ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress.

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.

Immunological dynamic characteristics in acute myeloid leukemia predict the long-term outcomes and graft-versus host-disease occurrences post-transplantation.

To investigate the relationship between immune dynamic and graft-versus-host-disease (GVHD) risk, 111 initial diagnostic acute myeloid leukemia patients were reviewed. The flow cytometry data of 12 major lymphocyte subsets in bone marrow (BM) from 60 transplant patients at four different time points were analyzed. Additionally, 90 immune subsets in peripheral blood (PB) of 11 post-transplantation on day 100 were reviewed. Our results demonstrated that transplant patients had longer OS compared to non-transplant patients (P < 0.001). Among transplant patients, those who developed GVHD showed longer OS than those without GVHD (P < 0.05). URD donors and CMV-negative status donors were associated with improved OS in transplant patients (P < 0.05). Importantly, we observed a decreased Th/Tc ratio in BM at initial diagnostic in patients with GVHD compared to those without GVHD (P = 0.034). Receiver operating characteristic analysis indicated that a low Th/Tc ratio predicted an increased risk of GVHD with a sensitivity of 44.44% and specificity of 87.50%. Moreover, an increased T/NK ratio in BM of post-induction chemotherapy was found to be associated with GVHD, with a sensitivity of 75.76% and specificity of 65.22%. Additionally, we observed a decreased percentage of NK1 (CD56-CD16+NK) in PB on day 100 post-transplantation in the GVHD group (P < 0.05). These three indicators exhibit promising potential as specific and useful biomarkers for predicting GVHD. These findings provide valuable insights for the early identification and management of GVHD risk, thereby facilitating the possibility of improving patient outcomes.

Performance Evaluation of a Novel Artificial Intelligence-Assisted Digital Microscopy System for the Routine Analysis of Bone Marrow Aspirates.

Bone marrow aspiration (BMA) smear analysis is essential for diagnosis, treatment, and monitoring of a variety of benign and neoplastic hematological conditions. Currently, this analysis is performed by manual microscopy. We conducted a multicenter study to validate a computational microscopy approach with an artificial intelligence-driven decision support system. A total of 795 BMA specimens (615 Romanowsky-stained and 180 Prussian blue-stained) from patients with neoplastic and other clinical conditions were analyzed, comparing the performance of the Scopio Labs X100 Full Field BMA system (test method) with manual microscopy (reference method). The system provided an average of 1,385 ± 536 (range, 0-3,131) cells per specimen for analysis. An average of 39.98 ± 19.64 fields of view (range, 0-140) per specimen were selected by the system for analysis, of them 87% ± 21% (range, 0%-100%) were accepted by the qualified operators. These regions were included in an average of 17.62 ± 7.24 regions of interest (range, 1-50) per specimen. The efficiency, sensitivity, and specificity for primary and secondary marrow aspirate characteristics (maturation, morphology, and count assessment), as well as overall interuser agreement, were evaluated. The test method showed a high correlation with the reference method for comprehensive BMA evaluation, both on Romanowsky- (90.85% efficiency, 81.61% sensitivity, and 92.88% specificity) and Prussian blue-stained samples (90.0% efficiency, 81.94% sensitivity, and 93.38% specificity). The overall agreement between the test and reference methods for BMA assessment was 91.1%. For repeatability and reproducibility, all standard deviations and coefficients of variation values were below the predefined acceptance criteria both for discrete measurements (coefficient of variation below 20%) and differential measurements (SD below 5%). The high degree of correlation between the digital decision support system and manual microscopy demonstrates the potential of this system to provide a high-quality, accurate digital BMA analysis, expediting expert review and diagnosis of BMA specimens, with practical applications including remote BMA evaluation and possibly new opportunities for the research of normal and neoplastic hematopoiesis.

Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways.

BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

Programmable Thermo-Responsive Actuation of Hydrogels via Light-Guided Surface Growth of Active Layers on Shape Memory Substrates.

Hydrogel shape memory and actuating functionalities are heavily pursued and have found great potential in various application fields. However, their combination for more flexible and complicated morphing behaviors is still challenging. Herein, it is reported that by controlling the light-initiated polymerization of active hydrogel layers on shape memory hydrogel substrates, advanced morphing behaviors based on programmable hydrogel shapes and actuating trajectories are realized. The formation and photo-reduction-induced dissociation of Fe3+ -carboxylate coordination endow the hydrogel substrates with the shape memory functionality. The photo-reduced Fe2+ ions can diffuse from the substrates into the monomer solutions to initiate the polymerization of the thermally responsive active layers, whose actuating temperatures and amplitudes can be facially tuned by controlling their thicknesses and compositions. One potential application, a shape-programmable 3D hook that can lift an object with a specific shape, is also unveiled. The demonstrated strategy is extendable to other hydrogel systems to realize more versatile and complicated actuating behaviors.

Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately four new cases per 100,000 persons per year. Standard treatment for AML consists of induction chemotherapy with remission achieved in 50 to 75% of cases. Unfortunately, most patients will relapse and die from their disease, as 5-y survival is roughly 29%. Therefore, other treatment options are urgently needed. In recent years, immune-based therapies have led to unprecedented rates of survival among patients with some advanced cancers. Suppression of T cell function in the tumor microenvironment is commonly observed and may play a role in AML. We found that there is a significant association between T cell infiltration in the bone marrow microenvironment of newly diagnosed patients with AML and increased overall survival. Functional studies aimed at establishing the degree of T cell suppression in patients with AML revealed impaired T cell function in many patients. In most cases, T cell proliferation could be restored by blocking the immune checkpoint molecules PD-1, CTLA-4, or TIM3. Our data demonstrate that AML establishes an immune suppressive environment in the bone marrow, in part through T cell checkpoint function.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

A mixed blessing for liver transplantation patients - Rapamycin.

BACKGROUND: Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES: In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS: Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS: Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.

Phylogenetic analyses of 41 Y-STRs and machine learning-based haplogroup prediction in the Qingdao Han population from Shandong province, Eastern China.

BACKGROUND: Known for its rich history and culture, Qingdao is a typical symbol of Chinese maritime culture. Its unique genetic landscape has aroused interest among geneticists and forensic scientists. However, the genetic landscape of Qingdao has never been uncovered. AIM: This investigation intends to provide light on Qingdao's paternal genetic diversity and its evolutionary connections to other Han subgroups. SUBJECTS AND METHODS: The genetic polymorphisms of 41 Y-chromosomal short tandem repeat (STR) loci in the Qingdao Han were investigated using SureID® PathFinder Plus Kit. Phylogenetic studies were performed using genotype data from 52 East Asian groups at 23 common Y-STR loci. A multidimensional scaling plot and cladogram were constructed. Linear Discriminant Analysis (LDA) was carried out for predicting categories among the Han people. The k-nearest neighbour (kNN) algorithm was utilised to designate Y-SNP haplogroups for each haplotype. RESULTS: The Qingdao Han were genetically far from the Tibeto-Burman populations and close with the Han people from northern China. LDA indicated a deep integration among the present-day Han people. By the kNN model, the predicted O2a2 and O2a1 were shown to be the predominant Y-SNP haplogroups. CONCLUSIONS: This study would be helpful for reconstructing the patrilineal history in China and establishing a more comprehensive Y-STR database.

Cytogenetically Cryptic Acute Promyelocytic Leukemia: A Diagnostic Challenge.

Cytogenetically cryptic acute promyelocytic leukemia (APL) is rare, characterized by typical clinical and morphological features, but lacks t(15;17)(q24;q21)/PML::RARA translocation seen in conventional karyotyping or FISH. The prompt diagnosis and treatment of APL are critical due to life-threatening complications associated with this disease. However, cryptic APL cases remain a diagnostic challenge that could mislead the appropriate treatment. We describe four cryptic APL cases and review reported cases in the literature. Reverse transcriptase polymerase chain reaction (RT-PCR) is the most efficient diagnostic modality to detect these cases, and alternative methods are also discussed. This study highlights the importance of using parallel testing methods to diagnose cryptic APL cases accurately and effectively.

Phylogenetic analyses of the 19 STR loci in X chromosome revealed discriminant forensic characteristics for Chinese Daur and Oroqen minorities.

In respect of forensic genetics, X-STRs are widely applied for deficiency paternity cases. Given the popularization of AGCU-X19 STR Kit in China, there has been investigation conducted into the genetic data and forensic parameters of 19 X-STR loci in many of the Chinese ethnic groups, which makes it possible to perform nationwide phylogenetic comparation. To evaluate the allele and haplotype diversity of 19 X-STR loci and to explore their forensic efficiency in the Daur and Oroqen minorities, unrelated healthy Daur (n = 86) and Oroqen (n = 165) individuals were recruited from Heilongjiang province, so as to reveal the phylogenetic relationship between the two minorities and other Chinese ethnic groups. Of the Daur and Oroqen minorities, 172 and 183 alleles at the 19 X-STR loci were observed, respectively. Haplotype diversity exceeded 0.9 among all the linkage clusters. High cumulative value was observed for the power of discrimination, the probability of exclusion, and the mean exclusion chance for deficiency cases (normal trios and duo cases). As revealed by this study, the panel of 19 X-STR loci is an effective supplementary tool for the kinship test of the studied nationalities.

Construction of Cu(I)-Organic Frameworks with Effective Sorption Behavior for Iodine and Congo Red.

The assembly of a tetradentate pyridine-derived ligand with CuX has afforded two isostructural Cu(I)-organic frameworks [Cu2X2(TBD)·DMF]n (X = Cl for 1 and Br for 2) in this work. Structural analysis indicates that the compounds feature hybrid layered architectures, and the three-dimensional supramolecular frameworks are finally fabricated through the alternative stacking of adjacent layers wherein large open channels are simultaneously constructed. The chemical stability has been studied showing the excellent skeleton maintenance of the prepared solids in various solvents and even in water. Moreover, the iodine and dye sorption performance for compound 1 has been further tested. The Cu(I)-based metal-organic framework exhibits outstanding sorption and separation abilities on the targeted species, which could be considered as a promising adsorbent with high efficiency and selectivity.

Differentiation of leukemic blasts is not completely blocked in acute myeloid leukemia.

Hematopoiesis, the formation of blood cells, involves the hierarchical differentiation of immature blast cells into mature, functional cell types and lineages of the immune system. Hematopoietic stem cells precisely regulate self-renewal versus differentiation to balance the production of blood cells and maintenance of the stem cell pool. The canonical view of acute myeloid leukemia (AML) is that it results from a combination of molecular events in a hematopoietic stem cell that block differentiation and drive proliferation. These events result in the accumulation of primitive hematopoietic blast cells in the blood and bone marrow. We used mathematical modeling to determine the impact of varying differentiation rates on myeloblastic accumulation. Our model shows that, instead of the commonly held belief that AML results from a complete block of differentiation of the hematopoietic stem cell, even a slight skewing of the fraction of cells that differentiate would produce an accumulation of blasts. We confirmed this model by interphase fluorescent in situ hybridization (FISH) and sequencing of purified cell populations from patients with AML, which showed that different leukemia-causing molecular abnormalities typically thought to block differentiation were consistently present in mature myeloid cells such as neutrophils and monocytes at similar levels to those in immature myeloid cells. These findings suggest reduced or skewed, rather than blocked, differentiation is responsible for the development of AML. Approaches that restore normal regulation of hematopoiesis could be effective treatment strategies.

[Germplasm resource evaluation of Chrysanthemi Indici Flos based on color and chemical components].

This study explored the correlation between color and chemical components of Chrysanthemi Indici Flos(CIF), aiming at providing a reference for its procurement, evaluation, and breeding. Colorimeter and ultra-performance liquid chromatograph(UPLC) were used to determine the color(lightness-shade chromaticity value L~*, red-green chromaticity value a~*, yellow-blue chromati-city value b~*) and chemical components(cynaroside, linarin, luteolin, apigenin, and chlorogenic acid) of 84 CIF germplasms, respectively. Diversity analysis, correlation analysis, regression analysis, and cluster analysis were performed. The results showed that the color and chemical components of CIF were diversified. Chlorogenic acid was in significantly positive correlation with L~* and b~* and significantly negative correlation with a~*. Cynaroside and grey relational grade γ_i of chemical components were in significantly po-sitive correlation with b~* and L~*, respectively, whereas linarin, luteolin, and apigenin had no significant correlation with L~*, a~*, or b~*. The 84 CIF germplasms were clustered into 4 clades. In addition, germplasms in clade Ⅲ had higher γ_i and total color value(E~*_(ab)) than those in other clades, with the best quality and color, and a germplasm with the highest quality, bright yellow color, and highest content of linarin was screened out in this clade. Thus, CIF with bright yellow color had high content of cymaroside and chlorogenic acid and thereby high quality. In summary, the color can be used to quickly predict the quality of CIF. Our results provided data for the evaluation of CIF quality by color and a reference for its procurement and breeding.

A novel somatic PLCG2 variant associated with resistance to BTK and SYK inhibition in chronic lymphocytic leukemia.

The treatment of chronic lymphocytic leukemia (CLL) has been transformed by the use of targeted small molecules inhibiting components of the B cell receptor (BCR) signaling pathway (Haematologica, 103, 2018 and e204; Curr Hematol Malig Rep, 14, 2019, 302). Chief among these is ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), which produces deep, durable responses in CLL with good tolerability (Haematologica, 103, 2018 and e204). Though prolonged exposure to the drug can exert selective pressure on CLL cells and allow for the emergence of drug-resistant clones, primary ibrutinib treatment failure is rare (Expert Rev Hematol, 11 and 2018, 185; N Engl J Med, 370, 2014 and 2352; N Engl J Med, 373, 2015 and 25, 2425; Blood, 128, 2016 and 2199). Activating mutations in the gene PLCG2, which encodes a downstream target of BTK, appear to enable constitutive BCR signaling and have been associated with ibrutinib resistance (Int J Cancer, 146 and 2020, 85; J Clin Oncol, 35, 2017 and 1437; Blood, 126, 2015 and 61). In recent years, novel investigational agents have targeted other components of the BCR pathway. Among these is entospletinib, an orally bioavailable, selective inhibitor of splenic tyrosine kinase (SYK) (Blood, 126, 2015 and 1744), which lies upstream of the enzyme phospholipase C-gamma-2 (PLCG2). Here, we describe a patient who was found to harbor a novel somatic variant of PLCG2 and experienced a lack of treatment response to both ibrutinib and entospletinib.

Metal-Free Synthesis of Heteroaryl Amines or Their Hydrochlorides via an External-Base-Free and Solvent-Free C-N Coupling Protocol.

Herein, a metal-free and solvent-free protocol was developed for the C-N coupling of heteroaryl halides and amines, which afforded numerous heteroaryl amines or their hydrochlorides without any external base. Further investigations elucidated that the basicity of amines and specific interactions derived from the X-ray crystallography analysis of 3j'·HCl played pivotal roles in the reactions. Moreover, this protocol was scalable to gram scales and applicable to drug molecules, which demonstrated its practical value for further applications.

Forensic and phylogenetic analyses of populations in the Tibetan-Yi corridor using 41 Y-STRs.

Y-chromosome haplotypes of 527 non-related males (176 Han, 186 Tibetan, and 165 Yi) in the Tibetan-Yi corridor were analyzed using SureID® PathFinder Plus. In the populations of Han, Tibetans, and Yi, the haplotype diversity was 0.9989, 0.9981, and 0.9993, respectively, and the discrimination capacity was 0.9148, 0.8925, and 0.9576, respectively. Phylogenetic relationships among 12 studied ethnic groups and 7 other ethnic groups in the Tibetan-Yi corridor were investigated. Both multi-dimensional scaling analysis and phylogenetic reconstructions indicated that Tibetans appeared separated from the Han and Yi ethnic groups in the Tibetan-Yi corridor. Their genetic homogeneity or heterogeneity has not entirely been affected by their geographical distance and linguistic origin.

Key factors and potential drug combinations of nonalcoholic steatohepatitis: Bioinformatic analysis and experimental validation-based study.

BACKGROUND: Nonalcoholic fatty liver disease and its advanced stage, nonalcoholic steatohepatitis (NASH), are the major cause of hepatocellular carcinoma (HCC) and other end-stage liver disease. However, the potential mechanism and therapeutic strategies have not been clarified. This study aimed to identify potential roles of miRNA/mRNA axis in the pathogenesis and drug combinations in the treatment of NASH. METHODS: Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R. Then we obtained differentially expressed genes (DE-genes). DAVID database was used for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. Protein-protein interaction (PPI) networks were used for the identification of hub genes. We found upstream regulators of hub genes using miRTarBase. The expression and correlation of key miRNA and its targets were detected by qPCR. Drug Pair Seeker was employed to predict drug combinations against NASH. The expression of miRNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database. RESULTS: Ninety-four DE-genes were accessed. GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism. Eleven genes were identified as hub genes in PPI networks, and they were highly expressed in cells with vigorous lipid metabolism. hsa-miR-335-5p was the upstream regulator of 9 genes in the 11 hub genes, and it was identified as a key miRNA. The hub genes were highly expressed in NASH models, while hsa-miR-335-5p was lowly expressed. The correlation of miRNA-mRNA was established by qPCR. Functional verification indicated that hsa-miR-335-5p had inhibitory effect on the development of NASH. Finally, drug combinations were predicted and the expression of miRNA and hub genes in HCC was identified. CONCLUSIONS: In the study, potential miRNA-mRNA pathways related to NASH were identified. Targeting these pathways may be novel strategies against NASH.

Gene flow and phylogenetic analyses of paternal lineages in the Yi-Luo valley using Y-STR genetic markers.

BACKGROUND: The Yi-Luo valley witnessed the most significant socio-political transformation of China and was deeply implicated in several enormous migrations of the Han population. However, little has been done to clarify its paternal genetic variation or phylogenetic relationship, particularly concerning the genetic evidence of their migrations. AIM: This study aims to uncover the population genetic characteristics in the Yi-Luo valley and provide genetic evidence for its people's migrations. SUBJECTS AND METHODS: Seventeen Y-STR loci included in the AmpFlSTR®Yfiler™ were typed in 2,314 individuals from seven different regions along the Yi-Luo valley. A multidimensional scaling plot and neighbor-joining tree were constructed for nationwide genetic comparisons. Y-haplogroup frequencies and migration rates were estimated among the studied populations. Gene flows were detected by different migration models and directions. RESULTS: The predicted Y-haplogroups demonstrated the predominance of O2a2. Genetic affinities were observed among Han, Hakka, Danmin, and Bai. Anhui was shown to be the most crucial transfer spot for the Hakkas when they moved out of the Central Plains to South China. CONCLUSIONS: This study reveals the genetic landscape of paternal lineages living in the Yi-Luo valley and enriches our understanding of the great migration in Chinese history.