The intestinal epithelium is highly regenerative. Rapidly proliferating LGR5+ crypt base columnar (CBC) cells are responsible for epithelial turnover needed to maintain intestinal homeostasis. Upon ...tissue damage, loss of LGR5+ CBCs can be compensated by activation of quiescent +4 intestinal stem cells (ISCs) or early progenitor cells to restore intestinal regeneration. LGR5+ CBC self-renewal and ISC conversion to LGR5+ cells are regulated by external signals originating from the ISC niche. In contrast, little is known about intrinsic regulatory mechanisms critical for maintenance of LGR5+ CBC homeostasis. We found that LGR5 expression in intestinal crypt cells is controlled by the circadian core clock gene BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A. BMAL1 directly activated transcription of Mex3a. MEX3A in turn bound to and stabilized Lgr5 mRNA. Bmal1 depletion reduced Mex3a and Lgr5 expression and led to increased ferroptosis, which consequently decreased LGR5+ CBC numbers and increased the number of crypt cells expressing +4 ISC marker BMI1. Together, these findings reveal a BMAL1-centered intrinsic regulatory pathway that maintains LGR5 expression in the crypt cells and suggest a potential mechanism contributing to ISC homeostasis.
Introduction
Surgeons are a unique group of healthcare professionals who are at risk for developing work-related musculoskeletal symptoms (WMS). The diversity of operating skills for laparoscopic and ...endovascular procedures impose different physical demands on surgeons, who also work under time pressure. The present study aims to examine the physical and psychosocial factors and their association with WMS among general surgeons in Hong Kong.
Method
A survey was conducted among surgeons working in the General Surgery departments in public hospitals of Hong Kong. Over 500 questionnaires were mailed and 135 surgeons completed the survey successfully (response rate 27%). Questions included demographics, workload, ergonomic and psychosocial factors. The relationship of these factors with WMS symptoms in the past 12 months was examined.
Results
Results indicated a high prevalence rate of WMS symptoms in surgeons, mainly in the neck (82.9%), low back (68.1%), shoulder (57.8%) and upper back (52.6%) regions. Sustained static and/or awkward posture was perceived as the factor most commonly associated with neck symptoms by 88.9% of respondents. Logistic regression showed the total score for physical ergonomic factors was the most significant predictor for all 4 body regions of musculoskeletal symptoms, with OR of 2.028 (95%CI 1.29–3.19) for the neck, 1.809 (1.34–2.43) for shoulder and 1.716 (1.24–2.37) for the lower back. Workstyle score was significantly associated with the symptom severity in the low back region (
P
= .003) but not with the other regions.
Conclusion
These results confirmed a strong association of physical and psychosocial factors with the musculoskeletal symptoms in surgeons. There is a potential for such musculoskeletal symptoms to escalate in the future, with rapid advances and increasing application of minimally invasive surgery.
Significance We used massively parallel sequencing to study the size profiles of plasma DNA samples at single-base resolution and in a genome-wide manner. We used chromosome arm-level z -score ...analysis (CAZA) to identify tumor-derived plasma DNA for studying their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These findings have shed light on fundamental biological characteristics of plasma DNA and related diagnostic applications for cancer.
The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z -score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell ...cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3β phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G
csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
Buildings erected in ancient China were often of wood and thatch and were particularly flammable. The ancient world developed a number of ways to minimize the damage caused by fire. An analysis of ...the architecture of ancient construction and urban planning, has revealed over a hundred fire prevention features. These items could be categorized into three groups, namely: symbolic features, building construction and urban planning. In the earlier literature of ancient China in which people had limited knowledge of fire, symbolic features based on their religious belief were emphasized. With the increase in construction experience, more tangible means of fire prevention were included in building design and urban planning. This paper briefly explores the changes of fire prevention means from early ancient period to Qing Dynasty. The reduction of damage caused by unwanted fire revealed the effectiveness of the evolution of fire prevention from symbolic features to urban planning.
This work proposes single crystal X-cut thin film Lithium Niobate (LN) resonators operating in a shear horizontal (SH 0 ) acoustic plate wave mode to achieve a high electromechanical coupling ...coefficient. In the fabrication process, we take advantage of the off-the-shelf single crystal X-cut LN dies on which surface micromachining technology is used to fabricate the devices. We design two fabrication process flows, each of which can be roughly divided into three parts. The first part is photolithography, primarily responsible for defining the electrodes and etching holes; this process for fabrication uses two masks. The second part is LN Reactive Ion Etching (RIE) process that defines the device edges. The third part is to etch the silicon dioxide beneath. Wet Hydro Fluoric (HF) chemistry is used to release the thin film structure. This study also reports measurement results of the SH 0 mode LN resonator with the high electromechanical coupling coefficient of 15.8%.
Epithelial ovarian cancer is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major ovarian cancer histotype, high-grade ...serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other ovarian cancer subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wild-type (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing ovarian cancer remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA-binding domain, was critical for tumorigenesis in WT p53-expressing ovarian cancer. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in ovarian cancer cells expressing WT p53.
Degradation of p53 mediated by MEX3A drives ovarian cancer growth by circumventing p53 tumor suppressive functions, suggesting targeting MEX3A as a potential strategy for treating of ovarian cancer expressing WT p53.
Background and objective
Few head‐to‐head evaluations of immune responses to different vaccines have been reported.
Methods
Surrogate virus neutralization test (sVNT) antibody levels of adults ...receiving either two doses of BNT162b2 (n = 366) or CoronaVac (n = 360) vaccines in Hong Kong were determined. An age‐matched subgroup (BNT162b2 n = 49 vs. CoronaVac n = 49) was tested for plaque reduction neutralization (PRNT) and spike‐binding antibody and T‐cell reactivity in peripheral blood mononuclear cells.
Results
One month after the second dose of vaccine, BNT162b2 elicited significantly higher PRNT50, PRNT90, sVNT, spike receptor binding, spike N‐terminal domain binding, spike S2 domain binding, spike FcR binding and antibody avidity levels than CoronaVac. The geometric mean PRNT50 titres in those vaccinated with BNT162b2 and CoronaVac vaccines were 251.6 and 69.45, while PRNT90 titres were 98.91 and 16.57, respectively. All of those vaccinated with BNT162b2 and 45 (91.8%) of 49 vaccinated with CoronaVac achieved the 50% protection threshold for PRNT90. Allowing for an expected seven‐fold waning of antibody titres over 6 months for those receiving CoronaVac, only 16.3% would meet the 50% protection threshold versus 79.6% of BNT162b2 vaccinees. Age was negatively correlated with PRNT90 antibody titres. Both vaccines induced SARS‐CoV‐2‐specific CD4+ and CD8+ T‐cell responses at 1 month post‐vaccination but CoronaVac elicited significantly higher structural protein‐specific CD4+ and CD8+ T‐cell responses.
Conclusion
Vaccination with BNT162b2 induces stronger humoral responses than CoronaVac. CoronaVac induces higher CD4+ and CD8+ T‐cell responses to the structural protein than BNT162b2.
Through the head‐to‐head comparison, vaccination with BNT162b2 induces significantly higher levels of SARS‐CoV‐2‐specific binding and neutralizing antibody responses compared to CoronaVac. CoronaVac induces higher CD4+ and CD8+ T‐cell responses to the structural protein than BNT162b2.
See related Editorial
The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of ...hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2-M phase cell-cycle arrest and stimulated β-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active β-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients.
Pentameric ligand-gated ion channels (pLGICs) mediate synaptic transmission and are sensitive to their lipid environment. The mechanism of phospholipid modulation of any pLGIC is not well understood. ...We demonstrate that the model pLGIC, ELIC (Erwinia ligand-gated ion channel), is positively modulated by the anionic phospholipid, phosphatidylglycerol, from the outer leaflet of the membrane. To explore the mechanism of phosphatidylglycerol modulation, we determine a structure of ELIC in an open-channel conformation. The structure shows a bound phospholipid in an outer leaflet site, and structural changes in the phospholipid binding site unique to the open-channel. In combination with streamlined alchemical free energy perturbation calculations and functional measurements in asymmetric liposomes, the data support a mechanism by which an anionic phospholipid stabilizes the activated, open-channel state of a pLGIC by specific, state-dependent binding to this site.
PDF
