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Studies in model microorganisms showed that cell division is highly vulnerable to high hydrostatic pressure (HHP). Disassembly of FtsZ filaments induced by HHP results in the failure of cell division and formation of filamentous cells in E. coli. The specific characteristics of FtsZ that allow for functional cell division in the deep-sea environments, especially in obligate piezophiles that grow exclusively under HHP condition, remain enigmatic. In this study, by using a self-developed HHP in-situ fixation apparatus, we investigated the effect of HHP on FtsZ by examining the subcellular localization of GFPtagged FtsZ in vivo and the stability of FtsZ filament in vitro. We compared the pressure tolerance of FtsZ proteins from pressure-sensitive strain Shewanella oneidensis MR-1 (FtsZSo) and obligately piezophilic strain Shewanella benthica DB21MT-2 (FtsZSb). Our findings showed that, unlike FtsZSo, HHP hardly affected the Z-ring formation of FtsZSb, and filaments composed of FtsZSb were more stable after incubation under 50 MPa. By constructing chimeric and single amino acid mutated FtsZ proteins, we identified five residues in the N-terminal GTPase domain of FtsZSb whose mutation would impair the Z-ring formation under HHP conditions. Overall, these results demonstrate that FtsZ from the obligately piezophilic strain exhibits superior pressure tolerance than its homologue from shallow water species, both in vivo and in vitro. Differences in pressure tolerance of FtsZ are largely attributed to the N-terminal GTPase domain. This represents the first in-depth study of the adaptation of microbial cytoskeleton protein FtsZ to high hydrostatic pressure, which may provide insights into understanding the complex bioprocess of cell division under extreme environments. [ABSTRACT FROM AUTHOR]

High hydrostatic pressure (HHP) regulated gene expression is one of the most commonly adopted strategies for microbial adaptation to the deep-sea environments. Previously we showed that the HHP-inducible trimethylamine N-oxide (TMAO) reductase improves the pressure tolerance of deep-sea strain Vibrio fluvialis QY27. Here, we investigated the molecular mechanism of HHPresponsive regulation of TMAO reductase TorA. By constructing torR and torS deletion mutants, we demonstrated that the two-component regulator TorR and sensor TorS are responsible for the HHP-responsive regulation of torA. Unlike known HHP-responsive regulatory system, the abundance of torR and torS was not affected by HHP. Complementation of the ΔtorS mutant with TorS altered at conserved phosphorylation sites revealed that the three sites were indispensable for substrate-induced regulation, but only the histidine located in the alternative transmitter domain was involved in pressure-responsive regulation. Taken together, we demonstrated that the induction of TMAO reductase by HHP is mediated through the TorRS system and proposed a bifurcation of signal transduction in pressure-responsive regulation from the substrate-induction. This work provides novel knowledge of the pressure regulated gene expression and will promote the understanding of the microbial adaptation to the deep-sea HHP environment. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the effect of hypothyroidism and thyroxine replacement therapy on the prognosis of nasopharyngeal carcinoma (NPC) patients. Methods: The clinical data of 284 NPC patients, who received intensity‐modulated radiation therapy (IMRT) between January 2011 and December 2016, were retrospectively analyzed. Results: Hypothyroidism occurred in 38% of patients. Patients with hypothyroidism had significantly better disease‐free survival (DFS) (p = 0.002) and relapse‐free survival (RFS) (p = 0.008). Multivariate analysis showed that hypothyroidism was a positive independent prognostic factor (DFS and RFS). Among the patients with hypothyroidism, thyroxine replacement therapy did not yield inferior survival (DFS, RFS, all p > 0.05). Conclusions: The NPC patients with complete response are at risk of hypothyroidism, which is attributable to escalating dose. These patients experienced clinical hypothyroidism could be adequately treated with thyroid hormone replacement. Further investigation of the underlying biological mechanism and potential therapeutic implications are required. [ABSTRACT FROM AUTHOR]

aimed to explore the short- and long-term efficacy of surgery for early-stage NPC. Methods: We retrospectively evaluated 341 patients diagnosed with early-stage NPC between September 2010 and December 2015. Among them, 58 patients underwent endoscopic nasopharyngectomy combined with chemoradiotherapy, whereas 283 patients underwent conventional chemoradiotherapy. The patients who underwent concurrent chemoradiotherapy or radiotherapy alone were matched to patients who underwent surgery in a 1:2 ratio using propensity score matching to analyze the clinical efficacy of each therapeutic modality. The primary endpoint was survival, and the secondary endpoints were tumor regression rate and reduction in Epstein–Barr virus (EBV)-DNA levels. Results: After matching, 156 patients were enrolled (58 patients in the surgery group; 98 patients in the non-surgery group). The baseline data of the matched patients had good inter-group comparability (All P> 0.05). The surgery group had significantly higher 5-year overall survival (98.30% vs. 91.70%), disease-free survival (98.30% vs. 81.40%), and recurrence-free survival (100.00% vs. 90.10%) rates than did the non-surgery group (All P< 0.05). In total, 0 and 14 patients in the surgery and non-surgery groups, respectively, had residual cancer at the end of treatment (P=0.001). All patients in the surgery group tested negative for EBV-DNA, whereas two patients in the non-surgery group tested positive. The incidence of hematologic toxicity during treatment was similar between the two groups (All P> 0.05). Still, the incidence of severe oral mucositis was lower in the surgery group than in the non-surgery group (37.9% vs. 54.08%, P=0.051). Conclusion: Surgery can improve the clearance rate of EB virus and reduce tumor residue. Surgery may be a safe and effective treatment for early NPC. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical characteristics of nasopharyngeal carcinoma (NPC) and a concomitant hepatitis B virus (HBV) infection, as well as the potential effects of HBV infection and antiviral therapy on prognosis. Methods: We conducted a retrospective chart review of all NPC patients from December 2010 to December 2014. After collecting medical records and conducting follow‐ups on patients, a total of 876 eligible NPC patients were included. For each patient, medical records were reviewed. Factors predictive of outcome were compared using the log‐rank test and Cox regression analysis. Results: Among the 876 participants, 106 (12.1%) patients were HBV‐infected patients. The hepatitis B surface antigen‐positive [HBsAg(+)] group had a lower CD4+ T cell count than the HBsAg(−) group (P =.048). Among patients with stage I/II NPC, 5‐year overall survival (OS), disease‐free survival (DFS), relapse‐free survival, and distant metastasis‐free survival (DMFS) of the HBsAg(+) group were 82.5%, 70.7%, 87.7%, and 76.6%, respectively, whereas those of the HBsAg(−) group were 91.4%, 86.0%, 93.8%, and 92.1%, respectively. Statistically significant differences in OS, DFS, and DMFS existed between both groups (P =.017,.018, and.004, respectively). The multivariate analysis indicated that HBsAg status and N stage are independent risk factors affecting OS, DFS, and DMFS of NPC patients. A statistically significant difference in 5‐year DMFS existed between the antivirus (90.0%) and no‐antivirus groups (70.0%) (P =.043). Conclusions: Hepatitis B virus infection is an independent risk factor for early stage NPC, which may be associated with its reduced immune functions compared to the HBsAg(−) group. Anti‐HBV treatment may improve the prognosis of HBV‐infected NPC patients. [ABSTRACT FROM AUTHOR]

Dead-times are necessary in switching output stage to avoid shoot-through current between the high side (HS) and the low side (LS) power transistors. However, excessively long dead-times can lead to unwanted reverse conduction and power loss. Sensing the duration of reverse conductions are especially difficult for high-voltage enhancement mode (e-mode) gallium nitride (GaN) HEMTs due to their fast switching speed. High-precision sensing circuits are required for dead-time correction as the load current changes and to withstand large voltage swings. Traditional CMOS-based sensing circuits (e.g. standard logic gates) are not suitable for GaN-based converters as they can only handle limited voltage ranges. In addition, severe undershoots (up to -4 V) may damage the sensing circuit. Here, a gate driver IC for e-mode GaN power output stages capable of detecting the presence of reverse conduction with a best resolution of 0.66 ns, a dead-time adjustment resolution of 0.33 ns, and with on-chip closed-loop control is presented. In addition, a novel reverse conduction sensing circuit that can accommodate the large voltage swings at the switching node (SW) is also described. [ABSTRACT FROM AUTHOR]

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults. [ABSTRACT FROM AUTHOR]

Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high-dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells (HL-60) after treatment with Ara-C to reveal its antitumor mechanism. The metabolic results revealed that four nucleotides (ATP, ADP, CDP, and dCTP) could be used as potential biomarkers indicating the benefit of high-dose Ara-C over lower dose Ara-C treatment. Combining metabolic perturbation and cell cycle analysis, we conjectured that, apart from the acknowledged mechanism of Ara-C on tumor inhibition, high-dose Ara-C could present a specific action pathway. It was suggested that the pronounced rise in AMP/ATP ratio induced by high-dose Ara-C can trigger AMP-activated protein kinase (AMPK) and subsequently Forkhead Box, class O (FoxO), to promote cell cycle arrest. Moreover, the significant decrease in CDP pool induced by high-dose Ara-C might further accelerate the reduction of dCTP, which then aggravates DNA synthesis disturbance. As a result, all of these alterations led to heightened tumor inhibition. This study provides new insight in the investigation of potential mechanisms in the clinical benefits of high-dose Ara-C in therapy for AML. [ABSTRACT FROM AUTHOR]

Flagella of some pathogens or marine microbes are sheathed by an apparent extension of the outer cell membrane. Although flagellar sheath has been reported for almost 60 years, little is known about its function and the mechanism of its assembly. Recently, we have observed a novel type of sheath that encloses a flagellar bundle, instead of a single flagellum, in a marine magnetotactic bacterium MO-1. Here, we reported isolation and characterization of the sheath which can be described as a six-start, right-handed helical tubular structure with a diameter of about 100 nm, and a pitch of helix of about 260 nm. By proteomic, microscopic and immunolabelling analyses, we showed that the sheath of MO-1 consists of glycoprotein with an apparent molecular mass > 350 kDa. This protein, named sheath-associated protein (Sap), shows homology with bacterial adhesins and eukaryotic calcium-dependent adherent proteins (cadherin). Most importantly, we showed that calcium ions mediate the assembly of the tubular-shaped sheath and disintegration of the sheath was deleterious for smooth swimming of MO-1 cells. The disintegrated sheath was efficiently reconstituted in vitro by adding calcium ions. Altogether, these results demonstrate a novel bacterial Ca-dependent surface architecture, which is essential for bacterial swimming. [ABSTRACT FROM AUTHOR]

Describes the discovery of an apparent transition between active and non-active second-harmonic generation (SHG) in the NaNb[sub 3]O[sub 8] solid solutions with the tetragonal tungsten bronze structure. Observation of powder SHG with a magnitude comparable to KH[sub 2]PO[sub 4] upon addition of Nb[sub 2]O[sub 5]; Observation of microcracks and ferroelectric domain boundaries.