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Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3[beta]-hydroxysteroid dehydrogenase-1 (3[beta]HSD1) serves as the rate- limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3[beta]HSD1 in driving CRPC. In postmenopausal women, 3[beta]HSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3[beta]HSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3[beta]HSD1 cellular activity and generation of [[DELTA].sup.4], 3-keto-substrates of 5[alpha]- reductase and aromatase, including in patient tissues. BMX directly interacts with 3[beta]HSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3[beta]HSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers., Introduction Metastatic prostate cancer requires systemic therapy. Androgen deprivation therapy (ADT) with medical or surgical castration is the front-line treatment and is now frequently combined with other therapies; however, it [...]

Biomimetic and thermoresponsive hemostatic hydrogels based on gelatin (G), hyaluronic acid (HA), and poly-N-isopropylacrylamide (PNIPAM) have emerged as promising hemostats, but their performances are currently limited by the drawbacks of conventional grafting strategies, and the complicated operation and safety risk associated with photo-cross-linking or chemical cross-linking. It is highly appealing yet challenging to develop a facile strategy to prepare a physically cross-linked hemostatic hydrogel with rapid gelation and a robust network. Herein, an injectable, thermosensitive, and physically cross-linked double-network hemostatic hydrogel was prepared through simply blending G/HA with the linear PNIPAM (L-P) synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. The G/HA/L-P hydrogel could be conveniently injected via a syringe and cured in situ at body temperature. Its comprehensive performance could be tuned and optimized by adjusting the molecular weight of L-P and the proportions of components. Due to the non-covalent interactions including hydrogen bonding, hydrophobic interactions, and chain entanglements within the hydrogel network, the optimal performance of the G/HA/L-P hydrogel was achieved, i.e., gelation time 7–10 s, storage modulus 89 ± 3.5 kPa, adhesion strength 19.3 ± 2.5 kPa, and burst pressure 256 ± 27 mmHg. Meanwhile, the hydrogel exhibited significant coagulation effects in vitro and effective hemostatic properties in vivo. This work offers a simple and efficient strategy to fabricate high-performance smart hemostatic hydrogels. [ABSTRACT FROM AUTHOR]

Straw returning has gradually been adopted as an effective approach to address the serious degradation of farmland. However, the carbon/nitrogen (C/N) ratio of rice straw is generally too high for microorganisms to decompose the organic materials and release nutrients, which may minimize the benefits of straw returning to the agricultural production system. This study aimed to investigate the effects of straw returning on rice production and propose optimum nitrogen (N) management for early rice production under a straw returning system. The total N fertilizer that was evaluated was 165 kg N ha-1, urea (46% N), applied in different proportions in three stages of rice cultivation: basal, tillering, and panicle. Using no straw returning with the N fertilizer ratio of basal:tillering:panicle = 5:2:3 treatment (T1) as the control, four different N fertilizer ratios of basal:tillering:panicle, including 5:2:3 (T2), 5:2:2 (T3), 5:4:1 (T4), and 5:5:0 (T5) were set under straw returning. The return of straw decreased the available N in the soil at the tillering stage, and impeded root growth and the crop canopy from establishing, which decreased the effective panicles by 10.1% compared with that of T1, limiting the increases in rice grain yield. Increasing the N fertilizer ratio 10–20% (T3 and T4) at the tillering stage effectively increased the content of soil ammonium and nitrate nitrogen, improved the root growth, and increased the root activities by 16.0–40.5% at the tillering stage. As a result, the effective panicle number increased by 5.1–16.2%. Among these, T4 treatment maximized the benefits of straw returning the most. Additionally, increasing the N fertilizer ratio at the tillering stage increased the shoot uptake across the early rice growing season and synchronized crop N uptake with the accumulation of carbon assimilates, which enhanced the crop growth rate and increased the rice yield by 13.5–25.1%. It is concluded that increasing the N fertilizer ratio by 20% at the tillering stage is a promising strategy to increase the availability of N in the phases of high demand for this nutrient. [ABSTRACT FROM AUTHOR]

This paper aims to discuss the implementation of data analysis and information management for elderly nursing care from a data-driven perspective. It addresses the current challenges of in-home caregivers, providing a basis for decision making in analyzing nursing service content and evaluating job performance. The characteristics of caregivers' activities were analyzed during the design of a wearable device-wearing scheme and a sensor data collection system. XGBoost, SVM, and Random Forest models were used in the experiments, with the Cuckoo search algorithm employed to optimize the XGBoost model parameters. Based on the control group experiment, it was confirmed that the XGBoost model, after adjusting the parameters using the Cuckoo search algorithm, exhibited better recognition performance than the SVM and RandomForest models, and the accuracy reached 0.9438. Wearable devices present high recognition accuracy in caregiver activity recognition research, which greatly improves the inspection of caregivers' work and further promotes the completion of services. This study actively explores the applications of information technology and artificial intelligence theory to address practical problems and effectively promote the digitalization and intelligent development of the elderly nursing care industry. [ABSTRACT FROM AUTHOR]

Parasite-specific CD4+ Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4+ Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G− ITGAM/CD11b+ ADGRE1/F4/80− cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G− ITGAM+ ADGRE1− cell-derived CCL2 selectively interacted with CCR2 on CD4+ Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4+ Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4+ Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines. Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1. [ABSTRACT FROM AUTHOR]