The Dual Energy X-Ray Absorptiometry (DXA) is the gold standard for measuring BMD and bone mineral content (BMC). In general, DXA is ideal for pediatric use. However, the development of specific standards for particular geographic regions limits its use and application for certain socio-cultural contexts. Additionally, the anthropometry may be a low cost and easy to use alternative method in epidemiological contexts. The goal of our study was to develop regression equations for predicting bone health of children and adolescents based on anthropometric indicators to propose reference values based on age and sex.

The microtubule-based motor dynein generates pulling forces for centrosome centration and mitotic spindle positioning in animal cells. How the essential dynein activator dynactin regulates these functions of the motor is incompletely understood. Here, we dissect the role of dynactin's microtubule binding activity, located in the p150 CAP-Gly domain and an adjacent basic patch, in the C. elegans zygote. Analysis of p150 mutants engineered by genome editing suggests that microtubule tip tracking of dynein-dynactin is dispensable for targeting the motor to the cell cortex and for generating robust cortical pulling forces. Instead, mutations in p150's CAP-Gly domain inhibit cytoplasmic pulling forces responsible for centration of centrosomes and attached pronuclei. The centration defects are mimicked by mutations of α-tubulin's C-terminal tyrosine, and both p150 CAP-Gly and tubulin tyrosine mutants decrease the frequency of early endosome transport from the cell periphery towards centrosomes during centration. Our results suggest that p150 GAP-Gly domain binding to tyrosinated microtubules promotes initiation of dynein-mediated organelle transport in the dividing one-cell embryo, and that this function of p150 is critical for generating cytoplasmic pulling forces for centrosome centration.

Mycobacterium tuberculosis (Mtb) and helminth infections elicit antagonistic immune effector functions and are co-endemic in several regions of the world. We therefore hypothesized that helminth infection may influence Mtb-specific T-cell immune responses. We evaluated the cytokine profile of Mtb-specific T cells in 72 individuals with pulmonary TB disease recruited from two Sub-Saharan regions with high and moderate helminth burden i.e. 55 from Tanzania (TZ) and 17 from South Africa (SA), respectively. We showed that Mtb-specific CD4 T-cell functional profile of TB patients from Tanzania are primarily composed of polyfunctional Th1 and Th2 cells, associated with increased expression of Gata-3 and reduced expression of T-bet in memory CD4 T cells. In contrast, the cytokine profile of Mtb-specific CD4 T cells of TB patients from SA was dominated by single IFN-γ and dual IFN-γ/TNF-α and associated with TB-induced systemic inflammation and elevated serum levels of type I IFNs. Of note, the proportion of patients with Mtb-specific CD8 T cells was significantly reduced in Mtb/helminth co-infected patients from TZ. It is likely that the underlying helminth infection and possibly genetic and other unknown environmental factors may have caused the induction of mixed Th1/Th2 Mtb-specific CD4 T cell responses in patients from TZ. Taken together, these results indicate that the generation of Mtb-specific CD4 and CD8 T cell responses may be substantially influenced by environmental factors in vivo. These observations may have major impact in the identification of immune biomarkers of disease status and correlates of protection.

In this study, we investigated the applicability of NMR-based metabolomics to discriminate strain-dependent fermentation characteristics of lactic acid bacteria (LAB), which are important microorganisms for fermented food production. To evaluate the discrimination capability, six type strains of Lactobacillus species and six additional L. brevis strains were used focusing on i) the difference between homo- and hetero-lactic fermentative species and ii) strain-dependent characteristics within L. brevis. Based on the differences in the metabolite profiles of fermented vegetable juices, non-targeted principal component analysis (PCA) clearly separated the samples into those inoculated with homo- and hetero-lactic fermentative species. The separation was primarily explained by the different levels of dominant metabolites (lactic acid, acetic acid, ethanol, and mannitol). Orthogonal partial least squares discrimination analysis, based on a regions-of-interest (ROIs) approach, revealed the contribution of low-abundance metabolites: acetoin, phenyllactic acid, p-hydroxyphenyllactic acid, glycerophosphocholine, and succinic acid for homolactic fermentation; and ornithine, tyramine, and γ-aminobutyric acid (GABA) for heterolactic fermentation. Furthermore, ROIs-based PCA of seven L. brevis strains separated their strain-dependent fermentation characteristics primarily based on their ability to utilize sucrose and citric acid, and convert glutamic acid and tyrosine into GABA and tyramine, respectively. In conclusion, NMR metabolomics successfully discriminated the fermentation characteristics of the tested strains and provided further information on metabolites responsible for these characteristics, which may impact the taste, aroma, and functional properties of fermented foods.

The tea-oil camellia (Camellia oleifera) is the most important oil plant in southern China, and has a strong resistance to drought and barren soil. Understanding the molecular mechanisms of drought tolerance would greatly promote its cultivation and molecular breeding.

TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8-/-) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8-/-mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8-/-mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.

The autism and schizophrenia spectra overlap to a large degree in the social and interpersonal domains. Similarly, abnormal excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) neurotransmitter concentrations have been reported for both spectra, with the interplay of these neurotransmitters important for cortical excitation to inhibition regulation. This study investigates whether these neurotransmitter abnormalities are specific to the shared symptomatology, and whether the degree of abnormality increases with increasing symptom severity. Hence, the relationship between the glutamate/GABA ratio and autism and schizophrenia spectrum traits in an unmedicated, subclinical population was investigated.

The pan lymphocyte marker CD45 exists in various isoforms arising from alternative splicing of the exons 4, 5 and 6. While naïve T cells express CD45RA translated from an mRNA containing exon 4, exons 4-6 are spliced out to encode the shorter CD45R0 in antigen-experienced effector/memory T cells. The SNP C77G (rs17612648) is located in exon 4 and blocks the exon's differential splicing from the pre-mRNA, enforcing expression of CD45RA. Several studies have linked C77G to autoimmune diseases but lack of validation in other cohorts has left its role elusive. An incidental finding in an ovarian cancer patient cohort from West Norway (Bergen region, n = 312), suggested that the frequency of C77G was higher among ovarian cancer patients than in healthy Norwegians (n = 1,357) (3.0% vs. 1.8% allele frequency). However, this finding could not be validated in a larger patient cohort from South-East Norway (Oslo region, n = 1,198) with 1.2% allele frequency. Hence, C77G is not associated with ovarian cancer in the Norwegian population. However, its frequency was increased in patients with FIGO stage II, endometrioid histology or an age at diagnosis of 60 years or older indicating a possible association with a less aggressive cancer type.

The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with angiotensin II and phenylephrine enhanced GRK2 expression leading to enhanced signaling via protein kinase B (PKB or Akt), consecutively inhibiting glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte hypertrophy. Our data show that enhanced GRK2 expression triggers cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity.

Infection by enveloped coronaviruses (CoVs) initiates with viral spike (S) proteins binding to cellular receptors, and is followed by proteolytic cleavage of receptor-bound S proteins, which prompts S protein-mediated virus-cell membrane fusion. Infection therefore requires close proximity of receptors and proteases. We considered whether tetraspanins, scaffolding proteins known to facilitate CoV infections, hold receptors and proteases together on cell membranes. Using knockout cell lines, we found that the tetraspanin CD9, but not the tetraspanin CD81, formed cell-surface complexes of dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, and the type II transmembrane serine protease (TTSP) member TMPRSS2, a CoV-activating protease. This CD9-facilitated condensation of receptors and proteases allowed MERS-CoV pseudoviruses to enter cells rapidly and efficiently. Without CD9, MERS-CoV viruses were not activated by TTSPs, and they trafficked into endosomes to be cleaved much later and less efficiently by cathepsins. Thus, we identified DPP4:CD9:TTSP as the protein complexes necessary for early, efficient MERS-CoV entry. To evaluate the importance of these complexes in an in vivo CoV infection model, we used recombinant Adenovirus 5 (rAd5) vectors to express human DPP4 in mouse lungs, thereby sensitizing the animals to MERS-CoV infection. When the rAd5-hDPP4 vectors co-expressed small RNAs silencing Cd9 or Tmprss2, the animals were significantly less susceptible, indicating that CD9 and TMPRSS2 facilitated robust in vivo MERS-CoV infection of mouse lungs. Furthermore, the S proteins of virulent mouse-adapted MERS-CoVs acquired a CD9-dependent cell entry character, suggesting that CD9 is a selective agent in the evolution of CoV virulence.

In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection.

The etiology of pulmonary infections in HIV patients is determined by several variables including geographic region and availability of antiretroviral therapy.

The aim of the study was to characterize the vascular effects of rice bran enzymatic extract (RBEE). ApoE-/- mice were fed a high-fat/cholesterol diet (HFD) or HFD supplemented with 5% RBEE for 21 weeks. RBEE prevented development of atherosclerotic plaques and oxidative stress in mouse aorta as well as the down-regulation of markers of mitochondrial biogenesis. Analysis of the bioactive components identified ferulic acid (FA) as responsible component. In healthy human volunteers, FA intake reduced NADPH oxidase activity, superoxide release, apoptosis and necrosis in peripheral blood mononuclear cells. Differentiation and proliferation of endothelial progenitor cells were improved. In summary, the study identifies FA as a major active component of rice bran, which improves expression of mitochondrial biogenesis and dynamics markers and reduces oxidative stress in a mouse model of vascular damage as well as in endothelial cells and human mononuclear cells.

Vicarious pain perception has been an influential paradigm for investigating the social neuroscience of empathy. This research has highlighted the importance of both shared representations (i.e., involved in both experiencing first-hand physical pain and observing pain) and mechanisms that discriminate between self and other. The majority of this research has been conducted in healthy younger adults using a group-average approach. There are, however, known inter-individual differences that can contribute to vicarious experience. One factor relates to the degree to which individuals experience reportable pain-like sensations/feelings in response to seeing others in pain. Here we conduct the first systematic investigation of the neural basis of conscious vicarious pain in a large sample of participants. Using cluster analysis, we firstly demonstrate that consciously experiencing the pain of others is surprisingly prevalent and, exists in two forms: one group experiences sensory and localised pain whilst the other group report affective and non-localised experiences. Building on this, we used electroencephalography (EEG) and structural brain imaging to examine the neural correlates of vicarious pain in the three different groups. We find that the dominant electrophysiological marker used to index vicarious pain in previous studies (mu and beta suppression) was only found to be significant in the sensory and localised pain responder group (with a sensitive null result in the 'neurotypical' group). Finally, using voxel-based morphometry (VBM) we identify a common differences in the two pain responder groups relative to typical adults; namely increased grey-matter in insula and somatosensory cortex and reduced grey matter in the right temporo-parietal junction (rTPJ). We suggest that the latter reflects a reduced ability to distinguish bodily self and other, and may be a common factor distinguishing conscious from unconscious vicarious experience.

A series of thiazolo[5,4-d]pyrimidine derivatives were designed through the atom replacement strategy based on biologically validated scaffolds and then evaluated for their antiproliferative activities on cancer cell lines. The structure-activity relationship studies were conducted, leading to the identification of compound 22, which exhibited good antiproliferative activity against HGC-27 with an IC50 value of 1.22 μM and low toxicity against GES-1 cells. Mechanistic studies showed that compound 22 inhibited the colony formation and migration of HGC-27 as well as induced apoptosis. The western blot experiments proved that compound 22 up-regulated expression of Bax, down-regulated expression levels of Bcl-2 and cleaved caspased-3/9. These findings indicate that compound 22 may serve as a template for designing new agents for the treatment of human gastric cancers. The atom replacement strategy could be viable strategy for designing new anticancer drugs and may find its applications in drug design.

Since the relative age effect (RAE) characterizes a problem in all age categories of alpine ski racing and soccer and the fact that, yet, to date the underlying factors have not been well investigated, the aim of the present study was to assess the influence of the biological maturity status on the RAE among youth alpine ski racers (YSR) and soccer players (SP). In total, 183 male and female YSR selected for national final races and 423 male SP selected for Elite Youth Development Centres were investigated. Additionally, a comparison group of 413 non-athletes was evaluated. The birth months were split into four relative age quarters. The biological maturity status was assessed by the age at peak height velocity (APHV) method; according to the M±SD of the comparison group, the athletes were divided into normal, early and late maturing. Chi2-tests indicated a significant RAE among YSR (χ2(3,N = 183) = 18.0; p<0.001; ω = 0.31) and SP (χ2(3,N = 423) = 33.1; p<0.001; ω = 0.28). In total, only a small number of late maturing athletes were present (0.5-2.3%). Among relatively younger athletes, high percentages of early maturing athletes were found (43.1-43.3%). The findings indicate that relatively younger and less mature athletes are marginalized or totally excluded in alpine ski racing and soccer. Thus, selection criteria in both sports are effectively based on early biological development and relatively older age, both of which should be considered in future in the talent selection process. In this context, the easy feasible method of assessing the APHV can be used.

MicroRNAs (miRNAs) have been proven to be critical players in many different types of tumors including esophageal squamous cell carcinoma (ESCC).

Metabolic syndrome (MetS) was a risk factor for cardiovascular diseases, yet the prevalence of MetS among nonagenarians and centenarians was rarely reported. Here we investigated the prevalence of MetS and its components among nonagenarians and centenarians in our Zhuang population from Bama, Guangxi Zhuang Autonomous Region, China.

The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

The Suv39h1 and Suv39h2 histone lysine methyltransferases are hallmark enzymes at mammalian heterochromatin. We show here that the mouse Suv39h2 enzyme differs from Suv39h1 by containing an N-terminal basic domain that facilitates retention at mitotic chromatin and provides an additional affinity for major satellite repeat RNA. To analyze an RNA-dependent interaction with chromatin, we purified native nucleosomes from mouse ES cells and detect that Suv39h1 and Suv39h2 exclusively associate with poly-nucleosomes. This association was attenuated upon RNaseH incubation and entirely lost upon RNaseA digestion of native chromatin. Major satellite repeat transcripts remain chromatin-associated and have a secondary structure that favors RNA:DNA hybrid formation. Together, these data reveal an RNA-mediated mechanism for the stable chromatin interaction of the Suv39h KMT and suggest a function for major satellite non-coding RNA in the organization of an RNA-nucleosome scaffold as the underlying structure of mouse heterochromatin.