Dynamics design of a non-natural transcription factor responding to androst-4-ene-3,17-dione.

The production of androst-4-ene-3,17-dione (AD) by the steroidal microbial cell factory requires transcription factors (TFs) to participate in metabolic regulation. However, microbial cell factory lacks effective TFs that can respond to AD in its metabolic pathway. Additionally, finding and obtaining natural TFs that specifically respond to AD is a complex and onerous task. In this study, we devised an artificial TF that responds to AD, termed AdT, based on structure-guided molecular dynamics (MD) simulation. According to MD analysis of the conformational changes of AdT after binding to AD, an LBD in which the N- and C-termini exhibited convergence tendencies was used as a microswitch to guide the assembly of a DNA-binding domain lexA, a linker (GGGGS)2, and a transcription activation domain B42 into an artificial TF. As a proof of design, a AD biosensor was designed and constructed in yeast on the basis of the ligand-binding domain (LBD) of hormone receptor. In addition, the transcription factor activity of AdT was increased by 1.44-fold for its variant F320Y. Overall, we created non-natural TF elements for AD microbial cell factory, and expected that the design TF strategy will be applied to running in parallel to the signaling machinery of the host cell.

Orchestrating apoptosis and ferroptosis through enhanced sonodynamic therapy using amorphous UIO-66-CoOx.

The development of efficient and multifunctional sonosensitizers is crucial for enhancing the efficacy of sonodynamic therapy (SDT). Herein, we have successfully constructed a CoOx-loaded amorphous metal-organic framework (MOF) UIO-66 (A-UIO-66-CoOx) sonosensitizer with excellent catalase (CAT)- and glutathione-oxidase (GSH-OXD)-like activities. The A-UIO-66-CoOx exhibits a 2.6-fold increase in singlet oxygen (1O2) generation under ultrasound (US) exposure compared to crystalline UIO-66 sonosensitizer, which is attributed to its superior charge transfer efficiency and consistent oxygen (O2) supply. Additionally, the A-UIO-66-CoOx composite reduces the expression of glutathione peroxidase (GPX4) by depleting glutathione (GSH) through Co3+ and Co2+ valence changes. The high levels of highly cytotoxic 1O2 and deactivation of GPX4 can lead to lethal lipid peroxidation, resulting in concurrent apoptosis and ferroptosis. Both in vitro and vivo tumor models comprehensively confirmed the enhanced SDT antitumor effect using A-UIO-66-CoOx sonosensitizer. Overall, this study emphasizes the possibility of utilizing amorphization engineering to improve the effectiveness of MOFs-based sonosensitizers for combined cancer therapies.

Five new eremophilane-type sesquiterpenes from the fresh roots of Rehmannia glutinosa.

Five undescribed eremophilane-type sesquiterpenes, remophilanetriols E-I (1-5), along with seven known compounds (6-12) were isolated from the fresh roots of Rehmannia glutinosa. Their structures were characterized by extensive spectroscopic data analysis and their absolute configurations were determined by comparing their calculated electronic circular dichroism (ECD) spectra and experimental ECD spectra. The anti-pulmonary fibrosis activities of all compounds were evaluated in vitro by MTT methods, and compounds 2, 8, 10, and 12 exhibited excellent anti-pulmonary fibrosis activities. In addition, compound 2 can reduce the levels of ROS and apoptosis in TGF-ß1-induced BEAS-2B cells.

Sodium oligomannate's amelioration of reproductive and metabolic phenotypes in a letrozole-induced PCOS-like mouse model depends on the gut microbiome.

It has been well-established that there is a connection between polycystic ovary syndrome (PCOS) pathology and gut microbiome dysbiosis. A marine-derived oligosaccharide, GV-971, has been reported to alter gut microbiota and alleviate Aß amyloidosis. In this study, the effects of GV-971 on PCOS-like mice were explored. Mice were randomly assigned into four groups: control, letrozole, letrozole + GV-971, control + GV-971. Glucose metabolism in PCOS-like mice was ameliorated by GV-971, while the reproductive endocrine disorder of PCOS-like mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes in ovaries of PCOS-like mice were improved. GV-971 restored the fertility of PCOS-like mice and significantly increase the number of litters. Furthermore, GV-971 treatment effectively mitigated abnormal bile acid metabolism. Notably, after GV-971 intervention, gut microbiota alpha-diversity was considerably raised and the relative abundance of Firmicutes was reduced. In conclusion, the hyperinsulinemia and hyperandrogenemia of PCOS-like mice were alleviated by GV-971 intervention, which was associated with mitigating bile acid metabolism and modulating gut microbiota.

Functional magnetic resonance imaging for staging chronic kidney disease: a systematic review and meta-analysis.

INTRODUCTION: The commonly used clinical indicators are not sensitive and comprehensive enough to evaluate the early staging of chronic kidney disease (CKD). This study aimed to evaluate the differences in arterial spin labeling (ASL) and blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-MRI) parameter values among patients at various stages of chronic kidney disease and healthy individuals. METHODS: Electronic databases PubMed, Web of Science, Cochrane, and Embase were searched from inception to March 29, 2024, to identify relevant studies on ASL and BOLD in CKD. The renal blood flow (RBF) and apparent relaxation rate (R2*) values were obtained from healthy individuals and patients with various stages of CKD. The meta-analysis was conducted using STATA version 12.0. The random-effects model was used to obtain estimates of the effects, and the results were expressed as 95% confidence intervals (CIs) and mean differences (MDs) of continuous variables. RESULTS: A total of 18 published studies were included in this meta-analysis. The cortical RBF and R2* values and medulla RBF values were considerably distinct between patients with various stages of CKD and healthy controls (MD, - 78.162; 95% CI, - 85.103 to - 71.221; MD, 2.440; 95% CI, 1.843 to 3.037; and MD, - 36.787; 95% CI, - 47.107 to - 26.468, respectively). No obvious difference in medulla R2* values was noted between patients with various stages of CKD and healthy controls (MD, - 1.475; 95% CI, - 4.646 to 1.696). CONCLUSION: ASL and BOLD may provide complementary and distinct information regarding renal function and could potentially be used together to gain a more comprehensive understanding of renal physiology.

Characterization and prevention of flame burns caused by electric bicycle battery chargers: results from a 7-year experience.

OBJECTIVE: With the recent exponential increase in express deliveries across China, the number of patients with flame burns caused by electric bicycle battery chargers (BEBBC) has markedly increased in burn units. In this study, we aimed to characterize BEBBC to systematically explore measures to prevent their occurrence. METHODS: We performed a retrospective chart review of patients with flame burns who visited the Burn Department of Rui Jin Hospital between January 2015 and December 2021. RESULTS: Sixty-three patients with BEBBC and 1412 with types of other flame burn were included in this study. Fifty-six of the 63 BEBBC cases occurred between 9 pm and 7 am. BEBBC incidents involved a higher incidence of group burn in which multiple individuals were affected. Non-local patients with BEBBC were significantly younger than their local counterparts. BEBBC had a higher mortality than types of other flame burn. CONCLUSIONS: The rising incidence of BEBBC calls for greater attention because of the associated high mortality and heavy burden on society. Enacting related legislation, disseminating information to the public, and improving treatment to control infection can help prevent BEBBC, increase its cure rate, and reduce patient mortality.

8-OHdG mediates the association of co-exposure to fifty-five typical endocrine-disrupting chemicals with renal function: a cross-section investigation in Southern Chinese adults.

Individual typical endocrine-disrupting chemicals (EDCs), including organophosphate triesters (OPEs), parabens, triclosan (TCS), bisphenols, benzophenones (BPs), phthalates (PAEs), and synthetic phenolic antioxidants (SPAs), are associated with renal dysfunction. However, the combined effects and underlying mechanisms of mixed EDC exposure on renal function remain unclear. Two hundred ninety-nine adult participants were enrolled in the cross-sectional survey conducted in Guangzhou, China. Urinary levels of 7 OPEs, 6 parabens, TCS, 14 bisphenols, 8 BPs, 15 PAEs, 4 SPAs, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined, and estimated glomerular filtration rate (eGFR) was served as the outcome index. We found elevated levels of diphenyl phosphate (DPP), bisphenol A (BPA), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-butyl phthalate (MBP) showed dose-responsive associations with eGFR decline, However, nonlinear associations were observed for bis(2-butoxyethyl) hydrogen phosphate (BBOEP), TCS, 4-hydroxybenzophenone (HBP), mono-n-pentyl phthalate (MnPP), and mono-benzyl phthalate (MBzP). The quantile-based g-computation model demonstrated that a quartile increase in the EDC mixture corresponded to a 0.383-SD decrease (95% CI - 0.658 ~ - 0.108, P = 0.007) in eGFR. Notably, BPA was identified as the primary contributor to this effect. Moreover, 8-OHdG mediated the eGFR decline associated with EDC mixtures with a mediation proportion of 25.49%. A sex-modified effect was also observed (P = 0.004), indicating that exposure to the mixture of EDC was linked to more pronounced renal dysfunction in females. Our novel findings suggest that exposure to a typical mixture of EDCs is associated with renal dysfunction in the general adult population of Southern China. Furthermore, 8-OHdG may play a role in the pathogenesis of EDC mixture-related renal dysfunction.

Graphical models for identifying pore-forming proteins.

Pore-forming toxins (PFTs) are proteins that form lesions in biological membranes. Better understanding of the structure and function of these proteins will be beneficial in a number of biotechnological applications, including the development of new pest control methods in agriculture. When searching for new pore formers, existing sequence homology-based methods fail to discover truly novel proteins with low sequence identity to known proteins. Search methodologies based on protein structures would help us move beyond this limitation. As the number of known structures for PFTs is very limited, it's quite challenging to identify new proteins having similar structures using computational approaches like deep learning. In this article, we therefore propose a sample-efficient graphical model, where a protein structure graph is first constructed according to consensus secondary structures. A semi-Markov conditional random fields model is then developed to perform protein sequence segmentation. We demonstrate that our method is able to distinguish structurally similar proteins even in the absence of sequence similarity (pairwise sequence identity < 0.4)-a feat not achievable by traditional approaches like HMMs. To extract proteins of interest from a genome-wide protein database for further study, we also develop an efficient framework for UniRef50 with 43 million proteins.

Relationship of serum total cholesterol and triglyceride with risk of mortality in maintenance hemodialysis patients: a multicenter prospective cohort study.

OBJECTIVE: The relationship between serum total cholesterol (TC) and triglyceride (TG) levels and mortality in maintenance hemodialysis (MHD) patients remains inconsistent. We aimed to explore the individual and combined association of TC and TG levels with the risk of mortality in Chinese MHD patients. METHODS: 1036 MHD patients were enrolled in this multicenter, prospective cohort study. The serum levels of total cholesterol and triglycerides were measured at baseline. The primary outcome was all-cause mortality and secondary outcome was cardiovascular disease (CVD) mortality. RESULTS: During a median follow-up duration of 4.4 years (IQR= 2.0-7.9 years), 549 (53.0%) patients died, and 297 (28.7%) deaths were attributed to CVD. Compared with patients with TC levels in the first three quartiles (<182.5 mg/dL), a significantly higher risk of all-cause mortality was found in participants with TC in the fourth quartile (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.17-1.76). However, a significantly lower risk of all-cause mortality was observed in participants with TG in the fourth quartile (≥193.9 mg/dL) (HR, 0.78; 95%CI: 0.63-0.98), compared with participants with TG in the first three quartiles. Similar trends were observed in CVD mortality. When analyzed jointly, patients with lower TC (<182.5 mg/dL) and higher TG (≥193.9 mg/dL) levels had the lowest risk of all-cause mortality and CVD mortality.Conclusions: In MHD patients in southern China, higher TC levels were associated with higher risk of mortality, while higher TG levels were related to lower risk of mortality. Patients with lower TC and higher TG levels had the best survival prognosis.

Total ankle replacement versus ankle fusion for end-stage ankle arthritis: A meta-analysis.

PURPOSE: This study aims to systematically review the efficacy and safety of total ankle replacement (TAR) and ankle fusion (AF) as treatment options for end-stage ankle arthritis. METHODS: A comprehensive literature search was conducted on data from multiple databases, including PubMed, The Cochrane Library, Construction and Building Materials, Embase, Web of Science, and Scopus for RCTs and prospective cohort studies comparing TAR and AF in patients with end-stage ankle arthritis from inception up to June, 2023. Our primary outcomes of interest included patients' clinical function scores and complications. We employed Review Manager 5.4 and Stata/MP 14.0 software for the meta-analysis. RESULTS: Our analysis incorporated 13 comparative studies, including 11 prospective studies, one pilot RCT, and one RCT. The pooled results revealed no significant difference in postoperative Short Form-36 scores between the TAR and AF groups (MD = -1.19, 95% CI: -3.89 to 1.50, p = .39). However, the postoperative Foot and Ankle Ability Measure scores in the AF group were significantly higher than in the TAR group (MD = 8.30, 95% CI: 1.01-15.60, p = .03). There was no significant difference in postoperative complication rates between the TAR and AF groups (RR = 0.95, 95% CI: 0.59 to 1.54, p = .85). CONCLUSION: Currently available evidence suggests no significant disparity in postoperative outcomes between TAR and AF. In the short term, TAR demonstrates better clinical scores than AF and lower complication rates. Conversely, in the long term, AF exhibits superior clinical scores and lower complication rates, although this difference is not statistically significant.

Application of Response Surface-Corrected Finite Element Model and Bayesian Neural Networks to Predict the Dynamic Response of Forth Road Bridges under Strong Winds.

With the rapid development of big data, the Internet of Things (IoT), and other technological advancements, digital twin (DT) technology is increasingly being applied to the field of bridge structural health monitoring. Achieving the precise implementation of DT relies significantly on a dual-drive approach, combining the influence of both physical model-driven and data-driven methodologies. In this paper, two methods are proposed to predict the displacement and dynamic response of structures under strong winds, namely, a Bayesian Neural Network (BNN) model based on Bayesian inference and a finite element model (FEM) method modified based on genetic algorithms (GAs) and multi-objective optimization (MOO) using response surface methodology (RSM). The characteristics of these approaches in predicting the dynamic response of large-span bridges are explored, and a comparative analysis is conducted to evaluate their differences in computational accuracy, efficiency, model complexity, interpretability, and comprehensiveness. The characteristics of the two methods were evaluated using data collected on the Forth Road Bridge (FRB) as an example under unusual weather conditions with strong wind action. This work proposes a dual-driven approach, integrating machine learning and FEM with GNSS and Earth Observation for Structural Health Monitoring (GeoSHM), to bridge the gap in the limited application of dual-driven methods primarily applied for small- and medium-sized bridges to large-span bridge structures. The research results show that the BNN model achieved higher R2 values for predicting the Y and Z displacements (0.9073 and 0.7969, respectively) compared to the FEM model (0.6167 and 0.6283). The BNN model exhibited significantly faster computation, taking only 20 s, while the FEM model required 5 h. However, the physical model provided higher interpretability and the ability to predict the dynamic response of the entire structure. These findings help to promote the further integration of these two approaches to obtain an accurate and comprehensive dual-driven approach for predicting the structural dynamic response of large-span bridge structures affected by strong wind loading.

Tripedal DNA Walker as a Signal Amplifier Combined with a Potential-Resolved Multicolor Electrochemiluminescence Strategy for Ultrasensitive Detection of Prostate Cancer Staging Indicators.

A multicolor electrochemiluminescence (ECL) biosensor based on a closed bipolar electrode (BPE) array was proposed for the rapid and intuitive analysis of three prostate cancer staging indicators. First, [Irpic-OMe], [Ir(ppy)2(acac)], and [Ru(bpy)3]2+ were applied as blue, green, and red ECL emitters, respectively, whose mixed ECL emission colors covered the whole visible region by varying the applied voltages. Afterward, we designed a simple Mg2+-dependent DNAzyme (MNAzyme)-driven tripedal DNA walker (TD walker) to release three output DNAs. Immediately after, three output DNAs were added to the cathodic reservoirs of the BPE for incubation. After that, we found that the emission colors from the anode of the BPE changed as a driving voltage of 8.0 V was applied, mainly due to changes in the interfacial potential and faradaic currents at the two poles of the BPE. Via optimization of the experimental parameters, cutoff values of such three indicators at different clinical stages could be identified instantly with the naked eye, and standard precision swatches with multiple indicators could be prepared. Finally, in order to precisely determine the prostate cancer stage, the multicolor ECL device was used for clinical analysis, and the resulting images were then compared with standard swatches, laying the way for accurate prostate cancer therapy.

Two new iridoid glycosides from the whole plant of Rehmania piasezkii.

Two new iridoid glycosides, piasezkiiosides A (1) and B (2), were isolated from aqueous extract of the whole plant of Rehmannia piasezkii. Their structures were established from the spectroscopic data, chemical transformation, and X-ray diffraction analysis. Compound 1 exhibited weak hepatoprotective activity against APAP-induced HepG2 cell damage.

A new 3,4-dihydroisocoumarin and an antiinflammatory coumarin from the roots of Saposhnikovia divaricata (Turcz.) Schischk.

Phytochemical investigation of the roots of Saposhnikovia divaricata (Turcz.) Schischk resulted in the isolation of twelve coumarin derivatives including one new 3,4-dihydroisocoumarin (1) and eleven known 3,4-unsubstituted coumarins (2-12). Structural elucidation of compounds 1-12 was established by 1D and 2D NMR spectra referring to the literature, together with high-resolution mass spectrometric analysis. LPS-induced RAW264.7 inflammatory cell model was used to determine the potential antiinflammation activity of all the isolated compounds in vitro. The results showed that compound 3 significantly inhibited the production of lipopolysaccharide (LPS)-induced NO in macrophages (IC50 = 4.54 ± 1.71 µM), more active than the positive control (L-NMMA).

Bilateral Focal Choroidal Excavation and Central Serous Chorioretinopathy Coexisting in a Male Patient.

Background: Here, we report a case of a male patient with bilateral focal choroidal excavation (FCE) and central serous chorioretinopathy (CSC). A 33-year-old man complained of mild blurring of vision in the right eye. Optical coherence tomography (OCT) revealed FCE in both eyes, with subretinal fluid in both eyes and serous pigment epithelial detachment in the right eye. Standard laser fluence (50 J/cm2) was used in the right eye, and a subthreshold micropulse laser (SML) was simultaneously used in the left eye. Follow-up visits were recommended. At his last visit (5 months after treatment), the visual acuity was 16/20 in the right eye and 20/20 in the left eye and OCT showed a completed resolution of SRF. Conclusion: FCE is defined as a localized depression of the choroid detected by OCT. It may be congenital or acquired secondarily. We present a case of uncommon focal choroidal excavation and central serous chorioretinopathy (CSC) coexisting in both eyes at a relatively young age in which visual acuity was improved and subretinal fluid (SRF) completely resolved with laser treatment. Timely treatment can promote SRF absorption and improve vision.

Design, synthesis, and evaluation of the novel ozagrel-paeonol codrug with antiplatelet aggregation activities as a potent anti-stroke therapeutic agent.

Introduction: Ischemic stroke is the second most common chronic disease worldwide and is associated with high morbidity and mortality. Thromboembolism and platelet aggregation are the most characteristic features of stroke. Other than aspirin, no standard, accepted, or effective treatment for acute ischemic stroke has been established. Consequently, it is essential to identify novel therapeutic compounds for this condition. Methods: In this study, novel ozagrel/paeonol-containing codrugs were synthesized and characterized using 1H-NMR, 13C-NMR, and mass spectroscopy. Their antiplatelet aggregation activity was evaluated, with compound PNC3 found to exhibit the best effect. Subsequently, studies were conducted to assess its neuroprotective effect, pharmacokinetic properties and model its binding mode to P2Y12 and TXA2, two proteins critical for platelet aggregation. Results: The results indicated that PNC3 has good bioavailability and exerts protective effects against oxygen-glucose deprivation injury in PC12 cells. Molecular docking analysis further demonstrated that the compound interacts with residues located in the active binding sites of the target proteins. Conclusion: The codrugs synthesized in this study display promising pharmacological activities and have the potential for development as an oral formulation.

Light-driven phase transition of diffractive optical elements based on liquid crystal elastomers.

Diffractive optical element is advantageous for miniaturization, arraying and integration of optical systems. They have been widely used in beam shaping, diffractive imaging, generating beam arrays, spectral optimization and other aspects. Currently, the vast majority of diffractive optics are not tunable. This limits the applicability and functionality of these devices. Here we report a tunable diffractive optical element controlled by light in the visible band. The diffractive optical element consists of a square gold microarray deposited on a deformable substrate. The substrate is made of a liquid crystal elastomer. When pumped by a 532 nm laser, the substrate is deformed to change the crystal lattice. This changes the far-field diffraction pattern of the device. The proposed concept establishes a light-controlled soft platform with great potential for tunable/reconfigurable photonic devices, such as filters, couplers, holograms and structural color displays.

Two Novel Genetic Variants Involved in the Oxygen Sensing Pathway in JAK2-unmutated Erythrocytosis.

JAK2-unmutated erythrocytosis or non-polycythemia vera erythrocytosis is a rare condition comprising both acquired and hereditary forms. Although acquired erythrocytosis has been well-studied, hereditary erythrocytosis remains poorly studied. Genetic alterations associated with hereditary erythrocytosis include mutations in erythropoietin receptor and erythropoietin (EPO), altered oxygen affinity mutations, and variants associated with the oxygen-sensing pathway. We established a molecular diagnostic approach based on these genes and retrospectively evaluated. Peripheral blood from 56 erythrocytosis patients, lacking JAK2 mutation, were screened for oxygen-sensing pathway abnormalities. Two novel mutations were identified in the EGLN1 gene: NM_022051.2:c.712G > C (p.Gly238Arg) and NM_022051.2:c.122A > C (p.Tyr41Ser) in two patients separately. Notably, both reported heterozygous mutations were absent in the population database. Predictions using multiple computer software indicated that these two missense mutations were harmful and induced a highly conserved amino acid change in EGLN1. Patients with the two mutations exhibited normal serum EPO levels and high hemoglobin and hematocrit levels. Additionally, three other variants of genes were identified in the oxygen-sensing pathway, including endothelial PAS domain protein 1 (EPAS1) rs184760160(2/56), and EGLN1 rs186996510(2/56), rs555121182(2/56). These variants were categorized as benign or likely benign. Our findings provide a framework for etiological research and highlight the importance of screening for genetic mutations associated with erythrocytosis in clinical practice.

High-enhancement photoluminescence of monolayer MoS2 in hybrid plasmonic systems.

Monolayer molybdenum disulfide (M o S 2) has a weak light-matter interaction due to ultrathin thickness, which limits its potential application in lasing action. In this study, we propose a hybrid structure consisting of a nanocavity and Au nanoparticles to enhance the photon emission efficiency of monolayer M o S 2. Numerical simulations show that photoluminescence (PL) emission is significantly enhanced by introducing localized surface plasmon resonance (LSPR) to the proposed structure. Furthermore, an exciton energy band system is proposed to elucidate the physical mechanism of the PL process. By optimizing the spacer thickness, a high Purcell enhancement factor of 95 can be achieved. The results provided by this work pave the way to improve the PL efficiency of two-dimensional (2D) material, which constitutes a significant step towards the development of nanodevices such as nanolasers and sensors.