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Purinergic receptors have been shown to be involved in neuronal development, but the functions of specific subtypes of P2 receptors during neuronal development remain elusive. In this study we investigate the distribution of P2X 7 receptors (P2X 7 Rs) in the embryonic rat brain using in situ hybridization. At E15.5, P2X 7 R mRNA was observed in the ventricular zone and subventricular zone, and colocalized with nestin, indicating that P2X 7 R might be expressed in neural progenitor cells (NPCs). P2X 7 R mRNA was also detected in the subgranular zone and dentate gyrus of the E18.5 and P4 brain. To investigate the roles of P2X 7 R and elucidate its mechanism, we established NPC cultures from the E15.5 rat brain. Stimulation of P2X 7 Rs induced Ca 2+ influx, inhibited proliferation, altered cell cycle progression and enhanced the expression of neuronal markers, such as TUJ1 and MAP2. Similarly, knockdown of P2X 7 R by shRNA nearly abolished the agonist-stimulated increases in intracellular Ca 2+ concentration and the expression of TUJ1 and NeuN. Furthermore, stimulation of P2X 7 R induced activation of ERK1/2, which was inhibited by the removal of extracellular Ca 2+ and treatment with blockers for P2X 7 R and PKC activity. Stimulation of P2X 7 R also induced translocation of PKC α and PKC γ , but not of PKC β , whereas knockdown of either PKC α or PKC γ inhibited ERK1/2 activation. Inhibition of PKC or p-ERK1/2 also caused a decrease in the number of TUJ1-positive cells and a concomitant increase in the number of GFAP-positive cells. Taken together, the activation of P2X 7 R in NPCs induced neuronal differentiation through a PKC-ERK1/2 signaling pathway.

We identified a stem cell donor with chromosomally integrated human herpesvirus (HHV)–6 and monitored the recipient for HHV-6 after transplantation. The appearance and subsequent increase in HHV-6 load paralleled engraftment and an increase in white blood cell count. Fluorescent in situ hybridization analysis showed integrated HHV-6 on chromosome band 17p13.3 in the donor and in the recipient after transplantation but not in the recipient before transplantation. The increase in viral load due to the genetic transmission of integrated HHV-6 could have been misinterpreted as substantial active infection and, thus, led to the administration of toxic antiviral therapy. We suggest that the confounding influence of integration be considered in laboratory investigations associating HHV-6 with disease

Purpose Ataxia–Telangiectasia Mutated ( ATM ) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p  < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p  < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p  < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p  < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases ( p  = 0.027, p  = 0.018). Conclusion This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

This nationwide population-based retrospective cohort study evaluated the risk of developing prostate cancer among patients with gonorrhea. We identified cases of newly diagnosed gonorrhea in men between 2000 and 2010 from the Taiwan National Health Insurance Research Database. Each patient with gonorrhea was matched to four controls, based on age and index year. All subjects were followed up from the index date to December 31, 2010. The Cox proportional hazards regression model was used to assess the risk of prostate cancer. A total of 355 men were included in the study group, and 1,420 age-matched subjects without gonorrhea were included in the control group. After adjusting for age, comorbidities, urbanization level, hospital level, and monthly income, gonorrhea was significantly associated with an increased risk of prostate cancer (adjusted hazard ratio = 5.66, 95% confidence interval = 1.36–23.52). Men aged 45–70 years and those with lower monthly income were more strongly associated with prostate cancer in the study group than the control group. The higher risk for developing prostate cancer were also found in those without syphilis, without genital warts, without diabetes mellitus, without chronic obstructive pulmonary disease, without benign prostatic hypertrophy, without chronic prostatitis, and without alcoholism. The Kaplan–Meier analysis showed the risk of prostate cancer was significantly higher in the study group than in the control group. Gonorrhea may be involved in the development of prostate cancer. More intensive screening and prevention interventions for prostate cancer should be recommended in men with gonorrhea.

EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in many aggressive cancer types, including melanoma. We recently showed that EphA2 is also upregulated by ultraviolet radiation and is able to induce apoptosis. These findings suggest that EphA2 may have different, even paradoxical, effects on viability depending on the cellular context and that EphA2 mediates a delicate balance between life and death of the cell. To functionally clarify EphA2's role in melanoma, we analyzed a panel of melanoma cell lines and found that EphA2 levels are elevated in a significant fraction of the samples. Specific depletion of EphA2 in high-expressing melanoma cells using short hairpin RNA led to profound reductions in cellular viability, colony formation and migration in vitro and a dramatic loss of tumorigenic potential in vivo . Stable introduction of EphA2 into low-expressing cell lines enhanced proliferation, colony formation and migration, further supporting its pro-malignant phenotype. Interestingly, transient expression of EphA2 and/or Braf V600E in non-transformed melanocytes led to significant and additive apoptosis. These results verify that EphA2 is an important oncogene and potentially a common source of ‘addiction’ for many melanoma cells. Moreover, acute induction of EphA2 may purge genetically susceptible cells, thereby uncovering a more aggressive population that is in fact dependent on the oncogene.

Summary Objective To identify factors associated with development of systemic lupus erythematosus (SLE) among patients evaluated at a tertiary care Lupus Center for potential SLE. Methods We identified patients first seen at the Brigham and Women's Hospital Lupus Center between 1 January 1992 and 31 December 2012 and thought to have potential SLE by a board‐certified rheumatologist. All had 1–3 SLE ACR criteria at initial visit and > 2 follow‐up visits ≥ 3 months apart. We reviewed medical records through 15 May 2013 for: SLE signs and symptoms, autoimmune serologies, prescriptions and diagnoses by board‐certified rheumatologists. Bivariable analyses and multivariable logistic regression models were used to identify independent predictors of developing SLE. Results Two hundred and sixty four patients met inclusion criteria. At initial visit, mean age was 39.2 (SD 12.4) years, 94% were female and 67% white. Mean number of SLE ACR criteria was 2.7 (SD 1.0) and 88% were antinuclear antibody (ANA) positive at initial consultation. Mean follow‐up time was 6.3 (SD 4.3) years and 67% were prescribed hydroxychloroquine in follow‐up. At most recent visit, 56 (21%) had been diagnosed with SLE; 47 (18%) were thought not to have SLE and 161 (61%) were still considered to have potential SLE. In multivariable regression models, oral ulcers (OR 2.40, 95% CI 1.03–5.58), anti‐dsDNA (OR 2.59, 95% CI 1.25–5.35) and baseline proteinuria or cellular casts (OR 16.20, 95% CI 1.63–161.02) were independent predictors of developing SLE. The most common other final diagnoses included fibromyalgia, Sjögren's syndrome, mixed connective tissue disease and cutaneous lupus. Conclusion Among patients with potential SLE at initial consultation, 21% were diagnosed with definite SLE within 6.3 years. Oral ulcers, anti‐dsDNA and proteinuria or cellular casts were independent predictors of developing definite SLE. A better means of accurately identifying those who will develop SLE among those presenting with potential disease is necessary.

Age-dependent conformational stability of human serum albumin was determined by the method of fluorescent bilayer liposome assay. After pre-heating at 80 °C, albumin in the sera of 74-year-old healthy subjects exhibited hydrophobic effects on liposomes and made liposomal membrane phospholipids more susceptible to hydrolysis by the lipolytic enzyme phospholipase A2. In contrast, albumin in the sera of 24-year-old individuals was stable at 80 °C and displayed no increased hydrophobic effects on liposomes. The results suggest that albumin in the sera of 74-year-old subjects is more easily converted to a misfolded form in which its protein structure is altered when compared to albumin in the sera of 24-year-old individuals. Misfolded albumin can lose its ability to carry out its normal homeostatic functions and may promote alterations in membrane integrity under inflammatory conditions. However, our investigation has limitations that include the lack of testing sera from large numbers of individuals across a broad range of age to validate our preliminary observations of age-dependent differences in albumin stability and its interactions with liposomes.

[...]emerging evidence suggests that changes in motor control are likely to result in increased stiffness of the spine and reduce the use of preparatory movement. [...]exercise interventions should aim to restore and optimise the balance between spinal stability and movement.

Recent studies on genome assembly from short-read sequencing data reported the limitation of this technology to reconstruct the entire genome even at very high depth coverage. We investigated the limitation from the perspective of information theory to evaluate the effect of repeats on short-read genome assembly using idealized (error-free) reads at different lengths. We define a metric H(k) to be the entropy of sequencing reads at a read length k and use the relative loss of entropy ΔH(k) to measure the impact of repeats for the reconstruction of whole-genome from sequences of length k. In our experiments, we found that entropy loss correlates well with de-novo assembly coverage of a genome, and a score of ΔH(k)>1% indicates a severe loss in genome reconstruction fidelity. The minimal read lengths to achieve ΔH(k)<1% are different for various organisms and are independent of the genome size. For example, in order to meet the threshold of ΔH(k)<1%, a read length of 60 bp is needed for the sequencing of human genome (3.2 10(9) bp) and 320 bp for the sequencing of fruit fly (1.8×10(8) bp). We also calculated the ΔH(k) scores for 2725 prokaryotic chromosomes and plasmids at several read lengths. Our results indicate that the levels of repeats in different genomes are diverse and the entropy of sequencing reads provides a measurement for the repeat structures. The proposed entropy-based measurement, which can be calculated in seconds to minutes in most cases, provides a rapid quantitative evaluation on the limitation of idealized short-read genome sequencing. Moreover, the calculation can be parallelized to scale up to large euakryotic genomes. This approach may be useful to tune the sequencing parameters to achieve better genome assemblies when a closely related genome is already available.