Niche-specific control of tissue function by regulatory T cells-Current challenges and perspectives for targeting metabolic disease.

Tissue regulatory T cells (Tregs) exert pivotal functions in both immune and metabolic regulation, maintaining local tissue homeostasis, integrity, and function. Accordingly, Tregs play a crucial role in controlling obesity-induced inflammation and supporting efficient muscle function and repair. Depending on the tissue context, Tregs are characterized by unique transcriptomes, growth, and survival factors and T cell receptor (TCR) repertoires. This functional specialization offers the potential to selectively target context-specific Treg populations, tailoring therapeutic strategies to specific niches, thereby minimizing potential side effects. Here, we discuss challenges and perspectives for niche-specific Treg targeting, which holds promise for highly efficient and precise medical interventions to combat metabolic disease.

Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration.

Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.

N,N-Dimethylglycine Sodium Salt Exerts Marked Anti-Inflammatory Effects in Various Dermatitis Models and Activates Human Epidermal Keratinocytes by Increasing Proliferation, Migration, and Growth Factor Release.

N,N-dimethylglycine (DMG) is a naturally occurring compound being widely used as an oral supplement to improve growth and physical performance. Thus far, its effects on human skin have not been described in the literature. For the first time, we show that N,N-dimethylglycine sodium salt (DMG-Na) promoted the proliferation of cultured human epidermal HaCaT keratinocytes. Even at high doses, DMG-Na did not compromise the cellular viability of these cells. In a scratch wound-closure assay, DMG-Na augmented the rate of wound closure, demonstrating that it promotes keratinocyte migration. Further, DMG-Na treatment of the cells resulted in the upregulation of the synthesis and release of specific growth factors. Intriguingly, DMG-Na also exerted robust anti-inflammatory and antioxidant effects, as assessed in three different models of human keratinocytes, mimicking microbial and allergic contact dermatitis as well as psoriasis and UVB irradiation-induced solar dermatitis. These results identify DMG-Na as a highly promising novel active compound to promote epidermal proliferation, regeneration, and repair, and to exert protective functions. Further preclinical and clinical studies are under investigation to prove the seminal impact of topically applied DMG-Na on relevant conditions of the skin and its appendages.

Aging Aggravates Cachexia in Tumor-Bearing Mice.

BACKGROUND: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models. METHODS: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer. RESULTS: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients. CONCLUSIONS: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.

Crisis-driven innovation and fundamental human needs: A typological framework of rapid-response COVID-19 innovations.

As a microcosm for future challenges, the COVID-19 pandemic exhibits increasingly transboundary dynamics, causing interconnected problems across multiple societal systems. To examine the role of innovations as a social mechanism to reconcile these arising challenges, we view the unfolding of the pandemic through the lens of a content analysis of 707 innovation projects that address the fundamental human needs of consumers and businesses. This study proposes a novel procedure to characterize large-scale innovative activities via text mining and employs a theoretical framework for identifying the pressing societal needs amidst crises. Our typology of rapid-response COVID-19 innovations exhibits a diverse set of domains ranging from technological innovations to what may be described as frugal and social innovations. We provide evidence for the growing prevalence of social needs beyond the basic notion of safety during the early months of the crisis. Our contributions show that a structural model of innovation activities and their latent drivers may help policy makers and innovators to move toward achieving a systemic reaction to such crises.

Affective compatibility with the self modulates the self-prioritisation effect.

The "self" shapes the way in which we process the world around us. It makes sense then, that self-related information is reliably prioritised over non self-related information in cognition. How might other factors such as self-compatibility shape the way self-relevant information is prioritised? The present work asks whether affective consistency between the self and arbitrarily self-associated stimuli influences the degree to which self-prioritisation can be observed. To this end, participants were asked to associate themselves with either a positive or a negative concept and to then indicate if a given stimulus (Experiment 1: Emotional faces; Experiment 2: Luminance cues) and an identity label matched. If affective consistency is key to self-prioritisation, negative constructs should dampen self-prioritisation and positive constructs should boost self-prioritisation because the self is universally construed as positive. Indeed, the results of the two experiments indicate that participants who made the negative association had more difficulty confirming whether the stimulus and the label matched than those who made the positive association. The implications of this finding are discussed in terms of "self" theories that span various levels of information processing. The data reveal that self-referential information processing goes beyond a default elevation of priority to the self.

Caffeine and Its Pharmacological Benefits in the Management of Androgenetic Alopecia: A Review.

Caffeine, particularly after ingestion, is well known to exert various pharmacological effects. A growing body of evidence implicates the ingestion of caffeine with beneficial effects on several diseases. The easy penetration of caffeine across the skin barrier and into human skin makes caffeine an ideal compound for topical application. Hair loss is known to negatively affect the quality of life and predispose to depression and anxiety. Androgenetic alopecia (AGA) is the most common type of hair loss in both men and women. To date, only few approved drug-based treatments for AGA exist, and these are inevitably associated with side effects. Therefore, the development of topical treatments based on well-tolerated natural ingredients such as caffeine to alleviate hair loss may provide a much-needed alternative to drug-based approaches.

Inducing illusory control ensures persistence when rewards fade and when others outperform us.

Persisting even when the rewards of continued effort are fading is essential for achieving long-term goals, skills, and good health, alike. Yet, we often quit when things get hard. Here, we tested whether augmenting the feeling of control through external measures increases persistence under such discouraging circumstances. In two laboratory experiments, we first induced illusory control by manipulating the base-rate of positive outcomes and then tested the effect of this elevation of participants' perceived control upon their persistence under diminishing returns and in a competition against a stronger opponent. Induced illusory control significantly enhanced people's persistence in both of these motivationally challenging situations. Our findings demonstrate that motivation is dependent upon perceived, rather than objective, control, and reveal that this can be leveraged to counteract quitting behavior when things get hard, for instance in rehabilitation, physical activity interventions, or other training settings.

Short-term cold exposure supports human Treg induction in vivo.

OBJECTIVE: Obesity and type-2 diabetes (T2D) are metabolic diseases that represent a critical health problem worldwide. Metabolic disease is differentially associated with fat distribution, while visceral white adipose tissue (VAT) is particularly prone to obesity-associated inflammation. Next to their canonical function of immune suppression, regulatory T cells (Tregs) are key in controlling adipose tissue homeostasis. Towards understanding the molecular underpinnings of metabolic disease, we focus on how environmental-metabolic stimuli impinge on the functional interplay between Tregs and adipose tissue. Here, cold exposure or beta3-adrenergic signaling are a promising tool to increase energy expenditure by activating brown adipose tissue, as well as by reducing local inflammation within fat depots by supporting immunosuppressive Tregs. However, in humans, the underlying mechanisms that enable the environmental-immune crosstalk in the periphery and in the respective tissue remain currently unknown. METHODS: We used combinatorial approaches of next generation humanized mouse models and in vitro and in vivo experiments together with beta3-adrenergic stimulation to dissect the underlying mechanisms of human Treg induction exposed to environmental stimuli such as cold. To test the translational relevance of our findings, we analyzed samples from the FREECE study in which human subjects were exposed to individualized cooling protocols. Samples were analyzed ex vivo and after in vitro Treg induction using qRT-PCR, immunofluorescence, as well as with multicolor flow cytometry and cell sorting. RESULTS: In vivo application of the beta3-adrenergic receptor agonist mirabegron in humanized mice induced thermogenesis and improved the Treg induction capacity of naïve T cells isolated from these animals. Using samples from the human FREECE study, we demonstrate that a short-term cold stimulus supports human Treg induction in vitro and in vivo. Mechanistically, we identify BORCS6 encoding the Ragulator-interacting protein C17orf59 to be significantly induced in human CD4+ T cells upon short-term cold exposure. Strong mTOR signaling is known to limit successful Treg induction and thus likely by interfering with mTOR activation at lysosomal surfaces, C17orf59 improves the Treg induction capacity of human naïve T cells upon cold exposure. CONCLUSIONS: These novel insights into the molecular underpinnings of human Treg induction suggest an important role of Tregs in linking environmental stimuli with adipose tissue function and metabolic diseases. Moreover, these discoveries shed new light on potential approaches towards tailored anti-inflammatory concepts that support human adipose tissue homeostasis by enabling Tregs.

A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.

Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)-mediated NFAT5, which interferes with FoxP3+ Treg induction. Blocking miRNA181a or NFAT5 increases Treg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.

A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function.

Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3+ regulatory T cells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how T cells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction in vitro and in vivo. CD4+ T cell proteomes revealed higher expression of Foxp3 regulatory networks in response to cold or ADRB3 stimulation in vivo reflecting Treg induction. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated in CD4+ T cells by either ADRB3 stimulation or cold exposure, suggesting contribution to Treg induction. By loss- and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T cell-specific Stat6/Pten axis links cold exposure or ADRB3 stimulation with Foxp3+ Treg induction and adipose tissue function. Our findings offer a new mechanistic model in which tissue-specific Tregs maintain adipose tissue function.

Adipose-tissue regulatory T cells: Critical players in adipose-immune crosstalk.

Obesity and type-2 diabetes (T2D) are associated with metabolic defects and inflammatory processes in fat depots. FoxP3+ regulatory T cells (Tregs) control immune tolerance, and have an important role in controlling tissue-specific inflammation. In this mini-review we will discuss current insights into how cross-talk between T cells and adipose tissue shapes the inflammatory environment in obesity-associated metabolic diseases, focusing on the role of CD4+ T cells and Tregs. We will also highlight potential opportunities for how the immunoregulatory properties of Tregs could be harnessed to control inflammation in obesity and T2D and emphasize the critical need for more research on humans to establish mechanisms that are conserved in both mice and humans.

Optical assembly of bio-hybrid micro-robots.

The combination of micro synthetic structures with bacterial flagella motors represents an actual trend for the construction of self-propelled micro-robots. The development of methods for fabrication of these bacteria-based robots is a first crucial step towards the realization of functional miniature and autonomous moving robots. We present a novel scheme based on optical trapping to fabricate living micro-robots. By using holographic optical tweezers that allow three-dimensional manipulation in real time, we are able to arrange the building blocks that constitute the micro-robot in a defined way. We demonstrate exemplarily that our method enables the controlled assembly of living micro-robots consisting of a rod-shaped prokaryotic bacterium and a single elongated zeolite L crystal, which are used as model of the biological and abiotic components, respectively. We present different proof-of-principle approaches for the site-selective attachment of the bacteria on the particle surface. The propulsion of the optically assembled micro-robot demonstrates the potential of the proposed method as a powerful strategy for the fabrication of bio-hybrid micro-robots.

Site-specific immobilization of proteins at zeolite L crystals by nitroxide exchange reactions.

Site-selective immobilization of dyes and different protein recognizing entities at the surface of zeolite L crystals using mild radical nitroxide exchange reactions is reported. Exposure of these crystals to aqueous protein solutions leads to site-selective immobilization of proteins onto the crystals.

Comparison of the new high sensitive cardiac troponin T with myoglobin, h-FABP and cTnT for early identification of myocardial necrosis in the acute coronary syndrome.

BACKGROUND: We sought to determine the performance of the new high sensitivity cardiac troponin T assay (TnThs) for early diagnosis of myocardial infarction in patients with suspected acute coronary syndrome (ACS) and compare it with the fourth generation cTnT assay, myoglobin and heart-type fatty acid binding protein (h-FABP). METHODS: Ninety-four patients with diagnosis of suspected ACS without ST-segment elevation admitted to our chest pain unit were included. Patients were divided according to time from onset of symptoms to presentation into an early presenter group (<4 h) and a late presenter group (≥4 h). A median of six samples (range 2-8) were available per patient. The diagnostic performance of TnThs was assessed using ROC analysis. Areas under the curve (AUC) of baseline and follow-up results of TnThs, cTnT, myoglobin, and h-FABP were compared using c statistics. RESULTS: The TnThs assay allows an excellent prediction of non-ST-segment elevation myocardial infarction (non-STEMI) at presentation, particularly among late presenters. A follow-up sample improves diagnostic performance in a time-dependent manner. The AUC of TnThs was superior to cTnT at all time points. The performance of TnThs was at least as good as myoglobin and h-FABP at presentation and during follow-up. CONCLUSIONS: A baseline sample of TnThs allows an earlier prediction of non-STEMI than the less sensitive and precise fourth generation cTnT assay. Probably, this excellent performance of TnThs at baseline and follow-up could obviate the need for other early markers of necrosis in future.

Iridium-catalyzed C-H activation versus directed ortho metalation: complementary borylation of aromatics and heteroaromatics.

Systematic studies are presented demonstrating the complementarity of directed ortho metalation (DoM) and Ir-catalyzed strategies for the provision of borylated aromatics and their subsequent Suzuki-Miyaura coupling reactions. A new concept, the use of the TMS group, readily introduced by DoM, as a latent regiodirective moiety to overcome the otherwise problematic production of isomeric borylated product mixtures is presented. Additional electrophile-induced ipso-deborylation and DoM reactions of the Bpin products are described.