Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

Snai2-deficient cells are radiosensitive to DNA damage. The function of Snai2 in response to DNA damage seems to be critical for its function in normal development and cancer. Here, we applied a functional genomics approach that combined gene-expression profiling and computational molecular network analysis to obtain global dissection of the Snai2-dependent transcriptional response to DNA damage in primary mouse embryonic fibroblasts (MEFs), which undergo p53-dependent growth arrest in response to DNA damage. Although examination of the response showed that overall expression of p53 target gene expression patterns was similarly altered in both control and Snai2-deficient cells, we have identified and validated candidate Snai2 target genes linked to Snai2 gene function in response to DNA damage. This work defines for the first time the effect of Snai2 on p53 target genes in cells undergoing growth arrest, elucidates the Snai2-dependent molecular network induced by DNA damage, points to novel putative Snai2 targets, and suggest a mechanistic model, which has implications for cancer management

Social Network Organization, Structure, and Patterns of Influence Within a Community of Transgender Women in Lima, Peru: Implications for Biomedical HIV Prevention.

Understanding social network structures can contribute to the introduction of new HIV prevention strategies with socially marginalized populations like transgender women (TW). We conducted 20 semi-structured interviews and four focus groups (n = 32) with TW from selected social networks in Lima, Peru between May and July, 2015. Participants described layers of social influence from diverse actors in their social networks. The majority identified a close relative as their primary social support, with whom they confided secrets but avoided issues of transgender identity, sexuality, and sex work. Participants described close circles of TW friends with whom they shared information about gender identity, body modification, and sexual partners, but avoided issues like HIV. Community leadership included political leaders (who advocated for transgender rights) as well as social leaders (who introduced TW to hormone therapy, body modification, and commercial sex). Detailed analysis of TW social networks can contribute to implementation and acceptability of new HIV prevention technologies

African American patients with gout: efficacy and safety of febuxostat vs allopurinol

<p>Abstract</p> <p>Background</p> <p>African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects.</p> <p>Methods</p> <p>This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study.</p> <p>Results</p> <p>Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m²; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (<it>p </it>< 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (<it>p </it>< 0.001) and allopurinol (<it>p </it>= 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (<it>p </it>< 0.05). Efficacy rates in all treatment groups regardless of renal function were comparable between African American and Caucasian subjects, as were AE rates.</p> <p>Conclusions</p> <p>In African American subjects with significant comorbidities, febuxostat 80 mg is significantly more efficacious than either febuxostat 40 mg or allopurinol 200/300 mg. Febuxostat was well tolerated in this African American population.</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/10/15</url></p

Beaming into the Rat World: Enabling Real-Time Interaction between Rat and Human Each at Their Own Scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human’s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale

FUS-DDIT3 Prevents the Development of Adipocytic Precursors in Liposarcoma by Repressing PPARγ and C/EBPα and Activating eIF4E

FUS-DDIT3 is a chimeric protein generated by the most common chromosomal translocation t(12;16)(q13;p11) linked to liposarcomas, which are characterized by the accumulation of early adipocytic precursors. Current studies indicate that FUS-DDIT3- liposarcoma develops from uncommitted progenitors. However, the precise mechanism whereby FUS-DDIT3 contributes to the differentiation arrest remains to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here we have characterized the adipocyte regulatory protein network in liposarcomas of FUS-DITT3 transgenic mice and showed that PPARgamma2 and C/EBPalpha expression was altered. Consistent with in vivo data, FUS-DDIT3 MEFs and human liposarcoma cell lines showed a similar downregulation of both PPARgamma2 and C/EBPalpha expression. Complementation studies with PPARgamma but not C/EBPalpha rescued the differentiation block in committed adipocytic precursors expressing FUS-DDIT3. Our results further show that FUS-DDIT3 interferes with the control of initiation of translation by upregulation of the eukaryotic translation initiation factors eIF2 and eIF4E both in FUS-DDIT3 mice and human liposarcomas cell lines, explaining the shift towards the truncated p30 isoform of C/EBPalpha in liposarcomas. Suppression of the FUS-DDIT3 transgene did rescue this adipocyte differentiation block. Moreover, eIF4E was also strongly upregulated in normal adipose tissue of FUS-DDIT3 transgenic mice, suggesting that overexpression of eIF4E may be a primary event in the initiation of liposarcomas. Reporter assays showed FUS-DDIT3 is involved in the upregulation of eIF4E in liposarcomas and that both domains of the fusion protein are required for affecting eIF4E expression. CONCLUSIONS/SIGNIFICANCE: Taken together, this study provides evidence of the molecular mechanisms involve in the disruption of normal adipocyte differentiation program in liposarcoma harbouring the chimeric gene FUS-DDIT3.Research in ISG group is supported partially by FEDER and by MEC (SAF2006-03726), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), CDTEAM project (CENIT-Ingenio 2010) and MEC Consolider-Ingenio 2010 (Ref. CSD2007-0017).Research in ISG group is supported partially by FEDER and by MEC (SAF2006-03726 and PETRI N° 95-0913.OP), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), CDTEAM project (CENIT-Ingenio 2010) and MEC Consolider-Ingenio 2010 (Ref. CSD2007-0017). MSM is supported by the Ramon y Cajal Scientific Spanish Program, Fondo Investigacion Sanitaria (FIS PI04-1271), Junta de Castilla y León (SA085A06) and Fundación Manuel Solorzano, University of Salamanca.Peer reviewe

Evaluation of anti-biofilm activity of acidic amino acids and synergy with ciprofloxacin on Staphylococcus aureus biofilms

Acidic amino acids, aspartic acid (Asp) and glutamic acid (Glu) can enhance the solubility of many poorly soluble drugs including ciprofloxacin (Cip). One of the mechanisms of resistance within a biofilm is retardation of drug diffusion due to poor penetration across the matrix. To overcome this challenge, this work set to investigate novel counter ion approach with acidic amino acids, which we hypothesised will disrupt the biofilm matrix as well as simultaneously improve drug effectiveness. The anti-biofilm activity of D-Asp and D-Glu was studied on Staphylococcus aureus biofilms. Synergistic effect of combining D-amino acids with Cip was also investigated as a strategy to overcome anti-microbial resistance in these biofilms. Interestingly at equimolar combinations, D-Asp and D-Glu were able to significantly disperse (at 20 mM and 40 mM) established biofilms and inhibit (at 10 mM, 20 mM and 40 mM) new biofilm formation in the absence of an antibiotic. Moreover, our study confirmed L-amino acids also exhibit anti-biofilm activity. The synergistic effect of acidic amino acids with Cip was observed at lower concentration ranges (<40 mM amino acids and <90.54 µM, respectively), which resulted in 96.89% (inhibition) and 97.60% (dispersal) reduction in CFU with exposure to 40 mM amino acids. Confocal imaging indicated that the amino acids disrupt the honeycomb-like extracellular DNA (eDNA) meshwork whilst also preventing its formation

Hypertension in the very old; prevalence, awareness, treatment and control: a cross-sectional population-based study in a Spanish municipality

<p>Abstract</p> <p>Background</p> <p>Information on hypertension in the very elderly is sparse. Until recently evidence of benefits from pharmacological treatment was inconclusive. We estimated the prevalence of hypertension in subjects aged 80 or more, the proportion of awareness, treatment and control. Explanatory variables associated with good control were also studied.</p> <p>Methods</p> <p>Cross sectional, population-based study, conducted in Martorell, an urban Spanish municipality, in 2005. By simple random sampling from the census, 323 subjects aged 80 or more were included. Patients were visited at home or in the geriatric institution and after giving informed consent, the study variables were collected. These included: supine and standing blood pressure and information about diagnosis and treatment of hypertension. The estimation and 95% confidence interval were obtained and a logistic regression model was used to study explanatory variables associated with blood pressure below 140/90 mm Hg.</p> <p>Results</p> <p>The prevalence of hypertension was 72.8% (95%CI: 69.5 – 76.6%) and 93% of the patients were aware of this condition, of whom 96.3% (95%CI: 93.65 – 97.9%) had been prescribed pharmacological treatment and 30.7% (95%CI: 25.8 – 36.1%) had blood pressure below 140/90 mm Hg. Some of the patients (43%) had one antihypertensive drug and 39.5% had two in combination. Explanatory variables associated with blood pressure below 140/90 mm Hg included prescription of a diuretic, OR: 0.31 (95%CI: 0.14 – 0.66), and history of ischemic heart disease, OR: 0.21 (95%CI: 0.1 – 0.47).</p> <p>Conclusion</p> <p>The prevalence of hypertension in population aged 80 or more was over 70%. Most patients were aware of this condition and they had antihypertensive medication prescribed. Approximately one third of treated patients had blood pressure below 140/90 mm Hg. Patients with heart disease and with diuretics had more frequently blood pressure below this value.</p