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Spinal cord injury (SCI) induces both primary uncontrollable mechanical injury and secondary controllable degeneration, which further results in the activation of cell death cascades that mediate delayed tissue damage. To alleviate its impairments and seek for an effective remedy, mRNA differential display was used to investigate gene mRNA expression profiling in mice following SCI. A specific Zinc finger and BTB domain-containing protein, CIBZ, was discovered to implicate in the SCI process for the first time. Further researches indicated that CIBZ was extensively distributed in various tissues, and the expression level was highest in muscle, followed by spinal cord, large intestine, kidney, spleen, thymus, lung, cerebrum, stomach, ovary and heart, respectively. After injury, the CIBZ expression decreased dramatically and reached the lowest level at 8 h, but it gradually increased to the maximal level at 7 d. Caspase-3 and C-terminal-binding protein (CtBP), two CIBZ-related proteins, showed similar tendency. Interestingly, p53 expression remained constant in all groups. Via flow cytometry (FCM) analysis, it was found that the cell death rate in SCI group markedly increased and reached the highest value 1 d after surgery and the mitochondrial transmembrane potential (ΔΨm) at 1 d was the lowest in all groups. Taken together, it is suggested that: (i) in the presence of CtBP, CIBZ gene is involved in secondary injury process and trigger the activation of apoptotic caspase-3 and bax genes independent of p53; (ii) abrupt down-regulation of CtBP at 8 h is a sign of mitochondria dysfunction and the onset of cell death; (iii) it could be used as an inhibitor or target drug of caspase-3 gene to improve spinal cord function.

Transmembrane protein TMEM16A, which encodes calcium-activated chloride channel has been implicated in tumorigenesis. Overexpression of TMEM16A is associated with poor prognosis and low overall survival in multiple cancers including lung adenocarcinoma, making it a promising biomarker and therapeutic target. In this study, three structure-related sesquiterpene lactones (mecheliolide, costunolide and dehydrocostus lactone) were extracted from the traditional Chinese medicine Aucklandiae Radix and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on the proliferation and migration of lung adenocarcinoma cells were examined. Whole-cell patch clamp experiments showed that these sesquiterpene lactones potently inhibited recombinant TMEM16A currents in a concentration- dependent manner. The half-maximal concentration (IC50) values for three tested sesquiterpene lactones were 29.9 ± 1.1 μM, 19.7 ± 0.4 μM, and 24.5 ± 2.1 μM, while the maximal effect (Emax) values were 100.0% ± 2.8%, 85.8% ± 0.9%, and 88.3% ± 4.6%, respectively. These sesquiterpene lactones also significantly inhibited the endogenous TMEM16A currents and proliferation, and migration of LA795 lung cancer cells. These results demonstrate that mecheliolide, costunolide and dehydrocostus lactone are novel TMEM16A inhibitors and potential candidates for lung adenocarcinoma therapy. [ABSTRACT FROM AUTHOR]

Background AIDS is a very hazardous infectious disease. The analysis of AIDS incidence and mortality trends and the age-period-cohort influence on them, may provide insights into the formulation of AIDS related prevention and control policies. Objective To assess AIDS incidence and mortality trends, and the impact of age, period and cohort on the incidence and mortality of AIDS in China from 2004 to 2018. Methods In March 2022, from the online direct reporting system of the Data-center of China Health Science, number of AIDS patients, AIDS incidence, number of patients dying of AIDS, AIDS mortality in China during 2004—2018 were extracted from the overall information during the period. The Joinpoint regression model was used to estimate the trend of AIDS incidence and mortality, and to calculate the annual percent change (APC) and average annual percent change (AAPC) . The age-period-cohort model was used to assess the influence of age, period and cohort on the trend of AIDS incidence and mortality. Results During the period from 2004 to 2018, the incidence of AIDS in China increased from 0.248 9/100 000 to 4.956 9/100 000, and AIDS mortality increased from 0.060 5/100 000 to 1.431 2/100 000. Joinpoint regression analysis revealed that the incidence and mortality of AIDS in China had an average annual increase of 22.70%〔95%CI (20.70%, 24.80%) 〕and 18.80%〔95%CI (12.10%, 25.90%) 〕in the period, respectively (P

The amine-catalyzed inverse electron demand Diels-Alder reaction of unsymmetrical tetrazines with aldehydes and ketones was investigated. We found that only one regioisomer could be observed when pyrrolidine was applied as the catalyst. Using this reaction, fluorogenic dyes could be developed with a tetrazine unit as the "triggering group". [ABSTRACT FROM AUTHOR]

In response to DNA damage, the cellular decision of life versus death involves an intricate network of multiple factors that play critical roles in regulation of DNA repair, cell cycle, and cell death. DNA damage checkpoint proteins are crucial for maintaining DNA integrity and normal cellular functions, but they may also reduce the effectiveness of cancer treatment. Here we report the involvement of Cdk5 activator p35-binding protein C53 in regulation of apoptosis induced by genotoxic stress through modulating Cdk1-cyclin B1 function. C53 was originally identified as a Cdk5 activator p35-binding protein and a caspase substrate. Importantly, our results demonstrated that C53 deficiency conferred partial resistance to genotoxic agents such as etoposide and x-ray irradiation, whereas ectopic expression of C53 rendered cells susceptible to multiple genotoxins that usually trigger G2/M arrest. Furthermore, we found that Cdk1 activity was required for etoposide-induced apoptosis of HeLa cells. Overexpression of C53 promoted Cdk1 activity and nuclear accumulation of cyclin B1, whereas C53 deficiency led to more cytoplasmic retention of cyclin B1, suggesting that C53 acts as a pivotal player in modulating the G2/M DNA damage checkpoint. Finally, C53 and cyclin B1 co-localize and associate in vivo, indicating a direct role of C53 in regulating the Cdk1-cyclin B1 complex. Taken together, our results strongly indicate that in response to genotoxic stress, C53 serves as an important regulatory component of the G2/M DNA damage checkpoint. By overriding the G2/M checkpoint-mediated inhibition of Cdk1-cyclin B1 function, ectopic expression of C53 may represent a novel approach for chemo- and radio-sensitization of cancer cells. [ABSTRACT FROM AUTHOR]

We tested the impact of personalized telephone calls from service center representatives on health plan enrollment in California's Affordable Care Act Marketplace, Covered California, using a randomized controlled trial. The study sample included 79,522 consumers who had applied but not selected a plan. Receiving a call increased enrollment by 2.7 percentage points (22.5 percent) overall. Among subgroups, receiving a call significantly increased enrollment among consumers with income below 200 percent of the federal poverty level (4.0 percentage points or 47.6 percent for consumers with incomes below 150 percent of poverty and 4.0 percentage points or 36.4 percent for consumers with incomes of 150-199 of poverty), as well as those who were referred from Medicaid 2.9 percentage points or 53.7 percent), those ages 30-50 (2.4 percentage points or 23.3 percent) or older than age 50 (5.1 percentage points or 34.2 percent), those who were Hispanic (2.3 percentage points or 31.1 percent), and those whose preferred spoken language was Spanish 3.2 percentage points or 74.4 percent) or English (2.6 percentage points or 18.6 percent). The intervention provided a two-to-one return on investment. Yet absolute enrollment in the target population remained low; persistent enrollment barriers may have limited the intervention's impact. These findings inform implementation of the American Rescue Plan Act of 2021, which expands eligibility for subsidized coverage. [ABSTRACT FROM AUTHOR]

A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a-/-Rag1-/- mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Rorγt+ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorγt alleviated the spontaneous colonic inflammation in Gpr109a-/-Rag1-/- mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a-/-Rag1-/- mice. The ceca of Gpr109a-/-Rag1-/- mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1-/- mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies. [ABSTRACT FROM AUTHOR]

C53/LZAP (also named as Cdk5rap3) is a putative tumor suppressor that plays important roles in multiple cell signaling pathways, including DNA damage response and NF-κB signaling. Yet how its function is regulated remains largely unclear. Here we report the isolation and characterization of two novel C53/LZAP-interacting proteins, RCAD (Regulator of C53/ LZAP and DDRGK1) and DDRGK1 (DDRGK domain-containing protein 1). Our co-immunoprecipitation assays confirmed their interactions, while gel filtration assay indicated that C53/ LZAP and RCAD may form a large protein complex. Intriguingly, we found that RCAD knockdown led to dramatic reduction of C53/LZAP and DDRGK1 proteins. We also found that C53/LZAP and DDRGK1 became more susceptible to the proteasome-mediated degradation in RCAD knockdown cells, whereas their ubiquitination was significantly attenuated by RCAD overexpression. In addition, we found that RCAD, like C53/LZAP, also plays an important role in regulation of NF-κB signaling and cell invasion. Taken together, our findings strongly suggest that RCAD is a novel regulator of C53/LZAP tumor suppressor and NF-κB signaling. [ABSTRACT FROM AUTHOR]