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1.
Comput Biol Med ; 135: 104550, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34147856

RESUMO

SARS-CoV-2 has caused a worldwide epidemic of coronavirus disease 19 (COVID-19). Antibody drugs present an effective weapon for tens of millions of COVID-19 patients. Antibodies disrupting the interactions between the receptor-binding domain (RBD) of SARS-CoV-2 S protein and the angiotensin converting enzyme 2 (ACE2) effectively block SARS-CoV-2 cell entry into host cells. In order to rapidly develop more potent neutralizing antibodies, we utilized virtual scanning mutageneses and molecular dynamics simulations to optimize the antibody of P2B-2F6 isolated from single B cells of SARS-CoV-2 infected patients. Two potent P2B-2F6 mutants, namely H:V106R and H:V106R/H:P107Y, were found to possess higher binding affinities with the RBD domain of SARS-CoV-2 than others. Polar interactions are preferred near 106 and 107 paratope residues of the heavy chain. The mutations also increase the hydrogen-bonding network formed between the antibody and the RBD. Notably, the optimized antibodies possess potential neutralizing activity against the alarming SARS-CoV-2 variant of N501Y. This study provides insights into structure-based optimization of antibodies with higher affinity to the antigen. We hope that our proposed antibody mutants could contribute to the development of improved therapies against COVID-19.

2.
Pharmacol Res ; 170: 105701, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34087353

RESUMO

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is commonly used to treat EGFR-mutant non-small-cell lung cancer (NSCLC). However, acquired resistance to mutant EGFR (T790M) can evolve following osimertinib treatment. High reactive oxygen species (ROS) levels in lung cancer cells can influence heme levels and have an impact on osimertinib resistance. Here, we found that heme levels were increased in osimertinib resistant EGFR-mutant NSCLC cell lines and plasma heme levels were also elevated in osimertinib-treated EGFR-mutant NSCLC patients. The antimalarial drug dihydroartemisinin (DHA), which has anticancer effects and requires heme, was tested to determine its potential to revert osimertinib resistance. DHA downregulated the expression of heme oxygenase 1 and inhibited cell proliferation in osimertinib-resistant EGFR-mutant NSCLC cells (PC9-GR4-AZD1), which was further enhanced by addition of 5-aminolevulinic acid, protoporphyrin IX and hemin. DHA was synergistic with osimertinib in inhibiting cell proliferation and colony formation of all osimertinib-resistant cell lines tested. Combination treatment with osimertinib and DHA also increased the levels of ROS, downregulated the phosphorylation or protein levels of several RTKs that often are overexpressed in osimertinib-resistant EGFR-mutant NSCLC cells, and inhibited tumor growth without toxicity in a PC9-GR4-AZD1 xenograft mouse model. The results suggest that DHA is able to reverse the resistance to osimertinib in EGFR-mutant NSCLC by elevating ROS level and impair heme metabolism.

3.
Cell Calcium ; 97: 102429, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34087722

RESUMO

Psoriasis is an immune-mediated chronic inflammatory skin disease characterized by erythema, scales, and infiltration of the skin, which causes deleterious effects on patient quality of life. TRP channel played important roles in the generation and conductance of itch signal . According to our results, psoriasis induced itch was TRPV4 dependent, and TRPV4 expression in both epidermis and DRG were up-regulated in psoriasis. Thus, TRPV4 is an attractive candidate for treating psoriasis induced itch. Cimifugin is a common compound in antipruritic Chinese medicine. In our study, GSK1016790A, a TRPV4 channel specific agonist, induced acute itch was inhibited by cimifugin in a dose-dependent manner. Furthermore, cimifugin treatment reduced the scratching behavior and reversed the TRPV4 up-regulation induced by psoriasis. In particular, cimifugin decreased GSK1016790A induced calcium response both in HaCaT cells and DRG neurons. Importantly, in TRPV4 transfected HEK293 cells, GSK101 induced calcium response was also significantly inhibited by cimifugin pretreatment. Consistent with our calcium imaging result, cimifugin pretreatment also inhibited GSK101 induced inward currents. Our study delineated a new role of TRPV4 in psoriasis and emphasized the antipruritic effect of cimifugin, which opened a new avenue to itch management in psoriasis.

4.
Pestic Biochem Physiol ; 176: 104874, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119219

RESUMO

Apolygus lucorum could cause severe economic damage to crops in China. The pest has been controlled by pyrethroids, and the target of pyrethroids is voltage-gated sodium channel (Nav). Double mutation (L1002F/D941G) was detected in a field-strain of A. lucorum . We found there was single mutation L1002F and double mutation L1002F/D941G, but no single mutation D941G in the field. The tail currents of L1002F and L1002F/D941G were reduced by two types pyrethroid. In contrast, D941G showed a similar activity as wild type channel. D941G and L1002F are both located in domain II but do not face the pyrethroid-binding pocket directly, suggesting that they might affect the insecticide-binding allosterically. L1002F/D941G has significantly different responses to pyrethroids compared to the wild type, but D941G alone has little effect compared to wild type. Our finding demonstrates that some mutation do not cause resistance by itself but can enhance the resistance combined with other mutations.


Assuntos
Heterópteros/genética , Resistência a Inseticidas , Inseticidas , Piretrinas , Animais , China , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Mutação , Piretrinas/farmacologia
5.
Magn Reson Imaging ; 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34146651

RESUMO

PURPOSE: This study aimed at introducing short-T1/T2 compartment to MR fingerprinting (MRF) at 3 T. Water that is bound to myelin macromolecules have significantly shorter T1 and T2 than free water and can be distinguished from free water by multi-compartment analysis. METHODS: We developed a new multi-inversion-recovery (mIR) water mapping-MRF based on an unbalanced steady-state coherent sequence (FISP). mIR pulses with an interval of 400 or 500 repetition times (TRs) were inserted into the conventional FISP MRF sequence. Data from our proposed mIR MRF was used to quantify different compartments, including myelin water, gray matter free water, and white matter free water, of brain water by virtue of the iterative non-negative least square (NNLS) with reweighting. Three healthy volunteers were scanned with mIR MRF on a clinical 3 T MRI. RESULTS: Using an extended phase graph simulation, we found that our proposed mIR scheme with four IR pulses allowed differentiation between short and long T1/T2 components. For in vivo experiments, we achieved the quantification of myelin water, gray matter water, and white matter water at an image resolution of 1.17 × 1.17 × 5 mm3/pixel. As compared to the conventional MRF technique with single IR, our proposed mIR improved the detection of myelin water content. In addition, mIR MRF using spiral-in/out trajectory provided a higher signal level compared with that with spiral-out trajectory. Myelin water quantification using mIR MRF with 4 IR and 5 IR pulses were qualitatively similar. Meanwhile, 5 IR MRF showed fewer artifacts in myelin water detection. CONCLUSION: We developed a new mIR MRF sequence for the rapid quantification of brain water compartments.

6.
J Transl Med ; 19(1): 224, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34044859

RESUMO

BACKGROUND: It has been established that microRNA (miR)-449a is anti-tumorigenic in cancers, including lung cancer. Therefore, this study further explored miR-449a-mediated mechanism in lung cancer, mainly focusing on lysine demethylase 3A/hypoxia-induced factor-1α (KDM3A/HIF-1α) axis. METHODS: miR-449a, KDM3A and HIF-1α levels in lung cancer tissues and cell lines (A549, H1299 and H460) were measured. Loss- and gain-of-function assays were performed and then cell proliferation, cell cycle, apoptosis, invasion and migration were traced. The relationship between KDM3A, miR-449a and HIF-1α was verified. Tumor growth in vivo was also monitored. RESULTS: Both lung cancer tissues and cells exhibited reduced miR-449a and raised KDM3A and HIF-1α levels. miR-449a interacted with KDM3A; HIF-1α could bind with KDM3A. Up-regulating miR-449a hindered while suppressing miR-449a induced lung cancer development via mediating HIF-1α. Elevating KDM3A promoted cellular aggression while down-regulating KDM3A had the opposite effects. Up-regulating KDM3A or HIF-1α negated up-regulated miR-449a-induced effects on cellular growth in lung cancer. Restoring miR-449a impaired tumorigenesis in vivo in lung cancer. CONCLUSION: It is eventually concluded that miR-449a delays lung cancer development through suppressing KDM3A/HIF-1α axis.

7.
Nat Commun ; 12(1): 2648, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976193

RESUMO

The neural mechanisms of fear-associated thermoregulation remain unclear. Innate fear odor 2-methyl-2-thiazoline (2MT) elicits rapid hypothermia and elevated tail temperature, indicative of vasodilation-induced heat dissipation, in wild-type mice, but not in mice lacking Trpa1-the chemosensor for 2MT. Here we report that Trpa1-/- mice show diminished 2MT-evoked c-fos expression in the posterior subthalamic nucleus (PSTh), external lateral parabrachial subnucleus (PBel) and nucleus of the solitary tract (NTS). Whereas tetanus toxin light chain-mediated inactivation of NTS-projecting PSTh neurons suppress, optogenetic activation of direct PSTh-rostral NTS pathway induces hypothermia and tail vasodilation. Furthermore, selective opto-stimulation of 2MT-activated, PSTh-projecting PBel neurons by capturing activated neuronal ensembles (CANE) causes hypothermia. Conversely, chemogenetic suppression of vGlut2+ neurons in PBel or PSTh, or PSTh-projecting PBel neurons attenuates 2MT-evoked hypothermia and tail vasodilation. These studies identify PSTh as a major thermoregulatory hub that connects PBel to NTS to mediate 2MT-evoked innate fear-associated hypothermia and tail vasodilation.


Assuntos
Medo/fisiologia , Hipotermia/metabolismo , Núcleo Solitário/metabolismo , Núcleo Subtalâmico/metabolismo , Canal de Cátion TRPA1/metabolismo , Animais , Regulação da Temperatura Corporal/fisiologia , Medo/psicologia , Hipotermia/induzido quimicamente , Hipotermia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Optogenética/métodos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Canal de Cátion TRPA1/genética , Tiazóis , Vasodilatação/fisiologia
8.
Aging (Albany NY) ; 13(9): 13023-13038, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962398

RESUMO

Bladder cancer (BC) is a commonly occurring malignant tumor affecting the urinary tract. Zinc finger proteins (ZNFs) constitute the largest transcription factor family in the human genome and are therefore attractive biomarker candidates for BC prognosis. In this study, we profiled the expression of ZNFs in The Cancer Genome Atlas (TCGA) BC cohort and developed a novel prognostic signature based on 7 ZNF-coding genes. After external validation of the model in the GSE48276 dataset, we integrated the 7-ZNF-gene signature with patient clinicopathological data to construct a nomogram that forecasted 1-, 2-, and 3-year OS with good predictive accuracy. We then accessed The Genomics of Drug Sensitivity in Cancer database to predict the therapeutic drug responses of signature-defined high- and low-risk BC patients in the TCGA cohort. Greater sensitivity to chemotherapy was revealed in the low-risk group. Finally, we conducted gene set enrichment analysis of the signature genes and established, by applying the ESTIMATE algorithm, distinct correlations between the two risk groups and the presence of stromal and immune cell types in the tumor microenvironment. By allowing effective risk stratification of BC patients, our novel ZNF gene signature may enable tailoring more intensive treatment for high-risk patients.

9.
Cell ; 184(12): 3256-3266.e13, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34048699

RESUMO

Northern East Asia was inhabited by modern humans as early as 40 thousand years ago (ka), as demonstrated by the Tianyuan individual. Using genome-wide data obtained from 25 individuals dated to 33.6-3.4 ka from the Amur region, we show that Tianyuan-related ancestry was widespread in northern East Asia before the Last Glacial Maximum (LGM). At the close of the LGM stadial, the earliest northern East Asian appeared in the Amur region, and this population is basal to ancient northern East Asians. Human populations in the Amur region have maintained genetic continuity from 14 ka, and these early inhabitants represent the closest East Asian source known for Ancient Paleo-Siberians. We also observed that EDAR V370A was likely to have been elevated to high frequency after the LGM, suggesting the possible timing for its selection. This study provides a deep look into the population dynamics of northern East Asia.

10.
Plant Dis ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33822661

RESUMO

Panicle Hydrangea (Hydrangea paniculate) is an ornamental flowering plant native to China and Japan. In August 2019, leaf spot symptoms with about 30% disease incidence were observed on panicle hydrangea in two grower fields (about 0.1 ha in total) of Northeast Agriculture University, China (126.72°E, 45.74°N). Symptoms initially appeared on the lower and older leaves and showed small subcircular brown spots with dark-brown edges on both sides. As the disease progressed, the necrotic spots enlarged, became irregular, coalesced, and the infected leaf blighted in approximately 2 weeks. Panicle hydrangea leaf samples (n=15) from different plants that showed spot symptoms were collected and surface sterilized with 70% ethanol for 10 s, followed by 0.5% NaClO treatment for 4 min, and rinsed in sterile water 3 times. Thereafter, leaf samples were placed on potato dextrose agar (PDA) and incubated at 25°C for 7 days. Fifteen hyphal-tipped pure cultures were obtained. Colonies growing on PDA for 7 days were olive green to dark green, exhibited a velvet-like texture and sometimes were radially furrowed and wrinkled. Margins varied from white gray to dark green without prominent exudates. The back of the plate showed dark green to black. Conidiophores were up to 180 to 600 µm long, 2.8 to 4.5 µm wide (n=50), subcylindrical-filiform, straight, septate, and unbranched or rarely branched. Ramoconidia were 0 to 1 septate, cylindrical to clavate, smooth-walled, 8 to 22 µm long (n=50). Conidia were single-celled, lemon-shaped, smooth-walled and 2.0 to 5.0 µm (diameter) (n=50). To confirm the identity, three genomic DNA regions, internal transcribed spacer (ITS), partial translation elongation factor-1 alpha (EF), and actin (ACT) of the representative isolate BAI-1 were amplified with primer pairs ITS1/4, EF1-728F/986R, and ACT-512F/783R, respectively (Bensch et al. 2012; Jo et al. 2018). DNA sequences of the isolate from ITS, EF, and ACT showed 99.81% (514/515 bp), 99.10% (219/221 bp), and 99.54% (216/217 bp) nucleotide identity with those of C. tenuissimum CBS 125995, respectively (GenBank accession nos. HM148197, HM148442, and HM148687). The sequences of isolate BAI-1 were deposited in GenBank (accession nos. MW045455, MW052465, and MW052466). To fulfill Koch's postulates, five healthy 2-year-old panicle hydrangea plants grown in pots were surface sterilized with 70% ethanol, washed twice with sterile distilled water, and sprayed with a conidial suspension of strain BAI-1 (adjusted to 1×106 conidia/ml using a hemocytometer), maintained in a greenhouse at 25°C and 85% relative humidity. Five plants sprayed with sterilized water served as controls. The inoculated plants showed leaf spot symptoms that were similar to those previously observed in the fields after 7 days, whereas control leaves remained healthy. The fungus was reisolated from symptomatic leaves and its identity was confirmed by morphological and molecular method. These experiments were repeated twice. So far, C. tenuissimum was reported to cause leaf spot of alfalfa (Han et al. 2019) and castor (Liu et al. 2019). To our knowledge, this is the first report of leaf spot disease in panicle hydrangea caused by C. tenuissimum in China. Leaf spot has a negative effect on the aesthetic value of panicle hydrangea, and this report will assist with monitoring distribution of the disease as well as developing management recommendations.

11.
Curr Drug Metab ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906588

RESUMO

BACKGROUND: The hepatotoxic pyrrolizidine alkaloids (PAs) were reported to increase bile acid (BA) levels in rat. However, it is still unclear whether the production of highly reactive dehydropyrrolizidine through CYP450s is directly relevant to BA changes. OBJECTIVE: To further explore the mechanism by which metabolic activation of PAs induced BA changes, the effect of impaired or enhanced metabolic activation on the BA profiling and BA-related synthesis and transport genes were investigated and the involvement of Nrf2 pathway were explored. METHODS: Blood and liver samples were collected after intragastrical administration of 35 mg/kg retrorsine or saline for seven days in wild-type (WT) and Nrf2 KO mice. CYP450 inhibitor, 1-aminobenzotriazole (ABT), or gamma-glutamylcysteine synthetase inhibitor, L-buthionine-sulfoximine (BSO) were employed in WT mice. Retrorsine-induced hepatotoxicity was evaluated by a biochemical method and H&E staining method. Serum BAs were quantified by high-performance liquid chromatography/triple quadrupole mass spectrometry. Blood pyrrole-protein adducts were semiquantified by high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. The gene and protein expression of BA-related transporters and enzymes in the liver were measured by a quantitative real-time PCR method and western blotting method. RESULTS: The BA concentrations in serum were increased in the retrorsine-treated WT mice, along with the up-regulation of BA transporters, Ostß, Mrp3, Mrp4, and Mrp2. When ABT was co-administered, the altered BA levels and Mrp4 mRNA and protein levels were reversed, accompanied by a 50% reduction of 6,7-dihydro-7-hydroxy-1- hydroxymethyl-5H-pyrrolizine (DHP) formation. When BSO was co-administered, serum BAs were not further increased but Ostß, Mrp3, Mrp4 mRNA, and Mrp4 protein level continuously increased. The induction of Mrp4 by retrorsine among the tested BA transporters was the only one that was abolished or enhanced in the presence of ABT or BSO. The Nrf2 protein levels in the nucleus increased in the retrorsine-treated WT mice, which were remarkably repressed by co-administration of ABT and enhanced by co-administration of BSO. In Nrf2 KO mice receiving retrorsine, the bile acids and the mRNA and protein levels of Mrp2, Mrp3, Mrp4, and Ostß were hardly changed, indicating the direct role of Nrf2 in retrorsine-induced BA changes in WT mice. CONCLUSION: The activation of Nrf2 translocation by the formation of the reactive metabolite of PAs induced the expressions of BA transporters and changed serum BA levels. Mrp4 was a sensitive biomarker for the perturbation of redox status caused by the formation of dehydropyrrolizidine.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33806526

RESUMO

In some countries, including China, primary health care is rarely utilized because of medical personnel shortages at primary medical and health care institutions (PMHCIs). Several studies suggest that the most effective solution is to guide qualified doctors and medical graduates to work in PMHCIs, but the studies and measures have been formulated only from the perspective of the government and PMHCIs; few have considered the subjective willingness of medical personnel. Therefore, it is necessary to explore the measures to develop human resources of PMHCIs from the guiding object. This research was divided into two parts based on implicit theory and a lexical approach. The first part collected the factors affecting their choosing PMHCIs for employment, and the second part used exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and structural equation modeling (SEM) to explore the dimensions and paths of the influencing factors. At last, seven factors were obtained from the EFA, and the SEM hypothesis fit the data well. Internal Organization Development, Patient Factor, Remuneration and Development, and Family Support had a significantly positive effect on the Sense of Gain of medical personnel seeking employment at PMHCIs, whereas both Job Responsibilities and Condition of the City Where the PMHCI Is Located had no significant effect. In addition, the indirect effects of Internal Organization Development and Condition of the City Where the PMHCI Is Located on the Sense of Gain were significant. The Patient Factor, Family Support, and Remuneration and Development significantly mediated the relationship between the internal and external environment of the institution and the Sense of Gain, whereas the mediating effect of Job Responsibilities was not significant. The improvement of family support, remuneration and development, and patient factors increase the willingness of medical personnel to seek employment at PMHCIs. In addition, the internal and external environments of a PMHCI play a vital role in guiding medical personnel to PMHCIs for employment. This research provides theoretical support for improving the development of human resources, guiding medical personnel to work in PMHCIs, and promoting the use of primary care services.


Assuntos
Atenção à Saúde , Médicos , China , Instalações de Saúde , Humanos , Recursos Humanos
13.
Sci Adv ; 7(14)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33789892

RESUMO

Xinjiang is a key region in northwestern China, connecting East and West Eurasian populations and cultures for thousands of years. To understand the genetic history of Xinjiang, we sequenced 237 complete ancient human mitochondrial genomes from the Bronze Age through Historical Era (41 archaeological sites). Overall, the Bronze Age Xinjiang populations show high diversity and regional genetic affinities with Steppe and northeastern Asian populations along with a deep ancient Siberian connection for the Tarim Basin Xiaohe individuals. In the Iron Age, in general, Steppe-related and northeastern Asian admixture intensified, with North and East Xinjiang populations showing more affinity with northeastern Asians and South Xinjiang populations showing more affinity with Central Asians. The genetic structure observed in the Historical Era of Xinjiang is similar to that in the Iron Age, demonstrating genetic continuity since the Iron Age with some additional genetic admixture with populations surrounding the Xinjiang region.

14.
Zool Res ; 42(3): 280-286, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33855818

RESUMO

DNA studies of endangered or extinct species often rely on ancient or degraded remains. The majority of ancient DNA (aDNA) extraction protocols focus on skeletal elements, with skin and hair samples rarely explored. Similar to that found in bones and teeth, DNA extracted from historical or ancient skin and fur samples is also extremely fragmented with low endogenous content due to natural degradation processes. Thus, the development of effective DNA extraction methods is required for these materials. Here, we compared the performance of two DNA extraction protocols (commercial and custom laboratory aDNA methods) on hair and skin samples from decades-old museum specimens to Iron Age archaeological material. We found that apart from the impact sample-specific taphonomic and handling history has on the quantity and quality of DNA preservation, skin yielded more endogenous DNA than hair of the samples and protocols tested. While both methods recovered DNA from ancient soft tissue, the laboratory method performed better overall in terms of DNA yield and quality, which was primarily due to the poorer performance of the commercial binding buffer in recovering aDNA.


Assuntos
DNA Antigo/análise , Cães , Presbytini , Análise de Sequência de DNA/veterinária , Manejo de Espécimes/veterinária , Animais , Museus , Análise de Sequência de DNA/métodos , Manejo de Espécimes/métodos
15.
Org Lett ; 23(9): 3274-3277, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33881880

RESUMO

Two novel natural products, beetleane A (1) and epicoane A (2), were obtained from the metabolites of an endophytic Epicoccum nigrum. Compound 1 has a unique beetlelike structure that is constructed by the fusion and further fold of an unusual [5.5.5.6]trioxafenestrane with a cycloheptane ring. Compound 2 possesses a compact cagelike structure with a unique 6/5/5/5/6/6/5 heptacyclic ring system. Both 1 and 2 showed strong antiliver fibrosis activity in vitro.

16.
Elife ; 102021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33876725

RESUMO

The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted syndrome in humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive therapeutics for skin inflammation.

17.
Plants (Basel) ; 10(4)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807152

RESUMO

Filamentous temperature-sensitive protein Z (Tubulin/FtsZ) family is a group of conserved GTP-binding (guanine nucleotide-binding) proteins, which are closely related to plant tissue development and organ formation as the major component of the cytoskeleton. According to the published genome sequence information of cassava (Manihot esculenta Crantz), 23 tubulin genes (MeTubulins) were identified, which were divided into four main groups based on their type and phylogenetic characteristics. The same grouping generally has the same or similar motif composition and exon-intron structure. Collinear analysis showed that fragment repetition event is the main factor in amplification of cassava tubulin superfamily gene. The expression profiles of MeTubulin genes in various tissue were analyzed, and it was found that MeTubulins were mainly expressed in leaf, petiole, and stem, while FtsZ2-1 was highly expressed in storage root. The qRT-PCR results of the FtsZ2-1 gene under hormone and abiotic stresses showed that indole-3-acetic acid (IAA) and gibberellin A3 (GA3) stresses could significantly increase the expression of the FtsZ2-1 gene, thereby revealing the potential role of FtsZ2-1 in IAA and GA3 stress-induced responses.

18.
Mol Brain ; 14(1): 49, 2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676528

RESUMO

Antibiotics affect gut microbial composition, leading to Gut-Brain-Axis imbalance and neurobehavioral changes. However, the intestinal dysbacteriosis associated behavior changes are not consistently reported. It is not clear whether these changes are transient or permanent. The neuroprotective effect of probiotics against intestinal dysbacteriosis induced alternations needs to be determined either. In the present study, oral antibiotic mixture including Ampicillin, Streptomycin, and Clindamycin was utilized to induce intestinal dysbacteriosis in mice. Antibiotics application triggered mechanical allodynia in von frey test and spontaneous pain in open field test. It also resulted in increased anxiety and depressive-like behaviors and damaged spatial memory performance. After application of probiotics, the mechanical allodynia and spontaneous pain were alleviated significantly. The anxiety behaviors, depressive-like behaviors and recognitive performance were ameliorative as well. By using Fos protein as a marker, it is found that the sensory, emotion and memory related brain regions were activated in mice with intestinal dysbacteriosis. Our study is not only helpful for enriching our basic knowledge for understanding the changed pain responses and related brain disorders in antibiotics-induced dysbacteriosis mice, but also beneficial for providing a more comprehensive mechanistic explanation for the regulation of antibiotics and probiotics on gut microbiota and relevant alternations in animal neurological behaviors.

19.
Nat Neurosci ; 24(4): 542-553, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33686297

RESUMO

In humans, tissue injury and depression can both cause pain hypersensitivity, but whether this involves distinct circuits remains unknown. Here, we identify two discrete glutamatergic neuronal circuits in male mice: a projection from the posterior thalamic nucleus (POGlu) to primary somatosensory cortex glutamatergic neurons (S1Glu) mediates allodynia from tissue injury, whereas a pathway from the parafascicular thalamic nucleus (PFGlu) to anterior cingulate cortex GABA-containing neurons to glutamatergic neurons (ACCGABA→Glu) mediates allodynia associated with a depression-like state. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that POGlu and PFGlu populations undergo different adaptations in the two conditions. Artificial manipulation of each circuit affects allodynia resulting from either tissue injury or depression-like states, but not both. Our study demonstrates that the distinct thalamocortical circuits POGlu→S1Glu and PFGlu→ACCGABA→Glu subserve allodynia associated with tissue injury and depression-like states, respectively, thus providing insights into the circuit basis of pathological pain resulting from different etiologies.


Assuntos
Depressão/fisiopatologia , Hiperalgesia/fisiopatologia , Vias Neurais/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Animais , Masculino , Camundongos , Neurônios/fisiologia
20.
Healthcare (Basel) ; 9(2)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673001

RESUMO

The continuous growth in total health expenditure (THE) has become a social issue of common concern in most countries. In China, the total health expenditure (THE) is maintaining a rapid growth trend that is higher than that of the economy, which has become increasingly obvious in the 21st century and has brought a heavy burden to the government and residents. To analyze the main driving factors of THE in China in the 21st century and establish a predictive model, gray system theory was employed to explore the correlation degree between THE and nine hot topics in the areas of the economy, population, health service utilization, and policy using national data from 2000 to 2018. Additionally, a New Structure of the Multivariate Gray Prediction Model of THE was established and compared with the traditional grey model and widely used BP neural network to evaluate the prediction effectiveness of the model. We concluded that the Chinese government and society have played a crucial role in reducing residents' medical burden. Besides this, the improved economy and aging population have increased the demand for health services, leading to the continual increase in THE. Lastly, the improved NSGM(1,N) model achieved good prediction accuracy and has unique advantages in simulating and predicting THE, which can provide a basis for policy formulation.

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