The role of transforming growth factor-ß (TGF-ß) in the formation of exhausted CD8 + T cells.

CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-ß (TGF-ß) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-ß is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-ß in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.

Neuro-cardiac-guided transcranial magnetic stimulation: Unveiling the modulatory effects of low-frequency and high-frequency stimulation on heart rate.

Transcranial magnetic stimulation (TMS) is pivotal in the field of major depressive disorder treatment. Due to its unsatisfied response rate, an increasing number of researchers have turned their attention towards optimizing TMS site localization. Since the influence of TMS in reducing heart rate (HR) offers insights into its regulatory impact on the autonomic nervous system, a novel approach, called neurocardiac-guided TMS (NCG-TMS), has been proposed to pinpoint the brain region eliciting the maximal individual reduction in HR as a personalized optimal stimulation target. The present study intends to systematically explore the effects of stimulation frequency, left and right hemispheres, stimulation positions, and individual differences on HR modulation using the NCG-TMS method. In experiment 1, low-frequency TMS was administered to 30 subjects, and it was found that low-frequency NCG-TMS significantly downregulated HR, with more significant effects in the right hemisphere than in the left hemisphere and the prefrontal cortex than in other brain areas. In experiment 2, high-frequency NCG-TMS stimulation was administered to 30 subjects, showing that high-frequency NCG-TMS also downregulated HR and had the greatest modulatory effect in the right prefrontal region. Simultaneously, both experiments revealed sizeable individual variability in the optimal stimulation site, which in turn validated the feasibility of the NCG-TMS method. In conclusion, the present experiments independently replicated the effect of NCG-TMS, provided an effect of high-/low-frequency TMS stimulation to downregulate HR, and identified a right lateralization of the HR modulation effect.

Multi-Scenario Validation and Assessment of a Particulate Matter Sensor Monitor Optimized by Machine Learning Methods.

OBJECTIVE: The aim was to evaluate and optimize the performance of sensor monitors in measuring PM2.5 and PM10 under typical emission scenarios both indoors and outdoors. METHOD: Parallel measurements and comparisons of PM2.5 and PM10 were carried out between sensor monitors and standard instruments in typical indoor (2 months) and outdoor environments (1 year) in Shanghai, respectively. The optimized validation model was determined by comparing six machining learning models, adjusting for meteorological and related factors. The intra- and inter-device variation, measurement accuracy, and stability of sensor monitors were calculated and compared before and after validation. RESULTS: Indoor particles were measured in a range of 0.8-370.7 µg/m3 and 1.9-465.2 µg/m3 for PM2.5 and PM10, respectively, while the outdoor ones were in the ranges of 1.0-211.0 µg/m3 and 0.0-493.0 µg/m3, correspondingly. Compared to machine learning models including multivariate linear model (ML), K-nearest neighbor model (KNN), support vector machine model (SVM), decision tree model (DT), and neural network model (MLP), the random forest (RF) model showed the best validation after adjusting for temperature, relative humidity (RH), PM2.5/PM10 ratios, and measurement time lengths (months) for both PM2.5 and PM10, in indoor (R2: 0.97 and 0.91, root-mean-square error (RMSE) of 1.91 µg/m3 and 4.56 µg/m3, respectively) and outdoor environments (R2: 0.90 and 0.80, RMSE of 5.61 µg/m3 and 17.54 µg/m3, respectively), respectively. CONCLUSIONS: Sensor monitors could provide reliable measurements of PM2.5 and PM10 with high accuracy and acceptable inter and intra-device consistency under typical indoor and outdoor scenarios after validation by RF model. Adjusting for both climate factors and the ratio of PM2.5/PM10 could improve the validation performance.

Identification and Characterization of Pectate Lyase as a Novel Allergen in Artemisia sieversiana Pollen.

INTRODUCTION: Artemisia species are widely spread in north hemisphere. Artemisia sieversiana pollen is one of the common pollen allergens in the north of China. At present, seven allergens were identified and had been listed officially from A. sieversiana pollen, but the remaining allergens are still insufficiently studied, which need to be found. METHODS: Pectate lyase was purified from the extracts of A. sieversiana pollen by anion exchange, size exclusion, and HPLC-hydrophobic interaction chromatography. The gene of A. sieversiana pectate lyase (Art si pectate lyase) was cloned and expressed in Escherichia coli. The enzyme activity and circular dichroism (CD) spectrum of natural and recombinant proteins were analyzed. The allergenicity of Art si pectate lyase was characterized by enzyme-linked immunosorbent assay (ELISA), Western blot, inhibition ELISA, and basophil activation test. The allergen's physicochemical properties, three-dimensional structure, sequence profiles with homologous allergens and phylogenetic tree were analyzed by in silico methods. RESULTS: Natural Art si pectate lyase (nArt si pectate lyase) was purified from A. sieversiana pollen extracts by three chromatographic strategies. The cDNA sequence of Art si pectate lyase had a 1191-bp open reading frame encoding 396 amino acids. Both natural and recombinant pectate lyase (rArt si pectate lyase) exhibited similar CD spectrum, and nArt si pectate lyase had higher enzymatic activity. Moreover, the specific immunoglobulin E (IgE) binding rate against nArt si pectate lyase and rArt si pectate lyase was determined as 40% (6/15) in patients' serum with Artemisia species pollen allergy by ELISA. The nArt si pectate lyase and rArt si pectate lyase could inhibit 76.11% and 47.26% of IgE binding activities to the pollen extracts, respectively. Art si pectate lyase was also confirmed to activate patients' basophils. Its structure contains a predominant motif of classic parallel helical core, consisting of three parallel ß-sheets, and two highly conserved features (vWiDH, RxPxxR) which may contribute to pectate lyase activity. Moreover, Art si pectate lyase shared the highest sequence identity of 73.0% with Art v 6 among currently recognized pectate lyase allergen, both were clustered into the same branch in the phylogenetic tree. CONCLUSION: In this study, pectate lyase was identified and comprehensively characterized as a novel allergen in A. sieversiana pollen. The findings enriched the allergen information for this pollen and promoted the development of component-resolved diagnosis and molecular therapy of A. sieversiana pollen allergy.

Cholesterol sulfate-mediated ion-pairing facilitates the self-nanoassembly of hydrophilic cationic mitoxantrone.

HYPOTHESIS: Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the use of a hydrophobic ion-pairing strategy to enhance the nano-assembly of MTO. EXPERIMENTS: We employed biocompatible sodium cholesteryl sulfate (SCS) as a modification module to form stable ion pairs with MTO, which balanced the intermolecular forces and facilitated nano-assembly. PEGylated MTO-SCS nanoassemblies (pMS NAs) were prepared via nanoprecipitation. We systematically evaluated the effect of the ratio of the drug module (MTO) to the modification module (SCS) on the nanoassemblies. FINDINGS: The increased lipophilicity of MTO-SCS ion pair could significantly improve the encapsulation efficiency (∼97 %) and cellular uptake efficiency of MTO. The pMS NAs showed prolonged blood circulation, maintained the same level of tumor antiproliferative activity, and exhibited reduced toxicity compared with the free MTO solution. It is noteworthy that the stability, cellular uptake, cytotoxicity, and in vivo pharmacokinetic behavior of the pMS NAs increased in proportion to the molar ratio of SCS to MTO. This study presents a self-assembly strategy mediated by ion pairing to overcome the challenges commonly associated with the poor assembly ability of hydrophilic cationic drugs.

Synthesis and clinical application of representative small-molecule dipeptidyl Peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus (T2DM).

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels, which can cause many diseases, including osteoporosis, fractures, arthritis, and foot complications. The inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in glucose metabolism regulation, are essential for managing Type 2 Diabetes Mellitus (T2DM). The inhibition of DPP-4 has become a promising treatment approach for T2DM because it can increase levels of active glucagon-like peptide-1 (GLP-1), leading to improved insulin secretion in response to glucose and reduced release of glucagon. The review commences by elucidating the role of DPP-4 in glucose homeostasis and its significance in T2DM pathophysiology. Furthermore, it presents the mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity profiles of small-molecule DPP-4 inhibitors across various clinical stages. This comprehensive review provides valuable insights into the synthesis and clinical application of DPP-4 inhibitors, serving as an invaluable resource for researchers, clinicians, and pharmaceutical professionals interested in diabetes therapeutics and drug development.

Crusting-fabricated three-dimensional soy-based scaffolds for cultured meat production: A preliminary study.

Crusting has been developed as a non-chemical and non-machine intensive scaffold fabrication method. This method is based on the self-assembling ability of soy biomolecules, allowing the fabrication of a three-dimensional network for cell growth. Preliminary characterization revealed differences in pore size, water absorption, and degradation between pure soy-based scaffold (Y2R) and with added glycerol (Y2G). The Fourier-transform infrared spectrum absorbance peaks of functional groups related to proteins, carbohydrates, and lipids hinted the integration of soy biomolecules potentially via the Maillard reaction, as supported by the visible browning of the scaffold surface. Microscopic images revealed aligned myotubes in both scaffolds, with Y2G myotubes having greater proximity after 72 h of proliferation. Both spontaneous and electro-stimulated contractions were recorded as early as 72 h in proliferation medium. Crusting-fabricated soy-based scaffolds can further be explored for its application in cultured meat production.

Boarding pyroptosis onto nanotechnology for cancer therapy.

Pyroptosis, a non-apoptotic programmed cellular inflammatory death mechanism characterized by gasdermin (GSDM) family proteins, has gathered significant attention in the cancer treatment. However, the alarming clinical trial data indicates that pyroptosis-mediated cancer therapeutic efficiency is still unsatisfactory. It is essential to integrate the burgeoning biomedical findings and innovations with potent technology to hasten the development of pyroptosis-based antitumor drugs. Considering the rapid development of pyroptosis-driven cancer nanotherapeutics, here we aim to summarize the recent advances in this field at the intersection of pyroptosis and nanotechnology. First, the foundation of pyroptosis-based nanomedicines (NMs) is outlined to illustrate the reliability and effectiveness for the treatment of tumor. Next, the emerging nanotherapeutics designed to induce pyroptosis are overviewed. Moreover, the cross-talk between pyroptosis and other cell death modalities are discussed, aiming to explore the mechanistic level relationships to provide guidance strategies for the combination of different types of antitumor drugs. Last but not least, the opportunities and challenges of employing pyroptosis-based NMs in potential clinical cancer therapy are highlighted.

Integrative analyses on the ciliates Colpoda illuminate the life history evolution of soil microorganisms.

Microorganisms play a central role in sustaining soil ecosystems and agriculture, and these functions are usually associated with their complex life history. Yet, the regulation and evolution of life history have remained enigmatic and poorly understood, especially in protozoa, the third most abundant group of organisms in the soil. Here, we explore the life history of a cosmopolitan species-Colpoda steinii. Our analysis has yielded a high-quality macronuclear genome for C. steinii, with size of 155 Mbp and 37,123 protein-coding genes, as well as mean intron length of ~93 bp, longer than most other studied ciliates. Notably, we identify two possible whole-genome duplication events in C. steinii, which may account for its genome being about twice the size of C. inflata's, another co-existing species. We further resolve the gene expression profiles in diverse life stages of C. steinii, which are also corroborated in C. inflata. During the resting cyst stage, genes associated with cell death and vacuole formation are upregulated, and translation-related genes are downregulated. While the translation-related genes are upregulated during the excystment of resting cysts. Reproductive cysts exhibit a significant reduction in cell adhesion. We also demonstrate that most genes expressed in specific life stages are under strong purifying selection. This study offers a deeper understanding of the life history evolution that underpins the extraordinary success and ecological functions of microorganisms in soil ecosystems.IMPORTANCEColpoda species, as a prominent group among the most widely distributed and abundant soil microorganisms, play a crucial role in sustaining soil ecosystems and promoting plant growth. This investigation reveals their exceptional macronuclear genomic features, including significantly large genome size, long introns, and numerous gene duplications. The gene expression profiles and the specific biological functions associated with the transitions between various life stages are also elucidated. The vast majority of genes linked to life stage transitions are subject to strong purifying selection, as inferred from multiple natural strains newly isolated and deeply sequenced. This substantiates the enduring and conservative nature of Colpoda's life history, which has persisted throughout the extensive evolutionary history of these highly successful protozoa in soil. These findings shed light on the evolutionary dynamics of microbial eukaryotes in the ever-fluctuating soil environments. This integrative research represents a significant advancement in understanding the life histories of these understudied single-celled eukaryotes.

Molecular mechanisms and potential therapeutic targets in the pathogenesis of hypertension in visceral adipose tissue induced by a high-fat diet.

Background: Hypertension (HTN) presents a significant global public health challenge with diverse causative factors. The accumulation of visceral adipose tissue (VAT) due to a high-fat diet (HFD) is an independent risk factor for HTN. While various studies have explored pathogenic mechanisms, a comprehensive understanding of impact of VAT on blood pressure necessitates bioinformatics analysis. Methods: Datasets GSE214618 and GSE188336 were acquired from the Gene Expression Omnibus and analyzed to identify shared differentially expressed genes between HFD-VAT and HTN-VAT. Gene Ontology enrichment and protein-protein interaction analyses were conducted, leading to the identification of hub genes. We performed molecular validation of hub genes using RT-qPCR, Western-blotting and immunofluorescence staining. Furthermore, immune infiltration analysis using CIBERSORTx was performed. Results: This study indicated that the predominant characteristic of VAT in HTN was related to energy metabolism. The red functional module was enriched in pathways associated with mitochondrial oxidative respiration and ATP metabolism processes. Spp1, Postn, and Gpnmb in VAT were identified as hub genes on the pathogenic mechanism of HTN. Proteins encoded by these hub genes were closely associated with the target organs-specifically, the resistance artery, aorta, and heart tissue. After treatment with empagliflozin, there was a tendency for Spp1, Postn, and Gpnmb to decrease in VAT. Immune infiltration analysis confirmed that inflammation and immune response may not be the main mechanisms by which visceral adiposity contributes to HTN. Conclusions: Our study pinpointed the crucial causative factor of HTN in VAT following HFD. Spp1, Postn, and Gpnmb in VAT acted as hub genes that promote elevated blood pressure and can be targets for HTN treatment. These findings contributed to therapeutic strategies and prognostic markers for HTN.

Risk factors and prediction model for new-onset hypertensive disorders of pregnancy: a retrospective cohort study.

Background and aims: Hypertensive disorders of pregnancy (HDP) is a significant cause of maternal and neonatal mortality. This study aims to identify risk factors for new-onset HDP and to develop a prediction model for assessing the risk of new-onset hypertension during pregnancy. Methods: We included 446 pregnant women without baseline hypertension from Liyang People's Hospital at the first inspection, and they were followed up until delivery. We collected maternal clinical parameters and biomarkers between 16th and 20th weeks of gestation. Logistic regression was used to determine the effect of the risk factors on HDP. For model development, a backward selection algorithm was applied to choose pertinent biomarkers, and predictive models were created based on multiple machine learning methods (generalised linear model, multivariate adaptive regression splines, random forest, and k-nearest neighbours). Model performance was evaluated using the area under the curve. Results: Out of the 446 participants, 153 developed new-onset HDP. The HDP group exhibited significantly higher baseline body mass index (BMI), weight change, baseline systolic/diastolic blood pressure, and platelet counts than the control group. The increase in baseline BMI, weight change, and baseline systolic and diastolic blood pressure significantly elevated the risk of HDP, with odds ratios and 95% confidence intervals of 1.10 (1.03-1.17), 1.10 (1.05-1.16), 1.04 (1.01-1.08), and 1.10 (1.05-1.14) respectively. Restricted cubic spline showed a linear dose-dependent association of baseline BMI and weight change with the risk of HDP. The random forest-based prediction model showed robust performance with the area under the curve of 0.85 in the training set. Conclusion: This study establishes a prediction model to evaluate the risk of new-onset HDP, which might facilitate the early diagnosis and management of HDP.

Analysis of current technology status for the industrialization of cultured meat.

Cultured meat is expected to become an important material for future food production; however, contrary to initial expectations, the full-scale industrialization of cultured meat is slow and the actual level and opened technology amount is very limited. This study reviews the publicly available technologies of cultured meat and suggests future developmental directions and research agenda. As a result of analyzing papers, patents, and press releases published over the past 10 years, it was found that cultured meat production technology is still at the prototype production level. This is because most papers published are about culture medium and scaffold development, culture conditions, and there is almost no research on finished cultured meat products. Worldwide, most of the filed patents are for producing cultured meat principles; most of them do not use food-grade materials and are not economically feasible for industrialization. Therefore, future research on the industrialization of cultured meat should focus on effective acquisition technologies for satellite cells; cell lineage and undifferentiated state maintenance technologies; the development of serum-free media and culture devices; the prevention of genetic modification, safety verification, and mass production. Furthermore, basic research on mechanisms and influencing factors related to cultured meat production is warranted.

The Color-Developing Methods for Cultivated Meat and Meat Analogues: A Mini-Review.

Novel meat-inspired products, such as cell-cultivated meat and meat analogues, embrace environmental sustainability, food safety and security, animal welfare, and human health, but consumers are still hesitant to accept these products. The appearance of food is often the most persuasive determinant of purchasing decisions for food. Producing cultivated meat and meat analogues with similar characteristics to conventional meat could lead to increased acceptability, marketability, and profitability. Color is one of the sensorial characteristics that can be improved using color-inducing methods and colorants. Synthetic colorants are cheap and stable, but natural pigments are regarded as safer components for novel food production. The complexity of identifying specific colorants to imitate both raw and cooked meat color lies in the differences in ingredients and methods used to produce meat alternatives. Research devoted to improving the sensorial characteristics of meat analogues has noted various color-inducing methods (e.g., ohmic cooking and pasteurization) and additives (e.g., lactoferrin, laccase, xylose, and pectin). Additionally, considerations toward other meat components, such as fat, can aid in mimicking conventional meat appearance. For instance, the use of plant-based fat replacers and scaffolds can produce a marked sensory enhancement without compromising the sustainability of alternative meats. Moving forward, consumer-relevant sensorial characteristics, such as taste and texture, should be prioritized alongside improving the coloration of meat alternatives.

Current Research, Industrialization Status, and Future Perspective of Cultured Meat.

Expectations for the industrialization of cultured meat are growing due to the increasing support from various sectors, such as the food industry, animal welfare organizations, and consumers, particularly vegetarians, but the progress of industrialization is slower than initially reported. This review analyzes the main issues concerning the industrialization of cultured meat, examines research and media reports on the development of cultured meat to date, and presents the current technology, industrialization level, and prospects for cultured meat. Currently, over 30 countries have companies industrializing cultured meat, and around 200 companies that are developing or industrializing cultured meat have been surveyed globally. By country, the United States has over 50 companies, accounting for more than 20% of the total. Acquiring animal cells, developing cell lines, improving cell proliferation, improving the efficiency of cell differentiation and muscle production, or developing cell culture media, including serum-free media, are the major research themes related to the development of cultured meat. In contrast, the development of devices, such as bioreactors, which are crucial in enabling large-scale production, is relatively understudied, and few of the many companies invested in the development of cultured meat have presented products for sale other than prototypes. In addition, because most information on key technologies is not publicly available, it is not possible to determine the level of technology in the companies, and it is surmised that the technology of cultured meat-related startups is not high. Therefore, further research and development are needed to promote the full-scale industrialization of cultured meat.

Study on the Digestion-Induced Changes in the Characteristics and Bioactivity of Korean Native and Overseas Cattle-Derived Peptides.

This study was conducted to compare and analyze the changes in the biochemical characteristics and biological activity of peptide extracts derived from Chickso, Hanwoo, and Wagyu beef during digestion. The results of the in vitro digestion analysis revealed that the digestion rate, total free amino acid content, and antioxidant and antihypertensive activities of Chickso loin and shank myofibrillar proteins were significantly higher (p<0.05) than those of Hanwoo and Wagyu loin and shank myofibrillar proteins. Particularly, the peptide extracts of Chickso loin and shank had a high angiotensin-converting enzyme inhibitory activity. In mice in vivo digestion experiment, the blood serum of mice fed with Chickso loin peptide extract (<10 kDa) showed the highest antioxidant enzyme activity. Thus, Chickso peptide extracts were deemed to be similar or more bioactive than Hanwoo and Wagyu peptide extracts, and can be used as bioactive materials.

Analytical Methods and Effects of Bioactive Peptides Derived from Animal Products: A Mini-Review.

Peptides with bioactive effects are being researched for various purposes. However, there is a lack of overall research on pork-derived peptides. In this study, we reviewed the process of obtaining bioactive peptides, available analytical methods, and the study of bioactive peptides derived from pork. Pepsin and trypsin, two representative protein digestive enzymes in the body, are hydrolyzed by other cofactors to produce peptides. Bicinchoninic acid assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, chromatography, and in vitro digestion simulation systems are utilized to analyze bioactive peptides for protein digestibility and molecular weight distribution. Pork-derived peptides mainly exhibit antioxidant and antihypertensive activities. The antioxidant activity of bioactive peptides increases the accessibility of amino acid residues by disrupting the three-dimensional structure of proteins, affecting free radical scavenging, reactive oxygen species inactivation, and metal ion chelating. In addition, the antihypertensive activity decreases angiotensin II production by inhibiting angiotensin converting enzyme and suppresses blood pressure by blocking the AT1 receptor. Pork-derived bioactive peptides, primarily obtained using papain and pepsin, exhibit significant antioxidant and antihypertensive activities, with most having low molecular weights below 1 kDa. This study may aid in the future development of bioactive peptides and serve as a valuable reference for pork-derived peptides.

Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment.

SARS-CoV-2 prevalence in wildlife 2020-2022: a worldwide systematic review and meta-analysis.

The widespread transmission of SARS-CoV-2 in humans poses a serious threat to public health security, and a growing number of studies have discovered that SARS-CoV-2 infection in wildlife and mutate over time. This article mainly reports the first systematic review and meta-analysis of the prevalence of SARS-CoV-2 in wildlife. The pooled prevalence of the 29 included articles was calculated by us using a random effects model (22.9%) with a high heterogeneity (I2 = 98.7%, p = 0.00). Subgroup analysis and univariate regression analysis found potential risk factors contributing to heterogeneity were country, wildlife species, sample type, longitude, and precipitation. In addition, the prevalence of SARS-CoV-2 in wildlife increased gradually over time. Consequently, it is necessary to comprehensively analyze the risk factors of SARS-CoV-2 infection in wildlife and develop effective control policies, as well as to monitor the mutation of SARS-CoV-2 in wildlife at all times to reduce the risk of SARS-CoV-2 transmission among different species.

Identification of high sugar diet-induced dysregulated metabolic pathways in muscle using tissue-specific metabolic models in Drosophila.

Individual tissues perform highly specialized metabolic functions to maintain whole-body homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, a lack of tissue-specific metabolic models makes it challenging to quantitatively assess the metabolic processes of individual tissues and disease models in this organism. To address this issue, we reconstructed 32 tissue-specific genome-scale metabolic models (GEMs) using pseudo-bulk single cell transcriptomics data, revealing distinct metabolic network structures across tissues. Leveraging enzyme kinetics and flux analyses, we predicted tissue-dependent metabolic pathway activities, recapitulating known tissue functions and identifying tissue-specific metabolic signatures, as supported by metabolite profiling. Moreover, to demonstrate the utility of tissue-specific GEMs in a disease context, we examined the effect of a high sugar diet (HSD) on muscle metabolism. Together with 13C-glucose isotopic tracer studies, we identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a rate-limiting enzyme in response to HSD. Mechanistically, the decreased GAPDH activity was linked to elevated NADH/NAD+ ratio, caused by disturbed NAD+ regeneration rates, and oxidation of GAPDH. Furthermore, we introduced a pathway flux index to predict and validate additionally perturbed pathways, including fructose and butanoate metabolism. Altogether, our results represent a significant advance in generating quantitative tissue-specific GEMs and flux analyses in Drosophila, highlighting their use for identifying dysregulated metabolic pathways and their regulation in a human disease model.

Parenting beliefs and practices as precursors to academic outcomes in Chinese children.

Due to the rapid sociocultural changes in China, Chinese parents' childrearing beliefs and practices have undergone dramatic transformations. Against this context, this study examined whether Chinese parents' endorsement of progressive and traditional childrearing beliefs would predict children's academic achievement, as well as whether parenting practices would mediate this association. This study utilized a longitudinal design and followed 206 Chinese families for 2 years from the end of preschool to Grade 2. Parents showed greater endorsement of progressive than traditional childrearing beliefs, as well as higher use of authoritative than authoritarian parenting practices. Parents' childrearing beliefs in preschool predicted children's math achievement in Grade 2 via authoritative parenting. However, parenting beliefs were unrelated to authoritarian parenting, and authoritarian parenting did not predict any of the child academic outcomes in Grade 2. The findings suggest Chinese parents' orientations toward progressive parenting beliefs and authoritative parenting practices. They also highlight the utility of parenting beliefs in explaining disparities in early academic achievement. The nonsignificant findings pertinent to authoritarian parenting call for re-examination of the cultural meaning and effects of authoritarian parenting in Chinese society.