Alterations in cortical thickness have been identified in major depressive disorder (MDD), but findings have been variable and inconsistent. To date, no reliable tools have been available for the meta-analysis of surface-based morphometric (SBM) studies to effectively characterize what has been learned in previous studies, and drug treatments may have differentially impacted findings. We conducted a comprehensive meta-analysis of magnetic resonance imaging (MRI) studies that explored cortical thickness in medication-free patients with MDD, using a newly developed meta-analytic mask compatible with seed-based d mapping (SDM) meta-analytic software. We performed the meta-regression to explore the effects of demographics and clinical characteristics on variation in cortical thickness in MDD. Fifteen studies describing 529 patients and 586 healthy controls (HCs) were included. Medication-free patients with MDD, relative to HCs, showed a complex pattern of increased cortical thickness in some areas (posterior cingulate cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) and decreased cortical thickness in others (gyrus rectus, orbital segment of the superior frontal gyrus, and middle temporal gyrus). Most findings in the whole sample analysis were confirmed in a meta-analysis of studies recruiting medication-naive patients. Using the new mask specifically developed for SBM studies, this SDM meta-analysis provides evidence for regional cortical thickness alterations in MDD, mainly involving increased cortical thickness in the default mode network and decreased cortical thickness in the orbitofrontal and temporal cortex.

Antibodies specific for the hemagglutinin (HA) protein of influenza virus are critical for protective immunity to infection. Our studies show that CD4 T cells specific for epitopes derived from HA are the most effective in providing help for the HA-specific B cell responses to infection and vaccination. In this study, we asked whether HA epitopes recognized by CD4 T cells in the primary response to infection are equally distributed across the HA protein or if certain segments are enriched in CD4 T cell epitopes. Mice that collectively expressed eight alternative MHC (Major Histocompatibility Complex) class II molecules, that would each have different peptide binding specificities, were infected with an H1N1 influenza virus. CD4 T cell peptide epitope specificities were identified by cytokine EliSpots. These studies revealed that the HA-specific CD4 T cell epitopes cluster in two distinct regions of HA and that some segments of HA are completely devoid of CD4 T cell epitopes. When located on the HA structure, it appears that the regions that most poorly recruit CD4 T cells are sequestered within the interior of the HA trimer, perhaps inaccessible to the proteolytic machinery inside the endosomal compartments of antigen presenting cells.

Lysozyme is one of the most important anti-bacterial effectors in the innate immune system of animals. Besides its direct antibacterial enzymatic activity, lysozyme displays other biological properties, pointing toward a significant anti-inflammatory effect, many aspects of which are still elusive. Here we investigate the perturbation of gene expression profiles induced by lysozyme in a monocyte cell line in vitro considering a perspective as broad as the whole transcriptome profiling. The results of the RNA-seq experiment show that lysozyme induces transcriptional modulation of the TNF-α/IL-1β pathway genes in U937 monocytes. The analysis of transcriptomic profiles with IPA® identified a simple but robust molecular network of genes, in which the regulation trends are fully consistent with the anti-inflammatory activity of lysozyme. This study provides the first evidence in support of the anti-inflammatory action of lysozyme on the basis of transcriptomic regulation data resulting from the broad perspective of a whole-transcriptome profiling. Such important effects can be achieved with the supplementation of relatively low concentrations of lysozyme, for a short time of exposure. These new insights allow the potential of lysozyme in pharmacological applications to be better exploited.

Peste des petits ruminants (PPR) is one of the highly contagious transboundary viral diseases of small ruminants. Host microRNA (miRNA) expression patterns may change in response to virus infection, and it mainly works as a post-transcriptional moderator in gene expression and affects viral pathogenesis and replication. In this study, the change of miRNA expression profile in peripheral blood lymphocyte (PBMC) from sheep inoculated with PPR vaccine virus in vivo as well as primary sheep testicular (ST) cells inoculated with PPR vaccine virus in vitro were determined via deep sequencing technology. In PBMC cells, 373 and 115 differentially expressed miRNAs (DEmiRNAs) were identified 3 days and 5 days post inoculated (dpi), respectively. While, 575 DEmiRNAs were identified when comparing miRNA profiles on 5 dpi with 3 dpi. Some of the DEmiRNAs were found to change significantly via time-course during PPR vaccine virus inoculated. Similarly, in ST cells, 136 DEmiRNAs were identified at 3 dpi in comparison with mock-inoculation. A total of 12 DEmiRNAs were validated by real-time quantitative PCR (RT-qPCR). The oar-miR-150, oar-miR-370-3p and oar-miR-411b-3p were found common differentially expressed in both PPR vaccine virus-inoculated PBMC cells and ST cells. Targets prediction and functional analysis of the DEmiRNAs uncovered mainly gathering in antigen processing and presentation pathways, protein processing in endoplasmic reticulum pathways and cell adhesion molecules pathways. Our study supplies information about the DEmiRNAs in PPR vaccine virus-inoculated PBMC cells and ST cells, and provides clues for further understanding the function of miRNAs in PPR vaccine virus replication.

The transmission of Macacine alphaherpesvirus 1 (McHV-1) from macaques, the natural host, to humans causes encephalitis. In contrast, human infection with Cercopithecine alphaherpesvirus 2 (CeHV-2), a closely related alphaherpesvirus from African vervet monkeys and baboons, has not been reported and it is believed that CeHV-2 is apathogenic in humans. The reasons for the differential neurovirulence of McHV-1 and CeHV-2 have not been explored on a molecular level, in part due to the absence of systems for the production of recombinant viruses. Here, we report the generation of a fosmid-based system for rescue of recombinant CeHV-2. Moreover, we show that, in this system, recombineering can be used to equip CeHV-2 with reporter genes. The recombinant CeHV-2 viruses replicated with the same efficiency as uncloned, wt virus and allowed the identification of cell lines that are highly susceptible to CeHV-2 infection. Collectively, we report a system that allows rescue and genetic modification of CeHV-2 and likely other alphaherpesviruses. This system should aid future analysis of CeHV-2 biology.

The genus Lasianthus (Rubiaceae) consists of approximately 180 species, of which the greatest species diversity is found in tropical Asia. Some of the Lasianthus species have been used in folk medicine to treat tinnitus, arthritis, fever, and bleeding. Lasianthus verticillatus (Lour.) Merr. (Syn. Lasianthus trichophlebus auct. non Hemsl.) is a shrub, branchlets terete about 1.5-3 m in height. This paper studies the chemical composition of the leaves of L. verticillatus for the first time, which resulted in the isolation of five undescribed iridoid glucosides, lasianosides A-E (1-5), together with three known compounds (6-8). The undescribed structures of isolated compounds (1-5) were characterized by physical and spectroscopic data analyses, including one-dimensional (1D) and two-dimensional (2D) NMR, IR, UV, and high-resolution electrospray ionization mass spectra (HR-ESI-MS). Furthermore, the electronic circular dichroism data determined the absolute configurations of the new compounds. The free radical scavenging properties of isolated compounds was assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and their cytotoxicity was assessed toward human lung cancer cell line A549 by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Among the isolated compounds, 3 and 4 displayed potent radical scavenging activities with IC50 values of 30.2 ± 1.8 and 32.0 ± 1.2 µM, which were comparable to that of Trolox (29.2 ± 0.39 µM), respectively, while 5 possessed moderate activity with an IC50 value of 46.4 ± 2.3 µM. None of the isolated compounds exerted cytotoxicity against human cell line A549. As a result, lasianosides C, D, and E have the potential to be non-toxic safe antioxidant agents.

A well-nourished and healthy population is a central tenet of sustainable development. In South Africa, cultural beliefs and food taboos followed by some pregnant women influence their food consumption, which impacts the health of mothers and children during pregnancy and immediately afterwards. We documented food taboos and beliefs amongst pregnant isiXhosa women from five communities in the Kat River Valley, South Africa. A mixed-methods approach was used, which was comprised of questionnaire interviews with 224 women and nine focus group discussions with 94 participants. Overall, 37% of the women reported one or more food practices shaped by local cultural taboos or beliefs. The most commonly avoided foods were meat products, fish, potatoes, fruits, beans, eggs, butternut and pumpkin, which are rich in essential micronutrients, protein and carbohydrates. Most foods were avoided for reasons associated with pregnancy outcome, labour and to avoid an undesirable body form for the baby. Some pregnant women consumed herbal decoctions for strengthening pregnancy, facilitating labour and overall health of both themselves and the foetus. Most learnt of the taboos and practices from their own mother or grandmother, but there was also knowledge transmission in social groups. Some pregnant women in the study may be considered nutritionally vulnerable due to the likelihood of decreased intake of nutrient-rich foods resulting from cultural beliefs and food taboos against some nutritious foods. Encouraging such women to adopt a healthy diet with more protein-rich foods, vegetables and fruits would significantly improve maternal nutrition and children's nutrition. Adhering to culturally appropriate nutrition education may be an important care practice for many pregnant women in the Kat River Valley.

Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977), on major adverse cardiovascular events (MACEs) and all-cause mortality in patients with coronary artery disease (CAD). We studied 770 patients (673 males, 64.8 ± 8.3 years) with known or suspected stable CAD. LTL and mtDNA4977 deletion were assessed in peripheral blood using qRT-PCR. During a median follow-up of 5.4 ± 1.2 years, MACEs were 140 while 86 deaths were recorded. After adjustments for confounding risk factors, short LTLs and high mtDNA4977 deletion levels acted independently as predictors of MACEs (HR: 2.2, 95% CI: 1.2-3.9, p = 0.01 and HR: 1.7, 95% CI: 1.1-2.9, p = 0.04; respectively) and all-cause mortality events (HR: 2.1, 95% CI: 1.1-4.6, p = 0.04 and HR: 2.3, 95% CI: 1.1-4.9, p = 0.02; respectively). Patients with both short LTLs and high mtDNA4977 deletion levels had an increased risk for MACEs (HR: 4.3; 95% CI: 1.9-9.6; p = 0.0006) and all-cause mortality (HR: 6.0; 95% CI: 2.0-18.4; p = 0.001). The addition of mtDNA4977 deletion to a clinical reference model was associated with a significant net reclassification improvement (NRI = 0.18, p = 0.01). Short LTL and high mtDNA4977 deletion showed independent and joint predictive value on adverse cardiovascular outcomes and all-cause mortality in patients with CAD. These findings strongly support the importance of evaluating biomarkers of physiological/biological age, which can predict disease risk and mortality more accurately than chronological age.

Reaction of 1-adamantyl carbohydrazide (1) with various substituted benzaldehydes and acetophenones yielded the corresponding hydrazide-hydrazones with a 1-adamantane carbonyl moiety. The new synthesized compounds were tested for activities against some Gram-negative and Gram-positive bacteria, and the fungus Candida albicans. Compounds 4a, 4b, 5a, and 5c displayed potential antibacterial activity against tested Gram-positive bacteria and C. albicans, while compounds 4e and 5e possessed cytotoxicity against tested human cancer cell lines.

In Ghana, a blood group and rhesus type test is one of the essential recommended screening tests for women during antenatal care since blood transfusion is a key intervention for haemorrhage. We estimated the spatial accessibility to health facilities for blood group and type point-of-care (POC) testing in the Upper East Region (UER), Ghana.

High mobility group box B (HMGB) proteins are pivotal in the development of cancer. Although the proteomics of prostate cancer (PCa) cells has been reported, the involvement of HMGB proteins and their interactome in PCa is an unexplored field of considerable interest. We describe herein the results of the first HMGB1/HMGB2 interactome approach to PCa. Libraries constructed from the PCa cell line, PC-3, and from patients' PCa primary tumor have been screened by the yeast 2-hybrid approach (Y2H) using HMGB1 and HMGB2 baits. Functional significance of this PCa HMGB interactome has been validated through expression and prognosis data available on public databases. Copy number alterations (CNA) affecting these newly described HMGB interactome components are more frequent in the most aggressive forms of PCa: those of neuroendocrine origin or castration-resistant PCa. Concordantly, adenocarcinoma PCa samples showing CNA in these genes are also associated with the worse prognosis. These findings open the way to their potential use as discriminatory biomarkers between high and low risk patients. Gene expression of a selected set of these interactome components has been analyzed by qPCR after HMGB1 and HMGB2 silencing. The data show that HMGB1 and HMGB2 control the expression of several of their interactome partners, which might contribute to the orchestrated action of these proteins in PCa.

Dyslipidemia has been associated with vascular complications of type 1 diabetes mellitus (T1DM). We examined the proton nuclear magnetic resonance (NMR)-assessed lipoprotein subclass profiles in subjects with T1DM compared with those of healthy subjects and assessed the potential relationship of these profiles with arterial stiffness.

The 'superbug' infection caused by metallo-β-lactamases (MβLs) has grown into an emergent health threat. Given the clinical importance of MβLs, a novel scaffold, dithiocarbamate, was constructed. The obtained molecules, DC1, DC8 and DC10, inhibited MβLs NDM-1, VIM-2, IMP-1, ImiS and L1 from all three subclasses, exhibiting an IC50 < 26 μM. DC1 was found to be the best inhibitor of ImiS (IC50 < 0.22 μM). DC1-2, DC4, DC8 and DC10 restored antimicrobial effects of cefazolin and imipenem against E. coli-BL21, producing NDM-1, ImiS or L1, and DC1 showed the best inhibition of E. coli cells, expressing the three MβLs, resulting in a 2-16-fold reduction in the minimum inhibitory concentrations (MICs) of both antibiotics. Kinetics and isothermal titration calorimetry (ITC) assays showed that DC1 exhibited a reversible, and partially mixed inhibition, of NDM-1, ImiS and L1, with Ki values of 0.29, 0.14 and 5.06 µM, respectively. Docking studies suggest that the hydroxyl and carbonyl groups of DC1 form coordinate bonds with the Zn (II) ions, in the active center of NDM-1, ImiS and L1, thereby inhibiting the activity of the enzymes. Cytotoxicity assays showed that DC1, DC3, DC7 and DC9 have low toxicity in L929 mouse fibroblastic cells, at a dose of up to 250 μM. These studies revealed that the dithiocarbamate is a valuable scaffold for the development of MβLs inhibitors.

Cytokinins (CKs) are a family of evolutionarily conserved growth regulating hormones. While CKs are well-characterized in plant systems, these N6-substituted adenine derivatives are found in a variety of organisms beyond plants, including bacteria, fungi, mammals, and the social amoeba, Dictyostelium discoideum. Within Dictyostelium, CKs have only been studied in the late developmental stages of the life cycle, where they promote spore encapsulation and dormancy. In this study, we used ultra high-performance liquid chromatography-positive electrospray ionization-high resolution tandem mass spectrometry (UHPLC-(ESI+)-HRMS/MS) to profile CKs during the Dictyostelium life cycle: growth, aggregation, mound, slug, fruiting body, and germination. Comprehensive profiling revealed that Dictyostelium produces 6 CK forms (cis-Zeatin (cZ), discadenine (DA), N6-isopentenyladenine (iP), N6-isopentenyladenine-9-riboside (iPR), N6-isopentenyladenine-9-riboside-5' phosphate (iPRP), and 2-methylthio-N6-isopentenyladenine (2MeSiP)) in varying abundance across the sampled life cycle stages, thus laying the foundation for the CK biosynthesis pathway to be defined in this organism. Interestingly, iP-type CKs were the most dominant CK analytes detected during growth and aggregation. Exogenous treatment of AX3 cells with various CK types revealed that iP was the only CK to promote the proliferation of cells in culture. In support of previous studies, metabolomics data revealed that DA is one of the most significantly upregulated small molecules during Dictyostelium development, and our data indicates that total CK levels are highest during germination. While much remains to be explored in Dictyostelium, this research offers new insight into the nature of CK biosynthesis, secretion, and function during Dictyostelium growth, development, and spore germination.

Seven new butanolides, peltanolides A-G (1-7), and two lignan glucosides, peltasides A (8) and B (9), along with eleven known compounds, 10-20, were isolated from a crude CH3OH/CH2Cl2 (1:1) extract of the fruit of Hernandia nymphaeifolia (Hernandiaceae). The structures of 1-9 were characterized by extensive 1D and 2D NMR spectroscopic and HRMS analysis. The absolute configurations of newly isolated compounds 1-9 were determined from data obtained by optical rotation and electronic circular dichroism (ECD) exciton chirality methods. Butanolides and lignan glucosides have not been isolated previously from this genus. Several isolated compounds were evaluated for antiproliferative activity against human tumor cell lines. Lignans 15 and 16 were slightly active against chemosensitive tumor cell lines A549 and MCF-7, respectively. Furthermore, both compounds displayed significant activity (IC50 = 5 µM) against a P-glycoprotein overexpressing multidrug-resistant tumor cell line (KB-VIN) but were less active against its parent chemosensitive cell line (KB).

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate iron metabolism. We evaluated the association of the copy number of the glutathione S-transferase M1 (GSTM1) gene and degree of iron overload among patients with SCA. We compared LIC in 38 children with SCA and ≥12 lifetime erythrocyte transfusions stratified by GSTM1 genotype. Baseline LIC was measured using magnetic resonance imaging (MRI), R2*MRI within 3 months prior to, and again after, starting iron unloading therapy. After controlling for weight-corrected transfusion burden (mL/kg) and splenectomy, mean pre-chelation LIC (mg/g dry liver dry weight) was similar in all groups: GSTM1 wild-type (WT) (11.45, SD±6.8), heterozygous (8.2, SD±4.52), and homozygous GSTM1 deletion (GSTM1-null; 7.8, SD±6.9, p = 0.09). However, after >12 months of chelation, GSTM1-null genotype subjects had the least decrease in LIC compared to non-null genotype subjects (mean LIC change for GSTM1-null = 0.1 (SD±3.3); versus -0.3 (SD±3.0) and -1.9 (SD±4.9) mg/g liver dry weight for heterozygous and WT, respectively, p = 0.047). GSTM1 homozygous deletion may prevent effective chelation in children with SCA and iron overload.

Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, phenolics like flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and structurally rearranged by gut microbiota, yielding smaller and more polar metabolites like phenyl-γ-valerolactones, phenylvaleric acids and their conjugates. The present work investigated the ability of F3O-derived metabolites to cross the blood-brain barrier (BBB), by linking five experimental models with increasing realism. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those most likely to cross the BBB. Some of these metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3',4'-dihydroxyphenyl)-γ-valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-γ-valerolactone-sulfate (3',4' isomer) in the brain. This work highlighted, with different experimental models, the BBB permeability of one of the main F3O-derived metabolites. It may support the neuroprotective effects of phenolic-rich foods in the frame of the "gut-brain axis".

In cancer research, population-based survival analysis has played an important role. In this article, we conduct survival analysis on patients with brain tumors using the SEER (Surveillance, Epidemiology, and End Results) database from the NCI (National Cancer Institute). It has been recognized that cancer survival models have spatial and temporal variations which are caused by multiple factors, but such variations are usually not "abrupt" (that is, they should be smooth). As such, spatially and temporally pooling all data and analyzing each spatial/temporal point separately are either inappropriate or ineffective. In this article, we develop and implement a spatial- and temporal-smoothing technique, which can effectively accommodate spatial/temporal variations and realize information borrowing across spatial/temporal points. Simulation demonstrates effectiveness of the proposed approach in improving estimation. Data on a total of 123,571 patients with brain tumors diagnosed between 1911 and 2010 from 16 SEER sites is analyzed. Findings different from separate estimation and simple pooling are made. Overall, this study may provide a practically useful way for modeling the survival of brain tumor (and other cancers) using population data.

Bacterial hormone-sensitive lipases (bHSLs), which are homologous to the catalytic domains of human HSLs, have received great interest due to their uses in the preparation of highly valuable biochemicals, such as drug intermediates or chiral building blocks. Here, a novel cold-active HSL from Halocynthiibacter arcticus (HaHSL) was examined and its enzymatic properties were investigated using several biochemical and biophysical methods. Interestingly, HaHSL acted on a large variety of substrates including tertiary alcohol esters and fish oils. Additionally, this enzyme was highly tolerant to high concentrations of salt, detergents, and glycerol. Furthermore, immobilized HaHSL retained its activity for up to six cycles of use. Homology modeling suggested that aromatic amino acids (Trp23, Tyr74, Phe78, Trp83, and Phe245) in close proximity to the substrate-binding pocket were important for enzyme activity. Mutational analysis revealed that Tyr74 played an important role in substrate specificity, thermostability, and enantioselectivity. In summary, the current study provides an invaluable insight into the novel cold-active HaHSL from H. arcticus, which can be efficiently and sustainably used in a wide range of biotechnological applications.

Heat stress negatively impacts the health and milk production of dairy cows, and ruminal microbial populations play an important role in dairy cattle's milk production. Currently there are no available studies that investigate heat stress-associated changes in the rumen microbiome of lactating dairy cattle. Improved understanding of the link between heat stress and the ruminal microbiome may be beneficial in developing strategies for relieving the influence of heat stress on ruminants by manipulating ruminal microbial composition. In this study, we investigated the ruminal bacterial composition and metabolites in heat stressed and non-heat stressed dairy cows. Eighteen lactating dairy cows were divided into two treatment groups, one with heat stress and one without heat stress. Dry matter intake was measured and rumen fluid from all cows in both groups was collected. The bacterial 16S rRNA genes in the ruminal fluid were sequenced, and the rumen pH and the lactate and acetate of the bacterial metabolites were quantified. Heat stress was associated with significantly decreased dry matter intake and milk production. Rumen pH and rumen acetate concentrations were significantly decreased in the heat stressed group, while ruminal lactate concentration increased. The influence of heat stress on the microbial bacterial community structure was minor. However, heat stress was associated with an increase in lactate producing bacteria (e.g., Streptococcus and unclassified Enterobacteriaceae), and with an increase in Ruminobacter, Treponema, and unclassified Bacteroidaceae, all of which utilize soluble carbohydrates as an energy source. The relative abundance of acetate-producing bacterium Acetobacter decreased during heat stress. We concluded that heat stress is associated with changes in ruminal bacterial composition and metabolites, with more lactate and less acetate-producing species in the population, which potentially negatively affects milk production.