The antagonism between MCT-1 and p53 affects the tumorigenic outcomes

<p>Abstract</p> <p>Background</p> <p>MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains ambiguous. We speculate that MCT-1 may counteract p53 through the diverse mechanisms that determine the tumorigenic outcomes.</p> <p>Results</p> <p>MCT-1 has now identified as a novel target gene of p53 transcriptional regulation. MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 suppresses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in a p53-dependent or a p53-independent fashion, according to the genotoxic mechanism. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth are irrepressible by p53 reactivation <it>in vivo</it>, the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by MCT-1 oncoprotein.</p> <p>Conclusions</p> <p>The oppositions between MCT-1 and p53 are firstly confirmed at multistage processes that include transcription control, mRNA metabolism, and protein expression. MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development.</p

Urban expansion and agricultural land loss in China: A multiscale perspective

China’s rapid urbanization has contributed to a massive agricultural land loss that could threaten its food security. Timely and accurate mapping of urban expansion and urbanization-related agricultural land loss can provide viable measures to be taken for urban planning and agricultural land protection. In this study, urban expansion in China from 2001 to 2013 was mapped using the nighttime stable light (NSL), normalized difference vegetation index (NDVI), and water body data. Urbanization-related agricultural land loss during this time period was then evaluated at national, regional, and metropolitan scales by integrating multiple sources of geographic data. The results revealed that China’s total urban area increased from 31,076 km2 in 2001 to 80,887 km2 in 2013, with an average annual growth rate of 13.36%. This widespread urban expansion consumed 33,080 km2 of agricultural land during this period. At a regional scale, the eastern region lost 18,542 km2 or 1.2% of its total agricultural land area. At a metropolitan scale, the Shanghai–Nanjing–Hangzhou (SNH) and Pearl River Delta (PRD) areas underwent high levels of agricultural land loss with a decrease of 6.12% (4728 km2) and 6.05% (2702 km2) of their total agricultural land areas, respectively. Special attention should be paid to the PRD, with a decline of 13.30% (1843 km2) of its cropland. Effective policies and strategies should be implemented to mitigate urbanization-related agricultural land loss in the context of China’s rapid urbanization

Interplay between Cell Migration and Neurite Outgrowth Determines SH2B1β-Enhanced Neurite Regeneration of Differentiated PC12 Cells

The regulation of neurite outgrowth is crucial in developing strategies to promote neurite regeneration after nerve injury and in degenerative diseases. In this study, we demonstrate that overexpression of an adaptor/scaffolding protein SH2B1β promotes neurite re-growth of differentiated PC12 cells, an established neuronal model, using wound healing (scraping) assays. Cell migration and the subsequent remodeling are crucial determinants during neurite regeneration. We provide evidence suggesting that overexpressing SH2B1β enhances protein kinase C (PKC)-dependent cell migration and phosphatidylinositol 3-kinase (PI3K)-AKT-, mitogen activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) kinase (MEK)-ERK-dependent neurite re-growth. Our results further reveal a cross-talk between pathways involving PKC and ERK1/2 in regulating neurite re-growth and cell migration. We conclude that temporal regulation of cell migration and neurite outgrowth by SH2B1β contributes to the enhanced regeneration of differentiated PC12 cells

Three Chinese pedigrees of A20 haploinsufficiency: clinical, cytokine and molecular characterization

ObjectiveHaploinsufficiency of A20 (HA20) is a newly described rare autoinflammatory disease caused by TNFAIP3 gene mutations. HA20 has seldom been documented in the Chinese population. Herein, we report eight patients with HA20 from three unrelated families in China.MethodsEight Chinese Han patients were diagnosed with HA20 in our department from 2018 to 2021. Their clinical data and genotypes were carefully documented and studied. The newly identified variants were functionally verified. We also conducted a systematic literature review of HA20, and the clinical characteristics and genotype of HA20 between the Chinese population and other populations were compared.ResultsEight HA20 patients from three families comprised six adults and two children. There was one man and seven women. The clinical characteristics included recurrent oral ulcers (8/8, 100%), fever (4/8, 50%), perianal ulcer (3/8, 38%), skin lesions (2/8, 25%), arthritis (1/8, 13%), and uveitis (1/8, 13%). Three TNFAIP3 variants, A547T, c.1906+2T&gt;G, and R271X, were identified. Two novel variants, A547T and c.1906+2T&gt;G, were validated to be pathogenic in our study. In a literature review a total of 126 patients with HA20 reported by 35 articles were included. The clinical phenotype of Chinese HA20 patients was similar to that of patients from other populations except for a lower frequency of genital ulcers (16.7% vs. 54.4%, p &lt; 0.01). Autoantibodies were detectable in approximately one-third of the 126 patients, among which ANA and anti-thyroid antibodies were commonly seen.ConclusionThe rarity and diversity of phenotypes make the diagnosis of HA20 a huge challenge to physicians. HA20 should be considered in child-onset patients with manifestations that resemble Behçet’s syndrome, especially those whose family members have similar symptoms. Gene testing is critically helpful for the diagnosis of HA20. Two novel TNFAIP3 variants, A547T and c.1906+2T&gt;G, were identified in this study

Double Trouble of Air Pollution by Anthropogenic Dust

With urbanization worldwide in recent decades, anthropogenic dust (AD) emissions due to heavy urban construction and off-road vehicle use have been increasing. Its perturbations on urban air pollution at the global scale are still unclear. Based on observations, we found that a high urban AD optical depth is often accompanied by severe non-dust aerosol optical depth in the planetary boundary layer (PBL), both magnitudes even comparable. To investigate the causes, an AD emission inventory constrained by satellite retrievals is implemented in a global climate model. The results show that AD-induced surface radiative cooling of up to -15.9 +/- 4.0 W m(-2) regionally leads to reduced PBL height, which deteriorates non-dust pollution, especially over India and northern China, in addition to the tremendous direct AD contribution to pollutants. The estimated global total premature mortality due to AD is 0.8 million deaths per year and is more severe in populous regions.Peer reviewe

A Survey on Evaluation of Large Language Models

Large language models (LLMs) are gaining increasing popularity in both academia and industry, owing to their unprecedented performance in various applications. As LLMs continue to play a vital role in both research and daily use, their evaluation becomes increasingly critical, not only at the task level, but also at the society level for better understanding of their potential risks. Over the past years, significant efforts have been made to examine LLMs from various perspectives. This paper presents a comprehensive review of these evaluation methods for LLMs, focusing on three key dimensions: what to evaluate, where to evaluate, and how to evaluate. Firstly, we provide an overview from the perspective of evaluation tasks, encompassing general natural language processing tasks, reasoning, medical usage, ethics, educations, natural and social sciences, agent applications, and other areas. Secondly, we answer the `where' and `how' questions by diving into the evaluation methods and benchmarks, which serve as crucial components in assessing performance of LLMs. Then, we summarize the success and failure cases of LLMs in different tasks. Finally, we shed light on several future challenges that lie ahead in LLMs evaluation. Our aim is to offer invaluable insights to researchers in the realm of LLMs evaluation, thereby aiding the development of more proficient LLMs. Our key point is that evaluation should be treated as an essential discipline to better assist the development of LLMs. We consistently maintain the related open-source materials at: https://github.com/MLGroupJLU/LLM-eval-survey.Comment: 23 page

The potential role of RNA N6-methyladenosine in primary Sjögren’s syndrome

ObjectiveThe pathogenesis of primary Sjögren’s syndrome (pSS) remains incompletely understood. The N6-methyladenosine (m6A) RNA modification, the most abundant internal transcript modification, has close associations with multiple diseases. This study aimed to investigate the role of m6A in patients with pSS.Materials and methodsThis study enrolled 44 patients with pSS, 50 age- and gender-matched healthy controls (HCs), and 11 age- and gender-matched patients with non-SS sicca. We detected the messenger RNA (mRNA) levels of m6A elements (including METTL3, WTAP, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2), ISG15, and USP18 in peripheral blood mononuclear cells (PBMCs) from patients with pSS, patients with non-SS sicca, and HCs. The clinical characteristics and laboratory findings of patients with pSS and patients with non-SS sicca were also collected. We used binary logistic regression to determine if m6A elements were risk factors for pSS.ResultsThe mRNA levels of m6A writers (METTL3 and RBM15), erasers (ALKBH5 and FTO), and readers (YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2) were all significantly higher in PBMCs from patients with pSS than in HCs. The mRNA levels of m6A writers (METTL3 and WTAP) and readers (YTHDF2, YTHDF3, and YTHDC2) were lower in PBMCs from patients with pSS compared to patients with non-SS sicca. The expression of METTL3, RBM15, FTO, YTHDF1, YTHDF2, YTHDC1, and YTHDC2 was positively correlated with the level of C-reactive protein (CRP) of patients with pSS. The mRNA level of YTHDF1 in PBMCs from patients with pSS was negatively correlated with the EULAR Sjögren’s syndrome disease activity index (ESSDAI) score. In patients with pSS, FTO, YTHDC1, and YTHDC2 were also related to white blood cells (WBCs), neutrophils, lymphocytes, and monocytes. Increased mRNA level of ALKBH5 in PBMCs was a risk factor for pSS, as determined by binary logistic regression analysis. The mRNA level of ISG15 was positively correlated with that of FTO, YTHDF2, YTHDF3, and YTHDC2 in patients with pSS.ConclusionCompared with HCs, the expression of METTL3, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 was considerably higher in PBMCs from patients with pSS. In comparison with patients with non-SS sicca, the expression of METTL3, WTAP, YTHDF2, YTHDF3, and YTHDC2 was reduced in PBMCs from patients with pSS. The m6A elements correlating with clinical variables may indicate the disease activity and inflammation status of pSS. Elevated expression of ALKBH5 was a risk factor for pSS. The dynamic process of m6A modification is active in pSS. m6A elements (FTO, YTHDF2, YTHDF3, or YTHDC2) might target ISG15, stimulate the expression of ISG15, and activate the type I IFN signaling pathway, playing an active role in initiating the autoimmunity in pSS