TME and blood. In contrast to solid cancer tissue, T-cells in the TME of HL are highly polyclonal at first diagnosis and show only minor clonal expansion during anti-PD1 immune checkpoint blockade (ICB). At relapse and during ICB, pre-amplified T-cell populations increase in the TME of solid cancers but to a much lesser extent in HL. In contrast, T-cell populations in the peripheral blood of HL patients display higher clonality than healthy controls reaching clonality levels comparable to solid cancer. However, pre-amplified blood T-cells in HL patients show only minor additional clonal expansion during ICB. Moreover, blood-derived T-cells do not repopulate the TME of HL to the same extent as observed in solid cancers. Thus, the T-cell repertoire in the TME of HL appears unique by a relatively low clonal T-cell content and the exclusion of clonally expanded T-cells from the peripheral blood. Exclusion of clonally expanded tumor-specific T-cells from the TME may present a novel mechanism of immune evasion in HL.
Diagnostic accuracy of 2D-SWE ultrasound for liver fibrosis assessment in MASLD: A multi-level random effects model meta-analysis
Authors: Madalina-Gabriela Taru, Dan-Corneliu Leucuta, Monica Lupsor-Platon, Laura Turco, Silvia Ferri, Ahmed Hashim, Olga Hilda Orasan, Bogdan Procopet, Horia Stefanescu, Maria Cristina Morelli, Fabio Piscaglia, Federico Ravaioli
Journal: Hepatology (2024)

Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes significant healthcare burdens. Early detection of advanced fibrosis and cirrhosis in MASLD is essential due to their unfavourable outcomes. This multi-level random-effects meta-analysis aimed to provide the best evidence for the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE) in detecting liver fibrosis in biopsy-proven MASLD.
Letter to the editor: The race against time in genetic testing for PALF
Authors: Fernanda Monge Urrea, Joseph Valamparampil, Robert Hegarty
Journal: Hepatology (2024)

1Paediatric Liver, GI and Nutrition Centre, King´s College Hospital 2Liver Unit, Birmingham Women´s and Children´s Hospital Correspondence Robert Hegarty, King's College Hospital. Email: [email protected]
Allogeneic umbilical cord-derived mesenchymal stromal cells as treatment for systemic lupus erythematosus: a single-centre, open-label, dose-escalation, phase 1 study
Authors: Dominique Farge, Lucie Biard, Ben Weil, Virginie Girault, Pauline Lansiaux, Ingrid Munia, Séverine Loisel, Catney Charles, Judikael Saout, Matthieu Resche-Rigon, Anne Sophie Korganow, Clément Beuvon, Grégory Pugnet, Carlotta Cacciatore, Noémie Abisror, Jean Luc Taupin, Audrey Cras, Mark W Lowdell, Karin Tarte
Journal: The Lancet Rheumatology (2024)
Prevalence, management, health-care burden, and 90-day outcomes of prolonged mechanical ventilation in the paediatric intensive care unit (LongVentKids): an international, prospective, cross-sectional cohort study
Authors: Atsushi Kawaguchi, Analia Fernandez, Florent Baudin, Fabrizio Chiusolo, Jan H Lee, Joe Brierley, José Colleti, Karl Reiter, Kyung Won Kim, Yolanda Lopez Fernandez, Martin Kneyber, Marti Pons-Òdena, Natalie Napolitano, Robert J Graham, Tatsuya Kawasaki, Daniel Garros, Gonzalo Garcia Guerra, Philippe Jouvet
Journal: The Lancet Child & Adolescent Health (2024)
Revolutionizing treatment for disorders of consciousness: a multidisciplinary review of advancements in deep brain stimulation
Authors: Yi Yang, Tian-Qing Cao, Sheng-Hong He, Lu-Chen Wang, Qi-Heng He, Ling-Zhong Fan, Yong-Zhi Huang, Hao-Ran Zhang, Yong Wang, Yuan-Yuan Dang, Nan Wang, Xiao-Ke Chai, Dong Wang, Qiu-Hua Jiang, Xiao-Li Li, Chen Liu, Shou-Yan Wang
Journal: Military Medical Research (2024)

Abstract Among the existing research on the treatment of disorders of consciousness (DOC), deep brain stimulation (DBS) offers a highly promising therapeutic approach. This comprehensive review documents the historical development of DBS and its role in the treatment of DOC, tracing its progression from an experimental therapy to a detailed modulation approach based on the mesocircuit model hypothesis. The mesocircuit model hypothesis suggests that DOC arises from disruptions in a critical network of brain regions, providing a framework for refining DBS targets. We also discuss the multimodal approaches for assessing patients with DOC, encompassing clinical behavioral scales, electrophysiological assessment, and neuroimaging techniques methods. During the evolution of DOC therapy, the segmentation of central nuclei, the recording of single-neurons, and the analysis of local field potentials have emerged as favorable technical factors that enhance the efficacy of DBS treatment. Advances in computational models have also facilitated a deeper exploration of the neural dynamics associated with DOC, linking neuron-level dynamics with macroscopic behavioral changes. Despite showing promising outcomes, challenges remain in patient selection, precise target localization, and the determination of optimal stimulation parameters. Future research should focus on conducting large-scale controlled studies to delve into the pathophysiological mechanisms of DOC. It is imperative to further elucidate the precise modulatory effects of DBS on thalamo-cortical and cortico-cortical functional connectivity networks. Ultimately, by optimizing neuromodulation strategies, we aim to substantially enhance therapeutic outcomes and greatly expedite the process of consciousness recovery in patients.