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Estrogen receptor (ER)-α has long been a potential target in ER-α-positive breast cancer therapeutics. In this study, we integrated ER-α-related bioinformatic data at different levels to systematically explore the mechanistic and therapeutic implications of ER-α. Firstly, we identified ER-α-interacting proteins and target genes of ER-α-regulating microRNAs (miRNAs), and analyzed their functional gene ontology (GO) annotations of those ER-α-associated proteins. In addition, we predicted ten consensus miRNAs that could target ER-α, and screened candidate traditional Chinese medicine (TCM) compounds that might hit diverse conformations of ER-α ligand binding domain (LBD). These findings may help to uncover the mechanistic implications of ER-α in breast cancer at a systematic level, and provide clues of miRNAs- and small molecule modulators- based strategies for future ER-α-positive breast cancer therapeutics.

Abstract IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.

BackgroundNeurodegenerative diseases including AD is currently one of intractable problems globally due to the insufficiency of intervention strategies. Long-term infection of Toxoplasma gondii (T. gondii) can induce cognitive impairment in hosts, which is closely implicated in the pathogenesis of neurodegenerative diseases. Aconitate decarboxylase 1 (Acod1) and its produced metabolite itaconate (termed Acod1/itaconate axis), have recently attracted extensive interests due to its anti-inflammatory role in macrophages. However, whether the axis can influence cognitive function remains unknown. MethodsA chronic T. gondii-infected mice (C57BL/6J) model was established via administration of cysts by gavage. Novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests were used to evaluate the behavior performance. Transmission electron microscopy, immunofluorescence, RT-PCR, western-blotting and RNA sequencing were utilized to determine the pathological changes, neuroinflammation and transcription profile in hippocampus tissues post infection, respectively. Moreover, the protective effect of Acod1/itaconate axis in T. gondii-induced cognitive deficits was evaluated.ResultsWe found that the latent infection of the parasite impaired the cognitive function, which was assessed behaviorally by novel location (NL), novel object recognition (NOR), Y-maze spatial memory and nest building tests. RNA sequencing of hippocampus showed that the infection downregulated the expression of genes related to synaptic plasticity, transmission and cognitive behavior. To our attention, the infection robustly upregulated the expression of genes associated with pro-inflammatory responses, which was characterized by microglia activation and disorder of Acod1/itaconate axis. Interestingly, administration of dimethyl itaconate (DI, an itaconate derivative with cell membrane permeability) could significantly ameliorate the cognitive deficits induced by T. gondii, which was proved by improvement of behavior performance and synaptic ultrastructure impairment, and lower accumulation of pro-inflammatory microglia. Notably, DI administration had a potential therapeutic effect on the cognitive deficits and synaptic impairment induced by the parasitic infection.ConclusionsOverall, these findings provide a novel insight for the pathogenesis of T. gondii-related cognitive deficits in hosts, and also provide a novel clue for the potential therapeutic strategies.

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperaturesensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background Clonorchis sinensis infection could trigger strong immune responses in mice and humans. However, whether the C.sinensis infection has an impact on arthritis is unknown. Here we investigated the effect of C.sinensis infection on type II collagen-induced arthritis in BALB/c mice. Results The mice were firstly infected with 45 C.sinensis metacercariae by oral gavage. Four weeks later, arthritis in mice was induced by type II collagen. Joint inflammation with severe redness and swelling in hind paws was observed in type II collagen-induced arthritis (CIA) mice. Besides, the physical activity was significantly reduced, but the respiratory exchange ratio was increased in CIA mice. Compared with CIA mice, C.sinensis infection could increase the severity of arthritis in CIA mice, based on the results of disease score and pathological changes. Compared to CIA mice, increased neutrophils and Ly6Chi monocytes, decreased B cells and CD4+T cells, were found in C.sinensis infected CIA mice. Besides these, C.sinensis infected mice also displayed significantly higher levels of serum IL-4 and IL-17 than those in CIA mice. Conclusions Taken together, our data suggest that C.sinensis infection have a bad effect on arthritis, and could induce the abnormality of the immune response in mice with CIA.

High-fat (HF) diet-induced neuroinflammation and cognitive decline in humans and animals have been associated with microbiota dysbiosis via the gut-brain axis. Our previous studies revealed that excretory-secretory products (ESPs) derived from the larval Echinococcus granulosus (E. granulosus) function as immunomodulators to reduce the inflammatory response, while the parasitic infection alleviates metabolic disorders in the host. However, whether ESPs can improve cognitive impairment under obese conditions remain unknown. This study aimed to investigate the effects of E. granulosus-derived ESPs on cognitive function and the microbiota-gut-brain axis in obese mice. We demonstrated that ESPs supplementation prevented HF diet-induced cognitive impairment, which was assessed behaviorally by nest building, object location, novel object recognition, temporal order memory, and Y-maze memory tests. In the hippocampus (HIP) and prefrontal cortex (PFC), ESPs suppressed neuroinflammation and HF diet-induced activation of the microglia and astrocytes. Moreover, ESPs supplementation improved the synaptic ultrastructural impairments and increased both pre- and postsynaptic protein levels in the HIP and PFC compared to the HF diet-treated group. In the colon, ESPs reversed the HF diet-induced gut barrier dysfunction, increased the thickness of colonic mucus, upregulated the expression of zonula occludens-1 (ZO-1), attenuated the translocation of bacterial endotoxins, and decreased the colon inflammation. Notably, ESPs supplementation alleviated the HF diet-induced microbiota dysbiosis. After clarifying the role of antibiotics in obese mice, we found that broad-spectrum antibiotic intervention abrogated the effects of ESPs on improving the gut microbiota dysbiosis and cognitive decline. Overall, the present study revealed for the first time that the parasite-derived ESPs alleviate gut microbiota dysbiosis and improve cognitive impairment induced by a high-fat diet. This finding suggests that parasite-derived molecules may be used to explore novel drug candidates against obesity-associated neurodegenerative diseases.

A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 (JAK2) gene (JAK2V617F) has been detected in myeloid cells of some individuals with higher levels of proinflammatory cytokine production such as interleukin (IL)-6. However, the mechanisms by which JAK2V617F mutation mediating those cytokines remain unclear. We, therefore, established JAK2V617F-expressing murine macrophages (JAK2V617F macrophages) and found that the levels of p-STAT3 were markedly elevated in JAK2V617F macrophages in association with an increase in IL-6 production. However, inhibition of STAT3 by C188-9 significantly decreased the production of IL-6. Furthermore, the JAK2V617F mutation endowed macrophages with an elevated glycolytic phenotype in parallel with aberrant expression of PKM1. Interestingly, silencing of PKM1 inactivated STAT3 in parallel with reduced IL-6 production. In contrast, ectopic expression of PKM1 elevated IL-6 production via STAT3 activation. Importantly, the JAK2V617F mutation contributed to PKM1 protein stabilization via blockade of lysosomal-dependent degradation via chaperone-mediated autophagy (CMA), indicating that the JAK2V617F mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.

The dynamic behavior of a PPSRC beam–column joint is related to constraint effect, strength deterioration and strain rate effect. Then, it can be assessed by bearing capacity, stiffness degradation, displacement ductility and energy consumption. The results show that the increased strain rate causes growth in ring stiffness, bearing capacity and energy consumption of PPSRC beam–column joints. However, the influence of shear span-to-depth ratio on dynamic mechanical properties of PPSRC beam–column joints is more obvious than that of strain rate. Regardless of strain rate, the bearing capacity, initial stiffness, ring stiffness and energy consumption of PPSRC beam–column joints decrease as the shear span-to-depth ratio increases. Moreover, the ring stiffness under reverse direction is smaller than that the under forward direction at each displacement level. However, the stiffness degradation under a lower shear span-to-depth ratio is more obvious than that under a higher shear span-to-depth ratio. Moreover, the displacement ductility with a higher shear span-to-depth ratio is better than that with a lower shear span-to-depth ratio. Finally, the mechanical properties of PPSRC beam–column joints are affected by the extension length of partial steel plate, and the reasonable extension length of the partial steel plate in the column is affected by the shear span-to-depth ratio.

Computer game is the drosophila in the field of artificial intelligence, which has attracted the attention of researchers in artificial intelligence, and has become an advantageous testbed for the research of cognitive intelligence. Poker game can be modeled as dynamic games with imperfect information, definite boundaries and fixed rules. Computer poker AI needs such abilities as dynamic decision-making with incomplete information, identification of misleading and fraudulent behaviors by opponents, and multi-round chips and risk management. Firstly , the development of computer poker game was introduced, which represented by Texas Hold’em poker. Then, typical intelligence game model algorithm, key techniques and existing main problems of computer poker were reviewed analysis. Finally, the future development trends and application prospect of computer intelligent poker game were discussed for cognitive intelligence.