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Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM., Introduction In mammals, the liver is a master organ in the regulation of glucose and lipid metabolism in response to nutritional and hormonal stimuli (1). During the fasting state, hepatic [...]

Interventions to prevent HIV-1 infection and alternative tools in HIV cure therapy remain pressing goals. Recently, numerous broadly neutralizing HIV-1 monoclonal antibodies (bNAbs) have been developed that possess the characteristics necessary for potential prophylactic or therapeutic approaches. However, formulation complexities, especially for multiantibody deliveries, long infusion times, and production issues could limit the use of these bNAbs when deployed, globally affecting their potential application. Here, we describe an approach utilizing synthetic DNA-encoded monoclonal antibodies (dmAbs) for direct in vivo production of prespecified neutralizing activity. We designed 16 different bNAbs as dmAb cassettes and studied their activity in small and large animals. Sera from animals administered dmAbs neutralized multiple HIV-1 isolates with activity similar to that of their parental recombinant mAbs. Delivery of multiple dmAbs to a single animal led to increased neutralization breadth. Two dmAbs, PGDM1400 and PGT121, were advanced into nonhuman primates for study. High peak- circulating levels (between 6 and 34 [micro]g/ml) of these dmAbs were measured, and the sera of all animals displayed broad neutralizing activity. The dmAb approach provides an important local delivery platform for the in vivo generation of HIV-1 bNAbs and for other infectious disease antibodies., Introduction In just over four decades since its global emergence, the AIDS epidemic has taken millions of lives. While there have been exceptional advances in antiretroviral therapies, there remains a [...]

Low level light therapy (LLLT) has numerous therapeutic benefits, including improving wound healing, but the precise mechanisms involved are not well established; in particular, the underlying role of cytochrome C oxidase (C-ox) as the primary photoacceptor and the associated biochemical mechanisms still require further investigation. We previously showed the nitric oxide (NO) donating drug nitrosyl-cobinamide (NO-Cbi) enhances wound healing through a cGMP/cGMP-dependent protein kinase/ERK1/2 mechanism. Here, we show that the combination of LLLT and NO-Cbi markedly improves wound healing compared to either treatment alone. LLLT-enhanced wound healing proceeded through an electron transport chain-C-ox-dependent mechanism with a reduction of reactive oxygen species and increased adenosine triphosphate production. C-ox was validated as the primary photoacceptor by three observations: increased oxygen consumption, reduced wound healing in the presence of sodium azide, and disassociation of cyanide, a known C-ox ligand, following LLLT. We conclude that LLLT and NO-Cbi accelerate wound healing through two independent mechanisms, the electron transport chain-C-ox pathway and cGMP signaling, respectively, with both resulting in ERK1/2 activation.

Currently available cyanide antidotes must be given by intravenous injection over 5-10 min, making them ill-suited for treating many people in the field, as could occur in a major fire, an industrial accident, or a terrorist attack. These scenarios call for a drug that can be given quickly, e.g., by intramuscular injection. We have shown that aquohydroxocobinamide is a potent cyanide antidote in animal models of cyanide poisoning, but it is unstable in solution and poorly absorbed after intramuscular injection. Here we show that adding sodium nitrite to cobinamide yields a stable derivative (referred to as nitrocobinamide) that rescues cyanide-poisoned mice and rabbits when given by intramuscular injection. We also show that the efficacy of nitrocobinamide is markedly enhanced by coadministering sodium thiosulfate (reducing the total injected volume), and we calculate that ∼1.4 mL each of nitrocobinamide and sodium thiosulfate should rescue a human from a lethal cyanide exposure.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway integrates environmental clues to regulate cell growth and survival. We showed previously that depriving cells of a single essential amino acid rapidly and reversibly arrests purine synthesis. Here we demonstrate that amino acids via mammalian target of rapamycin 2 and IκB kinase regulate Akt activity and Akt association and phosphorylation of transketolase (TKT), a key enzyme of the nonoxidative pentose phosphate pathway (PPP). Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. Mice fed a lysine-deficient diet for 2 days show decreased Akt activity, TKT activity, and purine synthesis in multiple organs. These results provide a mechanism whereby Akt coordinates amino acid availability with glucose utilization, purine synthesis, and RNA and DNA synthesis.

The practical use of Zn metal anodes in aqueous zinc batteries is impeded by the growth of dendrites, anode corrosion, and hydrogen evolution reaction in aqueous electrolytes. In this study, a simple, energy‐efficient, and scalable approach is reported to mitigate these detrimental issues effectively. Using 1‐hexanethiol (HT), a hydrophobic self‐assembled mercaptan layer (SAML) with a highly ordered structure is in situ created on the surface of the Zn anode. This ultrathin interfacial structure guides uniform Zn deposition and shields the Zn anode from water and oxygen‐induced corrosion, thus effectively inhibiting dendrite formation and side reactions. Consequently, the HT‐Zn electrode showcases impressive electrochemical stability and reversibility, and the as‐assembled HT‐Zn||I2 full cell delivers increased specific capacity (from 112 to 155 mAh g−1 at 1 A g−1) and ultra‐stable cyclability (zero capacity decay during the extended 1500 cycles at 4 A g−1). To validate the effectiveness of this simple and scalable method, a large‐sized pouch cell is prepared, which can be stably operated for 1000 cycles with a capacity decay of merely 0.0098% per cycle and Coulombic efficiency exceeding 99.1%. The presented SAML strategy highlights the potential of molecular engineering in improving the performance of aqueous zinc batteries. [ABSTRACT FROM AUTHOR]

Benefiting from large-scale pretrained vision language models (VLMs), the performance of visual question answering (VQA) has approached human oracles. However, finetuning such models on limited data often suffers from overfitting and poor generalization issues, leading to a lack of model robustness. In this paper, we aim to improve input robustness from an information bottleneck perspective when adapting pretrained VLMs to the downstream VQA task. Input robustness refers to the ability of models to defend against visual and linguistic input variations, as well as shortcut learning involved in inputs. Generally, the representations obtained by pretrained VLMs inevitably contain irrelevant and redundant information for a specific downstream task, resulting in statistically spurious correlations and insensitivity to input variations. To encourage representations to converge to a minimal sufficient statistic in multimodal learning, we propose Correlation Information Bottleneck (CIB), which seeks a tradeoff between compression and redundancy in representations by minimizing the mutual information (MI) between inputs and representations while maximizing the MI between outputs and representations. Moreover, we derive a tight theoretical upper bound for the mutual information between multimodal inputs and representations, incorporating different internal correlations that guide models to learn more robust representations and facilitate modality alignment. Extensive experiments consistently demonstrate the effectiveness and superiority of the proposed CIB in terms of input robustness and accuracy. [ABSTRACT FROM AUTHOR]

As an important choice of strategic transformation of energy enterprises, digital transformation has a profound impact on the stock price fluctuation of enterprises. From the perspective of dynamic capacity and environmental regulation, analyzes influences of digital transformation upon energy companies' share movement volatility, constructs a theoretical model that considers digital transformation and stock price volatility as the primary effects, dynamic capabilities as the mediator, and environmental regulation as the moderator. In addition, the study employs data from China's A-share listed energy enterprises from 2013 to 2020, utilizing a fixed-effect model to perform an empirical test. The findings demonstrate a significant positive correlation between the digital transformation of energy enterprises and the volatility of stock prices, indicating that the greater the extent of digital transformation, the higher the volatility of enterprise stock prices. Among the dimensions of dynamic capability, only adaptability and innovation ability appears to mediate the relation between digital transformation and stock price fluctuation. Moreover, environmental regulation positively moderates the relationship between digital transformation and the learning ability dimension. Finally, from the macro and micro levels, this study puts forward the policies and supportive measures to stabilize the stock price of energy enterprises, and suggestions on how to implement the digital transformation strategy reasonably according to their own development status and characteristics to provide valuable insights for encouraging the digital transformation among energy firms. [ABSTRACT FROM AUTHOR]

Tunnel junctions (TJs) offer a unique approach to utilizing nonequilibrium tunneling injection of holes and have demonstrated potential applications in ultraviolet (UV) emitters. However, high operating voltage caused by the wide bandgap of the III‐nitrides has impeded the further promotion of TJ. Here, 275 nm n+‐Al0.45Ga0.55N/p+‐Al0.5Ga0.5N ultrathin tunnel junction (UTJ) deep‐UV light‐emitting diodes (LEDs) are developed for minimizing the electrical losses and achieve, to the current knowledge, the lowest operating voltage (5.7 V) at 300 mA reported to date. This study discovers that Mg‐Si co‐doping occurs in the n+‐Al0.45Ga0.55N layer during the growth of n+‐Al0.45Ga0.55N/p+‐Al0.5Ga0.5N UTJ due to the memory and diffusion effect of Mg, which leads to the formation of Ohmic contact between high‐work‐function Ni/Au and Mg‐Si co‐doped n+‐ Al0.45Ga0.55N layer in UTJ. The Zener diode, fluorine resin, and optimally designed glass lens are incorporated into the chip encapsulation to enhance the reliability and optical performance of the device. Furthermore, a high‐efficiency sterilization deep‐UV light source is developed integrated with 120 UTJ deep‐UV LED chips. Complete surface inactivation at a long irradiation distance (20 cm) is achieved within only seconds using the high‐power sterilization deep‐UV light source. These results indicate that UTJ is promising in developing deep UV LEDs and their integrated light sources. [ABSTRACT FROM AUTHOR]

TRP channels have an important role in regulating the function of gastrointestinal epithelial cells. The aim of this study was to investigate the molecular mechanisms of genes associated with TRP channels in Crohn's disease (CD) by bioinformatics approach and to identify potential key biomarkers. In our study, we identified TRP channel-related differentially expressed genes (DEGs) based on the GSE95095 dataset and the TRP channel-related gene set from the GeneCards database. Hub genes (CXCL8, HIF1A, NGF, JUN, IL1A) were identified by the PPI network and validated by the external GSE52746 dataset. Immune infiltration analysis revealed that CXCL8 was significantly correlated with B cells memory, NK cells activated, Mast cells resting, Mast cells activated, and Neutrophils. GSEA of CXCL8 results showed inositol phosphate metabolism, RNA polymerase, propanoate metabolism, MAPK signaling pathway, base excision repair, and Calcium signaling pathway. In addition, we constructed a lncRNA-miRNA-mRNA ceRNA network and a drug–gene interaction network. Finally, we performed in vitro experiments to verify that LPS induced CXCL8 expression in HT-29 cells and that knockdown of CXCL8 inhibited the inflammatory stimulatory effects of LPS. This study reveals that CXCL8 plays an important role in the pathogenesis of Crohn's disease and is expected to be a novel biomarker. [ABSTRACT FROM AUTHOR]

Glucose tetrasaccharide (Glc4) and maltotetraose (M4) are important biomarkers for Pompe disease and other glycogen storage diseases (GSDs). With the development of new treatments for GSDs, more specific and sensitive bioanalytical methods are needed to determine biomarkers. In recent years, differential mobility spectrometry (DMS) has become an effective analytical technique with high selectivity and specificity. This study aimed to develop an efficient analytical method for the two urinary tetrasaccharide metabolites using DMS and apply it to patients with GSDs (type Ib and II). Urine samples were directly diluted and injected into liquid chromatography-differential mobility spectrometry tandem mass spectrometry (LC-DMS-MS/MS). Chromatographic separation was performed on an Acquity™ UPLC BEH Amide column (2.1 × 50 mm, 1.7 μm) with a short gradient elution of 2.6 min. DMS-MS/MS was used to detect two urinary tetrasaccharide metabolites in a negative multiple reaction monitoring mode with isopropanol as a modifier. A total of 20 urine samples from 6 healthy volunteers and 10 patients with GSDs (type Ib and II) were collected for analysis. The method was linear over a concentration range of 0.5~100.0 µg/mL for each urinary tetrasaccharide (r≥0.99). The intra- and inter-day precision RSD% were less than 14.3%, and the accuracy RE% were in the range of −14.3~13.4%. The relative matrix effect was between 86.6 and 114.3%. No carryover or interference was observed. Patients with GSDs (type Ib and II) had significantly higher median urinary Glc4 (P=0.001) and M4 (P=0.012) excretion than healthy subjects. The developed method was simple, rapid, sensitive, and specific. It was successfully applied to healthy volunteers and patients with GSDs (type Ib and II). DMS technology greatly improved analysis efficiency and provided high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Central Bank Digital Currency (CBDC) pledges to realize a vast array of new functionalities, such as frictionless consumer payment and money-transfer systems, as well as precise supervision of money circulation, thereby enabling a number of new financial instruments and monetary policy levers. This study proposes, from a system feedback loop and cybernetics perspective, a Dynamic Issuance Mechanism (DIM) for CBDC that can theoretically enhance the vitality of economic operations. In accordance with this mechanism, the central bank implements dynamic issuance by monitoring cash leakage in real-time, so as to maintain the stability of the amount of money circulating on the market, thereby boosting the currency turnover rate and financial vitality. To demonstrate the efficacy of the DIM, we employ the Agent-Based Modeling (ABM) tool to develop a macroeconomic simulation model for qualitative analysis that includes four entities: Central Bank, households, firms, and commercial banks. The multi-cycle operation process of the model includes a variety of economic indicators demonstrating that DIM has the potential to boost economic vitality and social production efficiency without exerting an adverse effect on citizens' incomes, commodity prices, or the stability of the macroeconomic system. Finally, the function principle and potential risks of DIM are explained from a systems perspective, which offers a novel perspective for the functional design of CBDC and highlights that the hierarchical structure is a meaningful domain as the developmental direction. [ABSTRACT FROM AUTHOR]