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RB 81 - Google Drive

APOBEC3 enzymes are important components of the innate immune system to counteract diverse viral infections that cells may encounter2,97. APOBEC3-mediated deamination of viral genomes blocks the production of new viruses by generating lethal mutations, leading to the loss of function of newly synthesized viral proteins and viral genome degradation2,7,97. In contrast, mutations induced by APOBEC3 enzymes can also drive viral evolution and the production of new viral variants with altered features resistant to cell defense mechanisms2,7,98. The double-edged sword of APOBEC3 deamination activity suggests that APOBEC3 enzymes may have developed other mechanisms, in parallel to inducing mutations, to inhibit viral replication and prevent viral evolution. In this study, we discovered that A3B modulates the innate immune response at different stages of viral infections and defined the specific mechanism. First, we showed that A3B promotes PKR activation-induced SG formation and translation shutdown to limit viral protein synthesis. Second, we found that A3B protects RNA-associated SGs from RNase L-mediated RNA decay to promote G3BP1-RNA condensates and SG formation (refer to the models shown in Fig. 10).

RB 81 - Google Drive

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A number of exercise training studies (e.g., 5-10 weeks) incorporating creatine supplementation have shown no increases in total body water (TBW). For example, resistance-trained males who received creatine at a dose of 0.3 g/kg lean body mass/day for 7 days (approximately 20 g/day) followed by 4 weeks at 0.075 g/kg lean body mass/day for 28 days (approximately 5 g/day) experienced no significant change in ICW, ECW, or TBW [40]. Furthermore, resistance-trained males who consumed creatine supplementation (20 g/day for seven days followed by 5 g/day for 21 days) had no significant increase in ICW, ECW, or TBW [41]. Similarly, males and females ingesting creatine (0.03 g/kg/day for six weeks) experienced no significant increase in TBW [42]. Six weeks of creatine supplementation in non-resistance-trained males at a dosage of 0.3 g/kg lean body mass for five days followed by 0.075 g/kg lean body mass for 42 days produced no significant changes in TBW [43]. In contrast, when assessing TBW, ICW, and ECW content before and after 28 days of creatine supplementation in healthy males and females (n = 32), Powers et al. [44] showed that creatine supplementation was effective at increasing muscle creatine content which was associated with an increase in body mass and TBW but did not alter ICW or ECW volumes. In a recent study examining the effects of creatine supplementation combined with resistance exercise for 8 weeks, Ribeiro et al. [45] found a significant increase in TBW (7.0%) and ICW (9.2%) volume compared to placebo (TBW: 1.7%; ICW: 1.6%), with both groups similarly increasing ECW (CR: 1.2% vs. Placebo = 0.6%). Importantly, the ratio of skeletal muscle mass to ICW remained similar in both groups. It is important to highlight that the ICW is an important cellular signal for protein synthesis and thus drives an increase in muscle mass over time [46].

As a result of hormone-driven changes in endogenous creatine synthesis, creatine transport, and creatine kinase (CK) kinetics, creatine bioavailability throughout various stages of female reproduction is altered, highlighting the potential positive implications for creatine supplementation in females [29]. The implications of hormone-related changes in creatine kinetics has been largely overlooked in performance-based studies [29]. Specifically, creatine supplementation may be of particular importance during menses, pregnancy, post-partum, perimenopause and postmenopause. Creatine kinase, as well as enzymes associated with creatine synthesis, are influenced by estrogen and progesterone [1]. Creatine kinase levels are significantly elevated during menstruation [162], with CK levels decreasing throughout the menstrual cycle, pregnancy, and with age. The lowest range of CK values have been reported during early pregnancy (20 weeks or less), equating to about half the concentration found at peak levels (teenage girls) [162, 163].

Metabolic adaptation is one of the essential hallmarks of cancer to sustain replication and survival stress (1). Based on available nutrients, tumor cells alter their metabolic pathways for the biosynthesis of macromolecules and mitochondrial ATP synthesis. Metabolic reprogramming plays a pivotal role in tumor cell survival during metastatic dissemination, circulation, and colonization in distant organs, thus driving the successful formation of metastatic lesions (2). Hence, understanding the metabolic checkpoints that drive aggressive metastatic cancer holds promise as an effective therapeutic strategy.

Dysregulation of lipid metabolism is a hallmark of prostate cancer progression (3). In prostate tumors, there is an increased demand for de novo lipogenesis, which is supported by elevated levels of rate-limiting enzymes such as fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD; ref. 4). Expressions of these genes are regulated by transcription factors sterol regulatory element-binding protein 1 and androgen receptor (AR; ref. 5), and coregulated by steroid receptor coactivator-2 (SRC-2; also known as NCOA2/GRIP1/TIF2). SRC-2 is highly amplified and overexpressed in patients with advanced prostate cancer (6), causing stimulation of lipogenesis by elevating the expression of FASN and SCD even in castrate amounts of circulating androgen (7). Despite this knowledge, it remains largely unknown how these nuclear transcriptional regulators communicate with mitochondrial machineries to drive a sustained flow of carbon flux to support elevated demands for lipids.

Mitochondrial citrate is the precursor metabolite required for lipogenesis, which is exported to the cytosol for conversion into acetyl-CoA and subsequently into malonyl CoA for de novo biosynthesis of fatty acids (8). The regulation of citrate metabolism is unique in prostate glands compared with other organs. Normal prostatic cells mostly depend on diet-derived lipids for fatty acid synthesis and secrete a large amount of citrate into the prostatic fluid as an energy source for sperm (9). This is biochemically achieved by increasing the influx of zinc into the mitochondria, which functions as a competitive inhibitor of aconitase 2 (ACO2) enzyme, a reversible enzyme that catalyzes the stereo-specific isomerization of citrate to isocitrate via cis-aconitate (10). Regulation of ACO2 enzyme activity is pivotal to maintain increased levels of citrate in prostate tumors, and mutations in tricarboxylic acid (TCA) enzymes such as isocitrate dehydrogenase 1 (IDH1) frequently observed in other cancer types are rare in prostate adenocarcinoma. During prostate cancer progression, zinc import into the mitochondria is reduced, and in absence of the competitive inhibitor, ACO2 enzyme becomes functional (11). The increased demand for citrate is facilitated by ACO2; however, the underlying mechanisms and regulatory signals that directly potentiate the sustained activity of the enzyme remain elusive. Because reactivation of ACO2 is a biochemical feature during prostate cancer progression (12), we asked the question of whether this enzymatic regulation functions as the essential metabolic adaptive response to drive lethal prostate cancer. Moreover, none of the studies have yet investigated the mechanisms that escalate the sustained ACO2 enzymatic activity, nor do we know whether this metabolic regulation is vital for progression of the disease to distant organs. In the present study, we sought to identify the molecular functions of ACO2 in prostate cancer and define the mechanisms regulating its sustained enzyme activity, with the anticipation that these mitochondrial programming could serve as fundamental determinants of metastatic competence.

Although oncogenesis initiates in the primary prostate, metastasis remains the leading cause of death. Notably, prostate tumors metastasize to specific organs such as liver, lymph nodes, and most frequently bone. Our study revealed a distinct genetic alteration that drives metabolic adaptation of tumor cells for survival and successful homing in the bone. In particular, we demonstrated that the notable oncogene SRC-2 functions as a transcriptional repressor of the SIRT3 gene to retain elevated levels of enzymatically active acetylated ACO2. This process favors increased tumor cell survival, growth, enhanced bioenergetic capabilities, and lipid metabolism, all of which are vital for providing sufficient metabolic flexibility to thrive in distant organs.

Yes true we are also Structural consultants and already shared lakhs of files with our 2-3 users. Now due to this shortcut features, we are unable to save many of our coded excels or other file. Once opened directly on drive its making file corrupt. I shared this issues with google Development team but after month of research they finally declined to revert our drive to original.

See im image how our internal communication has badly affected due to this link Shortcut feature. I ll say that this is one of the most poor feature. Google has given option to not opt for this feature from admin console, but even that option is not effective for all users. request google team to look into it.

In response to growth factors stimulation, receptor tyrosine kinases (RTKs) and other membrane receptors activate the RAS/MAPK/ERK and PI3K/AKT signaling pathways [80,81]. In the context of cancer cells where autocrine and paracrine activation of growth factor receptors contribute to tumor progression, RUNX2 undergoes phosphorylation by both ERK and AKT kinases. ERK phosphorylation sites in RUNX2 (S43, S301, S309 and S510) have been identified and functionally characterized [82]. The double S301A/S319A phosphorylation site mutation significantly reduces expression of VEGF, MMP9 and SPP1, migration and invasion of human prostate cancer cell lines and in vivo growth of tumor cell xenografts [83]. Another study demonstrates that activation of the TAK1-MKK3/6-p38 MAPK axis leads to phosphorylation of RUNX2 by p38, promoting RUNX2 association with the co-activator CREB-binding protein, CBP, which is required to regulate osteoblast genetic programs [84]. Signaling crosstalk represents an important component regulating RUNX2 as a driver of tumor progression via phosphorylation. The phosphorylation of RUNX2 by AKT, ERK and p38 and the effect of these phosphorylation events on RUNX2 activity have to be contextualized in tumor cells exhibiting continuous cross-talk between the RAS/MAPK and PI3K/AKT pathways [80]. In addition to being a downstream target of this crosstalk, RUNX2 also acts on this crosstalk. RUNX2 promotes the crosstalk between MEK/ERK and PI3K/AKT via EGFR in human MCF-10A mammary epithelial cells [85]. 041b061a72


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