UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.

The H3K27 lysine-specific demethylase UTX is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through non-catalytic functions, a property shared with its catalytically inactive Y-chromosome paralogue, UTY. In keeping with this, we demonstrate concomitant loss/mutation of UTX and UTY in multiple human cancers. Mechanistically, global genomic profiling revealed only minor changes in H3K27Me3, but significant and bidirectional alterations of H3K27Ac and chromatin accessibility, a predominant loss of H3K4Me1 modifications, alterations in ETS and GATA factor binding and altered gene expression upon Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programsThis study was primarily funded by a joint Bloodwise Program Grant (17006) to B.H. and G.S.V. Work in the Huntly lab is also funded by an ERC consolidator award (grant 647685 COMAL), a CRUK program award, the Medical Research Council, (MRC) the Welcome Trust (WT) and the Cambridge NIHR BRC. We acknowledge the WT/MRC center grant (097922/Z/11/Z) and support from WT strategic award 100140. G.S.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). The Vassiliou laboratory is also supported by the Kay Kendall Leukemia Fund and core funding from the Sanger Institute (WT098051)

What motivates farmers to adopt low-carbon agricultural technologies? Empirical evidence from thousands of rice farmers in Hubei province, central China

Low-carbon agriculture is essential for protecting the global climate and sustainable agricultural economics. Since China is a predominantly agricultural country, the adoption of low-carbon agricultural technologies by local farmers is crucial. The past literature on low-carbon technologies has highlighted the influence of demographic, economic, and environmental factors, while the psychological factors have been underexplored. A questionnaire-based approach was used to assess the psychological process underlying the adoption of low-carbon agricultural technologies by 1,114 Chinese rice farmers in this paper, and structural equation modeling (SEM) was empirically employed to test our theoretical model

Sedative-sparing effect of acupuncture in gastrointestinal endoscopy: systematic review and meta-analysis

ObjectiveThis study aimed to perform a systematic review and meta-analysis to identify the efficacy of acupuncture therapy (including manual acupuncture and electroacupuncture) performed before or during gastrointestinal endoscopy with propofol as the main sedative, compared with placebo, sham acupuncture, or no additional treatment other than the same sedation.MethodsA systematic search was performed through PubMed, Embase, Web of Science, Cochrane Library, Chinese Biomedical Databases (CBM), Wanfang database, China National Knowledge Infrastructure (CNKI), SinoMed, and Chinese Scientific Journal Database (VIP) to collect randomized controlled trials published before 5 November 2022. Bias assessment of the included RCTs was performed according to Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). Stata16.0 software was used to perform statistical analysis, sensitivity analysis, and publication bias analysis. The primary outcome was sedative consumption, and the secondary outcomes included the incidence of adverse events and wake-up time.ResultsA total of 10 studies with 1331 participants were included. The results showed that sedative consumption [mean difference (MD) = −29.32, 95% CI (−36.13, −22.50), P < 0.001], wake-up time [MD = −3.87, 95% CI (−5.43, −2.31), P < 0.001] and the incidence of adverse events including hypotension, nausea and vomiting, and coughing (P < 0.05) were significantly lower in the intervention group than in the control group.ConclusionAcupuncture combined with sedation reduces sedative consumption and wake-up time compared with sedation alone in gastrointestinal endoscopy; this combined approach allows patients to regain consciousness more quickly after examination and lower the risk of adverse effects. However, with the limited quantity and quality of relevant clinical studies, caution must be applied until more high-quality clinical studies verify and refine the conclusions.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?, identifier: CRD42022370422

Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies.

Cohesin complex disruption alters gene expression, and cohesin mutations are common in myeloid neoplasia, suggesting a critical role in hematopoiesis. Here, we explore cohesin dynamics and regulation of hematopoietic stem cell homeostasis and differentiation. Cohesin binding increases at active regulatory elements only during erythroid differentiation. Prior binding of the repressive Ets transcription factor Etv6 predicts cohesin binding at these elements and Etv6 interacts with cohesin at chromatin. Depletion of cohesin severely impairs erythroid differentiation, particularly at Etv6-prebound loci, but augments self-renewal programs. Together with corroborative findings in acute myeloid leukemia and myelodysplastic syndrome patient samples, these data suggest cohesin-mediated alleviation of Etv6 repression is required for dynamic expression at critical erythroid genes during differentiation and how this may be perturbed in myeloid malignancies

Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective: Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods: Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by nextgeneration sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results: Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions: The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH. Arch Endocrinol Metab. 2016;60(4):323-

Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.

FLT3 internal tandem duplication (FLT3ITD) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation-driven leukemias.P.G. is funded by the Wellcome Trust (109967/Z/15/Z) and was previously supported by the Academy of medical Sciences and Lady Tata Memorial Trust. The Huntly lab is funded by European Research Council, MRC, Bloodwise, the Kay Kendall Leukaemia Fund, the Cambridge NIHR Biomedical Research Centre, and core support grants to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute. C.F. and A.S.H.C are funded by the Medical Research Council, Core Grant to the Cancer Unit. P.M-P. is supported by a grant from Cancer Research UK (C56179/A21617). D.S. is a Postdoctoral Fellow of the Mildred-Scheel Organisation, German Cancer Aid. This research was supported by the CIMR Flow Cytometry Core Facility. We would like to thank the Welcome Trust Sanger Institute facility for the MiSeq run

Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective: Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods: Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by next-generation sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results: Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions: The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH

Myristate and the ecology of AM fungi : significance, opportunities, applications and challenges

A recent study by Sugiura and coworkers reported the nonsymbiotic growth and spore production of an arbuscular mycorrhizal (AM) fungus, Rhizophagus irregularis, when the fungus received an external supply of certain fatty acids, myristates (C:14). This discovery follows the insight that AM fungi receive fatty acids from their hosts when in symbiosis. If this result holds up and can be repeated under nonsterile conditions and with a broader range of fungi, it has numerous consequences for our understanding of AM fungal ecology, from the level of the fungus, at the plant community level, and to functional consequences in ecosystems. In addition, myristate may open up several avenues from a more applied perspective, including improved fungal culture and supplementation of AM fungi or inoculum in the field. We here map these potential opportunities, and additionally offer thoughts on potential risks of this potentially new technology. Lastly, we discuss the specific research challenges that need to be overcome to come to an understanding of the potential role of myristate in AM ecology