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Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations.

Front Physiol 2021 23;12:612233. Epub 2021 Mar 23.

Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia.

Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components. How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. Read More

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Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias.

Cancer Gene Ther 2021 Apr 8. Epub 2021 Apr 8.

Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.

Cabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Read More

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Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice.

Acta Neuropathol Commun 2021 Apr 8;9(1):65. Epub 2021 Apr 8.

USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, 33613, USA.

The microtubule associated protein tau is an intrinsically disordered phosphoprotein that accumulates under pathological conditions leading to formation of neurofibrillary tangles, a hallmark of Alzheimer's disease (AD). The mechanisms that initiate the accumulation of phospho-tau aggregates and filamentous deposits are largely unknown. In the past, our work and others' have shown that molecular chaperones play a crucial role in maintaining protein homeostasis and that imbalance in their levels or activity can drive tau pathogenesis. Read More

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Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis.

Atherosclerosis 2021 Mar 25;324:58-68. Epub 2021 Mar 25.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551. Electronic address:

Background And Aims: Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire 'gain-of-function' isoDGR motifs that might play a role in atherosclerotic pathology.

Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Read More

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Decreased excitatory drive onto hilar neuronal nitric oxide synthase expressing interneurons in chronic models of epilepsy.

Brain Res 2021 Apr 5:147467. Epub 2021 Apr 5.

Department of Physiology, Liaoning Provincial Key Laboratory of Cerebral Diseases, Dalian Medical University, Dalian, China.

Excitation-inhibition imbalance of GABAergic interneurons is predisposed to develop chronic temporal lobe epilepsy (TLE). We have previously shown that virtually every neuronal nitric oxide synthase (nNOS)-positive cell is a GABAergic inhibitory interneuron in the denate gyrus. The present study was designed to quantify the number of nNOS-containing hilar interneurons using stereology in pilocapine- and kainic acid (KA)-exposed transgenic adult mice that expressed GFP under the nNOS promoter. Read More

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Oligophrenin-1 moderates behavioral responses to stress by regulating parvalbumin interneuron activity in the medial prefrontal cortex.

Neuron 2021 Apr 1. Epub 2021 Apr 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Ample evidence indicates that individuals with intellectual disability (ID) are at increased risk of developing stress-related behavioral problems and mood disorders, yet a mechanistic explanation for such a link remains largely elusive. Here, we focused on characterizing the syndromic ID gene oligophrenin-1 (OPHN1). We find that Ophn1 deficiency in mice markedly enhances helpless/depressive-like behavior in the face of repeated/uncontrollable stress. Read More

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Targeting Gys1 with AAV-SaCas9 Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.

Neurotherapeutics 2021 Apr 8. Epub 2021 Apr 8.

Division of Neurology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Many adult and most childhood neurological diseases have a genetic basis. CRISPR/Cas9 biotechnology holds great promise in neurological therapy, pending the clearance of major delivery, efficiency, and specificity hurdles. We applied CRISPR/Cas9 genome editing in its simplest modality, namely inducing gene sequence disruption, to one adult and one pediatric disease. Read More

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DNA breaks-mediated fitness cost reveals RNase HI as a new target for selectively eliminating antibiotic resistant bacteria.

Mol Biol Evol 2021 Apr 8. Epub 2021 Apr 8.

Instituto Gulbenkian de Ciência, Oeiras, 2780-156, Portugal.

Antibiotic resistance often generates defects in bacterial growth called fitness cost. Understanding the causes of this cost is of paramount importance, as it is one of the main determinants of the prevalence of resistances upon reducing antibiotics use. Here we show that the fitness costs of antibiotic resistance mutations that affect transcription and translation in Escherichia coli strongly correlate with DNA breaks, which are generated via transcription-translation uncoupling, increased formation of RNA-DNA hybrids (R-loops) and elevated replication-transcription conflicts. Read More

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A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy.

Eur Heart J 2021 Apr 8. Epub 2021 Apr 8.

Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany.

Aims : In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.

Methods And Results : Neointima formation was induced by wire injury in mouse femoral arteries. Read More

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Increased excitatory synaptic transmission associated with adult seizure vulnerability induced by early life inflammation in mice.

J Neurosci 2021 Apr 6. Epub 2021 Apr 6.

Hotchkiss Brain Institute

Early life inflammatory-stress increases seizure susceptibility later in life. However, possible sex- and age-specific differences and the associated mechanisms are largely unknown. C57/BL6 mice were bred in house, and female and male pups were injected with lipopolysaccharide (LPS, 100 μg/kg ) or vehicle control (saline solution) at postnatal day 14 (p14). Read More

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Correction to: Development of a Novel Orthotopic Gastric Cancer Mouse Model.

Biol Proced Online 2021 Apr 7;23(1). Epub 2021 Apr 7.

The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA.

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Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction.

Arterioscler Thromb Vasc Biol 2021 Apr 8:ATVBAHA121316153. Epub 2021 Apr 8.

Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler.

Objective: In response to inflammatory insult, endothelial cells express cell adhesion molecules and TF (tissue factor), leading to increased adhesion of leukocytes to the endothelium and activation of coagulation. Enhanced coagulation could further exacerbate inflammation. Identifying key signaling molecule(s) that drive both inflammation and coagulation may help devise effective therapeutic strategies to treat inflammatory and thrombotic disorders. Read More

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Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression.

Cell Death Dis 2021 Apr 6;12(4):359. Epub 2021 Apr 6.

Unitat d'Immunologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.

Dose of Trp53, the main keeper of genome stability, influences tumorigenesis; however, the causes underlying and driving tumorigenesis over time by the loss of a single p53 allele are still poorly characterized. Here, we found that single p53 allele loss specifically impacted the oxidative, DNA damage and inflammatory status of hematopoietic lineages. In particular, single Trp53 allele loss in mice triggered oxidative stress in peripheral blood granulocytes and spleenocytes, whereas lack of two Trp53 alleles produced enhanced oxidative stress in thymus cells, resulting in a higher incidence of lymphomas in the Trp53 knockout (KO) mice compared with hemizygous (HEM). Read More

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A Single Dose of Self-Transcribing and Replicating RNA Based SARS-CoV-2 Vaccine Produces Protective Adaptive Immunity In Mice.

Mol Ther 2021 Apr 3. Epub 2021 Apr 3.

Viral Research and Experimental Medicine Center (ViREMiCS), SingHealth Duke-NUS Academic Medical Center, Singapore; Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore.

A self-transcribing and replicating RNA (STARR) based vaccine (LUNAR®-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolong SARS-CoV-2 spike glycoprotein expression. Read More

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Discovery and Optimization of 2-1λ-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

J Med Chem 2021 Apr 6. Epub 2021 Apr 6.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2-1λ-quinoline-2,5(6)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (-, ). Read More

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An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.

Elife 2021 Apr 6;10. Epub 2021 Apr 6.

Department of Pathology and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAF driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. Read More

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BMP pathway antagonism by Grem1 regulates epithelial cell fate in intestinal regeneration.

Gastroenterology 2021 Apr 2. Epub 2021 Apr 2.

Intestinal Stem Cell Biology Lab, Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford NIHR Biomedical Research Centre, Oxford, UK. Electronic address:

Background And Aims: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signalling. The Bone Morphogenetic Protein (BMP) pathway has a physiological, pro-differentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signalling pathways that regulate this adaptive reprogramming are not well understood. Read More

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Western-style diet impedes colonization and clearance of Citrobacter rodentium.

PLoS Pathog 2021 Apr 5;17(4):e1009497. Epub 2021 Apr 5.

Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, United States of America.

Western-style diet (WSD), which is high in fat and low in fiber, lacks nutrients to support gut microbiota. Consequently, WSD reduces microbiota density and promotes microbiota encroachment, potentially influencing colonization resistance, immune system readiness, and thus host defense against pathogenic bacteria. Here we examined the impact of WSD on infection and colitis in response to Citrobacter rodentium. Read More

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High-Resolution Metabolomics of 50 Neurotransmitters and Tryptophan Metabolites in Feces, Serum, and Brain Tissues Using UHPLC-ESI-Q Exactive Mass Spectrometry.

ACS Omega 2021 Mar 15;6(12):8094-8103. Epub 2021 Mar 15.

Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Daur Drive, CB7431, Chapel Hill, North Carolina 27599, United States.

Recent evidence indicates that tryptophan metabolites and neurotransmitters are potential mediators of the microbiome-gut-brain interaction. Here, a high-resolution ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) assay was developed and validated for quantifying 50 neurotransmitters, tryptophan metabolites, and bacterial indole derivatives in mouse serum, feces, and brain. The lower limit of quantitation for the 50 compounds ranged from 0. Read More

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Genetic background but not prostatic epithelial beta-catenin influences susceptibility of male mice to testosterone and estradiol-induced urinary dysfunction.

Am J Clin Exp Urol 2021 15;9(1):121-131. Epub 2021 Feb 15.

University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.

Urinary voiding dysfunction in aging men can cause bothersome symptoms and irreparable tissue damage. Underlying mechanisms are not fully known. We previously demonstrated that subcutaneous, slow-release testosterone and estradiol implants (T+E2) drive a pattern of urinary voiding dysfunction in male mice that resembles that of aging men. Read More

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February 2021

Structural and Functional Characterization of Fibronectin in Extracellular Vesicles From Hepatocytes.

Front Cell Dev Biol 2021 18;9:640667. Epub 2021 Mar 18.

Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.

Extracellular vesicles (EVs) are membrane-limited nanoparticles that are liberated by cells and contain a complex molecular payload comprising proteins, microRNA, RNAs, and lipids. EVs may be taken up by other cells resulting in their phenotypic or functional reprogramming. In the liver, EVs produced by non-injured hepatocytes are involved in the maintenance of hepatic homeostasis or therapeutic outcomes following injury while EVs produced by damaged hepatocytes may drive or exacerbate liver injury. Read More

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Pulmonary Inflammatory Response from Co-exposure to LPS and Glyphosate.

Environ Toxicol Pharmacol 2021 Mar 31:103651. Epub 2021 Mar 31.

University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan, S7N 5B4, Canada.

Agricultural airborne work exposures are complex in nature and workplace exposures are a risk for respiratory outcomes in workers. Endotoxin and glyphosate are two common agents in agricultural exposures. While endotoxin (lipopolysaccaride, LPS) is a potent inflammatory agent it explains only a portion of the respiratory inflammatory response. Read More

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Genetic disruption of bassoon in two mutant mouse lines causes divergent retinal phenotypes.

FASEB J 2021 May;35(5):e21520

Department of Biology, Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Bassoon (BSN) is a presynaptic cytomatrix protein ubiquitously present at chemical synapses of the central nervous system, where it regulates synaptic vesicle replenishment and organizes voltage-gated Ca channels. In sensory photoreceptor synapses, BSN additionally plays a decisive role in anchoring the synaptic ribbon, a presynaptic organelle and functional extension of the active zone, to the presynaptic membrane. In this study, we functionally and structurally analyzed two mutant mouse lines with a genetic disruption of Bsn-Bsn and Bsn -using electrophysiology and high-resolution microscopy. Read More

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Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer.

Cancers (Basel) 2021 Mar 16;13(6). Epub 2021 Mar 16.

Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USA.

The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Read More

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Diet-Induced Obesity Promotes the Upregulation of Fas Expression on T-cells.

Biology (Basel) 2021 Mar 12;10(3). Epub 2021 Mar 12.

School of Laboratory Medicine and Medical Sciences (SLMMS), College of Health Sciences, University of KwaZulu-Natal, Durban 4013, South Africa.

This study was conducted to assess the expression of Fas (CD95) and programmed cell death-1 (PD-1) on circulating T-cells in obesity using a diet-induced obesity mouse model. Furthermore, we aimed to determine if there are any associations between metabolic disorders and the expression of T-cell regulatory markers. A total of 12 male C57BL/6 mice were randomized into either a high-fat diet (HFD) or low-fat diet (LFD) group for 8 weeks ( = 6/group). Read More

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An Improved Synthesis of N-(4-[F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models.

Molecules 2021 Mar 19;26(6). Epub 2021 Mar 19.

Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A* STAR), 11 Biopolis Way, #01-02 Helios, Singapore 138667, Singapore.

Positron emission tomography (PET) imaging of activated T-cells with -(4-[F]fluorobenzoyl)-interleukin-2 ([F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. Read More

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Treatment with Cyclic AMP Activators Reduces Glioblastoma Growth and Invasion as Assessed by Two-Photon Microscopy.

Cells 2021 Mar 4;10(3). Epub 2021 Mar 4.

Department of Neurosurgery, Friedrich-Alexander University, 91054 Erlangen, Germany.

(1) Background: Despite progress in surgery and radio-chemotherapy of glioblastoma (GB), the prognosis remains very poor. GB cells exhibit a preference for hypoxia to maintain their tumor-forming capacity. Enhancing oxidative phosphorylation-known as the anti-Warburg effect-with cyclic AMP activators has been demonstrated to drive GB cells from proliferation to differentiation thereby reducing tumor growth in a cell culture approach. Read More

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Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. Read More

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CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.

We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive 'brain hardware upgrade' and enhanced performance. In this fundamental circle, brain cells, challenged by motor-cognitive tasks, experience functional hypoxia, triggering the expression of EPO among other genes. We attested hypoxic cells by a transgenic reporter approach under the ubiquitous CAG promoter, with Hif-1α oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase. Read More

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Dehydroepiandrosterone Effect on : Molecular Mechanisms Associated to Parasite Death.

Microorganisms 2021 Mar 2;9(3). Epub 2021 Mar 2.

Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, AP 70228, Ciudad de México 04510, Mexico.

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite . This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as and , among others. Read More

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