Anaerobic Cultures from Preserved Tissues of Baby Mammoth

Microbiological analysis of several cold-preserved tissue samples from the Siberian baby mammoth known as Lyuba revealed a number of culturable bacterial strains that were grown on anaerobic media at 4 C. Lactic acid produced by LAB (lactic acid bacteria) group, usually by members of the genera Carnobacterium and Lactosphera, appears to be a wonderful preservative that prevents other bacteria from over-dominating a system. Permafrost and lactic acid preserved the body of this one-month old baby mammoth and kept it in exceptionally good condition, resulting in this mammoth being the most complete such specimen ever recovered. The diversity of novel anaerobic isolates was expressed on morphological, physiological and phylogenetic levels. Here we discuss the specifics of the isolation of new strains, differentiation from trivial contamination, and preliminary results for the characterization of cultures

The Effects of Nicotine in the Neonatal Quinpirole Rodent Model of Psychosis: Neural Plasticity Mechanisms and Nicotinic Receptor Changes

Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 receptor sensitivity persistent throughout the animal’s lifetime. In Experiment 1, we analyzed the role of α7 and α4β2 nicotinic receptors (nAChRs) in nicotine behavioral sensitization and on the brain-derived neurotrophic factor (BDNF) response to nicotine in NQ- and neonatally saline (NS)-treated rats. In Experiment 2, we analyzed changes in α7 and α4β2 nAChR density in the nucleus accumbens (NAcc) and dorsal striatum in NQ and NS animals sensitized to nicotine. Male and female Sprague-Dawley rats were neonatally treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1–21. Animals were given ip injections of either saline or nicotine (0.5 mg/kg free base) every second day from P33 to P49 and tested on behavioral sensitization. Before each injection, animals were ip administered the α7 nAChR antagonist methyllycaconitine (MLA; 2 or 4 mg/kg) or the α4β2 nAChR antagonist dihydro beta erythroidine (DhβE; 1 or 3 mg/kg). Results revealed NQ enhanced nicotine sensitization that was blocked by DhβE. MLA blocked the enhanced nicotine sensitization in NQ animals, but did not block nicotine sensitization. NQ enhanced the NAcc BDNF response to nicotine which was blocked by both antagonists. In Experiment 2, NQ enhanced nicotine sensitization and enhanced α4β2, but not 7, nAChR upregulation in the NAcc. These results suggest a relationship between accumbal BDNF and α4β2 nAChRs and their role in the behavioral response to nicotine in the NQ model which has relevance to schizophrenia, a behavioral disorder with high rates of tobacco smoking

Incidence of WHO stage 3 and 4 conditions following initiation of Anti-Retroviral Therapy in resource limited settings

To determine the incidence of WHO clinical stage 3 and 4 conditions during early anti-retroviral therapy (ART) in resource limited settings (RLS)

Recent Incarceration, Substance Use, Overdose, and Service Use Among People Who Use Drugs in Rural Communities

Importance: Drug use and incarceration have a substantial impact on rural communities, but factors associated with the incarceration of rural people who use drugs (PWUD) have not been thoroughly investigated. Objective: To characterize associations between recent incarceration, overdose, and substance use disorder (SUD) treatment access among rural PWUD. Design, setting, and participants: For this cross-sectional study, the Rural Opioid Initiative research consortium conducted a survey in geographically diverse rural counties with high rates of overdose across 10 US states (Illinois, Wisconsin, North Carolina, Oregon, Kentucky, West Virginia, Ohio, Massachusetts, New Hampshire, and Vermont) between January 25, 2018, and March 17, 2020, asking PWUD about their substance use, substance use treatment, and interactions with the criminal legal system. Participants were recruited through respondent-driven sampling in 8 rural US regions. Respondents who were willing to recruit additional respondents from their personal networks were enrolled at syringe service programs, community support organizations, and through direct community outreach; these so-called seed respondents then recruited others. Of 3044 respondents, 2935 included participants who resided in rural communities and reported past-30-day injection of any drug or use of opioids nonmedically via any route. Data were analyzed from February 8, 2022, to September 15, 2023. Exposure: Recent incarceration was the exposure of interest, defined as a report of incarceration in jail or prison for at least 1 day in the past 6 months. Main outcomes and measures: The associations between PWUD who were recently incarcerated and main outcomes of treatment use and overdose were examined using logistic regression. Results: Of 2935 participants, 1662 (56.6%) were male, 2496 (85.0%) were White; the mean (SD) age was 36 (10) years; and in the past 30 days, 2507 (85.4%) reported opioid use and 1663 (56.7%) reported injecting drugs daily. A total of 1224 participants (41.7%) reported recent incarceration, with a median (IQR) incarceration of 15 (3-60) days in the past 6 months. Recent incarceration was associated with past-6-month overdose (adjusted odds ratio [AOR], 1.38; 95% CI, 1.12-1.70) and recent SUD treatment (AOR, 1.62; 95% CI, 1.36-1.93) but not recent medication for opioid use disorder (MOUD; AOR, 1.03; 95% CI, 0.82-1.28) or currently carrying naloxone (AOR, 1.02; 95% CI, 0.86-1.21). Conclusions and relevance: In this cross-sectional study of PWUD in rural areas, participants commonly experienced recent incarceration, which was not associated with MOUD, an effective and lifesaving treatment. The criminal legal system should implement effective SUD treatment in rural areas, including MOUD and provision of naloxone, to fully align with evidence-based SUD health care policies.</p

US Cancer Centers of Excellence Strategies for Increased Inclusion of Racial and Ethnic Minorities in Clinical Trials

PURPOSE:: Participation of racial and ethnic minority groups (REMGs) in cancer trials is disproportionately low despite a high prevalence of certain cancers in REMG populations. We aimed to identify notable practices used by leading US cancer centers that facilitate REMG participation in cancer trials. METHODS:: The National Minority Quality Forum and Sustainable Healthy Communities Diverse Cancer Communities Working Group developed criteria by which to identify eligible US cancer centers-REMGs comprise 10% or more of the catchment area; a 10% to 50% yearly accrual rate of REMGs in cancer trials; and the presence of formal community outreach and diversity enrollment programs. Cancer center leaders were interviewed to ascertain notable practices that facilitate REMG accrual in clinical trials. RESULTS:: Eight cancer centers that met the Communities Working Group criteria were invited to participate in in-depth interviews. Notable strategies for increased REMG accrual to cancer trials were reported across five broad themes: commitment and center leadership, investigator training and mentoring, community engagement, patient engagement, and operational practices. Specific notable practices included increased engagement of health care professionals, the presence of formal processes for obtaining REMG patient/caregiver input on research projects, and engagement of community groups to drive REMG participation. Centers also reported an increase in the allocation of resources to improving health disparities and increased dedication of research staff to REMG engagement. CONCLUSION:: We have identified notable practices that facilitate increased participation of REMGs in cancer trials. Wide implementation of such strategies across cancer centers is essential to ensure that all populations benefit from advances in an era of increasingly personalized treatment of cancer

Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis

Background: Impaired signaling in the IFN-g/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. Objective: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. Methods: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-g/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. Results: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-g–induced gene expression, but we found impaired responses to IFN-g restimulation. Conclusion: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-g–mediated inflammationFil: Sampaio, Elizabeth P.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados Unidos. Instituto Oswaldo Cruz. Laboratorio de Leprologia; BrasilFil: Hsu, Amy P.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Pechacek, Joseph. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Hannelore I.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados Unidos. Erasmus Medical Center. Department of Medical Microbiology and Infectious Disease; Países BajosFil: Dias, Dalton L.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Paulson, Michelle L.. Clinical Research Directorate/CMRP; Estados UnidosFil: Chandrasekaran, Prabha. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Rosen, Lindsey B.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Carvalho, Daniel S.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados Unidos. Instituto Oswaldo Cruz, Laboratorio de Leprologia; BrasilFil: Ding, Li. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Vinh, Donald C.. McGill University Health Centre. Division of Infectious Diseases; CanadáFil: Browne, Sarah K.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Datta, Shrimati. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Allergic Diseases. Allergic Inflammation Unit; Estados UnidosFil: Milner, Joshua D.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Allergic Diseases. Allergic Inflammation Unit; Estados UnidosFil: Kuhns, Douglas B.. Clinical Services Program; Estados UnidosFil: Long Priel, Debra A.. Clinical Services Program; Estados UnidosFil: Sadat, Mohammed A.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Host Defenses. Infectious Diseases Susceptibility Unit; Estados UnidosFil: Shiloh, Michael. University of Texas. Southwestern Medical Center. Division of Infectious Diseases; Estados UnidosFil: De Marco, Brendan. University of Texas. Southwestern Medical Center. Division of Infectious Diseases; Estados UnidosFil: Alvares, Michael. University of Texas. Southwestern Medical Center. Division of Allergy and Immunology; Estados UnidosFil: Gillman, Jason W.. University of Texas. Southwestern Medical Center. Division of Infectious Diseases; Estados UnidosFil: Ramarathnam, Vivek. University of Texas. Southwestern Medical Center. Division of Infectious Diseases; Estados UnidosFil: de la Morena, Maite. University of Texas. Southwestern Medical Center. Division of Allergy and Immunology; Estados UnidosFil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Moreira, Ileana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutierrez"; ArgentinaFil: Uzel, Gulbu. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Johnson, Daniel. University of Chicago. Comer Children; Estados UnidosFil: Spalding, Christine. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Zerbe, Christa S.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados UnidosFil: Wiley, Henry. National Eye Institute. Clinical Trials Branch; Estados UnidosFil: Greenberg, David E.. University of Texas. Southwestern Medical Center. Division of Infectious Diseases; Estados UnidosFil: Hoover, Susan E.. University of Arizona. College of Medicine. Valley Fever Center for Excellence; Estados UnidosFil: Rosenzweig, Sergio D.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Host Defenses Infectious Diseases Susceptibility Unit; Estados Unidos. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Primary Immunodeficiency Clinic; Estados UnidosFil: Galgiani, John N.. University of Arizona. College of Medicine. Valley Fever Center for Excellence; Estados UnidosFil: Holland, Steven M.. National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Infectious Diseases. Immunopathogenesis Section; Estados Unido

Siderophore-Mediated Zinc Acquisition Enhances Enterobacterial Colonization of the Inflamed Gut

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or “Nissle”) exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin’s affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae

Differential Effects of MYH9 and APOL1 Risk Variants on FRMD3 Association with Diabetic ESRD in African Americans

Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with non-diabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9—a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e.g., rs942280 interaction p-value = 9.3E−7 additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR = 1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR = 0.80; homogeneity p-value = 4.3E−4). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes