Transposable Elements in TDP-43-Mediated Neurodegenerative Disorders

Elevated expression of specific transposable elements (TEs) has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases

Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD

Searching for synergy: combining systemic daptomycin treatment with localised phage therapy for the treatment of experimental pneumonia due to MRSA.

OBJECTIVE Bacteriophages (or phages) are viruses which infect and lyse bacteria. The therapeutic use of phages (phage therapy) has regained attention in the last decades as an alternative strategy to treat infections caused by antimicrobial-resistant bacteria. In clinical settings it is most likely that phages are administered adjunct to antibiotics. For successful phage therapy it is therefore crucial to investigate different phage-antibiotic combinations in vivo. This study aimed to elucidate the combinatorial effects of systemic daptomycin and nebulised bacteriophages for the treatment of experimental pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). RESULTS Using a rat model of ventilator-associated pneumonia caused by MRSA, the simultaneous application of intravenous daptomycin and nebulised phages was not superior to aerophage therapy alone at improving animal survival (55% vs. 50%), or reducing bacterial burdens in the lungs, or spleen. Thus, this combination does not seem to be of benefit for use in patients with MRSA pneumonia

Understanding the experiences of middle school girls who have received help for non-suicidal self-injury

This study aimed to understand the experiences of middle school girls who have engaged in non-suicidal self-injury (NSSI) and have received professional help for these behaviors. Participants described engaging in NSSI in response to uncomfortable feelings and invasive negative thoughts. They reported that engaging in NSSI decreased their uncomfortable feelings. While each participant had at least one person in her life who knew about her NSSI, participants did not feel supported or validated by these people. Participants were not completely honest with their therapists because they were afraid of being misunderstood, dismissed, or getting others into trouble. Despite these things, participants wanted support and understanding about who they are as unique individuals, why they are struggling, and why they self-injure. They also wanted to be in a transparent therapeutic relationship where they felt respected and accepted. Unfortunately, they did not describe relationships with their therapists as possessing these qualities. Professionals would better meet the need of adolescents by clearly discussing confidentiality, boundaries, conveying respect and acceptance, and recognizing the uniqueness of their clients. Assessing for self-harm and treatment reluctance should be done in the context of resistance to therapy and a sensitivity to judgment. </jats:p

Bacteriophages Improve Outcome in Experimental Staphylococcus Aureus Ventilator Associated Pneumonia.

RATIONALE Infections caused by multidrug resistant bacteria are a major clinical challenge. Phage therapy is a promising alternative antibacterial strategy. OBJECTIVE To evaluate the efficacy of intravenous phage therapy for the treatment of ventilator associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats. METHODS A randomized blinded controlled experimental study compared intravenous teicoplanin (3mg/kg, n=12), a cocktail of four phages (2-3 x 10^9 plaque forming units/ml of 2003, 2002, 3A and K, n=12) and combination of both (n=11), given two, 12 and 24 hours after induction of pneumonia, then once daily for four days. The primary outcome was survival at day four. Secondary outcomes were bacterial and phage densities in lungs and spleen, histopathological scoring of infection within the lungs and inflammatory biomarkers in blood. MEASUREMENTS AND MAIN RESULTS Treatment with either phages or teicoplanin increased survival from 0% to 58% and 50% respectively (p<0.005). Combination of phage with antibiotics did not further improve outcome (45% survival). Animal survival correlated with reduced bacterial burden in the lung (1.2 x 10^6 CFU/g of tissue for survivors versus 1.2 x 10^9 CFU/g for non-surviving animals, p<0.0001), as well as improved histopathological outcomes. Phage multiplication within the lung occurred during treatment. IL-1β increased for all treatment groups over the course of therapy. CONCLUSIONS Phage therapy was as effective as teicoplanin in improving survival and decreasing bacterial load within the lungs of rats infected with methicillin-resistant S. aureus. Combining antibiotics with phage therapy did not further improve outcomes. Key Words: bacteriophage; antibiotic resistance, microbial; pneumonia, ventilator associated