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Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process. Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten–eleven family proteins (TET) using alpha‐ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the circulatory AKG concentration was reduced in middle‐aged mice (10‐month‐old) compared with young mice (2‐month‐old). Through AKG administration replenishing the AKG pool, aged mice were associated with the lower body weight gain and fat mass, and improved glucose tolerance after challenged with high‐fat diet (HFD). These metabolic changes are accompanied by increased expression of brown adipose genes and proteins in inguinal adipose tissue. Cold‐induced brown/beige adipogenesis was impeded in HFD mice, whereas AKG rescued the impairment of beige adipocyte functionality in middle‐aged mice. Besides, AKG administration up‐regulated Prdm16 expression, which was correlated with an increase of DNA demethylation in the Prdm16 promoter. In summary, AKG supplementation promotes beige adipogenesis and alleviates HFD‐induced obesity in middle‐aged mice, which is associated with enhanced DNA demethylation of the Prdm16 gene. The circulatory alpha‐ketoglutarate concentration was dramatically reduced in aged mice. Alpha‐ketoglutarate administration facilitates DNA demethylation in the Prdm16 promoter, which enhances its expression and brown/beige adipogenesis and improves metabolic health of aged mice challenged with high‐fat diet.

In clay-sand reservoirs, shale volume affects porosity and permeability, with porosity governing storage capacity; these properties influence reserve and productivity predictions, which directly affect reservoir and economic assessments. Estimates of porosity and shale volume from independent log-based methods may introduce coupled biases, whereas those from joint inversion better honor their interdependence. Joint inversion has traditionally relied on simplified assumptions or extra data; in contrast, recent data-driven approaches capture complex log patterns. However, purely data-driven methods suffer from feature-target shifts and cannot enforce inter-target dependencies. To address these limitations, a two-stage deep learning framework combining self-supervised log modeling with core-calibrated low-rank adaptation (CCLoRA) is proposed for joint porosity and shale volume prediction. First, a Conditional Score-based Diffusion Imputation (CSDI) model is self-supervised on synthetic logs generated from empirical formulas. This enables learning of plausible log sequence structures and confers partial robustness to feature-target shifts without extensive labeled data. Second, core-scale petrophysical relationships are transferred to the log scale through well-specific feature replacement using CCLoRA. This corrects residual feature-target shifts and enforces inter-target dependencies between the two parameters with minimal fine-tuning cost. Experiments on well-consolidated sandstones show the full pipeline outperforms multiple deep learning baselines, delivering accurate and physically consistent estimates.

Astragalus polysaccharide (APS) is an important bioactive component of Astragalus membranaceus which is used as an anti-diabetes herb in traditional Chinese medicine. The objective of this study was to investigate the effects and mechanisms of APS on insulin-sensitizing of adipocytes. Mouse 3T3-L1 preadipocytes were used as a model. The results showed that APS increased preadipocytes proliferation in a dose dependent manner, and 0.1 μg/mL APS sufficiently increased Proliferating Cell Nuclear Antigen (PCNA) content (p < 0.01). Moreover, APS enhanced intracellular lipid accumulation and mRNA expression of proliferator-activated receptor γ (PPARγ, p < 0.01), CCAAT/enhancer binding protein α (C/EBPα, p < 0.01) and fatty acid binding protein (aP2, p < 0.01). As expected, corresponding protein contents were elevated. Importantly, APS increased 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake (p < 0.01). Meanwhile, both mRNA and protein content of glucose transporter 4 (Glut4) were elevated by APS (p < 0.01). The APS treatment enhanced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1, p < 0.05) and phosphor-Akt content (p < 0.01). Besides, phosphorylated AMP-activated protein kinase (AMPK) content was increased in the APS treated cells (p < 0.01). Taken together, APS improved insulin sensitivity by enhancing glucose uptake, possibly through AMPK activation. These results suggested that APS might be a therapeutic candidate for insulin resistance.

Background Vitamin A and retinoic acid (RA, a metabolite of vitamin A), are inextricably involved to the development of skeletal muscle in animals. However, the mechanisms regulating skeletal muscle development by vitamin A remain poorly reported. The current study designed to investigate the underlying mechanism of vitamin A affecting myogenic differentiation of lamb myoblasts through transcriptome sequencing (RNA-Seq) and gene function validation experiments. It provides a theoretical basis for elucidating the regulation of vitamin A on skeletal muscle development as well as for improving the economic benefits of the mutton sheep industry. Results Newborn lambs were injected with 7,500 IU vitamin A, and longissimus dorsi (LD) muscle tissue was surgically sampled for RNA-Seq analysis and primary myoblasts isolation at 3 weeks of age. The results showed that a total of 14 down-regulated and 3 up-regulated genes, were identified between control and vitamin A groups. Among them, BHLHE40 expression was upregulated in vitamin A group lambs. Furthermore, BHLHE40 expression is significantly increased after initiation of differentiation in myoblasts, and RA addition during differentiation greatly promoted BHLHE40 mRNA expression. In vitro, RA inhibited myoblasts proliferation and promoted myoblasts myogenic differentiation through BHLHE40 . Moreover, BHLHE40 was proved to inhibit the expression of the DNA binding inhibitor 3 ( ID3 ), and meanwhile, ID3 could effectively promote myoblasts proliferation and inhibit myoblasts myogenic differentiation. Conclusions Taken together, our results suggested that vitamin A inhibited myoblasts proliferation and promoted myoblasts myogenic differentiation by inhibiting ID3 expression through BHLHE40.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. The 3′ untranslated region (UTR) of this β-CoV contains essential cis-acting RNA elements for the viral genome transcription and replication. These elements include an equilibrium between an extended bulged stem-loop (BSL) and a pseudoknot. The existence of such an equilibrium is supported by reverse genetic studies and phylogenetic covariation analysis and is further proposed as a molecular switch essential for the control of the viral RNA polymerase binding. Here, we report the SARS-CoV-2 3′ UTR structures in cells that transcribe the viral UTRs harbored in a minigene plasmid and isolated infectious virions using a chemical probing technique, namely dimethyl sulfate (DMS)-mutational profiling with sequencing (MaPseq). Interestingly, the putative pseudoknotted conformation was not observed, indicating that its abundance in our systems is low in the absence of the viral nonstructural proteins (nsps). Similarly, our results also suggest that another functional cis-acting element, the three-helix junction, cannot stably form. The overall architectures of the viral 3′ UTRs in the infectious virions and the minigene-transfected cells are almost identical.

RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.

A mab cluster associated with 3-aminobenzoic acid (3AB) degradation was identified in Comamonas sp. QT12. However, the cellular response of Comamonas sp. QT12 to 3-aminobenzoic acid remains unclear. In this study, label-free quantitative proteome analysis based on LC–MS/MS was used to study the protein expression difference of strain QT12 under the condition of using 3AB (3AB) and citric acid/ammonium chloride as substrates (3ABCon). A total of 2068 proteins were identified, of which 239 were significantly up-regulated in 3AB group, 124 were significantly down-regulated in 3AB group, 624 were expressed only in 3AB group, and 216 were expressed only in 3ABCon group in 3AB group. KEGG pathway analysis found that 83 pathways were up-regulated and 49 pathways were down-regulated, In GO analysis, 315 paths were up-regulated and 156 paths were down-regulated. There were 6 genes in the mab cluster that were only detected in the 3AB group.The mab cluster was found to be related to degradation of 3AB. By knockout, it was found that the growth rate of the mutant △ orf 7 and △ orf 9 were slowed down. HPLC results showed that the mutant △ orf 7 and △ orf 9 could still degrade 3AB, it was found that orf7 , orf9 were not key genes about 3AB degradation and they could be replaced by other genes in strain QT12. These findings improve our understanding of the molecular mechanisms underlying the cellular response of 3AB degradation in Comamonas bacterium.

Background Vitamin A (VA) and its metabolite, retinoic acid (RA), are of great interest for their wide range of physiological functions. However, the regulatory contribution of VA to mitochondrial and muscle fiber composition in sheep has not been reported. Method Lambs were injected with 0 (control) or 7,500 IU VA palmitate into the biceps femoris muscle on d 2 after birth. At the age of 3 and 32 weeks, longissimus dorsi (LD) muscle samples were obtained to explore the effect of VA on myofiber type composition. In vitro, we investigated the effects of RA on myofiber type composition and intrinsic mechanisms. Results The proportion of type I myofiber was greatly increased in VA-treated sheep in LD muscle at harvest. VA greatly promoted mitochondrial biogenesis and function in LD muscle of sheep. Further exploration revealed that VA elevated PGC-1α mRNA and protein contents, and enhanced the level of p38 MAPK phosphorylation in LD muscle of sheep. In addition, the number of type I myofibers with RA treatment was significantly increased, and type IIx myofibers was significantly decreased in primary myoblasts. Consistent with in vivo experiment, RA significantly improved mitochondrial biogenesis and function in primary myoblasts of sheep. We then used si-PGC-1α to inhibit PGC-1α expression and found that si-PGC-1α significantly abrogated RA-induced the formation of type I myofibers, mitochondrial biogenesis, MitoTracker staining intensity, UQCRC1 and ATP5A1 expression, SDH activity, and enhanced the level of type IIx muscle fibers. These data suggested that RA improved mitochondrial biogenesis and function by promoting PGC-1α expression, and increased type I myofibers. In order to prove that the effect of RA on the level of PGC-1α is caused by p38 MAPK signaling, we inhibited the p38 MAPK signaling using a p38 MAPK inhibitor, which significantly reduced RA-induced PGC-1α and MyHC I levels. Conclusion VA promoted PGC-1α expression through the p38 MAPK signaling pathway, improved mitochondrial biogenesis, and altered the composition of muscle fiber type. Graphical Abstract

We propose a novel inverse analysis method that utilizes shockwaves to detect the operational condition of tested rock. To achieve this back analysis, an in-depth investigation of the dynamic properties of granite specimens was conducted. The dynamic properties of the granite specimens were investigated using a triaxial cyclic loading machine, under different confining pressures, loading frequencies, stress amplitudes, and numbers of cycles, and a dynamic response model was constructed from the test data. The results show that the dynamic elastic modulus increased with the increase in confining pressure, while its damping ratio decreased. The dynamic elastic modulus and damping ratio increased with the increase in loading frequency. As the dynamic stress amplitude increased, the dynamic elastic modulus of the granite increased, but the dynamic damping ratio decreased. As the number of cycles increased, the dynamic elastic modulus and dynamic damping ratio of the granite decreased and gradually stabilized. The modified Duncan–Chang model was used to construct the dynamic response model of the specimens. It is worth saying that the correlation coefficient of the model is low at a loading frequency of 20 Hz. This indicates that the frequency has a greater effect on the dynamic response of the specimen compared with the confining pressure. The conclusions obtained from these tests can be used to study more comprehensively the interaction and causal relationship between different factors, and to prepare for the next steps of tunnel rock stress-state prediction.

The Pusangguo skarn is a newly discovered Cu-Pb-Zn deposit in the Gangdese metallogenic belt, Tibet. In order to constrain the age of the deposit and the source of hydrothermal fluids, various types of titanite and coexisting minerals in the Pusangguo deposit were studied. The titanite occurring interstitially in fresh granodiorite is magmatic and characterized by high REE, Y, Mn, and Lu/Hf ratios, and high crystallization temperatures (700 to 750 °C). The titanite growing with, or included in, diopside in the prograde endoskarn, or occurring with epidote, calcite, and quartz in the retrograde exoskarn, is hydrothermal titanite characterized by low REE, Y, Mn, and Lu/Hf ratios. The titanite in the retrograde exoskarn typically contains a REE-enriched early core characterized by a negative Eu anomaly, and an overgrowth REE-depleted rim with a positive Eu anomaly. The secondary-ion mass spectrometry U-Pb dating of titanite drilled from thin sections of retrograde exoskarn shows intercept ages of 14.91 ± 0.31 Ma, which are consistent with the granodiorite age (14.63 ± 0.30 Ma), indicating coeval emplacement of granodiorite and skarn mineralization at ~ 14.7 Ma. In addition, in situ epidote and calcite Sr isotopes and titanite Nd isotopes, all analyzed in the same retrograde exoskarn thin section, show similar Sr-Nd isotopic compositions to magmatic plagioclase and granodiorite (whole rock), indicating that the retrograde hydrothermal fluids were directly derived from, or had the same origin as, the granodiorite.