The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a ...significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.
More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer's disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ...ordered protein aggregate with a lamellar cross-β structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilisin Carlsberg, but not by trypsin or plasmin.
The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of ...PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1 , SLUG, and SNAIL . This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.
Co-infection with Plasmodium and chikungunya virus (CHIKV) has been reported in humans, but the impact of co-infection on pathogenesis remains unclear. Here, we show that prior exposure to Plasmodium ...suppresses CHIKV-associated pathologies in mice. Mechanistically, Plasmodium infection induces IFNγ, which reduces viraemia of a subsequent CHIKV infection and suppresses tissue viral load and joint inflammation. Conversely, concomitant infection with both pathogens limits the peak of joint inflammation with no effect on CHIKV viraemia. Reduced peak joint inflammation is regulated by elevated apoptosis of CD4
T-cells in the lymph nodes and disrupted CXCR3-mediated CD4
T-cell migration that abolishes their infiltration into the joints. Virus clearance from tissues is delayed in both infection scenarios, and is associated with a disruption of B cell affinity-maturation in the spleen that reduces CHIKV-neutralizing antibody production.
ABSTRACT
In this paper, we investigate the impact of correlated noise on fast radio burst (FRB) searching. We found that (1) the correlated noise significantly increases the false alarm probability; ...(2) the signal-to-noise ratios (S/N) of the false positives become higher; (3) the correlated noise also affects the pulse width distribution of false positives, and there will be more false positives with wider pulse width. We use 55-h observation for M82 galaxy carried out at Nanshan 26m radio telescope to demonstrate the application of the correlated noise modelling. The number of candidates and parameter distribution of the false positives can be reproduced with the modelling of correlated noise. We will also discuss a low S/N candidate detected in the observation, for which we demonstrate the method to evaluate the false alarm probability in the presence of correlated noise. Possible origins of the candidate are discussed, where two possible pictures, an M82-harboured giant pulse and a cosmological FRB, are both compatible with the observation.
Ionizing radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, and cerebrovascular injuries. We investigated a population of mice that recovered from high-dose ...radiation to live normal life spans. These "elite-survivors" harbored distinct gut microbiota that developed after radiation and protected against radiation-induced damage and death in both germ-free and conventionally housed recipients. Elevated abundances of members of the bacterial taxa
and
were associated with postradiation restoration of hematopoiesis and gastrointestinal repair. These bacteria were also found to be more abundant in leukemia patients undergoing radiotherapy, who also displayed milder gastrointestinal dysfunction. In our study in mice, metabolomics revealed increased fecal concentrations of microbially derived propionate and tryptophan metabolites in elite-survivors. The administration of these metabolites caused long-term radioprotection, mitigation of hematopoietic and gastrointestinal syndromes, and a reduction in proinflammatory responses.
Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine ...factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes.
ABSTRACT
We present our piggyback search for fast radio bursts using the Nanshan 26 m Radio Telescope and the Kunming 40 m Radio Telescope. The observations are performed in the L band from 1380 to ...1700 MHz at Nanshan and the Sband from 2170 to 2310 MHz at Kunming. We built the roach2-based FFT spectrometer and developed the real-time transient search software. We introduce a new radio interference mitigation technique named zero-DM matched filter and give the formula of the signal-to-noise ratio loss in the transient search. Though we have no positive detection of bursts in about 1600 and 2400 h data at Nanshan and Kunming, respectively, an intriguing peryton was detected at Nanshan, from which hundreds of bursts were recorded. Perytons are terrestrial radio signals that mimic celestial fast radio bursts. They were first reported at Parkes and identified as microwave oven interferences later. The bursts detected at Nanshan show similar frequency swept emission and have double-peaked profiles. They appeared in different sky regions in about tens of minutes observations and the dispersion measure index is not exactly 2, which indicates the terrestrial origin. The peryton differs drastically from the known perytons detected at Parkes, because it appeared in a precise period of p = 1.712 87 ± 0.000 04 s. Its origin remains unknown.
Background and Objective
Periodontitis is a severe chronic inflammatory disease and one of the most prevalent non‐communicable chronic diseases that affects the majority of the world's adult ...population. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this dreadful disease. In this study, we utilized adeno‐associated virus (AAV) expressing cathepsin K (Ctsk) small hairpin (sh)RNA (AAV‐sh‐Ctsk) to silence Ctsk in vivo and subsequently evaluated its impact in periodontitis as a potential therapeutic strategy for this disease.
Material and Methods
We used a known mouse model of periodontitis, in which wild‐type BALB/cJ mice were infected with Porphyromonas gingivalis W50 in the maxillary and mandibular periodontium to induce the disease. AAV‐sh‐Ctsk was then administrated locally into the periodontal tissues in vivo, followed by analyses to assess progression of the disease.
Results
AAV‐mediated Ctsk silencing drastically protected mice (> 80%) from P. gingivalis‐induced bone resorption by osteoclasts. In addition, AAV‐sh‐Ctsk administration drastically reduced inflammation by impacting the expression of many inflammatory cytokines as well as T‐cell and dendritic cell numbers in periodontal lesions.
Conclusion
AAV‐mediated Ctsk silencing can simultaneously target both the inflammation and bone resorption associated with periodontitis through its inhibitory effect on immune cells and osteoclast function. Thereby, AAV‐sh‐Ctsk administration can efficiently protect against periodontal tissue damage and alveolar bone loss, establishing this AAV‐mediated local silencing of Ctsk as an important therapeutic strategy for effectively treating periodontal disease.
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