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1.
Nat Neurosci ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632286

RESUMO

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 µg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 µg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.

2.
ACS Chem Neurosci ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32644793

RESUMO

Merazin hydrate (MH), an essential ingredient of Fructus aurantii, has been identified to have an antidepressant-like effect. However, the molecular mechanisms of MH modulate depressive behavior are largely uncharacterized. Here, in lipopolysaccharide-induced mice, we identified that a single administration of MH recovered depressive behaviors and down-regulated the expressions of neuronal nitric oxide synthase (nNOS) in the hippocampus after 1 day. Activation of nNOS by l-arginine led to depressive behaviors, and inhibition of nNOS contributed to antidepressive behaviors. Notably, MH only reversed the expression of nNOS's downstream NF-κB and not the CREB/BDNF pathway in the hippocampus, and MH's antidepressant-like effects were prevented by Asatone (an agonist of NF-κB) and not H89 (an antagonist of CREB). MH also normalized the expressions of GFAP and IB-1 in dentate gyrus in the hippocampus and inflammatory factors such as IL-1ß, IL-10, and TNF-α in serum. Overall, our studies reveal the molecular mechanisms of MH's antidepressant-like effect.

3.
Diabetes ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647036

RESUMO

Diabetic peripheral neuropathy (DPN) is a long-term complication of diabetes with a complicated pathogenesis. AMP-activated protein kinase (AMPK) senses oxidative stress and mitochondrial function playing a central role in the regulation of DPN. Here, we reported that DW14006 (2-(3-(7-chloro-6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid) as a direct AMPKα activator efficiently ameliorated DPN in both streptozotocin (STZ)-induced type 1 and BKS db/db type 2 diabetic mice. DW14006 administration highly enhanced neurite outgrowth of dorsal root ganglion (DRG) neuron and improved neurological function in diabetic mice. The underlying mechanisms have been intensively investigated. DW14006 treatment improved mitochondrial bioenergetics profiles and restrained oxidative stress and inflammation in diabetic mice by targeting AMPKα, which has been verified by assay against the STZ-induced diabetic mice injected with adeno associated virus AAV8-AMPKα-RNAi. To our knowledge, our work might be the first report on the amelioration of direct AMPKα activator on DPN by counteracting multiple risk factors including mitochondrial dysfunction, oxidative stress and inflammation, and DW14006 has been highlighted as a potential leading compound in the treatment of DPN.

4.
Nanoscale ; 12(29): 15767-15774, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32729861

RESUMO

Survival data have shown little therapeutic improvement in pancreatic ductal adenocarcinoma (PDAC) over the past several decades, mostly due to aggressive growth and resistance to therapy. Glutathione (GSH) depletion in PDAC may serve as a strategy to suppress tumour malignancy and sensitize tumour cells to therapy. Herein, novel l-cysteine-based poly(disulfide amide) polymers were fabricated to deliver a histone methyltransferase G9a inhibitor (UNC0638) that can simultaneously block GSH biosynthesis and clear cellular GSH levels in PDAC. The optimal UNC0638 nanodrug (NPUNC0638) had the desired particle size, reasonable drug loading capacity, and GSH-controlled drug release. Moreover, compared to UNC0638 alone, NPUNC0638 showed better efficacy in inhibiting cell viability, arresting the cell cycle, inducing apoptosis, and suppressing the invasion and self-renewal capacity of PDAC cells. Furthermore, NPUNC0638 was found to be tumour-specific and well tolerated with no apparent toxicity to vital organs and haematopoietic stem and progenitor cells. Additionally, treatment with NPUNC0638 provided favourable outcomes in the PDAC xenograft model. Therefore, this work presents a potent drug delivery platform to overcome the GSH-induced malignant potential of PDAC.

5.
J Infect Dis ; 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32702113

RESUMO

BACKGROUND: Signaling Lymphocytic Activation Molecule Family-7 (SLAMF7) functions an immune checkpoint molecule on macrophages in anti-tumor immunity. However, its role in bacterial infection remains largely unknown. METHODS: Bone marrow-derived macrophages (BMDMs) isolated from wild type (WT) or SLAMF7 knockout (KO) mice were infected with bacteria or treated with LPS/IFN-γ to investigate the expression and function of SLAMF7 in macrophage polarization. Pseudomonas aeruginosa (P. aeruginosa) keratitis murine model was established to explore the effect of SLAMF7 on P. aeruginosa keratitis, using WT vs SLAMF7 KO mice, or recombinant SLAMF7 vs PBS-treated mice, respectively. RESULTS: SLAMF7 expression was enhanced on M1-polarized or bacterial-infected macrophages, and infiltrating macrophages in P. aeruginosa-infected mouse corneas. SLAMF7 promoted M2 polarization by inducing STAT6 activation. In vivo data showed that SLAMF7 KO aggravated, while treatment with recombinant SLAMF7 alleviated, corneal inflammation and disease severity. Besides, blockage of M2 polarization by Arg-1 inhibitor abrogated the effect of recombinant SLAMF7 in disease progression. CONCLUSIONS: SLAMF7 expression in macrophages was induced upon M1-polarization or bacteria-infection and alleviated corneal inflammation and disease progression of P. aeruginosa keratitis via promoting M2 polarization. These findings may provide a potential strategy for the treatment of P. aeruginosa keratitis.

6.
Zhen Ci Yan Jiu ; 45(7): 592-8, 2020 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-32705837

RESUMO

OBJECTIVE: To compare the therapeutic effect and safety in treatment of functional constipation between electroacupuncture (EA) and gastro-kinetic drugs. METHODS: Using "functional constipation", "prucalopride", "mosapridecitrate", "electro-acupuncture" and "randomized controlled trial", both in Chinese and English, as search terms, the articles of randomized controlled trial (RCT) regarding to the comparison of therapeutic effect on functional constipation in the patients between EA and gastro-kinetic drugs were retrieved from CMB, Wanfang, VIP, CNKI, OpenGrey, CINAHL, Cochrane Library, JBI, PubMed, WOS and Ovid databases. The retrieval time was from the establishment date to June 2018. The two researchers screened articles, extracted data and assessed literature quality in reference to Cochrane Handbook. Using RevMan 5.3 software, the meta-analysis was conducted. RESULTS: A total of 11 articles were included finally, with 744 patients involved. It was found after meta-analysis that in EA group, the weekly spontaneous defecation frequency, constipation related quality of life in patients, depression relief and incidence of adverse reaction were all better than those in gastro-kinetic medication group. The therapeutic effect of the improvements in stool character and defecation difficulty in EA group were better or similar to that in gastro-kinetic medication group. CONCLUSION: Regarding the therapeutic effect and safety in treatment of functional constipation, the results of electroacupuncture are superior or similar to gastro-kinetic medication, presenting a satisfactory therapeutic prospect.

7.
Parasit Vectors ; 13(1): 354, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680557

RESUMO

BACKGROUND: Accurate quantification of infection intensity is essential to estimate infection patterns of avian haemosporidian parasites in order to understand the evolution of host-parasite associations. Traditional microscopy is cost-effective but requires high-quality blood smears and considerable experience, while the widely used semi-quantitative qPCR methods are mostly employed with ideal, laboratory-based golden samples and standard curves, which may limit the comparison of parasitemia from different laboratories. METHODS: Here we present a digital droplet PCR (ddPCR) protocol for absolute quantification of avian haemosporidians in raptors. Novel primers were designed that target a conserved fragment of a rRNA region of the mitochondrial genome of the parasites. Sensitivity and repeatability were evaluated compared to qPCR and other assays. RESULTS: This ddPCR assay enables accurate quantification of haemosporidian parasites belonging to Plasmodium, Haemoproteus and Leucocytozoon with minimum infection quantities of 10-5 (i.e. one parasite copy in 105 host genomes) without the use of standard curves. Quantities assessed by ddPCR were more accurate than qPCR using the same primers through reduction of non-specific amplification in low-intensity samples. The ddPCR technique was more consistent among technical duplicates and reactions, especially when infection intensities were low, and this technique demonstrated equal sensitivity with high correspondence (R2 = 0.97) compared to the widely used qPCR assay. Both ddPCR and qPCR identified more positive samples than the standard nested PCR protocol for the cytb gene used for barcoding avian haemosporidians. CONCLUSIONS: We developed a novel ddPCR assay enabling accurate quantification of avian haemosporidians without golden samples or standard curves. This assay can be used as a robust method for investigating infection patterns in different host-parasite assemblages and can facilitate the comparison of results from different laboratories.

8.
Science ; 369(6502): 403-413, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32703874

RESUMO

Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.

9.
J Tradit Chin Med ; 40(3): 414-421, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32506855

RESUMO

OBJECTIVE: To determine the constituent compounds of Danggui buxue decoction (DBD) involved and the potential mechanisms mediating its effects, with specific reference to lipids playing a role in the initiation of diabetic atherosclerosis. METHODS: Liquid chromatography-tandem mass spectrometry was used to identify and quantify the absorbed bioactive compounds (ABCs) present in DBD. Goto-Kakizaki (GK) rats were randomly allocated to a diabetes atherosclerosis (DA) group, a DBD group, and an ABC group (10 per group), which were all high-fat diet-fed. The treated rats were administered DBD (4 g/kg) or ABCs (in amounts equal to those present in DBD) once daily for 28 d, and a control group of Wistar rats were administered vehicle. Body mass gain, fasting blood glucose, and homeostasis assessment of insulin resistance (HOMA- IR) were measured. Serum triglyceride (TG), cholesterol (CHOL), high density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL- C) and tumor necrosis factor-α (TNF-α) concentrations were determined. Hematoxylin and eosin staining and microscopy were used to characterize the abdominal aorta and the expression of lipogenic genes was quantified in this vessel. RESULTS: Seven ABCs were identified in rat serum: ferulic acid, formononetin, calycosin, astragaloside, caffeic acid, ligustilide, and butyphthalide. DBD significantly reduced HOMA-IR, the serum concentrations of TG, CHOL, and LDL-C, and the expression of the lipogenic genes monocyte chemotactic protein 1, Fas, intercellular adhesion molecule 1, and Cd36 in aorta; and significantly increased the mRNA expression of Scd1 in aorta. CONCLUSION: DBD affects lipid metabolism in the early stage of atherosclerosis in diabetic GK rats, with the mechanism likely involving the regulation of lipid metabolic genes in vessels. The contribution of ABCs to the effect of DBD on lipid metabolism was 24%-101%.

11.
BMC Anesthesiol ; 20(1): 149, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539742

RESUMO

BACKGROUND: Propofol is among the most frequently used anesthetic agents, and it has the potential for abuse. The N-methyl-D-aspartate (NMDA) receptors are key mediators neural plasticity, neuronal development, addiction, and neurodegeneration. In the present study, we explored the role of these receptors in the context of rat propofol self-administration. METHODS: Sprague-Dawley Rats were trained to self-administer propofol (1.7 mg/kg/infusion) using a fixed-ratio (FR) schedule over the course of 14 sessions (3 h/day). After training, rats were intraperitoneally administered the non-competitive NDMA receptor antagonist MK-801, followed 10 min later by a propofol self-administration session. RESULTS: After training, rats successfully underwent acquisition of propofol self-administration, as evidenced by a significant and stable rise in the number of active nose-pokes resulting in propofol administration relative to the number of control inactive nose-pokes (P < 0.01). As compared to control rats, rats that had been injected with 0.2 mg/kg MK-801 exhibited a significantly greater number of propofol infusions (F (3, 28) = 4.372, P < 0.01), whereas infusions were comparable in the groups administered 0.1 mg/kg and 0.4 mg/kg of this compound. In addition, MK-801 failed to alter the numbers of active (F (3, 28) = 1.353, P > 0.05) or inactive (F (3, 28) = 0.047, P > 0.05) responses in these study groups. Animals administered 0.4 mg/kg MK-801 exhibited significantly fewer infusions than animals administered 0.2 mg/kg MK-801 (P = 0.006, P < 0.01). In contrast, however, animals in the 0.4 mg/kg MK-801 group displayed a significant reduction in the number of active nose-poke responses (F (3, 20) = 20.8673, P < 0.01) and the number of sucrose pellets (F (3, 20) = 23.77, P < 0.01), while their locomotor activity was increased (F (3, 20) = 22.812, P < 0.01). CONCLUSION: These findings indicate that NMDA receptors may play a role in regulating rat self-administration of propofol.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32553881

RESUMO

OBJECTIVES: To evaluate the efficacy, safety and completion rate of three-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients. METHODS: Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months follow-up. Safety profile and complete rates were evaluated. RESULTS: A total of 1,227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n=254) vs observation (n=259). Twenty-eight participants were diagnosed with active TB, 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank P=0.055). On per-protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank P=0.01). Due to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 adverse events (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity. CONCLUSION: Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02430259.

13.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(6): 561-566, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32571452

RESUMO

OBJECTIVE: To investigate the current status of antibiotic use for very and extremely low birth weight (VLBW/ELBW) infants in neonatal intensive care units (NICUs) of Hunan Province. METHODS: The use of antibiotics was investigated in multiple level 3 NICUs of Hunan Province for VLBW and ELBW infants born between January, 2017 and December, 2017. RESULTS: The clinical data of 1 442 VLBW/ELBW infants were collected from 24 NICUs in 2017. The median antibiotic use duration was 17 days (range: 0-86 days), accounting for 53.0% of the total length of hospital stay. The highest duration of antibiotic use was up to 91.4% of the total length of hospital stay, with the lowest at 14.6%. In 16 out of 24 NICUs, the antibiotic use duration was accounted for more than 50.0% of the hospitalization days. There were 113 cases with positive bacterial culture grown in blood or cerebrospinal fluid, making the positive rate of overall bacterial culture as 7.84%. The positive rate of bacterial culture in different NICUs was significantly different from 0% to 14.9%. The common isolated bacterial pathogens Klebsiella pneumoniae was 29 cases (25.7%); Escherichia coli 12 cases (10.6%); Staphylococcus aureus 3 cases (2.7%). The most commonly used antibiotics were third-generation of cephalosporins, accounting for 41.00% of the total antibiotics, followed by penicillins, accounting for 32.10%, and followed by carbapenems, accounting for 13.15%. The proportion of antibiotic use time was negatively correlated with birth weight Z-score and the change in weight Z-score between birth and hospital discharge (rs=-0.095, -0.151 respectively, P<0.01), positively correlated with death/withdrawal of care (rs=0.196, P<0.01). CONCLUSIONS: Antibiotics used for VLBW/ELBW infants in NICUs of Hunan Province are obviously prolonged in many NICUs. The proportion of routine use of third-generation of cephalosporins and carbapenems antibiotics is high among the NICUs.


Assuntos
Recém-Nascido de Peso Extremamente Baixo ao Nascer , Antibacterianos , Peso ao Nascer , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Inquéritos e Questionários
14.
Artigo em Inglês | MEDLINE | ID: mdl-32510190

RESUMO

For applications in energy storage and conversion, many metal oxide (MO)/C composite fibers have been synthesized using cellulose as the template. However, MO particles in carbon fibers usually experience anomalous growth to a size of >200 nm, which is detrimental to the overall performance of the composite. In this paper, we report the successful development of a generic approach to synthesize a fiber composite with highly dispersed MO nanoparticles (10-80 nm) via simple swelling, nitrogen doping, and carbonization of the cellulose microfibril. The growth of the MO nanoparticles is confined by the structure of the microfibrils. Density functional theory calculation further reveals that the doped N atoms supply ample nucleation sites for size confinement of the nanoparticles. The encapsulation structure of small MO nanoparticles in the conductive carbon matrix improves their electrochemical performance. For example, the formed SnOx/carbon nanocomposite exhibits high specific capacities of 1011.0 mA h g-1 at 0.5 A g-1 and 581.8 mA h g-1 at 5 A g-1. Moreover, the fiber-like nanocomposite can be combined with carbon nanotubes to form a flexible binder-free electrode with a capacity of ∼10 mA h cm-2, far beyond the commercial level. The process developed in this study offers an alternative approach to sophisticated electrospinning for the synthesis of other fiber-like MO/carbon nanocomposites for versatile applications.

15.
Carbohydr Polym ; 242: 116387, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32564851

RESUMO

Chitosan-based macroparticle is a common carrier for enzyme immobilization applied in food industry. Driven by the requirement of large carrier pores for the biomacromolecular substrates such as protein, the eggshell membrane powder (ESMP) was employed as multifunctional porogen to improve the physicochemical structure of chitosan-based macroparticles. The prepared macroparticles were characterized by SEM, XRD, FTIR, Raman spectroscopy, nitrogen adsorption-desorption isotherms, and thermogravimetric analysis. The results showed that an increase of ESMP percentage could improve the porosity of macro holes in macroparticles, and it also enlarged the size of mesopores. Moreover, the ESMP significantly increased (P < 0.05) the amount of papain immobilization, whereas the specific activity of immobilized papain achieved a maximum value of 871.95 U/mg at CSESM2 and then declined with the increase of ESMP. Therefore, the inclusion of 20 % ESMP in chitosan-based macroparticles gave the highest activity of its immobilized protease.

16.
J Sci Food Agric ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483817

RESUMO

BACKGROUND: Artificial sweeteners have been used widely as substitutes for sugar for several decades. In recent years they have been reported to be harmful to human health - especially to glucose absorption. However, as conclusions from previous studies using a single Caco-2 cell model were not consistent, further studies with a more suitable cell model are needed. RESULTS: We established a co-culture model with enterocyte Caco-2 and enteroendocrine NCI-H716 cell lines cultured in transwell inserts. The effects of artificial sweeteners, enhancing the glucose transport rate, lasted for 60 min and then began to diminish. Most importantly, different artificial sweeteners with the same sweetness intensity had similar effects on glucose transport. The sodium / glucose co-transporter member 1 (SGLT1) mRNA expression levels increased significantly with an initial glucose concentration of 20 mM, while glucose transporter 2 (GLUT2) mRNA expression significantly increased with initial glucose concentrations of 20 mM and 60 mM. CONCLUSION: Based on the Caco-2/NCI-H716 co-culture model, SGLT1 and GLUT2 mediated the enhancing effects of artificial sweeteners on glucose transport, depending on the sweetness intensity and initial glucose concentration.

17.
Int J Parasitol ; 50(8): 611-619, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32598873

RESUMO

Infection patterns of avian haemosporidians result from the evolution of their associations with hosts, and can be shaped by multiple biotic factors. However, at the level of parasite species, few studies have investigated the details of the temporal dynamics of infection patterns in wild bird communities. We hereby studied a wild bird community in southern Sweden to investigate two generalist parasites (cyt b lineages PARUS1 and WW2) of the morphological species Haemoproteus majoris in their main host species (tits and warblers, respectively) to look for seasonal (spring to autumn) and age class related variation in infection patterns. For both lineages, we detected a similar temporal pattern in prevalence and infection intensity, with peak levels during the main nesting season in adults and a few weeks later in juveniles. Infections in juveniles were detected as soon as they started to be caught by mist nets, implying that they became infected when still in the nest or during the first weeks post-fledging. The initially high intensities in juveniles were followed by a significant decrease during the hatching year, emphasising the importance of studying haemosporidian infections in nestlings and fledglings. Both prevalence and infection intensity in adults increased from spring to early summer, either due to spring relapses or new infections. Both prevalence and infection intensity declined in adults at the time when independent juveniles of the respective species started to appear, suggesting that the rate of parasite withdrawal from blood exceeded the rates of new infections gained and relapses of previous infections. Prevalence in both juveniles and adults approached zero towards the end of the summer.

18.
Yi Chuan ; 42(5): 493-505, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32431300

RESUMO

Xinjiang inbred cattle is a population which has been highly inbred for 45 years. However, the breed origin of this population cannot be traced back due to the lack of original records. To demonstrate the genetic background of Xinjiang inbred cattle, we analysed the worldwide genomic information of 16 cattle breeds using principal components analysis, and Admixture method. Furthermore, the shared SNP markers of Xinjiang inbred cattle, local Kazakh cattle, Holstein cattle, and Xinjiang Brown cattle were extracted to calculate population genetic parameters and genomic inbreeding indicators in order to evaluate the magnitude of inbreeding in each population. We also evaluated the relationship between inbreeding indicators and body size in the Xinjiang inbred population. Finally, the high frequency runs of homozygosity (ROH) regions for Xinjiang inbred cattle and local Kazakh population were selected for genes and QTL annotations. These results demonstrate that the ancestry proportions of inbreeding breed are similar to those of Kazakh cattle. The genomic homozygosity of Xinjiang inbred cattle is significantly higher than other populations; the inbreeding depression is observed in body size to a certain extent because body size decreased when corresponding homozygosity increased. Totally, six basic bio-pathways and 32 QTL regions that related to bovine economical traits were annotated. Our results provide the insights into breeding strategies, future protection, and utilization plan design for this special genetic material-Xinjiang inbred cattle.

19.
ACS Nano ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32401009

RESUMO

Tuberculosis (TB) causes a global burden with its high rates of infection and death, especially the irrepressible threats of latent infection and drug resistance. Therefore, it is important to construct efficient theranostics for the prevention and control of TB. Herein, we created a targeted theranostic strategy for TB with a rifampicin-loaded aggregation-induced emission (AIE) carrier and performed testing in laboratory animals. The AIE carrier was constructed to localize in the granulomas and emit fluorescent signals at the early stage of infection, enabling the early diagnosis of TB. Subsequently, reactive oxygen species (ROS) were generated to eradicate infection, and the loaded rifampicin (RIF) was released for the synergistic treatment of persistent bacteria. Furthermore, targeted TB therapy was performed with the light-controlled release of ROS and accurate delivery of RIF, which realizes an anti-infection effect, providing an especially important treatment for drug-resistant TB. Thus, targeted theranostics for TB in laboratory animals possess the potential to become granulomas-tracking and anti-infection strategies for the diagnosis and treatment of TB.

20.
J Med Chem ; 63(9): 4579-4602, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32282200

RESUMO

2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (Ki = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.

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