Untargeted serum metabolomic profiles and breast density in young women.

PURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

Concomitant assessment of PD-1 and CD56 expression identifies subsets of resting cord blood Vδ2 T cells with disparate cytotoxic potential.

Vγ9Vδ2 T lymphocytes are programmed for broad antimicrobial responses with rapid production of Th1 cytokines even before birth, and thus thought to play key roles against pathogens in infants. The process regulating Vδ2 cell acquisition of cytotoxic potential shortly after birth remains understudied. We observed that perforin production in cord blood Vδ2 cells correlates with phenotypes defined by the concomitant assessment of PD-1 and CD56. Bulk RNA sequencing of sorted Vδ2 cell fractions indicated that transcripts related to cytotoxic activity and NK function are enriched in the subset with the highest proportion of perforin+ cells. Among differentially expressed transcripts, IRF8, previously linked to CD8 T cell effector differentiation and NK maturation, has the potential to mediate Vδ2 cell differentiation towards cytotoxic effectors. Our current and past results support the hypothesis that distinct mechanisms regulate Vδ2 cell cytotoxic function before and after birth, possibly linked to different levels of microbial exposure.

Does COVID-19 affect sperm quality in males? the answer may be yes, but only temporarily.

BACKGROUND: The Corona Virus Disease 2019 (COVID-19) pandemic has raised concerns regarding its potential impact on male reproductive health. However, the impact of COVID-19 on sperm quality remains uncertain. This retrospective study aimed to investigate the short-term and relatively long-term effects of COVID-19 infection on sperm quality. METHODS: A total of 85 males with fertility requirements, who underwent semen evaluation at Guilin People's Hospital between June 2022 and July 2023, were included in the study. Changes in semen parameters were analyzed across three specific timeframes: within 6 months before COVID-19 infection, within 3 months after COVID-19 infection, and 3-6 months after COVID-19 recovery. RESULTS: The results revealed that the sperm concentration and total sperm number were significantly lower after infection compared to before, while in the recovery period, the sperm concentration, total sperm count, progressive motility, and normal morphology significantly increased. Comparing the three periods, the most significant difference was observed in sperm concentration, which exhibited a significant decrease after infection but returned to normal levels after recovery from COVID-19. CONCLUSIONS: These findings suggest that COVID-19 may exert some impact on sperm quality, particularly evidenced by decreased sperm concentration post-infection. Fortunately, these effects on semen parameters appear to be temporary, with gradual restoration of semen parameters within 3-6 months after recovery. However, further research is needed to explore the underlying mechanisms and long-term implications of these observed changes in semen parameters.

Learning Curve for No-Touch Vein Harvesting Technique in Off-Pump Coronary Artery Bypass Grafting.

INTRODUCTION: This study aims to evaluate the learning curve associated with the no-touch vein harvesting technique in off-pump coronary artery bypass grafting (CABG), highlighting its impact on surgical proficiency. METHODS: We employed logarithmic curve fitting to analyze the learning curves of 160 patients undergoing no-touch CABG, with a detailed retrospective examination of 89 patients who received three grafts using Cumulative Sum (CUSUM) analysis. Patients were categorized into two phases: the initial learning phase and the subsequent mastery phase, based on the chronological order of surgeries. We then compared perioperative outcomes between these phases. RESULTS: The learning curve for the no-touch vein harvesting technique was quantitatively established at 51 cases via CUSUM analysis, with supporting evidence from logarithmic curve fitting indicating a significant proficiency milestone. In the mastery phase, median operative times, aorta-saphenous vein graft (SVG) anastomosis, and SVG inspection durations were notably reduced (230 vs. 250 minutes, P = 0.002; 11.5 vs. 13.0 minutes, P = 0.025; 9.0 vs. 11.0 minutes, P = 0.002, respectively), alongside decreased initial 48-hour chest tube drainage, shorter postoperative hospital stays, and fewer incidences of delayed leg incision healing compared to the learning phase [312.6 (140.7) ml vs. 401.0 (233.5) ml, P = 0.029; 11.0 d vs. 12.0 d, P = 0.026; 15.7% vs. 2.6%, P = 0.043)]. CONCLUSION: Cardiac surgeons adopting the full-incision SVG harvesting method for no-touch CABG undergo a discernible learning curve before achieving early proficiency. It is crucial, especially during the initial learning phase, to focus on aorta-SVG anastomosis, the meticulous inspection for bleeding, and the management of wound complications to optimize patient outcomes.

Laminar Flow on Endothelial Cells Suppresses eNOS O-GlcNAcylation to Promote eNOS Activity.

[Figure: see text].

Mining on Alzheimer's diseases related knowledge graph to identity potential AD-related semantic triples for drug repurposing.

BACKGROUND: To date, there are no effective treatments for most neurodegenerative diseases. Knowledge graphs can provide comprehensive and semantic representation for heterogeneous data, and have been successfully leveraged in many biomedical applications including drug repurposing. Our objective is to construct a knowledge graph from literature to study the relations between Alzheimer's disease (AD) and chemicals, drugs and dietary supplements in order to identify opportunities to prevent or delay neurodegenerative progression. We collected biomedical annotations and extracted their relations using SemRep via SemMedDB. We used both a BERT-based classifier and rule-based methods during data preprocessing to exclude noise while preserving most AD-related semantic triples. The 1,672,110 filtered triples were used to train with knowledge graph completion algorithms (i.e., TransE, DistMult, and ComplEx) to predict candidates that might be helpful for AD treatment or prevention. RESULTS: Among three knowledge graph completion models, TransE outperformed the other two (MR = 10.53, Hits@1 = 0.28). We leveraged the time-slicing technique to further evaluate the prediction results. We found supporting evidence for most highly ranked candidates predicted by our model which indicates that our approach can inform reliable new knowledge. CONCLUSION: This paper shows that our graph mining model can predict reliable new relationships between AD and other entities (i.e., dietary supplements, chemicals, and drugs). The knowledge graph constructed can facilitate data-driven knowledge discoveries and the generation of novel hypotheses.

Childhood adiposity, serum metabolites and breast density in young women.

BACKGROUND: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density. METHODS: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation. RESULTS: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV. CONCLUSIONS: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

Transcriptome profiling reveals that VNPP433-3ß, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers.

Cancer stem cells (CSCs) virtually present in all tumors albeit in small numbers are primarily responsible for driving cancer progression, metastasis, drug resistance, and recurrence. Prostate cancer (PCa) is the second most frequent cancer in men worldwide, and castration resistant prostate cancer (CRPC) remains a major challenge despite the tremendous advancements in medicine. Currently, none of the available treatment options are effective in treating CRPC. We earlier reported that VNPP433-3ß, the lead next-generation galeterone analog is effective in treating preclinical in vivo models of CRPC. In this study using RNA-seq, cytological, and biochemical methods, we report that VNPP433-3ß inhibits prostate CSCs by targeting key pathways critical to stemness and epithelial-mesenchymal transition. VNPP433-3ß inhibits CSCs in PCa, presumably by degrading the androgen receptor (AR) thereby decreasing the AR-mediated transcription of several stem cell markers including BMI1 and KLF4. Transcriptome analyses by RNA-seq, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis demonstrate that VNPP433-3ß inhibits transcription of several genes and functional pathways critical to the prostate CSCs thereby inhibiting CSCs in PCa besides targeting the bulk of the tumor.

Photodynamic Priming Modulates Endothelial Cell-Cell Junction Phenotype for Light-activated Remote Control of Drug Delivery.

The blood-brain barrier (BBB) remains a major obstacle for drug delivery to the central nervous system. In particular, the tight and adherens junctions that join the brain capillary endothelial cells limit the diffusion of various molecules from the bloodstream into the brain. Photodynamic priming (PDP) is a non-cytotoxic modality that involves light activation of photosensitizers to photochemically modulate nearby molecules without killing the cells. Here we investigate the effects of sub-lethal photochemistry on junction phenotype (i.e., continuous, punctate, or perpendicular), as well as the BBB permeability in a transwell model of human brain microvascular endothelial cells (HBMECs). We showed that PDP decreases the continuous junction architecture by ~20%, increases the perpendicular junction architecture by ~40%, and has minimal impact on cell morphology in HBMECs. Furthermore, transwell permeability assay revealed that PDP improves the HBMEC permeability to dextran or nanoliposomes by up to 30-fold for 6-9 days. These results suggest that PDP could safely reverse the mature brain endothelial junctions without killing the HBMECs. This study not only emphasizes the critical roles of PDP in the modulation junction phenotype, but also highlights the opportunity to further develop PDP-based combinations that opens the cerebrum endothelium for enhanced drug transporter across the BBB.

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages.

Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme ß-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8-10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.

Decrease in SHP-1 enhances myometrium remodeling via FAK activation leading to labor.

Preterm birth is one of the most common complications during human pregnancy and is associated with a dramatic switch within the uterus from quiescence to contractility. However, the mechanisms underlying uterine remodeling are largely unknown. Protein kinases and phosphatases play critical roles in regulating the phosphorylation of proteins involved in the smooth muscle cell functions. In the present study, we found that Src-homology phosphatase type-1 (SHP-1, PTPN6) was significantly decreased in human myometrium in labor compared with that not in labor. Timed-pregnant mice injected intraperitoneally with the specific SHP-1 inhibitor protein tyrosine phosphatase inhibitor I (PTPI-1) manifested significantly preterm labor, with enriched plasmalemmal dense plaques between myometrial cells and increased phosphorylation at Tyr397 and Tyr576/577 sites of focal adhesion kinase (FAK) in myometrial cells, which remained to the time of labor, whereas the phosphorylation levels of ERK1/2 and phosphatidylinositol 3 kinase (PI3K) showed a rapid increase upon PTPI-1 injection but fell back to normal at the time of labor. The Tyr576/577 in FAK played an important role in the interaction between FAK and SHP-1. Knockdown of SHP-1 dramatically increased the spontaneous contraction of human uterine smooth muscle cells (HUSMCs), which was reversed by coinfection of a FAK-knockdown lentivirus. PGF2α downregulated SHP-1 via PLCß-PKC-NF-κB or PI3K-NF-κB pathways, suggesting the regenerative downregulation of SHP-1 enhances the uterine remodeling and plasticity by activating FAK and subsequent focal adhesion pathway, which eventually facilitates myometrium contraction and leads to labor. The study sheds new light on understanding of mechanisms that underlie the initiation of labor, and interventions for modulation of SHP-1 may provide a potential strategy for preventing preterm birth.

Alcohol consumption and serum metabolite concentrations in young women.

PURPOSE: Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the association. We used global metabolomics profiling to identify serum metabolites and metabolic pathways that could potentially mediate the alcohol-breast cancer association. METHODS: A cross-sectional analysis of reported alcohol consumption and serum metabolite concentrations was conducted among 211 healthy women 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-Up Study (DISC06). Alcohol-metabolite associations were evaluated using multivariable linear mixed-effects regression. RESULTS: Alcohol was significantly (FDR p < 0.05) associated with several serum metabolites after adjustment for diet composition and other potential confounders. The amino acid sarcosine, the omega-3 fatty acid eicosapentaenoate, and the steroid 4-androsten-3beta,17beta-diol monosulfate were positively associated with alcohol intake, while the gamma-tocopherol metabolite gamma-carboxyethyl hydroxychroman (CEHC) was inversely associated. Positive associations of alcohol with 2-methylcitrate and 4-androsten-3beta,17beta-diol disulfate were borderline significant (FDR p < 0.10). Metabolite set enrichment analysis identified steroids and the glycine pathway as having more members associated with alcohol consumption than expected by chance. CONCLUSIONS: Most of the metabolites associated with alcohol in the current analysis participate in pathways hypothesized to mediate the alcohol-breast cancer association including hormonal, one-carbon metabolism, and oxidative stress pathways, but they could also affect risk via alternative pathways. Independent replication of alcohol-metabolite associations and prospective evaluation of confirmed associations with breast cancer risk are needed.

Gene Expression Signatures Characterized by Longitudinal Stability and Interindividual Variability Delineate Baseline Phenotypic Groups with Distinct Responses to Immune Stimulation.

Human immunity exhibits remarkable heterogeneity among individuals, which engenders variable responses to immune perturbations in human populations. Population studies reveal that, in addition to interindividual heterogeneity, systemic immune signatures display longitudinal stability within individuals, and these signatures may reliably dictate how given individuals respond to immune perturbations. We hypothesize that analyzing relationships among these signatures at the population level may uncover baseline immune phenotypes that correspond with response outcomes to immune stimuli. To test this, we quantified global gene expression in peripheral blood CD4+ cells from healthy individuals at baseline and following CD3/CD28 stimulation at two time points 1 mo apart. Systemic CD4+ cell baseline and poststimulation molecular immune response signatures (MIRS) were defined by identifying genes expressed at levels that were stable between time points within individuals and differential among individuals in each state. Iterative differential gene expression analyses between all possible phenotypic groupings of at least three individuals using the baseline and stimulated MIRS gene sets revealed shared baseline and response phenotypic groupings, indicating the baseline MIRS contained determinants of immune responsiveness. Furthermore, significant numbers of shared phenotype-defining sets of determinants were identified in baseline data across independent healthy cohorts. Combining the cohorts and repeating the analyses resulted in identification of over 6000 baseline immune phenotypic groups, implying that the MIRS concept may be useful in many immune perturbation contexts. These findings demonstrate that patterns in complex gene expression variability can be used to define immune phenotypes and discover determinants of immune responsiveness.

The effect of screening and treatment of Ureaplasma urealyticum infection on semen parameters in asymptomatic leukocytospermia: a case-control study.

BACKGROUND: Ureaplasma urealyticum (UU) infection, as well as asymptomatic leukocytospermia, whether it has effect on semen parameters and whether it needs screening and treatment is still a confusing and controversial topic for clinicians. METHODS: Among 1530 adult males who visited Guilin People's Hospital due to infertility, 295 were diagnosed with asymptomatic leukocytospermia, and 95 were further screened for UU-positive. 81 UU-positive asymptomatic leukocytospermia patients received 7-day or 14-day treatment plan with doxycycline, and 70 cases were cured. The semen parameters of non-leukocytospermia, leukocytospermia, UU-positive leukocytospermia and UU-negative leukocytospermia groups were compared, and the differences between the two treatment plans and the semen parameters before UU treatment and 1 month after UU-cured were compared. RESULTS: Compared with non-leukocytospermia patients, the sperm concentration, progressive motility (PR), and normal morphology of patients with leukocytospermia decreased, while those with UU-positive leukocytospermia performed more significantly. The PR, total motility, and normal morphology of UU-positive leukocytospermia patients were significantly lower than those of UU-negative leukocytospermia patients (all p < 0.001). The UU cure rates of the 7-day and 14-day treatment plan with doxycycline was 84.62% and 89.66% (p = 0.738), respectively, and the sperm concentration, PR, total motility, and normal morphology of the cured UU-positive leukocytospermia patients were all increased after 1 month (p = 0.001, p = 0.022, p = 0.004 and p = 0.008, respectively). CONCLUSIONS: It is significant to screen and treat UU infection in asymptomatic leukocytospermia for improving sperm quality. Where appropriate, the 7-day treatment plan with doxycycline may be a good choice.

Exploring the effect of library preparation on RNA sequencing experiments.

RNA sequencing (RNA-seq) has become the widely preferred choice for surveying the genome-wide transcriptome complexity in many organisms. However, the broad adaptation of this methodology into the clinic still needs further evaluation of potential effect of sample preparation factors on its analytical reliability using patient samples. In this study, we examined the impact of three major sample preparation factors (i.e., cDNA library storage time, the quantity of input RNA, and cryopreservation of cell samples) on sequence biases, gene expression profiles, and enriched biological functions using RNAs isolated from primary B cell and CD4+ cell blood samples of healthy subjects. Our comprehensive comparison results suggested that different cDNA library storage time, quantity of input RNA, and cryopreservation of cell samples did not significantly alter gene transcriptional expression profiles generated by RNA-seq experiments. These findings shed new lights on the potential applications of RNA-seq technique to patient samples in a regular clinical setting.

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor.

The 2002-3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.

A statistical analysis of vaccine-adverse event data.

BACKGROUND: Vaccination has been one of the most successful public health interventions to date, and the U.S. FDA/CDC Vaccine Adverse Event Reporting System (VAERS) currently contains more than 500,000 reports for post-vaccination adverse events that occur after the administration of vaccines licensed in the United States. The VAERS dataset is huge, contains very large dimension nominal variables, and is complex due to multiple listing of vaccines and adverse symptoms in a single report. So far there has not been any statistical analysis conducted in attempting to identify the cross-board patterns on how all reported adverse symptoms are related to the vaccines. METHODS: For studies of the relationship between vaccines and reported adverse events, we consider a partial VAERS dataset which includes all reports filed over a period of 24 years between 1990-2013. We propose a neighboring method to process this dataset for dealing with the complications caused by multiple listing of vaccines and adverse symptoms in a single report. Then, the combined approaches based on our neighboring method and novel utilization of data visualization techniques are employed to analyze the large dimension dataset for characterization of the cross-board patterns of the relations between all reported vaccines and events. RESULTS: The results of our analysis indicate that those events or symptoms with overall high occurrence frequencies are positively correlated, and those most frequently occurred adverse symptoms are mostly uncorrelated or negatively correlated under different bacteria vaccines, but they are in many cases positively correlated under different virus vaccines, especially under flu vaccines. No particular patterns are shown under live vs. inactive vaccines. CONCLUSIONS: This article identifies certain cross-board patterns of the relationship between the vaccines and the reported adverse events or symptoms. This helps for better understanding the VAERS data, and provides a useful starting point for the development of statistical models and procedures to further analyze the VAERS data.

Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation.

Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.

Experimental measurement of supercontinuum coherence in highly nonlinear soft-glass photonic crystal fibers.

We present experimental measurements illustrating the power-dependent coherence evolution for supercontinuum generated in highly nonlinear SF6 photonic crystal fibers. The measurements were performed for fiber lengths close to and much longer than the soliton fission length. Simulations of the spectral evolution were also carried out to accompany the experimental observation. Many parameters were estimated by matching the simulated and the measured evolution. Both the measured and the simulated coherence evolution confirm the association between coherence degradation and soliton fission.

Experimental measurement of supercontinuum coherence in tellurite photonic crystal fibers.

Spectral and coherence evolutions were measured for supercontinuum (SC) generated in a 2.7 cm highly nonlinear tellurite photonic crystal fiber. Numerical simulations were performed based on the generalized nonlinear Schrödinger equation with noise. The measurements show that coherence degradation first occurs after soliton fission, and then spreads to longer wavelengths as the average power of the SC increases. The solitonic coherence shows much slower degradation than the overall coherence.