Abstract
We present a systematic study of particle transport by diffusion in young pulsar wind nebulae (PWNe). We selected nine bright sources that are well resolved with the Chandra X-ray ...Observatory. We analyzed archival data to obtain their radial profiles of photon index (Γ) and surface brightness (Σ) in a consistent way. These profiles were then fit with a pure diffusion model that was tested on Crab, 3C 58, and G21.5−0.9 before. In addition to the spectral softening due to the diffusion, we calculated the synchrotron power and built up the theoretical surface brightness profile. For each source, we performed separate fits to the Γ and Σ profiles. We found that these two profiles of most PWNe are similar, except for Crab and Vela. Both profiles can be well described by our model, suggesting that diffusion dominates the particle transport in most sampled PWNe. The discrepancy of parameters between the Γ and Σ profiles is relatively large for 3C 58 and G54.1+0.3. This difference could be attributed to the elongated shape, reflecting boundary, and the nonuniform magnetic field. Finally, we found no significant correlations between diffusion parameters and physical parameters of PWNe and pulsars.
Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations ...have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
Background and Objective
It is known that chronic periodontal infection can magnify the cytokine responses in patients with diabetes. Hyperglycemia increases the proinflammatory status, including the ...levels of advanced glycation end‐products (AGEs), in patients with periodontitis. However, whether AGEs have additional effects on the production of those proinflammatory cytokines in diabetic patients with periodontitis is still unknown. To examine in vitro the effect of hyperglycemia and AGEs on the amounts of interleukin (IL)‐6 and IL‐8 produced in periodontally infected gingiva, human gingival fibroblasts (HGFs) were stimulated with glucose, AGE‐modified bovine serum albumin (AGE‐BSA) and Porphyromonas gingivalis LPS in the present study.
Material and Methods
Primary culture of HGFs was incubated with various concentrations of AGE‐BSA (0, 50, 100 and 200 μg/mL) and LPS (0, 10, 100 or 1000 ng/mL) at two different glucose concentrations – normal glucose (5 mm) and high glucose (25 mm). The amounts of IL‐6 and IL‐8 produced by HGFs were evaluated using ELISA. Expression of the AGE receptor on HGFs was determined by flow cytometry.
Results
High glucose stimulated a significant increase in the production of IL‐6 and IL‐8 by HGFs compared with normal glucose. This enhanced production of IL‐6 and IL‐8 could also be observed in the presence of LPS and/or AGE‐BSA. When both LPS and AGE‐BSA were present, especially at high concentrations (≥ 500 μg/mL of LPS and ≥ 25 μg/mL of AGE‐BSA), a synergistic effect on IL‐8 production was found in the high‐glucose condition.
Conclusions
A synergistic effect of the production of IL‐8 could be induced in HGFs with the combination of high glucose, LPS and AGEs.
Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have ...evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients.
This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD) and death during a follow-up period of 24 months.
Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model.
In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.
The associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined by a ...prospective study using serially measured seromarkers. This study aimed to assess the importance of spontaneous HBeAg, HBV DNA and HBsAg seroclearance in the prediction of HCC risk.
This study included 2946 HBsAg seropositive individuals who were seronegative for antibodies against HCV and free of liver cirrhosis. Serial serum samples collected at study entry and follow-up health examinations were tested for HBeAg, HBV DNA and HBsAg. Cox proportional hazards models were used to calculate the HRs of developing HCC after seroclearance of HBV markers.
The HR (95% CI) of developing HCC after seroclearance of HBeAg, HBV DNA and HBsAg during follow-up was 0.63 (0.38 to 1.05), 0.24 (0.11 to 0.57) and 0.18 (0.09 to 0.38), respectively, after adjustment for age, gender and serum level of alanine aminotransferase at study entry. High HBV DNA levels at the seroclearance of HBeAg (mean±SD, 4.35±1.64 log10 IU/mL) may explain the non-significant association between HBeAg seroclearance and HCC risk. Among HBeAg seronegative participants with detectable serum HBV DNA at study entry, the lifetime (30-75-years-old) cumulative incidence of HCC was 4.0%, 6.6% and 14.2%, respectively, for those with seroclearance of both HBV DNA and HBsAg, seroclearance of HBV DNA only, and seroclearance of neither.
Spontaneous seroclearance of HBV DNA and HBsAg are important predictors of reduced HCC risk.
Aim
To evaluate the effect of 2,3,5,4′‐tetrahydroxystilbene‐2‐O‐β‐D‐glucoside (THSG) on cell proliferation and examine the mechanisms of THSG‐enhanced proliferative potential in human dental pulp ...stem cells (hDPSC).
Methodology
After treatment with THSG, hDPSC were collected. Cell viability was determined by MTS assay, while messenger RNA (mRNA) expressions of proliferation and stem cell markers were analyzed using real‐time PCR. Flow cytometry was also conducted to analysis protein expression of stem cell markers. A colony‐forming unit assay of hDPSC was carried out. Cellular telomerase activity was also identified using real‐time PCR. In addition, proliferation‐related proteins involved in the effects of THSG on hDPSC were analyzed by Western blotting. Data were analyzed using one‐way analysis of variance and two‐tailed Student's t‐test.
Results
Cell viability, colony‐forming rates and telomerase activities of hDPSCs were enhanced after THSG treatment. mRNA expressions of proliferation markers (including expressions of NAD+‐dependent histone deacetylase sirtuin 1 (SIRT1), proliferating cell nuclear antigen (PCNA), cyclin D1 and ribonucleotide reductase subunit M2 (RRM2)) increased significantly after THSG treatment (P < 0.05). Treatment with THSG for 3 h significantly augmented SIRT1 protein expression (P < 0.05). Furthermore, activities of proliferation‐related proteins (including AMP‐activated protein kinase (AMPK) and extracellular signal‐regulated kinase (ERK) had also significantly increased at 3 h (P < 0.05). After THSG treatment, increased gene and protein expressions of pluripotent‐like stem cell markers (including NANOG, OCT4, and SOX2) were observed.
Conclusions
2,3,5,4′‐Tetrahydroxystilbene‐2‐O‐β‐glucoside treatment enhanced the renewal ability and proliferative potential of hDPSCs via the AMPK/ERK/SIRT1 axis, which may provide a novel autogenic cell‐based therapeutic strategy in regenerative dentistry.
We report on a timing and spectral analysis of the young, high magnetic field rotation-powered pulsar (RPP) B1509−58 using Chandra continuous-clocking mode observation. The pulsar's X-ray light curve ...can be fit by the two Gaussian components and the pulsed fraction shows moderate energy dependence over the Chandra band. The pulsed X-ray spectrum is well described by a power law with a photon index 1.16(4), which is harder than the values measured with RXTE/PCA and NuSTAR. This result supports the log-parabolic model for the broadband X-ray spectrum. With the unprecedented angular resolution of Chandra, we clearly identified off-pulse X-ray emission from the pulsar, and its spectrum is best fit by a power law plus blackbody model. The latter component has a temperature of ∼0.14 keV with a bolometric luminosity comparable to the luminosities of other young and high magnetic field RPPs, and it lies between the temperature of magnetars and typical RPPs. In addition, we found that the nonthermal X-ray emission of PSR B1509−58 is significantly softer in the off-pulse phase than in the pulsed phase, with the photon index varying between 1.0 and 1.8 and anticorrelated with the flux. This is similar to the behavior of three other young pulsars. We interpreted it as different contributions of pair-creation processes at different altitudes from the neutron star surface according to the outer-gap model.
•We surveyed the use of machine learning to inform predictive models in mood disorders.•We include studies that use machine learning algorithms to identify predictors of therapeutic outcomes in ...uni/bipolar depression.•Classification algorithms informed by neuroimaging, phenomenological, and genetic data were able to predict therapeutic outcomes with an overall accuracy of 0.82.•Predictive models integrating multiple data types performed better when compared to models with single lower-dimension data types (p <0.01).•Machine learning provides opportunity to parse clinical heterogeneity and characterize moderators of disease risk and trajectory.
No previous study has comprehensively reviewed the application of machine learning algorithms in mood disorders populations. Herein, we qualitatively and quantitatively evaluate previous studies of machine learning-devised models that predict therapeutic outcomes in mood disorders populations.
We searched Ovid MEDLINE/PubMed from inception to February 8, 2018 for relevant studies that included adults with bipolar or unipolar depression; assessed therapeutic outcomes with a pharmacological, neuromodulatory, or manual-based psychotherapeutic intervention for depression; applied a machine learning algorithm; and reported predictors of therapeutic response. A random-effects meta-analysis of proportions and meta-regression analyses were conducted.
We identified 639 records: 75 full-text publications were assessed for eligibility; 26 studies (n=17,499) and 20 studies (n=6325) were included in qualitative and quantitative review, respectively. Classification algorithms were able to predict therapeutic outcomes with an overall accuracy of 0.82 (95% confidence interval CI of 0.77, 0.87). Pooled estimates of classification accuracy were significantly greater (p < 0.01) in models informed by multiple data types (e.g., composite of phenomenological patient features and neuroimaging or peripheral gene expression data; pooled proportion 95% CI = 0.930.86, 0.97) when compared to models with lower-dimension data types (pooledproportion=0.680.62,0.74to0.850.81,0.88).
Most studies were retrospective; differences in machine learning algorithms and their implementation (e.g., cross-validation, hyperparameter tuning); cannot infer importance of individual variables fed into learning algorithm.
Machine learning algorithms provide a powerful conceptual and analytic framework capable of integrating multiple data types and sources. An integrative approach may more effectively model neurobiological components as functional modules of pathophysiology embedded within the complex, social dynamics that influence the phenomenology of mental disorders.
COVID-19 pandemic has resulted in an unprecedented increased usage of Personal protective equipment (PPE) by healthcare-workers. PPE usage causes headache in majority of users. We evaluated changes ...in cerebral hemodynamics among healthcare-workers using PPE.
Frontline healthcare-workers donning PPE at our tertiary center were included. Demographics, co-morbidities and blood-pressure were recorded. Transcranial Doppler (TCD) monitoring of middle cerebral artery was performed with 2-MHz probe. Mean flow velocity (MFV) and pulsatility index (PI) were recorded at baseline, after donning N95 respirator-mask, and after donning powered air-purifying respirator (PAPR), when indicated. End-tidal carbon-dioxide (ET-CO2) pressure was recorded for participants donning PAPR in addition to the N95 respirator-mask.
A total of 154 healthcare-workers (mean age 29 ± 12 years, 67% women) were included. Migraine was the commonest co-morbidity in 38 (25%) individuals while 123 (80%) developed de-novo headache due to N95 mask. Donning of N95 respirator-mask resulted in significant increase in MFV (4.4 ± 10.4 cm/s, p < 0.001) and decrease in PI (0.13 ± 0.12; p < 0.001) while ET-CO2 increased by 3.1 ± 1.2 mmHg (p < 0.001). TCD monitoring in 24 (16%) participants donning PAPR and N95 respirator mask together showed normalization of PI, accompanied by normalization of ET-CO2 values within 5-min. Combined use of N95 respirator-mask and PAPR was more comfortable as compared to N95 respirator-mask alone.
Use of N95 respirator-mask results in significant alterations in cerebral hemodynamics. However, these effects are mitigated by the use of additional PAPR. We recommend the use of PAPR together with the N95 mask for healthcare-workers doing longer duties in the hospital wards.
•Most N95 mask users develop de novo headache or worsening of pre-existing headache.•End-tidal carbon dioxide levels increase while donning N95 respirator mask.•Significant cerebral hemodynamic changes occur during donning of N95 mask.•Powered air-purifying respirator restores N95 mask induced cerebral hemodynamic changes.
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