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Obesity and major depressive disorder (MDD) are both significant health issues that have been increasing in prevalence and are associated with multiple comorbidities. Obesity and MDD have been shown to be bidirectionally associated, and they are both influenced by genetics and environmental factors. However, the molecular mechanisms that link these two diseases are not yet fully understood. It is possible that these diseases are connected through the actions of the cAMP/protein kinase A (PKA) pathway. Within this pathway, adenylate cyclase 3 ( Show less

Lipoprotein lipase (LPL) is a multifunctional protein that catalyzes the hydrolysis of plasma triglycerides, releasing free fatty acids, which play critical roles in the metabolism and transport of lipids. The transcription of Show less

Heat stress has deleterious effects on physiological and performance traits in livestock. Within this context, using tropically adapted cattle breeds in pure herds or terminal crossbreeding schemes to explore heterosis is attractive for increasing animal production in warmer climate regions. This study aimed to identify biological processes, pathways, and potential biomarkers related to thermotolerance in Caracu, a tropically adapted beef cattle breed, by proteomic analysis of blood plasma. To achieve this goal, 61 bulls had their thermotolerance evaluated through a heat tolerance index. A subset of 14 extreme animals, including the seven most thermotolerant (HIGH group) and the seven least thermotolerant (LOW group), had their blood plasma samples used for proteomic analysis by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The differentially regulated proteins detected between HIGH and LOW groups were used to perform functional enrichment analysis and a protein-protein interaction network analysis. A total of 217 proteins were detected only in the HIGH thermotolerant group and 51 only in the LOW thermotolerant group. In addition, 81 and 87 proteins had significantly higher and lower abundancies in the HIGH group, respectively. Regarding proteins with the highest absolute log-fold change values, we highlighted those encoded by DUSP5, IGFALS, ROCK2, RTN4, IRAG1, and NNT genes based on their functions. The functional enrichment analysis detected several biological processes, molecular functions, and pathways related to cellular responses to stress, immune system, complement system, and hemostasis in both HIGH and LOW groups, in addition to terms and pathways related to lipids and calcium only in the HIGH group. Protein-protein interaction (PPI) network revealed as important nodes many proteins with roles in response to stress, hemostasis, immune system, inflammation, and homeostasis. Additionally, proteins with high absolute log-fold change values and proteins detected as essential nodes by PPI analysis highlighted herein are potential biomarkers for thermotolerance, such as ADRA1A, APOA1, APOB, APOC3, C4BPA, CAT, CFB, CFH, CLU, CXADR, DNAJB1, DNAJC13, DUSP5, FGA, FGB, FGG, HBA, HBB, HP, HSPD1, IGFALS, IRAG1, KNG1, NNT, OSGIN1, PROC, PROS1, ROCK2, RTN4, RYR1, TGFB2, VLDLR, VTN, and VWF. Identifying potential biomarkers, molecular mechanisms and pathways that act in response to heat stress in tropically adapted beef cattle contributes to developing strategies to improve performance and welfare traits in livestock under tropical climates. Show less

We demonstrate a bipartition technique using a superlattice architecture to access correlations between alternating planes of a mesoscopic array of spin-3 chromium atoms trapped in a 3D optical lattice. Using this method, we observe that out-of-equilibrium dynamics driven by long-range dipolar interactions lead to spin anticorrelations between the two spatially separated subsystems. Our bipartite measurements reveal a subtle interplay between the anisotropy of the 3D dipolar interactions and that of the lattice structure, without requiring single-site addressing. We compare our results to theoretical predictions based on a truncated cumulant expansion and a new cluster semiclassical method that we use to investigate correlations at the microscopic scale. Comparison with a high-temperature analytical model reveals quantum thermalization at a high negative spin temperature. Show less

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients. Show less

Macroautophagy/autophagy research often involves overexpressing proteins to investigate their localization, function and activity. However, this approach can disturb the inherent balance of cellular components, potentially affecting the integrity of the autophagy process. With the advent of genome-editing techniques like CRISPR-Cas9, it is now possible to tag endogenous proteins with fluorescent markers, enabling the study of their behaviors under more physiologically relevant conditions. Nevertheless, conventional microscopy methods have limitations in characterizing the behaviors of proteins expressed at endogenous levels. This challenge can be overcome by single-molecule localization microscopy (SMLM) methods, which provide single-molecule sensitivity and super-resolution imaging capabilities. In our recent study, we used SMLM in combination with genome editing to explore the behavior of endogenous ULK1 during autophagy initiation, yielding unprecedented insights into the autophagy initiation process. Show less

Prediabetes is defined as a hyperglycemic state between normal glucose metabolism and diabetes mellitus. It is also recognized as a predisposing factor for cardiovascular disease. Apolipoprotein is a constituent of lipoproteins, and its ratio levels (ApoB/ApoA1 ratio) are considered an independent risk factor for cardiovascular diseases. This study aimed to evaluate the apolipoprotein ratio (ApoB/ApoA1 ratio) and lipoprotein ratio (low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio) in prediabetes in relation to glycemic levels and establish the association between apolipoprotein and lipoprotein ratios in prediabetic individuals and their glycemic levels. A case-control study was conducted among 150 participants, 75 with prediabetes and 75 apparently healthy individuals (with no prediabetes or diabetes), from January 1, 2023 to December 30, 2023. The parameters involved are fasting serum glucose, insulin, blood HbA1c%, HDL-C, LDL-C, apolipoprotein A, apolipoprotein B, and lipoprotein(a) (Lp(a)), measured using different principles. Prediabetes was more predominant in males (58.7%), particularly those aged over 40 years (74.7%). The mean Lp(a) (46.18±11.66 mg/dl), LDL-C/HDL-C ratio (1.74±0.96), and ApoB/ApoA ratio (1.10±0.62) were significantly higher among prediabetic individuals. Moreover, these ratios were insignificantly higher in prediabetic individuals with HbA1c level (5.8-6.4%) and fasting glucose level (100-125 mg/dl) than those with lower levels. Prediabetic individuals exhibited a notably elevated average level of Lp(a), as well as increased mean ApoB/ApoA1 ratio and mean LDL-C/HDL-C ratio compared to individuals who were apparently healthy. Show less

This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the A case-control study was conducted to investigate the association between CAD and Results of the polymorphism study indicated that the The Show less

Cardiovascular disease (CVD) is a leading cause of global mortality. Early intervention and prevention of CVD depend on accurately predicting the risk of CVD. This study aimed to investigate the association between the TyG index and the risk of coronary heart disease (CHD), congestive heart failure (CHF), heart attack (HA), stroke, and hypertension (HTN) among patients without diabetes in the United States. In this retrospective, cross-sectional study, we used data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2020. We conducted several regression analysis models and calculated the sensitivity and specificity of (TyG) index for predicting the onset of CHD, CHF, HA, stroke, and HTN. A total of 10,937 individuals without diabetes participated in our study. Individuals with a TyG index greater than 8.96 displayed significant increasing in various parameters, including BMI, systolic/diastolic blood pressure, total cholesterol, LDL, and Apo-B levels (p < 0.001). Almost all regression models ensured that a higher TyGI value was associated with higher odds of having CHD, CHF, HA, stroke, and HTN, which patients with a TyGI value higher than 8.96 have odds ratios of 2.24-5.58 for CHD, 1.68-4.42 for stroke, 2.45-3.77 for HA and 1.75-3.93 for HTN comparing than patients with a TyGI value lower than 8.11 (p-value < 0.05).We evaluated the predictive value of the TyG index for each endpoint, obtaining the following area under the curve (AUC) values: 54.75% for CHF (95% CI: 0.542-0.614), 52.32% for stroke (95% CI: 0.529-0.584), 55.67% for HA (95% CI: 0.595-0.646), 55.59% for HTN (95% CI: 0.574-0.597), and 50.31% for CHD (95% CI: 0.592-0.646). The TyG index showed a strong correlation with cardiovascular risk factors in individuals without diabetes, however it was a poor predictor of almost studied cardiovascular diseases. Show less

Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between Show less

Obesity is characterized by low-grade chronic inflammation, which can be modulated by lipid mediators derived from omega-3 ( To analyze the effect of an Seventy-six subjects with obesity were divided into two groups: omega-3 (1.5 g of The The diet supplemented with EPA and DHA is ideal for providing the direct products that bypass the synthesis step affected by the Show less

FADS1 rs174556 polymorphism influences on dietary fats metabolism and type 2 diabetes (T2DM). This study aimed to compare the effect of three oils of sesame, canola and sesame-canola on cardio metabolic factors across genotypes of rs174556 variant in patients with type 2 of diabetes. This study was a randomized triple-blind three-way cross-over clinical trial. 95 Subjects with T2DM replaced their regular dietary oil with sesame oil, canola oil, or sesame-canola oil for three 9-week phases and completed the study. There were three anthropometric measurements, blood sampling and biochemical assessments at the beginning, middle, and at the end of each phase for assessments. Genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In the crude model, there was an interaction between consumed oils and rs174556 variant on serum concentration of Apolipoprotein A-I (ApoA-1). During intake of sesame oil, lower levels of triglycerides (TG) were observed in individuals with TT genotype compared to C allele carriers' allele, which remained significant in adjusted models. Compared to C allele carrier's, the people with TT genotype experienced significant increase and decrease in serum levels of HDL and TG, respectively in adjusted models. Also, the subjects who consumed sesame-canola oil had lower serum concentrations of fasting blood glucose than those who received sesame and canola oils, regardless of used oils and genotypes. FADS1 Gene variant (rs174556) might modify cardiometabolic changes following dietary vegetable oils. Larger longitudinal studies especially randomized clinical trials are needed to clarify these associations. Show less

Renal tubular epithelial cells are vulnerable to stress-induced damage, including excessive lipid accumulation and aging, with ANGPTL4 potentially playing a crucial bridging role between these factors. In this study, RNA-sequencing was used to identify a marked increase in ANGPTL4 expression in kidneys of diet-induced obese and aging mice. Overexpression and knockout of ANGPTL4 in renal tubular epithelial cells (HK-2) was used to investigate the underlying mechanism. Subsequently, ANGPTL4 expression in plasma and kidney tissues of normal young controls and elderly individuals was analyzed using ELISA and immunohistochemical techniques. RNA sequencing results showed that ANGPTL4 expression was significantly upregulated in the kidney tissue of diet-induced obesity and aging mice. In vitro experiments demonstrated that overexpression of ANGPTL4 in HK-2 cells led to increased lipid deposition and senescence. Conversely, the absence of ANGPTL4 appears to alleviate the impact of free fatty acids (FFA) on aging in HK-2 cells. Additionally, aging HK-2 cells exhibited elevated ANGPTL4 expression, and stress response markers associated with cell cycle arrest. Furthermore, our clinical evidence revealed dysregulation of ANGPTL4 expression in serum and kidney tissue samples obtained from elderly individuals compared to young subjects. Our study findings indicate a potential association between ANGPTL4 and age-related metabolic disorders, as well as injury to renal tubular epithelial cells. This suggests that targeting ANGPTL4 could be a viable strategy for the clinical treatment of renal aging. Show less

Copy number alterations (CNAs) are significant in tumor initiation and progression. Identifying these aberrations is crucial for targeted therapies and personalized cancer diagnostics. Next-generation sequencing (NGS) methods present advantages in scalability and cost-effectiveness, surpassing limitations associated with reference assemblies and probe capacities in traditional laboratory approaches. This retrospective study evaluated CNAs in 50 FFPE tumor samples (breast cancer, ovarian carcinoma, pancreatic cancer, melanoma, and prostate carcinoma) using Illumina's TruSight Oncology 500 (TSO500) and the Affymetrix Oncoscan Molecular Inversion Probe (OS-MIP) (ThermoFisher Scientific, Waltham, MA, USA). NGS analysis with the NxClinical 6.2 software demonstrated a high sensitivity and specificity (100%) for CNA detection, with a complete concordance rate as compared to the OS-MIP. All 54 known CNAs were identified by NGS, with gains being the most prevalent (63%). Notable CNAs were observed in Show less

Glioblastoma is a highly aggressive brain tumour that creates an immunosuppressive microenvironment. Microglia, the brain's resident immune cells, play a crucial role in this environment. Glioblastoma cells can reprogramme microglia to create a supportive niche that promotes tumour growth. However, the mechanisms controlling the acquisition of a transcriptome associated with a tumour-supportive microglial reactive state are not fully understood. In this study, we investigated changes in the transcriptional profile of BV2 microglia exposed to C6 glioma cells. RNA-sequencing analysis revealed a significant upregulation of microglial inhibitor of DNA binding 1 (Id1) and Id2, helix-loop-helix negative transcription regulatory factors. The concomitant regulation of microglial ETS proto-oncogene 2, transcription factor (ETS2)-target genes, i.e., Dusp6, Fli1, Jun, Hmox1, and Stab1, led us to hypothesize that ETS2 could be regulated by ID proteins. In fact, ID2-ETS2 protein interactions increased in microglia exposed to glioma cells. In addition, perturbation of the ID2-ETS2 transcriptional axis influenced the acquisition of a microglial tumour-supportive phenotype. ID2 and ETS2 genes were found to be expressed by the tumour-associated microglia isolated from human glioblastoma tumour biopsies. Furthermore, ID2 and ETS2 gene expressions exhibited inverse prognostic values in patients with glioma in cohorts from The Cancer Genome Atlas. Collectively, our findings indicate that the regulation of ETS2 by ID2 plays a role in the transcriptional regulation of microglia in response to stimuli originating from glioblastoma cells, information that could lead to developing therapeutic strategies to manipulate microglial tumour-trophic functions. Show less

The vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), its nuclear receptor VDR (vitamin D receptor) and hundreds of their target genes are not only key regulators of calcium homeostasis, but also important modulators of the immune system. Innate immune cells like monocytes use VDR for efficient differentiation and are very responsive to vitamin D. So far, most information on the gene regulatory function of vitamin D and its physiological impact had been obtained from in vitro studies using supraphysiological doses of 1,25(OH)2D3. Therefore, medical experiments like the study VitDHiD (NCT03537027), where 25 healthy individuals were supplemented once with a vitamin D3 bolus (80,000 IU), provide important insight into the response to vitamin D under in vivo conditions. In this study, we inspected 452 in vivo vitamin D target genes from peripheral blood mononuclear cells (PBMCs) detected in VitDHiD and found 61 of them involved in eight major KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways of innate immunity. Under in vivo conditions in healthy individuals vitamin D either silences five pathways of innate immunity, stabilizes two and increases one, so that acute inflammation is suppressed and the release of cytokines is kept under control. A ranking of the 61 target genes by inducibility, basal expression and multiple involvements in the pathways highlighted the genes NFKBIA (NFκB inhibitor alpha), NFKBIZ, FOSL2 (FOS like 2, AP1 transcription factor subunit), JDP2 (Jun dimerization protein 2), PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1), CLEC7A (C-type lectin domain containing 7A), DUSP6 (dual specificity phosphatase 6), NCF2 (neutrophil cytosolic factor 2), PLCB1 (phospholipase C beta 1), PLCG2 and TNFAIP3 (TNF alpha induced protein 3). In conclusion, vitamin D's in vivo effect on innate immunity in healthy adults is mediated by the interconnection of the pathways of neutrophil extracellular trap formation, Toll-like receptor, chemokine and phagosome signaling, NOD-like receptor, C-type lectin receptor, apoptosis and interleukin 17 through a limited set of proteins encoded by key target genes. Show less

The endothelial glycocalyx, located at the luminal surface of the endothelium, plays an important role in the regulation of leukocyte adhesion, vascular permeability, and vascular homeostasis. Endomucin (EMCN), a component of the endothelial glycocalyx, is a mucin-like transmembrane glycoprotein selectively expressed by venous and capillary endothelium. We have previously shown that knockdown of EMCN impairs retinal vascular development in vivo and vascular endothelial growth factor 165 isoform (VEGF165)-induced cell migration, proliferation, and tube formation by human retinal endothelial cells in vitro and that EMCN is essential for VEGF165-stimulated clathrin-mediated endocytosis and signaling of VEGF receptor 2 (VEGFR2). Clathrin-mediated endocytosis is an essential step in receptor signaling and is of paramount importance for a number of receptors for growth factors involved in angiogenesis. In this study, we further investigated the molecular mechanism underlying EMCN's involvement in the regulation of VEGF-induced endocytosis. In addition, we examined the specificity of EMCN's role in angiogenesis-related cell surface receptor tyrosine kinase endocytosis and signaling. We identified that EMCN interacts with AP2 complex, which is essential for clathrin-mediated endocytosis. Lack of EMCN did not affect clathrin recruitment to the AP2 complex following VEGF stimulation, but it is necessary for the interaction between VEGFR2 and the AP2 complex during endocytosis. EMCN does not inhibit VEGFR1 and FGFR1 internalization or their downstream activities since EMCN interacts with VEGFR2 but not VEGFR1 or FGFR1. Additionally, EMCN also regulates VEGF121-induced VEGFR2 phosphorylation and internalization. Show less

The transcription factor achaete-scute complexhomolog 1 (ASCL1) is a lineage oncogene that is central in growth and survival of the majority of small cell lung cancers and neuroendocrine (NE) non-small cell lung cancers (NSCLC) that express it. Targeting ASCL1, or its downstream pathways, remains a challenge. Small cell lung cancers and NSCLC-NE that express ASCL1 exhibit relatively low ERK1/2 activity, in dramatic contrast to NSCLCs in which the ERK pathway plays a major role in pathogenesis. ERK1/2 inhibition in ASCL1-expressing lung tumor cells revealed downregulation of ERK1/2 pathway suppressors SPRY4, SPRED1, DUSP6, and the transcription factor ETV5, which regulates DUSP6. Chromatin immunoprecipitation sequencing demonstrated that these genes are bound by ASCL1. Availability of a pharmacologic inhibitor directed mechanistic studies toward DUSP6, an ERK1/2-selective phosphatase, in a subset of ASCL1-high NE lung tumors. Inhibition of DUSP6 increased active ERK1/2, which accumulated in the nucleus. Pharmacologic and genetic inhibition of DUSP6 reduced proliferation and survival of these cancers. Resistance developed in DUSP6-knockout cells, indicating a bypass mechanism. Although targeting ASCL1 remains a challenge, our findings suggest that expression of ASCL1, DUSP6, and low phospho-ERK1/2 identifies NE lung cancers for which DUSP6 may be a therapeutic target. Show less

Drinking alcohol is considered one of the risk factors for development of diabetes mellitus. Recently, it was reported that selenoprotein P levels in blood are increased by ethanol intake. However, the mechanism by which ethanol increases selenoprotein P has not been elucidated. The expression of selenoprotein P protein and its mRNA were increased in a concentration- and time-dependent manner when human liver-derived HepG2 cells were treated with ethanol. Levels of AMPK and JNK proteins, which have been known to regulate selenoprotein P transcription, were unchanged by ethanol treatment. However, the amount of nuclear FoxO3a, a transcription factor of SeP, was increased. This was associated with dephosphorylation of ERK1 but not ERK2. It was found that ERK1 was dephosphorylated by activation of dual-specific phosphatase 5 and dual-specific phosphatase 6. However, the phosphorylation of MEK by ERK phosphokinase was not affected by ethanol treatment. These results suggest that the ethanol-induced increase in SeP levels occurs by enhanced transcription of SeP mRNA via the DUSP5/6-ERK1-FoxO3a pathway. Show less

The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring Show less

Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens. Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB. We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure. Show less

Cancer immunotherapy is administered for first-line, second-line, neoadjuvant, or adjuvant treatment of advanced, metastatic, and recurrent cancer in the liver, gastrointestinal tract, and genitourinary tract, and other solid tumors. Erdafitinib is a fibroblast growth factor receptor (FGFR) inhibitor, and it is an adenosine triphosphate competitive inhibitor of FGFR1, FGFR2, FGFR3, and FGFR4. Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1 (PD-1) and its ligand that exert intrinsic antitumor mechanisms. The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents, indicate a new concept in the treatment of advanced, metastatic, and recurrent hepatic and gastrointestinal carcinomas. Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life. Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas, or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy. The literature in the field is not definite, and so far, there has been no consensus on the best approach in this situation. At present, as it is described in this editorial, the decision is applied on a case-by-case basis. Show less

Cancer is rarely the straightforward consequence of an abnormality in a single gene, but rather reflects a complex interplay of many genes, represented as gene modules. Here, we leverage the recent advances of model-agnostic interpretation approach and develop CGMega, an explainable and graph attention-based deep learning framework to perform cancer gene module dissection. CGMega outperforms current approaches in cancer gene prediction, and it provides a promising approach to integrate multi-omics information. We apply CGMega to breast cancer cell line and acute myeloid leukemia (AML) patients, and we uncover the high-order gene module formed by ErbB family and tumor factors NRG1, PPM1A and DLG2. We identify 396 candidate AML genes, and observe the enrichment of either known AML genes or candidate AML genes in a single gene module. We also identify patient-specific AML genes and associated gene modules. Together, these results indicate that CGMega can be used to dissect cancer gene modules, and provide high-order mechanistic insights into cancer development and heterogeneity. Show less

The retina is composed of neuronal layers that include several types of interneurons and photoreceptor cells, and separate underlying retinal pigment epithelium (RPE), Bruch's membrane, and choroid. Different regions of the human retina include the fovea, macula, and periphery, which have unique physiological functions and anatomical features. These regions are also unique in their protein expression, and corresponding cellular and molecular responses to physiological and pathophysiological stimuli. Skeie and Mahajan analyzed regional protein expression in the human choroid-RPE complex. Mitogen-Activated Protein Kinase (MAPK) signaling pathways have been implicated in responses to stimuli such as oxidative stress and inflammation, which are critical factors in retina diseases including age-related macular degeneration. We, therefore, analyzed the Skeie and Mahajan, 2014, dataset for regional differences in the expression of MAPK-related proteins and discussed the potential implications in retinal diseases presenting with regional signs and symptoms. Regional protein expression data from the Skeie and Mahajan, 2014, study were analyzed for members of signaling networks involving MAPK and MAPK-related proteins, categorized by specific MAPK cascades, such as p38, ERK1/2, and JNK1/2, both upstream or downstream of the respective MAPK and MAPK-related proteins. We were able to identify 207 MAPK and MAPK-related proteins, 187 of which belonging to specific MAPK cascades. A total of 31 of these had been identified in the retina with two proteins, DLG2 and FLG downstream, and the other 29 upstream, of MAPK proteins. Our findings provide evidence for potential molecular substrates of retina region-specific disease manifestation and potential new targets for therapeutics development. Show less

Hepatitis B is a significant public health issue worldwide. Long noncoding RNAs (lncRNAs) are pivotal in biological mechanisms. The involvement of lncRNAs in hepatitis Hepatitis B remains incompletely understood. This study sought to explore the potential of certain lncRNAs as diagnostic and prognostic markers in hepatitis B, and their ability to differentiate between clinical disease subgroups. Plasma samples from 204 individuals diagnosed with hepatitis B were meticulously examined for the presence of specific lncRNAs, focusing on those known to be associated with hepatitis B as indicated in the literature. In this study, gene expression levels of 14 lncRNAs were analyzed in three subgroups (chronic, recovered and inactive HBsAg carriers) and compared with those in the healthy control group. The downregulation of the RN7SL1 and Alpha-280 genes in all patients indicates potential diagnostic lncRNAs. ZFHX2-AS1 expression was consistently lower in all subgroups, while SRA1 showed high expression in recovered hepatitis B patients, indicating that it is a descriptive marker. DLG2-AS2 expression increased in the chronic hepatitis B but decreased in the other groups. These findings reveal the prognostic importance of lncRNAs in hepatitis B. The expression levels of ZFHX2-AS1, RN7SL1, PCAT-1, PCA3, SRA1 and Alpha-280 have been identified as crucial biomarkers for the diagnosis of hepatitis B and for distinguishing between its clinical subgroups. A strong association between hepatitis B disease and the gene expression of the DLG2-AS2, HOTTIP, HOTAIRM1, HOXA11-AS, NOS2P3, LINC02665, MEG9, and RNY5 lncRNAs has been suggested. Show less

27 years after the yeast genome sequencing, the function of many ORFs remain unknown. Despite the evolutionary distance between human and yeast, homology with the conserved DEAH/DExH-box helicase domains allowed us to list DHX29, DHX36 and DHX57 as three putative homologs of the yeast Ylr419wp. Functional studies first linked the Ylr419w protein to the translating ribosome and cross-linking and analysis of cDNA (CRAC) experiments determined the precise region of Ylr419wp in contact with the ribosome. It corresponds to the loop of the h16 helix in the 18S rRNA designing the translation initiation factor DHX29, as the functional homolog of Ylr419wp. Show less

Blood composition is indicative of health-related traits such as immunity and metabolism. The use of molecular genetics to investigate alterations in these attributes in laying ducks is a novel approach. Our objective was to employ genome - wide association studies (GWAS) and haplotype - sharing analysis to identify genomic regions and potential genes associated with 11 blood components in Shaoxing ducks. Our findings revealed 35 SNPs and 1 SNP associated with low-density lipoprotein cholesterol (LDL) and globulin (GLB), respectively. We identified 36 putative candidate genes for the LDL trait in close proximity to major QTLs and key loci. Based on their biochemical and physiological properties, Show less

RNA Guanine-quadruplexes (rG4s) are important nucleic acid structures that govern vital biological processes. Although numerous tools have been developed to target rG4s, few specific tools are capable of discerning individual rG4 of interest. Herein, we design and synthesize the first L-aptamer-antisense oligonucleotide (ASO) conjugate, L-Apt.4-1c-ASO15nt(APP), with a focus on recognizing the amyloid precursor protein (APP) rG4 region as an example. The L-aptamer module binds with the rG4 structure, whereas ASO hybridizes with flanking sequences. Together, these two modules enhance the precise recognition of APP rG4. We demonstrate that the L-Apt.4-1c-ASO15nt(APP) conjugate can interact with the APP rG4 region with sub-nanomolar binding affinity, and distinguish APP rG4 from other G4s and non-G4s in vitro and in cells. We also show that L-Apt.4-1c-ASO15nt(APP) can inhibit APP protein expression. Notably, we investigate the inhibitory mechanism of this newly developed tool, and reveal that it controls gene expression by hindering DHX36 protein from unraveling the rG4, as well as by promoting translational inhibition and RNase H-mediated mRNA knockdown activity. Our novel L-aptamer-ASO conjugate tool not only enables the specific recognition of rG4 region of interest, but also allows efficient gene control via targeting rG4-containing transcripts in cells. Show less