Distinct roles of NMB and GRP in itch transmission

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord

SigRec: Automatic Recovery of Function Signatures in Smart Contracts

Millions of smart contracts have been deployed onto Ethereum for providing various services, whose functions can be invoked. For this purpose, the caller needs to know the function signature of a callee, which includes its function id and parameter types. Such signatures are critical to many applications focusing on smart contracts, e.g., reverse engineering, fuzzing, attack detection, and profiling. Unfortunately, it is challenging to recover the function signatures from contract bytecode, since neither debug information nor type information is present in the bytecode. To address this issue, prior approaches rely on source code, or a collection of known signatures from incomplete databases or incomplete heuristic rules, which, however, are far from adequate and cannot cope with the rapid growth of new contracts. In this paper, we propose a novel solution that leverages how functions are handled by Ethereum virtual machine (EVM) to automatically recover function signatures. In particular, we exploit how smart contracts determine the functions to be invoked to locate and extract function ids, and propose a new approach named type-aware symbolic execution (TASE) that utilizes the semantics of EVM operations on parameters to identify the number and the types of parameters. Moreover, we develop SigRec , a new tool for recovering function signatures from contract bytecode without the need of source code and function signature databases. The extensive experimental results show that SigRec outperforms all existing tools, achieving an unprecedented 98.7 percent accuracy within 0.074 seconds. We further demonstrate that the recovered function signatures are useful in attack detection, fuzzing and reverse engineering of EVM bytecode

Comparison of netupitant/palonosetron with 5-hydroxytryptamine-3 receptor antagonist in preventing of chemotherapy-induced nausea and vomiting in patients undergoing hematopoietic stem cell transplantation

BackgroundThe use of 5-hydroxytryptamine-3 receptor antagonists (5HT3RA) has long been considered the standard regimen for preventing chemotherapy-induced nausea and vomiting (CINV) prior to hematopoietic stem cell transplantation (HSCT). However, their therapeutic outcomes have been unsatisfactory. NEPA, an oral formulation combining the neurokinin-1 receptor antagonist netupitant and the 5HT3RA palonosetron, has received regulatory approval for the management of highly and moderately emetogenic chemotherapy. This study aims to compare the efficacy of NEPA with that of 5HT3RA alone in preventing CINV among patients undergoing multiday conditioning chemotherapy prior to HSCT.Patients and methodsWe conducted a retrospective analysis of patients who underwent HSCT between September 2019 and September 2022. Efficacy outcomes were assessed based on the rates of patients achieving complete response (CR: no emesis and no use of rescue medication), complete control (CC: CR without significant nausea), no vomiting, and no significant nausea.ResultsThe NEPA group consisted of 106 patients, while the 5HT3RA group included 107 patients. The NEPA group exhibited significantly higher rates of CR compared to the 5HT3RA group during the overall phase (71.7% vs. 32.7%, P<0.001), acute phase (78.3% vs. 43.0%, P<0.001), and delayed phase (84.9% vs. 58.9%, P<0.001). Similarly, rates of CC, no vomiting, and no significant nausea were significantly better in the NEPA group across all phases (P<0.001).ConclusionNEPA demonstrated superior efficacy compared to 5HT3RA in preventing CINV during all phases of multiday conditioning regimens among patients undergoing HSCT

Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages

CodeFuse-13B: A Pretrained Multi-lingual Code Large Language Model

Code Large Language Models (Code LLMs) have gained significant attention in the industry due to their wide applications in the full lifecycle of software engineering. However, the effectiveness of existing models in understanding non-English inputs for multi-lingual code-related tasks is still far from well studied. This paper introduces CodeFuse-13B, an open-sourced pre-trained code LLM. It is specifically designed for code-related tasks with both English and Chinese prompts and supports over 40 programming languages. CodeFuse achieves its effectiveness by utilizing a high quality pre-training dataset that is carefully filtered by program analyzers and optimized during the training process. Extensive experiments are conducted using real-world usage scenarios, the industry-standard benchmark HumanEval-x, and the specially designed CodeFuseEval for Chinese prompts. To assess the effectiveness of CodeFuse, we actively collected valuable human feedback from the AntGroup's software development process where CodeFuse has been successfully deployed. The results demonstrate that CodeFuse-13B achieves a HumanEval pass@1 score of 37.10%, positioning it as one of the top multi-lingual code LLMs with similar parameter sizes. In practical scenarios, such as code generation, code translation, code comments, and testcase generation, CodeFuse performs better than other models when confronted with Chinese prompts.Comment: 10 pages with 2 pages for reference

Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity

Increasing evidence demonstrates that berberine (BBR) is beneficial for obesity-associated nonalcoholic fatty liver disease (NAFLD). However, it remains to be elucidated how BBR improves aspects of NAFLD. Here we revealed an AMP-activated protein kinase (AMPK)-independent mechanism for BBR to suppress obesity-associated inflammation and improve hepatic steatosis. In C57BL/6J mice fed a high-fat diet (HFD), treatment with BBR decreased inflammation in both the liver and adipose tissue as indicated by reduction of the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines. BBR treatment also decreased hepatic steatosis, as well as the expression of acetyl-CoA carboxylase and fatty acid synthase. Interestingly, treatment with BBR did not significantly alter the phosphorylation state of AMPK in both the liver and adipose tissue of HFD-fed mice. Consistently, BBR treatment significantly decreased the phosphorylation state of JNK1 in both hepatoma H4IIE cells and mouse primary hepatocytes in both dose-dependent and time-dependent manners, which was independent of AMPK phosphorylation. BBR treatment also caused a decrease in palmitate-induced fat deposition in primary mouse hepatocytes. Taken together, these results suggest that BBR actions on improving aspects of NAFLD are largely attributable to BBR suppression of inflammation, which is independent of AMPK.National Institutes of Health [HL108922, HL095556, R01DK095828, R01DK095862]; National Natural Science Foundation of China [81100562/H0711]; Hatch Program of the National Institutes of Food and Agriculture (NIFA)SCI(E)[email protected]; [email protected]

Environmental effects on AGN activity via extinction-free mid-infrared census

How does the environment affect active galactic nucleus (AGN) activity? We investigated this question in an extinction-free way, by selecting 1120 infrared galaxies in the AKARI North Ecliptic Pole Wide field at redshift z ≤ 1.2. A unique feature of the AKARI satellite is its continuous 9-band infrared (IR) filter coverage, providing us with an unprecedentedly large sample of IR spectral energy distributions (SEDs) of galaxies. By taking advantage of this, for the first time, we explored the AGN activity derived from SED modelling as a function of redshift, luminosity, and environment. We quantified AGN activity in two ways: AGN contribution fraction (ratio of AGN luminosity to the total IR luminosity), and AGN number fraction (ratio of number of AGNs to the total galaxy sample). We found that galaxy environment (normalised local density) does not greatly affect either definitions of AGN activity of our IRG/LIRG samples (log LTIR ≤ 12). However, we found a different behavior for ULIRGs (log LTIR > 12). At our highest redshift bin (0.7 ≲ z ≲ 1.2), AGN activity increases with denser environments, but at the intermediate redshift bin (0.3 ≲ z ≲ 0.7), the opposite is observed. These results may hint at a different physical mechanism for ULIRGs. The trends are not statistically significant (p ≥ 0.060 at the intermediate redshift bin, and p ≥ 0.139 at the highest redshift bin). Possible different behavior of ULIRGs is a key direction to explore further with future space missions (e.g., JWST, Euclid, SPHEREx)