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1.
Nucleic Acids Res ; 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33978756

RESUMO

HIV-1 reverse transcription initiates at the primer binding site (PBS) in the viral genomic RNA (gRNA). Although the structure of the PBS-segment undergoes substantial rearrangement upon tRNALys3 annealing, the proper folding of the PBS-segment during gRNA packaging is important as it ensures loading of beneficial host factors. DHX9/RNA helicase A (RHA) is recruited to gRNA to enhance the processivity of reverse transcriptase. Because the molecular details of the interactions have yet to be defined, we solved the solution structure of the PBS-segment preferentially bound by RHA. Evidence is provided that PBS-segment adopts a previously undefined adenosine-rich three-way junction structure encompassing the primer activation stem (PAS), tRNA-like element (TLE) and tRNA annealing arm. Disruption of the PBS-segment three-way junction structure diminished reverse transcription products and led to reduced viral infectivity. Because of the existence of the tRNA annealing arm, the TLE and PAS form a bent helical structure that undergoes shape-dependent recognition by RHA double-stranded RNA binding domain 1 (dsRBD1). Mutagenesis and phylogenetic analyses provide evidence for conservation of the PBS-segment three-way junction structure that is preferentially bound by RHA in support of efficient reverse transcription, the hallmark step of HIV-1 replication.

2.
Infect Genet Evol ; 92: 104893, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33964472

RESUMO

Candida albicans (C. albicans) is a common cause of vulvovaginal candidiasis (VVC). In this paper, the genetic diversity and molecular epidemiology of 173C. albicans strains were investigated by multilocus sequence typing (MLST). A total of 52 diploid sequence types (DSTs) were recognized, and 27 (51.9%) of which have not been reported in the MLST database. Genotyping was performed on the multiple isolates collected from patients with recurrent VVC (RVVC, referring to VVC which attacks more than 4 times in one year) in different acute infectious phases. The results showed that 59.1% (26/44) of the patients suffered a relapse, with DST 79 (65.4%) as the dominant genotype. The etiology of the remaining 40.9% (18/44) of patients was reinfection, and the main genotypes included DST 79 (33.3%), DST 124 (8.6%) and DST 1895 (8.6%). DST 79 (45%) and DST 1395 (7.5%) were the main isolates of VVC patients, while DST 79 (24.1%), DST 727 (6.9%), DST 732 (6.9%) and DST 1867 (6.9%) were the main types of healthy volunteers. The results of the genotypes between RVVC patients and other groups were statistically different. Furthermore, cluster analysis was carried out on 1468 isolates, among which 1337 were downloaded from the MLST database, 130 were divided into 8 Clades in the present study and the remaining one was taken as a singleton. 92.3% isolates from relapse patients, 58.3% isolates from re-infected patients, 77.5% isolates from VVC patients and 51.7% isolates from volunteers were distributed in Clade 1. The analysis of the genotypes of multiple isolates from RVVC patients further demonstrated that point mutation and loss of heterozygosity contributed to the microevolution of C. albicans.

3.
Alzheimers Res Ther ; 13(1): 93, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947453

RESUMO

BACKGROUND: We aimed to investigate the tau biomarker discrepancies of Alzheimer's disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET). METHODS: In the Alzheimer's Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-ß (Aß) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared. RESULTS: Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF- 15.6%, plasma-/CSF+ 15.3%, plasma+/PET- 22.4%, and plasma-/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aß pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF- and plasma-/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aß burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aß pathology. CONCLUSIONS: Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

4.
J Phys Chem Lett ; : 4530-4536, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961442

RESUMO

Aggregation-induced luminescence quenching of carbon nanodots (CDs) is the main obstacle for their applications in solid-state light emitting devices. Herein, we developed a one-step synthesis of solid-state emissive CDs with surface aluminum-based polymerization by adding AlCl3 in citric acid and urea via a microwave-heating dehydration process. Due to the strong coordination ability of Al ions with N and O atoms, considerable steric hindrance of Al-based cross-linked polymerization was introduced on the surface of the CDs, which not only avoided aggregation of the green emissive carbon cores but also facilitated efficient energy transfer from the blue emissive polymerized surface to the green emissive carbon cores in aggregates, leading to enhanced green emissions with a photoluminescence quantum yield (PLQY) of 72.7% in the solid state.

5.
Colloids Surf B Biointerfaces ; 204: 111796, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33933879

RESUMO

The efficiency of energy transfer from guanine nucleotide to terbium ion (Tb3+) is affected by the phosphate group significantly. Compared with the biomolecules 5'-GMP (guanosine monophosphate), guanosine diphosphate (GDP) exhibits better sensitize ability to Tb3+ ions luminescence. Assisted with the carboxycoumarin ligand, we synthesized a more stable optical Coumarin@GDP-Tb polymer with the characteristic emission peaks located on 440 nm and 545 nm in this work. The Coumarin@GDP-Tb polymer is not only rich in metal binding sites, but also maintains a moderate ionic binding force, which helps metal ions to bind or leave it easily. Experiment result shows that Coumarin@GDP-Tb polymer has the appropriate binding force for Fe2+ ions, which can be destroyed by sulfur ions (S2-) as the formation of FeS precipitation. Based on this, Coumarin@GDP-Tb was designed as the ratio fluorescence probe for sulfur ions detection, where the fluorescence at 545 nm can be selectively quenched by Fe2+ ions, while that at 440 nm was unaffected, in the presence of S2- ions, the quenched fluorescence can be recovered remarkably. With the increasing S2- ions from 0.1-45 µM, the ratio of fluorescence intensity at 545 nm to 440 nm (F545/F440) is linear to S2- concentration, and the detection limit of S2- was calculated to be 0.073 µM. Contrast to those fluorescence probes with single wavelength emission, Coumarin@GDP-Tb displays a comparable sensitivity, the introduced self-adjust wavelength improved the detection accuracy efficiently. The above 98.1 % recovery rates of S2- ions in the actual water sample demonstrated the practicability of Coumarin@GDP-Tb fluorescence probe.

6.
Front Endocrinol (Lausanne) ; 12: 605736, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912130

RESUMO

Purpose: Laron syndrome (LS) is a severe growth disorder caused by GHR gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, GHR gene variants were investigated and further in vitro functional verification was carried out. Methods: Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and GHR gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting. Results: All of the four patients were male, and the median height was -4.72 SDS. Four GHR gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05). Conclusions: Two novel GHR gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the GHR mutations contributed to the pathological condition of LS patients.

7.
Animals (Basel) ; 11(3)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800722

RESUMO

The main objectives of this study were to perform a systematic review of genomic regions associated with various behavioral traits in the main farmed mammals and identify key candidate genes and potential causal mutations by contrasting the frequency of polymorphisms in cattle breeds with divergent behavioral traits (based on a subjective clustering approach). A total of 687 (cattle), 1391 (pigs), and 148 (sheep) genomic regions associated with 37 (cattle), 55 (pigs), and 22 (sheep) behavioral traits were identified in the literature. In total, 383, 317, and 15 genes overlap with genomic regions identified for cattle, pigs, and sheep, respectively. Six common genes (e.g., NR3C2, PITPNM3, RERG, SPNS3, U6, and ZFAT) were found for cattle and pigs. A combined gene-set of 634 human genes was produced through identified homologous genes. A total of 313 out of 634 genes have previously been associated with behavioral, mental, and neurologic disorders (e.g., anxiety and schizophrenia) in humans. Additionally, a total of 491 candidate genes had at least one statistically significant polymorphism (p-value < 0.05). Out of those, 110 genes were defined as having polymorphic regions differing in greater than 50% of exon regions. Therefore, conserved genomic regions controlling behavior were found across farmed mammal species and humans.

8.
Insects ; 12(3)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33808968

RESUMO

Plants release an array of volatile chemicals into the air to communicate with other organisms in the environment. Insect attack triggers emission of herbivore-induced plant volatiles (HIPVs). How insect herbivores use these odors to plan their detoxification systems is vital for insect adaptation to environmental xenobiotics. Here we show that the larvae of Helicoverpa armigera (Hübner), a broadly polyphagous lepidopteran herbivore, have the capacity to use plant volatiles as cues to upregulate multiple detoxification systems, including cytochrome P450 monooxygenases (P450s), for detoxification of insecticides. Olfactory exposure of the fifth instars to two terpene volatiles limonene and nerolidol, and two green-leaf volatiles 2-heptanone and cis-3-hexenyl acetate significantly reduced larval susceptibility to the insecticide methomyl. However, larval pretreatment with piperonyl butoxide (PBO), a known P450 inhibitor, neutralized the effects of volatile exposure. Furthermore, larval exposure to the four plant volatiles enhanced activities of P450 enzymes in midguts and fatbodies, and upregulated expression of CYP6B2, CYP6B6 and CYP6B7, P450s involved in detoxification of the insecticide. Larval exposure to 2-heptanone and limonene volatiles also enhanced activities of glutathione-s-transferase and carboxylesterase. Our findings suggest that olfactory exposure to HIPVs enhances larval insecticide tolerance via induction of detoxification P450s.

9.
mBio ; 12(2)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906925

RESUMO

Unlike nucleobase modifications in canonical restriction-modification systems, DNA phosphorothioate (PT) epigenetic modification occurs in the DNA sugar-phosphate backbone when the nonbridging oxygen is replaced by sulfur in a double-stranded (ds) or single-stranded (ss) manner governed by DndABCDE or SspABCD, respectively. SspABCD coupled with SspE constitutes a defense barrier in which SspE depends on sequence-specific PT modifications to exert its antiphage activity. Here, we identified a new type of ssDNA PT-based SspABCD-SspFGH defense system capable of providing protection against phages through a mode of action different from that of SspABCD-SspE. We provide further evidence that SspFGH damages non-PT-modified DNA and exerts antiphage activity by suppressing phage DNA replication. Despite their different defense mechanisms, SspFGH and SspE are compatible and pair simultaneously with one SspABCD module, greatly enhancing the protection against phages. Together with the observation that the sspBCD-sspFGH cassette is widely distributed in bacterial genomes, this study highlights the diversity of PT-based defense barriers and expands our knowledge of the arsenal of phage defense mechanisms.IMPORTANCE We recently found that SspABCD, catalyzing single-stranded (ss) DNA phosphorothioate (PT) modification, coupled with SspE provides protection against phage infection. SspE performs both PT-simulated NTPase and DNA-nicking nuclease activities to damage phage DNA, rendering SspA-E a PT-sensing defense system. To our surprise, ssDNA PT modification can also pair with a newly identified 3-gene sspFGH cassette to fend off phage infection with a different mode of action from that of SspE. Interestingly, both SspFGH and SspE can pair with the same SspABCD module for antiphage defense, and their combination provides Escherichia coli JM109 with additive phage resistance up to 105-fold compared to that for either barrier alone. This agrees with our observation that SspFGH and SspE coexist in 36 bacterial genomes, highlighting the diversity of the gene contents and molecular mechanisms of PT-based defense systems.

10.
J Psychiatr Res ; 137: 498-505, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33798978

RESUMO

OBJECTIVE: Observational studies have suggested that subjective wellbeing and personality traits link to risk of Alzheimer's disease (AD), but it is unclear if these associations are causal. METHODS: We performed two-sample Mendelian randomization to assess potential causality. Genetic associations were obtained from the largest genome-wide association studies in Social Science Genetic Association Consortium (N = 298,420), Genetics of Personality Consortium (N = 81,036), and four independent consortia of AD (N = 455,258). We run the inverse variance weighted (IVW) approach as one primary analysis. A Bonferroni-corrected threshold of p < 8.33 × 10-3 was considered significant, and p values between 8.33 × 10-3 and 0.05 were considered to be suggestive of an association. RESULTS: The suggestive association with decreased risk of AD was noted for a genetically predicted 1-SD increase in subjective wellbeing (odds ratio = 0.963, 95% confidence interval = 0.930-0.997; p = 0.032). Genetically predicted greater neuroticism was significantly associated with lower subjective wellbeing (ß = -0.077; p = 0.004). No putative personality traits were significantly associated with AD risk after correction for multiple tests, including agreeableness (ß = -0.0010; p = 0.477), conscientiousness (ß = 0.0018; p = 0.270), openness (ß = 0.0004; p = 0.738), neuroticism (ß = -0.0098; p = 0.262), or extraversion (ß = 0.0120; p = 0.262). CONCLUSIONS: Subjective wellbeing may independently reduce the risk of AD. Residual confounding is likely to be responsible for the previous observational relationships between personality traits and AD.

11.
J Org Chem ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33855855

RESUMO

Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A (1) and B (2) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.

12.
Acta Pharmacol Sin ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850273

RESUMO

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.

13.
Molecules ; 26(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808108

RESUMO

Solvothermal synthesis of multiple dihydropyrimidinones at a time has been developed in inexpensive and green bio-based solvent lactic acid without any additional catalysts or additives. By this method, thirty new dihydropyrimidinone derivatives were synthesized in two batches and characterized. All of the compounds were screened by Eg5 motor protein ATPase assay, and the positive compounds were tested against the Caco-2 cell line, HeLa cell line, L929 cell line and T24 cell line in vitro. Among them, compound C9 exhibited the best inhibitory activity against motor protein ATPase with an IC50 value of 30.25 µM and significant cytotoxic activity in the micromolar range against the cells above. The Lineweaver-Burk plot revealed that compound C9 was a mixed-type Eg5 inhibitor. A molecular modeling study using the Discovery Studio program was performed, where compound C9 exhibited good binding interaction with Eg5 motor protein ATPase, and this was consistent with the attained experimental results.

14.
J Alzheimers Dis ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33814452

RESUMO

Mutations in ITM2B have been found to be associated with familial Danish dementia (FDD) and familial British dementia (FBD). Here, we describe a patient with dementia caused by a novel ITM2B p. *267Leuext *11 mutation. The patient presented with dementia, ataxia, deafness, and paraplegia. Amyloid PET and Tau PET showed abnormal deposition of amyloid and tau protein in brain. Summarized from previous 26 FBD and FDD cases, the clinical phenotype of ITM2B; p. *267Leuext *11 mutation in ITM2B is different from the features of FBD and FDD. Our findings increased genetic knowledge of familial dementia and extend the ethnic distribution of ITM2B mutations.

15.
Biol Res Nurs ; : 10998004211009606, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33874782

RESUMO

PURPOSES: Women with diabetes (WD) are more severely impacted by the consequence of suboptimal diabetes control. This study aims to examine the impact of demographic and disease characteristics, baseline self-stigma, role strain, diabetes distress on Hemoglobin A1C (A1C) levels, quality of life (D-QoL) and 6-month A1C levels in younger WD. METHODS: This study was a 6-month prospective study. In total, 193 WD aged 20-64 years were selected by convenience sampling from three outpatient clinics in Taiwan. Demographic and disease characteristics, self-stigma, role strain, diabetes distress, A1C levels, and D-QoL were collected at baseline. A1C levels were further collected 6 months later. Structural equation modeling was conducted to test the hypothesized model. RESULTS: The final model supported that higher baseline D-QoL directly associated with lower concurrent A1C levels and indirectly associated with lower 6-month A1C levels through baseline A1C levels. Higher baseline self-stigma, role strain, and diabetes distress directly associated with lower baseline D-QoL, and indirectly associated with higher 6-month A1C levels through D-QoL. CONCLUSION: Improving self-stigma, role strain, and diabetes distress should be considered as promising strategies to improve D-QoL in young WD. D-QoL plays a mediation role between baseline self-stigma, role strain, diabetes distress and subsequent glycemic control in younger WD. Enhancing baseline D-QoL is fundamental to improve subsequent glycemic control.

16.
J Hematol Oncol ; 14(1): 60, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849617

RESUMO

BACKGROUND: Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear. METHODS: RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed. RESULTS: CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells. CONCLUSIONS: The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients.

17.
Phys Rev E ; 103(3): L030102, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33862711

RESUMO

Engineered swift equilibration (ESE) is a class of driving protocols that enforce an equilibrium distribution with respect to external control parameters at the beginning and end of rapid state transformations of open, classical nonequilibrium systems. ESE protocols have previously been derived and experimentally realized for Brownian particles in simple, one-dimensional, time-varying trapping potentials; one recent study considered ESE in two-dimensional Euclidean configuration space. Here we extend the ESE framework to generic, overdamped Brownian systems in arbitrary curved configuration space and illustrate our results with specific examples not amenable to previous techniques. Our approach may be used to impose the necessary dynamics to control the full temporal configurational distribution in a wide variety of experimentally realizable settings.

18.
AIDS ; 35(Suppl 1): S29-S38, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33867487

RESUMO

BACKGROUND: Machine learning has the potential to help researchers better understand and close the gap in HIV care delivery in large metropolitan regions such as Mecklenburg County, North Carolina, USA. OBJECTIVES: We aim to identify important risk factors associated with delayed linkage to care for HIV patients with novel machine learning models and identify high-risk regions of the delay. METHODS: Deidentified 2013-2017 Mecklenburg County surveillance data in eHARS format were requested. Both univariate analyses and machine learning random forest model (developed in R 3.5.0) were applied to quantify associations between delayed linkage to care (>30 days after diagnosis) and various risk factors for individual HIV patients. We also aggregated linkage to care by zip codes to identify high-risk communities within the county. RESULTS: Types of HIV-diagnosing facility significantly influenced time to linkage; first diagnosis in hospital was associated with the shortest time to linkage. HIV patients with lower CD4+ cell counts (<200/ml) were twice as likely to link to care within 30 days than those with higher CD4+ cell count. Random forest model achieved high accuracy (>80% without CD4+ cell count data and >95% with CD4+ cell count data) to predict risk of delay in linkage to care. In addition, we also identified top high-risk zip codes of delayed linkage. CONCLUSION: The findings helped public health teams identify high-risk communities of delayed HIV care continuum across Mecklenburg County. The methodology framework can be applied to other regions with HIV epidemic and challenge of delayed linkage to care.

19.
Arterioscler Thromb Vasc Biol ; : ATVBAHA121316293, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33910370

RESUMO

OBJECTIVE: The objective of this study is to determine the role of JAK3 (Janus kinase 3) in reendothelialization after vascular injury. METHODS AND RESULTS: By using mouse carotid artery wire injury and rat balloon injury model, we found that JAK3 regulates reendothelialization and endothelial cell proliferation after vascular injury. JAK3 and phospho-JAK3 levels were increased in neointimal smooth muscle cells in response to vascular injury in mice. JAK3 deficiency dramatically attenuated the injury-induced intimal hyperplasia in carotid arteries of both male and female mice. Importantly, JAK3 deficiency caused an increased rate of reendothelialization following mechanical injury. Likewise, knockdown of JAK3 in medial smooth muscle cells elicited an accelerated reendothelialization with reduced intimal hyperplasia following balloon injury in rat carotid arteries. Interestingly, knockdown of JAK3 restored the expression of smooth muscle cell contractile protein smooth muscle α-actin in injury-induced intimal smooth muscle cells while increased the proliferating endothelial cells in the intima area. CONCLUSIONS: Our results demonstrate a novel role of JAK3 in the regeneration of endothelium after vascular injury, which may provide a new strategy to enhance reendothelialization while suppressing neointimal formation for effective vascular repair from injury.

20.
J Nephrol ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33914255

RESUMO

OBJECTIVE: The objective of the study was to investigate the effects of low-dose aspirin (LDA) during pregnancy on the prevention of preeclampsia in patients with chronic kidney disease (CKD). METHODS: The clinical data of pregnant women with CKD were retrospectively analyzed at Peking University First Hospital between January 2013 and January 2020. Among 287 pregnant women with stage 1-2 CKD, 63 patients who were treated with LDA were included in study group 1, and 63 patients who were not treated with aspirin were allocated to control group 1. Among 41 pregnant women with stage 3-5 CKD, 22 patients who were treated with LDA were included in study group 2, and 19 patients were allocated to control group 2. Pregnancy outcomes of the patients with stage 1-2 and stage 3-5 CKD who received LDA during pregnancy and those who did not were compared. RESULTS: No significant difference was observed in the incidence of preeclampsia or severe preeclampsia between study and control group 1. The patients in study group 2 had a lower incidence of severe preeclampsia than those in control group 2 (3/22 [13.6%] vs. 8/19 [42.1%], P = 0.04). Among the patients with stage 3-5 CKD, LDA therapy during pregnancy was associated with a lower risk of severe preeclampsia (odds ratio = 0.22, 95% confidence interval: 0.074-0.993; P = 0.049). CONCLUSIONS: LDA therapy during pregnancy can reduce the risk of severe preeclampsia in patients with stage 3-5 CKD. Prospective studies are  needed to further explore the preventive effects of aspirin on preeclampsia in patients with stage 1-2 CKD.

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