Anti-dense fine speckled 70 (DFS70) autoantibodies: correlates and increasing prevalence in the United States

ObjectiveRecent studies report high-titer anti-dense fine speckled 70 (DFS70) autoantibodies in persons with inflammatory conditions, but the clinical significance remains unclear. Our goals were to estimate anti-DFS70 autoantibody prevalence, identify correlates, and assess time trends.MethodsSerum antinuclear antibodies (ANA) were measured by indirect immunofluorescence assay on HEp-2 cells in 13,519 participants ≥12 years old from three time periods (1988–1991, 1999–2004, 2011–2012) of the National Health and Nutrition Examination Survey. ANA-positive participants with dense fine speckled staining were evaluated for anti-DFS70 antibodies by enzyme-linked immunosorbent assay. We used logistic models adjusted for survey-design variables to estimate period-specific anti-DFS70 antibody prevalence in the US, and we further adjusted for sex, age, and race/ethnicity to identify correlates and assess time trends.ResultsWomen were more likely than men (odds ratio (OR)=2.97), black persons were less likely than white persons (OR=0.60), and active smokers were less likely than nonsmokers (OR=0.28) to have anti-DFS70 antibodies. The prevalence of anti-DFS70 antibodies increased from 1.6% in 1988-1991 to 2.5% in 1999-2004 to 4.0% in 2011-2012, which corresponds to 3.2 million, 5.8 million, and 10.4 million seropositive individuals, respectively. This increasing time trend in the US population (P<0.0001) was modified in some subgroups and was not explained by concurrent changes in tobacco smoke exposure. Some, but not all, anti-DFS70 antibody correlates and time trends resembled those reported for total ANA.ConclusionMore research is needed to elucidate anti-DFS70 antibody triggers, their pathologic or potentially protective influences on disease, and their possible clinical implications

Relationship between Reproductive Allocation and Relative Abundance among 32 Species of a Tibetan Alpine Meadow: Effects of Fertilization and Grazing

Background: Understanding the relationship between species traits and species abundance is an important goal in ecology and biodiversity science. Although theoretical studies predict that traits related to performance (e.g. reproductive allocation) are most directly linked to species abundance within a community, empirical investigations have rarely been done. It also remains unclear how environmental factors such as grazing or fertilizer application affect the predicted relationship. Methodology: We conducted a 3-year field experiment in a Tibetan alpine meadow to assess the relationship between plant reproductive allocation (RA) and species relative abundance (SRA) on control, grazed and fertilized plots. Overall, the studied plant community contained 32 common species. Principal Findings: At the treatment level, (i) RA was negatively correlated with SRA on control plots and during the first year on fertilized plots. (ii) No negative RA–SRA correlations were observed on grazed plots and during the second and third year on fertilized plots. (iii) Seed size was positively correlated with SRA on control plots. At the plot level, the correlation between SRA and RA were not affected by treatment, year or species composition. Conclusions/Significance: Our study shows that the performance-related trait RA can negatively affect SRA within communities, which is possibly due to the tradeoffs between clonal growth (for space occupancy) and sexual reproduction. We propose that if different species occupy different positions along these tradeoffs it will contribute to biodiversity maintenance in local communities or even at lager scale

Cardiovascular Effects of Excess Growth Hormone: How Real is the Threat?

Patients with acromegaly carry a high risk of developing cardiovascular diseases (CVD). In fact, CVD is the leading cause of mortality among this group of patients. The most frequent cardiovascular complications are heart failure (HF), valvular disease, hypertension, arrhythmias, and coronary artery disease (CAD). The pathophysiology centers on the family of growth hormone (GH). These hormones are involved in normal cardiac development and function; however, excess of insulin-like growth factor-1 (IGF-1), the principally active hormone, can also cause negative effects on the cardiovascular system. HF in acromegaly usually presents with biventricular enlargement and diastolic dysfunction and is strongly associated with the duration of GH excess rather than the degree of hormone elevation. There is a high prevalence of valvular disease affecting aortic and mitral valves among patients with longer disease duration. The development of hypertension in acromegaly may be attributed to the effects of chronic GH/IGF-1 excess on different organ systems, which act via several mechanisms. The aspect of arrhythmia and CAD complicating acromegaly are currently not fully understood

Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFβ cell cycle arrest

<p>Abstract</p> <p>Background</p> <p>TGFβ is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFβ in disease. We asked how <it>Rb</it>-deficiency would affect responses to TGFβ-induced cell cycle arrest.</p> <p>Results</p> <p>Primary hepatocytes isolated from <it>Rb-floxed </it>mice were infected with an adenovirus expressing CRE-recombinase to delete the <it>Rb </it>gene. In control cells treatment with TGFβ prevented cells to enter S phase via decreased cMYC activity, activation of P16^INK4Aand P21^Cipand reduction of E2F activity. In <it>Rb</it>-null hepatocytes, cMYC activity decreased slightly but P16^INK4Awas not activated and the great majority of cells continued cycling. <it>Rb </it>is therefore central to TGFβ-induced cell cycle arrest in hepatocytes. However some <it>Rb</it>-null hepatocytes remained sensitive to TGFβ-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21^Cip1and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of <it>p53 </it>and <it>p21</it>^{<it>Cip1</it>}. Hepatocytes deficient in <it>p53 or p21</it>^{<it>Cip1 </it>}showed diminished growth inhibition by TGFβ. Double deficiency had a similar impact showing that in cells containing functional pRb; P21^Cipand P53 work through the same pathway to regulate G1/S in response to TGFβ. In <it>Rb</it>-deficient cells however, <it>p53 </it>but not <it>p21</it>^{<it>Cip </it>}deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity.</p> <p>Conclusion</p> <p>The present results show that otherwise genetically normal hepatocytes with disabled <it>p53</it>, <it>p21</it>^{<it>Cip1 </it>}or <it>Rb </it>genes respond less well to the antiproliferative effects of TGFβ. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21^Cip1and P53 in hepatocytes may represent an additional new mechanism of escape from TGFβ-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.</p

A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests

Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary – albeit often ineffective – treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.Stanley Medical Research InstituteNational Institutes of Health (U.S.) (R01DA028301)National Institutes of Health (U.S.) (R01DA030321

Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

Pre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.Alum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion

Biofilm Development on Caenorhabditis elegans by Yersinia Is Facilitated by Quorum Sensing-Dependent Repression of Type III Secretion

Yersinia pseudotuberculosis forms biofilms on Caenorhabditis elegans which block nematode feeding. This genetically amenable host-pathogen model has important implications for biofilm development on living, motile surfaces. Here we show that Y. pseudotuberculosis biofilm development on C. elegans is governed by N-acylhomoserine lactone (AHL)-mediated quorum sensing (QS) since (i) AHLs are produced in nematode associated biofilms and (ii) Y. pseudotuberculosis strains expressing an AHL-degrading enzyme or in which the AHL synthase (ypsI and ytbI) or response regulator (ypsR and ytbR) genes have been mutated, are attenuated. Although biofilm formation is also attenuated in Y. pseudotuberculosis strains carrying mutations in the QS-controlled motility regulator genes, flhDC and fliA, and the flagellin export gene, flhA, flagella are not required since fliC mutants form normal biofilms. However, in contrast to the parent and fliC mutant, Yop virulon proteins are up-regulated in flhDC, fliA and flhA mutants in a temperature and calcium independent manner. Similar observations were found for the Y. pseudotuberculosis QS mutants, indicating that the Yop virulon is repressed by QS via the master motility regulator, flhDC. By curing the pYV virulence plasmid from the ypsI/ytbI mutant, by growing YpIII under conditions permissive for type III needle formation but not Yop secretion and by mutating the type III secretion apparatus gene, yscJ, we show that biofilm formation can be restored in flhDC and ypsI/ytbI mutants. These data demonstrate that type III secretion blocks biofilm formation and is reciprocally regulated with motility via QS

Post-mortem volatiles of vertebrate tissue

Volatile emission during vertebrate decay is a complex process that is understood incompletely. It depends on many factors. The main factor is the metabolism of the microbial species present inside and on the vertebrate. In this review, we combine the results from studies on volatile organic compounds (VOCs) detected during this decay process and those on the biochemical formation of VOCs in order to improve our understanding of the decay process. Micro-organisms are the main producers of VOCs, which are by- or end-products of microbial metabolism. Many microbes are already present inside and on a vertebrate, and these can initiate microbial decay. In addition, micro-organisms from the environment colonize the cadaver. The composition of microbial communities is complex, and communities of different species interact with each other in succession. In comparison to the complexity of the decay process, the resulting volatile pattern does show some consistency. Therefore, the possibility of an existence of a time-dependent core volatile pattern, which could be used for applications in areas such as forensics or food science, is discussed. Possible microbial interactions that might alter the process of decay are highlighted