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Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells 1 , 2 . Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity 3 – 5 ; however, a truly safe and effective logic-gated CAR has remained elusive 6 . Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules. We show that certain proximal signalling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumours in vivo while bypassing upstream signalling proteins, including CD3ζ. The primary role of ZAP-70 is to phosphorylate LAT and SLP-76, which form a scaffold for signal propagation. We exploited the cooperative role of LAT and SLP-76 to engineer logic-gated intracellular network (LINK) CAR, a rapid and reversible Boolean-logic AND-gated CAR T cell platform that outperforms other systems in both efficacy and prevention of on-target, off-tumour toxicity. LINK CAR will expand the range of molecules that can be targeted with CAR T cells, and will enable these powerful therapeutic agents to be used for solid tumours and diverse diseases such as autoimmunity 7 and fibrosis 8 . In addition, this work shows that the internal signalling machinery of cells can be repurposed into surface receptors, which could open new avenues for cellular engineering. Logic gating is used to develop a CAR T cell platform that is highly specific and allows the activity of T cells to be restricted to the encounter of two antigens, thus reducing on-target, off-tumour toxicity.

BackgroundFecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium. difficile infection (rCDI). FMT capsules have emerged, and it is unknown if delivery location and dose impact efficacy.MethodsWe compared two cohorts of patients receiving two capsule formulations: gastric release (FMTgr) and targeted colonic release (FMTcr) at two different sites. Cohort A received FMTgr at (1) high dose: 60 capsules and low dose: 30 capsules. Patients in Cohort B received FMTcr at (1) high dose: 30 capsules (2) low dose: 10 capsules. Clinical cure rates and adverse events were monitored through week 8. Paired t-tests were used to compare diversity pre- and post-FMT.Results51 rCDI patients were enrolled. Cohort A contained n = 20 and Cohort B contained n = 31. Overall cure at week 8 for FMTgr was 75% (15/20) compared to 80.6% for FMTcr, (25/31), p = 0.63. Both formulations were safe with no serious adverse events. FMTcr was superior at increasing gut microbial diversity.DiscussionTo our knowledge, this is the first study to compare targeted delivery of FMT capsules. While both capsules were safe and efficacious, microbial engraftment patterns were superior in FMTcr.

T‐type voltage‐gated calcium channels (VGCCs) are comparatively understudied in large conduit artery function relative to the well‐characterized L‐type channel subtype. This study investigates the vascular roles of T‐type VGCCs in the aorta and renal artery of healthy rabbits using functional reactivity assays and immunofluorescence and further elucidates the interaction between T‐type VGCC activity and the nitric oxide (NO) signalling pathway. T‐type VGCCs contributed to contractile responses induced by phenylephrine and angiotensin II in both arteries. Moreover, in the renal artery, the contribution of T‐type VGCCs in response to phenylephrine increased in the absence of NO and was associated with endothelium‐dependent vasodilation. Immunofluorescence analysis revealed co‐localization of Ca V 3.1 with endothelial nitric oxide synthase in the renal artery, but not in the aorta, suggesting a vasodilatory role in renal circulation. These findings highlight vascular bed‐specific functions of T‐type VGCCs and their interaction with endothelial pathways in the renal artery. What is the central question of this study? Do T‐type voltage‐gated calcium channels (VGCCs) regulate vascular tone in large conduit arteries, and is their function artery‐specific or influenced by endothelial factors? What is the main finding and its importance? T‐type VGCCs contribute to vasoconstriction in both the aorta and renal artery and mediate vasodilation exclusively in the renal artery. Their activity is enhanced under nitric oxide (NO) deficiency, and Cav3.1 colocalizes with eNOS only in the renal artery. This highlights a functional, artery‐specific role for T‐type VGCCs in conduit vessels, with implications for vascular regulation and endothelial signaling.

Probiotics are living microorganisms recognized for conferring health benefits on the host by modulating the gut microbiota. They interact with various signaling pathways, including the aryl hydrocarbon receptor (AhR), which plays a crucial role in maintaining intestinal homeostasis and immune function. The activation of AhR by probiotics has been associated with benefits such as improved intestinal barrier function, reduced inflammation, and modulation of immune responses. This systematic review aims to summarize current knowledge on the signaling of AhR, mediated by probiotics in physiological conditions and gastrointestinal pathologies. We conducted a comprehensive search across databases, including PubMed and Embase, up until July 2024. Out of 163 studies screened, 18 met the inclusion criteria. Our findings revealed in healthy populations that probiotic consumption increases the production of AhR ligands promoting intestinal immune tolerance. Furthermore, in populations with gastrointestinal pathologies, probiotics ameliorated symptoms through AhR activation by Trp metabolites, leading to the upregulation of the anti-inflammatory response.

The cerebellum is responsible for complex motor functions, like maintaining balance and stance, coordination of voluntary movements, motor learning, and cognitive tasks. During aging, most of these functions deteriorate, which results in falls and accidents. The aim of this work was to elucidate the effect of a standardized pomegranate extract during four months of supplementation in elderly mice to prevent frailty and improve the oxidative state. Male C57Bl/6J eighteen-month-old mice were evaluated for frailty using the “Valencia Score” at pre-supplementation and post-supplementation periods. We analyzed lipid peroxidation in the cerebellum and brain cortex and the glutathione redox status in peripheral blood. In addition, a set of aging-related genes in cerebellum and apoptosis biomarkers was measured via real-time polymerase chain reaction (RT-PCR). Our results showed that pomegranate extract supplementation improved the motor skills of C57Bl/6J aged mice in motor coordination, neuromuscular function, and monthly weight loss, but no changes in grip strength and endurance were found. Furthermore, pomegranate extract reversed the increase in malondialdehyde due to aging in the cerebellum and increased the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the blood. Finally, aging and apoptosis biomarkers improved in aged mice supplemented with pomegranate extract in the cerebellum but not in the cerebral cortex.

The original version of the article unfortunately contained an error in article title. The corrected title is ‘Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Low Dose’.

Litter size is an essential trait in rabbit meat production but with low heritability. A selection experiment for ovulation rate has been performed for 10 generations to improve litter size in rabbits. The selected line increased two ova more than the control line but nevertheless a negative correlation was observed with prenatal survival. A transcriptomic study was performed, using microarrays, in ovarian tissue from females belonging to the selected line and the control line. Our results showed 1357 differential expressed genes and nineteen potential biomarkers associated with prenatal mortality, which could explain differences between litter size in rabbits. Cell death was the most relevant process.

Background and Objectives. Neonatal sepsis is a serious condition with a high rate of mortality and morbidity. Currently, the gold standard for sepsis diagnosis is a positive blood culture, which takes 48–72 h to yield results. We hypothesized that identifying differentially expressed miRNA pattern in neonates with late-onset Gram-positive sepsis would help with an earlier diagnosis and therapy. Methods. This is a prospective observational study in newborn infants with late-onset Gram positive bacterial sepsis and non-septic controls. Complementary to blood culture, an aliquot of 0.5 mL of blood was used to determine small non-coding RNA expression profiling using the GeneChip miRNA 4.0 Array. Results. A total of 11 very low birth-weight neonates with late-onset Gram-positive sepsis and 16 controls were analyzed. Further, 217 differentially expressed miRNAs were obtained between both groups. Subsequently, a combined analysis was performed with these miRNAs and 4297 differentially expressed genes. We identified 33 miRNAs that regulate our mRNAs, and the most relevant biological processes are associated with the immune system and the inflammatory response. Conclusions. The miRNA profiling in very low birth-weight neonates distinguishes late-onset Gram-positive sepsis versus control neonates.

This is a narrative review about the mechanisms involved in bacterial sepsis in preterm infants, which is an illness with a high incidence, morbidity, and mortality. The role of the innate immune response and its relationship with oxidative stress in the pathogenesis are described as well as their potential implementation as early biomarkers. Moreover, we address the impact that all the mechanisms triggered by sepsis have on the dysbiosis and the changes on neonatal microbiota.

Background: We previously described a novel micronutrient blend that behaves like a putative calorie restriction mimetic. The aim of this paper was to analyze the beneficial effects of our micronutrient blend in mice and C. elegans, and compare them with calorie restriction. Methods: Whole transcriptomic analysis was performed in the brain cortex, skeletal muscle and heart in three groups of mice: old controls (30 months), old + calorie restriction and old + novel micronutrient blend. Longevity and vitality were tested in C. elegans. Results: The micronutrient blend elicited transcriptomic changes in a manner similar to those in the calorie-restricted group and different from those in the control group. Subgroup analysis revealed that nuclear hormone receptor, proteasome complex and angiotensinogen genes, all of which are known to be directly related to aging, were the most affected. Furthermore, a functional analysis in C. elegans was used. We found that feeding C. elegans the micronutrient blend increased longevity as well as vitality. Conclusions: We describe a micronutrient supplement that causes similar changes (transcriptomic and promoting longevity and vitality) as a calorie restriction in mice and C. elegans, respectively, but further studies are required to confirm these effects in humans.