tbuckley/cabot-search huggingface dataset:
Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial
Authors: Johannes F. E. Mann, Peter Rossing, George Bakris, Nicolas Belmar, Heidrun Bosch-Traberg, Robert Busch, David M. Charytan, Samy Hadjadj, Pieter Gillard, José Luis Górriz, Thomas Idorn, Linong Ji, Kenneth W. Mahaffey, Vlado Perkovic, Søren Rasmussen, Roland E. Schmieder, Richard E. Pratley, Katherine R. Tuttle
Journal: Nature Medicine (2024)

Abstract People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use ( N = 550) or no use ( N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death or CV death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide versus placebo (95% confidence interval: 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (hazard ratio 1.07; 95% confidence interval: 0.69, 1.67; P = 0.755) and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (hazard ratio 0.73; 0.63, 0.85; P &lt; 0.001; P interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total estimated glomerular filtration rate slope (ml min −1 /1.73 m 2 /year) were 0.75 (−0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in the non-SGLT2i subgroup, P interaction 0.237. Semaglutide benefits on major CV events and all-cause death were similar regardless of SGLT2i use ( P interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 .
Ionizable nanoemulsions for RNA delivery into the central nervous system – importance of diffusivity
Authors: Mireya L Borrajo, Aloia Quijano, Philipp Lapuhs, Ana I Rodriguez-Perez, Shubaash Anthiya, José L Labandeira-Garcia, Rita Valenzuela, María José Alonso
Journal: Journal of Controlled Release (2024)

Lipid nanoparticles (LNPs) currently dominate the RNA delivery landscape; however their limited diffusivity hampers targeted tissue dissemination, and, hence, their capacity for intracellular drug delivery. This is especially relevant for tissues such as the central nervous system (CNS), where overcoming proactive brain barriers is crucial for the efficacy of genetic therapeutics. This research aimed to create ionizable nanoemulsions (iNEs), a new generation of RNA delivery systems with enhanced diffusivity. The developed iNEs (consisting of the combination of C12-200, DOPE, Vitamin E, and DMG-PEG) with a size below 100 nm, neutral surface charge, and high RNA loading capacity, showed excellent cell viability and transfection efficiency in various cellular models, including neurons, astrocytes, and microglia. Subsequently, iNEs containing mRNA GFP were tested for CNS transfection, highlighting their exceptional diffusivity and selective transfection of neurons following intra-parenchymal administration.
GenBase: A Nucleotide Sequence Database
Authors: Congfan Bu, Xinchang Zheng, Xuetong Zhao, Tianyi Xu, Xue Bai, Yaokai Jia, Meili Chen, Lili Hao, Jingfa Xiao, Zhang Zhang, Wenming Zhao, Bixia Tang, Yiming Bao
Journal: Genomics Proteomics & Bioinformatics (2024)

The rapid advancement of sequencing technologies poses challenges in managing the large volume and exponential growth of sequence data efficiently and on time. To address this issue, we present GenBase (https://ngdc.cncb.ac.cn/genbase), an open-access data repository that follows the International Nucleotide Sequence Database Collaboration (INSDC) data standards and structures, for efficient nucleotide sequence archiving, searching, and sharing. As a core resource within the National Genomics Data Center (NGDC) of the China National Center for Bioinformation (CNCB; https://ngdc.cncb.ac.cn), GenBase offers bilingual submission pipeline and services, as well as local submission assistance in China. GenBase also provides a unique Excel format for metadata description and feature annotation of nucleotide sequences, along with a real-time data validation system to streamline sequence submissions. As of April 23, 2024, GenBase received 68,251 nucleotide sequences and 689,574 annotated protein sequences across 414 species from 2319 submissions. Out of these, 63,614 (93%) nucleotide sequences and 620,640 (90%) annotated protein sequences have been released and are publicly accessible through GenBase's web search system, File Transfer Protocol (FTP), and Application Programming Interface (API). Additionally, in collaboration with INSDC, GenBase has constructed an effective data exchange mechanism with GenBank and started sharing released nucleotide sequences. Furthermore, GenBase integrates all sequences from GenBank with daily updates, demonstrating its commitment to actively contributing to global sequence data management and sharing.
Endogenous retroviruses in multiple sclerosis: A network-based etiopathogenic model
Authors: Stefano T. Censi, Renato Mariani-Costantini, Alberto Granzotto, Valentina Tomassini, Stefano L. Sensi
Journal: Ageing Research Reviews (2024)

The present perspective article proposes an etiopathological model for multiple sclerosis pathogenesis and progression associated with the activation of human endogenous retroviruses. We reviewed preclinical, clinical, epidemiological, and evolutionary evidence indicating how the complex, multi-level interplay of genetic traits and environmental factors contributes to multiple sclerosis. We propose that in this process, endogenous retroviruses transactivation acts as a critical node in disease development. We also discuss the rationale for combined anti-retroviral therapy in multiple sclerosis as a disease-modifying therapeutic strategy. Finally, we propose that the immuno-pathogenic process triggered by endogenous retrovirus activation can be extended to aging and aging-related neurodegeneration. In this regard, endogenous retroviruses can be envisioned to act as epigenetic noise, favoring the proliferation of disorganized cellular subpopulations and accelerating system-specific "aging". Since inflammation and aging are two sides of the same coin (plastic dis-adaptation to external stimuli with system-specific degree of freedom), the two conditions may be epiphenomenal products of increased epigenomic entropy. Inflammation accelerates organ-specific aging, disrupting communication throughout critical systems of the body and producing symptoms. Overlapping neurological symptoms and syndromes may emerge from the activity of shared molecular networks that respond to endogenous retroviruses' reactivation.
Is exposure to pesticides associated with biological aging? A systematic review and meta-analysis
Authors: Shanshan Zuo, Vidhya Sasitharan, Gian Luca Di Tanna, Judith M. Vonk, Maaike De Vries, Moustafa Sherif, Balázs Ádám, Juan Carlos Rivillas, Valentina Gallo
Journal: Ageing Research Reviews (2024)

Exposure to pesticides is a risk factor for various diseases, yet its association with biological aging remains unclear. We aimed to systematically investigate the relationship between pesticide exposure and biological aging. PubMed, Embase and Web of Science were searched from inception to August 2023. Observational studies investigating the association between pesticide exposure and biomarkers of biological aging were included. Three-level random-effect meta-analysis was used to synthesize the data. Risk of bias was assessed by the Newcastle-Ottawa Scale. Twenty studies evaluating the associations between pesticide exposure and biomarkers of biological aging in 10,368 individuals were included. Sixteen reported telomere length and four reported epigenetic clocks. Meta-analysis showed no statistically significant associations between pesticide exposure and the Hannum clock (pooled β = 0.27; 95%CI: -0.25, 0.79), or telomere length (pooled Hedges'g = -0.46; 95%CI: -1.10, 0.19). However, the opposite direction of effect for the two outcomes showed an indication of possible accelerated biological aging. After removal of influential effect sizes or low-quality studies, shorter telomere length was found in higher-exposed populations. The existing evidence for associations between pesticide exposure and biological aging is limited due to the scarcity of studies on epigenetic clocks and the substantial heterogeneity across studies examining telomere length. High-quality studies incorporating more biomarkers of biological aging, focusing more on active chemical ingredients of pesticides and accounting for potential confounders are needed to enhance our understanding of the impact of pesticides on biological aging.
Acute kidney injury in Staphylococcus aureus bacteraemia: a recurrent events analysis
Authors: David T.P. Buis, Thomas W. van der Vaart, Asna Mohan, Jan M. Prins, Jan T.M. van der Meer, Marc J.M. Bonten, Lily Jakulj, Cornelis H. van Werkhoven, Kim C.E. Sigaloff
Journal: Clinical Microbiology and Infection (2024)

ObjectivesTo estimate risk factors for AKI and the effect of AKI on mortality in Staphylococcus aureus bacteremia, while taking into account recurrent AKI episodes, competing risks, time-varying variables and time-varying effects.MethodsWe performed an unplanned analysis using data from a multicenter cohort study of patients with SAB. Primary outcome was cumulative incidence of AKI, according to KDIGO definitions.ResultsWe included 453 patients in this study of whom 194 (43%) patients experienced one or more AKI episodes. Age (HR 1.013, 95% CI 1.001 – 1.024), Charlson comorbidity index (HR 1.07, 95% CI 1.01 - 1.14), prior chronic kidney disease (HR 1.76, 95% CI 1.28 – 2.42), septic shock (HR 3.28, 95% CI 2.31 – 4.66), persistent bacteremia (HR 1.53, 95% CI 1.08 – 2.17) and vancomycin therapy (HR 1.80, 95% CI 1.05 – 3.09) were independently associated with AKI, but flucloxacillin, cefazolin, rifampicin and aminoglycoside therapy were not. After adjustment for confounders and immortal time bias, AKI was associated with an increased risk of 90-day mortality (HR 4.26, 95% CI 2.91 – 6.23).ConclusionsIncidence of AKI in SAB is high and a substantial proportion of patients develops recurrent episodes of AKI after recovery. AKI is specifically linked to the use of vancomycin and not to anti-staphylococcal penicillins. Clinical outcome of patients with SAB complicated by AKI is worse than previously estimated.
Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development
Authors: Weidong Liu, Yuhua Wang, Shuxin Yao, Guoqiang Han, Jin Hu, Rong Yin, Fuling Zhou, Ying Cheng, Haojian Zhang
Journal: Genomics Proteomics & Bioinformatics (2024)

Abstract Hematopoietic homeostasis is maintained by hematopoietic stem cells (HSCs), and it is tightly controlled at multiple levels to sustain the self-renewal capacity and differentiation potential of HSCs. Dysregulation of self-renewal and differentiation of HSCs leads to the development of hematologic diseases, including acute myeloid leukemia (AML). Thus, understanding the underlying mechanisms of HSC maintenance and the development of hematologic malignancies is one of the fundamental scientific endeavors in stem cell biology. N 6-methyladenosine (m6A) is a common modification in mammalian messenger RNAs (mRNAs) and plays important roles in various biological processes. In this study, we performed a comparative analysis of the dynamics of the RNA m6A methylome of hematopoietic stem and progenitor cells (HSPCs) and leukemia-initiating cells (LICs) in AML. We found that RNA m6A modification regulates the transformation of long-term HSCs into short-term HSCs and determines the lineage commitment of HSCs. Interestingly, m6A modification leads to reprogramming that promotes cellular transformation during AML development, and LIC-specific m6A targets are recognized by different m6A readers. Moreover, the very long chain fatty acid transporter ATP-binding cassette subfamily D member 2 (ABCD2) is a key factor that promotes AML development, and deletion of ABCD2 damages clonogenic ability, inhibits proliferation, and promotes apoptosis of human leukemia cells. This study provides a comprehensive understanding of the role of m6A in regulating cell state transition in normal hematopoiesis and leukemogenesis, and identifies ABCD2 as a key factor in AML development.
A quick paster type of soluble nanoparticle microneedle patch for the treatment of obesity
Authors: Songyue Chen, Junbo Wang, Liyu Sun, Fangzhi Xia, Wenzhe Li, Lan Yuan, Chang Liu, Peishan Li, Chunjie Bao, Mengjie Wang, Guiling Wang, Jianwei Li, Ying Xie, Wanliang Lu
Journal: Biomaterials (2024)
Deciphering Structural Traits for Thermal and Kinetic Stability Across Protein Family Evolution through Ancestral Sequence Reconstruction
Authors: Pablo A Cea, Myriam Pérez, Sixto M Herrera, Sebastián M Muñoz, Nicolás Fuentes-Ugarte, José Coche-Miranda, Pablo Maturana, Victoria Guixé, Victor Castro-Fernandez
Journal: Molecular Biology and Evolution (2024)

Abstract Natural proteins are frequently marginally stable, and an increase in environmental temperature can easily lead to unfolding. As a result, protein engineering to improve protein stability is an area of intensive research. Nonetheless, since there is usually a high degree of structural homology between proteins from thermophilic organisms and their mesophilic counterparts, the identification of structural determinants for thermoadaptation is challenging. Moreover, in many cases, it has become clear that the success of stabilization strategies is often dependent on the evolutionary history of a protein family. In the last few years, the use of ancestral sequence reconstruction (ASR) as a tool for elucidation of the evolutionary history of functional traits of a protein family has gained strength. Here, we used ASR to trace the evolutionary pathways between mesophilic and thermophilic kinases that participate in the biosynthetic pathway of vitamin B1 in bacteria. By combining biophysics approaches, X-ray crystallography, and molecular dynamics simulations, we found that the thermal stability of these enzymes correlates with their kinetic stability, where the highest thermal/kinetic stability is given by an increase in small hydrophobic amino acids that allow a higher number of interatomic hydrophobic contacts, making this type of interaction the main support for stability in this protein architecture. The results highlight the potential benefits of using ASR to explore the evolutionary history of protein sequence and structure to identify traits responsible for the kinetic and thermal stability of any protein architecture.
Improvements of the shape and strength of the diaphragm after endoscopic lung volume reduction
Authors: Olivier Taton, Pierre Alain Gevenois, Alain Van Muylem, Benjamin Bondue, Sébastien Van Laethem, Dimitri Leduc
Journal: Thorax (2024)

Endoscopic lung volume reduction improves lung function, quality of life and exercise capacity in severe emphysema patients. However, its effect on the diaphragm function is not well understood. We hypothesised that endoscopic lung volume reduction increases its strength by modifying its shape.
High-dose vitamin D supplementation does not improve outcome in a cutaneous melanoma population: results of a randomized double-blind placebo-controlled study (ViDMe trial)
Authors: Julie De Smedt, Sofie Van Kelst, Laudine Janssen, Vivien Marasigan, Veerle Boecxstaens, Kris Bogaerts, Ann Belmans, Dirk Vanderschueren, Katleen Vandenberghe, Oliver Bechter, Claudia Aura, Diether Lambrechts, Tinne Strobbe, Gabriella Emri, Arjen Nikkels, Marjan Garmyn
Journal: British Journal of Dermatology (2024)

Observational studies in cutaneous melanoma (CM) have indicated an inverse relationship between levels of 25-hydroxyvitamin D and Breslow thickness, in addition to a protective effect of high 25-hydroxyvitamin D levels on clinical outcome.
The human developing cerebral cortex is characterized by an elevated <i>de novo</i> expression of lncRNAs in excitatory neurons
Authors: David A Morales-Vicente, Ana C Tahira, Daisy Woellner-Santos, Murilo S Amaral, Maria G Berzoti-Coelho, Sergio Verjovski-Almeida
Journal: Molecular Biology and Evolution (2024)

Abstract The outstanding human cognitive capacities are computed in the cerebral cortex, a mammalian-specific brain region and the place of massive biological innovation. Long noncoding RNAs have emerged as gene regulatory elements with higher evolutionary turnover than mRNAs. The many long noncoding RNAs identified in neural tissues make them candidates for molecular sources of cerebral cortex evolution and disease. Here, we characterized the genomic and cellular shifts that occurred during the evolution of the long noncoding RNA repertoire expressed in the developing cerebral cortex and explored putative roles for these long noncoding RNAs in the evolution of the human brain. Using transcriptomics and comparative genomics, we comprehensively annotated the cortical transcriptomes of humans, rhesus macaques, mice, and chickens and classified human cortical long noncoding RNAs into evolutionary groups as a function of their predicted minimal ages. Long noncoding RNA evolutionary groups showed differences in expression levels, splicing efficiencies, transposable element contents, genomic distributions, and transcription factor binding to their promoters. Furthermore, older long noncoding RNAs showed preferential expression in germinative zones, outer radial glial cells, and cortical inhibitory (GABAergic) neurons. In comparison, younger long noncoding RNAs showed preferential expression in cortical excitatory (glutamatergic) neurons, were enriched in primate and human-specific gene co-expression modules, and were dysregulated in neurodevelopmental disorders. These results suggest different evolutionary routes for older and younger cortical long noncoding RNAs, highlighting old long noncoding RNAs as a possible source of molecular evolution of conserved developmental programs; conversely, we propose that the de novo expression of primate- and human-specific young long noncoding RNAs is a putative source of molecular evolution and dysfunction of cortical excitatory neurons, warranting further investigation.
A structural and metabolic framework for classifying pre-clinical tuberculosis infection phenotypes using 18F-FDG PET-CT: a prospective cohort analysis following<i>M. tuberculosis</i>exposure
Authors: Jee Whang Kim, Sonam Vadera, Meedya Sharifpour, Amrita Bajaj, Anver Kamil, Pranabashis Haldar
Journal: Thorax (2024)

Tuberculosis (TB) control efforts are limited by ineffective characterisation of tuberculosis infection (TBI) —a heterogeneous spectrum of pre-clinical infection states, invisible to tools of routine clinical screening, that are associated with variable risk of progression to TB disease. In this prospective study, we use positron emission tomography-CT (PET-CT) as a high-resolution imaging modality to characterise and classify structural and metabolic features observed in 16 asymptomatic household TB contacts with normal chest radiographs. We identify four feature patterns that associate with distinct clinical and microbiological outcomes, supporting potential utility of PET-CT for objective classification of TBI phenotypes.
Rational fusion design inspired by cell-penetrating peptide: SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer's disease
Authors: Kang Qian, Peng Yang, Yixian Li, Ran Meng, Yunlong Cheng, Lingling Zhou, Jing Wu, Shuting Xu, Xiaoyan Bao, Qian Guo, Pengzhen Wang, Minjun Xu, Dongyu Sheng, Qizhi Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. In 3 × Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.
Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia
Authors: Federico Pozzo, Gabriela Forestieri, Filippo Vit, Giulia Ianna, Erika Tissino, Tamara Bittolo, Robel Papotti, Annalisa Gaglio, Lodovico Terzi di Bergamo, Agostino Steffan, Jerry Polesel, Pietro Bulian, Roberta Laureana, Agostino Tafuri, Annalisa Chiarenza, Francesco Di Raimondo, Jacopo Olivieri, Francesco Zaja, Luca Laurenti, Maria Ilaria Del Principe, Massimiliano Postorino, Giovanni Del Poeta, Riccardo Bomben, Antonella Zucchetto, Davide Rossi, Valter Gattei
Journal: Leukemia (2024)

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4