Misfolding and aggregation of microtubule-associated tau protein is implicated in a variety of neurodegenerative disorders (named tauopathies), including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). AD is the most common type of dementia associated with aging, and CTE is a special tauopathy that mostly affects contact sports athletes (such as those active in American football and boxing). Experimental studies have found that tau acetylated on residue K353 exhibited a declined aggregation propensity; however, the underlying molecular mechanism remains elusive. In this study, we performed replica exchange and conventional molecular dynamics simulations of acetylated and unacetylated tau protein models in an explicit solvent. Our results revealed that the acetylated R4 (the fourth microtubule-binding repeat domain) dimer showed less β structure and more disordered conformations than the unacetylated one. K353 acetylation weakened peptide–peptide interactions and interrupted the salt-bridge network, thus inhibiting R4 dimerization. Besides, K353 acetylation reduced the β-sheet structure probability and induced loosely packed conformations of R3–R4 (the third and fourth microtubule-binding repeat regions) protofibrils. The replacement of the charged group by acyl on K353 resulted in the loss of K353–D358 salt bridges, leading to the enlargement of the β6−β7 angle and the distance between the carboxyl-terminal and β-turn region, finally eliciting an opened "H" configuration. Our work provided a clear picture of the inhibitory mechanisms of K353 acetylation on tau at the microscopic level, which may be helpful in the development of new therapeutics against tauopathies from the perspective of post-translational modification (PTMs).
Extremely high-temperature lightning generates NOx by electrolyzing nitrogen and oxygen molecules and affects ozone concentration. The Pearl River Delta is located in the world's high-value area of lightning density, and lightning-generated NOx (LNOx) cannot be ignored. In this study, the Guangdong-Hong Kong-Macao Lightning Location System and multi-site atmospheric composition data were used to investigate the effects of lightning activity on atmospheric composition in the PRD region. The distribution density of lightning locations in Guangdong Province is gradually decreasing from the center, i.e., the south-central part of Guangzhou City, to the surrounding area; and its frequency during 2013-2021 shows a downward trend dominated by urban areas. The thunderstorm increased the surface NOx concentration at urban stations by 13.84% to 20.47%. A lower lightning frequency and low background concentration indicated that the natural nitrogen source contribution from lightning at suburban sites was low. The average decrease in O3 concentration at urban stations (15.92-25.06%) was significantly higher than that at suburban stations (5.34-8.95%) due to the influence of titration and lower actinic radiation. There was a greater fluctuation in NOx and O3 concentrations during the typical events, and the surface NOx concentration is most significantly responsive to LNOx on lightning striking the meteorology tower. This phenomenon has not been reported but is consistent with the laboratory-based observations suggesting the amount of LNO increases with peak current. LNOx has a significant impact on air quality in the PRD during the high convective season. More in situ and vertical distribution observations are necessary to explore the impact of LNOx on the ground.
Abstract Background Temporary ileostomy (TI) has proven effective in reducing the severity of anastomotic leakage after rectal cancer surgery; however, some ileostomies fail to reverse over time, leading to conversion into a permanent stoma (PS). In this study, we aimed to investigate the preoperative risk factors and cumulative incidence of TI non-closure after sphincter-preserving surgery for rectal cancer. Materials and Methods We conducted a meta-analysis after searching the Embase, Web of Science, PubMed, and MEDLINE databases from their inception until November 2023. We collected all published studies on the risk factors related to TI non-closure after sphincter-preserving surgery for rectal cancer. Results A total of 1610 studies were retrieved, and 13 studies were included for meta-analysis, comprising 3026 patients. The results of the meta-analysis showed that the identified risk factors included older age (p = 0.03), especially > 65 years of age (p = 0.03), male sex (p = 0.009), American Society of Anesthesiologists score ≥ 3 (p = 0.004), comorbidity (p = 0.001), and distant metastasis (p < 0.001). Body mass index, preoperative hemoglobin, preoperative albumin, preoperative carcinoma embryonic antigen, tumor location, neoadjuvant chemoradiotherapy, smoking, history of abdominal surgery, and open surgery did not significantly change the risk of TI non-closure Conclusion We identified five preoperative risk factors for TI non-closure after sphincter-preserving surgery for rectal cancer. This information enables surgeons to identify high-risk groups before surgery, inform patients about the possibility of PS in advance, and consider performing protective colostomy or Hartmann surgery.
The purposes of this study were to analyze the relation between enhancement patterns on dynamic enhanced MRI and histologic microvessel patterns of solitary pulmonary nodules (SPNs) and to address the topic of false-positive findings in differentiating SPNs with dynamic MRI.Sixty-eight patients with 68 pathologically proven SPNs (diameter
Objective Split-dose polyethylene glycol (PEG) is routinely used for bowel preparation before colonoscopy. This study aimed to investigate the composition of gut microbiota and its functions in pediatric patients undergoing split-dose PEG bowel preparation for colonoscopy to understand the stability and resilience of gut microbiota. Material and methods From September to December 2021, 19 pediatric patients were enrolled at Shenzhen Children’s Hospital and 76 samples (4 time points) were analyzed using metagenomics. Time points included Time_1 (one day before bowel preparation), Time_2 (one day after colonoscopy), Time_3 (two weeks after bowel preparation), and Time_4 (four weeks after bowel preparation). Result Alpha diversity comparison at both the species and gene levels showed a decrease in community richness after colonoscopy, with little statistical significance. However, the Shannon diversity index significantly decreased ( P <0.05) and gradually returned to pre-preparation levels at two weeks after bowel preparation. The genus level analysis showed six genera ( Eubacterium , Escherichia , Intertinibacter , Veillonella , Ruminococcaceae unclassified , and Coprobacillus ) significantly different across the four time periods. Additionally, at the species level, the abundance of Escherichia coli , Bacteroides fragilis , and Veillonella parvula significantly increased at one day after colonoscopy before gradually decreasing at two weeks after bowel preparation. In contrast, the abundance of Intertinibacter bartlettii decreased at one day after colonoscopy but then recovered at two weeks after bowel preparation, reaching the preoperative level at four weeks after bowel preparation. Furthermore, five functional pathways (base excision repair, biosynthesis of ansamycins, biosynthesis of siderophore group nonribosomal peptide, flavonoid biosynthesis, and biosynthesis of type II polyketide products) were significantly different across the four time periods, with recovery at two weeks after bowel preparation and reaching preoperative levels at four weeks after bowel preparation. Conclusions Gut microbiota at the genus level, species level, and functional pathways are impacted in pediatric patients undergoing split-dose PEG bowel preparation and colonoscopy, with recovery two weeks following bowel preparation. However, the phylum level was not impacted. Modifications in gut microbiota composition and function may be investigated in future studies of bowel preparation. This study highlights the stability and resilience of gut microbiota among pediatric patients during bowel preparation.
Figure S2. The KEGG pathway analysis in parental genes of DECs. The KEGG pathway analysis in parental genes of DECs at the P2 stage (A), P3 stage (B), and P4 stage (C), respectively. (TIF 615 kb)
The abnormal self-assembly of amyloid-β (Aβ) peptides into toxic fibrillar aggregates is associated with the pathogenesis of Alzheimer's disease (AD). The inhibition of β-sheet-rich oligomer formation is considered as the primary therapeutic strategy for AD. Previous experimental studies reported that norepinephrine (NE), one of the neurotransmitters, is able to inhibit Aβ aggregation and disaggregate the preformed fibrils. Moreover, exercise can markedly increase the level of NE. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations to investigate the conformational ensemble of Aβ1–42 dimer with and without NE molecules. Our results show that without NE molecules, Aβ1–42 dimer transiently adopts a β-hairpin-containing structure, and the β-strand regions of this β-hairpin (residues 15QKLVFFA21 and 33GLMVGGVV40) strongly resemble those of the Aβ fibril structure (residues 15QKLVFFA21 and 30AIIGLMVG37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide β-sheet content and suppress the formation of the above-mentioned β-hairpin, leading to a more disordered coil-rich Aβ dimer. Five dominant binding sites are identified, and the central hydrophobic core 16KLVFFA21 site and C-terminal 31IIGLMV36 hydrophobic site are the two most favorable ones. Our data reveal that hydrophobic, aromatic stacking, hydrogen-bonding and cation-π interactions synergistically contribute to the binding of NE molecules to Aβ peptides. MD simulations of Aβ1–42 protofibril show that NE molecules destabilize Aβ protofibril by forming H-bonds with residues D1, A2, D23, and A42. This work reveals the molecular mechanism by which NE molecules inhibit Aβ1–42 aggregation and disaggregate Aβ protofibrils, providing valuable information for developing new drug candidates and exercise therapy against AD.
To validate ascending aorta-lower abdominal aorta bypass grafting treatment for patients with descending aortic coarctation and an aortic valve disease.The three patients in whom a descending atypical aortic coarctation was associated with an aortic valve disease were treated with one stage surgical treatment with aortic bypass grafting through the diaphragm and aortic valve replacement in our heart center. Operative technique consisted of performing ascending aorta-lower abdominal aorta bypass grafting through diaphragm muscle and implementing aortic valve replacement. The mean time for extracorporeal circulation and occluding clamp of aorta was recorded. Blood pressure data for pre- and post-operation was measured in the limbs. Computer-enhanced transvenous angiograms of pre- and post-operation were applied for detection of aortic stenosis. The other adverse events were noticed in outpatient service during a follow-up period.The mean extracorporeal circulation time was 54 ± 11 min. The mean time for occluding clamp of aorta was 34 ± 6 min. An arterial pressure gradient was totally corrected after surgical treatment. Post-operation computer-enhanced transvenous angiograms showed the grafts to be open with a fluent flow. The patients had no gastrointestinal tract complications. No adverse event was noticed during a follow-up period in outpatient service.Treatment of ascending aorta-lower abdominal aorta bypass is advisable for patients with descending aortic coarctation and an aortic valve disease.
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