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1.
Bioresour Technol ; 295: 122266, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31669871

RESUMO

The production of value added chemicals from CO2 is of critical importance for the practical application of microbial electrosynthesis (MES). Here, a binary electron donor (ED) design (using electrode and ethanol) was introduced to provide an efficient caproate production with the bioconversion of both CO2 and ethanol. A maximum caproate production rate of 2.41 ±â€¯0.69 g L-1 d-1, and a final concentration of 7.66 ±â€¯1.38 g L-1 was achieved. Caproate production selectivity based on the substrate increased to 91.47 ±â€¯0.58% (Binary EDs) from 32.22 ±â€¯32.58% (open circuit Electrode ED). An observed amount of 23.43 ±â€¯0.69% of carbon within the final binary ED products originated from the CO2. This work proves for the first time the potential of caproate production from CO2 utilization and ethanol upgrading using solid electrodes to regulate the chain elongation process.

2.
Bioresour Technol ; 294: 122237, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31683454

RESUMO

Free volatile fatty acids such as free acetic acid (FAA) and free butyrate acid (FBA) are true inhibitors of hydrogenotrophic methanogens (HM) in mixed culture. However, their inhibitory effects on pure culture of HM remain unclear. In this study, a typical HM of Methanobacterium formicicum demonstrated no difference in toxicity conferred by FAA, free propionate acid (FPA), or FBA in regard to the specific methanogenic activity (SMA) based on the C50% (0.19, 0.17, and 0.23 g/L, respectively) and recoverable concentration values (0.97, 0.69, and 0.61 g/L, respectively). These results were within the same order of magnitude. The concentrations of FAA, FBA, and FPA all correlated well with the SMA values according to the inhibition model. Additionally, changes in the activity of the electron transport system also agreed well with the trend in the SMA variation. Together, the results of this study provide a benchmark to control methanogenesis during industrial applications.


Assuntos
Euryarchaeota , Methanobacterium , Butiratos , Metano , Propionatos
3.
J Ethnopharmacol ; : 112336, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669102

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aglaia odorata Lour. is a traditional Chinese medicinal plant possessing properties of improving blood circulation, and it is widely used in the treatment of dizziness, traumatic injuries and bruises. AIM OF STUDY: In this study, we are aimed to investigate the cerebral protection effect of the extracts from leaves of Aglaia odorata Lour. (ELA) and the potential mechanism in vivo and in vitro. MATERIALS AND METHODS: The therapeutic effect of ELA on ischemic cerebral stroke was measured on a middle cerebral artery occlusion (MCAO) rat model. Protective effect of ELA on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cells was measured by MTT assay. The apoptotic cells were observed by Hoechst 33258 staining and acridine orange/ethidium bromide double staining assay. Mitochondria were observed by Mitotracker staining assay. The mitochondrial membrane potential was determined by JC-1 staining assay. Western blot was used to investigate the effects of ELA on apoptosis-related proteins. RESULTS: We showed that ELA was an effective neuroprotective agent. In vivo experiments, ELA exerted significant protective effect on MCAO model. TTC staining showed that ELA could reduce cerebral infarction area against MCAO insult. HE and Nissl's staining indicated that ELA could reverse the damage of cortex and hippocampus caused by MCAO. In vitro experiments, ELA showed significant protective effect on OGD/R-induced PC12 cells by reducing the number of apoptotic cells, increasing mitochondrial membrane potential, and reducing superoxide aggregation, further suppressing mitochondrial caspase-9/3 apoptosis pathway. Moreover, protective effect of ELA on mitochondrial function may be exerted by inhibiting p53/Puma signal pathway. CONCLUSION: Our results suggest that ELA exerts a marked neuroprotective effect against cerebral ischemia potentially via suppressing p53/Puma-mediated mitochondrial caspase-9/3 apoptosis pathway.

4.
J Pharm Biomed Anal ; : 112936, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31672581

RESUMO

The combination of notoginseng total saponins (NS) and safflower total flavonoids (SF), namely CNS, presents a synergistic protection effect on the myocardial ischemia rats. The aim of this study was to find the clues for their synergistic actions by comparing the biliary metabolism and excretion profiles after oral administration of CNS and its individual extracts. An ultra-performance liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometer (UPLC-QTRAP-MS/MS) platform was used to identify and quantify the CNS-derived components in bile. The neutral losses, precursor ions, and predictive multiple reaction monitoring (pMRM) scans were firstly used to detect the CNS-derived ingredients in vivo. A total of 43 components, including 38 flavonoids and 5 ginsenosides were tentatively identified according to the previously established chemical and metabolic profiles of NS and SF. Afterwards, the primary circulating and biological components, hydroxysafflor yellow A (HSYA), ginsenosides Rg1 (GRg1), Re (GRe), and Rd (GRd) were chosen to compare the bile excretion between CNS and its individual extract groups, by using a validated LC-MRM-MS/MS method. The approach was proved to be well satisfied the related requirements from the guidelines of FDA (specificity, calibration curve, sensitivity, precision, accuracy, matrix effect, recovery, and stability). Comparing with the SF and NS groups, the combination group did not affect the metabolic pathways of the CNS-related components, however, it decreased the cumulative excretion ratios of HSYA, GRg1, GRe, and GRd. In conclusion, the compatibility of SF and NS could reduce the bile excretion of the CNS-derived compounds, which may be one of the reasons for the enhancement of anti-myocardial ischemia after combination.

5.
Nucleic Acids Res ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31598675

RESUMO

Transcription factors (TFs) and their target genes have important functions in human diseases and biological processes. Gene expression profile analysis before and after knockdown or knockout is one of the most important strategies for obtaining target genes of TFs and exploring TF functions. Human gene expression profile datasets with TF knockdown and knockout are accumulating rapidly. Based on the urgent need to comprehensively and effectively collect and process these data, we developed KnockTF (http://www.licpathway.net/KnockTF/index.html), a comprehensive human gene expression profile database of TF knockdown and knockout. KnockTF provides a number of resources for human gene expression profile datasets associated with TF knockdown and knockout and annotates TFs and their target genes in a tissue/cell type-specific manner. The current version of KnockTF has 570 manually curated RNA-seq and microarray datasets associated with 308 TFs disrupted by different knockdown and knockout techniques and across multiple tissue/cell types. KnockTF collects upstream pathway information of TFs and functional annotation results of downstream target genes. It provides details about TFs binding to promoters, super-enhancers and typical enhancers of target genes. KnockTF constructs a TF-differentially expressed gene network and performs network analyses for genes of interest. KnockTF will help elucidate TF-related functions and potential biological effects.

6.
J Cereb Blood Flow Metab ; : 271678X19881449, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594437

RESUMO

Successful recanalization of the occluded vessel as early as possible has been widely accepted as the key principle of acute ischemic stroke (AIS) treatment. Unfortunately, for many years, the vast majority of AIS patients were prevented from receiving effective recanalization therapy because of a narrow therapeutic window. Recently, a series of inspiring clinical trials have indicated that more patients may benefit from delayed recanalization during an expanded therapeutic window, even up to 24 h after symptom onset. However, could potentially salvageable brain tissue (penumbra) in patients who do not receive medication within 24 h still possible to be saved?

7.
Artigo em Inglês | MEDLINE | ID: mdl-31595843

RESUMO

ß-D-2'-C-Methyl-2,6-diaminopurine ribonucleoside (2'-C-Me-DAPN) phosphoramidate prodrug (DAPN-PD) is a selective hepatitis C virus inhibitor that is metabolized intracellularly into two active metabolites: 2'-C-Methyl-DAPN triphosphate (2'-C-Me-DAPN-TP) and 2'-C-methyl-guanosine 5'-triphosphate (2'-C-Me-GTP). BMS-986094 and IDX-184 are also bioconverted to 2'-C-Me-GTP. A phase IIb clinical trial with BMS-986094 was abruptly halted due to adverse cardiac and renal effects. Herein, we developed an efficient large scale synthesis of DAPN-PD and determined intracellular pharmacology of DAPN-PD in comparison with BMS-986094 and IDX-184, versus Huh-7, HepG2 and interspecies primary hepatocytes and human cardiomyocytes. Imaging data of drug treated human cardiomyocytes was found to be most useful in determining toxicity potential as no obvious beating rate change was observed for IDX-184 up to 50 µM up at 48 h. However, with BMS-986094 and DAPN-PD at 10 µM changes to both beat rate and rhythm were noted.

8.
Transl Psychiatry ; 9(1): 267, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636273

RESUMO

Despite the substantial progress made in identifying genetic defects in autism spectrum disorder (ASD), the etiology for majority of ASD individuals remains elusive. Maternal exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug during pregnancy in human, has long been considered a risk factor to contribute to ASD susceptibility in offspring from epidemiological studies in humans. The similar exposures in murine models have provided tentative evidence to support the finding from human epidemiology. However, the apparent difference between rodent and human poses a significant challenge to extrapolate the findings from rodent models to humans. Here we report for the first time the neurodevelopmental and behavioral outcomes of maternal VPA exposure in non-human primates. Monkey offspring from the early maternal VPA exposure have significantly reduced NeuN-positive mature neurons in prefrontal cortex (PFC) and cerebellum and the Ki67-positive proliferating neuronal precursors in the cerebellar external granular layer, but increased GFAP-positive astrocytes in PFC. Transcriptome analyses revealed that maternal VPA exposure disrupted the expression of genes associated with neurodevelopment in embryonic brain in offspring. VPA-exposed juvenile offspring have variable presentations of impaired social interaction, pronounced stereotypies, and more attention on nonsocial stimuli by eye tracking analysis. Our findings in non-human primates provide the best evidence so far to support causal link between maternal VPA exposure and neurodevelopmental defects and ASD susceptibility in humans.

9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(9): 1041-1047, 2019 Sep 28.
Artigo em Chinês | MEDLINE | ID: mdl-31645495

RESUMO

OBJECTIVE: To investigate the value of ventricular tachycardia (VT) score in diagnosing pre-excited tachycardia.
 Methods: Twelve-lead electrocardiograph results were obtained from 30 patients at pre-excited tachycardia attacking stage who were diagnosed by electrophysiology. We scored pre-excitation tachycardia based on the VT score. To analyze the electrocardiogram of pre-excited tachycardia using 7 diagnostic indicators of the VT score and calculate the specificity of 7 diagnostic indicators and right superior axis (-90º to ±180º), the differences were compared among VT score of 2 points and brugada, Wellens, and Vereckei algorithms in diagnosing pre-excited tachycardia. According to the specificity of Vereckei, Wellens, and Brugada algorithms, and VT scores from low to high, their prediction value and differences were analyzed.
 Results: Single indicator such as atrioventricular (AV) dissociation or right superior axis (-90º to ±180º) showed the highest specificity (100%) for identifying pre-excited tachycardia. No patient with VT score was ≥3 points, and the specificity was 100%. The specificity of VT score of 2 point was higher than that of Brugada, Wellens, or Vereckei algorithms in the diagnosing pre-excited tachycardia (76.7% vs 50.0%, 23.3% or 20.0%, P<0.05). The specificity of Vereckei, Wellens, and Brugada algorithms and VT score were gradually increased after each of stepwise individually eliminated VT (20.0%, 40.0%, 66.7%, 83.3%, P<0.05). However, there was no significant difference in the specificity in the remaining false positive cases between the 4 methods and VT score.
 Conclusion: VT score ≥3 points can identify pre-excited tachycardia and VT with 100% specificity. VT score of 2 points cannot completely distinguish pre-excited tachycardia from VT, but specificity of VT score with 2 points is obviously higher than that of Brugada, Wellens, and Vereckei algorithms.

10.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 500-505, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642226

RESUMO

OBJECTIVE: To evaluate the expression of translocator protein (TSPO) in brain tissue within 72 h after subarachnoid hemorrhage (SAH) in mice. METHODS: Forty-four C57BL/6J mice were randomly divided into two groups, 17 in the Sham group and 27 in the SAH group. SAH mice model was performed by endovascular perforation as previously described with slight modifications. Sham group mice were performed by the same method but without piercing the blood vessels. Before and 6 h, 24 h, 48 h, 72 h after modeling, the two groups were scored with modified Garcia score for neurological function. At 6 h, 24 h, 48 h, 72 h after modeling, the mice were sacrificed. Sham group mice were sacrificed at 24 h after modeling. The expression of TSPO in brain tissue was evaluated by Western blot, positron emission tomography-computed tomography (PET-CT) and immunofluorescence staining. Fluorescent double staining was used to assess the relationship of TSPO and microglia. RESULTS: The neurological function scores of the SAH group mice decreased with time and then increased. The expression of TSPO in the brain tissue increased first and then decreased with time, and there was a negative correlation between them (r=-0.615 6, P < 0.01). PET-CT showed that the tracer intake of mouse brain tissue after SAH was higher than that of Sham group, and the difference was statistically significant (P < 0.05). Immunofluorescence staining showed that TSPO increased in the parietal cortex and basal cortex of the SAH group. And fluorescent double staining suggested that TSPO colocalized with Iba-1 which was a specific marker of microglia. CONCLUSIONS: In the early brain injury after SAH, the expression of TSPO in brain is widely increased, and the expression level increases first and then decreases. TSPO could participate in the activation of microglia and regulate the occurrence and development of brain injury after SAH.

11.
Nat Immunol ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636463

RESUMO

Natural killer (NK) cells have crucial roles in tumor surveillance. We found that tumor-infiltrating NK cells in human liver cancers had small, fragmented mitochondria in their cytoplasm, whereas liver NK cells outside tumors, as well as peripheral NK cells, had normal large, tubular mitochondria. This fragmentation was correlated with reduced cytotoxicity and NK cell loss, resulting in tumor evasion of NK cell-mediated surveillance, which predicted poor survival in patients with liver cancer. The hypoxic tumor microenvironment drove the sustained activation of mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) in NK cells, resulting in excessive mitochondrial fission into fragments. Inhibition of mitochondrial fragmentation improved mitochondrial metabolism, survival and the antitumor capacity of NK cells. These data reveal a mechanism of immune escape that might be targetable and could invigorate NK cell-based cancer treatments.

12.
Am J Pathol ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31610172

RESUMO

Acetaminophen (APAP) overdose-induced hepatotoxicity is the leading cause of drug-induced liver injury worldwide. The related injury pathogenesis is mainly focused on the liver. Here, we report that gut barrier disruption may also be involved in APAP hepatotoxicity. APAP administration led to gut leakiness and colonic epithelial chemokine (C-C motif) ligand 7 (CCL7) up-regulation. Intestinal epithelial cell (IEC)-specific CCL7 transgenic mice (CCL7tgIEC mice) showed markedly increased myosin light chain kinase (MLCK) phosphorylation and elevated gut permeability and bacterial translocation into the liver compared to wild-type mice. Global transcriptome analysis revealed that the expression of hepatic pro-inflammatory genes was enhanced in CCL7tgIEC mice compared to wild-type animals. Moreover, CCL7 overexpression in intestinal epithelial cells significantly augmented APAP-induced acute liver injury. Our data provides new evidence that dysfunction of CCL7-mediated gut barrier integrity may be an important contributor to APAP-induced hepatotoxicity.

13.
G3 (Bethesda) ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604824

RESUMO

Genome-wide association studies (GWAS) have gained central importance for the identification of candidate loci underlying complex traits. Single nucleotide polymorphism (SNP) markers are mostly used as genetic variants for the analysis of genotype-phenotype associations in populations, but closely linked SNPs that are grouped into haplotypes are also exploited. The benefit of haplotype-based GWAS approaches versus SNP-based approaches is still under debate because SNPs in high linkage disequilibrium provide redundant information. To overcome some constraints of the commonly-used haplotype-based GWAS in which only consecutive SNPs are considered for haplotype construction, we propose a new method called functional haplotype-based GWAS (FH GWAS). FH GWAS is featured by combining SNPs into haplotypes based on the additive and epistatic effects among SNPs. Such haplotypes were termed functional haplotypes (FH). As shown by simulation studies, the FH GWAS approach clearly outperformed the SNP-based approach unless the minor allele frequency of the SNPs making up the haplotypes is low and the linkage disequilibrium between them is high. Applying FH GWAS for the trait flowering time in a large Arabidopsis thaliana population with whole-genome sequencing data revealed its potential empirically. FH GWAS identified all candidate regions which were detected in SNP-based and two other haplotype-based GWAS approaches. In addition, a novel region on chromosome 4 was solely detected by FH GWAS. Thus both the results of our simulation and empirical studies demonstrate that FH GWAS is a promising method and superior to the SNP-based approach even if almost complete genotype information is available.

14.
Trauma Violence Abuse ; : 1524838019881738, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31630666

RESUMO

So far, no Chinese- or English-language journal investigations have been carried out on the entirety of research published on intimate partner violence (IPV) in China. Accordingly, the main purpose of this study was to analyze the contents of the totality of published IPV research articles indexed in China National Knowledge Infrastructure (CNKI). Specifically, the study aimed to investigate the input and output factors relating to published articles concerned with IPV, including their authors and contents. The CNKI was selected for investigation and analysis because it is the largest and most consulted academic online library in China. The analysis was conducted on 3,595 peer-reviewed journal articles on IPV over a 37-year period covering 1982-2018. The findings revealed that only 68 (1.89%) of the articles were empirically and quantitatively based. Findings among these 68 articles show that total contribution of IPV research has increased significantly over time in China, with increasing growth in the past two decades especially. Results also present summaries concerned with the reviewed studies' inputs (i.e., researchers' organizational affiliations, funding sources, and geographic settings), outputs (i.e., authors, journals, classifications, pages, topics, key words, definitions, theoretical approaches, samples, and methods), and outcomes (i.e., citations, downloads, prevalence rates, and correlates of violence). To sum, this is the first exploratory study of the unique and diverse body of IPV research in the Chinese-language and scientific literature. Overall, the study's results both help to inform future IPV research in China and foster and inform communications concerning IPV research globally.

15.
Mol Biol Evol ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633786

RESUMO

Phylogenetic trees and data are often stored in incompatible and inconsistent formats. The outputs of software tools that contain trees with analysis findings are often not compatible with each other, making it hard to integrate the results of different analyses in a comparative study. The treeio package is designed to connect phylogenetic tree input and output. It supports extracting phylogenetic trees as well as the outputs of commonly used analytical software. It can link external data to phylogenies and merge tree data obtained from different sources, enabling analyses of phylogeny-associated data from different disciplines in an evolutionary context. Treeio also supports export of a phylogenetic tree with heterogeneous associated data to a single tree file, including BEAST compatible NEXUS and jtree formats; these facilitate data sharing as well as file format conversion for downstream analysis. The treeio package is designed to work with the tidytree and ggtree packages. Tree data can be processed using the tidy interface with tidytree and visualized by ggtree. The treeio package is released within the Bioconductor and rOpenSci projects. It is available at https://www.bioconductor.org/packages/treeio/.

16.
J Neurovirol ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654372

RESUMO

This case report presents a 1-year-old boy from China, with sudden onset of fever, convulsion, and sleepiness, screened for viral DNA in blood and cerebrospinal fluid (CSF) sample using next-generation sequencing (NGS) to diagnose herpes simplex virus type 1 (HSV-1) encephalitis, further validated by PCR. After acyclovir treatment, the patient's symptom disappeared and HSV-1 DNA unique reads decreased from 4290 to zero in CSF, and from 23 to zero in blood detected by NGS. The clinical presentation and outcome were consistent with the pathogenic diagnostic results of NGS. NGS of CSF samples can be used as a diagnostic assay for HSV-1 encephalitis and also might be a semi-quantitative method for evaluation of treatment effect.

17.
Nucleic Acids Res ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665430

RESUMO

Enhancers are a class of cis-regulatory elements that can increase gene transcription by forming loops in intergenic regions, introns and exons. Enhancers, as well as their associated target genes, and transcription factors (TFs) that bind to them, are highly associated with human disease and biological processes. Although some enhancer databases have been published, most only focus on enhancers identified by high-throughput experimental techniques. Therefore, it is highly desirable to construct a comprehensive resource of manually curated enhancers and their related information based on low-throughput experimental evidences. Here, we established a comprehensive manually-curated enhancer database for human and mouse, which provides a resource for experimentally supported enhancers, and to annotate the detailed information of enhancers. The current release of ENdb documents 737 experimentally validated enhancers and their related information, including 384 target genes, 263 TFs, 110 diseases and 153 functions in human and mouse. Moreover, the enhancer-related information was supported by experimental evidences, such as RNAi, in vitro knockdown, western blotting, qRT-PCR, luciferase reporter assay, chromatin conformation capture (3C) and chromosome conformation capture-on-chip (4C) assays. ENdb provides a user-friendly interface to query, browse and visualize the detailed information of enhancers. The database is available at http://www.licpathway.net/ENdb.

18.
PLoS One ; 14(10): e0223445, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31652267

RESUMO

Geese are extremely well-adapted to utilizing plant-derived roughage in their diet, so the grass must be added to commercial diets under intensive rearing systems. However, it is unclear whether the gut microbiota will change significantly when adding different proportions of ryegrass. In this study, 240 healthy male Yangzhou geese (28 days old) with similar body weights were randomly divided into four groups and fed different proportions grass (CK, whole commercial diets; EG1, ryegrass: commercial diets = 1.5:1; EG2, ryegrass: commercial diets = 2:1; EG3, ryegrass: commercial diets = 3:1) respectively. When the geese grew to 70 days old, their intestines were collected and high-throughput sequencing technology was performed to investigate the microbial diversity in the caecum of geese with different dietary supplements. There was no obvious change in the alpha diversity of gut microbiota of geese with ryegrass intake (P > 0.05) and the composition of dominant bacterium (including Bacteroidetes and Firmicutes) was also similar. However, the ratio between Firmicutes and Bacteroidetes was remarkably reduced with ryegrass intake (P < 0.05), and the relative abundance of 30 operational taxonomic units (OTUs) significantly differed. Additionally, the content of cellulose-degrading microbiota such as Ruminiclostridium and Ruminococcaceae UCG-010 were significantly increased in geese fed with increasing amounts of grass. Finally, the functional profiles of the goose gut microbiota were explored using the PICRUSt tool. Carbohydrate metabolism and amino acid metabolism were dominant metabolic pathways. Lipid metabolism was significantly increased in EG3 compared that in the CK group (P < 0.05). Interestingly, Turicibacter and Parasutterella may have affected abdominal fat deposition as grass intake increased. Taken together, although the diversity of bacterial communities was similar in geese fed with different proportions of ryegrass, cellulose-degrading microbiota (Ruminiclostridium and Ruminococcaceae UCG-010) were abundant and the lipid metabolic pathway was enriched, which may reduce abdominal fat accumulation in high-ryegrass fed geese.

19.
Placenta ; 88: 28-35, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31606612

RESUMO

PURPOSE: To evaluate the effect of maternal hyperoxygenation on placental perfusion in normal and Fetal Growth Restricted (FGR) pregnancies using Intravoxel Incoherent Motion (IVIM). METHODS: Ten FGR pregnancies and twenty-five normal pregnancies underwent IVIM examinations before and after maternal hyperoxygenation (95% O2, 5% CO2) using a 1.5T MR scanner. The IVIM parameters (fp, Dt, Dp) were determined for the placentas of both groups. The IVIM parameters within and between groups and their correlations with Doppler findings were statistically analyzed. ROC analysis was performed to evaluate the diagnostic power of IVIM derived parameters. RESULTS: Before maternal hyperoxygenation, the perfusion fraction fp was significantly lower in the FGR group than that in the normal group (22.88±10.29 (%) vs. 36.28±9.70 (%), p = 0.000). After maternal hyperoxygenation, fp decreased significantly in the normal group (36.28±9.70 (%) vs. 29.93±10.25 (%), p = 0.032), whereas it remained relatively stable in the FGR group (22.88±10.29 (%) vs. 24.38±13.67 (%), p = 0.508). An increase of Dt was found only for the normal group and Dp did not changed significantly after maternal hyperoxygenation. There existed a negative correlation between fppre and umbilical artery pulsatility index (PI) (r = -0.385, p < 0.05) as well as Dtpost and PI (r = -0.574, p < 0.01). The fppre displayed a best diagnostic power of all parameters with the area under curve (AUC) of 0.912. CONCLUSION: The perfusion fraction, fp, is able to distinguish FGR from normal pregnancies by its value pre and by its change (or lack thereof) post maternal hyperoxygenation. IVIM may potentially help improve the diagnosis of placenta function as it relates to disease.

20.
J Neuroinflammation ; 16(1): 182, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31561750

RESUMO

BACKGROUND: Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/ß, and other pro-inflammatory cytokines. METHODS: Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. RESULTS: In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. CONCLUSION: These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

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