Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis

<p>Abstract</p> <p>Background</p> <p>Glucocorticoid (GC) resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL). In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex) treatment.</p> <p>Methods</p> <p>Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. Fluorescence-activated cell sorting (FACS) analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR), the cell cycle regulatory proteins, and apoptosis associated proteins.</p> <p>Results</p> <p>10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G₁-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK) inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR) expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1.</p> <p>Conclusion</p> <p>Our data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G₀/G₁phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting new therapeutic approach for GC resistant T-ALL patients.</p

CoderEval: A Benchmark of Pragmatic Code Generation with Generative Pre-trained Models

Code generation models based on the pre-training and fine-tuning paradigm have been increasingly attempted by both academia and industry, resulting in well-known industrial models such as Codex, CodeGen, and PanGu-Coder. To evaluate the effectiveness of these models, multiple existing benchmarks are proposed, including only cases of generating a standalone function, i.e., a function that may invoke or access only built-in functions and standard libraries. However, non-standalone functions, which typically are not included in the existing benchmarks, constitute more than 70% of the functions in popular open-source projects, and evaluating models' effectiveness on standalone functions cannot reflect these models' effectiveness on pragmatic code generation scenarios. To help bridge the preceding gap, in this paper, we propose a benchmark named CoderEval, consisting of 230 Python and 230 Java code generation tasks carefully curated from popular real-world open-source projects and a self-contained execution platform to automatically assess the functional correctness of generated code. CoderEval supports code generation tasks from six levels of context dependency, where context refers to code elements such as types, APIs, variables, and consts defined outside the function under generation but within the dependent third-party libraries, current class, file, or project. CoderEval can be used to evaluate the effectiveness of models in generating code beyond only standalone functions. By evaluating three code generation models on CoderEval, we find that the effectiveness of these models in generating standalone functions is substantially higher than that in generating non-standalone functions. Our analysis highlights the current progress and pinpoints future directions to further improve a model's effectiveness by leveraging contextual information for pragmatic code generation

Effects of exercise interventions on negative emotions, cognitive performance and drug craving in methamphetamine addiction

IntroductionMethamphetamine is currently one of the most commonly used addictive substances with strong addiction and a high relapse rate. This systematic review aims to examine the effectiveness of physical activity in improving negative emotions, cognitive impairment, and drug craving in people with methamphetamine use disorder (MUD).MethodsA total of 17 studies out of 133 found from Embase and PubMed were identified, reporting results from 1836 participants from MUD populations. Original research using clearly described physical activity as interventions and reporting quantifiable outcomes of negative mood, cognitive function and drug craving level in people with MUD were eligible for inclusion. We included prospective studies, randomized controlled trials, or intervention studies, focusing on the neurological effects of physical activity on MUD.ResultsTaken together, the available clinical evidence showed that physical activity-based interventions may be effective in managing MUD-related withdrawal symptoms.DiscussionPhysical exercise may improve drug rehabilitation efficiency by improving negative emotions, cognitive behaviors, and drug cravings.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024530359

Sociodemographic and obstetric characteristics of stillbirths in China: a census of nearly 4 million health facility births between 2012 and 2014

Background Very little is known about the burden and determinants of stillbirths in China. We used data from a national surveillance system for health facility births to compute a stillbirth rate representative of all facility births in China and to explore sociodemographic and obstetric factors associated with variation in the stillbirth rate. Methods We used data from China’s National Maternal Near Miss Surveillance System between Jan 1, 2012, and Dec 31, 2014, which covers 441 hospitals in 326 urban districts and rural counties. The surveillance aimed to enumerate all maternal deaths and near misses in health facilities, and collected data prospectively for all pregnant or post-partum women admitted to the obstetric department. We restricted the analysis to births of 28 or more completed weeks of gestation or 1000 g or heavier birthweight. We examined the strength of association between sociodemographic characteristics, gestational age, and obstetric complications and stillbirths using logistic regression, taking account of the sampling strategy and clustering of births within hospitals and in cases of more than one birth per woman. Findings There were 3 956 836 births and 37 855 stillbirths, giving a stillbirth rate of 8·8 per 1000 births (95% CI 8·8–8·9). The stillbirth rate was particularly high for women younger than 15 years of age (59·9 stillbirths per 1000 births), those who had not sought antenatal care (38·3 per 1000), the unmarried (32·5 per 1000), those with no education (26·9 per 1000), or those who had had four or more births (23·2 per 1000). A high proportion (29 319 [78·2%] of 37 514) of stillbirths occurred at gestational ages of younger than 37 weeks, and about two thirds (24 787 [66·1%] of 37 514) were in women without any maternal complication at the time of birth. Of babies born at normal gestations (37–41 weeks), maternal complications substantially increased the risk of stillbirth (odds ratio comparing antepartum or intrapartum complications with no complication 3·96 [95% CI 3·66–4·29]), but only a small proportion (1638 [4·4%] of 37 514) of stillbirths fell into this group. Interpretation Our analysis of nearly 4 million births in 441 health facilities in China suggests a stillbirth rate of 8·8 per 1000 births between 2012 and 2014. Stillbirths do not feature in the Chinese Government’s 5 year plans and most information systems do not include stillbirths. The Government need to start paying attention to stillbirths and invest strategically in antenatal care, particularly for the most disadvantaged women, including the very young, unmarried, and illiterate, and those at high parity

Tumor regression rate, PD-L1 expression, pembrolizumab/nab-paclitaxel–based regimens, squamous cell carcinoma, and comorbidities were independently associated with efficacy of neoadjuvant chemoimmunotherapy in non-small cell lung cancer

BackgroundNeoadjuvant chemoimmunotherapy (NCIO) is more effective than neoadjuvant immunotherapy alone for pathological response in non-small cell lung cancer (NSCLC) patients, but the processes for determining patient suitability for its implementation are not clear. We aimed to identify the most relevant factors and build a convenient model to select NSCLC patients who would benefit most from NCIO.Methods We retrospectively collected the clinical data of patients with locally advanced NSCLC who received NCIO followed by surgery at our institution between January 2019 and July 2022.ResultsA total of 101 eligible stage IIB-IIIC NSCLC patients were included. After NCIO, all patients successfully underwent surgical resection. A total of 46.53% (47/101) of patients achieved pathological complete response (pCR), and 70.30% (71/101) achieved major pathologic response (MPR). Tumor regression rate (adjusted odds ratio OR = 12.33), PD-L1 expression (adjusted odds ratio (OR) = 9.66), pembrolizumab/nab-paclitaxel–based regimens (adjusted OR = 4.92), and comorbidities (adjusted OR = 0.16) were independently associated with pCR rate (all P &lt; 0.05). Tumor regression rate (adjusted OR = 8.45), PD-L1 expression (adjusted OR = 5.35), and presence of squamous cell carcinoma (adjusted OR = 7.02) were independently associated with MPR rate (all P &lt; 0.05). We established and validated an easy-to-use clinical model to predict pCR (with an area under the curve [AUC] of 0.848) and MPR (with an AUC of 0.847). Of note, the present study showed that CD4+ T-cell count/rate and total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels in the peripheral blood of pre-NCIO patients were also significantly correlated with pathological response in univariate analyses.ConclusionsThe tumor regression rate, PD-L1 expression, pembrolizumab/nab-paclitaxel–based regimens, presence of squamous cell carcinoma, and comorbidities were the main influential factors for incidence of pCR/MPR in patients with stage IIB-IIIC NSCLC in the present study. Through predictive models, we can predict who will benefit most from NCIO prior to the emergence of clinical outcomes in locally advanced NSCLC

A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking

Histone lysine methyltransferase complexes are essential for chromatin organization and gene regulation. Whether any of this machinery functions in membrane traffic is unknown. In this study, we report that mammal Dpy-30 (mDpy-30), a subunit of several histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) complexes, resides in the nucleus and at the trans-Golgi network (TGN). The TGN targeting of mDpy-30 is mediated by BIG1, a TGN-localized guanine nucleotide exchange factor for adenosine diphosphate ribosylation factor GTPases. Altering mDpy-30 levels changes the distribution of cation-independent mannose 6-phosphate receptor (CIMPR) without affecting that of TGN46 or transferrin receptor. Our experiments also indicate that mDpy-30 functions in the endosome to TGN transport of CIMPR and that its knockdown results in the enrichment of internalized CIMPR and recycling endosomes near cell protrusions. Much like mDpy-30 depletion, the knockdown of Ash2L or RbBP5, two other H3K4MT subunits, leads to a similar redistribution of CIMPR. Collectively, these results suggest that mDpy-30 and probably H3K4MT play a role in the endosomal transport of specific cargo proteins

Simulation Studies for the First Pathfinder of the CATCH Space Mission

The Chasing All Transients Constellation Hunters (CATCH) space mission is an intelligent constellation consisting of 126 micro-satellites in three types (A, B, and C), designed for X-ray observation with the objective of studying the dynamic universe. Currently, we are actively developing the first Pathfinder (CATCH-1) for the CATCH mission, specifically for type-A satellites. CATCH-1 is equipped with Micro Pore Optics (MPO) and a 4-pixel Silicon Drift Detector (SDD) array. To assess its scientific performance, including the effective area of the optical system, on-orbit background, and telescope sensitivity, we employ the Monte Carlo software Geant4 for simulation in this study. The MPO optics exhibit an effective area of $41$ cm$^2$ at the focal spot for 1 keV X-rays, while the entire telescope system achieves an effective area of $29$ cm$^2$ at 1 keV when taking into account the SDD detector's detection efficiency. The primary contribution to the background is found to be from the Cosmic X-ray Background. Assuming a 625 km orbit with an inclination of $29^\circ$, the total background for CATCH-1 is estimated to be $8.13\times10^{-2}$ counts s$^{-1}$ in the energy range of 0.5--4 keV. Based on the background within the central detector and assuming a Crab-like source spectrum, the estimated ideal sensitivity could achieve $1.9\times10^{-12}$ erg cm$^{-2}$ s$^{-1}$ for an exposure of 10$^4$ s in the energy band of 0.5--4 keV. Furthermore, after simulating the background caused by low-energy charged particles near the geomagnetic equator, we have determined that there is no need to install a magnetic deflector

Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

The DNA methyltransferase Dnmt3a has high expression in terminally differentiated macrophages; however, its role in innate immunity remains unknown. Here we report that deficiency in Dnmt3a selectively impaired the production of type I interferons triggered by pattern-recognition receptors (PRRs), but not that of the proinflammatory cytokines TNF and IL-6. Dnmt3a-deficient mice exhibited enhanced susceptibility to viral challenge. Dnmt3a did not directly regulate the transcription of genes encoding type I interferons; instead, it increased the production of type I interferons through an epigenetic mechanism by maintaining high expression of the histone deacetylase HDAC9. In turn, HDAC9 directly maintained the deacetylation status of the key PRR signaling molecule TBK1 and enhanced its kinase activity. Our data add mechanistic insight into the crosstalk between epigenetic modifications and post-translational modifications in the regulation of PRR signaling and activation of antiviral innate immune responses

Hybridization as a threat in climate relict Nuphar pumila (Nymphaeaceae)

Field studies and conceptual work on hybridization-mediated extinction risk in climate relicts are extremely rare. Nuphar pumila (Nymphaeaceae) is one of the most emblematic climate relicts in Europe with few isolated populations in the Alpine arc. The extent of introgression with related lowland and generalist species Nupharlutea has never been studied using molecular methods. All biogeographical regions where N.pumila naturally occurs in the neighbourhood of the Alpine arc were sampled and studied using nuclear microsatellite markers. Furthermore, we used forward-in-time simulations and Approximate Bayesian Computation to check whether an introgression scenario fits with the observed admixture patterns and estimated the demographic parameters associated with this process. Our study confirms ongoing hybridization between N.pumila and N.lutea and validates it by the use of population models. More than 40 % of investigated N.pumila individuals were admixed and hybrids were found in over 60 % of studied populations. The introgression is bidirectional and is most likely a result of very recent gene flow. Our work provides strong evidence for rapid extinction risk and demographic swamping between specialized climatic relicts and closely related generalists. The remaining pure populations of N.pumila are rare in the Alpine arc and deserve high conservation priority