EGFR-targeting oxygen-saturated nanophotosensitizers for orchestrating multifaceted antitumor responses by counteracting immunosuppressive milieu.

High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O2, has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX)-mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O2 serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O2 can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFRhigh cSCC but also to extend its applicability to other EGFRhigh malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies.

Rapidly molded sodium alginate/soy protein adhesive hydrogel with 808-nm laser inhibition of infected wounds.

Infected wounds produce pus and heal slowly. To address this issue, we developed a rapid-setting SP/SA@BP-C hydrogel by combining sodium alginate (SA) and soy protein (SP) with black phosphorus (BP) grafted with clarithromycin (Cla) and incorporating Ca2+ for chelation. This hydrogel dressing exhibits excellent photothermal (PT) and photodynamic (PD) bacteriostatic effects without biotoxicity, making it suitable for treating infected wounds. Characterization confirmed its successful fabrication, and the bacteriostatic effect demonstrated over 99 % efficacy through the synergistic effects of PT, PD, and Cla. Cellular studies indicated nontoxicity and a promoting effect on cell proliferation (121.6 %). In the mouse-infected wound model, the hydrogel led to complete healing in 12 days, with good recovery of the skin's superficial dermal layer and appendages. Consequently, SP/SA@BP-C is a natural hydrogel dressing with promising properties.

Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K.

A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.

Astrocyte allocation during brain development is controlled by Tcf4-mediated fate restriction.

Astrocytes in the brain exhibit regional heterogeneity contributing to regional circuits involved in higher-order brain functions, yet the mechanisms controlling their distribution remain unclear. Here, we show that the precise allocation of astrocytes to specific brain regions during development is achieved through transcription factor 4 (Tcf4)-mediated fate restriction based on their embryonic origin. Loss of Tcf4 in ventral telencephalic neural progenitor cells alters the fate of oligodendrocyte precursor cells to transient intermediate astrocyte precursor cells, resulting in mislocalized astrocytes in the dorsal neocortex. These ectopic astrocytes engage with neocortical neurons and acquire features reminiscent of dorsal neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during the differentiation of oligodendrocyte precursor cells derived from the ventral telencephalon, thereby restricting the fate to the oligodendrocyte lineage in the dorsal neocortex. Together, our findings highlight a previously unappreciated role for Tcf4 in regulating astrocyte allocation, offering additional insights into the mechanisms underlying neurodevelopmental disorders linked to Tcf4 mutations.

Engineering AIEgens-Tethered Gold Nanoparticles with Enzymatic Dual Self-Assembly for Amplified Cancer-Specific Phototheranostics.

Accurate imaging and precise treatment are critical to controlling the progression of pancreatic cancer. However, current approaches for pancreatic cancer theranostics suffer from limitations in tumor specificity and invasive surgery. Herein, a pancreatic cancer-specific phototheranostic modulator (AuHQ) dominated by aggregation-induced emission (AIE) luminogens-tethered gold nanoparticles is meticulously designed to facilitate prominent fluorescence-photoacoustic bimodal imaging-guided photothermal immunotherapy. Once reaching the pancreatic tumor microenvironment (TME), the peptide Ala-Gly-Phe-Ser-Leu-Pro-Ala-Gly-Cys (AGFSLPAGC) linkage within AuHQ can be specifically cleaved by the overexpressed enzyme Cathepsin E (CTSE), triggering the dual self-assembly of AuNPs and AIE luminogens. The aggregation of AuNPs mediated by enzymatic cleavage results in potentiated photothermal therapy (PTT) under near-infrared (NIR) laser irradiation, induced immunogenic cell death (ICD), and enhanced photoacoustic imaging. Simultaneously, AIE luminogen aggregates formed by hydrophobic interaction can generate AIE fluorescence, enabling real-time and specific fluorescence imaging of pancreatic cancer. Furthermore, coadministration of an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor with AuHQ can address the limitations of PTT efficacy imposed by the immunosuppressive TME and leverage the synergistic potential to activate systemic antitumor immunity. Thus, this well-designed phototheranostic modulator AuHQ facilitates the intelligent enzymatic dual self-assembly of imaging and therapeutic agents, providing an efficient and precise approach for pancreatic cancer theranostics.

In Situ Ligand-Transformation-Assisted Assembly of a Polyoxometalate and Silver-Phosphine Oxide Cluster for Colorimetric Detection of Phenol Contaminants.

In situ ligand transformation strategies represent an efficient pathway for constructing function-oriented polyoxometalate (POM)-based crystalline materials. Herein, three POM-based hybrid networks were synthesized through in situ transformation of the phosphine ligand, formulated as [Ag(dppeo)6][H2PMo12O40]·5H2O (1), [Ag(dedpo)]4[SiW12O40]·6H2O (2), and [Ag(dppeo)]3[PW12O40]·3H2O (3) (dedpo = (2-(diphenylphosphaneyl)ethyl)diphenylphosphine oxide; dppeo = ethane-1,2-diylbis(diphenylphosphine oxide)). During the synthesis of these compounds, the 1,2-diphenylphosphine ethane molecule underwent in situ oxidation, transforming into dppeo and dedpo ligands, respectively. Compound 1 features a supramolecular architecture assembled from [Ag(dppeo)3]+/[Ag2(dppeo)6]2+ cationic clusters with disordered Ag centers and protonated [H2PMo12O40]- anions. Compound 2 presents a 3-D POM-supported metal-organic framework consisting of binuclear [Ag(dedpo)]22+ units, {-dedpo-Ag-dedpo-} chains, and [SiW12O40]4- polyoxoanions. Compound 3 displays a 2-D layered structure formed by {-dppeo-Ag3-dppeo-} chains and [PW12O40]3- clusters. Pronounced argentophilic interactions are observed in compounds 1 and 3. The three compounds demonstrate satisfactory heterogeneous catalytic activity in the colorimetric detection reactions toward phenol pollutants with detection limits of 1.73, 1.92, and 4.6 µM, respectively. Additionally, compounds 1-3 show high anti-interference capabilities and high sensitivity in differentiating phenol from its halogenated derivatives. This work presents some guidance for designing specific function-oriented POM-based materials via an in situ ligand transformation strategy.

Healthy lifestyle associated with dynamic progression of type 2 diabetes: A multi-state analysis of a prospective cohort.

Background: Although the association of a healthy lifestyle with type 2 diabetes (T2D) has been extensively studied, its impact on the dynamic trajectory, including progression, onset and prognosis, of T2D has not been investigated. Methods: Using data from the UK Biobank, 461 168 participants without diabetes or diabetes-related events were included. We incorporated four lifestyle factors to construct the healthy lifestyle score (HLS). We employed a multi-state model to examine the relationship between a healthy lifestyle and transition in T2D progression, including transitions from baseline to diabetes, complications, and further to death. The cumulative probability of above transitions based on the health lifestyle score was calculated. Results: The results indicated that adhering to 3-4 healthy lifestyles had an inverse association with the risk of transition from baseline to diabetes (hazard ratio (HR) = 0.966; 95% confidence interval (CI) = 0.935-0.998, P = 0.038), diabetes to complications (HR = 0.869; 95% CI = 0.818-0.923, P = 5.2 × 10-6), baseline to death (HR = 0.528; 95% CI = 0.502-0.553, P < 2 × 10-16, and diabetes to death (HR = 0.765; 95% CI = 0.591-0.990, P = 0.041) compared with maintaining 0-1 healthy lifestyles. In addition, the transition probability of the above transitions can be lower with maintaining 3-4 healthy lifestyles. Conclusions: Healthy lifestyles are negatively associated with the risk of multiple outcomes during the dynamic progression of T2D. Adherence to 3-4 healthy lifestyle behaviours before diabetes onset can lower the risk of developing T2D, further reducing the risk of diabetes complications and death in patients with T2D.

Spatial-temporal evolution patterns of influenza incidence in Xinjiang Prefecture from 2014 to 2023 based on GIS.

Using GIS technology, this study investigated the spatiotemporal distribution pattern of influenza incidence in Xinjiang from 2014 to 2023 based on influenza surveillance data. The study revealed a noticeable fluctuation trend in influenza incidence rates in Xinjiang, particularly notable spikes observed in 2019 and 2023. The results of the 3-year moving average showed a significant long-term upward trend in influenza incidence rates, confirmed by Theil-Sen method (MAD = 2.202, p < 0.01). Global spatial autocorrelation analysis indicated significant positive spatial autocorrelation in influenza incidence rates from 2016 and from 2018 to 2023 (Moran's I > 0, P < 0.05). Local spatial autocorrelation analysis further revealed clustering patterns in different regions, with high-high clustering and low-high clustering predominating in northern Xinjiang, and low-low clustering predominating in southern Xinjiang. Hotspot analysis indicated a progressive rise in the number of influenza incidence hotspots, primarily concentrated in northern Xinjiang, particularly in Urumqi, Ili Kazakh Autonomous Prefecture, and Hotan Prefecture. Standard deviation ellipse analysis and the trajectory of influenza incidence gravity center migration showed that the transmission range of influenza in Xinjiang has been expanding, with the epidemic center gradually moving northward. The spatiotemporal heterogeneity of influenza incidence in Xinjiang highlights the need for differentiated and precise influenza prevention and control strategies in different regions to address the changing trends in influenza prevalence.

Design, Synthesis, and Evaluation of the Antitubercular Activity of 5-Phenyl Substituted-5, 6-dihydropyrido[2, 3-d]pyrimidine-4, 7(3H, 8H)-dione Compounds.

Tuberculosis (TB) remains a major public health challenge, with research on new anti-TB drugs crucial for global TB elimination efforts. Here, we report a novel class of anti-TB agents. Especially, compounds 5b and 5j exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 µg/mL]. Chiral resolution was performed on compounds 5b and 5j; the isomers were evaluated for their activity and safety, confirming that the R-isomer 5bb and 5jb displayed significant anti-TB activity (MIC H37Rv: 0.03-0.06 µg/mL; MDR-Mtb: 0.125-0.06 µg/mL) and low hERG toxicity. Further evaluations on 5bb and 5jb demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of in vivo activity assessment indicate that 5bb and 5jb exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with Mycobacterium marinum. Based on these results, compounds 5bb and 5jb are considered promising candidates for further in-depth studies.

Predicting central lymph node metastasis in papillary thyroid cancer: A nomogram based on clinical, ultrasound and contrast­enhanced computed tomography characteristics.

Central lymph node (CLN) status is considered to be an important risk factor in patients with papillary thyroid carcinoma (PTC). The aim of the present study was to identify risk factors associated with CLN metastasis (CLNM) for patients with PTC based on preoperative clinical, ultrasound (US) and contrast-enhanced computed tomography (CT) characteristics, and establish a prediction model for treatment plans. A total of 786 patients with a confirmed pathological diagnosis of PTC between January 2021 to December 2022 were included in the present retrospective study, with 550 patients included in the training group and 236 patients enrolled in the validation group (ratio of 7:3). Based on the preoperative clinical, US and contrast-enhanced CT features, univariate and multivariate logistic regression analyses were used to determine the independent predictive factors of CLNM, and a personalized nomogram was constructed. Calibration curve, receiver operating characteristic (ROC) curve and decision curve analyses were used to assess discrimination, calibration and clinical application of the prediction model. As a result, 38.9% (306/786) of patients with PTC and CLNM(-) status before surgery had confirmed CLNM using postoperative pathology. In multivariate analysis, a young age (≤45 years), the male sex, no presence of Hashimoto thyroiditis, isthmic location, microcalcification, inhomogeneous enhancement and capsule invasion were independent predictors of CLNM in patients with PTC. The nomogram integrating these 7 factors exhibited strong discrimination in both the training group [Area under the curve (AUC)=0.826] and the validation group (AUC=0.818). Furthermore, the area under the ROC curve for predicting CLNM based on clinical, US and contrast-enhanced CT features was higher than that without contrast-enhanced CT features (AUC=0.818 and AUC=0.712, respectively). In addition, the calibration curve was appropriately fitted and decision curve analysis confirmed the clinical utility of the nomogram. In conclusion, the present study developed a novel nomogram for preoperative prediction of CLNM, which could provide a basis for prophylactic central lymph node dissection in patients with PTC.

Oxytocin Protects Nigrostriatal Dopamine Signal via Activating GABAergic Circuit in the MPTP-Induced Parkinson's Disease Model.

The most pronounced neuropathological feature of Parkinson's disease (PD) is the loss of dopamine (DA) neurons in the substantia nigra compacta (SNc), which depletes striatal DA. Hypothalamic oxytocin is found to be reduced in PD patients and closely interacts with the DA system, but the role of oxytocin in PD remains unclear. Here, the disturbances of endogenous oxytocin level and the substantia nigra (SN) oxytocin receptor expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model is observed, correlated with the striatal tyrosine hydroxylase (TH) expression reduction. Killing/silencing hypothalamic oxytocin neurons aggravates the vulnerability of nigrostriatal DA signal to MPTP, whereas elevating oxytocin level by intranasal delivery or microinjecting into the SN promotes the resistance. In addition, knocking out SN oxytocin receptors induces the time-dependent reductions of SNc DA neurons, striatal TH expression, and striatal DA level by increasing neuronal excitotoxicity. These results further uncover that oxytocin dampens the excitatory synaptic inputs onto DA neurons via activating oxytocin receptor-expressed SN GABA neurons, which target GABA(B) receptors expressed in SNc DA neuron-projecting glutamatergic axons, to reduce excitotoxicity. Thus, besides the well-known prosocial effect, oxytocin acts as a key endogenous factor in protecting the nigrostriatal DA system.

Targeting Autophagy: A Promising Therapeutic Strategy for Diabetes Mellitus and Diabetic Nephropathy.

Diabetes mellitus (DM) significantly impairs patients' quality of life, primarily because of its complications, which are the leading cause of mortality among individuals with the disease. Autophagy has emerged as a key process closely associated with DM, including its complications such as diabetic nephropathy (DN). DN is a major complication of DM, contributing significantly to chronic kidney disease and renal failure. The intricate connection between autophagy and DM, including DN, highlights the potential for new therapeutic targets. This review examines the interplay between autophagy and these conditions, aiming to uncover novel approaches to treatment and enhance our understanding of their underlying pathophysiology. It also explores the role of autophagy in maintaining renal homeostasis and its involvement in the development and progression of DM and DN. Furthermore, the review discusses natural compounds that may alleviate these conditions by modulating autophagy.

Phosphomolybdates for Dual-Mode Photoelectrochemical Sensing toward Trace Chromium(VI) and Tetracycline.

Highly sensitive photoelectrochemical (PEC) sensors for trace carcinogens, such as heavy metal chromium(VI) [Cr(VI)] and antibiotic tetracycline (TC) are crucial. Herein, by integration of photoactive and redox phosphomolybdates with conjugated organic components, types of dual-mode PEC sensors were synthesized for sensing trace Cr(VI) and TC pollutants, with formulas of (H2bimb)2[Co2(bimb)1.5][Co(H2O)4][Co(P4Mo6O31H6)2]·6H2O (1), (H2bib)2[Co(H2O)3][Co2(H2O)5][Co(P4Mo6O31H6)2]·9H2O (2), and (H2bib)6[Co(Hbib)2(H2O)5][Co(P4Mo6O31H7)2]2·15H2O (3), where bimb represents 1,4-bis(1-imidazolyl)benzene and bib is 4,4'-bis(imidazolyl)bibphenyl. Hybrid 1 consisted of a three-dimensional framework structure constructed by Co{P4Mo6}2 clusters and one-dimensional (1D) {Co-bimb} chains, hybrid 2 exhibited 1D Co ion-bridged Co{P4Mo6}2 chains hydrogen-bonding with [H2bib]2+ cations, and hybrid 3 showed a discrete hybrid structure built upon a Co{P4Mo6}2 cluster modified by the {Co-bib} unit. Hybrids 1-3 displayed wide spectral absorption and excellent electrochemical redox properties, enabling dual-mode PEC responses to Cr(VI) reduction and TC oxidation. For Cr(VI) detection, hybrids 1-3 exhibited high sensitivities of 364.40, 225.72, and 124.29 µA·µM-1 as well as "nM" level detection limits (LODs) of 4.9, 10.0, and 11.0 nM, respectively. For TC detection, the sensitivities of hybrids 1-3 were 494.72, 308.78, and 174.03 µA·µM-1 and the LODs were 5.2, 6.1, and 12.9 nM, respectively. This research offers significant insights into designing efficient PEC sensors for the detection of environmental pollutants.

ncRNA Coding Potential Prediction Using BiLSTM and Transformer Encoder-Based Model.

Many noncoding RNAs (ncRNAs) have been identified, and many of them play vital roles in various biological processes, including gene expression regulation, epigenetic regulation, transcription, and control. Recently, a few observations revealed that ncRNAs are translated into functional peptides. Moreover, many computational methods have been developed to predict the coding potential of these transcripts, which contributes to a deeper investigation of their functions. However, most of these are used to distinguish ncRNAs and mRNAs. It is important to develop a highly accurate computational tool for identifying the coding potential of ncRNAs, thereby contributing to the discovery of novel peptides. In this Article, we propose a novel BiLSTM And Transformer encoder-based model (nBAT) with intrinsic features encoded for ncRNA coding potential prediction. In nBAT, we introduce a learnable position encoding mechanism to better obtain the embeddings of the ncRNA sequence. Moreover, we extract 43 intrinsic features from different perspectives and encode these features into the Transformer encoder by calculating their distances. Our performance comparisons show that nBAT achieves a superior performance than the state-of-the-art methods for coding potential prediction on different datasets. We also apply the method to new ncRNAs for identifying the coding potential, and the results further indicate the competitive performance of nBAT. We expect the method can be exploited as a useful tool for high-throughput coding potential prediction for ncRNAs.

Diabetes specialist nurses' knowledge, skills, and personal attributes for providing competent health education practice, and its influencing factors: A cross-sectional survey.

BACKGROUND: The number of diabetes specialist nurse as well as their knowledge and skills have increased in Gansu Province since 2017. However, China has not fully addressed how to improve their professional skills to deliver effective health education. AIMS: To investigate the knowledge, skills, and personal attributes of competent health education practices among diabetes specialist nurses in Gansu Province, western China, and the potential influencing factors. DESIGN: Cross-sectional study. METHODS: In total, 178 diabetes specialist nurses from 45 hospitals participated in this study. Data were collected between December 2022 and April 2023 using the Nurse Health Education Competence Instrument (I-CepSE) and a self-report questionnaire. Descriptive and inferential statistics, including univariate and multiple linear regression analyses, were used to analyze data. RESULTS: The mean scores of overall I-CepSE, knowledge, skills, and personal attributes were 218.77 ± 31.65, 77.80 ± 18.27, 103.95 ± 13.75 and 37.02 ± 4.73, respectively. A shortage of nursing staff and heavy workload (81.4 %), lack of cooperation from patients (56.5 %), lack of access to educational resources during work placement (54.2 %), and nurses' lack of knowledge/skills in health education (53.1 %) were common barriers to health education implementation. The regression models for the overall health education competence domain were significant (P < 0.001) with R2 values ranging from 31.9 % to 50.5 %. Education level and years of experience in diabetes-related care were found to be significant on all knowledge, skills, and personal attitude scales (P < 0.05), and age was associated with diabetes specialist nurses' skills and personal attitude scores (P < 0.05). CONCLUSION: Diabetes specialist nurses demonstrated moderate to high levels of health education knowledge, skills, and attitudes. However, they lacked knowledge of pedagogical techniques and resources, with inadequate educational skills. This study suggests that reasonable nursing human resource allocation and continuous education and training are crucial for improving health education competence.

Construction of an orthogonal transport system for Saccharomyces cerevisiae peroxisome to efficiently produce sesquiterpenes.

Subcellular compartmentalization is a crucial evolution characteristic of eukaryotic cells, providing inherent advantages for the construction of artificial biological systems to efficiently produce natural products. The establishment of an artificial protein transport system represents a pivotal initial step towards developing efficient artificial biological systems. Peroxisome has been demonstrated as a suitable subcellular compartment for the biosynthesis of terpenes in yeast. In this study, an artificial protein transporter ScPEX5* was firstly constructed by fusing the N-terminal sequence of PEX5 from S. cerevisiae and the C-terminal sequence of PEX5. Subsequently, an artificial protein transport system including the artificial signaling peptide YQSYY and its enhancing upstream 9 amino acid (9AA) residues along with ScPEX5* was demonstrated to exhibit orthogonality to the internal transport system of peroxisomes in S. cerevisiae. Furthermore, a library of 9AA residues was constructed and selected using high throughput pigment screening system to obtain an optimized signaling peptide (oPTS1*). Finally, the ScPEX5*-oPTS1* system was employed to construct yeast cell factories capable of producing the sesquiterpene α-humulene, resulting in an impressive α-humulene titer of 17.33 g/L and a productivity of 0.22 g/L/h achieved through fed-batch fermentation in a 5 L bioreactor. This research presents a valuable tool for the construction of artificial peroxisome cell factories and effective strategies for synthesizing other natural products in yeast.

A study on the correlation between physical fitness index and executive function in Chinese adolescents.

OBJECTIVE: To explore the relationship between physical fitness index and executive function in Chinese adolescents, and to provide a reference for improving the development of executive function in Chinese adolescents. METHODS: From September to December 2023, 5336 adolescents aged 13 to 18 years were selected by stratified whole cluster random sampling method in six regions of China for physical fitness and executive function tests. The relationship between adolescent physical fitness index and executive function was analyzed using t-test, ANOVA, Pearson's correlation, and logistic regression. RESULTS: The correlation coefficients between adolescents' physical fitness index and inhibitory control reaction time were all 0.00094, p > 0.05; the correlation coefficients between adolescents' physical fitness index and working memory (1-back, 2-back) reaction time were -0.13 and -0.093, respectively, p < .05; the correlation coefficients between adolescents' physical fitness index and cognitive flexibility reaction time were -0.17 and -0.18, p < .05. Logistic regression analyses showed that 1-back, 2-back, and cognitive flexibility were significantly and positively correlated with physical fitness index in Models 1, 2, and 3 (all p values less than.01). The coefficients of inhibitory control were not significant in all three models (p > .05), and there was no significant relationship with physical fitness index. CONCLUSION: The physical fitness index of Chinese adolescents has a significant positive correlation with working memory and cognitive flexibility, but not with inhibitory control, i.e. the higher the physical fitness index, the better the working memory and cognitive flexibility.

Structures of SenB and SenA enzymes from Variovorax paradoxus provide insights into carbon-selenium bond formation in selenoneine biosynthesis.

Selenoneine, an ergothioneine analog, is important for antioxidation and detoxification. SenB and SenA are two crucial enzymes that form carbon-selenium bonds in the selenoneine biosynthetic pathway. To investigate their underlying catalytic mechanisms, we obtained complex structures of SenB with its substrate UDP-N-acetylglucosamine (UDP-GlcNAc) and SenA with N-α-trimethyl histidine (TMH). SenB adopts a type-B glycosyltransferase fold. Structural and functional analysis of the interaction network at the active center provide key information on substrate recognition and suggest a metal-ion-independent, inverting mechanism is utilized for SenB-mediated selenoglycoside formation. Moreover, the complex structure of SenA with TMH and enzymatic activity assays highlight vital residues that control substrate binding and specificity. Based on the conserved structure and substrate-binding pocket of the type I sulfoxide synthase EgtB in the ergothioneine biosynthetic pathway, a similar reaction mechanism was proposed for the formation of C-Se bonds by SenA. The structures provide knowledge on selenoneine synthesis and lay groundwork for further applications of this pathway.

Kernel Bayesian logistic tensor decomposition with automatic rank determination for predicting multiple types of miRNA-disease associations.

Identifying the association and corresponding types of miRNAs and diseases is crucial for studying the molecular mechanisms of disease-related miRNAs. Compared to traditional biological experiments, computational models can not only save time and reduce costs, but also discover potential associations on a large scale. Although some computational models based on tensor decomposition have been proposed, these models usually require manual specification of numerous hyperparameters, leading to a decrease in computational efficiency and generalization ability. Additionally, these linear models struggle to analyze complex, higher-order nonlinear relationships. Based on this, we propose a novel framework, KBLTDARD, to identify potential multiple types of miRNA-disease associations. Firstly, KBLTDARD extracts information from biological networks and high-order association network, and then fuses them to obtain more precise similarities of miRNAs (diseases). Secondly, we combine logistic tensor decomposition and Bayesian methods to achieve automatic hyperparameter search by introducing sparse-induced priors of multiple latent variables, and incorporate auxiliary information to improve prediction capabilities. Finally, an efficient deterministic Bayesian inference algorithm is developed to ensure computational efficiency. Experimental results on two benchmark datasets show that KBLTDARD has better Top-1 precision, Top-1 recall, and Top-1 F1 for new type predictions, and higher AUPR, AUC, and F1 values for new triplet predictions, compared to other state-of-the-art methods. Furthermore, case studies demonstrate the efficiency of KBLTDARD in predicting multiple types of miRNA-disease associations.

De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes.

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.