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Adenosine triphosphate (ATP) is an abundant molecule with crucial cellular roles as the energy currency and a building block of nucleic acids and for protein phosphorylation. Here we show that ATP mediates the phase separation of basic intrinsically disordered proteins (bIDPs). In the resulting condensates, ATP is highly concentrated (apparent partition coefficients up to 7700) and serves as bridges between bIDP chains. These liquid-like droplets have some of the lowest interfacial tension (∼25 pN/μm) but high zero-shear viscosities (1-15 Pa s) due to the bridged protein networks, and yet their fusion has some of the highest speeds (∼1 μm/ms). The rapid fusion manifests extreme shear thinning, where the apparent viscosity is lower than zero-shear viscosity by over 100-fold, made possible by fast reformation of the ATP bridges. At still higher concentrations, ATP does not dissolve bIDP droplets but results in aggregates and fibrils.

Objective: To verify the predictive value of the Second Revision of the International Staging System (R2-ISS) in newly diagnosed patients with multiple myeloma (MM) who underwent first-line autologous hematopoietic stem cell transplantation (ASCT) in a new drug era in China. Methods: This multicenter retrospective cohort study enrolled patients with newly diagnosed MM from three centers in China (Beijing Chao-Yang Hospital, Capital Medical University; the First Affiliated Hospital, Sun Yat-Sen University, and the Second Affiliated Hospital of Naval Medical University) from June 2008 to June 2018. A total of 401 newly diagnosed patients with MM who were candidates for ASCT were enrolled in this cohort, all received proteasome inhibitor and/or immunomodulator-based induction chemotherapy followed by ASCT. Baseline and follow-up data were collected. The patients were regrouped using R2-ISS. Progression-free survival (PFS) and overall survival (OS) were analyzed. The Kaplan-Meier method was used to analyze the survival curve and two survival curves were compared using the log-rank test. Cox regression analysis were performed to analyze the relationship between risk factors and survival. Results: The median age of the patients was 53 years (range 25-69 years) and 59.5% (240 cases) were men. Newly diagnosed patients with renal impairment accounted for 11.5% (46 cases). According to Revised-International Staging System (R-ISS), 74 patients (18.5 %) were diagnosed with stage Ⅰ, 259 patients (64.6%) with stage Ⅱ, and 68 patients (17.0%) with stage Ⅲ. According to the R2-ISS, the distribution of patients in each group was as follows: 50 patients (12.5%) in stage Ⅰ, 95 patients (23.7%) in stage Ⅱ, 206 patients (51.4%) in stage Ⅲ, and 50 patients (12.5%) in stage Ⅳ. The median follow-up time was 35.9 months (range, 6-119 months). According to the R2-ISS stage, the median PFS in each group was: 75.3 months for stage Ⅰ; 62.0 months for stage Ⅱ, 39.2 months for stage Ⅲ, and 30.3 months for stage Ⅳ; and the median OS was not reached, 86.6 months, 71.6 months, and 38.5 months, respectively. There were statistically significant differences in PFS and OS between different groups (both P <0.001). Multivariate Cox regression analysis showed that stages Ⅲ and Ⅳ of the R2-ISS were independent prognostic factors for PFS ( HR =2.37, 95% CI 1.30-4.30; HR =4.50, 95% CI 2.35-9.01) and OS ( HR =4.20, 95% CI 1.50-11.80; HR =9.53, 95% CI 3.21-28.29). Conclusions: The R2-ISS has significant predictive value for PFS and OS for transplant-eligible patients with MM in the new drug era. However, the universality of the R2-ISS still needs to be further verified in different populations.

Aims: Deoxynivalenol (DON), namely vomitoxin, is one of the most prevalent fungal toxins in cereal crops worldwide. However, the underlying toxic mechanisms of DON remain largely unknown., Main Methods: DON exposure-caused changes in the murine plasma metabolome and gut microbiome were investigated by an LC-MS/MS-based nontargeted metabolomics approach and sequencing of 16S rRNA in fecal samples, respectively. Cellular models were then used to validate the findings from the metabolomics study., Key Findings: DON exposure increased intestinal barrier permeability evidenced by its-mediated decrease in colonic Claudin 5 and E-cadherin, as well as increases in colonic Ifn-γ, Cxcl9, Cxcl10, and Cxcr3. Furthermore, DON exposure resulted in a significant increase in murine plasma levels of deoxycholic acid (DCA). Also, DON exposure led to gut microbiota dysbiosis, which was associated with DON exposure-caused increase in plasma DCA. In addition, we found not only DON but also DCA dose-dependently caused a significant increase in the levels of IFN-γ, CXCL9, CXCL10, and/or CXCR3, as well as a significant decrease in the expression levels of Claudin 5 and/or E-cadherin in the human colonic epithelial cells (NCM460)., Significance: DON-mediated increase in DCA contributes to DON-caused intestinal injury. DCA may be a potential therapeutic target for DON enterotoxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jun-Yan Liu reports financial support was provided by Chongqing Municipal Natural Science Foundation-Education Commission., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

KDF1 has been reported to be correlated with carcinogenesis. However, its role and mechanism are far from clear. To explore the possible role and underlying mechanism of KDF1 in lung adenocarcinoma (LUAD), we investigated KDF1 expression in LUAD tissues and the influence of KDF1 in the phenotype of LUAD cells (A549 and PC-9) as well as the underlying mechanism. Compared to non-tumor lung epithelial cells, KDF1 was upregulated in the cancer cells of the majority of LUAD patients, and its expression was correlated with tumor size. Patients with enhanced KDF1 in cancer cells (compared with paired adjacent non-neoplastic lung epithelial cells) had shorter overall survival than patients with no increased KDF1 in cancer cells. Knockdown of KDF1 inhibited the migration, proliferation and invasion of LUAD cells in vitro. And overexpression of KDF1 increased the growth of the subcutaneous tumors in mice. In terms of molecular mechanisms, overexpression of KDF1 induced the expression of AKT, p-AKT and p-STAT3. In KDF1-overexpressing A549 cells, inhibition of the STAT3 pathway decreased the level of AKT and p-AKT, whereas inhibition of the AKT pathway had no effect on the activation of STAT3. Inhibition of STAT3 or AKT pathways reversed the promoting effects of KDF1 overexpression on the LUAD cell phenotype and STAT3 inhibition appeared to have a better effect. Finally, in the cancer cells of LUAD tumor samples, the KDF1 level was observed to correlate positively with the level of p-STAT3. All these findings suggest that KDF1, which activates STAT3 and the downstream AKT pathway in LUAD, acts as a tumor-promoting factor and may represent a therapeutic target.

Clear cell carcinoma (CCC), endometrioid carcinoma (EC), and serous carcinoma (SC) are the major histological subtypes of epithelial ovarian cancer (EOC), whose differences in carcinogenesis are still unclear. Here, we undertake comprehensive proteomic profiling of 80 CCC, 79 EC, 80 SC, and 30 control samples. Our analysis reveals the prognostic or diagnostic value of dysregulated proteins and phosphorylation sites in important pathways. Moreover, protein co-expression network not only provides comprehensive view of biological features of each histological subtype, but also indicates potential prognostic biomarkers and progression landmarks. Notably, EOC have strong inter-tumor heterogeneity, with significantly different clinical characteristics, proteomic patterns and signaling pathway disorders in CCC, EC, and SC. Finally, we infer MPP7 protein as potential therapeutic target for SC, whose biological functions are confirmed in SC cells. Our proteomic cohort provides valuable resources for understanding molecular mechanisms and developing treatment strategies of distinct histological subtypes., (© 2023. The Author(s).)

Polysaccharides are the principal component in Chinese yam ( Dioscorea opposita Thunb.) bulbils . The properties and antifatigue of polysaccharides from yam bulbils (PYB) were identified and compared. Their molecular weights (PYB-1 and PYB-2) were approximately 145 and 11 kDa, respectively, with active β-configurations. Meanwhile, the antifatigue activities of PYBs were tested in mice via exhaustive swimming tests (EST). The EST results indicated that PYB-1 and PYB-2 significantly prolonged swimming time in mice ( p  < .05). Associated with this increase was a rise in hepatic glycogen content and antioxidant enzyme (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)) activity, along with a decline in blood urea nitrogen, lactic acid, and malondialdehyde levels. The results showed that molecular weight might contribute to the antifatigue effects of PYBs. Additionally, antioxidant tests showed that PYB-1 had stronger free-radical scavenging activity than PYB-2. Taken together, the findings indicated that PYBs exhibited effective antifatigue and antioxidant activities providing additional evidence supporting the use of PYBs as functional food ingredients for relieving fatigue., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Amyloid beta (Aβ) aggregation is a slow process without seeding or assisted nucleation. Sodium dodecyl sulfate (SDS) micelles stabilize Aβ42 small oligomers (in the dimer to tetramer range); subsequent SDS removal leads to a 150-kD Aβ42 oligomer. Dodecylphosphorylcholine (DPC) micelles also stabilize an Aβ42 tetramer. Here we investigate the detergent-assisted oligomerization pathway by solid-state NMR spectroscopy and molecular dynamics simulations. SDS- and DPC-induced oligomers have the same structure, implying a common oligomerization pathway. An antiparallel β-sheet formed by the C-terminal region, the only stable structure in SDS and DPC micelles, is directly incorporated into the 150-kD oligomer. Three Gly residues (at positions 33, 37, and 38) create holes that are filled by the SDS and DPC hydrocarbon tails, thereby turning a potentially destabilizing feature into a stabilizing factor. These observations have implications for endogenous Aβ aggregation at cellular interfaces., (© 2023. The Author(s).)

Systemic pesticide exposure through nectar is a growing global concern linked to loss of insect diversity, especially pollinators. The insecticide sulfoxaflor and the fungicide tebuconazole are currently widely used systemic pesticides which are toxic to certain pollinators. However, their metabolisms in floral or extrafloral nectar under different application methods have not yet been well studied. Hibiscus rosa-sinensis was exposed to sulfoxaflor and tebuconazole via soil drenching and foliar spraying. Sulfoxaflor, tebuconazole, and their main metabolites in floral and extrafloral nectar, soil, and leaves were identified and quantified using liquid chromatography coupled with triple quadrupole mass spectrometry (LC-QqQ MS). The chemical compositions of unexposed and contaminated H. rosa-sinensis floral nectar or extrafloral nectar were compared using regular biochemical methods. The activities of two pesticide detoxifying enzymes, glutathione-s-transferase and nitrile hydratase, in H. rosa-sinensis nectar were examined using LC-MS and spectrophotometry. The floral nectar proteome of H. rosa-sinensis was analysed using high-resolution orbitrap-based MS/MS analysis to screen for sulfoxaflor and tebuconazole detoxifying enzymes. H. rosa-sinensis can absorb sulfoxaflor and tebuconazole through its roots or leaf surfaces and secrete them into floral nectar and extrafloral nectar. Both sulfoxaflor and tebuconazole and their major metabolites were present at higher concentrations in extrafloral nectar than in floral nectar. X11719474 was the dominant metabolite of sulfoxaflor in the nectars we studied. Compared with soil application, more sulfoxaflor and tebuconazole remained in their original forms in floral nectar and extrafloral nectar after foliar application. Sulfoxaflor and tebuconazole exposure did not modify the chemical composition of floral or extrafloral nectar. No active components, including proteins in the nectar, were detected to be able to detoxify sulfoxaflor., Competing Interests: Declaration of Competing Interest Nothing declared., (Copyright © 2023. Published by Elsevier Inc.)

The SARS-CoV-2 E protein is a transmembrane (TM) protein with its N-terminus exposed on the external surface of the virus. At debate is its oligomeric state, let alone its function. Here, the TM structure of the E protein is characterized by oriented sample and magic angle spinning solid-state NMR in lipid bilayers and refined by molecular dynamics simulations. This protein was previously found to be a pentamer, with a hydrophobic pore that appears to function as an ion channel. We identify only a front-to-front, symmetric helix-helix interface, leading to a dimeric structure that does not support channel activity. The two helices have a tilt angle of only 6°, resulting in an extended interface dominated by Leu and Val sidechains. While residues Val14-Thr35 are almost all buried in the hydrophobic region of the membrane, Asn15 lines a water-filled pocket that potentially serves as a drug-binding site. The E and other viral proteins may adopt different oligomeric states to help perform multiple functions., (© 2023. The Author(s).)

Background: Preeclampsia is a pregnancy-specific multi-system disease with multi-factor and multi-mechanism characteristics. The cure for preeclampsia is to terminate the pregnancy and deliver the placenta. However, it will reduce the perinatal survival rate, prolong the pregnancy cycle, and increase the incidence of maternal complications. With relaxation of the birth policy, the number of elderly pregnant women has increased significantly, and the prevalence rate of preeclampsia has increased. Inappropriate treatment can seriously affect the normal postpartum life of pregnant women. Studies have shown that postpartum anxiety in women with preeclampsia can affect physical and mental health, as well as infant growth and development., Aim: To analyze the factors influencing preeclampsia in pregnant women complicated with postpartum anxiety, and to construct a personalized predictive model., Methods: We retrospectively studied 528 pregnant women with preeclampsia who delivered in Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine between January 2018 and December 2021. Their basic data were collected, and various physiological and biochemical indicators were obtained by laboratory examination. The self-rating anxiety scale was used to determine whether the women had postpartum anxiety 42 d after delivery. The independent factors influencing postpartum anxiety in early pregnant women with eclampsia were analyzed with multifactor logistic regression and a predictive model was constructed. The Hosmer-Lemeshow test and receiver operating characteristic (ROC) curve were used to evaluate the calibration and discrimination of the predictive model. Eighty pregnant women with preeclampsia admitted to our hospital from January 2022 to May 2022 were retrospectively selected to verify the prediction model., Results: We excluded 46 of the 528 pregnant women with preeclampsia because of loss to follow-up and adverse outcomes. A total of 482 cases completed the assessment of postpartum anxiety 42 d after delivery, and 126 (26.14%) had postpartum anxiety. Bad marital relationship, gender discrimination in family members, hematocrit (Hct), estradiol (E2) hormone and interleukin (IL)-6 were independent risk factors for postpartum anxiety in pregnant women with preeclampsia ( P < 0.05). Prediction model: Logit ( P ) = 0.880 × marital relationship + 0.870 × gender discrimination of family members + 0.130 × Hct - 0.044 × E2 + 0.286 × IL-6 - 21.420. The area under the ROC curve of the model was 0.943 (95% confidence interval: 0.919-0.966). The threshold of the model was -1.507 according to the maximum Youden index (0.757), the corresponding sensitivity was 84.90%, and the specificity was 90.70%. Hosmer-Lemeshow χ 2 = 5.900, P = 0.658. The sensitivity, specificity and accuracy of the model were 81.82%, 84.48% and 83.75%, respectively., Conclusion: Poor marital relationship, family gender discrimination, Hct, IL-6 and E2 are the influencing factors of postpartum anxiety in preeclampsia women. The constructed prediction model has high sensitivity and specificity., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

We investigated the effects of lifelong aerobic exercise and 8 months of detraining after 10 months of aerobic training on circulation, skeletal muscle oxidative stress, and inflammation in aging rats. Sprague-Dawley rats were randomly assigned to the control (CON), detraining (DET), and lifelong aerobic training (LAT) groups. The DET and LAT groups began aerobic treadmill exercise at the age of 8 months and stopped training at the 18th and 26th month, respectively; all rats were sacrificed when aged 26 months. Compared with CON, LAT remarkably decreased serum and aged skeletal muscle 4-hydroxynonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Superoxide dismutase 2(SOD2) levels were higher in the LAT group than in the CON group in skeletal muscle. However, DET remarkably decreased SOD2 protein expression and content in the skeletal muscle and increased malondialdehyde (MDA) level compared with LAT. Compared with LAT, DET remarkably downregulated adiponectin and upregulated tumor necrosis factor alpha (TNF-α) expression, while phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and 70-kDa ribosomal protein S6 kinase (P70S6K) protein expression decreased, and that of FoxO1 and muscle atrophy F-box (MAFbX) proteins increased in the quadriceps femoris. Adiponectin and TNF-α expression in the soleus muscle did not change between groups, whereas that of AKT, mammalian target of rapamycin (mTOR), and P70S6K was lower in the soleus in the DET group than in that in the LAT group. Compared with that in the LAT group, sestrin1 (SES1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the DET group was lower, whereas Keap1 mRNA expression was remarkably upregulated in the quadriceps femoris. Interestingly, the protein and mRNA levels of SES1, Nrf2, and Keap1 in soleus muscle did not differ between groups. LAT remarkably upregulated ferritin heavy polypeptide 1(FTH), glutathione peroxidase 4(GPX4), and solute carrier family 7member 11 (SLC7A11) protein expression in the quadriceps femoris and soleus muscles, compared with CON. However, compared with LAT, DET downregulated FTH, GPX4, and SLC7A11 protein expression in the quadriceps femoris and soleus muscles. Long-term detraining during the aging phase reverses the improvement effect of lifelong exercise on oxidative stress, inflammation, ferroptosis, and muscle atrophy in aging skeletal muscle. The quadriceps femoris is more evident than the soleus, which may be related to the different changes in the Keap1/Nrf2 pathway in different skeletal muscles., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Stroke survivors have long-term upper limb impairment, which impacts the quality of life (QOL) and social reintegration, but there is lack of effective therapeutic strategies and novel technologies. Customized multi-muscle functional electrical stimulation (FES) based on the muscle synergy of healthy adults and robotic-assisted therapy (RAT) have been proved efficacy respectively. Synergy-based FES combined with RAT can be a novel and more effective therapy for upper limb recovery of stroke survivors from the perspective of synergistic enhancement. However, few studies have examined the effectiveness of combined synergy-based FES and RAT, especially for motor control evaluated by reach-to-grasp (RTG) movements. The main objective of the following research protocol is to evaluate the effectiveness and efficacy, as well as adoptability, of FES-RAT and FES or RAT rehabilitation program for upper limb function improvement after stroke., Methods: This will be an assessor-blinded randomized controlled trial involving a 12-week intervention and a 6-month follow-up. Stratified randomization will be used to equally and randomly assign 162 stroke patients into the FES + conventional rehabilitation program (CRP) group, RAT + CRP group and FES-RAT + CRP group. Interventions will be provided in 5 sessions per week, with a total of 60 sessions. The primary outcome measurements will include the Fugl-Meyer Assessment and Biomechanical Assessment of RTG movements. The secondary outcome measurements will include quality of life and brain neuroplasticity assessments by MRI. Evaluations will be performed at five time points, including at baseline, 6 weeks and 12 weeks from the start of treatment, and 3 months and 6 months following the end of treatment. A two-way analysis of variance with repeated measures will be applied to examine the main effects of the group, the time factor and group-time interaction effects., Discussion: The results of the study protocol will provide high quality evidence for integrated synergy-based FES and RAT, and synergy-based FES alone and guide the design of more effective treatment methods for stroke rehabilitation., Trial Registration: ChiCTR2300071588., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Septic shock treatment remains a major challenge for intensive care units, despite the recent prominent advances in both management and outcomes. Vasopressors serve as a cornerstone of septic shock therapy, but there is still controversy over the timing of administration. Specifically, it remains unclear whether vasopressors should be used early in the course of treatment. Here, we provide a systematic review of the literature on the timing of vasopressor administration. Research was systematically identified through PubMed, Embase and Cochrane searching according to PRISMA guidelines. Fourteen studies met the eligibility criteria and were included in the review. The pathophysiological basis for early vasopressor use was classified, with the exploration on indications for the early administration of mono-vasopressors or their combination with vasopressin or angiotensinII. We found that mortality was 28.1%-47.7% in the early vasopressors group, and 33.6%-54.5% in the control group. We also investigated the issue of vasopressor responsiveness. Furthermore, we acknowledged the subsequent challenge of administration of high-dose norepinephrine via peripheral veins with early vasopressor use. Based on the literature review, we propose a possible protocol for the early initiation of vasopressors in septic shock resuscitation., Competing Interests: Conflict-of-interest statement: All authors declare that they have no competing interests., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Due to woodlands and farmlands being replaced by residential areas in cities, continuous urbanization resulting in frequent urban heat island effects, especially in summer when high temperature seriously threaten health and lives of citizens. Although scientists realized that reasonable residential area morphology could effectively regulate air temperature and improve microclimate, it is lack of air temperature regulation-oriented specifications and requirements on morphology of residential areas. In this study, we used three types of morphological parameters of 15 residential areas in Xuzhou City and air temperature data via field investigation to analyze air temperature regulation caused by residential area morphology. The results showed that key morphological parameters of residential areas were different in morning and afternoon. In morning, independent effects of mean building height, street aspect ratio, and complete aspect ratio contributed 15.4%, 7.3%, and 6.8%, while those of building density, sky view factor, and the ratio of building surface area to floor area were 21.1%, 23.1%, and 6.9% in afternoon, respectively. Threshold values of efficiency of morphological parameters of residential areas were different between morning and afternoon. There were significant correlations between some morphological parameters of residential area. The results could provide data support and methodological reference for residential areas design in Xuzhou and surrounding cities.

Liquid-liquid phase separation of protein solutions has regained heightened attention for its biological importance and pathogenic relevance. Coarse-grained models are limited when explaining residue-level effects on phase equilibrium. Here we report phase diagrams for γ-crystallins using atomistic modeling. The calculations were made possible by combining our FMAP method for computing chemical potentials and Brownian dynamics simulations for configurational sampling of dense protein solutions, yielding the binodal and critic temperature (T c ). We obtain a higher T c for a known high-T c γ-crystallin, γF, than for a low-T c paralog, γB. The difference in T c is corroborated by a gap in second virial coefficient. Decomposition of inter-protein interactions reveals one amino-acid substitution between γB and γF, from Ser to Trp at position 130, as the major contributor to the difference in T c . This type of analysis enables us to link phase equilibrium to amino-acid sequence and to design mutations for altering phase equilibrium., (© 2023. Springer Nature Limited.)

Alginate oligosaccharides (AOs) prepared through enzymatic reaction by diverse alginate lyases under relatively controllable and moderate conditions possess versatile biological activities. But widely used commercial alginate lyases are still rather rare due to their poor properties (e.g., lower activity, worse thermostability, ion tolerance, etc.). In this work, the alginate lyase Alyw208, derived from Vibrio sp. W2, was expressed in Yarrowia lipolytica of food grade and characterized in order to obtain an enzyme with excellent properties adapted to industrial requirements. Alyw208 classified into the polysaccharide lyase (PL) 7 family showed maximum activity at 35 °C and pH 10.0, indicating its cold-adapted and high-alkaline properties. Furthermore, Alyw208 preserved over 70% of the relative activity within the range of 10-55 °C, with a broader temperature range for the activity compared to other alginate-degrading enzymes with cold adaptation. Recombinant Alyw208 was significantly activated with 1.5 M NaCl to around 2.1 times relative activity. In addition, the endolytic Alyw208 was polyG-preferred, but identified as a bifunctional alginate lyase that could degrade both polyM and polyG effectively, releasing AOs with degrees of polymerization (DPs) of 2-6 and alginate monomers as the final products (that is, DPs 1-6). Alyw208 has been suggested with favorable properties to be a potent candidate for biotechnological and industrial applications., Competing Interests: The authors declare no conflict of interest.

The SAM/SAH riboswitch binds S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) with similar affinities. Mg 2+ is generally known to stabilize RNA structures by neutralizing phosphates, but how it contributes to ligand binding and conformational transition is understudied. Here, extensive molecular dynamics simulations (totaling 120 μs) predicted over 10 inner-shell Mg 2+ ions in the SAM/SAH riboswitch. Six of them line the two sides of a groove to widen it and thereby pre-organize the riboswitch for ligand entry. They also form outer-shell coordination with the ligands and stabilize an RNA-ligand hydrogen bond, which effectively diminishes the selectivity between SAM and SAH. One Mg 2+ ion unique to the apo form maintains the Shine-Dalgarno sequence in an autonomous mode and thereby facilitates its release for ribosome binding. Mg 2+ thus plays vital roles in SAM/SAH riboswitch function., (© 2023. The Author(s).)

Hydrocolloids as Additives have been used for improving the quality of frozen dough for a long time. In this work, the effects of sodium carboxymethyl cellulose (CMC) on quality changes of frozen dough in storage were studied. The water loss rate of the dough and water holding capacity were measured. Rheological and texture properties of the frozen dough were measured by a rheometer and a texture analyzer, respectively. Scanning electron microscopy (SEM) was used to characterize surface network structure and protein structure changes of the frozen dough. Our results reveal that the addition of CMC can inhibit the formation of ice crystals and recrystallization, thus effectively stabilizing the molecular structure of starch, and resulting in more uniform moisture distribution in the frozen dough. When 3% addition of CMC, the water holding capacity of the two kinds of dough reached the best, and the water loss rate of corn dough reached the lowest. The cohesion of the two kinds of dough reaches the maximum with 3 wt% addition of CMC, while the hardness and chewiness of wheat and corn multigrain dough reaches the maximum with 3 wt% and 4 wt% addition of CMC, respectively. The results show proper CMC addition (3 wt% and 4 wt%) finally improves the stability and qualities of the frozen dough. The research concerning the effects of CMC on quality of frozen dough provides better understanding for the frozen food industry., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Importance: Limited evidence supports kidney dysfunction as an indication for parathyroidectomy in asymptomatic primary hyperparathyroidism (PHPT)., Objective: To investigate the natural history of kidney function in PHPT and whether parathyroidectomy alters renal outcomes., Design: Matched control study., Setting: A vertically integrated health care system serving 4.6 million patients in Southern California., Participants: 6058 subjects with PHPT and 16 388 matched controls, studied from 2000 to 2016., Exposures: Biochemically confirmed PHPT with varying serum calcium levels., Main Outcomes: Estimated glomerular filtration rate (eGFR) trajectories were compared over 10 years, with cases subdivided by severity of hypercalcemia: serum calcium 2.62-2.74 mmol/L (10.5-11 mg/dL), 2.75-2.87 (11.1-11.5), 2.88-2.99 (11.6-12), and >2.99 (>12). Interrupted time series analysis was conducted among propensity-score-matched PHPT patients with and without parathyroidectomy to compare eGFR trajectories postoperatively., Results: Modest rates of eGFR decline were observed in PHPT patients with serum calcium 2.62-2.74 mmol/L (−1.0 mL/min/1.73 m2/year) and 2.75-2.87 mmol/L (−1.1 mL/min/1.73 m2/year), comprising 56% and 28% of cases, respectively. Compared with the control rate of −1.0 mL/min/1.73 m2/year, accelerated rates of eGFR decline were observed in patients with serum calcium 2.88-2.99 mmol/L (−1.5 mL/min/1.73 m2/year, P < .001) and >2.99 mmol/L (−2.1 mL/min/1.73 m2/year, P < .001), comprising 9% and 7% of cases, respectively. In the propensity score–matched population, patients with serum calcium >2.87 mmol/L exhibited mitigation of eGFR decline after parathyroidectomy (−2.0 [95% CI: −2.6 to −1.5] to −0.9 [95% CI: −1.5 to 0.4] mL/min/1.73 m2/year)., Conclusions and Relevance: Compared with matched controls, accelerated eGFR decline was observed in the minority of PHPT patients with serum calcium >2.87 mmol/L (11.5 mg/dL). Parathyroidectomy was associated with mitigation of eGFR decline in patients with serum calcium >2.87 mmol/L., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Worldwide, gastric cancer (GC) is a common lethal solid malignancy with a poor prognosis. Cuproptosis is a novel type of cell death mediated by protein lipoylation and may be related to GC prognosis., Aim: To offer new insights to predict GC prognosis and provide multiple therapeutic targets related to cuproptosis-related genes (CRGs) for future therapy., Methods: We collected data from several public data portals, systematically estimated the expression level and prognostic values of CRGs in GC samples, and investigated related mechanisms using public databases and bioinformatics., Results: Our results revealed that FDX1 , LIAS , and MTF1 were differentially expressed in GC samples and exhibited important prognostic significance in The Cancer Genome Atlas (TCGA) cohort. We constructed a nomogram model for overall survival and disease-specific survival prediction and validated it via calibration plots. Mecha-nistically, immune cell infiltration and DNA methylation prominently affected the survival time of GC patients. Moreover, protein-protein interaction network, KEGG pathway and gene ontology enrichment analyses demonstrated that FDX1 , LIAS , MTF1 and related proteins play key roles in the tricarboxylic acid cycle and cuproptosis. Gene Expression Omnibus database validation showed that the expression levels of FDX1 , LIAS , and MTF1 were consistent with those in the TCGA cohort. Top 10 perturbagens has been filtered by Connectivity Map., Conclusion: In conclusion, FDX1 , LIAS , and MTF1 could serve as potential prognostic biomarkers for GC patients and provide novel targets for immunotarget therapy., Competing Interests: Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

This study investigates the interaction between long non-coding RNAs (lncRNAs) and metabolic risk factors that contribute to coronary artery disease (CAD). A total transcriptome high throughput sequencing study was conducted on peripheral blood mononuclear cells from five patients with CAD and five healthy controls. Validation assay by qRT-PCR was conducted among 270 patients and 47 controls. Finally, to evaluate the lncRNAs' diagnostic value for CAD, the Spearman correlation test and receiver operating characteristic curve (ROC) analysis were utilized. Additionally, univariate and multivariate logistic regression along with crossover analyses were conducted to identify the interaction between lncRNA and environmental risk factors. A total of 2149 of 26,027 lncRNAs identified by RNA sequencing were differentially expressed in CAD patients compared to controls. Validation by qRT-PCR showed significantly different relative expression levels for lncRNAs PDXDC1-AS1, SFI1-AS1, RP13-143G15.3, DAPK1-IT1, PPIE-AS1, and RP11-362A1.1 between the two groups (all P<0.05). The area under the ROC values of PDXDC1-AS1 and SFI1-AS1 is 0.645 (sensitivity=0.443 and specificity=0.920) and 0.629 (sensitivity=0.571 and specificity=0.909), especially. Multivariate logistic regression analyses showed that lncRNAs PDXDC1-AS1 (OR=2.285, 95%CI=1.390-3.754, p=0.001) and SFI1-AS1 (OR=1.163, 95%CI=1.163-2.264, p=0.004) were protective factors against CAD. Under the additive model, cross-over analyses demonstrated significant interactions between lncRNAs PDXDC1-AS1 and smoking in relation to CAD risk (S=3.871, 95%CI=1.140-6.599). PDXDC1-AS1 and SFI1-AS1 were sensitive and specific biomarkers for CAD and exhibited synergistic effects with certain environmental factors. These results highlighted their potential use as CAD diagnostic biomarkers for future research., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To study the clinical features and related factors of invasive pulmonary aspergillosis (IPA) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: This retrospective study enrolled patients hospitalized for AECOPD in ten tertiary hospitals of China from September 2017 to July 2021. AECOPD patients with IPA were included as case group, AECOPD patients without IPA were randomly selected as control group from the same hospitals and same hospitalization period as the patients with IPA using the random function in the software of Microsoft Excel 2003, at a ratio of 2∶1. The clinical characteristics, treatment and outcome were compared between the two groups. Binary logistic regression model was used to analyze the factors associated with IPA in AECOPD patients. Results: A total of 14 007 inpatients with AECOPD were included in this study, and 300 patients were confirmed to have IPA, with an incidence rate of 2.14%. According to the above matching method, 600 AECOPD patients without aspergillus infection were enrolled as the control group. The age of the case group and the control group were (72.5±9.7) and (73.5±10.3) years old, with 78.0%( n =234) male and 76.8%( n =461) male, respectively. There were no significant differences in age and gender composition between the two groups (all P >0.05). The prognosis of case group was significantly worse than that of the control group, with longer hospital stay [ M ( Q 1 , Q 3 )], [14 (10-20) d vs 11 (8-15) d, P <0.001], higher ICU admission rate [16.3% (49 case) vs 10.0% (60 case), P =0.006], higher in-hospital mortality [4.0% (12 cases) vs 1.3% (8 cases), P =0.011], and higher hospitalization costs (28 000 ¥ vs 13 700 ¥, P <0.001). The smoking index of the case group and proportions of patients with diabetes mellitus, chronic pulmonary heart disease in the case group were significantly higher than those in control group (all P <0.05). In terms of clinical features, the proportions of patients with cough, expectoration, purulent sputum, hemoptysis and fever in the case group were higher than those in the control group, the serum albumin was significantly lower than that in the control group, and the proportions of patients with bronchiectasis and pulmonary bullae on imaging were significantly higher than those in the control group (all P <0.05). Diabetes ( OR =1.559, 95% CI : 1.084-2.243), chronic pulmonary heart disease ( OR =1.476, 95% CI : 1.075-2.028), bronchiectasis ( OR =1.506, 95% CI : 1.092-2.078), pulmonary bullae ( OR =1.988, 95% CI : 1.475-2.678) and serum albumin<35 g/L ( OR =1.786, 95% CI : 1.325-2.406) were the related factors of IPA in patients with AECOPD. Conclusions: The incidence of IPA in AECOPD patients is relatively high and the prognosis of these patients is worse. Diabetes, chronic pulmonary heart disease, bronchiectasis, pulmonary bulla, hypoproteinemia are the related factors of IPA in patients with AECOPD.

Background: This study aimed to explore the potential effects of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) patients using two detection methods: high-throughput sequencing and microarray., Methods: In this study, lncRNAs were detected in 20 newly diagnosed MM patients, with 10 patients analyzed by whole transcriptome-specific RNA sequencing and 10 patients analyzed by microarray (Affymetrix Human Clariom D). The expression levels of lncRNAs, microRNAs, and messenger RNAs (mRNAs) were analyzed, and the differentially expressed lncRNAs identified by both methods were selected. The significant differentially expressed lncRNAs were further validated using PCR., Results: This study established the aberrant expression of certain lncRNAs involved in the occurrence of MM, with AC007278.2 and FAM157C showing the most significant differences. The top 5 common pathways identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were the chemokine signaling pathway, inflammatory mediator regulation, Th17 cell differentiation, apoptosis, and NF-kappa B signaling pathway. Furthermore, three microRNAs (miRNAs) (miR-4772-3p, miR-617, and miR-618) were found to constitute competing endogenous RNA (ceRNA) networks in both sequencing and microarray analyses., Conclusions: By the combination analysis, our understanding of lncRNAs in MM will be increased significantly. More overlapping differentially expressed lncRNAs were found to predict therapeutic targets precisely., 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 © 2023 Lu, He, Wu, Zhou, Jian, Gao, Bao and Chen.)

Power law distributions are widely observed in chemical physics, geophysics, biology, and beyond. The independent variable x of these distributions has an obligatory lower bound and, in many cases, also an upper bound. Estimating these bounds from sample data is notoriously difficult, with a recent method involving O(N3) operations, where N denotes sample size. Here I develop an approach for estimating the lower and upper bounds that involve O(N) operations. The approach centers on calculating the mean values, x̂min and x̂max, of the smallest x and the largest x in N-point samples. A fit of x̂min or x̂max as a function of N yields the estimate for the lower or upper bound. Application to synthetic data demonstrates the accuracy and reliability of this approach., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Objectives: To investigate the prevalence rate of non-alcoholic fatty liver disease (NAFLD) in overweight/obese children who visit a hospital, and to explore the influencing factors of NAFLD, in order to provide a basis for the prevention of NAFLD in overweight/obese children., Methods: Overweight/obese children who visited Hunan Children's Hospital from June 2019 to September 2021 were recruited. The prevalence rate of NAFLD was examined. Logistic regression analysis was used to explore the factors influencing the development of NAFLD [non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH)]. Receiver operating characteristic curve analysis was used to evaluate the predictive value of the influencing factors for NAFL and NASH., Results: A total of 844 overweight/obese children aged 6-17 years were enrolled. The prevalence rate of NAFLD in overweight/obese children was 38.2% (322/844), among which the prevalence rates of NAFL and NASH were 28.8% (243/844) and 9.4% (79/844), respectively. Multivariate logistic regression analysis showed that the increase of waist-to-hip ratio (WHR) and low high-density lipoprotein cholesterol (HDL-C) were associated with the development of NAFL and NASH ( P <0.05). The receiver operating characteristic curve analysis showed that the combined measurement of WHR and HDL-C had a predictive value for NAFL (area under the curve: 0.653, 95% CI : 0.613-0.694), and for NASH (area under the curve: 0.771, 95% CI : 0.723-0.819)., Conclusions: The prevalence rate of NAFLD in overweight/obese children who visit a hospital is high. WHR and HDL-C are associated with the development of NAFLD and the combined measurement of WHR and HDL-C has a certain value for predicating the development of NAFLD.

Renal ischemia is the initial stage of kidney damage, leading to mitochondrial metabolism disorders and cell necrosis. In this study, we aimed to investigate the biological functions and potential mechanisms of miR-21 in protecting renal tubular epithelial cells from oxidative stress and apoptosis following oxygen glucose deprivation (OGD). Following an OGD injury, miR-21 levels increased in HK-2 renal tubular epithelial cells. Overexpression of miR-21 decreased the protein expressions of cleaved caspase-3, BAX, P53, cell apoptosis and increased Bcl-2 expression in HK-2 cells with OGD injury. In vivo studies found that miR-21 agomir reduced renal tissue apoptosis, while miR-21 antagomir increased it. In addition, overexpression of miR-21 reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) in HK-2 cells with OGD injury. However, miR-21 inhibition exhibited the opposite effect. A dual-luciferase reporter assay demonstrated that miR-21 directly regulates Toll-like receptor 4 (TLR4) by targeting the 3'-UTR of TLR4 mRNA. Overexpression of miR-21 led to decreased TLR4 protein expression, and TLR4 knockdown was shown to greatly increase AKT activity in HK-2 cells by in vitro kinase assay. Additionally, TLR4 knockdown promoted AKT phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression, while TLR4 overexpression inhibited these processes. Furthermore, AKT activation abolished the effect of TLR4 on HIF-1α, while AKT inhibition decreased the expression of TLR4 on HIF-1α in TLR4 knockdown HK-2 cells. Further study revealed that HIF-1α inhibition abolished the protective effect of miR-21 overexpression on ROS, LDH levels and cell apoptosis in HK-2 cells after OGD injury, which is indicated by increased levels of ROS and LDH, as well as increased cell apoptosis after HIF-1α inhibition in miR-21-treated HK-2 cells. In conclusion, miR-21 defends OGD-induced HK-2 cell injury via the TLR4/AKT/HIF-1α axis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

From January 2019 to December 2021, overweight and obese children who visited in health outpatient Center of Hunan Children's Hospital were studied to explore and analyze the rate, related factors and patterns of multimorbidity of overweight and obesity-related diseases in children in Hunan Province. Univariate and multivariate logistic regression models were used to analyze the multimorbidity-related factors of overweight and obesity-related diseases in children . Association rules (apriori algorithm) were used to explore the multimorbidity patterns of overweight and obesity-related diseases in children . A total of 725 overweight and obese children were included in this study. The multimorbidity rate of overweight and obesity-related diseases in children was 46.07% (334/725). Age, waist circumference, the frequency of food consumption such as hamburgers and fries and adding meals before bedtime were multimorbidity-related factors of overweight and obesity-related diseases in children. The multimorbidity associated with nonalcoholic fatty liver disease (NAFLD) was relatively common. The patterns with the top three support degrees were "NAFLD+dyslipidemia","NAFLD+hypertension" and "NAFLD+hyperuricemia". The patterns with the top three confidence and elevation degrees were "Hypertension+dyslipidemia => NAFLD","Hyperuricemia => NAFLD" and "NAFLD+hypertension => dyslipidemia".

Human WASP and N-WASP are homologous proteins that require the binding of multiple regulators, including the acidic lipid PIP 2 and the small GTPase Cdc42, to relieve autoinhibition before they can stimulate the initiation of actin polymerization. Autoinhibition involves intramolecular binding of the C-terminal acidic and central motifs to an upstream basic region and GTPase binding domain. Little is known about how a single intrinsically disordered protein, WASP or N-WASP, binds multiple regulators to achieve full activation. Here we used molecular dynamics simulations to characterize the binding of WASP and N-WASP with PIP 2 and Cdc42. In the absence of Cdc42, both WASP and N-WASP strongly associate with PIP 2 -containing membranes, through their basic region and also possibly through a tail portion of the N-terminal WH1 domain. The basic region also participates in Cdc42 binding, especially for WASP; consequently Cdc42 binding significantly compromises the ability of the basic region in WASP, but not N-WASP, to bind PIP 2 . PIP 2 binding to the WASP basic region is restored only when Cdc42 is prenylated at the C-terminus and tethered to the membrane. This distinction in the activation of WASP and N-WASP may contribute to their different functional roles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Metastasis is a landmark event for rapid postsurgical relapse and death of HCC patients. Although distinct genomic and transcriptomic profiling of HCC metastasis had been reported previously, the causal relationships of somatic mutants, mRNA levels and metastatic potentials were difficult to be established in clinic. Therefore, 11 human HCC cell lines and 7 monoclonal derivatives with definite metastatic potentials and tropisms were subjected to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). TP53, MYO5A, ROS1 and ARID2 were the prominent mutants of metastatic drivers in HCC cells. During HCC clonal evaluation, TP53, MYO5A and ROS1 mutations occurred in the early stage, EXT2 and NIN in the late stage. NF1 mutant was unique in lung tropistic cell lines, RNF126 mutant in lymphatic tropistic ones. PER1, LMO2, GAS7, NR4A3 expression levels were positively associated with relapse-free survival (RFS) of HCC patients. The integrative analysis revealed 58 genes exhibited both somatic mutation and dysregulated mRNA levels in high metastatic cells. Altogether, metastatic drivers could accumulate gradually at different stages during HCC progression, some drivers might modulate HCC metastatic potentials and the others regulate metastatic tropisms., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest in this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with high mortality rates. Viral and bacterial coinfection is the primary cause of AECOPD. How coinfection with these microbes influences host inflammatory response and the gut microbiota composition is not entirely understood., Methods: We developed a mouse model of AECOPD by cigarette smoke exposure and sequential infection with influenza H1N1 virus and non-typeable Haemophilus influenzae (NTHi). Viral and bacterial titer was determined using MDCK cells and chocolate agar plates, respectively. The levels of cytokines, adhesion molecules, and inflammatory cells in the lungs were measured using Bio-Plex and flow cytometry assays. Gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between cytokines and gut microbiota were determined using Spearman's rank correlation coefficient test., Results: Coinfection with H1N1 and NTHi resulted in more severe lung injury, higher mortality, declined lung function in COPD mice. H1N1 enhanced NTHi growth in the lungs, but NTHi had no effect on H1N1. In addition, coinfection increased the levels of cytokines and adhesion molecules, as well as immune cells including total and M1 macrophages, neutrophils, monocytes, NK cells, and CD4 + T cells. In contrast, alveolar macrophages were depleted. Furthermore, coinfection caused a decline in the diversity of gut bacteria. Muribaculaceae , Lactobacillus , Akkermansia , Lachnospiraceae , and Rikenella were further found to be negatively correlated with cytokine levels, whereas Bacteroides was positively correlated., Conclusion: Coinfection with H1N1 and NTHi causes a deterioration in COPD mice due to increased lung inflammation, which is correlated with dysbiosis of the gut microbiota., 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 © 2023 Wu, Li, Lin, Xiao, Liu, Mai, Zhou, Zeng, Cheng, Weng, Zhao, Chen, Jiang, Chen, Deng, Xie, Yang, Xia and Yang.)

Kinetics of NMDA receptor (NMDAR) ion channel opening and closing contribute to their unique role in synaptic signaling. Agonist binding generates free energy to open a canonical gate at the M3 helix bundle crossing. Single channel activity is characterized by clusters, or periods of rapid opening and closing, that are separated by long silent periods. A conserved glycine in the outer most transmembrane helices, the M4 helices, regulates NMDAR function. Here we find that the GluN1 glycine mainly regulates single channel events within a cluster, whereas the GluN2 glycine mainly regulates entry and exit from clusters. Molecular dynamics simulations suggest that, whereas the GluN2 M4 (along with GluN2 pre-M1) regulates the gate at the M3 helix bundle crossing, the GluN1 glycine regulates a 'gate' at the M2 loop. Subsequent functional experiments support this interpretation. Thus, the distinct kinetics of NMDARs are mediated by two gates that are under subunit-specific regulation., (© 2023. The Author(s).)

Mtb infects a quarter of the worldwide population. Most drugs for treating tuberculosis target cell growth and division. With rising drug resistance, it becomes ever more urgent to better understand Mtb cell division. This process begins with the formation of the Z-ring via polymerization of FtsZ and anchoring of the Z-ring to the inner membrane. Here we show that the transmembrane protein FtsQ is a potential membrane anchor of the Mtb Z-ring. In the otherwise disordered cytoplasmic region of FtsQ, a 29-residue, Arg/Ala-rich α-helix is formed that interacts with upstream acidic residues in solution and with acidic lipids at the membrane surface. This helix also binds to the GTPase domain of FtsZ, with implications for drug binding and Z-ring formation., (© 2023. The Author(s).)

Allosteric regulation of intrinsically disordered proteins (IDPs) is still vastly understudied compared to the counterpart of structured proteins. Here, we used molecular dynamics simulations to characterize the regulation of the IDP N-WASP by the binding of its basic region with inter- and intramolecular ligands (PIP 2 and an acidic motif, respectively). The intramolecular interactions keep N-WASP in an autoinhibited state; PIP 2 binding frees the acidic motif for interacting with Arp2/3 and thereby initiating actin polymerization. We show that PIP 2 and the acidic motif compete in binding with the basic region. However, even when PIP 2 is present at 30% in the membrane, the acidic motif is free of contact with the basic region ("open" state) in only 8.5% of the population. The very C-terminal three residues of the A motif are crucial for Arp2/3 binding; conformations where only the A tail is free are present at a much higher population than the open state (40- to 6-fold, depending on the PIP 2 level). Thus, N-WASP is competent for Arp2/3 binding before it is fully freed from autoinhibition.

Tau, as typical of intrinsically disordered proteins (IDPs), binds to multiple targets including microtubules and acidic membranes. The latter two surfaces are both highly negatively charged, raising the prospect of mimicry in their binding by tau. The tau-microtubule complex was recently determined by cryo-electron microscopy. Here, we used molecular dynamics simulations to characterize the dynamic binding of tau K19 to an acidic membrane. This IDP can be divided into three repeats, each containing an amphipathic helix. The three amphipathic helices, along with flanking residues, tether the protein to the membrane interface. The separation between and membrane positioning of the amphipathic helices in the simulations are validated by published EPR data. The membrane contact probabilities of individual residues in tau show both similarities to and distinctions from native contacts with microtubules. In particular, a Lys that is conserved among the repeats forms similar interactions with membranes and with microtubules, as does a conserved Val. This partial mimicry facilitates both the membrane anchoring of microtubules by tau and the transfer of tau from membranes to microtubules., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

While the roles of biomolecular condensates in health and disease are being intensely studied, it is equally important that their physical properties are characterized in order to achieve mechanistic understanding. Here we share some of the protocols developed in our lab for measuring thermodynamic and materials properties of condensates. These include a simple method for determining the droplet-phase concentrations of condensate components on a confocal microscope, and a method for determining the viscoelasticity of condensates by optical tweezers. These protocols are either generally applicable to biomolecular condensates or are unique for their characterization., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

We illustrate three methods for calculating the binodals of phase-separated condensates from molecular simulations. Because molecular simulations can only be carried out for small system sizes, correction for finite sizes may be required for making direct comparison between calculated results and experimental data. We first summarize the three methods and then present detailed implementation of each method on a Lennard-Jones fluid. In the first method, chemical potentials are calculated over a range of particle densities in canonical-ensemble simulations; the densities of the dilute and dense phases at the given temperature are then found by a Maxwell equal-area construction. In Gibbs-ensemble Monte Carlo, the exchange between separated dilute and dense phases is simulated to obtain their densities. Lastly, slab-geometry molecular dynamics simulations model the dilute and dense phases in coexistence and yield not only their densities but also their interfacial tension. The three types of simulations are carried out for a range of system sizes, and the results are scaled to generate the binodals corrected for finite system sizes. Size-corrected interfacial tension is also produced from slab-geometry molecular dynamics simulations., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Smoking affects sensory gating, as assessed by the event related potential P50, which is evoked by auditory stimuli and is considered to be involved in the pathophysiology of schizophrenia (SCZ). However, few studies have compared sensory gating and cognitive performance between smoking and non-smoking SCZ patients in the Chinese Han population., Methods: We recruited two groups of Chinese subjects: 128 male chronic SCZ patients and 76 male healthy controls, measuring cognition with the MATRICS Consensus Cognitive Battery (MCCB) and sensory gating with the P50 EEG components. Based on their smoking status, they were further divided into 4 subgroups: smoking SCZ patients, non-smoking SCZ patients, smoking healthy controls, and non-smoking healthy controls. We assessed psychopathological symptoms of the patients using the Positive and Negative Syndrome Scale (PANSS)., Results: Compared with healthy controls, SCZ patients had lower MCCB total score and scores of all 10 tests (all p < 0.05), while SCZ patients had higher S2 amplitudes and P50 ratios (both p < 0.05). When comparing smoking versus non-smoking SCZ patients, non-smokers had significantly better spatial span (p < 0.05). Furthermore, the S1 amplitude was negatively correlated with the Brief Visuospatial Memory Test (BVMT-R) in smoking patients (p < 0.05), while the S1 latency was negatively correlated with spatial span in non-smoking patients (p < 0.01)., Conclusions: Our finding shows a difference in the relationship between sensory gated P50 and cognition in smoking and non-smoking SCZ patients, suggesting that nicotine may improve cognitive and P50 deficits in SCZ patients., Competing Interests: Conflict of Interest Statement The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The protein structure prediction problem is solved, at last, thanks in large part to the use of artificial intelligence. The structures predicted by AlphaFold and RoseTTAFold are becoming the requisite starting point for many protein scientists. New frontiers, such as the conformational sampling of intrinsically disordered proteins, are emerging., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2022 Faculty Opinions Ltd.)

The brains of Alzheimer's disease (AD) patients contain numerous amyloid plaques that are diagnostic of the disease. The plaques are primarily composed of the amyloidogenic peptides proteins Aβ40 and Aβ42, which are derived by the processing of the amyloid pre-cursor protein (APP) by two proteases called β-secretase and γ-secretase. Aβ42 differs from Aβ40 in having two additional hydrophobic amino acids, ILE and ALA, at the C-terminus. A small percentage of AD is autosomal dominant (ADAD) and linked either to the genes for the presenilins, which are part of γ-secretase, or APP. Because ADAD shares most pathogenic features with widespread late-onset AD, Aβ peptides have become the focus of AD research. Fibrils formed by the aggregation of these peptides are the major component of plaques and were initially targeted in AD therapy. However, the fact that the abundance of plaques does not correlate well with cognitive decline in AD patients has led investigators to examine smaller Aβ aggregates called oligomers. The low levels and heterogeneity of Aβ oligomers have made the determination of their structures difficult, but recent structure determinations of oligomers either formed or initiated in detergents have been achieved. We report here on the structures of these oligomers and suggest how they may be involved in AD.

Objective: To compare the clinical efficacy and safety of hypomenthylating agents (HMA) combined with Venetoclax (VEN) and half dose priming regimen (CAG-like) in the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for intensive chemotherapy., Methods: The clinical data of 43 newly diagnosed elderly patients with AML who were not suitable for intensive chemotherapy in our hospital from April 2019 to October 2020 were retrospectively analyzed. Among them, 16 cases received HMA-VEN regimen and 27 cases received HMA-CAG-like regimen. The remission rate, early mortality and survival were compared between the two groups. And, the patients were grouped according to HCT-CI score. The effects of two different regimens in different groups on the efficacy and survival of patients were compared, and the prognosis of patients was further analyzed., Results: After one course of treatment, the total remission rate of HMA-VEN group and HMA-CAG-like group was 81.3% (13/16) and 51.9% (14/27), respectively, and the difference between the two groups was statistically significant (χ2=4.650, P =0.045). The median overall survival (OS) time of HMA-VEN group had not yet reached, while that of HMA-CAG-like group was 11.2 months, and the HMA-VEN group had a longer OS ( P =0.055). There was no tumor lysis syndrome occurred in both groups. The main adverse reactions were digestive tract reaction, bone marrow suppression and infection. The amount of agranulocytosis infection, pulmonary infection and platelet infusion in HMA-VEN group were significantly lower than those in HMA-CAG-like group ( P <0.05), while the time of agranulocytosis and amount of erythrocyte infusion were similar ( P >0.05). In HMA-Ven group 1 case died early, while in HMA-CAG-like group 8 cases died early due to pulmonary infection, respiratory failure, cerebral hemorrhage, and alveolar hemorrhage, the mortality in HMA-CAG-like group was significantly higher than that in HMA-VEN group ( P =0.043). Among 43 patients, there was a significant difference in OS between HCT score 0-2 group and ≥3 group ( P =0.033). In HMA-CAG-like group, patients with HCT score ≥3 had a worse prognosis ( P =0.01), while in HMA-VEN group patients showed no statistically significant difference in prognosis ( P =0.681). In HCT score 0-2 group, 9 cases receiving HMA-VEN regimen and 22 cases receiving HMA-CAG-like regimen showed no statistical difference in OS ( P =0.281). In HCT score ≥3 group, 7 cases receiving HMA-VEN regimen had a longer OS than 5 cases receiving HMA-CAG-like regimen ( P =0.015)., Conclusion: Venetoclax combined with HMA can achieve higher response rate, lower early mortality, and longer OS, especially in those with more comorbidities and poor tolerability.

Bacterial cell division begins with the formation of the Z-ring via polymerization of FtsZ and the localization of Z-ring beneath the inner membrane through membrane anchors. In Mycobacterium tuberculosis (Mtb), SepF is one such membrane anchor, but our understanding of the underlying mechanism is very limited. Here we used molecular dynamics simulations to characterize how SepF itself, a water-soluble protein, tethers to acidic membranes that mimic the Mtb inner membrane. In addition to an amphipathic helix (residues 1-12) at the N-terminus, membrane binding also occurs through two stretches of positively charged residues (Arg27-Arg37 and Arg95-Arg107) in the long linker preceding the FtsZ-binding core domain (residues 128-218). The additional interactions via the disordered linker stabilize the membrane tethering of SepF, and keep the core domain of SepF and hence the attached Z-ring close to the membrane. The resulting membrane proximity of the Z-ring in turn enables its interactions with and thus recruitment of two membrane proteins, FtsW and CrgA, at the late stage of cell division., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Phase separation of intrinsically disordered proteins (IDPs) is a phenomenon associated with many essential cellular processes, but a robust method to compute the binodal from molecular dynamics simulations of IDPs modeled at the all-atom level in explicit solvent is still elusive, due to the difficulty in preparing a suitable initial dense configuration and in achieving phase equilibration. Here we present SpiDec as such a method, based on spontaneous phase separation via spinodal decomposition that produces a dense slab when the system is initiated at a homogeneous, low density. After illustrating the method on four model systems, we apply SpiDec to a tetrapeptide modeled at the all-atom level and solvated in TIP3P water. The concentrations in the dense and dilute phases agree qualitatively with experimental results and point to binodals as a sensitive property for force-field parameterization. SpiDec may prove useful for the accurate determination of the phase equilibrium of IDPs., 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 Mazarakos, Prasad and Zhou.)

For intrinsically disordered proteins (IDPs), a pressing question is how sequence codes for function. Dynamics serves as a crucial link, reminiscent of the role of structure in sequence-function relations of structured proteins. To define general rules governing sequence-dependent backbone dynamics, we carried out long molecular dynamics simulations of eight IDPs. Blocks of residues exhibiting large amplitudes in slow dynamics are rigidified by local inter-residue interactions or secondary structures. A long region or an entire IDP can be slowed down by long-range contacts or secondary-structure packing. On the other hand, glycines promote fast dynamics and either demarcate rigid blocks or facilitate multiple modes of local and long-range inter-residue interactions. The sequence-dependent backbone dynamics endows IDPs with versatile response to binding partners, with some blocks recalcitrant while others readily adapting to intermolecular interactions.

China has the world's largest internal migrant population, called the floating population. Compared to local residents, the floating population utilizes different health services and relies heavily on health volunteer services for supplementary services. In this study, the theory of planned behavior model was used to study the willingness of volunteers to participate in floating population health volunteer services. We examined the effects of several factors on willingness to participate and found that attitude and subjective norm, but not perceived behavioral control, have significant predictive effects on willingness to participate in health volunteer services. Furthermore, altruistic values, social incentives, and personality traits not only have significant predictive effects on volunteer participation but also indirectly affect willingness through attitude and subjective norms. These findings help us understand what factors affect volunteers' willingness to provide health services to the floating population and have important implications for mobilizing volunteers for floating population health services., 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 Wu, Yu and Zhou.)