MRE11 promotes oral cancer progression through RUNX2/CXCR4/AKT/FOXA2 signaling in a nuclease-independent manner

MRE11, the nuclease component of RAD50/MRE11/NBS1 DNA repair complex which is essential for repair of DNA double-strand-breaks in normal cells, has recently garnered attention as a critical factor in solid tumor development. Herein we report the crucial role of MRE11 in oral cancer progression in a nuclease-independent manner and delineate its key downstream effectors including CXCR4. MRE11 expression in oral cancer samples was positively associated with tumor size, cancer stage and lymph node metastasis, and was predictive of poorer patient survival and radiotherapy resistance. MRE11 promoted cell proliferation/migration/invasion in a nuclease-independent manner but enhanced radioresistance via a nuclease-dependent pathway. The nuclease independent promotion of EMT and metastasis was mediated by RUNX2, CXCR4, AKT, and FOXA2, while CXCR4 neutralizing antibody mitigated these effects in vitro and in vivo. Collectively, MRE11 may serve as a crucial prognostic factor and therapeutic target in oral cancer, displaying dual nuclease dependent and independent roles that permit separate targeting of tumor vulnerabilities in oral cancer treatment

The IPIN 2019 Indoor Localisation Competition—Description and Results

IPIN 2019 Competition, sixth in a series of IPIN competitions, was held at the CNR Research Area of Pisa (IT), integrated into the program of the IPIN 2019 Conference. It included two on-site real-time Tracks and three off-site Tracks. The four Tracks presented in this paper were set in the same environment, made of two buildings close together for a total usable area of 1000 m 2 outdoors and and 6000 m 2 indoors over three floors, with a total path length exceeding 500 m. IPIN competitions, based on the EvAAL framework, have aimed at comparing the accuracy performance of personal positioning systems in fair and realistic conditions: past editions of the competition were carried in big conference settings, university campuses and a shopping mall. Positioning accuracy is computed while the person carrying the system under test walks at normal walking speed, uses lifts and goes up and down stairs or briefly stops at given points. Results presented here are a showcase of state-of-the-art systems tested side by side in real-world settings as part of the on-site real-time competition Tracks. Results for off-site Tracks allow a detailed and reproducible comparison of the most recent positioning and tracking algorithms in the same environment as the on-site Tracks

Interaction between <it>Serotonin Transporter</it> and <it>Serotonin Receptor 1 B</it> genes polymorphisms may be associated with antisocial alcoholism

<p>Abstract</p> <p>Background</p> <p>Several studies have hypothesized that genes regulating the components of the serotonin system, including <it>serotonin transporter</it> (<it>5-HTTLPR</it>) and <it>serotonin 1 B receptor (5-HT1B),</it> may be associated with alcoholism, but their results are contradictory because of alcoholism’s heterogeneity. Therefore, we examined whether the <it>5-HTTLPR</it> gene and <it>5-HT1B</it> gene <it>G861C</it> polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan.</p> <p>Methods</p> <p>We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (<it>n</it> = 120) and antisocial non-alcoholism (AS-N-ALC) group (<it>n</it> = 153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP.</p> <p>Results</p> <p>There were no significant differences in the genotypic frequency of the <it>5-HT1B G861C</it> polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the <it>5-HTTLPR S/S, S/L</it>_<it>G</it><it>,</it> and <it>L</it>_<it>G</it><it>/L</it>_<it>G</it> genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the <it>5-HTTLPR S/S, S/L</it>_<it>G</it><it>,</it> and <it>L</it>_<it>G/</it><it>L</it>_<it>G</it> genotypes may have interacted with the <it>5-HT1B G861C C/C</it> polymorphism and increased the risk of becoming antisocial alcoholism.</p> <p>Conclusion</p> <p>Our study suggests that neither the <it>5-HTTLPR</it> gene nor the <it>5-HT1B G861C</it> polymorphism alone is a risk factor for antisocial alcoholism in Taiwan’s Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.</p

Structural basis of adaptor-mediated protein degradation by the tail-specific PDZ-protease Prc

MepS is a peptidoglycan (PG) cross-link specific hydrolase needed for cell wall expansion and its cellular levels must be tightly regulated. Here the authors present the structure of the MepS degrading protease Prc bound to its adaptor NlpI and propose a model how the NlpI-Prc complex mediates MepS degradation

Poorer sustained attention in bipolar I than bipolar II disorder

<p>Abstract</p> <p>Background</p> <p>Nearly all information processing during cognitive processing takes place during periods of sustained attention. Sustained attention deficit is among the most commonly reported impairments in bipolar disorder (BP). The majority of previous studies have only focused on bipolar I disorder (BP I), owing to underdiagnosis or misdiagnosis of bipolar II disorder (BP II). With the refinement of the bipolar spectrum paradigm, the goal of this study was to compare the sustained attention of interepisode patients with BP I to those with BP II.</p> <p>Methods</p> <p>In all, 51 interepisode BP patients (22 with BP I and 29 with BP II) and 20 healthy controls participated in this study. The severity of psychiatric symptoms was assessed by the 17-item Hamilton Depression Rating Scale and the Young Mania Rating Scale. All participants undertook Conners' Continuous Performance Test II (CPT-II) to evaluate sustained attention.</p> <p>Results</p> <p>After controlling for the severity of symptoms, age and years of education, BP I patients had a significantly longer reaction times (F_(2,68)= 7.648, <it>P </it>= 0.001), worse detectability (<it>d'</it>) values (F_(2,68)= 6.313, <it>P </it>= 0.003) and more commission errors (F_(2,68)= 6.182, <it>P </it>= 0.004) than BP II patients and healthy controls. BP II patients and controls scored significantly higher than BP I patients for <it>d' </it>(F = 6.313, <it>P </it>= 0.003). No significant difference was found among the three groups in omission errors and no significant correlations were observed between CPT-II performance and clinical characteristics in the three groups.</p> <p>Conclusions</p> <p>These findings suggested that impairments in sustained attention might be more representative of BP I than BP II after controlling for the severity of symptoms, age, years of education and reaction time on the attentional test. A longitudinal follow-up study design with a larger sample size might be needed to provide more information on chronological sustained attention deficit in BP patients, and to illustrate clearer differentiations between the three groups.</p

Drug Resistance Profile and Clinical Features for Hepatitis C Patients Experiencing DAA Failure in Taiwan

About 4% of the population in Taiwan are seropositive for anti-HCV Ab and 70% with HCV RNA. To address this high chronic hepatitis C disease load, Taiwan National Health Insurance started reimbursing genotype-specific DAAs in 2017 and pangenotype DAAs in mid-2018. With a 97% SVR12 rate, there were still 2–3% of patients that failed to clear HCV. To understand the causes of DAA failure in Taiwan, we conducted a multi-center, clinical, and virologic study. A total of 147 DAA-failure patients were recruited, and we searched HCV NS3/4A, NS5A and NS5B for known resistance-associated substitutions (RASs) by population sequencing, and conducted whole genome sequencing (WGS) for those without known RASs. A total of 107 patients received genotype-specific DAAs while 40 had pangenotype DAAs. Clinically, the important cause of failure is poor adherence. Virologically, common RASs in genotype-specific DAAs were NS5A-L31, NS5A-Y93, and NS5B-C316, while common RASs in pangenotype DAAs were NS5A-L31, NS5A-A/Q/R30, and NS5A-Y93. Additionally, new amino acid changes were found by WGS. Finally, we identified 12 cases with inconsistent baseline and post-treatment HCV genotypes, which is suggestive of re-infection rather than treatment failure. Our study described the drug resistance profile for DAA failure in Taiwan, showing differences from other countries

Effect of diabetes mellitus on risk of latent TB infection in a high TB incidence area: a community-based study in Taiwan

Objective: To investigate the association between diabetes and latent tuberculosis infections (LTBI) in high TB incidence areas. Design: Community-based comparison study. Setting: Outpatient diabetes clinics at 4 hospitals and 13 health centres in urban and rural townships. A community-based screening programme was used to recruit non-diabetic participants. Participants: A total of 2948 patients with diabetes aged older than 40 years were recruited, and 453 non-diabetic participants from the community were enrolled. Primary and secondary outcome measures: The interferon-gamma release assay (IGRA) and the tuberculin skin test were used to detect LTBI. The IGRA result was used as a surrogate of LTBI in logistic regression analysis. Results: Diabetes was significantly associated with LTBI (adjusted OR (aOR)=1.59; 95% CI 1.11 to 2.28) and age correlated positively with LTBI. Many subjects with diabetes also had additional risk factors (current smokers (aOR=1.28; 95% CI 0.95 to 1.71), comorbid chronic kidney disease (aOR=1.26; 95% CI 1.03 to 1.55) and history of TB (aOR=2.08; 95% CI 1.19 to 3.63)). The presence of BCG scar was protective (aOR=0.66; 95% CI 0.51 to 0.85). Duration of diabetes and poor glycaemic control were unrelated to the risk of LTBI. Conclusion: There was a moderately increased risk of LTBI in patients with diabetes from this high TB incidence area. This finding suggests LTBI screening for the diabetics be combined with other risk factors and comorbidities of TB to better identify high-risk groups and improve the efficacy of targeted screening for LTBI