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JOURNAL ARTICLE
Eva Hellsberg, Danila Boytsov, Qingyang Chen, Marco Niello, Michael Freissmuth, Gary Rudnick, Yuan-Wei Zhang, Walter Sandtner, Lucy R Forrest
Clearance of serotonin (5-hydroxytryptamine, 5-HT) from the synaptic cleft after neuronal signaling is mediated by serotonin transporter (SERT), which couples this process to the movement of a Na+ ion down its chemical gradient. After release of 5-HT and Na+ into the cytoplasm, the transporter faces a rate-limiting challenge of resetting its conformation to be primed again for 5-HT and Na+ binding. Early studies of vesicles containing native SERT revealed that K+ gradients can provide an additional driving force, via K+ antiport...
April 30, 2024: Proceedings of the National Academy of Sciences of the United States of America
#2
JOURNAL ARTICLE
Wenping Zeng, Canjun Li, Ruikun Wu, Xingguo Yang, Qingyan Wang, Bingqian Lin, Yanan Wei, Hao Li, Ge Shan, Lili Qu, Chunlei Cang
Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking...
April 23, 2024: PLoS Biology
#3
JOURNAL ARTICLE
Paula F Zamora, Thomas G Reidy, Catherine R Armbruster, Ming Sun, Daria Van Tyne, Paul E Turner, Jonathan L Koff, Jennifer M Bomberger
Phage therapy is a therapeutic approach to treat multidrug-resistant (MDR) infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. Using a panel of Pseudomonas aeruginosa phages and human airway epithelial cells (AECs) derived from a person with cystic fibrosis (CF), we determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment...
April 2024: PLoS Biology
#4
JOURNAL ARTICLE
Giuseppe Daniele, Andrea Tura, Alex Brocchi, Alessandro Saba, Beatrice Campi, Veronica Sancho-Bornez, Angela Dardano, Stefano Del Prato
OBJECTIVE: To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. RESEARCH DESIGN AND METHODS: Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m2) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity...
April 23, 2024: Diabetes Care
#5
JOURNAL ARTICLE
Bart R Thomson, Nina Schwendinger, Katrin Beckmann, Thomas Gentinetta, Daniel Couto, Sandra Wymann, Valérie Verdon, Raphael M Buzzi, Kevin Akeret, Peter W Kronen, Eva M Weinberger, Ulrike Held, Frauke Seehusen, Henning Richter, Dominik J Schaer, Michael Hugelshofer
Secondary brain injury (SBI) occurs with a lag of several days post-bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH) and is a strong contributor to mortality and long-term morbidity. aSAH-SBI coincides with cell-free hemoglobin (Hb) release into the cerebrospinal fluid. This temporal association and convincing pathophysiological concepts suggest that CSF-Hb could be a targetable trigger of SBI. However, sparse experimental evidence for Hb's neurotoxicity in vivo defines a significant research gap for clinical translation...
April 23, 2024: Translational Stroke Research
#6
REVIEW
Kaoru Yamada, Takeshi Iwatsubo
BACKGROUND: Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aβ and tau proteins. There has long been a keen interest among researchers in understanding how Aβ and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD. This finding has sparked interest in exploring the potential contribution of the glymphatic/meningeal lymphatic system in AD...
April 23, 2024: Cellular and Molecular Life Sciences: CMLS
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JOURNAL ARTICLE
Katerina Deike, Andreas Decker, Paul Scheyhing, Julia Harten, Nadine Zimmermann, Daniel Paech, Oliver Peters, Silka D Freiesleben, Luisa-Sophie Schneider, Lukas Preis, Josef Priller, Eike Spruth, Slawek Altenstein, Andrea Lohse, Klaus Fliessbach, Okka Kimmich, Jens Wiltfang, Claudia Bartels, Niels Hansen, Frank Jessen, Ayda Rostamzadeh, Emrah Düzel, Wenzel Glanz, Enise I Incesoy, Michaela Butryn, Katharina Buerger, Daniel Janowitz, Michael Ewers, Robert Perneczky, Boris-Stephan Rauchmann, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Christoph Laske, Matthias H Munk, Annika Spottke, Nina Roy, Michael Wagner, Sandra Roeske, Michael T Heneka, Frederic Brosseron, Alfredo Ramirez, Laura Dobisch, Steffen Wolfsgruber, Luca Kleineidam, Renat Yakupov, Melina Stark, Matthias C Schmid, Moritz Berger, Stefan Hetzer, Peter Dechent, Klaus Scheffler, Gabor C Petzold, Anja Schneider, Alexander Effland, Alexander Radbruch
OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD...
April 23, 2024: Investigative Radiology
#8
JOURNAL ARTICLE
James Brugarolas, Gregory Obara, Kathryn E Beckermann, Brian Rini, Elaine T Lam, James Hamilton, Thomas Schluep, Min Yi, So Wong, Zhongping Lily Mao, Erick Gamelin, Nizar M Tannir
PURPOSE: ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. PATIENTS AND METHODS: Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly...
April 23, 2024: Clinical Cancer Research
#9
JOURNAL ARTICLE
Megan Zercher, Jason A Coral, Diane Nabb, Griselda Powers, Alan Jones, Karla Johanning
Bioaccumulation predictions can be substantially improved by combining in vitro metabolic rate measurements derived from rainbow trout hepatocytes and/or hepatic S9 fractions with quantitative structure-activity relationship (QSAR) modeling approaches. Compared with in vivo testing guidelines Organisation for Economic Co-operation and Development (OECD) 305 and Office of Chemical Safety and Pollution Prevention (OCSPP; an office of the US Environmental Protection Agency) 850.1730, the recently adopted OECD test guidelines 319A and 319B are in vitro approaches that have the potential to provide a time- and cost-efficient, humane solution, reducing animal use while addressing uncertainties in bioaccumulation across species...
April 23, 2024: Environmental Toxicology and Chemistry
#10
JOURNAL ARTICLE
Matthew A Greenwald, Suzanne L Meinig, Lucas M Plott, Cristian Roca, Matthew G Higgs, Nicholas P Vitko, Matthew R Markovetz, Kaitlyn R Rouillard, Jerome Carpenter, Mehmet Kesimer, David B Hill, Jonathan C Schisler, Matthew C Wolfgang
UNLABELLED: The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including Pseudomonas aeruginosa , which is responsible for the majority of morbidity and mortality in MADs...
April 23, 2024: MBio
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REVIEW
Kahlio Mader, Lynn B Dustin
The vast majority of antibodies generated against a virus will be non-neutralising. However, this does not denote an absence of protective capacity. Yet, within the field, there is typically a large focus on antibodies capable of directly blocking infection (neutralising antibodies, NAbs) of either specific viral strains or multiple viral strains (broadly-neutralising antibodies, bNAbs). More recently, a focus on non-neutralising antibodies (nNAbs), or neutralisation-independent effects of NAbs, has emerged...
April 3, 2024: Antibodies
#12
JOURNAL ARTICLE
Yanbo Qiu, Xiaohua Yi, Xiaoqin Tang, Yanpei Wei, Beibei Zhang, Shunan Duan, Shuhui Wang, Xiuzhu Sun
Immunoglobulin is an essential component of the body's defense against pathogens, aiding in the recognition and clearance of foreign antigens. Research concerning immunoglobulin gene and its diversity of expression across different breeds within the same species is relatively scarce. In this study, we employed RACE (Rapid Amplification of cDNA Ends) technology, prepared DNA libraries, performed high-throughput sequencing, and conducted related bioinformatics analysis to analyze the differences in immunoglobulin gene diversity and expression at different periods in Hy-line brown hens, Lueyang black-bone chickens, and Beijing-You chickens...
April 23, 2024: Journal of Animal Science
#13
REVIEW
Jannik Prasuhn, Jiadi Xu, Jun Hua, Peter van Zijl, Linda Knutsson
The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved...
2024: Frontiers in Psychiatry
#14
JOURNAL ARTICLE
Erika L Smith, Gaël Panis, Selamawit Abi Woldemeskel, Patrick H Viollier, Peter Chien, Erin D Goley
In response to nutrient deprivation, bacteria activate a conserved stress response pathway called the stringent response (SR). During SR activation in Caulobacter crescentus , SpoT synthesizes the secondary messengers guanosine 5'-diphosphate 3'-diphosphate and guanosine 5'-triphosphate 3'-diphosphate (collectively known as (p)ppGpp), which affect transcription by binding RNA polymerase (RNAP) to down-regulate anabolic genes. (p)ppGpp also impacts the expression of anabolic genes by controlling the levels and activities of their transcriptional regulators...
April 2024: PNAS Nexus
#15
REVIEW
Mohsen Ghiasi, Peyman Kheirandish Zarandi, Abdolreza Dayani, Ali Salimi, Ehsan Shokri
The severe respiratory effects of the coronavirus disease 2019 (COVID-19) pandemic have necessitated the immediate development of novel treatments. The majority of COVID-19-related fatalities are due to acute respiratory distress syndrome (ARDS). Consequently, this virus causes massive and aberrant inflammatory conditions, which must be promptly managed. Severe respiratory disorders, notably ARDS and acute lung injury (ALI), may be treated safely and effectively using cell-based treatments, mostly employing mesenchymal stem cells (MSCs)...
December 2024: Regenerative Therapy
#16
REVIEW
Hovenia dulcis: a Chinese medicine that plays an essential role in alcohol-associated liver disease.
Yi-Xiang He, Meng-Nan Liu, Yang-Yang Wang, Hao Wu, Mei Wei, Jin-Yi Xue, Yuan Zou, Xin Zhou, Hui Chen, Zhi Li
Globally, alcohol-associated liver disease (ALD) has become an increased burden for society. Disulfirams, Benzodiazepines (BZDs), and corticosteroids are commonly used to treat ALD. However, the occurrence of side effects such as hepatotoxicity and dependence, impedes the achievement of desirable and optimal therapeutic efficacy. Therefore, there is an urgent need for more effective and safer treatments. Hovenia dulcis is an herbal medicine promoting alcohol removal clearance, lipid-lowering, anti-inflammatory, and hepatoprotective properties...
2024: Frontiers in Pharmacology
#17
REVIEW
Stephanie Tam, Darcy Wear, Christopher D Morrone, Wai Haung Yu
Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses...
April 22, 2024: Journal of Neurochemistry
#18
JOURNAL ARTICLE
Hui Chen, Xiangna Guan, Chi He, Tingting Lu, Xingyu Lin, Xuebin Liao
INTRODUCTION: Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T cells, B cells, dendritic cells and other immune cells. Loss of HPK1 kinase activity results in exacerbated cytokine secretion, enhanced T cell signaling, improved viral clearance, and thus increased restraint of tumor growth. These findings highlight HPK1 as a promising target for immuno-oncology treatments, culminating in the advancement of candidate compounds targeting HPK1 to clinical trials by several biotech enterprises...
April 22, 2024: Expert Opinion on Therapeutic Targets
#19
JOURNAL ARTICLE
Richard A Ward, John T Daugirdas
BACKGROUND: A kinetic model for beta-2-microglobulin removal and generation was used to explore the impact of adding hemodiafiltration on predialysis and time-averaged serum values. METHODS: The model was tested on data from the HEMO study and on a sample of patients undergoing high-flux hemodialysis. The impact of hemodiafiltration on beta-2-microglobulin levels was evaluated by modeling four randomized studies of hemodiafiltration vs. hemodialysis. The impact of residual kidney function on beta-2-microglobulin was tested by comparing results of previously reported measured data with model predictions...
April 23, 2024: Clinical Journal of the American Society of Nephrology: CJASN
#20
JOURNAL ARTICLE
Mahamadou D Camara, Yitian Zhou, Taís Nóbrega De Sousa, José P Gil, Abdoulaye A Djimde, Volker M Lauschke
BACKGROUND: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. RESULTS: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups...
April 22, 2024: Human Genomics
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