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Epithelial and stromal/mesenchymal limbal stem cells contribute to corneal homeostasis and cell renewal. Extracellular vesicles (EVs), including exosomes (Exos), can be paracrine mediators of intercellular communication. Previously, we described cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos in non-diabetic (N) and diabetic (DM) limbal epithelial cells (LECs). Presently, we quantify the miRNA and proteome profiles of human LEC-derived Exos and their regulatory roles in N- and DM-LSC. We revealed some miRNA and protein differences in DM vs. N-LEC-derived Exos cargos, including proteins involved in Exo biogenesis and packaging that may affect Exo production and ultimately cellular crosstalk and corneal function. Treatment by N-Exos, but not by DM-Exos, enhanced wound healing in cultured N-LSCs and increased proliferation rates in N and DM LSCs vs. corresponding untreated (control) cells. N-Exos-treated LSCs reduced the keratocyte markers ALDH3A1 and lumican and increased the MSC markers CD73, CD90, and CD105 vs. control LSCs. These being opposite to the changes quantified in wounded LSCs. Overall, N-LEC Exos have a more pronounced effect on LSC wound healing, proliferation, and stem cell marker expression than DM-LEC Exos. This suggests that regulatory miRNA and protein cargo differences in DM- vs. N-LEC-derived Exos could contribute to the disease state.

Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography-mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient's response and warrant further study.

Glycogen-autophagy (‘glycophagy’) is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.

Abstract Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

The increased prevalence of obese, pregnant women who have a higher risk of glucose intolerance warrants the need for nutritional interventions to improve maternal glucose homeostasis. In this study, the effect of a low-glycemic load (GL) (n = 28) was compared to a high-GL (n = 34) dietary intervention during the second half of pregnancy in obese women (body mass index (BMI) > 30 or a body fat >35%). Anthropometric and metabolic parameters were assessed at baseline (20 week) and at 28 and 34 weeks gestation. For the primary outcome 3h-glucose-iAUC (3h-incremental area under the curve), mean between-group differences were non-significant at every study timepoint (p = 0.6, 0.3, and 0.8 at 20, 28, and 34 weeks, respectively) and also assessing the mean change over the study period (p = 0.6). Furthermore, there was no statistically significant difference between the two intervention groups for any of the other examined outcomes (p ≥ 0.07). In the pooled cohort, there was no significant effect of dietary GL on any metabolic or anthropometric outcome (p ≥ 0.2). A post hoc analysis comparing the study women to a cohort of overweight or obese pregnant women who received only routine care showed that the non-study women were more likely to gain excess weight (p = 0.046) and to deliver large-for-gestational-age (LGA) (p = 0.01) or macrosomic (p = 0.006) infants. Thus, a low-GL diet consumed during the last half of pregnancy did not improve pregnancy outcomes in obese women, but in comparison to non-study women, dietary counseling reduced the risk of adverse outcomes.

Background:. This study considers observers’ reflexive responses to the rejuvenated face, and how instinctive responses relate to subjective judgment. We investigated observers’ reflexive perception of faces both pre and post surgical intervention during the early stages of visual processing. Subjective character attribution for all test images was also assessed by the same observers. Method:. Forty frontal facial images of 20 patients portraying the pre- and postoperative high superficial musculoaponeurotic system facelift along with variable concomitant procedures were studied. Nineteen lookzone regions were mapped post hoc onto each image. Forty observers examined the images, whereas an eye-tracking camera recorded their eye movements. Visual fixation data were recorded and analyzed. Observers also rated each image on the basis of five elemental positive character attributes. Results:. A statistically coherent but nonsignificant (P > 0.05) trend was identified with the surgical intervention resulting in greater attention being paid to the central triangle region of the face with reduction in attention to the facial periphery. Facial rejuvenation significantly increased the subjective character ratings of all five positively valenced attributes tested. Average age estimate of the photos decreased significantly from 54 to 48.6 years (true average age of 57.4 years). Conclusions:. We provide data illustrating both reflexive and subjective responses to facial rejuvenation. Observers reported a more favorable impression of the treated faces and evaluated them as being younger than their true age. A trend was detected for increased visual fixation of the central facial region following rejuvenation. Interpretation of these findings and indication for further research is provided.

Background: Having a pregnancy complicated by hypertensive disorders of pregnancy (HDP) and/or having a small or preterm baby put a woman at risk for later cardiovascular disease (CVD). It is uncertain if higher maternal CVD risk factors (reflected by increased peripartum CVD biomarker levels) account for this risk, or if experiencing a complicated pregnancy itself increases a woman's CVD risk (reflected by an increase in biomarker trajectories from early pregnancy to postpartum). Methods: We conducted a secondary analysis of an 8-week mindful eating and stress reduction intervention in 110 pregnant women. We used mixed linear regression analysis to compare CVD biomarker levels and trajectories, between women with and without a CVD-related pregnancy complication (including HDP [gestational hypertension or preeclampsia] or having a small for gestational age [

The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitate-and linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK.

Abstract Background Möbius (Moebius) and Poland’s syndromes are two rare congenital syndromes characterized by non-progressive bilateral (and often asymmetric) dysfunction of the 6th and 7th cranial nerves and hypoplasia of the pectoral muscles associated with chest wall and upper limb anomalies respectively. Manifest simultaneously as Poland-Möbius (Poland-Moebius) syndrome, debate continues as to whether this is a distinct nosological entity or represents phenotypic variation as part of a spectrum of disorders of rhomboencephalic development. Etiological hypotheses implicate both genetic and environmental factors. The PLXND1 gene codes for a protein expressed in the fetal central nervous system and vascular endothelium and is thus involved in embryonic neurogenesis and vasculogenesis. It is located at chromosome region 3q21-q22, a locus of interest for Möbius syndrome. Case presentation We present the first report of a patient with Poland-Möbius syndrome and a mutation in the PLXND1 gene. A child with Poland-Möbius syndrome and a maternally inherited missense variant (NM_015103.2:ex14:c.2890G > Ap.V964M) in the PLXND1 gene is described. In order to contextualize these findings, the literature was examined to identify other confirmed cases of Poland-Möbius syndrome for which genetic data were available. Fourteen additional cases of Poland-Möbius syndrome with genetic studies are described in the literature. None implicated the PLXND1 gene which has previously been implicated in isolated Möbius syndrome. Conclusions This report provides further evidence in support of a role for PLXND1 mutations in Möbius syndrome and reasserts the nosological link between Möbius and Poland’s syndromes. Level of evidence Level V, Descriptive Study.

BackgroundStress can lead to excessive weight gain. Mindfulness-based stress reduction that incorporates mindful eating shows promise for reducing stress, overeating, and improving glucose control. No interventions have tested mindfulness training with a focus on healthy eating and weight gain during pregnancy, a period of common excessive weight gain. Here, we test the effectiveness of such an intervention, the Mindful Moms Training (MMT), on perceived stress, eating behaviors, and gestational weight gain in a high-risk sample of low income women with overweight/obesity.MethodWe conducted a quasi-experimental study assigning 115 pregnant women to MMT for 8 weeks and comparing them to 105 sociodemographically and weight equivalent pregnant women receiving treatment as usual. Our main outcomes included weight gain (primary outcome), perceived stress, and depression.ResultsWomen in MMT showed significant reductions in perceived stress (β = - 0.16) and depressive symptoms (β = - 0.21) compared to the treatment as usual (TAU) control group. Consistent with national norms, the majority of women (68%) gained excessive weight according to Institute of Medicine weight-gain categories, regardless of group. Slightly more women in the MMT group gained below the recommendation. Among secondary outcomes, women in MMT reported increased physical activity (β = 0.26) and had lower glucose post-oral glucose tolerance test (β = - 0.23), being 66% less likely to have impaired glucose tolerance, compared to the TAU group.ConclusionA short-term intervention led to significant improvements in stress, and showed promise for preventing glucose intolerance. However, the majority of women gained excessive weight. A longer more intensive intervention may be needed for this high-risk population. Clinical Trials.gov #NCT01307683.

Epithelial and stromal/mesenchymal limbal stem cells contribute to corneal homeostasis and cell renewal. Extracellular vesicles (EVs), including exosomes (Exos), can be paracrine mediators of intercellular communication. Previously, we described cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos in non-diabetic (N) and diabetic (DM) limbal epithelial cells (LECs). Presently, we quantify the miRNA and proteome profiles of human LEC-derived Exos and their regulatory roles in N- and DM-LSC. We revealed some miRNA and protein differences in DM vs. N-LEC-derived Exos’ cargos, including proteins involved in Exo biogenesis and packaging that may affect Exo production and ultimately cellular crosstalk and corneal function. Treatment by N-Exos, but not by DM-Exos, enhanced wound healing in cultured N-LSCs and increased proliferation rates in N and DM LSCs vs. corresponding untreated (control) cells. N-Exos-treated LSCs reduced the keratocyte markers ALDH3A1 and lumican and increased the MSC markers CD73, CD90, and CD105 vs. control LSCs. These being opposite to the changes quantified in wounded LSCs. Overall, N-LEC Exos have a more pronounced effect on LSC wound healing, proliferation, and stem cell marker expression than DM-LEC Exos. This suggests that regulatory miRNA and protein cargo differences in DM- vs. N-LEC-derived Exos could contribute to the disease state.

Background:. Following high-quality surgical repair, children born with a cleft lip anomaly may still display lasting visual differences. We exposed control adults and parents of affected children to images of children with cleft deformity and compared their visual tracking patterns. The protocol investigated whether parental exposure to secondary cleft deformity heightens or diminishes visual attraction to this type of structural facial variation. Method:. Twenty participants (10 control adults, 10 parents of affected children) assessed 40 colored images of children's faces while their eye movements were tracked. Twenty-four control images and 16 repaired cleft lip images were displayed to observers. Nine bilateral facial aesthetic zones were considered as regions of interest. Percentage of time visually fixating within each region, and statistical differences in fixation duration percentage between the two participant groups and across the bilateral regions of interest were analyzed. Results:. While both groups of observers directed more visual attention to the nasal and oral regions of the cleft images than control images, parents of children with cleft lip spent significantly more time fixating on these areas (25% and 24% of the time, respectively) than did unaffected adults (14.6% and 19.3%; P < 0.001). Conclusions:. These results demonstrate that parents of cleft lip children exhibit heightened attention to this type of facial difference relative to the naive observer. These findings highlight that observer profile can meaningfully influence the perception of a facial deformity. Awareness of this information may enhance communication between surgeon and parents of an affected child by providing added insight into parental perspective.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

Abstract What is a normal face? A fundamental task for the facial reconstructive surgeon is to answer that question as it pertains to any given individual. Accordingly, it would be important to be able to place the facial appearance of a patient with congenital or acquired deformity numerically along their own continuum of normality, and to measure any surgical changes against such a personalized benchmark. This has not previously been possible. We have solved this problem by designing a computerized model that produces realistic, normalized versions of any given facial image, and objectively measures the perceptual distance between the raw and normalized facial image pair. The model is able to faithfully predict human scoring of facial normality. We believe this work represents a paradigm shift in the assessment of the human face, holding great promise for development as an objective tool for surgical planning, patient education, and as a means for clinical outcome measurement.

BACKGROUND:One of the fastest growing risk groups for early onset of diabetes is women with a recent pregnancy complicated by gestational diabetes, and for this group, Latinas are the largest at-risk group in the USA. Although evidence-based interventions, such as the Diabetes Prevention Program (DPP), which focuses on low-cost changes in eating, physical activity and weight management can lower diabetes risk and delay onset, these programs have yet to be tailored to postpartum Latina women. This study aims to tailor a IT-enabled health communication program to promote DPP-concordant behavior change among postpartum Latina women with recent gestational diabetes. The COM-B model (incorporating Capability, Opportunity, and Motivational behavioral barriers and enablers) and the Behavior Change Wheel (BCW) framework, convey a theoretically based approach for intervention development. We combined a health literacy-tailored health IT tool for reaching ethnic minority patients with diabetes with a BCW-based approach to develop a health coaching intervention targeted to postpartum Latina women with recent gestational diabetes. Current evidence, four focus groups (n = 22 participants), and input from a Regional Consortium of health care providers, diabetes experts, and health literacy practitioners informed the intervention development. Thematic analysis of focus group data used the COM-B model to determine content. Relevant cultural, theoretical, and technological components that underpin the design and development of the intervention were selected using the BCW framework. RESULTS:STAR MAMA delivers DPP content in Spanish and English using health communication strategies to: (1) validate the emotions and experiences postpartum women struggle with; (2) encourage integration of prevention strategies into family life through mothers becoming intergenerational custodians of health; and (3) increase social and material supports through referral to social networks, health coaches, and community resources. Feasibility, acceptability, and health-related outcomes (weight loss, physical activity, consumption of healthy foods, breastfeeding, and glucose screening) will be evaluated at 9 months postpartum using a randomized controlled trial design. CONCLUSIONS:STAR MAMA provides a DPP-based intervention that integrates theory-based design steps. Through systematic use of behavioral theory to inform intervention development, STAR MAMA may represent a strategy to develop health IT intervention tools to meet the needs of diverse populations. TRIAL REGISTRATION:ClinicalTrials.gov NCT02240420.

ObjectiveTo characterize the prevalence of and factors associated with clinicians' prenatal suspicion of a large baby; and to determine whether communicating fetal size concerns to patients was associated with labor and delivery interventions and outcomes.MethodsWe examined data from women without a prior cesarean who responded to Listening to Mothers III, a nationally representative survey of women who had given birth between July 2011 and June 2012 (n = 1960). We estimated the effect of having a suspected large baby (SLB) on the odds of six labor and delivery outcomes.ResultsNearly one-third (31.2%) of women were told by their maternity care providers that their babies might be getting "quite large"; however, only 9.9% delivered a baby weighing ≥4000 g (19.7% among mothers with SLBs, 5.5% without). Women with SLBs had increased adjusted odds of medically-induced labor (AOR 1.9; 95% CI 1.4-2.6), attempted self-induced labor (AOR 1.9; 95% CI 1.4-2.7), and use of epidural analgesics (AOR 2.0; 95% CI 1.4-2.9). No differences were noted for overall cesarean rates, although women with SLBs were more likely to ask for (AOR 4.6; 95% CI 2.8-7.6) and have planned (AOR 1.8; 95% CI 1.0-4.5) cesarean deliveries. These associations were not affected by adjustment for gestational age and birthweight.Conclusions for practiceOnly one in five US women who were told that their babies might be getting quite large actually delivered infants weighing ≥4000 g. However, the suspicion of a large baby was associated with an increase in perinatal interventions, regardless of actual fetal size.

Abstract Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy—specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) – in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.

Background:. A sensitive, objective, and universally accepted method of measuring facial deformity does not currently exist. Two distinct machine learning methods are described here that produce numerical scores reflecting the level of deformity of a wide variety of facial conditions. Methods:. The first proposed technique utilizes an object detector based on a cascade function of Haar features. The model was trained using a dataset of 200,000 normal faces, as well as a collection of images devoid of faces. With the model trained to detect normal faces, the face detector confidence score was shown to function as a reliable gauge of facial abnormality. The second technique developed is based on a deep learning architecture of a convolutional autoencoder trained with the same rich dataset of normal faces. Because the convolutional autoencoder regenerates images disposed toward their training dataset (ie, normal faces), we utilized its reconstruction error as an indicator of facial abnormality. Scores generated by both methods were compared with human ratings obtained using a survey of 80 subjects evaluating 60 images depicting a range of facial deformities [rating from 1 (abnormal) to 7 (normal)]. Results:. The machine scores were highly correlated to the average human score, with overall Pearson’s correlation coefficient exceeding 0.96 (P < 0.00001). Both methods were computationally efficient, reporting results within 3 seconds. Conclusions:. These models show promise for adaptation into a clinically accessible handheld tool. It is anticipated that ongoing development of this technology will facilitate multicenter collaboration and comparison of outcomes between conditions, techniques, operators, and institutions.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3–IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell–specific deletion of Atg16l1 and global Parkin–/– significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1–/– mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

UnlabelledOur goal was to determine total and directly measured free 25-hydroxy vitamin D (25(OH)D) serum levels in humans with a range of 25(OH)D levels and clinical conditions associated with low and high vitamin D binding protein levels. Serum samples and clinical data were collected from 106 subjects: 62 without cirrhosis or pregnancy, 24 cirrhotic patients with albumin

The Precambrian explosion led to the rapid appearance of most major animal phyla alive today. It has been argued that the complexity of life has steadily increased since that event. Here we challenge this hypothesis through the characterization of apoptosis in reef-building corals, representatives of some of the earliest animals. Bioinformatic analysis reveals that all of the major components of the death receptor pathway are present in coral with high-predicted structural conservation with Homo sapiens. The TNF receptor-ligand superfamilies (TNFRSF/TNFSF) are central mediators of the death receptor pathway, and the predicted proteome of Acropora digitifera contains more putative coral TNFRSF members than any organism described thus far, including humans. This high abundance of TNFRSF members, as well as the predicted structural conservation of other death receptor signaling proteins, led us to wonder what would happen if corals were exposed to a member of the human TNFSF (HuTNFα). HuTNFα was found to bind directly to coral cells, increase caspase activity, cause apoptotic blebbing and cell death, and finally induce coral bleaching. Next, immortalized human T cells (Jurkats) expressing a functional death receptor pathway (WT) and a corresponding Fas-associated death domain protein (FADD) KO cell line were exposed to a coral TNFSF member (AdTNF1) identified and purified here. AdTNF1 treatment resulted in significantly higher cell death (P < 0.0001) in WT Jurkats compared with the corresponding FADD KO, demonstrating that coral AdTNF1 activates the H. sapiens death receptor pathway. Taken together, these data show remarkable conservation of the TNF-induced apoptotic response representing 550 My of functional conservation.

ObjectiveOur goal was to compare direct quantitation of circulating free 25-hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions.Patients and methodsSerum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin

BackgroundWe examined the influence of race/ethnicity on appointment attendance, maternal psychiatric and medical diagnoses, and birth outcomes within a diverse, low income, high risk pregnant population to determine whether birth outcome disparities would be lessened in a sample with high biopsychosocial risk across all groups.MethodsData were retrospectively obtained on all women scheduled for appointments in the San Francisco Genera Hospital (SFGH) High-Risk Obstetrics (HROB) clinic during a three-month period. General linear model and logistic regression procedures were used to examine the associations of race/ethnicity with maternal characteristics, clinic attendance, and birth outcomes.ResultsOur sample included 202 maternal-infant pairs (Hispanic 57%, Black 16%, Asian 15%, White 12%). Racial/ethnic differences were seen in language (p < .001), gravidity (p < .001), parity (p = .005), appointment attendance (p < .001), diabetes (p = .005), psychiatric diagnosis (p = .02), illicit drug use (p < .001), smoking (p < .001). These maternal characteristics, including rate of attendance at specialized prenatal appointments, did not predict birth outcomes with the exception of an association between diabetes and earlier gestational age (p = .03). In contrast, Black maternal race/ethnicity was associated with earlier gestational age at birth (p = .004) and lower birth weight (p < .001) compared to Whites.ConclusionsWithin a diverse maternal population of high biopsychosocial risk, racial/ethnic disparities in birth outcomes persist. These disparities have implications for infant health trajectory throughout the lifecourse and for intervention implementation in high risk groups.

ObjectiveDescribe the attitudes, beliefs, and practices of U.S. obstetricians on the topic of prenatal environmental exposures.Study designA national online survey of American Congress of Obstetricians and Gynecologists (ACOG) fellows and 3 focus groups of obstetricians.ResultsWe received 2,514 eligible survey responses, for a response rate of 14%. The majority (78%) of obstetricians agreed that they can reduce patient exposures to environmental health hazards by counseling patients; but 50% reported that they rarely take an environmental health history; less than 20% reported routinely asking about environmental exposures commonly found in pregnant women in the U.S.; and only 1 in 15 reported any training on the topic. Barriers to counseling included: a lack of knowledge of and uncertainty about the evidence; concerns that patients lack the capacity to reduce harmful exposures; and fear of causing anxiety among patients.ConclusionU.S. obstetricians in our study recognized the potential impact of the environment on reproductive health, and the role that physicians could play in prevention, but reported numerous barriers to counseling patients. Medical education and training, evidence-based guidelines, and tools for communicating risks to patients are needed to support the clinical role in preventing environmental exposures that threaten patient health.

This article presents an approach to standalone verification of I/O Memory Management Unit with virtualization supporting. We presented the base architecture of the test system. The main problems encountered during the verification of IOMMU with virtualization support are considered. One of the key problems was the formation of translation table pages. The number of translation tables depends on the mode of IOMMU operation and the type of translation. As a solution of this problem the approach to the dynamic generation of translation tables is proposed. The algorithm for formation of translation table pages in the generator is presented. The problem of validating the translation of a virtual address into a physical one using two-level translation tables is solved. The features of the reference model implementation are considered. Reference model and test system which have been used for IOMMU verification of microprocessor with the 6th generation «Elbrus» architecture are described. The main components of the test system and the methods of communication between test system and IOMMU model are presented. The results of IOMMU verification are considered.

Mercury exposure during pregnancy can have serious health effects for a developing fetus including impacting the child's neurologic and cognitive development. Through biomonitoring in a low-income Latina population in California, we identified a patient with high levels of mercury and traced the source to face creams purchased in a pharmacy in Mexico.

Purpose: The availability of an objective outcome measure for facial reconstructive surgery remains elusive. Evaluations submitted by external raters or by patient self-report are subjective, and may unreliably convey how one is perceived by others. We are interested in observers’ instantaneous responses to the human face. The goal of modern facelift and associated procedures for facial rejuvenation are to achieved subtle differences that lead to the perception of youth and attractiveness, yet the observer cannot pinpoint what exactly have been done to the patient’s face. We explored the visual markers that lead to differential perception of patients before and after facial rejuvenation surgery (high SMAS facelift, neck lift, fat grafting, brow lifts and blepharoplasty). Methods: 40 images were obtained which portrayed pre and post operative photos of patients who underwent high SMAS facelift, fat grafting, and browlifts and blepharoplasty for facial rejuvenation. Photographs were obtained before and after surgical correction (>3 months postop). 40 observers examined the images while an infrared eye-tracking camera recorded their eye movements. The observers were then asked to rate the image for character attributes (attractiveness, trustworthiness, sociability, healthy, and capability, 1-7 scale, and also estimate the age of the patient). Results: (i) The surgical intervention was found to decrease observers’ attention to the cervical region, but did not change how other areas are perceived significantly.(ii) The surgical intervention was found to significantly increase the character ratings for all five attributes compared to pre op controls: (sociable 3.53 to 4.18, trustworthy 3.85 to 4.20, attractive 3.34 to 3.3.90, health 4.07 to 4.61, capable 3.91 to 4.43.(iii) Average age estimate of the photos decreased significantly from 54 years (SD 6) to 48.6 years (SD 5.2), with true average age of 57.4 (7.6). Conclusion: We provide data illustrating a novel and objective technique to evaluate the effect of reconstructive intervention for facial rejuvenation. Consistent with the goals of subtle facial rejuvenation, the observers did not detect any particular areas of difference post operatively, but gain a more favorable impression of the person, and also perceived them as younger by a decade compared to their true age.

Every pregnant woman in the United States is exposed to many and varied environmental chemicals. Rapidly accumulating scientific evidence documents that widespread exposure to environmental chemicals at levels that are encountered in daily life can impact reproductive and developmental health adversely. Preconception and prenatal exposure to environmental chemicals are of particular importance because they may have a profound and lasting impact on health across the life course. Thus, prevention of developmental exposures to environmental chemicals would benefit greatly from the active participation of reproductive health professionals in clinical and policy arenas.

BackgroundBecause prenatal counseling is associated with adherence to weight gain guidelines, we sought to identify patient-level characteristics associated with the receipt of counseling on weight gain, nutrition, and exercise during prenatal care.MethodsWe performed a secondary data analysis on a cohort of women enrolled in a prenatal counseling intervention study. We controlled for study group assignment (intervention versus usual care) as well as patient characteristics in a multivariable analysis. We performed three separate multivariable analyses for predictors of provider-patient discussions about (1) weight gain, (2) nutrition, and (3) exercise.ResultsThe cohort consisted of 311 predominantly low-income prenatal patients receiving care at several sites in the San Francisco Bay Area. Prepregnancy body mass index, nutrition knowledge, maternal age, parity, and type of insurance were not significantly associated with receipt of counseling about weight gain, nutrition, and exercise. In the multivariable analysis, white women were significantly less likely to be counseled about nutrition than non-white women (p=0.02). Former smokers were more likely to receive counseling about nutrition and exercise than never smokers (p