The secretin GspD of the type II secretion system (T2SS) forms a channel across the outer membrane in Gram-negative bacteria to transport substrates from the periplasm to the extracellular milieu. The lack of an atomic-resolution structure of the GspD channel hinders the investigation of substrate translocation mechanism of T2SS. Here we report cryo-EM structures of two GspD channels (∼1 MDa), from Escherichia coli K12 and Vibrio cholerae, at ∼3 Å resolution. The structures reveal a pentadecameric channel architecture, wherein three rings of GspD N domains form the periplasmic channel. The secretin domain constitutes a novel double β-barrel channel, with at least 60 β-strands in each barrel, and is stabilized by S domains. The outer membrane channel is sealed by β-strand-enriched gates. On the basis of the partially open state captured, we proposed a detailed gate-opening mechanism. Our structures provide a structural basis for understanding the secretin superfamily and the mechanism of substrate translocation in T2SS.

Background Evidence from cohort studies in North America and Europe indicates that long-term exposure to fine particulate matter (PM₂ • ₅) is associated with an increased mortality risk. However, this association has rarely been quantified at higher ambient concentrations. We estimated the hazard ratio (HR) for all-cause mortality from longterm exposure to PM₂ • ₅ in a well established Chinese cohort of older adults. Methods The Chinese Longitudinal Healthy Longevity Survey (CLHLS) is a prospective cohort study of men and women aged 65 years and older enrolled in 2008 and followed up through 2014 for mortality events. We studied individuals for whom residential locations were available in 2008 for linkage to 1 km grids of PM₂ • ₅ concentrations, derived from satellite remote sensing. Cox proportional hazards models were used to estimate the effect of long-term exposure to PM₂ • ₅ on all-cause mortality, controlling for age, sex, smoking status, drinking status, physical activity, body-mass index, household income, marital status, and education. We then used our results to estimate premature mortality related to PM₂ • ₅ exposure in the population aged 65 years and older in China in 2010. Findings 13 344 individuals in the CLHLS cohort had data for all timepoints, yielding follow-up data for 49 440 person-years. In a 3-year window, these individuals were exposed to a median PM₂ • ₅ concentration of 50•7 μg/m³ (range 6•7-113•3). The overall HR for a 10 μg/m³ increase in this value was 1•08 (95% CI 1•06-1•09). In stratified analyses, HRs were higher in rural than in urban locations, in southern versus northern regions, and with exposure to lower versus higher PM₂ • ₅ concentrations. Based on the overall HR, we estimated that 1 765 820 people aged 65 years and older in China in 2010 had premature mortality related to PM₂ • ₅ exposure. Interpretation Long-term exposure to PM₂ • ₅ is associated with an increased risk of all-cause mortality among adults aged 65 years and older in China, but the magnitude of the risk declines as the concentration of PM₂ • ₅ increases.

Over the past few decades, substantial evidence has convincingly revealed the existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree of cellular heterogeneity within the tumor. CSCs are functionally defined by their abilities of self-renewal and differentiation, often in response to cues from their microenvironment. Biological phenotypes of CSCs are regulated by the integrated transcriptional, post-transcriptional, metabolic, and epigenetic regulatory networks. CSCs contribute to tumor progression, therapeutic resistance, and disease recurrence through their sustained proliferation, invasion into normal tissue, promotion of angiogenesis, evasion of the immune system, and resistance to conventional anticancer therapies. Therefore, elucidation of the molecular mechanisms that drive cancer stem cell maintenance, plasticity, and therapeutic resistance will enhance our ability to improve the effectiveness of targeted therapies for CSCs. In this review, we highlight the key features and mechanisms that regulate CSC function in tumor initiation, progression, and therapy resistance. We discuss factors for CSC therapeutic resistance, such as quiescence, induction of epithelial-to-mesenchymal transition (EMT), and resistance to DNA damage-induced cell death. We evaluate therapeutic approaches for eliminating therapy-resistant CSC subpopulations, including anticancer drugs that target key CSC signaling pathways and cell surface markers, viral therapies, the awakening of quiescent CSCs, and immunotherapy. We also assess the impact of new technologies, such as single-cell sequencing and CRISPR-Cas9 screening, on the investigation of the biological properties of CSCs. Moreover, challenges remain to be addressed in the coming years, including experimental approaches for investigating CSCs and obstacles in therapeutic targeting of CSCs.

p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in > 50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.

With the rapid development, mass production, and pervasive distribution of smartphones in recent years, they have provided people with portable, cost-effective, and easy-to-operate platforms to build analytical biosensors for point-of-care (POC) applications and mobile health.