Xirp Proteins Mark Injured Skeletal Muscle in Zebrafish

Myocellular regeneration in vertebrates involves the proliferation of activated progenitor or dedifferentiated myogenic cells that have the potential to replenish lost tissue. In comparison little is known about cellular repair mechanisms within myocellular tissue in response to small injuries caused by biomechanical or cellular stress. Using a microarray analysis for genes upregulated upon myocellular injury, we identified zebrafish Xin-actin-binding repeat-containing protein1 (Xirp1) as a marker for wounded skeletal muscle cells. By combining laser-induced micro-injury with proliferation analyses, we found that Xirp1 and Xirp2a localize to nascent myofibrils within wounded skeletal muscle cells and that the repair of injuries does not involve cell proliferation or Pax7+ cells. Through the use of Xirp1 and Xirp2a as markers, myocellular injury can now be detected, even though functional studies indicate that these proteins are not essential in this process. Previous work in chicken has implicated Xirps in cardiac looping morphogenesis. However, we found that zebrafish cardiac morphogenesis is normal in the absence of Xirp expression, and animals deficient for cardiac Xirp expression are adult viable. Although the functional involvement of Xirps in developmental and repair processes currently remains enigmatic, our findings demonstrate that skeletal muscle harbours a rapid, cell-proliferation-independent response to injury which has now become accessible to detailed molecular and cellular characterizations

HIV-1, HSV-2 and syphilis among pregnant women in a rural area of Tanzania: Prevalence and risk factors

<p>Abstract</p> <p>Background</p> <p>Evidence suggests that a substantial proportion of new HIV infections in African countries are associated with herpes simplex virus type 2 (HSV-2). Thus, the magnitude of HSV-2 infection in an area may suggest the expected course of the HIV epidemic. We determined prevalence of genital herpes, syphilis and associated factors among pregnant women from a remote rural Tanzanian community that has a low but increasing HIV prevalence.</p> <p>Methods</p> <p>We analysed 1296 sera and responses to a standard structured questionnaire collected from pregnant women aged between 15–49 years, attending six different antenatal clinics within rural Manyara and Singida regions in Tanzania. Linked anonymous testing (with informed consent) of the serum for specific antibodies against HSV-2 was done using a non-commercial peptide- 55 ELISA. Antibodies against syphilis were screened by using rapid plasma reagin (RPR) and reactive samples confirmed by <it>Treponema pallidum </it>haemagglutination assay (TPHA).</p> <p>Results</p> <p>Previous analysis of the collected sera had shown the prevalence of HIV antibodies to be 2%. In the present study the prevalence of genital herpes and syphilis was 20.7% (95% CI: 18.53–23.00) and 1.6% (95% CI: 1.03–2.51), respectively. The presence of HSV-2 antibodies was associated with polygamy (OR 2.2, 95% CI: 1.62 – 3.01) and the use of contraceptives other than condoms (OR 1.7, 95% CI: 1.21 – 2.41). Syphilis was associated with reporting more than one lifetime sexual partner (OR 5.4, 95% CI: 1.88 – 15.76) and previous spontaneous abortion (OR 4.3, 95% CI: 1.52–12.02).</p> <p>Conclusion</p> <p>The low prevalence of HIV infection offers a unique opportunity for strengthening HIV prevention in a cost-effective manner. The identification and control of other prevalent curable STIs other than syphilis and specific intervention of HSV-2 in specific populations like pregnant women would be one among approaches towards preventing incident HIV infections.</p

Identification of Vascular and Hematopoietic Genes Downstream of etsrp by Deep Sequencing in Zebrafish

The transcription factor etsrp/Er71/Etv2 is a master control gene for vasculogenesis in all species studied to date. It is also required for hematopoiesis in zebrafish and mice. Several novel genes expressed in vasculature have been identified through transcriptional profiling of zebrafish embryos overexpressing etsrp by microarrays. Here we re-examined this transcriptional profile by Illumina RNA-sequencing technology, revealing a substantially increased number of candidate genes regulated by etsrp. Expression studies of 50 selected candidate genes from this dataset resulted in the identification of 39 new genes that are expressed in vascular cells. Regulation of these genes by etsrp was confirmed by their ectopic induction in etsrp overexpressing and decreased expression in etsrp deficient embryos. Our studies demonstrate the effectiveness of the RNA-sequencing technology to identify biologically relevant genes in zebrfish and produced a comprehensive profile of genes previously unexplored in vascular endothelial cell biology

A novel emergency department based prevention intervention program for people living with HIV: evaluation of early experiences

<p>Abstract</p> <p>Background</p> <p>HIV prevention is increasingly focused on people living with HIV (PLWH) and the role of healthcare settings in prevention. Emergency Departments (EDs) frequently care for PLWH, but do not typically endorse a prevention mission. We conducted a pilot exploratory evaluation of the first reported ED program to address the prevention needs of PLWH.</p> <p>Methods</p> <p>This retrospective observational cohort evaluation reviewed program records to describe the first six months of participants and programmatic operation. Trained counselors provided a risk assessment and counseling intervention combined with three linkage interventions: i) linkage to health care, ii) linkage to case management, and iii) linkage to partner counseling and referral.</p> <p>Results</p> <p>Of 81 self-identified PLWH who were approached, 55 initially agreed to participate. Of those completing risk assessment, 17/53 (32%, 95 CI 20% to 46%) reported unprotected anal/vaginal intercourse or needle sharing in the past six months with a partner presumed to be HIV negative. Counseling was provided to 52/53 (98%). For those requesting services, 11/15 (73%) were linked to healthcare, 4/23 (17%) were coordinated with case management, and 1/4 (25%) completed partner counseling and referral.</p> <p>Conclusion</p> <p>Given base resources of trained counselors, it was feasible to implement a program to address the prevention needs for persons living with HIV in an urban ED. ED patients with HIV often have unmet needs which might be addressed by improved linkage with existing community resources. Healthcare and prevention barriers for PLWH may be attenuated if EDs were to incorporate CDC recommended prevention measures for healthcare providers.</p

Pharmacological inhibition of PARP6 triggers multipolar spindle formation and demonstrates therapeutic effects in breast cancer

PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors. By screening a collection of PARP compounds for their ability to induce mitotic defects, we uncovered a robust correlation between PARP6 inhibition and induction of multipolar spindle (MPS) formation, which was phenocopied by PARP6 knockdown. Treatment with AZ0108, a PARP6 inhibitor with a favorable pharmacokinetic profile, potently induced the MPS phenotype, leading to apoptosis in a subset of breast cancer cells in vitro and antitumor effects in vivo. In addition, Chk1 was identified as a specific substrate of PARP6 and was further confirmed by enzymatic assays and by mass spectrometry. Furthermore, when modification of Chk1 was inhibited with AZ0108 in breast cancer cells, we observed marked upregulation of p-S345 Chk1 accompanied by defects in mitotic signaling. Together, these results establish proof-of-concept antitumor efficacy through PARP6 inhibition and highlight a novel function of PARP6 in maintaining centrosome integrity via direct ADP-ribosylation of Chk1 and modulation of its activity

Health and functional status among older people with HIV/AIDS in Uganda.

Background: In sub-Saharan Africa, little is known about the health and functional status of older people who either themselves are HIV infected or are affected by HIV and AIDS in the family. This aim of this study was to describe health among older people in association with the HIV epidemic. Methods: The cross-sectional survey consisted of 510 participants aged 50 years and older, equally divided into five study groups including; 1) HIV infected and on antiretroviral therapy (ART) for at least 1 year; 2) HIV infected and not yet eligible for ART; 3) older people who had lost a child due to HIV/AIDS; 4) older people who have an adult child with HIV/AIDS; 5) older people not known to be infected or affected by HIV in the family. The participants were randomly selected from ongoing studies in a rural and peri-urban area in Uganda. Data were collected using a WHO standard questionnaire and performance tests. Eight indicators of health and functioning were examined in an age-adjusted bivariate and multivariate analyses. Results: In total, 198 men and 312 women participated. The overall mean age was 65.8 and 64.5 years for men and women respectively. Men had better self-reported health and functional status than women, as well as lower self-reported prevalence of chronic diseases. In general, health problems were common: 35% of respondents were diagnosed with at least one of the five chronic conditions, including 15% with depression, based on algorithms; 31% of men and 35% of women had measured hypertension; 25% of men and 21% of women had poor vision test results. HIV-positive older people, irrespective of being on ART, and HIV-negative older people in the other study groups had very similar results for most health status and functioning indicators. The main difference was a significantly lower BMI among HIV-infected older people. Conclusion: The systematic exploration of health and well being among older people, using eight self-reported and objective health indicators, showed that basic health problems are very common at older ages and poorly addressed by existing health services. HIV-infected older people, however, whether on ART or not yet on ART, had a similar health and functional status as other older people