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Canesso MCC, Moreira TG, Faria AMC
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Compartmentalization of gut immune responses: Mucosal niches and lymph node peculiarities

IMMUNOLOGY LETTERS 2022 DEC; 251-252(?):86-90
The intestine is not a homogeneous organ, but rather organized spaces with specific niches and microenvironments filled with different cell types that are involved in physiological and inflammatory processes. The intestinal mucosa shows a high degree of architectural complexity and intratissue specialization that occurs according to luminal composition. These intratissue specialized environments are critical for the developmental and functional adaptation of immune cells in the gut and in the gut-draining lymph nodes. In this review we discuss the compartmentalization of gut immune responses and how the lymph nodes that drain different regions of the intestine are immunologically, anatomically, and physiologically distinct. We also propose that studies on gut immunity should consider the distinctive features of intestinal segments and the differences in their draining lymph nodes to fully understand the complexity of the gut immunological scenario.
Woods C, Contoreggi NH, Johnson MA, Milner TA, Wang G, Glass MJ
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Estrogen receptor beta activity contributes to both tumor necrosis factor alpha expression in the hypothalamic paraventricular nucleus and the resistance to hypertension following angiotensin II in female mice

NEUROCHEMISTRY INTERNATIONAL 2022 DEC; 161(?):? Article 105420
Sex differences in the sensitivity to hypertension and inflammatory processes are well characterized but insufficiently understood. In male mice, tumor necrosis factor alpha (TNF alpha) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension following slow-pressor angiotensin II (AngII) infusion. However, the role of PVN TNF alpha in the response to AngII in female mice is unknown. Using a combination of in situ hybridization, high-resolution electron microscopic immunohistochemistry, spatial-temporal gene silencing, and dihydroethidium microfluorography we investigated the influence of AngII on both blood pressure and PVN TNF alpha signaling in female mice. We found that chronic (14-day) infusion of AngII in female mice did not impact blood pressure, TNF alpha levels, the expression of the TNF alpha type 1 receptor (TNFR1), or the subcellular distribution of TNFR1 in the PVN. However, it was shown that blockade of estrogen receptor beta (ER beta), a major hypothalamic estrogen receptor, was accompanied by both elevated PVN TNF alpha and hypertension following AngII. Further, AngII hypertension following ER beta blockade was attenuated by inhibiting PVN TNF alpha signaling by local TNFR1 silencing. It was also shown that ER beta blockade in isolated PVN-spinal cord projection neurons (i.e. sympathoexcitatory) heightened TNF alpha-induced production of NADPH oxidase (NOX2)-mediated reactive oxygen species, molecules that may play a key role in mediating the effect of TNF alpha in hypertension. These results indicate that ER beta contributes to the reduced sensitivity of female mice to hypothalamic inflammatory cytokine signaling and hypertension in response to AngII.
Dhaouadi S, Bouchami O, Soufi L, Dhaouadi F, Chaari S, Bouglita W, Cherif A, de Lencastre H, Elandoulsi RB, Miragaia M
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Frequent dissemination and carriage of an SCC mec-mecC hybrid in methicillin-resistant Mammaliicoccus sciuri in farm animals from Tunisia

Objectives: In this study, we aimed to assess the extent of dissemination of methicillin-resistant Mammaliicoccus sciuri in animal farms in Tunisia and evaluate the distribution of virulence and methicillin resistance genes in the M. sciuri population.Methods: Staphylococci and mammaliicocci isolated from unhealthy animals and healthy humans from adjacent farms in Tunisia were characterized for antimicrobial susceptibility, biofilm formation, agglutination, and hemolysis abilities. Mammaliicoccus sciuri relatedness and content in antibiotic resistance and virulence genes were analyzed by whole-genome sequencing (WGS).Results: Mammaliicoccus sciuri was the most prevalent species (46.2%), showing the highest resistance rates to fusidic acid (94.6%), oxacillin (73%), penicillin (40.5%), clindamycin (37%), ciprofloxacin (27%), and cefoxitin (24.3%). Some isolates carried genes encoding resistance to nine different antibiotic classes. mecA was found in 35% of M. sciuri and mecC in 16.2%. All isolates carrying mecC were of S. sciuri subspecies carnaticus and carried the hybrid element SCC mec-mecC. Mammaliicoccus sciuri were able to produce strong biofilm (27%) and have clumping ability (16%). Additionally, they carried genes for capsule production ( cap8 , 100%), iron-regulated surface determinants ( isdE , 24%; isdG , 3%), and virulence regulation ( clpC and clpP , 100%). Single nucleotide polymorphisms (SNPs) analysis showed that 17 M. sciuri cross-transmission events probably occurred between different animal species and farms. Moreover, SCC mec was estimated to have been acquired five times by S. sciuri subsp. carnaticus.Conclusion: Multidrug resistant and pathogenic M. sciuri were frequently disseminated between different animal species within the farm environment. mecA and mecC can be disseminated by both frequent acquisition of the SCC mec element and clonal dissemination.(c) 2022 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( )
Brown JA, Sanidad KZ, Lucotti S, Lieber CM, Cox RM, Ananthanarayanan A, Basu S, Chen J, Shan MR, Amir M, Schmidt F, Weisblum Y, Cioffi M, Li TT, Rowdo FM, Martin ML, Guo CJ, Lyssiotis C, Layden BT, Dannenberg AJ, Bieniasz PD, Lee B, Inohara N, Matei I, Plemper RK, Zeng MY
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Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection

GUT MICROBES 2022 DEC 31; 14(1):? Article 2105609
The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.
Mansisidor AR, Risca VI
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Chromatin accessibility: methods, mechanisms, and biological insights

NUCLEUS 2022 DEC 31; 13(1):236-276
Access to DNA is a prerequisite to the execution of essential cellular processes that include transcription, replication, chromosomal segregation, and DNA repair. How the proteins that regulate these processes function in the context of chromatin and its dynamic architectures is an intensive field of study. Over the past decade, genome-wide assays and new imaging approaches have enabled a greater understanding of how access to the genome is regulated by nucleosomes and associated proteins. Additional mechanisms that may control DNA accessibility in vivo include chromatin compaction and phase separation - processes that are beginning to be understood. Here, we review the ongoing development of accessibility measurements, we summarize the different molecular and structural mechanisms that shape the accessibility landscape, and we detail the many important biological functions that are linked to chromatin accessibility.
Lee UJ, Mortola EN, Kim EJ, Long MY
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Evolution and maintenance of phenotypic plasticity

BIOSYSTEMS 2022 DEC; 222(?):? Article 104791
We introduce a novel framework for exploring the evolutionary consequences of phenotypic plasticity (adaptive and non-adaptive) integrating both genic and epigenetic effects on phenotype via stochastic differential equations and in-silico selection. In accordance with the most significant results derived from prior models, we demonstrate how plasticity is differentially favored when subjected to small vs large environmental shifts, how plasticity is transiently favorable while accommodating a new environment, and how plasticity decreases during epochs where the environment remains stable (canalization). In contrast to these models, however, by allowing the same phenotypic value to be produced via two different paths, i.e. deterministic, genic, vs stochastic, epigenetic mechanisms, we demonstrate when genic contributions alone cannot produce an optimal phenotype, plastic, epigenetic contributions will instead fully accommodate new environments, allowing for both adaptive and non-adaptive plasticity to evolve. Furthermore, we show that while rates of phenotypic accommodation are relatively constant under a wide range of selective conditions, selection will favor the most efficient route to adaptation: deterministic, genic response, or stochastic, plastic response. As a result, plasticity may evolve or canalization may occur within a given epoch depending on the relative mutation rate of genic and epigenetic contributions to phenotype, highlighting the importance of genetic conflict on the evolution of plasticity.
Schneeberger M, Brice NL, Pellegrino K, Parolari L, Shaked JT, Page KJ, Marchildon F, Barrows DW, Carroll TS, Tolpiko T, Mulligan VM, Newman R, Doyle K, Burli R, Barker DF, Glen A, Ortuno MJ, Nectow AR, Renier N, Cohen P, Carlton M, Heintz N, Friedman JM
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Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

NATURE METABOLISM 2022 NOV; 4(11):1495-+
Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders. Schneeberger et al. show that glutamatergic neurons within the dorsal raphe nucleus of the brainstem are enriched with the orexin 1 receptor Hcrtr1, which can be pharmacologically targeted to treat obesity in mice.
Collier AD, Yasmin N, Chang GQ, Karatayev O, Khalizova N, Fam M, Abdulai AR, Yu BY, Leibowitz SF
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Embryonic ethanol exposure induces ectopic Hcrt and MCH neurons outside hypothalamus in rats and zebrafish: Role in ethanol-induced behavioural disturbances

ADDICTION BIOLOGY 2022 NOV; 27(6):? Article e13238
Embryonic exposure to ethanol increases the risk for alcohol use disorder in humans and stimulates alcohol-related behaviours in different animal models. Evidence in rats and zebrafish suggests that this phenomenon induced by ethanol at low-moderate concentrations involves a stimulatory effect on neurogenesis and density of hypothalamic neurons expressing the peptides, hypocretin/orexin (Hcrt) and melanin-concentrating hormone (MCH), known to promote alcohol consumption. Building on our report in zebrafish showing that ethanol induces ectopic expression of Hcrt neurons outside the hypothalamus, we investigated here whether embryonic ethanol exposure also induces ectopic peptide neurons in rats similar to zebrafish and affects their morphological characteristics and if these ectopic neurons are functional and have a role in the ethanol-induced disturbances in behaviour. We demonstrate in rats that ethanol at a low-moderate dose, in addition to increasing Hcrt and MCH neurons in the lateral hypothalamus where they are normally concentrated, induces ectopic expression of these peptide neurons further anterior in the nucleus accumbens core and ventromedial caudate putamen where they have not been previously observed and causes morphological changes relative to normally located hypothalamic neurons. Similar to rats, embryonic ethanol exposure at a low-moderate dose in zebrafish induces ectopic Hcrt neurons anterior to the hypothalamus and alters their morphology. Notably, laser ablation of these ectopic Hcrt neurons blocks the behavioural effects induced by ethanol exposure, including increased anxiety and locomotor activity. These findings suggest that the ectopic peptide neurons are functional and contribute to the ethanol-induced behavioural disturbances related to the overconsumption of alcohol.
de Castro MV, Silva MVR, Naslavsky MS, Scliar MO, Nunes K, Passos-Bueno MR, Castelli EC, Magawa JY, Adami FL, Moretti AIS, de Oliveira VL, Boscardin SB, Cunha-Neto E, Kalil J, Jouanguy E, Bastard P, Casanova JL, Quinones-Vega M, Sosa-Acosta P, de Guedes JS, de Almeida NP, Nogueira FCS, Domont GB, Santos KS, Zatz M
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The oldest unvaccinated Covid-19 survivors in South America

IMMUNITY & AGEING 2022 NOV 16; 19(1):? Article 57
Background Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated. Results Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN. Conclusion These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.
Renert-Yuval Y, Pavel AB, Bose S, Gomez-Arias PJ, Rangel SM, Estrada YD, Paller AS, Guttman-Yassky E
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Tape strips capture atopic dermatitis-related changes in nonlesional skin throughout maturation

ALLERGY 2022 NOV; 77(11):3445-3447