Current status and challenges of model-informed drug discovery and development in China.

In the past decade, biopharmaceutical research and development in China has been notably boosted by government policies, regulatory initiatives and increasing investments in life sciences. With regulatory agency acting as a strong driver, model-informed drug development (MIDD) is transitioning rapidly from an academic pursuit to a critical component of innovative drug discovery and development within the country. In this article, we provided a cross-sectional summary on the current status of MIDD implementations across early and late-stage drug development in China, illustrated by case examples. We also shared insights into regulatory policy development and decision-making. Various modeling and simulation approaches were presented across a range of applications. Furthermore, the challenges and opportunities of MIDD in China were discussed and compared with other regions where these practices have a more established history. Through this analysis, we highlighted the potential of MIDD to enhance drug development efficiency and effectiveness in China's evolving pharmaceutical landscape.

Compact vacuum transfer devices for highly air-sensitive materials in scanning electron microscopy.

Surface analysis experiments on air-sensitive substances are challenging to avoid their contact with air, leading to inaccurate results due to oxidation or hygroscopicity. To address this issue, we designed a compact vacuum transfer device (VTD) and applied it to scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) experiments. Our VTD features a split structure that can be opened and separated in the SEM specimen exchange chamber via magnetic control. This design allows the SEM manufacturer's stub to be fed directly into the SEM specimen chamber, preventing damage to the instrument's internal components and avoiding restrictions on specimen height. Additionally, the compact design maximizes the utilization of sample accommodation space. Besides, it can be flexibly customized in different sizes and types of stubs to adapt electron microscopes from various manufacturers. To confirm the reliability of our device, we applied it to several highly air-sensitive samples for morphology and chemical composition analysis by SEM and EDS. The EDS results showed that the atomic percentage of Na reaches 94.55 % after 14 minutes and 93.44 % after 30 minutes of storage when transferring metallic sodium. Furthermore, our VTD enables airtight recycling and re-transfer of samples after the SEM (-EDS) experiments. These results demonstrate that our device has excellent practicality and airtightness, making it suitable for medium- and long-distance sample transfer between laboratories on the campus.

Comprehensive Evaluation of Long-Term Dentin Bond Strength, Water Sorption, Solubility, and Degree of Conversion of Self-Adhesive Resin Composites.

PURPOSE: To evaluate the long-term microtensile bond strength (µTBS) to dentin, water sorption (WSP) and solubility (WSL), and degree of conversion (DC) of self-adhesive resin composites (SACs). MATERIALS AND METHODS: The mid-coronal dentin of human molars was exposed, and teeth were randomly assigned to five groups according to the SACs (n = 10): 1. FIT SA F03 (FIT); 2. Experimental (EXP); 3. Fusio Liquid Dentin (FLD); 4. Vertise Flow (VER); 5. Constic (CON). The µTBS was evaluated after 24 hours (24 h) and 6 months (6 m) storage. A scanning electron microscope examined failure modes and resin-dentin interfaces. The WSP and WSL (n = 5) were evaluated following ISO 4049:2019 specifications, and DC (n = 3) was measured using Raman spectroscopy. The statistical analyses were performed accepting a significance level of p = 0.05. RESULTS: FIT, EXP, and FLD produced significantly higher µTBS median values than VER and CON after 24 h and 6 m (p 0.05). After 6m, the µTBS median of FIT and EXP significantly decreased (p 0.05), while FLD, VER, and CON showed no significant difference (p > 0.05). FLD and CON exhibited lower WSP than FIT, EXP, and VER (p 0.05). FLD presented the lowest (p 0.05), and VER revealed the highest WSL (p 0.05). FIT and EXP showed the highest (p 0.05), and VER demonstrated the lowest DC (p 0.05). CONCLUSIONS: Following the present study's design, SACs' bonding performance and physical properties remained restricted. Therefore, the application should be considered cautiously, and further clinical trials are necessary to evaluate their long-term performance.

Insights into the interactions of plant-associated bacteria and their role in the transfer of antibiotic resistance genes from soil to plant.

This study discussed the role of plant-associated microbiome in regulating ARG transfer in soil-plant systems. Results showed that target ARGs in plants were mainly derived from rhizosphere soil. Cooperative interactions among bacteria in rhizosphere soil, plant-roots, plant-shoots, and soil-roots-shoots systems occurred during ARG transfer. The number of modules and keystone taxa identified as positively correlated with ARG transfer in rhizosphere soil, roots, and shoots was 3 and 49, 3 and 41, 2 and 5, respectively. Among these modules, module 3 in roots was significantly positively correlated with module 3 in rhizosphere soils and module 2 in shoots, indicating that module 3 in roots played central hub roles in ARG transfer from rhizosphere soil to roost and shoots. This may be because module 3 in roots increased cell motility and xenobiotics biodegradation and metabolism. These keystone taxa mainly belonged to Proteobacteria that can carry ARGs to transfer in soil-plant systems, especially Clostridium-sensu_stricito and Pseudomonas in rhizosphere soil carried ARGs into the shoot. Additionally, they promoted ARG transfer by increasing plant biomass, net photosynthetic rate and water use efficiency. The findings helped reveal the mechanism of plant-associated bacterial interactions and provided understanding for potential risks of ARG transfer from soil to plants.

Expression of TGF-ß/Smad pathway-related indices in patients with isolated iliac artery aneurysms complicated with iliac arteriovenous fistula and their relationship with prognosis.

OBJECTIVE: This study investigated the expression of TGF-ß/Smad pathway-related indices in patients with isolated iliac artery aneurysms (IIAA) complicated with iliac arteriovenous fistula (IAVF) and their relationship with prognosis. METHODS: From January 2016 to June 2022, 83 patients with IIAA complicated with IAVF (Study group) and 54 patients with IIAA not complicated with IAVF (control group) were studied. The related indices of TGF-ß/Smad pathway were evaluated, and the effects of each index on the formation of IAVF were analyzed. The patients were divided into the survival group (64 cases) and death group (19 cases), and the prognostic value of indices in combination was analyzed. RESULTS: TGF-ß, p-Smad2, p-Smad3, p-JNK, and p-ERK in the study group were higher than those in the control group. Abnormal increase of pSmad3 expression was a risk factor for IAVF formation in patients with IIAA. TGF-ß level in the death group was higher than that in the survival group, and p-Smad3 and p-JNK proteins were higher than those in the survival group. The AUC value of indices in the TGF-ß/Smad pathway in combination was greater than that of each index alone. Abnormal increased expression of pSmad3 was a risk factor for prognosis of patients with IIAA complicated with IAVF. CONCLUSION: The abnormal increase of TGF-ß/Smad pathway-related indices is related to poor prognosis of patients with IIAA complicated with IAVF, and the combined detection of all indices has a predictive value for patients' prognosis.

Recursive partitioning analysis for survival stratification and early imaging prediction of molecular biomarker in glioma patients.

BACKGROUND: Glioma is the most common primary brain tumor with high mortality and disability rates. Recent studies have highlighted the significant prognostic consequences of subtyping molecular pathological markers using tumor samples, such as IDH, 1p/19q, and TERT. However, the relative importance of individual markers or marker combinations in affecting patient survival remains unclear. Moreover, the high cost and reliance on postoperative tumor samples hinder the widespread use of these molecular markers in clinical practice, particularly during the preoperative period. We aim to identify the most prominent molecular biomarker combination that affects patient survival and develop a preoperative MRI-based predictive model and clinical scoring system for this combination. METHODS: A cohort dataset of 2,879 patients was compiled for survival risk stratification. In a subset of 238 patients, recursive partitioning analysis (RPA) was applied to create a survival subgroup framework based on molecular markers. We then collected MRI data and applied Visually Accessible Rembrandt Images (VASARI) features to construct predictive models and clinical scoring systems. RESULTS: The RPA delineated four survival groups primarily defined by the status of IDH and TERT mutations. Predictive models incorporating VASARI features and clinical data achieved AUC values of 0.85 for IDH and 0.82 for TERT mutations. Nomogram-based scoring systems were also formulated to facilitate clinical application. CONCLUSIONS: The combination of IDH-TERT mutation status alone can identify the most distinct survival differences in glioma patients. The predictive model based on preoperative MRI features, supported by clinical assessments, offers a reliable method for early molecular mutation prediction and constitutes a valuable scoring tool for clinicians in guiding treatment strategies.

Dual-Drug Nanomedicine Assembly with Synergistic Anti-Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization.

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

Different structural connectivity patterns in the subregions of the thalamus, hippocampus, and cingulate cortex between schizophrenia and psychotic bipolar disorder.

OBJECTIVE: Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) are two major psychotic disorders with similar symptoms and tight associations on the psychopathological level, posing a clinical challenge for their differentiation. This study aimed to investigate and compare the structural connectivity patterns of the limbic system between SCZ and PBD, and to identify specific regional disruptions associated with psychiatric symptoms. METHODS: Using sMRI data from 146 SCZ, 160 PBD, and 145 healthy control (HC) participants, we employed a data-driven approach to segment the hippocampus, thalamus, hypothalamus, amygdala, and cingulate cortex into subregions. We then investigated the structural connectivity patterns between these subregions at the global and nodal levels. Additionally, we assessed psychotic symptoms by utilizing the subscales of the Brief Psychiatric Rating Scale (BPRS) to examine correlations between symptom severity and network metrics between groups. RESULTS: Patients with SCZ and PBD had decreased global efficiency (Eglob) (SCZ: adjusted P<0.001; PBD: adjusted P = 0.003), local efficiency (Eloc) (SCZ and PBD: adjusted P<0.001), and clustering coefficient (Cp) (SCZ and PBD: adjusted P<0.001), and increased path length (Lp) (SCZ: adjusted P<0.001; PBD: adjusted P = 0.004) compared to HC. Patients with SCZ showed more pronounced decreases in Eglob (adjusted P<0.001), Eloc (adjusted P<0.001), and Cp (adjusted P = 0.029), and increased Lp (adjusted P = 0.024) compared to patients with PBD. The most notable structural disruptions were observed in the hippocampus and thalamus, which correlated with different psychotic symptoms, respectively. CONCLUSION: This study provides evidence of distinct structural connectivity disruptions in the limbic system of patients with SCZ and PBD. These findings might contribute to our understanding of the neuropathological basis for distinguishing SCZ and PBD.

[Association between the triglyceride-glucose index and the incidence of nephrolithiasis in male individuals].

OBJECTIVE: To analyze the association between the triglyceride-glucose (TyG) index and the risk of nephrolithiasis across various demographic and clinical subgroups, aiming to enhance early diagnosis and treatment of nephrolithiasis and promote personalized care in diverse populations. METHODS: This cross-sectional study analyzed the medical records of 84 968 adults, stratified into three categories (low, middle, high) according to their TyG index scores. To evaluate the association between the TyG index and nephrolithiasis risk, multivariable Logistic regression models were employed, adjusting for potential confounders. Additionally, piecewise linear regression models were used to investigate the non-linear dynamics of the TyG index's relationship with nephrolithiasis risk. Subgroup analyses were performed to explore variations in the effects of the TyG index across different demographic and clinical populations. RESULTS: Increasing TyG index was associated with a higher risk of nephrolithiasis, rising from 4.36% in the low group to 8.96% in the high group (P < 0.001). In adjusted models, males in the middle and high TyG index categories demonstrated significantly elevated risks of nephrolithiasis, with odds ratios of 1.18 (95%CI: 1.07-1.31, P=0.002) and 1.29 (95%CI: 1.15-1.45, P < 0.001), respectively. Conversely, in females, the association was not statistically significant post-adjustment (OR=0.98, 95%CI: 0.82-1.16, P=0.778). Among males, for each unit increment in the TyG index below the critical threshold of 8.98, there was a notable 40% escalation in the risk of developing nephrolithiasis (OR=1.40, 95%CI: 1.24-1.58, P < 0.001). Surpassing this threshold, the TyG index no longer conferred a significant increase in risk (OR=0.91, 95%CI: 0.78-1.06, P=0.24). Subgroup analyses indicated that this association remained stable regardless of age, BMI, or hypertension status. CONCLUSION: The TyG index is positively associated with the risk of nephrolithiasis in males, demonstrating a nonlinear dose-response relationship that becomes especially pronounced at certain index levels. This biomarker could potentially serve as a valuable clinical tool for identifying males who are at a high risk of developing nephrolithiasis, thereby enabling targeted preventive strategies. Further research is urgently needed to explore the underlying mechanisms and to verify the applicability of these results across different populations.

Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure.

BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF. METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF. RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-ß-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without. CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

Airway epithelial-derived exosomes induce acute asthma exacerbation after respiratory syncytial virus infection.

Acute asthma exacerbation refers to the progressive deterioration of asthma symptoms that is always triggered by virus infection represented by respiratory syncytial virus (RSV). After RSV infection, exaggerated Th2-mediated pulmonary inflammation is the critical pathological response of asthmatic patients with acute exacerbation. Significantly, airway epithelial cells, being the primary targets of RSV infection, play a crucial role in controlling the pulmonary inflammatory response by releasing airway epithelial cell-derived exosomes (AEC-Exos), which potentially influence the development of asthma. However, the specific role of AEC-Exos in acute asthma exacerbation after RSV infection remains obscure. The purpose of this study was to determine the distinct function of AEC-Exos in exacerbating acute asthma following RSV infection. Blockade of exosomes by GW reduce the enhanced pulmonary inflammation significantly. Specifically, the enhanced Th2 inflammation was induced by AEC-Exos thorough transportation of hsa-miR-155-5p-Sirtuin 1 (SIRT1) pathway during acute asthma exacerbation. Targeted inhibition of hsa-miR-155-5p blocks the exaggerated Th2 inflammation effectively in mice with acute asthma exacerbation. In summary, our study showed that during acute asthma exacerbation after RSV infection, AEC-Exos promote the enhanced Th2 inflammation through transportation of increased hsa-miR-155-5p, which was mediated partly through SIRT1-mediated pathway. hsa-miR-155-5p is a potential biomarker for early prediction of acute asthma exacerbation.

Synergistic enhancement of pulsed light-induced H2 photoproduction in Chlamydomonas cells by optimal sulfite concentration and light waveform.

Pulsed light illumination stands out as a noteworthy technique for photosynthetic H2 production, playing a crucial role in eliminating O2 and activating hydrogenase enzymes. However, further improvements are essential to make H2 photoproduction suitable for future commercial applications. In our study, we observed a distinct enhancement in pulsed light-induced H2 photoproduction in the unicellular green alga Chlamydomonas reinhardtii when treated with the optimal concentration of the mild O2 scavenger Na2SO3. This improvement was a result of reduced O2 content, increased hydrogenase enzyme activity, and suppressed H2-uptake activity. Furthermore, our findings indicate that exposing Na2SO3-treated C. reinhardtii to optimal light waveform continues to significantly boost pulsed light-induced H2 photoproduction, attributed to the alleviation of impaired photosystem II activity. Altogether, the combined application of optimal sulfite concentration and light waveform effectively enhances pulsed light-induced photosynthetic H2 production in the green alga C. reinhardtii.

Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma.

BACKGROUND AND PURPOSE: Airway epithelial cells (AECs) regulate the activation of epithelial-mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure. EXPERIMENTAL APPROACH: The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA-sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma. KEY RESULTS: The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2-mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling. CONCLUSION AND IMPLICATIONS: Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2-mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.

Improved marine predators algorithm for engineering design optimization problems.

The Marine Predator Algorithm (MPA) has unique advantages as an important branch of population-based algorithms. However, it emerges more disadvantages gradually, such as traps to local optima, insufficient diversity, and premature convergence, when dealing with complex problems in practical industrial engineering design applications. In response to these limitations, this paper proposes a novel Improved Marine Predator Algorithm (IMPA). By introducing an adaptive weight adjustment strategy and a dynamic social learning mechanism, this study significantly improves the encounter frequency and efficiency between predators and preys in marine ecosystems. The performance of the IMPA was evaluated through benchmark functions, CEC2021 suite problems, and engineering design problems, including welded beam design, tension/compression spring design, pressure vessel design, and three-bar design. The results indicate that the IMPA has achieved significant success in the optimization process over other methods, exhibiting excellent performance in both solving optimal parameter solutions and optimizing objective function values. The IMPA performs well in terms of accuracy and robustness, which also proves its efficiency in successfully solving complex industrial engineering design problems.

Ge-Gen-Qin-Lian decoction alleviates the symptoms of type 2 diabetes mellitus with inflammatory bowel disease via regulating the AGE-RAGE pathway.

BACKGROUND: This study aimed to explore the mechanism of Ge-Gen-Qin-Lian decoction (GGQLD) in the alleviation of symptoms of type 2 diabetes mellitus (T2DM) with inflammatory bowel disease (IBD) by network pharmacology and experimental validation. METHODS: The active components and targets of GGQLD were identified from the TCMSP database. The potential therapeutic targets of T2DM and IBD were identified from the GEO database and 4 online disease target databases. The PPI network and KEGG/GO analyses were performed with the common targets among GGQLD, T2DM and IBD. Molecular docking was carried out between the core compounds and hub targets. To verify the above results, UHPLC-MS technology was used to identify the chemical compounds in GGQLD, and a T2DM with IBD rat model was used to explore the mechanism by which GGQLD treats T2DM with IBD. RESULTS: Totally, 70 potential therapeutic targets were identified among GGQLD, T2DM and IBD. Ten hub genes were selected from the PPI network. KEGG analysis revealed that GGQLD is tightly involved in the AGE-RAGE signaling pathway. Berberine, baicalein, wogonin, and quercitrin are the main active compounds of GGQLD. Animal experiments showed that GGQLD could decrease blood glucose and alleviate intestinal inflammation. Notably, the concentrations of AGEs, the expression of RAGE, c-JUN and NF-κB and the expression of inflammatory cytokines were decreased by GGQLD. CONCLUSIONS: Our study initially demonstrated that GGQLD has favorable anti-hyperglycemic and anti-intestinal inflammation effects in a T2DM with IBD rat model, and the AGE-RAGE pathway plays a vital role in this process.

Effects of a Multicomponent Intervention With Cognitive Training and Lifestyle Guidance for Older Adults at Risk of Dementia: A Randomized Controlled Trial.

Objective: This study examined the effects of a multicomponent intervention program on cognitive function in community-dwelling older adults with mild cognitive impairment (MCI) and subjective cognitive decline (SCD).Methods: This was a 2-arm, randomized controlled trial in which a multicomponent intervention was applied. Participants were recruited from June 2020 to August 2020, randomization and intervention began in August 2020, and the entire program ended in January 2021. It included cognitive training (mnemonic strategy training) and lifestyle guidance (diet, sleep, and exercise guidance) for 7 weeks. A total of 123 Chinese community-dwelling older adults experiencing MCI or SCD were randomly divided into a multicomponent intervention group (n = 62) and a health education group (n = 61). The global cognitive function was measured using the Mini-Mental State Examination (MMSE). The cognitive domains outcomes included memory functions measured using the immediate and delayed tests of the Auditory Verbal Learning Test (AVLT) and Logical Memory Test (LMT), and executive function and attention measured using the Digital Symbol Substitution Test (DSST) and Digit Span Test (DST). Data were collected at baseline and postintervention.Results: For cognitive outcome, the results of linear mixed-effect model showed significant time × group effects in the MMSE (Cohen d =0.63 [95% CI, 0.27 to 1.00], F = 10.25, P = .002). This study found significant time × group effects in AVLT-immediate (Cohen d = 0.47 [95% CI, 0.11 to 0.83], F = 8.18, P = .005), AVLT delayed (Cohen d = 0.45 [95% CI, 0.10 to 0.81], F = 4.59, P = .034), LMT-delayed (Cohen d = 0.71 [95% CI, 0.34 to 1.07], F = 4.59, P = .034), DSST (Cohen d = 0.27 [95% CI, -0.08 to 0.63], F = 4.83, P = .030), and DST (Cohen d =0.69 [95% CI, 0.33 to 1.05], F = 8.58, P = .004).Conclusions and Implications: The results support the feasibility and effectiveness of the multicomponent intervention program in improving cognitive function in community dwelling older adults at risk of dementia. The high adherence of this program shows its potential for promotion in the community and supports a larger and longer trial.Trial Registration: Chinese Clinical Trial Registry (ChiCTR2200061420).

A speech fluency brain network derived from gliomas.

The brain network of speech fluency has not yet been investigated via a study with a large and homogenous sample. This study analysed multimodal imaging data from 115 patients with low-grade glioma to explore the brain network of speech fluency. We applied voxel-based lesion-symptom mapping to identify domain-specific regions and white matter pathways associated with speech fluency. Direct cortical stimulation validated the domain-specific regions intra-operatively. We then performed connectivity-behaviour analysis with the aim of identifying connections that significantly correlated with speech fluency. Voxel-based lesion-symptom mapping analysis showed that damage to domain-specific regions (the middle frontal gyrus, the precentral gyrus, the orbital part of inferior frontal gyrus and the insula) and white matter pathways (corticospinal fasciculus, internal capsule, arcuate fasciculus, uncinate fasciculus, frontal aslant tract) are associated with reduced speech fluency. Furthermore, we identified connections emanating from these domain-specific regions that exhibited significant correlations with speech fluency. These findings illuminate the interaction between domain-specific regions and 17 domain-general regions-encompassing the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus and rolandic operculum, superior temporal gyrus, temporal pole, inferior temporal pole, middle cingulate gyrus, supramarginal gyrus, fusiform gyrus, inferior parietal lobe, as well as subcortical structures such as thalamus-implicating their collective role in supporting fluent speech. Our detailed mapping of the speech fluency network offers a strategic foundation for clinicians to safeguard language function during the surgical intervention for brain tumours.

Atomic Ruthenium-Promoted Cadmium Sulfide for Photocatalytic Production of Amino Acids from Biomass Derivatives.

Amino acids are the building blocks of proteins and are widely used as important ingredients for other nitrogen-containing molecules. Here, we report the sustainable production of amino acids from biomass-derived hydroxy acids with high activity under visible-light irradiation and mild conditions, using atomic ruthenium-promoted cadmium sulfide (Ru1/CdS). On a metal basis, the optimized Ru1/CdS exhibits a maximal alanine formation rate of 26.0 molAla ⋅ gRu -1 ⋅ h-1, which is 1.7 times and more than two orders of magnitude higher than that of its nanoparticle counterpart and the conventional thermocatalytic process, respectively. Integrated spectroscopic analysis and density functional theory calculations attribute the high performance of Ru1/CdS to the facilitated charge separation and O-H bond dissociation of the α-hydroxy group, here of lactic acid. The operando nuclear magnetic resonance further infers a unique "double activation" mechanism of both the CH-OH and CH3-CH-OH structures in lactic acid, which significantly accelerates its photocatalytic amination toward alanine.

Cyclocarya paliurus leaves alleviate high-sucrose diet-induced obesity by improving intestinal metabolic disorders.

High-sucrose diets are common in daily life but harmful to human health. Cyclocarya paliurus leaves (CPL) are a kind of tea used to alleviate metabolic diseases and are widely used in China. However, the effects of CPL on high-sucrose-induced obesity are unknown. This study aimed to describe the changes in gut metabolism induced by a high-sucrose diet and to reveal the potential mechanisms through which CPL alleviate high-sucrose diet-induced obesity. A high-sucrose-induced obesity model was generated in C57BL/6J and KM mice. The effects of CPL on obese mice were evaluated, and changes in the gut microbiota and intestinal metabolites induced by CPL treatment were observed. Furthermore, the fecal microbiota transplantation (FMT) method was used to prove that the effects of CPL on high-sucrose induced obesity depend on the changes of gut microbiota. The results of the C57BL/6J mouse experiment revealed that high-sucrose intake induced fat deposition and altered the gut microbiota. CPL treatment decreased fat deposition and alleviated disorders of the gut microbiota. Furthermore, CPL treatment increased the utilization of amnio acids, long fatty acids and saccharides and produced more bile acids, indole derivatives and less trimethylamine (TMA). A confirmatory experiment in KM mice also revealed that CPL can alleviate obesity, ameliorate intestinal metabolic disorders, and upregulate the expression of tight junction proteins in the intestinal mucosa. These results demonstrated that CPL could prevent high sucrose-induced obesity and generate more beneficial intestinal microbial metabolites but less harmful intestinal microbial metabolites.