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Proteins with intrinsically disordered regions (IDRs) often undergo phase separation to control their functions spatiotemporally. Changing the pH alters the protonation levels of charged sidechains, which in turn affects the attractive or repulsive force for phase separation. In a cell, the rupture of membrane-bound compartments, such as lysosomes, creates an abrupt change in pH. However, how proteins' phase separation reacts to different pH environments remains largely unexplored. Here, using extensive mutagenesis, NMR spectroscopy, and biophysical techniques, it is shown that the assembly of galectin-3, a widely studied lysosomal damage marker, is driven by cation-π interactions between positively charged residues in its folded domain with aromatic residues in the IDR in addition to π-π interaction between IDRs. It is also found that the sole two negatively charged residues in its IDR sense pH changes for tuning the condensation tendency. Also, these two residues may prevent this prion-like IDR domain from forming rapid and extensive aggregates. These results demonstrate how cation-π, π-π, and electrostatic interactions can regulate protein condensation between disordered and structured domains and highlight the importance of sparse negatively charged residues in prion-like IDRs., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Methamphetamine (METH) abuse is known to cause executive dysfunction. However, the molecular mechanism underlying METH induced executive dysfunction remains unclear. Go/NoGo experiment was performed in mice to evaluate METH-induced executive dysfunction. Immunoblot analysis of Nuclear factor-E2-related factor 2 (Nrf2), phosphorylated Nrf2 (p-Nrf2), heme-oxygenase-1 (HO-1), Glucose Regulated Protein 78(GRP78), C/EBP homologous protein (CHOP), Bcl-2, Bax and Caspase3 was performed to evaluate the levels of oxidative stress, endoplasmic reticulum (ER) stress and apoptosis in the dorsal striatum (Dstr). Malondialdehyde (MDA) levels and glutathione peroxidase (GSH-Px) activity was conducted to evaluate the level of oxidative stress. TUNEL staining was conducted to detect apoptotic neurons. The animal Go/NoGo testing confirmed that METH abuse impaired the inhibitory control ability of executive function. Meanwhile, METH down-regulated the expression of p-Nrf2, HO-1 and GSH-Px and activated ER stress and apoptosis in the Dstr. Microinjection of Tert-butylhydroxyquinone (TBHQ), an Nrf2 agonist, into the Dstr increased the expression of p-Nrf2, HO-1, and GSH-Px, ameliorated ER stress, apoptosis and executive dysfunction caused by METH. Our results indicated that the p-Nrf2/HO-1 pathway was potentially involved in mediating methamphetamine-induced executive dysfunction by inducing endoplasmic reticulum stress and apoptosis in the dorsal striatum., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cefepime and aztreonam are highly efficacious against H. influenzae, and resistant strains are rare. In this study, we isolated cefepime- and aztreonam-nonsusceptible H. influenzae strains and addressed the molecular basis of their resistance to cefepime and aztreonam., Methods: Two hundred and 28 specimens containing H. influenzae were screened, of which 32 isolates were enrolled and applied to antimicrobial susceptibility testing and whole-genome sequencing. Genetic variations that were detected in all nonsusceptible isolates with statistical significance by Fisher's exact tests were identified as cefepime or aztreonam nonsusceptibility related. Functional complementation assays were conducted to assess the in vitro effects of proteins with sequence substitutions on drug susceptibility., Results: Three H. influenzae isolates were nonsusceptible to cefepime, one of which was also nonsusceptible to aztreonam. Genes encoding TEM, SHV and CTX-M extended-spectrum β-lactamases were not detected in the cefepime- and aztreonam-nonsusceptible isolates. Five genetic variations in four genes and 10 genetic variations in five genes were associated with cefepime and aztreonam nonsusceptibility, respectively. Phylogenetic analyses revealed that changes in FtsI were correlated strongly with the MIC of cefepime and moderately with aztreonam. FtsI Thr532Ser-Tyr557His cosubstitution linked to cefepime nonsusceptibility and Asn305Lys-Ser385Asn-Glu416Asp cosubstitution to aztreonam nonsusceptibility. Functional complementation assays revealed that these cosubstitutions increased MICs of cefepime and aztreonam in susceptible H. influenzae isolates, respectively., Conclusions: Genetic variations relevant to resistant phenotypes of cefepime and aztreonam nonsusceptibility in H. influenzae were identified. Moreover, the effects of FtsI cosubstitutions on increasing MICs of cefepime and aztreonam in H. influenzae were demonstrated., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study investigated the relationship between gender and academic delay of gratification (ADOG) in college students and explored the mediating roles of anxiety/depressive mood and prospective memory to provide a theoretical intervention approach based on internal mechanisms., Methods: Random cluster sampling was conducted on 609 students from three universities situated in the Province of Anhui, China with the use of data from several questionnaires: the general information questionnaire, Generalized Anxiety Disorder Scale, Patient Health Questionnaire, Prospective and Retrospective Memory (PRM) Questionnaire, and ADOG Scale., Results: The females' anxiety and depression levels were lower than that of the males, while the female PRM and ADOG performance improved when compared to that of the males. Anxiety and depression were negatively correlated with PRM and ADOG, respectively, whereas the PRM and ADOG data demonstrated a positive correlation. Depression/anxiety and prospective memory also played a chain intermediary role between gender and ADOG., Conclusion: Gender not only directly affects college students' ADOG, but it also has indirect effects through depression/anxiety and prospective memory. Therefore, it is very important to treat students' mental health differently according to gender to improve prospective memory and delayed academic satisfaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiao, Song, Shao, Feng and Jiao.)

Background and Aims: Methamphetamine (MA) is a psychostimulant associated with a high relapse rate among patients with MA use disorder (MUD). Long-term use of MA is associated with mental disorders, executive dysfunction, aggressive behaviors, and impulsivity among patients with MUD. However, identifying which factors may be more closely associated with relapse has not been investigated. Thus, we aimed to investigate the psychological factors and the history of MA use that may influence MA relapse., Methods: This cross-sectional study included 168 male MUD patients (MUD group) and 65 healthy male residents (control group). Each patient was evaluated with self-report measures of executive dysfunction, psychopathological symptoms, impulsiveness, aggressiveness, and history of MA use. Data were analyzed with t -tests, analyses of variance, and correlation and regression analyses., Results: The MUD group reported greater executive dysfunction, psychopathological symptoms, impulsivity, and aggression than the control group. Lower age of first MA use was associated both with having relapsed one or more times and with having relapsed two or more times; greater executive dysfunction was associated only with having relapsed two or more times., Conclusion: Patients with MUD reported worse executive function and mental health. Current results also suggest that lower age of first MA use may influence relapse rate in general, while executive dysfunction may influence repeated relapse in particular. The present results add to the literature concerning factors that may increase the risk of relapse in individuals with MUD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mu, Wang, Wang, Xia, Zhao, Song, Li, Wang, Zhu, Li, Wang, Tang, Zhang, Song, Shao, Zhang, Xu and Jiao.)

Background: Endometrial cancer (EC) has been one of the most general cancers with respect to gynecological malignancies; however, there are debates on clinical strategies concerning treatments especially for patients with grade 3 (G3) endometroid endometrial cancer (EEC). Present study aimed to evaluate the lymphatic metastasis (LM) related factors and figure out the necessity of lymphadenectomy for G3 EEC patients., Methods: From January 2009 to April 2019, 3751 EC patients were admitted to Obstetrics and Gynecology Hospital of Fudan University. Clinical characteristics include age, grade, stage, and clinical pathological features. A total of 1235 EEC patients were involved in the multivariable analysis. Three hundred and eighty-one patients were involved in the survival analysis and the data attributed to sufficient follow-up information. Kaplan-Meier curve and log-rank test were utilized to analyze the survival rate., Results: Among the 1235 EEC patients, 181 (14.7%) were categorized as G3 and 1054 (85.3%) were grade 1 to grade 2 (G1-2). Multivariate analysis demonstrated that lymphovascular space invasion, adnexal involvement, and cervical stroma involvement were independent risk factors of LM in G3 cohort with odds ratio 3.4, 5.8, and 8.9; 95% confidence interval 1.1-10.6, 1.5-22.4, and 2.8-28.0, respectively. LM rates increased from 3.3% (3/92) to 75% (9/12) for G3 EEC cohort as related factor numbers increased from one to three. There were no differences between G3 and G1-2 EEC in overall survival and progression free survival. Additionally, no survival advantage was observed for G3 EEC patients at early stage with different plans of adjuvant treatment., Conclusions: For G3 EEC patients without other pathological positive factor, the LM rate is lower than those with other pathological positive factor. Survival analysis showed no difference between G3 cohort and G1-2 cohort. Also, different adjuvant treatments had no impact on the overall survival for G3 EEC patients., (Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background/aims: Splenectomy is regarded as an effective curative treatment for thrombocytopenia caused by hypersplenism in patients with cirrhosis. However, in clinical practice, thrombocytopenia is not resolved by splenectomy in all patients. This study aimed to evaluate the adverse factors responsible for platelet (PLT) counts below the normal lower limit following laparoscopic splenectomy and azygoportal disconnection (LSD)., Materials and Methods: We retrospectively evaluated the outcomes of 123 cirrhotic patients with portal hypertensive bleeding and secondary hypersplenism, who underwent LSD and who had PLT counts <125×109/L (non-normal group) or >125×109/L (normal group) at the postoperative month (POM) 3, between April 2014 and March 2017., Results: Sixteen patients (13.01%) had PLT counts <125×109/L at POM 3 after LSD, while the remaining 107 patients had normal counts. We analyzed 25 perioperative variables in both groups. A logistic multivariate regression identified age (relative risk [RR] 1.082, 95% confidence interval [CI] 1.018-1.150) and longitudinal spleen diameter (RR 0.977, 95% CI 0.955-1.000) as significant independent factors for the PLT count <125×109/L at POM 3. Bivariate correlation analysis showed that age >50 years and longitudinal spleen diameter <160 mm were threshold values for an increased risk of the PLT count <125×109/L at POM 3 after LSD., Conclusion: Age was an independent positive predictor and longitudinal spleen diameter an independent negative predictor of PLT count <125×109/L at POM 3 after LSD.

Epithelial ovarian cancer is prone to metastasizing at an early stage, but their mechanisms remain unclear. CRM1 is an important nuclear exportin and inhibitors targeting CRM1 has been explored as an anti-cancer strategy. In previous study, we observed that PEITC could combine with the hydrophobic pocket of CRM1. In this study, we focused on the effects of PEITC on EOC and its mechanisms. Results showed that IC 50 values of PEITC on SKOV3 and HO8910 cell line were 42.14 μM and 37.29 μM, respectively. PEITC inhibits the migration and invasion of SKOV3 and HO8910 cells in vitro. Oral administration of 10 μmol PEITC suppressed the metastasis of EOC in a xenograft mouse model in vivo. PEITC treatment decreased the expressions of CRM1 and mTOR (cargo protein of CRM1) in EOC cell lines and in xenograft mouse tissues. Moreover, CRM1-mediated nuclear export was attenuated by PEITC, mTOR accumulated in nucleus, expressions of mTOR S2448 and downstream effectors STAT3 S727 , MMP2 and MMP9 were decreased in a dose- and time-dependent manner. Furthermore, immunohistochemical analysis showed that CRM1 and mTOR were increased in EOC tissues compared with benign ovarian tumors, and related with advanced stage, type II EOC, positive peritoneal cytology and decreased overall survival. In addition, CRM1 was positively correlated with mTOR levels. In conclusion, our data demonstrated that PEITC suppresses the metastasis of EOC through inhibiting CRM1-mediated nuclear export, subsequently suppressing the mTOR-STAT3 pathway. Both CRM1 and mTOR were increased in EOC patients, providing a rationale for further clinical investigation of PEITC in EOC treatment.

Aim: To explore the effects of αA-crystallin in astrocyte gliosis after optic nerve crush (ONC) and the mechanism of α-crystallin in neuroprotection and axon regeneration., Methods: ONC was established on the Sprague-Dawley rat model and αA-crystallin (10(-4) g/L, 4 µL) was intravitreously injected into the rat model. Flash-visual evoked potential (F-VEP) was examined 14d after ONC, and the glial fibrillary acidic protein (GFAP) levels in the retina and crush site were analyzed 1, 3, 5, 7 and 14d after ONC by immunohistochemistry (IHC) and Western blot respectively. The levels of beta Tubulin (TUJ1), growth-associated membrane phosphoprotein-43 (GAP-43), chondroitin sulfate proteoglycans (CSPGs) and neurocan were also determined by IHC 14d after ONC., Results: GFAP level in the retina and the optic nerve significantly increased 1d after ONC, and reached the peak level 7d post-ONC. Injection of αA-crystallin significantly decreased GFAP level in both the retina and the crush site 3d after ONC, and induced astrocytes architecture remodeling at the crush site. Quantification of retinal ganglion cell (RGC) axons indicated αA-crystallin markedly promoted axon regeneration in ONC rats and enhanced the regenerated axons penetrated into the glial scar. CSPGs and neurocan expression also decreased 14d after αA-crystallin injection. The amplitude (N1-P1) and latency (P1) of F-VEP were also restored., Conclusion: Our results suggest α-crystallin promotes the axon regeneration of RGCs and suppresses the activation of astrocytes.

In the present work, we undertook the complete mitochondrial genome sequencing of an important liver cancer model inbred rat strain for the first time. The total length of the mitogenome was 16,308 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The mutation events were also reported.

Two novel sorbicillinoid analogues, (4'Z)-sorbicillin (1) and (2S)-2,3-dihydro-7-hydroxy-6-methyl-2-[(E)-prop-1-enyl]-chroman-4-one (2), together with three known compounds, (2S)-2,3-dihydro-7-hydroxy-6,8-dimethyl-2-[(E)-prop-1-enyl]-chroman-4-one (3), sorbicillin (4), and 2',3'-dihydrosorbicillin (5), were isolated from the culture broth of the fungus Trichoderma sp. associated with the seastar Acanthaster planci. Their structures were determined by analysis of the NMR and MS data. Compound I was the first example with a Z-configuration of the C-4'/C-5' double bond in the sorbyl side chain. Compounds 2 and 3 were uncommon monomeric sorbicillinoids with a cyclic sorbyl chain. 2, 3 and 5 showed moderate cytotoxic activities against various cancer cell lines.

Background: Laparoscopic liver resection (LLR) remains to be established as a safe and effective alternative to open liver resection (OLR) for hepatocellular carcinoma (HCC)., Aims: The aim of this meta-analysis is to compare laparoscopic versus open resection for HCC with regard to perioperative and oncologic outcomes., Methods: A literature search was performed to identify comparative studies reporting outcomes for both laparoscopic and open resection for HCC. Pooled odds ratios (OR) and weighted mean differences (WMD with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model., Results: Ten nonrandomized controlled studies matched the selection criteria and reported on 494 subjects, of whom 213 underwent LLR and 281 underwent OLR for HCC. Compared with the perioperative results of open surgery, reports on laparoscopic resection indicate potentially favourable outcomes in terms of operative blood loss (WMD: -160.57, 95% CI: -246.49 to -74.66), blood transfusion requirement (OR: 0.39, 95% CI: 0.18 to 0.86), postoperative morbidity (OR: 0.48, 95% CI: 0.29 to 0.78), and length of hospital stay (WMD: -5.53, 95% CI: -7.89 to -3.16). Concerning the oncologic outcomes, there was no difference between groups in surgical margin, overall survival and disease-free survival., Conclusions: LLR for HCC is superior to the OLR in terms of its perioperative results and does not compromise the oncological outcomes. Therefore, LLR may be an alternative choice for treatment of HCC.

A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.

Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed.

Aim: To carry out a hospital-based case-control study to investigate risk factors for intrahepatic cholangiocarcinoma (ICC) in China., Methods: A total of 312 ICC cases and 438 matched controls were included in the study. The presence of diabetes mellitus, hypertension, hepatolithiasis, primary sclerosing cholangitis, liver fluke infection (Clonorchis sinensis), was investigated through clinical records. Blood from all participants was tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression., Results: Compared with controls, ICC patients had a higher prevalence of HBsAg seropositivity (48.4% vs 9.6%, P<0.000), and hepatolithiasis (5.4% vs 1.1%, P=0.001). By multivariate analysis, the significant risk factors for development of ICC were HBsAg seropositivity (adjusted OR, 8.876, 95% CI, 5.973-13.192), and hepatolithiasis (adjusted OR, 5.765, 95% CI, 1.972-16.851). The prevalence of anti-HCV seropositivity, diabetes mellitus, hypertension, cigarette smoking, and alcohol consumption were not significantly different between cases and controls., Conclusion: These findings suggest that HBV infection and hepatolithiasis are strong risk factors for development of ICC in China.

Natural curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) isolated from Curcuma longa (turmeric), and synthetic curcumin analogs (A(1-7), B(1-7), C(1-6) and D(1-7)) were evaluated in vitro for the alpha-glucosidase inhibitory activity via UV and circular dichroism (CD) spectroscopy. The results indicated that natural curcuminoid compound 3 showed a remarkable inhibitory effect with IC(50) of 23.0 microM, and the synthetic compounds A(2), B(2), C(2) and D(2) showed potent inhibitory effects with IC(50) of 2.8, 2.6, 1.6 and 8.2 microM, respectively. Kinetic study exhibited that the mechanism of alpha-glucosidase inhibition of both 3 and C(2) was non-competitive. The structure activity relationship revealed that the ortho dihydroxyl groups could form a more tight interaction with alpha-glucosidase to exert more potential inhibitory activities.

In 1998, an epidemic of hand-foot-and-mouth disease and herpangina caused by enterovirus 71 occurred in Taiwan, leaving many fatalities and severely handicapped survivors in its wake. The reasons this rather common pathogen would cause such a large-scale epidemic remain unknown. A seroepidemiological survey to elucidate the epidemiological characteristics of this outbreak, including its incidence and case-fatality rates was undertaken. Microneutralization tests for antibodies against enterovirus 71 were used to screen four collections of serum samples: 1) 202 specimens taken from individuals > or = 4 years old in 1994; 2) 245 specimens collected from individuals of all ages in 1997; 3) 1,258 specimens collected from individuals of all ages in 1999; and 4) sera samples from a birth cohort of 81 children who had yearly blood samples taken from 1988-98. After the maternal antibody had declined, the seropositive rates began to increase with age. Approximately half of all children aged 6 years or older were enterovirus 71 seropositive. Significantly higher seropositive rates were noted in 1999 than in 1997, in children aged 0.5-3 years. The incidence of enterovirus 71 infection during the epidemic was estimated to be 13-22%, with the higher rates in younger children. The case-fatality rate was highest (96.96 per 100,000) in infants aged 6-11 months, and declined in older children. The results showed that enterovirus 71 is endemic in Taiwan. The apparent lack of large-scale enterovirus 71 activity in the 3 years before 1998 might have been the prelude to the epidemic's appearance in 1998, and might suggest that enterovirus 71 infection will reappear every few years. The lack of a protective antibody in younger children may account for the high incidence and case-fatality rate in this age group., (Copyright 2002 Wiley-Liss, Inc.)