Aberrant proliferation and migration of vascular smooth muscle cells (VSMC) have been closely linked to the development and progression of cardiovascular and cancer diseases. The cytoprotective enzyme heme oxygenase-1 (HO-1) has been shown to mediate anti-proliferative and anti-migratory effects in VSMC. This study investigates the effect of cannabidiol (CBD), a non-psychoactive cannabinoid, on HO-1 expression and disease-associated functions of human umbilical artery smooth muscle cells (HUASMC). HO-1 protein and mRNA were significantly increased by CBD in a time- and concentration-dependent manner. Although the expression of several cannabinoid-activated receptors (CB1, CB2, G protein-coupled receptor 55, transient receptor potential vanilloid 1) was verified in HUASMC, CBD was shown to induce HO-1 via none of these targets. Instead, the CBD-mediated increase in HO-1 protein was reversed by the glutathione precursor N-acetylcysteine, indicating the participation of reactive oxygen species (ROS) signaling; this was confirmed by flow cytometry-based ROS detection. CBD-induced HO-1 expression was accompanied by inhibition of growth factor-mediated proliferation and migration of HUASMC. However, neither inhibition of HO-1 activity nor knockdown of HO-1 protein attenuated CBD-mediated anti-proliferative and anti-migratory effects. Indeed, inhibition or depletion of HO-1 resulted in induction of apoptosis and intensified CBD-mediated effects on proliferation and migration. Collectively, this work provides the first indication of CBD-mediated enhancement of HO-1 in VSMC and potential protective effects against aberrant VSMC proliferation and migration. On the other hand, our data argue against a role of HO-1 in CBD-mediated inhibition of proliferation and migration while substantiating its anti-apoptotic role in oxidative stress-mediated cell fate.

The blood filtering organ in zebrafish embryos is the pronephros, which consists of two functional nephrons. Segmentation of a nephron into different domains is essential for its function and is well conserved among vertebrates. Zebrafish has been extensively used as a model to understand nephron segmentation during development. Here, we have identified EF-hand domain containing 2 (Efhc2) as a novel component of genetic programme regulating nephron segmentation in zebrafish. Human EFHC2 is a protein with one predicted calcium-binding EF-hand motif and three DM10 domains, whose function is unknown. EFHC2 has been implicated in several brain-related genetic diseases like Turner syndrome and juvenile myoclonic epilepsy. However, there is limited information on its normal physiological function.

Orange juice (OJ) contains numerous compounds some of which are known to play key roles in growth and survival of bacteria. This study aimed to investigate the effects of natural or processing-induced variations in OJ composition on the physiology of Escherichia coli. OJ and model OJ (MOJ) samples containing various sugars, organic acids, amino acids, or ascorbic acid were inoculated with E. coli K-12 MG1655 in different growth phases. The culturability, viability, and physiology of the cells were investigated during storage using plate counting and flow cytometry. Generally, stationary-phase cells displayed the greatest survival in both MOJ and OJ. Increase in incubation temperature from 4 to 22.5ºC caused a significant decrease in both healthy and culturable cell populations. Supplementation of MOJ with ascorbic acid and amino acids increased both the viability and culturability of the cells. Similar trends were observed in amino acid-supplemented OJ, albeit at a slower rate. In contrast, variations in sugar or organic acid composition had negligible effects on the physiological status of the cells. In summary, natural variation in ascorbic acid or amino acid concentrations could potentially have an adverse effect on the microbiological safety of orange juice.

Mono-culture fermentation by Rhizopus stolonifer could promote the healthiness of immune systems and cholesterol levels. Hence, we examined the effect of diet from mono-culture fermentation of Moringa oleifera seeds by R. stolonifer (MCF-MORS) on hematological parameters and fundamental indicators of hypercholesterolemia in rat. The animals were divided into six groups (n = 6). Group 1 was placed on basal diet. Group II, III, IV and V were placed on a basal diets supplemented with 7.5%, 15%, 22.5% and 30%, respectively, of MCF-MORS. Group VI was placed on basal diet fed with unfermented M. oleifera seeds (UF-MOS). The experiment lasted for eight weeks. The results revealed 7.5% MCF-MORS as better biological method to augment PCV, RBC and Hb count in animal model. Also, 7.5% and/or 15% MCF-MORS demonstrated highest levels in centrophils, neutrophils and eosinophils, whereas the levels of lymphocytes, basophils and monocytes showed no significant difference. Similarly, 7.5% and 15% MCF-MORS modulated LDL and HDL, respectively, better than UF-MOS; but showing no difference in cholesterol level. MCF-MORS also maintained architectural integrity of villi and splenocytes better than UF-MOS. We therefore concluded that diet from MCF-MORS at 7.5% and 15% modulates HDL, LDL, cholesterol and immune system-related disorders better than UF-MOS in rat model.

To investigate the correlation between chemical constituents and active ingredients of 13 types of Chinese mulberry fruits.

Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in inactivation of estrogens and their metabolites. Alterations in UGTs involved in estrogen metabolism, has been suggested to play a role in breast cancer risk. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs involved in estrogen metabolism in human breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ethnicity, and menopausal status in a group of human breast tumors and normal breast tissues, and 3) investigate the association between variations in the number of TA repeats in the promoter region of UGT1A1 to gene expression. Quantification of UGT mRNA in breast tissues revealed that UGT1A4, UGT1A10, and UGT2B7 mRNA levels were decreased in breast cancers as compared to normal breast tissues. UGT1A1 mRNA levels were also significantly decreased in breast cancers as compared to normal breast tissues (Tumor: 0.5 ± 0.2; Normal: 4.1 ± 1.3, p = 0.0006). UGT1A1 mRNA down-regulation was strongly correlated with postmenopausal status in breast cancer versus controls (p = 0.04). In all the UGT1A1 genotypes observed in our study, the mean mRNA levels was significantly decreased among breast cancer cases as compared to controls for UGT1A1*1/*1 (p = 0.004), UGT1A1*28/*28 (p = 0.03) and UGT1A1*28/*37 (p = 0.06). Our findings demonstrate that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis.

Immediate breast reconstruction after mastectomy due to cancer or as a prophylactic treatment is widely preferred to avoid psychosocial distress, poor body image, and diminished sexual well-being. An increasing number of women undergoing breast reconstruction are in childbearing age; however, only limited data are available on the cosmetic outcome of patients undergoing implant-based breast reconstruction with a surgical mesh and subsequent pregnancy. This is a case report of a female patient who underwent unilateral implant-based breast reconstruction with a titanized surgical mesh implant (TiLOOP Bra). Twenty-two months after reconstruction, the woman delivered a healthy child. No adverse events occurred. The patient breastfed with the contralateral breast. The cosmetic result and patient-reported outcome was excellent. Pregnancy after breast reconstruction with a synthetic surgical mesh is not contradictory to an excellent cosmetic outcome.

Circular RNA (circRNA) is a type of non-coding RNA molecule that affects the cellular regulatory network by sequestering microRNA (miRNA) like a sponge. This study was performed to identify differentially-expressed circRNA in oral squamous cell carcinomas (OSCCs). By high-throughput sequencing, microarray circRNA expression profiles were acquired from patients with OSCCs (n = 8) and controls (n = 8), which totaled 1921 existing circRNA molecules and 10021 novel circRNA molecules. Most of the circular RNA is from exons and distributed in the No. 1 and 2 chromosomes. Eight up-regulated and down-regulated circRNA molecules were identified as differentially-expressed in OSCCs. Among this, the expression of circ_000334, circ_006740, and circ_006371 are significantly down-regulated in 42 pairs of samples, which means that these circRNA molecules might be implicated in oncogenesis and development of OSCCs.

Frontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD-Tau) or TDP43 (FTLD-TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.

While prior Epstein-Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections.

We have previously shown that plasmablasts of the G1m1 allotype of IgG1 are selectively enriched in the cerebrospinal fluid of G1m1/G1m3 heterozygous patients with multiple sclerosis, whereas both allotypes are equally used in neuroborreliosis. Here, we demonstrate a strong preference for the G1m1 allotype in the intrathecal humoral immune responses against measles, rubella, and varicella zoster virus in G1m1/G1m3 heterozygous multiple sclerosis patients. Conversely, intrathecally synthesized varicella zoster virus-specific IgG1 in varicella zoster virus meningoencephalitis comprised both allotypes. This implies that G1m1 B cells are selected to the central nervous system of multiple sclerosis patients regardless of specificity and suggests that an antigen-independent mechanism could drive the intrathecal humoral immune response.

Fondaparinux is commonly used for treatment of heparin-induced thrombocytopenia (HIT) despite lack of approval for this indication. High quality randomized controlled trials of this agent are unlikely to be forthcoming.

Recent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme of the Kyn pathway.

Pulmonary arterial hypertension (PAH) is more prevalent in females. Paradoxically, female patients have better right ventricular (RV) function and higher survival rates than males. However, the effects of 17β-estradiol (E2) on RV function in PAH has not been studied. Twenty-four male rats were exposed to monocrotaline (MCT) to induce experimental PAH, while treated with E2 or vehicle respectively. Together with eight control rats, thirty-two rats were examined by echocardiography 4 weeks after drug administration. Echocardiographic measurement of RV function included: tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), RV fractional area change (RVFAC) and tricuspid annular systolic velocity (s'). RV free wall longitudinal strain (RVLSFW) and RV longitudinal shortening fraction (RVLSF) were also used to quantify RV function. RV morphology was determined by echocardiographic and histological analysis. TAPSE, RVFAC and s' were reduced, and RIMP was elevated in the MCT-treated group and vehicle-treated group, when compared with control group (P < 0.01). TAPSE, RVFAC and s' in the E2 group were higher, while RIMP was lower than those in the MCT-treated group and vehicle-treated group (P < 0.01). Myocardial functional parameters (RVLSFW and RVLSF) were also higher in the E2 group. Enhanced serum E2 levels were closely correlated with the improvement in RV functional parameters and enhancement of serum BNP levels (P < 0.01 for all groups). RV function decreased significantly in male rats with MCT-induced PAH, while E2 exhibited a protective effect on RV function, suggesting that E2 is a critical modulator of sex differences in PAH.

Features of embryonic development in birds traditionally have been assumed to be shared by sauropsids in general. Herein, we document a pattern of yolk processing and cellularization in the Eastern fence lizard (Sceloporus undulatus) that is fundamentally different from that of birds. In the avian pattern, cells of the yolk sac lining phagocytose, and digest yolk material. These cells release products of digestion into underlying blood vessels for transport back to the embryo. In contrast, microscopic examination of the developing eggs of S. undulatus reveals that the yolk mass is converted into vascularized, "spaghetti-like" strands that fill the yolk sac cavity. Three successive developmental stages are involved. First, the liquid yolk is invaded by proliferating endodermal cells, which phagocytose and digest the yolk material. These cells form clumps that progressively fill the yolk sac cavity. Second, small blood vessels derived from the yolk sac vasculature invade the yolk sac cavity. Third, the endodermal cells become organized in monolayers around these vessels. This arrangement provides a means by which large numbers of endodermal cells can digest yolk, with each cell being positioned to release products of digestion into an adjacent blood vessel for transport to the embryo. The mechanism of yolk processing in this lizard species is similar to that of recently studied snakes. From its phylogenetic distribution, we infer that this pattern probably is ancestral for squamate sauropsids.

Cell motility is an important but complex process; as cells move, new adhesions form at the front and adhesions disassemble at the back. To replicate this dynamic and spatiotemporally controlled asymmetry of adhesions and achieve motility in a minimal synthetic cell, we controlled the adhesion of a model giant unilamellar vesicle (GUV) to the substrate with light. For this purpose, we immobilized the proteins iLID and Micro, which interact under blue light and dissociate from each other in the dark, on a substrate and a GUV, respectively. Under blue light, the protein interaction leads to adhesion of the vesicle to the substrate, which is reversible in the dark. The high spatiotemporal control provided by light, allowed partly illuminating the GUV and generating an asymmetry in adhesions. Consequently, the GUV moves into the illuminated area, a process that can be repeated over multiple cycles. Thus, our system reproduces the dynamic spatiotemporal distribution of adhesions and establishes mimetic motility of a synthetic cell.

Environmental enteric dysfunction (EED), a subclinical disorder of the small intestine, and poor growth are associated with living in poor water, sanitation, and hygiene (WASH) conditions, but specific risk factors remain unclear. Nested within a birth cohort study, this study investigates relationships among water quality, EED, and growth in 385 children living in southwestern Uganda. Water quality was assessed using a portable water quality test when children were 6 months, and safe water was defined as lacking Escherichia coli contamination. Environmental enteric dysfunction was assessed using the lactulose:mannitol (L:M) test at 12-16 months. Anthropometry and covariate data were extracted from the cohort study, and associations were assessed using linear and logistic regression models. Less than half of the households (43.8%) had safe water, and safe versus unsafe water did not correlate with improved versus unimproved water source. In adjusted linear regression models, children from households with safe water had significantly lower log-transformed (ln) L:M ratios (β: -0.22, 95% confidence interval (CI): -0.44, -0.00) and significantly higher length-for-age (β: 0.29, 95% CI: 0.00, 0.58) and weight-for-age (β: 0.20, 95% CI: 0.05, 0.34) Z-scores at 12-16 months. Furthermore, in adjusted linear regression models, ln L:M ratios at 12-16 months significantly decreased with increasing length-for-age Z-scores at birth, 6 months, and 9 months (β: -0.05, 95% CI: -0.10, -0.004; β: -0.06, 95% CI: -0.11, -0.006; and β: -0.05, 95% CI: -0.09, -0.005, respectively). Overall, our data suggest that programs seeking to improve nutrition should address poor WASH conditions simultaneously, particularly related to household drinking water quality.

Maximal longevity of endotherms has long been considered to increase with decreasing specific metabolic rate, and thus with increasing body mass. Using a dataset of over 700 species, here I show that maximal longevity, age at sexual maturity, and postmaturity longevity across bird and mammalian species instead correlate primarily, and universally, with the number of cortical brain neurons. Correlations with metabolic rate and body mass are entirely explained by clade-specific relationships between these variables and numbers of cortical neurons across species. Importantly, humans reach sexual maturity and subsequently live just as long as expected for their number of cortical neurons, which eliminates the basis for earlier theories of protracted childhood and prolonged post-menopause longevity as derived human characteristics. Longevity might increase together with numbers of cortical neurons through their impact on three main factors: delay of sexual maturity, which postpones the onset of aging; lengthening of the period of viable physiological integration and adaptation, which increases postmaturity longevity; and improved cognitive capabilities that benefit survival of the self and of longer-lived progeny, and are conducive to prolonged learning and cultural transmission through increased generational overlap. Importantly, the findings indicate that theories of aging and neurodegenerative diseases should take absolute time lived besides relative "age" into consideration.

We investigate the structure and dynamics of proton solvation structures in mixed water/dimethyl sulfoxide (DMSO) solvents using two-color mid-infrared femtosecond pump-probe spectroscopy. At a water fraction below 20%, protons are mainly solvated as (DMSO-H)+ and (DMSO-H)+-H2O structures. We find that excitation of the OH-stretch vibration of the proton in (DMSO-H)+-H2O structures leads to an ultrafast contraction of the hydrogen bond between (DMSO-H)+ and H2O. This excited state relaxes rapidly with T1 = 95 ± 10 fs and leads in part to a strong local heating effect and in part to predissociation of the protonated cluster into (DMSO-H)+ and water monomers.

Today's scientific data are primarily stored and accessed via centralized Web-based infrastructure. Centralization has advantages but also carries risks such as link rot and content drift, which can hinder scientific progress. It is time to ask whether traditional, centralized Web architecture aligns with scholarly priorities and values, and to collaboratively move towards new approaches that do.