Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that ...interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling “fight or flight” responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.
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•IL-6 is the dominant endocrine cytokine induced by acute stress in mice•Stress-inducible IL-6 is produced in brown adipocytes via ADRB3 signaling•IL-6 is required for stress hyperglycemia and adaptive “fight or flight” responses•Stress-induced IL-6 decreases tolerance to a subsequent inflammatory challenge
During acute psychological stress, brown adipocytes initiate a chain of events mediated by adrenergic signaling and IL-6 release that metabolically fuels “fight or flight” adaptive responses but at the same time comes at an inflammatory cost.
The impacts of individual commensal microbes on immunity and disease can differ dramatically depending on the surrounding microbial context; however, the specific bacterial combinations that dictate ...divergent immunological outcomes remain largely undefined. Here, we characterize an immunostimulatory Allobaculum species from an inflammatory bowel disease patient that exacerbates colitis in gnotobiotic mice. Allobaculum inversely associates with the taxonomically divergent immunostimulatory species Akkermansia muciniphila in human-microbiota-associated mice and human cohorts. Co-colonization with A. muciniphila ameliorates Allobaculum-induced intestinal epithelial cell activation and colitis in mice, whereas Allobaculum blunts the A.muciniphila-specific systemic antibody response and reprograms the immunological milieu in mesenteric lymph nodes by blocking A.muciniphila-induced dendritic cell activation and T cell expansion. These studies thus identify a pairwise reciprocal interaction between human gut bacteria that dictates divergent immunological outcomes. Furthermore, they establish a generalizable framework to define the contextual cues contributing to the “incomplete penetrance” of microbial impacts on human disease.
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•Allobaculum isolates from ulcerative colitis patients exacerbate colitis in mice•Immunostimulatory Allo. sp. are inversely correlated with Akkermansia muciniphila•Co-colonization uniquely alters immune responses elicited by Allo. or A. muc. alone•“Epistatic” interspecies interactions have nonlinear impacts on host immunity
Microbial community context can critically alter commensal-induced immune responses. Here, Rice et al. describe a reciprocal interaction between a novel colitogenic human Allobaculum species and Akkermansia muciniphila that uniquely reprograms the immune responses elicited by either microbe alone, revealing nonlinear impacts of interspecies interactions on host immunity.
The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the ...small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.
The global adoption of AI-powered predictive policing, utilizing big data, is becoming a prevalent strategy for crime control and law enforcement enhancement. Recognizing its potential, Abu Dhabi ...Police places emphasis on officer training and collaborative efforts for crime prevention. As the integration of predictive policing continues within Abu Dhabi Police, the importance of exploring the value of training and collaborative learning becomes even more crucial (Abu Dhabi Police GHQ, 2020). This study's objective is to uncover the intricate relationship between crime mitigation performance and key factors, encompassing Predictive Policing Adoption, Specialised Technology Training, Innovative Officer Performance, and Collaborative Learning. Questionnaire survey was used to collect data from participants who are employees of the Abu Dhabi Crime Scene Department. A total of 316 valid responses were used in the development of multi-linear regression model to predict crime mitigation performance. By utilizing the developed multi-linear regression model, stakeholders can forecast Crime Mitigation Performance (CMP) by substituting the values of Predictive Policing Adoption (PPA), Specialised Technology Training (STT), Innovative Officer Performance (IOP), and Collaborative Learning (CL) into the formula. This predictive tool offers the Abu Dhabi Crime Scene Department a valuable resource to proactively assess and plan for crime mitigation outcomes, enhancing their strategic decision-making capabilities and fostering a more effective approach to law enforcement operations
Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor ...(AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner. Gene-expression analysis identified an AR-independent synergy-specific gene set signature upregulated upon abiraterone treatment that is dominated by pathways related to mitosis and the mitotic spindle. Abiraterone treatment alone caused defects in mitotic spindle orientation, failure of complete chromosome condensation, and improper cell division independently of its effects on AR signaling. These effects, although mild following abiraterone monotherapy, resulted in profound sensitization to the antimitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cancer cell death and entosis. In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared with either agent alone. Overall, this work establishes a mechanistic basis for the phase II clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment.
Abiraterone treatment induces mitotic defects that sensitize cancer cells to Plk1 inhibition, revealing an AR-independent mechanism for this synergistic combination that is applicable to a variety of cancer types.
Abstract Breast cancer remains a major global health issue, particularly affecting women and contributing significantly to mortality rates. Current treatments for estrogen receptor‐positive breast ...cancers, such as aromatase inhibitors, are effective but often come with side effects and resistance issues. This study addresses these gaps by targeting aromatase, an enzyme crucial for estrogen synthesis, which plays a pivotal role in breast cancer progression. The innovative approach involves synthesizing novel bis‐triazolopyridopyrimidines, designed to leverage the combined pharmacological benefits of pyridopyrimidine and 1,2,4‐triazole structures, known for their potent aromatase inhibition and anti‐cancer properties. These compounds were synthesized and characterized using 1 H‐NMR, 13 C‐NMR, and MS spectral analyses, and their anticancer efficacy was evaluated through MTT assays against MCF‐7 breast cancer cell lines in vitro. Molecular docking analyses revealed strong binding energies with aromatase, particularly for compounds 5 b , 5 c , 10 a , and 10 b , indicating their potential as effective aromatase inhibitors. The study highlights these compounds as promising candidates for further development as therapeutic agents against breast cancer.
The impacts of individual commensal microbes on immunity and disease can differ dramatically depending on the surrounding microbial context, yet the specific bacterial combinations that dictate ...divergent immunological outcomes remain largely undefined. Here, we characterize an immunostimulatory
Allobaculum
species from an inflammatory bowel disease patient that exacerbates colitis in gnotobiotic mice.
Allobaculum
inversely associates with the taxonomically-divergent immunostimulatory species
Akkermansia muciniphila
in human microbiota-associated mice and human cohorts. Co-colonization with
A. muciniphila
ameliorates
Allobaculum
-induced intestinal epithelial cell activation and colitis in mice, while
Allobaculum
blunts the
A. muciniphila
-specific systemic antibody response and reprograms the immunological milieu in mesenteric lymph nodes by blocking
A. muciniphila
-induced dendritic cell activation and T cell expansion. These studies thus identify a pairwise reciprocal interaction between human gut bacteria that dictates divergent immunological outcomes. Furthermore, they establish a generalizable framework to define the contextual cues contributing to the ‘incomplete penetrance’ of microbial impacts on human disease.
Microbial community context can critically alter commensal-induced immune responses. Here, Rice et al. describe a reciprocal interaction between a colitogenic human
Allobaculum
species and
Akkermansia muciniphila
that uniquely reprograms the immune responses elicited by either microbe alone, revealing non-linear impacts of interspecies interactions on host-immunity.
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