PRMT5 links lipid metabolism to contractile function of skeletal muscles.

Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels of Prmt5, we generated skeletal muscle-specific Prmt5 knockout (Prmt5MKO ) mice. We observe reduced muscle mass, oxidative capacity, force production, and exercise performance in Prmt5MKO mice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and accelerated degradation. Specifically, PRMT5 deletion reduces dimethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Moreover, Prmt5MKO impairs the repressive H4R3 symmetric dimethylation at the Pnpla2 promoter, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, skeletal muscle-specific double knockout of Pnpla2 and Prmt5 normalizes muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.

Hepatic Acat2 overexpression promotes systemic cholesterol metabolism and adipose lipid metabolism in mice.

AIMS/HYPOTHESIS: Acetyl coenzyme A acetyltransferase (ACAT), also known as acetoacetyl-CoA thiolase, catalyses the formation of acetoacetyl-CoA from acetyl-CoA and forms part of the isoprenoid biosynthesis pathway. Thus, ACAT plays a central role in cholesterol metabolism in a variety of cells. Here, we aimed to assess the effect of hepatic Acat2 overexpression on cholesterol metabolism and systemic energy metabolism. METHODS: We generated liver-targeted adeno-associated virus 9 (AAV9) to achieve hepatic Acat2 overexpression in mice. Mice were injected with AAV9 through the tail vein and subjected to morphological, physiological (body composition, indirect calorimetry, treadmill, GTT, blood biochemistry, cardiac ultrasonography and ECG), histochemical, gene expression and metabolomic analysis under normal diet or feeding with high-fat diet to investigate the role of ACAT2 in the liver. RESULTS: Hepatic Acat2 overexpression reduced body weight and total fat mass, elevated the metabolic rate, improved glucose tolerance and lowered the serum cholesterol level of mice. In addition, the overexpression of Acat2 inhibited fatty acid, glucose and ketone metabolic pathways but promoted cholesterol metabolism and changed the bile acid pool and composition of the liver. Hepatic Acat2 overexpression also decreased the size of white adipocytes and promoted lipid metabolism in white adipose tissue. Furthermore, hepatic Acat2 overexpression protected mice from high-fat-diet-induced weight gain and metabolic defects CONCLUSIONS/INTERPRETATION: Our study identifies an essential role for ACAT2 in cholesterol metabolism and systemic energy expenditure and provides key insights into the metabolic benefits of hepatic Acat2 overexpression. Thus, adenoviral Acat2 overexpression in the liver may be a potential therapeutic tool in the treatment of obesity and hypercholesterolaemia.

Dietary nutrition regulates intestinal stem cell homeostasis.

Intestinal stem cells (ISCs), which locate at the base of intestinal crypts, are key determinants of governing proliferation and differentiation of the intestinal epithelium. The surrounding cells of ISCs and their related growth factors form ISC niche, supporting ISC function and self-renewal. ISC has an underappreciated but emerging role as a sensor of dietary nutrients, which fate decisions is adjusted in response to nutritional states to regulate gut homeostasis. Here, we review endogenous and exogenous factors, such as caloric restriction, fasting, fat, glucose and trace element. They instruct ISCs via mTORC1, PPAR/CPT1α, PPARγ/ß-catenin, Wnt/GSK-3ß pathway, respectively, jointly affect intestinal homeostasis. These dietary responses regulate ISC regenerative capacity and may be a potential target for cancer prevention. However, without precise definitions of nutrition intervene, it will be difficult to generate sufficient data to extending our knowledge of the biological response of ISC on nutrients. More accurately modeling organoids or high-throughput automated organoid culture in microcavity arrays have provided unprecedented opportunities for modeling diet-host interactions. These major advances collectively provide new insights into nutritional regulation of ISC proliferation and differentiation and drive us ever closer to breakthroughs for regenerative medicine and disease treatment by nutrition intervention in the clinic.

Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment.

Nanocarriers have been widely studied and applied in the field of cancer treatment. However, conventional nanocarriers still suffer from complicated preparation processes, low drug loading, and potential toxicity of carriers themselves. To tackle the hindrance, carrier-free nanodrugs with biological activity have received increasing attention in cancer therapy. Extensive efforts have been made to exploit new self-assembly methods and mechanisms to expand the scope of carrier-free nanodrugs with enhanced therapeutic performance. In this review, we summarize the advanced progress and applications of carrier-free nanodrugs based on different types of assembly mechanisms and strategies, which involved noncovalent interactions, a combination of covalent bonds and noncovalent interactions, and metal ions-coordinated self-assembly. These carrier-free nanodrugs are introduced in detail according to their assembly and antitumor applications. Finally, the prospects and existing challenges of carrier-free nanodrugs in future development and clinical application are discussed. We hope that this comprehensive review will provide new insights into the rational design of more effective carrier-free nanodrug systems and advancing clinical cancer and other diseases (e.g., bacterial infections) infection treatment.

Recent Advances on Tuning the Interlayer Coupling and Properties in van der Waals Heterostructures.

2D van der Waals (vdW) heterostructures are receiving increasing research attention due to the theoretically amazing properties and unprecedented application potential. However, the as-synthesized heterostructures are generally underperforming due to the weak interlayer coupling, which inspires the researchers to find ways to modulate the interlayer coupling and properties, realizing the tailored performance for actual applications. There have been a lot of publications regarding the controllable regulation of the structures and properties of 2D vdW heterostructures in the past few years, while a review work summarizing the current advances is not yet available, though it is significant. This paper conducts a state-of-the-art review regarding the current research progress of performance modulation of vdW heterostructures by different techniques. First, the general synthesis methods of vdW heterostructures are summarized. Then, different performance modulation techniques, that is, mechanical-based, external fields-assisted, and particle beam irradiation-based methods, are discussed and compared in detail. Some of the newly proposed concepts are described. Thereafter, applications of vdW heterostructures with tailored properties are reviewed for the application prospects of the topic around this area. Moreover, the future research challenges and prospects are discussed, aiming at triggering more research interest and device applications around this topic.

The Autumn Years: Age Differences in Preferences for Sexually Dimorphic Faces.

Life history theory proposes that it is adaptive for older people to shift investment away from reproductive effort (such as mating) to survivorship. However, it remains unclear whether the shift is also present at the psychological level. We investigated this question by comparing preferences for mate choice-relevant cues, sexually dimorphic facial images, between older (60 years and older, n = 92) and younger adults (18-40 years, n = 86). Results showed that older adults had significantly smaller preferences for sexually dimorphic faces of both sexes than young adults. Specifically, both older men and women showed no significant preferences for sexually dimorphic traits when judging opposite-sex faces, and smaller preferences for masculine male faces and feminine female faces when judging same-sex faces. Young adults generally showed strong preferences for masculine male faces and feminine female faces. In Study 2, we confirmed that the absent/reduced preferences in older adults for sexually dimorphic faces did not result from poor visual ability. The smaller preferences for sexually dimorphic facial cues in older adults compared to young adults suggest that older adults may shift away from mating-oriented psychology as they become less fertile.

Targeted Lipidomics Analysis of Adipose and Skeletal Muscle Tissues by Multiple Reaction Monitoring Profiling.

Lipid homeostasis is critical for maintaining normal cellular functions including membrane structural integrity, cell metabolism, and signal transduction. Adipose tissue and skeletal muscle are two major tissues involved in lipid metabolism. Adipose tissue can store excessive lipids in the form of triacylglyceride (TG), which can be hydrolyzed to release free fatty acids (FFAs) under insufficient nutrition states. In the highly energy-demanding skeletal muscle, lipids serve as oxidative substrates for energy production but can cause muscle dysfunction when overloaded. Lipids undergo fascinating cycles of biogenesis and degradation depending on physiological demands, while dysregulation of lipid metabolism has been increasingly recognized as a hallmark of diseases such as obesity and insulin resistance. Thus, it is important to understand the diversity and dynamics of lipid composition in adipose tissue and skeletal muscle. Here, we describe the use of multiple reaction monitoring profiling, based on lipid class and fatty acyl chain specific fragmentation, to explore various classes of lipids in skeletal muscle and adipose tissues. We provide a detailed method for exploratory analysis of acylcarnitine (AC), ceramide (Cer), cholesteryl ester (CE), diacylglyceride (DG), FFA, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), and TG. Characterization of lipid composition within adipose tissue and skeletal muscle under different physiological situations will provide biomarkers and therapeutic targets for obesity-related diseases.

Recent progresses on ion beam irradiation induced structure and performance modulation of two-dimensional materials.

Two-dimensional (2D) materials are receiving significant attention for both fundamental research and industrial applications due to their unparalleled properties and wide application potential. In this case, the controllable modulation of their structures and properties is essential for the realization and further expansion of their applications. Accordingly, ion beam irradiation techniques, with large scope to adjust parameters, high manufacturing resolution, and a series of advanced equipment being developed, have been demonstrated to have obvious advantages in manipulating the structure and performance of 2D materials. In recent years, many research efforts have been devoted to uncovering the underlying mechanism and control rules regarding ion irradiation induced phenomena in 2D materials, aiming at fulfilling their application potential as soon as possible. Herein, we review the research progress in the interaction between energetic ions and 2D materials based on the energy transfer model, type of ion source, structural modulation, performance modification of 2D materials, and then their application status, aiming to provide useful information for researchers in this field and stimulating more research advances.

Current status and development direction of immunomodulatory therapy for intervertebral disk degeneration.

Intervertebral disk (IVD) degeneration (IVDD) is a main factor in lower back pain, and immunomodulation plays a vital role in disease progression. The IVD is an immune privileged organ, and immunosuppressive molecules in tissues reduce immune cell (mainly monocytes/macrophages and mast cells) infiltration, and these cells can release proinflammatory cytokines and chemokines, disrupting the IVD microenvironment and leading to disease progression. Improving the inflammatory microenvironment in the IVD through immunomodulation during IVDD may be a promising therapeutic strategy. This article reviews the normal physiology of the IVD and its degenerative mechanisms, focusing on IVDD-related immunomodulation, including innate immune responses involving Toll-like receptors, NOD-like receptors and the complement system and adaptive immune responses that regulate cellular and humoral immunity, as well as IVDD-associated immunomodulatory therapies, which mainly include mesenchymal stem cell therapies, small molecule therapies, growth factor therapies, scaffolds, and gene therapy, to provide new strategies for the treatment of IVDD.

Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma.

Human dedifferentiated liposarcoma (DDLPS) is a rare but lethal cancer with no driver mutations being identified, hampering the development of targeted therapies. We and others recently reported that constitutive activation of Notch signaling through overexpression of the Notch1 intracellular domain (NICDOE) in murine adipocytes leads to tumors resembling human DDLPS. However, the mechanisms underlying the oncogenic functions of Notch activation in DDLPS remains unclear. Here, we show that Notch signaling is activated in a subset of human DDLPS and correlates with poor prognosis and expression of MDM2, a defining marker of DDLPS. Metabolic analyses reveal that murine NICDOE DDLPS cells exhibit markedly reduced mitochondrial respiration and increased glycolysis, mimicking the Warburg effect. This metabolic switch is associated with diminished expression of peroxisome proliferator-activated receptor gamma coactivator 1α (Ppargc1a, encoding PGC-1α protein), a master regulator of mitochondrial biogenesis. Genetic ablation of the NICDOE cassette rescues the expression of PGC-1α and mitochondrial respiration. Similarly, overexpression of PGC-1α is sufficient to rescue mitochondria biogenesis, inhibit the growth and promote adipogenic differentiation of DDLPS cells. Together, these data demonstrate that Notch activation inhibits PGC-1α to suppress mitochondrial biogenesis and drive a metabolic switch in DDLPS.

Poly-ß-hydroxybutyrate alleviated diarrhea and colitis via Lactobacillus johnsonii biofilm-mediated maturation of sulfomucin.

Maintainance of sulfomucin is a key end point in the treatment of diarrhea and inflammatory bowel disease (IBD). However, the mechanisms underlying the microbial sense to sulfomucin are poorly understood, and to date, there are no therapies targeting the secretion and maturation of sulfomucin in IBD. Herein, we biosynthesized poly-ß-hydroxybutyrate (PHB) and found that PHB could alleviate inflammation caused by diarrhea and colitis by enhancing the differentiation of sulfomucin. Microbiota transplantation and clearance together demonstrate that PHB promoting sulfomucin is mediated by Lactobacillus johnsonii (L. johnsonii). Further studies revealed that PHB provides a favorable niche for L. johnsonii biofilm formation to resist disturbance and support its growth. L. johnsonii-biofilm alleviates colitis by regulating fucose residues to promote goblet cell differentiation and subsequent sulfomucin maturation. Importantly, PHB alleviates colitis by enhancing sulfomucin secretion and maturation in a L. johnsonii-dependent manner. PHB represents a class of guardians, acting as a safe probiotic-biofilm delivery system that significantly promotes probiotic proliferation. Altogether, this study adds weight to the possible role of probiotics and functional materials in the treatment of intestinal inflammation. The application of PHB and biofilm self-coating L. johnsonii carries high translational potential and may be of clinical relevance.

Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle.

Transcription factors (TFs) play key roles in regulating differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associating domains. Unexpectedly, Myod1Cre-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7CreER- or Rosa26CreER- driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remains to be elucidated.

Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of skeletal muscle.

Transcription factors (TFs) play key roles in regulating the differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associated domains. Unexpectedly, Myod1 Cre -driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7 CreER or Rosa26 CreER driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remain to be elucidated.

Agreement of intraocular pressure measurement with Corvis ST, non-contact tonometer, and Goldmann applanation tonometer in children with ocular hypertension and related factors.

AIM: To access the agreement of intraocular pressure (IOP) values obtained from biomechanically corrected tonometer [Corvis ST (CST)], non-contact tonometer (NCT), and Goldmann applanation tonometer (GAT) in children with NCT measured-IOP (NCT-IOP) values of 22 mm Hg or more, and related factors. METHODS: A total of 51 eyes with NCT-IOP≥22 mm Hg in children aged 7 to 14y were examined and IOP was measured by CST, NCT, and GAT. Based on GAT measured IOP (GAT-IOP), ocular hypertension (OHT) group (≥22 mm Hg, 24 eyes) and the non-OHT group (<22 mm Hg, 27 eyes) were defined. We compared the agreement of the three measurements, i.e., CST measured IOP (CST-IOP), GAT-IOP, and NCT-IOP, and further analyzed the correlation between the differences in tonometry readings, central corneal thickness (CCT), axial length (AL), optic disc rim volume, and age. RESULTS: Compared with the OHT group, thicker CCT, larger rim volume, and higher differences between NCT-IOP and GAT-IOP, were found in the non-OHT group. The differences between CST-IOP and GAT-IOP were lower than the differences between NCT-IOP and GAT-IOP in both groups. The mean differences in CST-IOP and GAT-IOP were 1.26 mm Hg (95% limit of agreement ranged from 0.1 to 2.41 mm Hg, OHT group) and 1.20 mm Hg (95% limit of agreement ranged from -0.5 to 3.00 mm Hg, non-OHT group), and the mean differences in NCT and GAT were 3.90 mm Hg (95% limit of agreement ranged from -0.19 to 9.70 mm Hg, OHT group) and 6.00 mm Hg (95% limit of agreement ranged from 1.50 to 10.50 mm Hg, non-OHT group). The differences between CST-IOP and GAT-IOP were not related to CCT, age, and AL in both groups; while the differences between NCT-IOP and GAT-IOP were related to CCT in the OHT group (r=0.93, P<0.001) and to CCT and AL in the non-OHT group (r=0.66, P<0.001, r=-0.81, P<0.001). CONCLUSION: The accuracy of NCT in the diagnosis of pediatric OHT is low. The agreement of CST-IOP and GAT-IOP was significantly higher in children with and without OHT than in those with NCT-IOP and GAT-IOP. Therefore, CST can be used as a good alternative for IOP measurement in children. The impacts of CCT and AL on NCT measurement need to be fully considered when managing childhood IOP.

Recent Research Progress in the Structure, Fabrication, and Application of MXene-Based Heterostructures.

Two-dimensional (2D) materials have received increasing attention in the scientific research community owing to their unique structure, which has endowed them with unparalleled properties and significant application potential. However, the expansion of the applications of an individual 2D material is often limited by some inherent drawbacks. Therefore, many researchers are now turning their attention to combine different 2D materials, making the so-called 2D heterostructures. Heterostructures can integrate the merits of each component and achieve a complementary performance far beyond a single part. MXene, as an emerging family of 2D nanomaterials, exhibits excellent electrochemical, electronic, optical, and mechanical properties. MXene-based heterostructures have already been demonstrated in applications such as supercapacitors, sensors, batteries, and photocatalysts. Nowadays, increasing research attention is attracted onto MXene-based heterostructures, while there is less effort spent to summarize the current research status. In this paper, the recent research progress of MXene-based heterostructures is reviewed, focusing on the structure, common preparation methods, and applications in supercapacitors, sensors, batteries, and photocatalysts. The main challenges and future prospects of MXene-based heterostructures are also discussed to provide valuable information for the researchers involved in the field.

Fabrication of Nanopore in MoS2-Graphene vdW Heterostructure by Ion Beam Irradiation and the Mechanical Performance.

Nanopore structure presents great application potential especially in the area of biosensing. The two-dimensional (2D) vdW heterostructure nanopore shows unique features, while research around its fabrication is very limited. This paper proposes for the first time the use of ion beam irradiation for creating nanopore structure in 2D vdW graphene-MoS2 heterostructures. The formation process of the heterostructure nanopore is discussed first. Then, the influence of ion irradiation parameters (ion energy and ion dose) is illustrated, based on which the optimal irradiation parameters are derived. In particular, the effect of stacking order of the heterostructure 2D layers on the induced phenomena and optimal parameters are taken into consideration. Finally, uniaxial tensile tests are conducted by taking the effect of irradiation parameters, nanopore size and stacking order into account to demonstrate the mechanical performance of the heterostructure for use under a loading condition. The results would be meaningful for expanding the applications of heterostructure nanopore structure, and can arouse more research interest in this area.

Drivers of university-business cooperation of university faculty from the social cognitive theory perspective.

As an independent research field, there is growing attention to university-business cooperation (UBC). However, few studies focus on the driving factors of UBC, which remains an open problem in this area. This study analyzes a broad mix of drivers underlying seven UBC activities, namely, curriculum development and design (CDD), student mobility (SD), lifelong learning (LLL), professional mobility (PM), research and development (R&D), commercialization (COM), and entrepreneurship (ENT), and discusses the internal mechanism and external environment of higher education institutions (HEIs) as the moderator variable affecting UBC activities and individual motivations. Specifically, based on the social cognition theory, the independent variables include motivations (money, career, research, education, and social), the internal mechanism (support mechanism, strategic mechanism, and management mechanism), and the external environment (policy environment, economic environment, and cultural environment) are designed. The aforementioned seven UBC activities are taken as dependent variables. This work takes university faculty as the research object. Through empirical analysis, it demonstrates that the combination of driving factors of different UBC activities has its particularity. Furthermore, the results showed that the internal mechanism and external environment of HEIs could positively moderate the relationship between individual motivations and UBC activities. In terms of theoretical contribution, this study reveals the combination of factors that drive university faculty to engage in UBC. On the other hand, it can provide a reference for policymakers and managers to better development of UBC.

Gut microbiota-stem cell niche crosstalk: A new territory for maintaining intestinal homeostasis.

Intestinal epithelium undergoes rapid cellular turnover, relying on the local niche, to support intestinal stem cells (ISCs) function and self-renewal. Research into the association between ISCs and disease continues to expand at a rapid rate. However, the detailed interaction of ISCs and gut microbes remains to be elucidated. Thus, this review witnessed major advances in the crosstalk between ISCs and gut microbes, delivering key insights into (1) construction of ISC niche and molecular mechanism of how to jointly govern epithelial homeostasis and protect against intestinal diseases with the participation of Wnt, bone morphogenetic protein, and Notch; (2) differentiation fate of ISCs affect the gut microbiota. Meanwhile, the presence of intestinal microbes also regulates ISC function; (3) microbiota regulation on ISCs by Wnt and Notch signals through pattern recognition receptors; (4) how do specific microbiota-related postbiotics influence ISCs to maintain intestinal epithelial regeneration and homeostasis that provide insights into a promising alternative therapeutic method for intestinal diseases. Considering the detailed interaction is still unclear, it is necessary to further explore the regulatory role of gut microbiota on ISCs to utilize microbes to alleviate gut disorders. Furthermore, these major advances collectively drive us ever closer to breakthroughs in regenerative medicine and cancer treatment by microbial transplantation in the clinic.

Development and Reliability and Validity Test to the Parenting Stress Questionnaire for Two-Child Mothers.

China is getting old before it gets rich. Among women of childbearing age, there seems to be little interest in having multiple children, and parenting stress may be one of the reasons. There are differences in the parenting stress felt by mothers with one child and those with two, but there is no questionnaire specifically aimed at the parenting stress felt by mothers of multiples in China. The purpose of the present study is to develop and verify a questionnaire specifically aimed at measuring the stress of two-child mothers in the Chinese context. We chose mothers as participants who were younger than 50 years old and their second child were younger than 18 years old as participants. The initial questionnaire was created after analyzing the results of 83 participants' open questionnaires and 16 participants' qualitative interviews. Item analysis and exploratory factor analysis were conducted with 279 participants. The final questionnaire was created after conducting reliability and validity tests on the responses of 263 participants to 23 items on the questionnaire covering four factors: characteristics of mother, environmental factor, characteristics of child, and relationship between the two siblings. The results of confirmatory factor analysis indicated that the four-factor model fit well (χ2/df = 2.00, CFI = 0.91, TLI = 0.90, SRMR = 0.06, RMSEA = 0.06). McDonald's omega coefficients and split-half reliability coefficients both ranged from 0.50 to 0.95. The questionnaire scores were significantly positively correlated with parental burnout, the regret of having a second child and parenting stress, and were significantly negatively correlated with the intention of having a third child and support for the three-child policy. Overall, the present study confirmed the reliability and validity of the parenting stress questionnaire for two-child mothers, which can be used to measure the parenting stress experienced by mothers of multiples in China.

ACSS3 in brown fat drives propionate catabolism and its deficiency leads to autophagy and systemic metabolic dysfunction.

Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl-CoA synthetase short-chain family member 3 (ACSS3), located on the mitochondrial inner membrane in brown adipocytes. Knockout of Acss3 gene (Acss3-/- ) in mice reduces brown adipose tissue (BAT) mass but increases white adipose tissue (WAT) mass, leading to glucose intolerance and insulin resistance that are exacerbated by high-fat diet (HFD). Intriguingly, Acss3-/- or HFD feeding significantly elevates propionate levels in BAT and serum, and propionate supplementation induces autophagy in cultured brown and white adipocytes. The elevated levels of propionate in Acss3-/- mice similarly drive adipocyte autophagy, and pharmacological inhibition of autophagy using hydroxychloroquine ameliorates obesity, hepatic steatosis and insulin resistance of the Acss3-/- mice. These results establish ACSS3 as the key enzyme for propionate metabolism and demonstrate that accumulation of propionate promotes obesity and Type 2 diabetes through triggering adipocyte autophagy.