Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.

The influence of exercise on postprandial triacylglycerol metabolism

Significance of skeletal muscle properties on fitness, long-term physical training and serum lipids.

Programmed and environmental determinants driving neonatal mucosal immune development.

Environmental enteric dysfunction: gut and microbiota adaptation in pregnancy and infancy

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells—a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention. Description Single-cell genomic profiling identifies epithelial and immune correlates of environmental enteropathy. Profiling environmental enteropathy Single-cell RNA sequencing (scRNA-seq) has been shown to be a powerful tool for understanding the pathophysiology of numerous disorders. Here, Kummerlowe et al. applied scRNA-seq on small intestine biopsies from patients with environmental enteropathy (EE), an intestinal subclinical condition prevalent in low-income countries, caused by exposure to environmental enteropathogens. The authors identified common pathways associated with the disease- and cell-type contribution to EE severity. Samples from patients with EE showed increased proinflammatory molecules and alterations in WNT- and MAPK-associated signaling, suggesting that targeting these pathways could be effective for treating EE.

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation

High-density lipoprotein (HDL)metabolism wasstudied ineight sedentary men before andafter 14and32-48weeksofexercise training. Subjects rodestationary bicycles 1hourdaily, 5days eachweekfor14weeks(n= 8),and4dayseachweekthereafter fora total of32-48weeks (n= 7)oftraining. HDLmetabolism was assessed with"1I-radiolabeled autologous HDL while subjects consumed defined diets. Maximal oxygenuptake increased 26±7% (p<O.001) after 14 weeksbutdidnotincrease further with more prolonged training. Bodyweight andestimated bodyfatdidnotchange. HDL cholesterol increased 5± 3mg/dl,andtriglycerides decreased 19±23mg/dlafter 14weeks(p<0.025 forboth), butthere were no additional changes with continued training. Postheparin plasma lipoprotein lipase activity was22%higher thanbaseline activity after both14(p<0.025) and32or more weeksofexercise. Incontrast, hepatic triglyceride lipase activity was 16+8% and15± 8% lower thanbaseline ateachmeasurement (p<0.005 forboth). Thedisappearance rateoftriglycerides after anintravenously administered fatsolution was 24±24% higher at14weeksand49±18%(p<0.005) higher after more prolonged training. Total andlow-density lipoprotein cholesterol andapolipoprotein A-Iand A-IIconcentrations attheendofstudy werenotdifferent frominitial values . Plasma volume was 8% aboveinitial values atbothpost-training measurements. Thebiological half-life of apolipoprotein A-Iwas unchanged at14weeksbutwas 10±13%longer (p= 0.07) and increased inall butonesubject attheendofthestudy. Half-life forapolipoprotein A-II was 8±8% (p-0.031) and11±14%(p=O.06) abovebaseline at14and32or more weeks, respectively. Thesynthetic rates forapolipoproteins A-IandA-IIwere notdifferent from baseline values at32-48weeks. Weconclude that 8-11monthsofexercise training inpreviously sedentary men enhances fattolerance andincreases HDL cholesterol concentrations by prolonging HDL survival. Thechanges inHDL apolipoprotein survival, however, donot approximate thedifferences previously notedbetween elite endurance athletes andsedentary men. Changes inHDL cholesterol concentration were notlarge andsuggest thatthepotehitial forexercise-related changes inHDL may bemodest inmany subjects. (Circulation 1988;78:25-34)

ModestChanges inHigh-Density Lipoprotein Concentration andMetabolism With Prolonged Exercise Training

Only three well-characterised cases of functional cure have been described in paediatric HIV infection over the past decade. This underlines the fact that early initiation of combination antiretroviral therapy (cART), whilst minimising the size of the viral reservoir, is insufficient to achieve cure, unless other factors contribute. In this review, we consider these additional factors that may facilitate functional cure in paediatric infection. Among the early life immune activity, these include HIV-specific cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell responses. The former have less potent antiviral efficacy in paediatric compared with adult infection, and indeed, in early life, NK responses have greater impact in suppressing viral replication than CTL. This fact may contribute to a greater potential for functional cure to be achieved in paediatric versus adult infection, since post-treatment control in adults is associated less with highly potent CTL activity, and more with effective antiviral NK cell responses. Nonetheless, antiviral CTL responses can play an increasingly effective role through childhood, especially in individuals expressing then ‘protective’ HLA-I molecules HLA-B*27/57/58:01/8101. The role of the innate system on preventing infection, in shaping the particular viruses transmitted, and influencing outcome is discussed. The susceptibility of female fetuses to in utero mother-to-child transmission, especially in the setting of recent maternal infection, is a curiosity that also provides clues to mechanisms by which cure may be achieved, since initial findings are that viral rebound is less frequent among males who interrupt cART. The potential of broadly neutralising antibody therapy to facilitate cure in children who have received early cART is discussed. Finally, we draw attention to the impact of the changing face of the paediatric HIV epidemic on cure potential. The effect of cART is not limited to preventing AIDS and reducing the risk of transmission. cART also affects which mothers transmit. No longer are mothers who transmit those who carry genes associated with poor immune control of HIV. In the cART era, a high proportion (>70% in our South African study) of transmitting mothers are those who seroconvert in pregnancy or who for social reasons are diagnosed late in pregnancy. As a result, now, genes associated with poor immune control of HIV are not enriched in mothers who transmit HIV to their child. These changes will likely influence the effectiveness of HLA-associated immune responses and therefore cure potential among children.

Role of Early Life Cytotoxic T Lymphocyte and Natural Killer Cell Immunity in Paediatric HIV Cure/Remission in the Anti-Retroviral Therapy Era

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Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation

ModestChanges inHigh-Density Lipoprotein Concentration andMetabolism With Prolonged Exercise Training

Role of Early Life Cytotoxic T Lymphocyte and Natural Killer Cell Immunity in Paediatric HIV Cure/Remission in the Anti-Retroviral Therapy Era