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Grain and flag leaf size are two important agronomic traits that influence grain yield in rice (Oryza sativa). Many QTLs and genes that regulate these traits individually have been identified, however, few QTLs and genes that simultaneously control these two traits have been identified. In this study, we conducted a genome-wide association analysis in rice and detected a major locus, WIDTH OF LEAF AND GRAIN (WLG), that associated with both grain and flag leaf width. WLG encodes a RING-domain E3 ubiquitin ligase. WLGhap.B, which possesses five SNP variations compared to WLGhap.A, encodes a protein with enhanced ubiquitination activity that confers increased rice leaf width and grain size, whereas mutation of WLG leads to narrower leaves and smaller grains. Both WLGhap.A and WLGhap.B interact with LARGE2, a HETC-type E3 ligase, however, WLGhap.B exhibits stronger interaction with LARGE2, thus higher ubiquitination activity towards LARGE2 compared with WLGhap.A. Lysine1021 is crucial for the ubiquitination of LARGE2 by WLG. Loss-of-function of LARGE2 in wlg-1 phenocopies large2-c in grain and leaf width, suggesting that WLG acts upstream of LARGE2. These findings reveal the genetic and molecular mechanism by which the WLG-LARGE2 module mediates grain and leaf size in rice, and suggest the potential of WLGhap.B in improving rice yield.
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Drought stress inhibits plant growth and agricultural production. Improving plant instantaneous water use efficiency (iWUE), which is strictly regulated by stomata, is an effective way to cope with drought stress. However, the mechanisms of iWUE regulation are poorly understood. Through genetic screening for suppressors of mpk12-4, an Arabidopsis (Arabidopsis thaliana) mutant with a major iWUE quantitative trait locus gene MITOGEN-ACTIVATED PROTEIN KINASE12 deleted, we identified HIGH LEAF TEMPERATURE1 (HT1). Genetic interaction and physiological analyses showed that MPK12 controls iWUE through multiple modules in a high CO2-induced stomatal closing pathway that regulate SLOW ANION CHANNEL-ASSOCIATED1 (SLAC1) activity. HT1 acts downstream of MPK12, whereas OPEN STOMATA1 (OST1) and GUARD CELL HYDROGEN PEROXIDE-RESISTANT1 (GHR1) function downstream of HT1 by activating SLAC1 in iWUE. Photosynthetic-CO2 response curves and biomass analyses under different water-supply conditions showed that HT1 dysfunction improved iWUE and also increased plant growth capacity, and products of HT1 putative orthologs from Brassica (Brassica napus) and rice (Oryza sativa) exhibited functions similar to that of Arabidopsis HT1 in iWUE and the CO2-signaling pathway. Our study revealed the mechanism of MPK12-mediated iWUE regulation in Arabidopsis and provided insight into the internal relationship between iWUE and CO2 signaling in guard cells and a potential target for improving crop iWUE and drought tolerance.
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OBJECTIVES: To analyse the prevalence of pathogenic variants in DEPDC5, NPRL2 and NPRL3 that encode the GATOR1 (GTPase-activating protein towards the Rags 1) complex, a modulator in the mammalian target of rapamycin (mTOR) pathway, and to define the characteristics of GATOR1-associated epilepsy. METHODS: Clinical details and whole-exome sequencing data of 170 novel probands with lesional or non-lesional epilepsy were retrieved. Candidate variants in GATOR1 genes were verified by Sanger sequencing, and cosegregate analysis was performed. The pathogenicity of variants and their effect on mTOR signalling were investigated. RESULTS: Two novel frameshift variants and one recurrent nonsense variant were detected in DEPDC5, with a prevalence of 1.8% (3 out of 170) in the whole cohort and 3.1% (3 out of 97) in focal epilepsies. These variants cosegregated in pedigrees with epilepsy, respectively. Rare missense variants in NPRL2 and NPRL3 did not segregate with epilepsy in families, respectively. Epileptic phenotypes of 21 patients with DEPDC5 variants showed focal seizures with non-lesional variable foci that were predominantly sleep-related, with a median onset age of 10 years (range 1-30). Seizure outcome was variable. About 24% of patients were drug-resistant, and seizure attacks were absent in 33% of variant carriers. Of 13 patients who experienced seizures, 54% tended to resolve spontaneously. Functional assessments showed that the three variants affected DEPDC5 expression. These loss-of-function (LoF) variants affected the DEPDC5-dependent inhibition of mTOR. CONCLUSIONS: Patients carrying DEPDC5-LoF variants might show a high prevalence of focal seizures with a dynamic phenotype, indicating reduced penetrance and self-resolving features. The associated epilepsy was caused by loss of inhibition of the mTOR pathway. The pathogenicity of missense variants in GATOR1 genes should be cautiously evaluated.
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Epilepsias Parciais , Epilepsia , Humanos , Epilepsias Parciais/genética , Epilepsia/epidemiologia , Epilepsia/genética , Proteínas Ativadoras de GTPase/genética , Mutação/genética , Convulsões/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
CoSb3 shows intrinsically excellent electric transport performance but high thermal conductivity, resulting in low thermoelectric performance. The use of graphene to form heterogeneous interfaces shows great potential for significantly lessening the lattice thermal conductivity (κL) in CoSb3-based composites. Molecular dynamics (MD) simulations are carried out in the present work to study the interfacial thermal conductance across the CoSb3-graphene interface in the temperature range of 300 K to 800 K. The interfacial thermal conductance exhibits irregular fluctuations with temperature and CoSb3 length. Furthermore, we explored the effect of graphene layers on the interfacial heat transport of the CoSb3-graphene system. The results demonstrate that graphene layers affect the interfacial thermal conductance due to the suppression of heat flux in multilayer graphene across the c-axis. The phonon density of states (PDOS) of the CoSb3-graphene system reveals a decreased low-frequency vibration mode at 0-7 THz and an enhanced high-frequency vibration mode compared with those of CoSb3, indicating that thermal transport can be effectively suppressed by the addition of graphene.
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Tuberous sclerosis complex (TSC) is mainly caused by variants in TSC1 and TSC2, which encodes hamartin protein and tuberin protein, respectively. Here, we report clinical and molecular characteristics of 18 families with TSC. High-throughput DNA sequencing was employed to detect variants in all the exons and flanking region of TSC1 and TSC2. TA clone and real-time PCR were performed to verify the pathogenicity of candidate variants. A total of 17 mutations were identified, including 13 mutations in TSC2 and 4 mutations in TSC1. Fifty-six percent (10/18) of the families carried de novo mutations, and 8 of these mutations were not reported previously. Most mutations detected were loss-of-function mutations (15/17). One splice-site mutation (TSC2 c.599 + 5G > A) caused abnormal splicing and was confirmed by in vitro analysis. Facial angiofibromas (94%) and epilepsy (89%) were the most prevalent clinical features in our patients. Treatment with anti-seizure medication (ASM) or in combination with rapamycin results in clinical remission in most patients with TSC-associated seizures (14/15). For genotype-phenotype correlation, patients in our cohort with TSC2 mutations had an earlier onset age and patients with TSC1 showed better response to ASM. Our study has expanded the spectrum of TSC1 and TSC2 causing TSC.
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Esclerose Tuberosa , Análise Mutacional de DNA/métodos , Éxons/genética , Humanos , Mutação , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Anxiety disorder is characterized by excessive fear, anxiety, and avoidance of perceived threats in internal to oneself or the environment, however, the underlying mechanisms are less well understood. Here, we show that transforming growth factor-ß-activated kinase 1 (Tak1) expressed in the astrocytes of mediobasal hypothalamus (MBH) plays a crucial role in anxiety-like behavior in mice. Our data demonstrate that deficiency of Tak1 in astrocytes increased anxiety level, but did not impact locomotor activity in mice. Astrocytic activation of Tak1 in the MBH mitigated the anxiety-like behavior, whereas suppression of Tak1 in MBH astrocytes promoted the anxiety-like behavior in mice. Collectively, these data suggest that Tak1 expressed in the MBH astrocytes could modulate the anxiety-like behavior in mice.
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Astrócitos , Hipotálamo , Animais , Ansiedade , CamundongosRESUMO
BACKGROUND: Paroxysmal kinesigenic dyskinesia is a spectrum of involuntary dyskinetic disorders with high clinical and genetic heterogeneity. Mutations in proline-rich transmembrane protein 2 have been identified as the major pathogenic factor. OBJECTIVES: We analyzed 600 paroxysmal kinesigenic dyskinesia patients nationwide who were identified by the China Paroxysmal Dyskinesia Collaborative Group to summarize the clinical phenotypes and genetic features of paroxysmal kinesigenic dyskinesia in China and to provide new thoughts on diagnosis and therapy. METHODS: The China Paroxysmal Dyskinesia Collaborative Group was composed of departments of neurology from 22 hospitals. Clinical manifestations and proline-rich transmembrane protein 2 screening results were recorded using unified paroxysmal kinesigenic dyskinesia registration forms. Genotype-phenotype correlation analyses were conducted in patients with and without proline-rich transmembrane protein 2 mutations. High-knee exercises were applied in partial patients as a new diagnostic test to induce attacks. RESULTS: Kinesigenic triggers, male predilection, dystonic attacks, aura, complicated forms of paroxysmal kinesigenic dyskinesia, clustering in patients with family history, and dramatic responses to antiepileptic treatment were the prominent features in this multicenter study. Clinical analysis showed that proline-rich transmembrane protein 2 mutation carriers were prone to present at a younger age and have longer attack duration, bilateral limb involvement, choreic attacks, a complicated form of paroxysmal kinesigenic dyskinesia, family history, and more forms of dyskinesia. The new high-knee-exercise test efficiently induced attacks and could assist in diagnosis. CONCLUSIONS: We propose recommendations regarding diagnostic criteria for paroxysmal kinesigenic dyskinesia based on this large clinical study of paroxysmal kinesigenic dyskinesia. The findings offered some new insights into the diagnosis and treatment of paroxysmal kinesigenic dyskinesia and might help in building standardized paroxysmal kinesigenic dyskinesia clinical evaluations and therapies. © 2020 International Parkinson and Movement Disorder Society.
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Distonia , China , Distonia/genética , Humanos , Masculino , Mutação/genética , Proteínas do Tecido Nervoso/genética , FenótipoRESUMO
The hypothalamus in the brain plays a pivotal role in controlling energy balance in vertebrates. Nutritional excess through high-fat diet (HFD) feeding can dysregulate hypothalamic signaling at multiple levels. Yet, it remains largely unknown in what magnitude HFD feeding may impact epigenetics in this brain region. Here, it is shown that HFD feeding can significantly alter hypothalamic epigenetic events, including posttranslational histone modifications, DNA methylation, and chromatin accessibility. The authors comprehensively analyze the chromatin immunoprecipitation-sequencing (ChIP-seq), methylated DNA immunoprecipitation-sequencing (MeDIP-seq), single nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), and RNA-seq data of the hypothalamus of C57 BL/6 mice fed with a chow or HFD for 1 to 6 months. The chromatins are categorized into 6 states using the obtained ChIP-seq data for H3K4me3, H3K27ac, H3K9me3, H3K27me3, and H3K36me3. A 1-month HFD feeding dysregulates histone modifications and DNA methylation more pronouncedly than that of 3- or 6-month. Besides, HFD feeding differentially impacts chromatin accessibility in hypothalamic cells. Thus, the epigenetic landscape is dysregulated in the hypothalamus of dietary obesity mice.
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Metilação de DNA , Obesidade , Camundongos , Animais , Obesidade/genética , Metilação de DNA/genética , Cromatina , Hipotálamo , Epigênese Genética/genéticaRESUMO
Silicon carbide (SiC) is a promising material for thermoelectric power generation. The characterization of thermal transport properties is essential to understanding their applications in thermoelectric devices. The existence of stacking faults, which originate from the "wrong" stacking sequences of Si-C bilayers, is a general feature of SiC. However, the effects of stacking faults on the thermal properties of SiC are not well understood. In this study, we evaluated the accuracy of Tersoff, MEAM, and GW potentials in describing the thermal transport of SiC. Additionally, the thermal conductivity of 3C/4H-SiC nanowires was investigated using non-equilibrium molecular dynamics simulations (NEMD). Our results show that thermal conductivity exhibits an increase and then saturation as the total lengths of the 3C/4H-SiC nanowires vary from 23.9 nm to 95.6 nm, showing the size effect of molecular dynamics simulations of the thermal conductivity. There is a minimum thermal conductivity, as a function of uniform period length, of the 3C/4H-SiC nanowires. However, the thermal conductivities of nanowires weakly depend on the gradient period lengths and the ratio of 3C/4H. Additionally, the thermal conductivity of 3C/4H-SiC nanowires decreases continuously from compressive strain to tensile strain. The reduction in thermal conductivity suggests that 3C/4H-SiC nanowires have potential applications in advanced thermoelectric devices. Our study provides insights into the thermal transport properties of SiC nanowires and can guide the development of SiC-based thermoelectric materials.
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OBJECTIVE: DNA methylation has been identified to play an important role in amyotrophic lateral sclerosis (ALS). Galectin-1, encoded by LGALS1 gene, has been proved to be associated with ALS. We aimed to investigate the association between the expression and methylation of LGALS1 in blood samples from ALS patients. METHODS: Forty-five patients diagnosed with ALS were enrolled. Thirty-two healthy relatives consisted the control group. Among them, samples from 12 patients and 12 controls consisted the exploration samples. In the exploration samples, mRNA expression levels were detected by quantitative real-time PCR. In all the samples, DNA methylation levels of one CpG island containing 12 CpG sites in the gene promoter were detected by bisulfite sequencing PCR, and galectin-1 levels were examined by enzyme linked immunosorbent assay. Associations between the gene expression and methylation level, as well as between the region-specific methylation level and clinical variables were calculated. RESULTS: The mRNA expression level of LGALS1 was significantly increased and the promoter of LGALS1 was hypomethylated in ALS patients. Serum galectin-1 levels were significantly elevated in the ALS patients. The ALS group had significantly lower methylation level at certain CpG sites than the control group. There were significant negative associations between abnormal expression and methylation of LGALS1, as well as between region-specific methylation levels and the age of onset. CONCLUSIONS: The aberrant expression and DNA methylation of LGALS1 and their association reveals epigenetic changes in ALS patients, which are helpful for early intervention and treatment for the disease.
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Esclerose Lateral Amiotrófica , Metilação de DNA , Galectina 1/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Ilhas de CpG , Galectina 1/metabolismo , Humanos , RNA Mensageiro/metabolismoRESUMO
Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of the central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological, and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of ß2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, for example, celastrol, might be a novel strategy for colorectal cancer treatment.
Colorectal (or 'bowel') cancer killed nearly a million people in 2018 alone: it is, in fact, the second leading cause of cancer death globally. Lifestyle factors and inflammatory bowel conditions such as chronic colitis can heighten the risk of developing the disease. However, research has also linked to the development of colorectal tumours to stress, anxiety and depression. This 'brain-gut' connection is particularly less-well understood. One brain region of interest is the hypothalamus, an almond-sized area which helps to regulate mood and bodily processes using chemical messengers that act on various cells in the body. For instance, Oxt neurons in the hypothalamus produce the hormone oxytocin which regulates emotional and social behaviours. These cells play an important role in modulating anxiety, stress and depression. To investigate whether they could also influence the growth of colorectal tumours, Pan et al. used various approaches to manipulate the activity of Oxt neurons in mice with colitis-associated cancer. Disrupting the Oxt neurons in these animals increased anxiety-like behaviours and promoted tumour growth. Stimulating these cells, on the other hand, suppressed cancer progression. Further experiments also showed that treating the mice with celastrol, a plant extract which can act on the hypothalamus, stimulated Oxt neurons and reduced tumour growth. In particular, the compound worked by acting on a nerve structure in the abdomen which relays messages to the gut. These preliminary findings suggest that the hypothalamus and its Oxt-producing neurons may influence the progression of colorectal cancer in mice by regulating the activity of an abdominal 'hub' of the nervous system. Modulating the activity of Oxt-producing neurons could therefore be a potential avenue for treatment.
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Neoplasias Colorretais/patologia , Hipotálamo/fisiologia , Ocitocina/fisiologia , Triterpenos Pentacíclicos/farmacologia , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana/toxicidade , Hipotálamo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ocitocina/metabolismoRESUMO
Store-operated calcium entry (SOCE) is pivotal in maintaining intracellular Ca2+ level and cell function; however, its role in obesity development remains largely unknown. Here, we show that the stromal interaction molecule 1 (Stim1), an endoplasmic reticulum (ER) Ca2+ sensor for SOCE, is critically involved in obesity development. Pharmacological blockade of SOCE in the brain, or disruption of Stim1 in hypothalamic agouti-related peptide (AgRP)-producing neurons (ASKO), significantly ameliorates dietary obesity and its associated metabolic disorders. Conversely, constitutive activation of Stim1 in AgRP neurons leads to an obesity-like phenotype. We show that the blockade of SOCE suppresses general translation in neuronal cells via the 2',5'-oligoadenylate synthetase 3 (Oas3)-RNase L signaling. While Oas3 overexpression in AgRP neurons protects mice against dietary obesity, deactivation of RNase L in these neurons significantly abolishes the effect of ASKO. These findings highlight an important role of Stim1 and SOCE in the development of obesity.
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Proteína Relacionada com Agouti/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Obesidade/prevenção & controle , Molécula 1 de Interação Estromal/deficiência , 2',5'-Oligoadenilato Sintetase/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Linhagem Celular Tumoral , Dieta Hiperlipídica , Modelos Animais de Doenças , Endorribonucleases/metabolismo , Células HEK293 , Humanos , Hipotálamo/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Molécula 1 de Interação Estromal/genética , Aumento de PesoRESUMO
BACKGROUND: Mutations in the SPAST gene are the most frequent cause of hereditary spastic paraplegia (HSP). We aim to extend the mutation spectrum of spastic paraplegia 4 (SPG4) and carried out experiment in vitro to explore the influence of the SPAST gene mutation on the function of corresponding protein. METHODS: Whole-exome sequencing (WES) combined with multiplex ligation-dependent probe amplification (MLPA) were performed in a cohort of 150 patients clinically diagnosed with HSP. We focus on screening for mutations in SPAST gene and carrying out functional experiments to assess the effects of the novel variants. RESULTS: A total of 34 different mutations in the SPAST gene were identified, of which 10 were novel, including 1 missense (c.1479T > A), 1 nonsense (c.766G > T), 3 splicing (c.1413 + 1_1413+4delGTAA, c.1729-1G > A and c.1536+2T > G) and 5 frameshift mutations (c.1094delC, c.885dupA, c.517_518delAG, c.280delG and c.908dupC). For 7 novel non-splicing mutations, functional study showed that accumulated M1 spastin colcocalized with microtubules which was different from a uniformly diffused M87 spastin. While an impairment in severing activity was observed in both mutant M1 and mutant M87, except for c.280delG. All 3 novel splicing variants w ere predicted to affect splicing by using bioinformatic programs. However, only c.1536+2T > G had no influence on splice site in vitro, which conflicts with the in-silico analysis. CONCLUSION: We genetically diagnosed 40 SPG4 patients. All the novel non-splicing mutations except for c.280delG were certified to exert an effect on the microtubule-severing and all the novel splicing mutations other than c.1536+2T > G would cause abnormal splicing of the spastin.
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Paraplegia/genética , Paraplegia Espástica Hereditária/genética , Espastina/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Mutação , Sequenciamento do Exoma , Adulto JovemRESUMO
A porous TiO2/BaTiO3 heterostructure composite has been developed as a polysulfide mediator for lithium-sulfur batteries. Superior electrochemical performance has been achieved, mainly attributed to the synergy of TiO2 and BaTiO3 with dual affinity to polysulfides from chemical and ferroelectric-induced polarization effects, and enhanced redox kinetics propelled by the TiO2/BaTiO3 heterojunctions.
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Vanadium oxides are promising anode materials for lithium-ion batteries (LIBs) due to their high capacity, good safety, and low cost. However, their practical application has been deferred by the poor rate capability and cycling stability. In this work, we report the designed synthesis of porous V2O3/VO2@carbon heterostructure electrode for high-performance LIBs. The synergic effects of porous nanostructures, phase hybridization with self-building electric field at heterointerface, and conductive carbon implantation effectively enhance the electronic/ionic conduction and buffer the volume variation in the composite material. Electrochemical tests reveal that the composite electrode exhibits high Li-ion storage capacities of 503 and 453 mAh/g at 100 and 500 mA/g, as well as good cycling stability with a retained capacity of 569 mAh/g over 105 cycles at 100 mA/g. In-depth kinetics analysis discloses that pseudocapacitive Li-ion storage process dominates in the composite electrode, which is probably enabled by efficient coupling of the heterostructure components. The strategy of in situ carbon implantation and phase hybridization presented herein may be extended to other electrode materials for rechargeable batteries with superior electrochemical properties.