Splicing factor TRA2A contributes to esophageal cancer progression via a noncanonical role in lncRNA m⁶A methylation

Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine-rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6A methyltransferase, METTL3, by silencing. MeRIP-qPCR, RNA pull-down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6A-modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co-IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity-based virtual screening in FDA-approved drugs repurposed nebivolol, a β1-adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis.</p

OmniQuant: Omnidirectionally Calibrated Quantization for Large Language Models

Large language models (LLMs) have revolutionized natural language processing tasks. However, their practical deployment is hindered by their immense memory and computation requirements. Although recent post-training quantization (PTQ) methods are effective in reducing memory footprint and improving the computational efficiency of LLM, they hand-craft quantization parameters, which leads to low performance and fails to deal with extremely low-bit quantization. To tackle this issue, we introduce an Omnidirectionally calibrated Quantization (OmniQuant) technique for LLMs, which achieves good performance in diverse quantization settings while maintaining the computational efficiency of PTQ by efficiently optimizing various quantization parameters. OmniQuant comprises two innovative components including Learnable Weight Clipping (LWC) and Learnable Equivalent Transformation (LET). LWC modulates the extreme values of weights by optimizing the clipping threshold. Meanwhile, LET tackles activation outliers by shifting the challenge of quantization from activations to weights through a learnable equivalent transformation. Operating within a differentiable framework using block-wise error minimization, OmniQuant can optimize the quantization process efficiently for both weight-only and weight-activation quantization. For instance, the LLaMA-2 model family with the size of 7-70B can be processed with OmniQuant on a single A100-40G GPU within 1-16 hours using 128 samples. Extensive experiments validate OmniQuant's superior performance across diverse quantization configurations such as W4A4, W6A6, W4A16, W3A16, and W2A16. Additionally, OmniQuant demonstrates effectiveness in instruction-tuned models and delivers notable improvements in inference speed and memory reduction on real devices. Codes and models are available at \url{https://github.com/OpenGVLab/OmniQuant}.Comment: Updated result with 2-bit quantization. A differentiable quantization method for LL

A HIV-1 heterosexual transmission chain in Guangzhou, China: a molecular epidemiological study

<p>Abstract</p> <p>Background</p> <p>We conducted molecular analyses to confirm four clustering HIV-1 infections (Patient A, B, C & D) in Guangzhou, China. These cases were identified by epidemiological investigation and suspected to acquire the infection through a common heterosexual transmission chain.</p> <p>Methods</p> <p><it>Env C2V3V4 </it>region, <it>gag p17/p24 </it>junction and partial <it>pol </it>gene of HIV-1 genome from serum specimens of these infected cases were amplified by reverse transcription polymerase chain reaction (RT-PCR) and nucleotide sequenced.</p> <p>Results</p> <p>Phylogenetic analyses indicated that their viral nucleotide sequences were significantly clustered together (bootstrap value is 99%, 98% and 100% in <it>env</it>, <it>gag </it>and <it>pol </it>tree respectively). Evolutionary distance analysis indicated that their genetic diversities of <it>env</it>, <it>gag </it>and <it>pol </it>genes were significantly lower than non-clustered controls, as measured by unpaired <it>t</it>-test (<it>env </it>gene comparison: <it>p </it>< 0.005; <it>gag </it>gene comparison: <it>p </it>< 0.005; <it>pol </it>gene comparison: <it>p </it>< 0.005).</p> <p>Conclusion</p> <p>Epidemiological results and molecular analyses consistently illustrated these four cases represented a transmission chain which dispersed in the locality through heterosexual contact involving commercial sex worker.</p

Synergism between lignite and high-sulfur petroleum coke in CO2 gasification

High-sulfur petroleum coke (PC) as solid waste has high treatment cost. Gasification technology can utilize PC and lignite for co-gasification. Organically combining the two is the key to expanding the adaptability of gasification raw materials. This work used thermal analysis technology to study the gasification reaction of PC and lignite systems in a CO2 atmosphere. The results show that the starting and end temperatures of the co-gasification of lignite/high-sulfur PC are lower than those of pure coke. The improved carbonization rate and gasification reaction index indicate that lignite improves the gasification performance. The gasification synergy factors are all greater than 1, indicating that the co-gasification process produces obvious synergism, and the synergism is more obvious in the gasification stage after 800°C. The lignite ash is gradually enriched on the surface of high-sulfur PC with the temperature increase, and the Ca and Fe elements have an obvious catalytic effect, but the catalytic effect has a saturation value. Ashes from lignite used as a multi-component gasification catalyst can increase the overall reactivity in the lignite/high-sulfur PC system, which can broaden the selection of gasification raw materials, and make efficient use of the resource characteristics of both

Strategic Analyses for a Cross-Basin Water Pollution Conflict Involving Heterogeneous Sanctions in Hongze Lake, China, within the GMCR Paradigm

The graph model for conflict resolution (GMCR) methodology was enhanced in this research for addressing cross-basin water pollution conflicts involving heterogeneous sanctions, as a more intuitive and straightforward definition for mixed unilateral improvements was proposed, followed by an integrated procedure for performing mixed stability analyses. Furthermore, the cross-border water pollution dispute that occurred in 2018 in Hongze Lake, China, is systematically modeled and strategically analyzed for the first time, using the improved GMCR method. In addition, an evolution analysis was carried out within the framework of GMCR for verifying the applicability of the eco-compensation mechanism in addressing cross-basin water pollution disputes. This case study demonstrates that the heterogeneity of sanctioning opponents could influence equilibrium outcomes and even change the evolution of conflict situations. Moreover, the developed novel approach is able to accurately predict the equilibrium outcomes of the conflict and provide more strategic insights and valuable findings in making effective conflict resolutions for solving cross-basin water pollution conflicts

Alcohol drinking alters oral microbiota to modulate the progression of alcohol-related liver disease

Summary: Alcohol-related liver disease (ALD) is one of the leading causes of liver-related death worldwide. However, roles of oral microbiota in regulating the progression of ALD remain unknown. Here, we fed mice with control or ethanol diet to establish chronic-plus-binge ALD model. 16S ribosomal DNA sequencing was performed on oral and cecum samples. We demonstrated that alcohol drinking influenced bacterial richness, microbial structure, and composition in oral samples of ethanol-fed mice compared with control mice. Alcohol consumption also remodeled relationships among oral microbes and altered functions of oral microbiota. Furthermore, oral microbiota, such as Streptococcus, Helicobacter, Alloprevotella, and Psychrobacter were closely associated with ALD parameters. Finally, we observed Sutterellaceae_uncultured, Dyella, and Gemmatimonas possibly translocated along with oral-gut axis and positively correlated with the severity of ALD. Altogether, alcohol consumption reprogramed composition and functions of oral microbiota to promote ALD progression, suggesting that oral microbes might become a new target for ALD therapy

Increasing HIV and decreasing syphilis prevalence in a context of persistently high unprotected anal intercourse, six consecutive annual surveys among men who have sex with men in Guangzhou, China, 2008 to 2013.

INTRODUCTION: Previous studies have reported a possibly increasing HIV prevalence among men who have sex with men (MSM) in China. However there have been limited systematic analyses of existing surveillance data to learn the trend of HIV prevalence and factors driving the trend. The aims of this study were to examine the trend of HIV prevalence among MSM in Guangzhou and to explore the role of unprotected anal intercourse (UAI) in the trend. METHODS: Snow-ball sampling was applied in the subject recruitment for the annual serological and behavioral surveys among MSM from 2008 to 2013. Data collected in the behavioral survey include demographic information, HIV related sexual behavior with men and women, access to HIV prevention services, and symptoms of sexually transmitted infections. Chi-square test was used to analyze the trend of HIV prevalence. Multivariate logistic regression was conducted to test the factors associated with HIV infection. RESULTS: HIV prevalence increased significantly from 5.0% in 2008 to 11.4% in 2013 while syphilis prevalence decreased from 17.4% to 3.3% in the same period. UAI rates were high and stable in every single year, ranging from 54.5% to 62.0%. Those who were having UAI (OR = 1.80, 95% confidence interval (CI): 1.26-2.58), being migrants, having more than 10 partners, and infected with syphilis had higher risk for HIV infection. CONCLUSIONS: HIV epidemic is expanding in Guangzhou. The persistently high UAI may have played a major role in the increasing trend of HIV prevalence. Targeted prevention program should be conducted among MSM who are migrants, low educational level, syphilis infected, or having multiple partners to encourage HIV test and change UAI behavior. The general high UAI calls for tailored intervention program to promote healthy culture and form a safe sex social norm in the MSM community

Attenuated Salmonella carrying siRNA-PD-L1 and radiation combinatorial therapy induces tumor regression on HCC through T cell-mediated immuno-enhancement

Abstract Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance