Loss of sialic acid side-chain -acetylation exacerbates colitis.

Sialic acids (Sias) are a diverse family of nine-carbon backbone monosaccharides occupying terminal positions on cell surface and secreted glycans and are abundant at mucosal surfaces. Sias can be modified with -acetyl esters on the side chain (C7 to C9) hydroxyls. Structural analysis and functional studies of these modifications are challenging due to chemical lability and variable resistance to sialidases.

Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease.

Alcohol-associated liver disease poses a global health burden with high mortality. Imbalances in the gut microbiota are important for disease progression. Using metagenomic sequencing of fecal samples from a multicenter, international cohort of patients with alcohol-associated hepatitis, we found that the presence of virulence factor KpsM, encoded in the genome of Escherichia coli (E.

Activation of intestinal endogenous retroviruses by alcohol exacerbates liver disease.

Alcohol-associated liver disease represents a significant global health challenge, with gut microbial dysbiosis and bacterial translocation playing a critical role in its pathogenesis. Patients with alcohol-associated hepatitis had increased fecal abundance of mammalian viruses, including retroviruses. This study investigated the role of endogenous retroviruses (ERVs) in the development of alcohol-associated liver disease.

Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors.

The proteasome is a proteolytic enzyme complex essential for protein homeostasis in mammalian cells and protozoan parasites like Trichomonas vaginalis (Tv), the cause of the most common, non-viral sexually transmitted disease. Tv and other protozoan 20S proteasomes have been validated as druggable targets for antimicrobials. However, low yields and purity of the native proteasome have hindered studies of the Tv 20S proteasome (Tv20S).

Mucosal vaccination in a murine gnotobiotic model of infection.

is an important protozoan cause of diarrheal disease worldwide, delayed development and cognitive impairment in children in low- and middle-income countries, and protracted post-infectious syndromes in developed regions. resides in the lumen and at the epithelial surface of the proximal small intestine but is not mucosa invasive. The protozoan parasite is genetically diverse with significant genome differences across strains and assemblages.

Antigiardial and antiamebic activities of fexinidazole and its metabolites: new drug leads for giardiasis and amebiasis.

The intestinal parasites and are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat giardiasis and amebiasis. Despite its efficacy, treatment failures in giardiasis occur in up to 5%-40% of cases.

Negative correlation between organ heteroplasmy, particularly hepatic heteroplasmy, and age at death revealed by post-mortem studies of m.3243A > G cases.

Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.

Development of subunit selective substrates for proteasome.

The protozoan parasite, (Tv) causes trichomoniasis, the most common, non-viral, sexually transmitted infection in the world. Only two closely related drugs are approved for its treatment. The accelerating emergence of resistance to these drugs and lack of alternative treatment options poses an increasing threat to public health.

Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes.

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e.

Conserved metabolic enzymes as vaccine antigens for giardiasis.

Giardia lamblia is a leading protozoal cause of diarrheal disease worldwide. Infection is associated with abdominal pain, malabsorption and weight loss, and protracted post-infectious syndromes. A human vaccine is not available against G.

Codelivery of Antigens and Adjuvant in Polymeric Nanoparticles Coated With Native Parasite Membranes Induces Protective Mucosal Immunity Against Giardia lamblia.

The protozoan pathogen Giardia lamblia is an important worldwide cause of diarrheal disease and malabsorption. Infection is managed with antimicrobials, although drug resistance and treatment failures are a clinical challenge. Prior infection provides significant protection, yet a human vaccine has not been realized.

Characterization of Metronidazole-Resistant Lines by Comparative Transcriptomics and Proteomics.

Metronidazole (MTZ) is a clinically important antimicrobial agent that is active against both bacterial and protozoan organisms. MTZ has been used extensively for more than 60 years and until now resistance has been rare. However, a recent and dramatic increase in the number of MTZ resistant bacteria and protozoa is of great concern since there are few alternative drugs with a similarly broad activity spectrum.

Fragmented QRS on electrocardiography as a predictor for diastolic cardiac dysfunction in type 2 diabetes.

Aims/introduction: Diastolic cardiac dysfunction in type 2 diabetes (DD2D) is a critical risk of heart failure with preserved ejection fraction. However, there is no established biomarker to detect DD2D. We aimed to investigate the predictive impact of fragmented QRS (fQRS) on electrocardiography on the existence of DD2D.

Colesevelam ameliorates non-alcoholic steatohepatitis and obesity in mice.

Background: Obesity, non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality worldwide. Bile acid dysregulation is a pivotal part in their pathogenesis. The aim of this study was to evaluate the bile acid sequestrant colesevelam in a microbiome-humanized mouse model of diet-induced obesity and steatohepatitis.

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein–coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor and all associated trafficking and signaling molecules.

The fecal mycobiome in non-alcoholic fatty liver disease.

Background & Aims: Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis.

Methods: We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder.

Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter.

Trichomoniasis is a common and widespread sexually-transmitted infection, caused by the protozoan parasite Trichomonas vaginalis. T. vaginalis lacks the biosynthetic pathways for purines and pyrimidines, making nucleoside metabolism a drug target.

Microbiota Modulates Cardiac Transcriptional Responses to Intermittent Hypoxia and Hypercapnia.

The microbiota plays a critical role in regulating organismal health and response to environmental stresses. Intermittent hypoxia and hypercapnia, a condition that represents the main hallmark of obstructive sleep apnea in humans, is known to induce significant alterations in the gut microbiome and metabolism, and promotes the progression of atherosclerosis in mouse models. To further understand the role of the microbiome in the cardiovascular response to intermittent hypoxia and hypercapnia, we developed a new rodent cage system that allows exposure of mice to controlled levels of O and CO under gnotobiotic conditions.

Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance in .

causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against and other protozoa but has significant human toxicity.