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1.
Cancer Discov ; 9(9): 1158-1160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31481404

RESUMO

In this issue of Cancer Discovery, Gu and colleagues developed a mouse model of myeloproliferative neoplasm driven by Nras G12D and Ezh2-/- , which cooperated to induce malignant transformation and metabolic reprogramming of leukemic stem cells at least in part through loss of normal epigenetic regulation of gene expression. Furthermore, their findings point to Ezh1 and branched chain amino acid metabolism as biological dependencies and potential therapeutic targets in myeloid neoplasms.See related article by Gu et al., p. 1228.

2.
Biosci Rep ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481525

RESUMO

OBJECTIVE: This study aimed to explore the relationship between Interleukin-17 receptor C (IL-17RC) gene polymorphism and ischemic stroke (IS). METHODS: 300 cases of IS patients and 300 cases of the healthy controls were selected. Serum of IS patients and the controls were collected. The relative mRNA levels of Interleukin (IL)-17, IL-17RC, IL-6, IL-8, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) by quantitative real time PCR (qRT-PCR). The protein expression of IL-17 and IL-17RC was determined by western blotting. IL-17RC genotype was identified by PCR amplification. The proportion of IL-17RC, single nucleotide polymorphism (SNP) and re37511 in IS and control group was determined. The treatment effect on IS and prognosis of patients with IL-17RC, SNP and re37511 was compared. RESULTS: The relative mRNA levels of IL-17, IL-17RC, IL-6, IL-8, G-CSF and GM-CSF in IS group were significantly higher than the control group. The protein expression of IL-17 and IL-17RC in IS group was also markedly higher than the control group. The proportion of IL-17RC re37511 in IS group was much larger than control group and proportion of IL-17RC much less. The percent of poor treatment effect in re37511 was much larger than IL-17RC. The percent of death and recrudescence in patients with IL-17RC re37511 was the highest. CONCLUSION: IS up-regulates the expression of IL-17 and IL-17RC. IL-17RC re37511 indicates the patients have a poorer treatment effect and prognosis.

3.
Cell Mol Immunol ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481754

RESUMO

Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.

4.
Acta Psychiatr Scand ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31483855

RESUMO

OBJECTIVE: About half or more of treatment-resistant depressed patients do not respond to ketamine, and few clinical predictors to gauge the most likely antidepressant response have been proposed. We explored whether depression subtypes are associated with response to ketamine. METHODS: Ninety-seven participants with depression were administered six repeated-dose intravenous ketamine and assessed for depression (Montgomery-Åsberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Rating Scale, HAMA), and suicidal ideation (Beck Scale for Suicidal Ideation, SSI) at baseline, 24 hours after each infusion, and 2 weeks after the whole treatment. Participants were classified by melancholic/anxious subtype. Individuals who met criteria for neither or both subtypes were classified separately, resulting in four mutually exclusive groups. RESULTS: Patients with melancholic or melancholic-anxious features were less likely to respond (e.g. day 13, melancholic-anxious vs. anxious, OR 0.138, 95% CI 0.032-0.584, p = 0.007) or remit (e.g. day 26, melancholic vs. no subtype, OR 0.182, 95% CI 0.035-0.960, p = 0.045) and took longer to achieve response/remission than those with anxious or no subtype features. Faster HAMA score reductions were observed in patients with anxious or melancholic-anxious features, and faster SSI score reductions were observed among those with melancholic-anxious features. CONCLUSIONS: Our study shows promising results for ketamine as a novel antidepressant preferentially for the treatment of non-melancholic or anxious depression. This article is protected by copyright. All rights reserved.

5.
Molecules ; 24(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484370

RESUMO

Sixteen new prenylated flavonoids, sinoflavonoids P-Z (1-11) and sinoflavonoids NA-NE (12-16), were isolated from the fruit of Sinopodophyllum hexandrum, along with eight known analogues (17-24). Their structures were elucidated on the basis of extensive spectroscopic data (HR-ESI-MS, 1H-NMR, 13C-NMR, HSQC, HMBC). The cytotoxic activities of compounds 1-18, 20, and 22 were evaluated by MTT assay. Compound 6 showed the most potent cytotoxicity in MCF-7, and HepG2 cell lines, with IC50 values of 6.25 and 3.83 µM, respectively.

6.
Eur Radiol ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31485837

RESUMO

OBJECTIVE: To investigate the natural history of persistent pulmonary pure ground-glass nodules (pGGNs) with deep learning-assisted nodule segmentation. METHODS: Between January 2007 and October 2018, 110 pGGNs from 110 patients with 573 follow-up CT scans were included in this retrospective study. pGGN automatic segmentation was performed on initial and all follow-up CT scans using the Dr. Wise system based on convolution neural networks. Subsequently, pGGN diameter, density, volume, mass, volume doubling time (VDT), and mass doubling time (MDT) were calculated automatically. Enrolled pGGNs were categorized into growth, 52 (47.3%), and non-growth, 58 (52.7%), groups according to volume growth. Kaplan-Meier analyses with the log-rank test and Cox proportional hazards regression analysis were conducted to analyze the cumulative percentages of pGGN growth and identify risk factors for growth. RESULTS: The mean follow-up period of the enrolled pGGNs was 48.7 ± 23.8 months. The median VDT of the 52 pGGNs having grown was 1448 (range, 339-8640) days, and their median MDT was 1332 (range, 290-38,912) days. The 12-month, 24.7-month, and 60.8-month cumulative percentages of pGGN growth were 10%, 25.5%, and 51.1%, respectively, and they significantly differed among the initial diameter, volume, and mass subgroups (all p < 0.001). The growth pattern of pGGNs may conform to the exponential model. Lobulated sign (p = 0.044), initial mean diameter (p < 0.001), volume (p = 0.003), and mass (p = 0.023) predicted pGGN growth. CONCLUSIONS: Persistent pGGNs showed an indolent course. Deep learning can assist in accurately elucidating the natural history of pGGNs. pGGNs with lobulated sign and larger initial diameter, volume, and mass are more likely to grow. KEY POINTS: • The pure ground-glass nodule (pGGN) segmentation accuracy of the Dr. Wise system based on convolution neural networks (CNNs) was 96.5% (573/594). • The median volume doubling time (VDT) of 52 pure ground-glass nodules (pGGNs) having grown was 1448 days (range, 339-8640 days), and their median mass doubling time (MDT) was 1332 days (range, 290-38,912 days). The mean time to growth in volume was 854 ± 675 days (range, 116-2856 days). • The 12-month, 24.7-month, and 60.8-month cumulative percentages of pGGN growth were 10%, 25.5%, and 51.1%, respectively, and they significantly differed among the initial diameter, volume, and mass subgroups (all p values < 0.001). The growth pattern of pure ground-glass nodules may conform to exponential model.

7.
J Clin Invest ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31487267

RESUMO

SAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERα to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF/galactosamine. In contrast, ERα agonist increased p53 and miR34a-5p which decreased SAB expression and hepatotoxicity in males. Hepatocyte-specific deletion of miR34a also increased severity of liver injury in females, which was prevented by GalNAc-ASO knockdown of Sab. Similar to mice, premenopausal human females also expressed high hepatic p53 and low SAB levels while age-matched males expressed low p53 and high SAB levels, but there was no sex difference of SAB expression in postmenopause. In conclusion, the level of SAB expression determined the severity of JNK dependent liver injury. Females expressed low hepatic SAB protein levels due to an ERα-p53-miR34a pathway which repressed SAB expression, accounting for resistance to liver injury.

8.
BMC Complement Altern Med ; 19(1): 244, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488111

RESUMO

BACKGROUND: Catalpol, a natural iridoid glycoside in Rehmannia glutinosa, can alleviate proteinuria associated with diabetic nephropathy (DN), however, whether catalpol has a protective effect against podocyte injury in DN remains unclear. METHODS: In this study, we used a high glucose (HG)-induced podocyte injury model to evaluate the protective effect and mechanism of catalpol against HG-induced podocyte injury. Cell viability was determined by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by commercial assay kits. Cell apoptosis and reactive oxygen species (ROS) were determined by using flow cytometry. Tumour necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) levels were determined by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl2-associated x (Bax), cleaved caspase-3, nicotinamide adenine dinucleotide phosphate oxidase enzyme 4 (NOX4), toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), p38 mitogen-activated protein kinase (p38 MAPK), phosphorylated p38 MAPK (p-p38 MAPK), nuclear factor kappa B inhibitor alpha (IκBα) and phosphorylated IκBα (p-IκBα) were measured by western blotting. In addition, Bcl-2, Bax, caspase-3 and nuclear factor kappa B (NF-κB) levels were determined by immunofluorescence staining. RESULTS: Catalpol significantly increased cell viability and decreased LDH release in HG-induced podocyte injury. Catalpol significantly decreased ROS generation, apoptosis, level of MDA, levels of inflammatory cytokine TNF-α, IL-1ß, and IL-6 and increased SOD activity in HG-induced podocyte injury. Moreover, catalpol significantly decreased expression of cleaved caspase-3, Bax, NOX4, TLR4, MyD88, p-p38 MAPK, p-IκBα and NF-κB nuclear translocation, as well as increased Bcl-2 expression in HG-induced podocyte injury. CONCLUSION: Catalpol can protect against podocyte injury by ameliorating apoptosis and inflammation. These protective effects may be attributed to the inhibition of NOX4, which alleviates ROS generation and suppression of the TLR4/MyD88 and p38 MAPK signaling pathways to prevent NF-κB activation. Therefore, catalpol could be a promising drug for the prevention of DN.

9.
Mol Psychiatry ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471575

RESUMO

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

10.
J Sci Food Agric ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31472017

RESUMO

BACKGROUND: Slight acidic electrolyzed water (SAEW) has been widely used in cleaning systems of fruit and vegetables. It strongly reduces microbial contamination. However, no information is available on whether SAEW offers the potential for fresh jujube cleaning. The purposes of this study were first, to compare the effectiveness of SAEW with commercial sanitizers (i.e. NaClO or Ca(ClO)2 ) on 'Jiancui' jujube; second, to determine the response of fruit decay, tissue alcium content, and quality attributes to dip application of Ca(NO3 )2 by concentration; and finally to investigate the effects of SAEW combined with calcium nitrate (Ca(NO3 )2 ) or calcium acetate (Ca(OAc)2 )) on fruit calcium uptake, quality attributes, and bioactive compounds. RESULTS: Fruits washed with NaClO, Ca(ClO)2 or an SAEW solution showed no difference in reduction of decay incidence. In contrast to NaClO treatment, SAEW or Ca(ClO)2 significantly retarded losses in fruit firmness (FF), green color (hue angle) and skin lightness (L*), and maintained intact pericarp tissue structure during storage at 1 °C. Application of Ca(NO3 )2 at 5-10 g L-1 effectively promoted Ca2+ uptake and minimized declines in FF and L* value, but had no effect on decay development. Adding 10 g L-1 Ca(NO3 )2 or Ca(OAc)2 to SAEW provided an additional benefit in increasing decay resistance, increasing Ca2+ into fruit, and increasing levels of bioactive compounds in jujube fruit. CONCLUSION: SAEW in combination with Ca(NO3 )2 or Ca(OAc)2 has commercial potential for fresh jujube disinfection and improving storage quality as a result of the cleaning processes. This article is protected by copyright. All rights reserved.

11.
Zhen Ci Yan Jiu ; 44(8): 547-53, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31475486

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) combined with rehabilitation training on regional cerebral blood flow (rCBF) and angiogenesis in rats with acute cerebral ischemia (ACI), so as to explore its mechanisms underlying improvement of ACI. METHODS: A total of 135 male SD rats were divided into 5 groups: sham-operation (sham), model, EA, rehabilitation training and EA+rehabilitation training (combined treatment) groups (n=27 rats in each group). The ACI model was established by occlusion of the middle cerebral artery with thread embolus. EA (2 Hz/20 Hz, 3-5 V) was applied to "Baihui" (GV20), "Shuigou" (GV26) and bilateral "Neiguan" (PC6) for 20 min, once daily for 14 days. The rehabilitation training including hair-brushing in an enriched environment (10 min), round wooden-stick turning (10 min), grid-board climbing (10 min), and treadmill running (30 min/d) was condacted once daily for 14 days. The rCBF was measured by Doppler ultrasound. The cerebral infarct volume (CIV) was measured after 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The expression of CD34+ in the ischemic penumbra region of brain tissue was detected by immunohistochemistry, and the expressions of angiogenesis-related factors as vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) proteins in the ischemic brain tissue were detected by Western blot. RESULTS: Following modeling, the rCBF levels at the 5 min, 3rd, 7th and 14th day were significantly decreased in the model group relevant to the sham group (P<0.01). After the intervention, the rCBF levels were significantly increased on day 3, 7 and 14 in the combined treatment group and on day 7 and 14 in both the EA and rehabilitation training groups in comparison with the model group (P<0.01). The CIV was obvious in the model group in comparison with the sham group (P<0.01), but was markedly smaller in the EA, rehabilitation training and combined treatment groups on day 3,7 and 14 than in the model group (P<0.01). The number of CD34+ positive cells, and the expression levels of VEGF, VEGFR2, and bFGF proteins in ischemic brain tissues were significantly higher on day 3, 7 and 14 in the model group than in the sham group (P<0.01, P<0.05), and were further up-regulated considerably at the 3 time-points in the 3 treatment groups (P<0.01, P<0.05). The therapeutic effect of EA+rehabilitation training was significantly superior to that of simple EA and simple rehabilitation training in up-regulating rCBF, CD34+ positive cell number, and expression levels of VEGF, VEGFR2 and bFGF, and in down-regulating the CIV on day 3,7 and 14 (P<0.05, P<0.01). No significant differences were found between the EA and rehabilitation groups in the above-mentioned 6 indexes (P>0.05). CONCLUSION: EA combined with rehabilitation training can reduce the infarct volume and increase rCBF in ACI rats, which is probably associated with its effects in promoting the expression of angiogenesis-related factors of ischemic brain tissues. The effect of EA combined with rehabilitation training is markedly better than that of EA and rehabilitation training alone.

12.
Cell Biol Int ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31475773

RESUMO

The transcription factor E2F4 is a key determinant of cell differentiation and cell cycle progression, but its function and regulatory mechanism are not completely understood. Here, we report that E2F4 acts as a positive regulator of the biosynthesis of milk components and proliferation of bovine mammary epithelial cells (BMECs). Overexpression of E2F4 in BMECs resulted in the upregulation of ß-casein, triglyceride, and lactose levels and increased cell proliferation, whereas E2F4 knockdown by siRNA had the opposite effects. We further detected that overexpression of E2F4 significantly increased the mRNA expression of mTOR, SREBP-1c, and Cyclin D1, and increased protein levels of SREBP-1c, and Cyclin D1, and the ratio of p-mTOR/mTOR, whereas E2F4 knockdown had the opposite effects. E2F4 was almost entirely located in the nucleus, and we further identified, via ChIP-qPCR analysis, that mTOR, SREBP-1c, and Cyclin D1 were E2F4 target genes, and exogenous administration of methionine, leucine, ß-estradiol, and prolactin markedly increased the protein levels of E2F4 and its binding to the promoters of these three genes. In summary, our data reveal that E2F4 responses to extracellular stimuli and regulates the expression of mTOR, SREBP-1c, and Cyclin D1 for milk biosynthesis and proliferation of BMECs. This article is protected by copyright. All rights reserved.

13.
J Agric Food Chem ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31475823

RESUMO

Amino acids can stimulate milk fat synthesis, but the underlying molecular mechanism is still largely unknown. In this study, we studied the regulatory role and corresponding molecular mechanism of cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) in amino acid-induced milk fat synthesis in mammary epithelial cells. We showed that leucine and methionine stimulated CRTC2 but not p-CRTC2(Ser171) expression and nuclear localization in cow mammary epithelial cells. Knockdown of CRTC2 decreased milk fat synthesis and sterol regulatory element binding protein 1c (SREBP-1c) expression and activation, whereas its overexpression had the opposite effects. Neither knockdown nor overexpression of CRTC2 affected ß-casein synthesis and phosphorylation of the machanistic target of rapamycin (mTOR), suggesting that CRTC2 only regulates milk fat synthesis. CRTC2 knockdown abolished the stimulation of leucine and methionine on SREBP-1c expression and activation. Knockdown or overexpression of CRTC2 did not affect the protein level of cAMP-response element-binding protein (CREB) and its phosphorylation, but decreased or increased the binding of p-CREB to the promoter of SREBP-1c gene and its mRNA expression, respectively. Mutation of Ser171 of CRTC2 did not alter the stimulation of CRTC2 on SREBP-1c expression and activation, further suggesting that CRTC2 functions in the nucleus. mTOR inhibition by rapamycin totally blocked the stimulation of leucine and methionine on CRTC2 expression. The expression of CRTC2 was dramatically higher in the mouse mammary gland of lactation period, compared with that of the dry and puberty periods, whereas p-CRTC2(Ser171) was not changed, further supporting that CRTC2 is a key transcription coactivator for milk fat synthesis. These results uncover that CRTC2 is a key transcription coactivator of amino acid-stimulated mTOR-mediated milk fat synthesis in mammary epithelial cells.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31363874

RESUMO

A Gram-stain negative, aerobic bacterium, designated strain YIM 78456T, was isolated from a hot spring sediment, Ngamring county, Tibet, south-west China. The taxonomic position of the isolate was investigated by a polyphasic approach. The novel isolate was found to be aerobic and rod-shaped. Colonies were observed to be pale yellow and circular. The strain was found to grow at pH 7.0-8.0 (optimum, pH 7.0), 45-65 °C (optimum, 55 °C) and in the presence of up to 1.5% NaCl. Comparison of the 16S rRNA gene sequence of strain YIM 78456T and other members of the genus Thermus showed sequence similarities ranging from 90.3 to 97.3%, with strain YIM 78456T showing close sequence similarity to Thermus caliditerrae YIM 77925T (97.3%). The phylogenetic trees based on 16S rRNA gene sequences showed that strain YIM 78456T forms a distinct clade with T. caliditerrae YIM 77925T. The predominant menaquinone was identified as MK-8 and the DNA G+C content was determined to be 65.1 mol%. The major cellular fatty acids (> 10%) were identified as iso-C15:0, anteiso-C15:0 and iso-C17:0. The polar lipids were found to consist of an aminophospholipid, a phospholipid and glycolipids. On the basis of the morphological and chemotaxonomic characteristics, as well as genotypic data, it is proposed that strain YIM 78456T represents a novel species of the genus Thermus, for which the name Thermus caldilimi sp. nov. is proposed. The type strain is YIM 78456T (= KCTC 52948T = NBRC 113036T).

15.
ACS Appl Mater Interfaces ; 11(34): 31237-31244, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31397997

RESUMO

Porous structure possesses full potentials to develop high-performance thermoelectric materials with low lattice thermal conductivity. In this study, the n-type porous nanostructured Bi2Te3 pellet is fabricated by sintering Bi2Te3 nanoplates synthesized with a facile solvothermal method. With adequate sublimations of Bi2TeO5 during the spark plasma sintering, homogeneously distributed pores and dense grain boundaries are successfully introduced into the Bi2Te3 matrix, causing strong phonon scatterings, from which an ultralow lattice thermal conductivity of <0.1 W m-1 K-1 is achieved in the porous nanostructured Bi2Te3 pellet. With the well-maintained decent electrical performance, a power factor of 10.57 µW cm-1 K-2 at 420 K, as well as the reduced lattice thermal conductivity, secured a promising zT value of 0.97 at 420 K, which is among the highest values reported for pure n-type Bi2Te3. This study provides the insight of realizing ultralow lattice thermal conductivity by synergistic phonon scatterings of pores and nanostructure in the n-type Bi2Te3-based thermoelectric materials.

16.
Sci Adv ; 5(8): eaax1101, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31453335

RESUMO

Meiosis is a specialized type of cell division that creates haploid germ cells and ensures their genetic diversity through homologous recombination. We show that the H3K4me3 reader ZCWPW1 is specifically required for meiosis prophase I progression in male but not in female germ cells in mice. Loss of Zcwpw1 in male mice caused a complete failure of synapsis, resulting in meiotic arrest at the zygotene to pachytene stage, accompanied by incomplete DNA double-strand break repair and lack of crossover formation, leading to male infertility. In oocytes, deletion of Zcwpw1 only somewhat slowed down meiosis prophase I progression; Zcwpw1-/- oocytes were able to complete meiosis, and Zcwpw1-/- female mice had normal fertility until mid-adulthood. We conclude that the H3K4me3 reader ZCWPW1 is indispensable for meiosis synapsis in males but is dispensable for females. Our results suggest that ZCWPW1 may represent a previously unknown, sex-dependent epigenetic regulator of germ cell meiosis in mammals.

17.
ISME J ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462715

RESUMO

Thaumarchaeota are responsible for a significant fraction of ammonia oxidation in the oceans and in soils that range from alkaline to acidic. However, the adaptive mechanisms underpinning their habitat expansion remain poorly understood. Here we show that expansion into acidic soils and the high pressures of the hadopelagic zone of the oceans is tightly linked to the acquisition of a variant of the energy-yielding ATPases via horizontal transfer. Whereas the ATPase genealogy of neutrophilic Thaumarchaeota is congruent with their organismal genealogy inferred from concatenated conserved proteins, a common clade of V-type ATPases unites phylogenetically distinct clades of acidophilic/acid-tolerant and piezophilic/piezotolerant species. A presumptive function of pumping cytoplasmic protons at low pH is consistent with the experimentally observed increased expression of the V-ATPase in an acid-tolerant thaumarchaeote at low pH. Consistently, heterologous expression of the thaumarchaeotal V-ATPase significantly increased the growth rate of E. coli at low pH. Its adaptive significance to growth in ocean trenches may relate to pressure-related changes in membrane structure in which this complex molecular machine must function. Together, our findings reveal that the habitat expansion of Thaumarchaeota is tightly correlated with extensive horizontal transfer of atp operons.

18.
Stem Cell Reports ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31447328

RESUMO

The mechanisms underlying the selective degeneration of medium spiny neurons (MSNs) in Huntington disease (HD) remain largely unknown. CTIP2, a transcription factor expressed by all MSNs, is implicated in HD pathogenesis because of its interactions with mutant huntingtin. Here, we report a key role for CTIP2 in protein phosphorylation via governing protein kinase A (PKA) signaling in human striatal neurons. Transcriptomic analysis of CTIP2-deficient MSNs implicates CTIP2 target genes at the heart of cAMP-Ca2+ signal integration in the PKA pathway. These findings are further supported by experimental evidence of a substantial reduction in phosphorylation of DARPP32 and GLUR1, two PKA targets in CTIP2-deficient MSNs. Moreover, we show that CTIP2-dependent dysregulation of protein phosphorylation is shared by HD hPSC-derived MSNs and striatal tissues of two HD mouse models. This study therefore establishes an essential role for CTIP2 in human MSN homeostasis and provides mechanistic and potential therapeutic insight into striatal neurodegeneration.

19.
Environ Sci Technol ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31442034

RESUMO

Metal contamination in soil, dust, and food matrices impacts the health of millions of people worldwide. During the past decades, various animal bioassays have been developed to determine relative bioavailability (RBA) of As, Pb, and Cd in contaminated soils, dust, and foods, which vary in operational approaches. This review discusses the strengths and weaknesses of different animal models (swine and mice), dosing schemes (single gavage dose, repeated gavage dose, daily repeated feeding, and free access to diet), and endpoints (blood, urine, and tissue) in metal-RBA measurement; compares metal-RBA obtained using mouse and swine bioassays, different dosing schemes, and different endpoints; and summarizes key findings on As-, Pb-, and Cd-RBA values in contaminated soils, dust, and foods. Future directions related to metal-RBA research are highlighted, including 1) comparison of metal-RBA determinations between different bioassays and different laboratories to ensure robust bioavailability data, 2) enhancing the metal-RBA database for contaminated dust and foods, 3) identification of physiological and physicochemical mechanisms responsible for variability in metal-RBA values, 4) formulation of strategies to decrease metal-RBA values in contaminated soils, dust, and foods, and 5) assessing the impacts of co-contaminants on metal-RBA measurement.

20.
Int J Nanomedicine ; 14: 5817-5829, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440049

RESUMO

Purpose: Acetylcholinesterase (AChE) plays a critical role in the transmission of nerve impulse at the cholinergic synapses. Design and synthesis of AChE inhibitors that increase the cholinergic transmission by blocking the degradation of acetylcholine can serve as a strategy for the treatment of AChE-associated disease. Herein, an operational targeted drug delivery platform based on AChE-responsive system has been presented by combining the unique properties of enzyme-controlled mesoporous silica nanoparticles (MSN) with clinical-used AChE inhibitor. Methods: Functionalized MSNs were synthesized by liquid phase method and characterized by using different analytical methods. The biocompatibility and cytotoxicity of MSNs were determined by hemolysis experiment and MTT assay, respectively. Comparison of AChE activity between drug-loading system and inhibitor was developed with kits and by ELISA method. The efficacy of drug-loaded nanocarriers was investigated in a mouse model. Results: Compared with AChE inhibitor itself, the inhibition efficiency of this drug delivery system was strongly dependent on the concentration of AChE. Only AChE with high concentration could cause the opening of pores in the MSN, leading to the controlled release of AChE inhibitor in disease condition. Critically, the drug delivery system can not only exhibit long duration of drug action on AChE inhibition but also reduce the hepatotoxicity in vivo. Conclusion: In summary, AChE-responsive drug release systems have been far less explored. Our results would shed lights on the design of enzyme controlled-release multifunctional system for enzyme-associated disease treatment.

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