The dynamic interplay of host and viral enzymes in type III CRISPR-mediated cyclic nucleotide signalling

This work was supported by a grant from the Biotechnology and Biological Sciences Research Council (Grant REF BB/S000313/1 to MFW) and the Wellcome Trust (Grant 210486/Z/18/Z to CMC).Cyclic nucleotide second messengers are increasingly implicated in prokaryotic anti-viral defence systems. Type III CRISPR systems synthesise cyclic oligoadenylate (cOA) upon detecting foreign RNA, activating ancillary nucleases that can be toxic to cells, necessitating mechanisms to remove cOA in systems that operate via immunity rather than abortive infection. Previously, we demonstrated that the Sulfolobus solfataricus type III-D CRISPR complex generates cyclic tetra-adenylate (cA4), activating the ribonuclease Csx1, and showed that subsequent RNA cleavage and dissociation acts as an ‘off-switch’ for the cyclase activity. Subsequently, we identified the cellular ring nuclease Crn1, which slowly degrades cA4 to reset the system (Rouillon et al., 2018), and demonstrated that viruses can subvert type III CRISPR immunity by means of a potent anti-CRISPR ring nuclease variant AcrIII-1. Here, we present a comprehensive analysis of the dynamic interplay between these enzymes, governing cyclic nucleotide levels and infection outcomes in virus-host conflict.Publisher PDFPeer reviewe

Tumors escape immunosurveillance by overexpressing the proteasome activator PSME3

The success of CD8+ T cell-based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and the possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during a pioneer round of mRNA translation (pioneer translation products, or PTPs) are an important source of tumor specific peptides which correlates with the aberrant splicing and transcription events associated with oncogenesis. Here we show that up-regulation of PSME3 proteasome activator in cancer cells results in increased destruction of PTP-derived peptides in the nucleus thus enabling cancer cell to subvert immunosurveillance. These findings unveil a previously unexpected role for PSME3 in antigen processing and identify PSME3 as a druggable target to improve the efficacy of cancer immunotherapy

Which antidepressants have demonstrated superior efficacy? A review of the evidence

A review of published evidence of superior efficacy of a particular antidepressant in major depressive disorder may assist clinicians in making considered treatment choices. To identify such candidates, an international group of experts met to assess published evidence (identified through searches in Medline and Embase databases and discussions with experts in the field) from randomized, controlled trials and meta-analyses comparing two antidepressants under conditions of fair comparison. Criteria were defined to judge the strength of evidence. Two pivotal studies in moderate-to-severe major depressive disorder that demonstrate superiority on the primary efficacy measure, or alternatively one pivotal study supported by consistent results from meta-analyses, was considered to constitute evidence for definite superiority. Three antidepressants met these criteria: clomipramine, venlafaxine, and escitalopram. Three antidepressants were found to have probable superiority: milnacipran, duloxetine, and mirtazapine. Only escitalopram was found to have definite superiority in the treatment of severe depression; probable superiority was identified for venlafaxine and possible superiority for milnacipran and clomipramine. This review of published data found evidence that only a very few antidepressants are shown to be more effective than other

Comercio, comerciantes y revolución en el Río de la Plata : Siglo XVIII - principios del siglo XIX

El objetivo de este texto es ordenar algunas preguntas que me hago en torno al lugar del comercio en la crisis de comienzos del siglo XIX en el Río de la Plata. Mucho se ha escrito sobre la aspiración al liberalismo económico por parte de un sector de la oligarquía rioplatense en tanto que una de las “causas” (para algunos la principal) de la revolución de independencia.Facultad de Humanidades y Ciencias de la Educació

Comercio, comerciantes y revolución en el Río de la Plata : Siglo XVIII - principios del siglo XIX

El objetivo de este texto es ordenar algunas preguntas que me hago en torno al lugar del comercio en la crisis de comienzos del siglo XIX en el Río de la Plata. Mucho se ha escrito sobre la aspiración al liberalismo económico por parte de un sector de la oligarquía rioplatense en tanto que una de las “causas” (para algunos la principal) de la revolución de independencia.Facultad de Humanidades y Ciencias de la Educació

Influence of the projection plane and the markers choice on the X-factor computation of the golf swing X-factor: a case study

Study of variability induced by the methology choice on the X-factor computation of the golf swing. Based on optoelectronic measurements. Variability of the choice of upper limb, plane of projection and instant of computation

Risk factors for upper-extremity musculoskeletal disorders in the working population.

OBJECTIVE: To assess the relative importance of personal and occupational risk factors for upper-extremity musculoskeletal disorders in the working population. METHODS: A total of 3,710 workers (58% men) participating in a surveillance program of musculoskeletal disorders in a French region in 2002-2005 were included. Upper-extremity musculoskeletal disorders were diagnosed by 83 trained occupational physicians performing a standardized physical examination. Personal factors and work exposure were assessed by a self-administered questionnaire. Statistical associations between musculoskeletal disorders, personal, and occupational factors were analyzed using logistic regression modeling. RESULTS: A total of 472 workers experienced at least 1 upper-extremity musculoskeletal disorder. The risk of upper-extremity musculoskeletal disorders increased with age for both sexes (P < 0.001, odds ratio [OR] < or =4.9 in men and < or =5.0 in women), and in cases of prior history of upper-extremity musculoskeletal disorders (OR 3.1 and 5.0, respectively, P < 0.001). In men, upper-extremity musculoskeletal disorders were associated with obesity (OR 2.2, P = 0.014), high level of physical demand (OR 2.0, P < 0.001), high repetitiveness of the task (OR 1.5, P = 0.027), postures with the arms at or above shoulder level (OR 1.7, P = 0.009) or with full elbow flexion (OR 1.6, P = 0.006), and high psychological demand (OR 1.5, P = 0.005). In women, upper-extremity musculoskeletal disorders were associated with diabetes mellitus (OR 4.9, P = 0.001), postures with extreme wrist bending (OR 2.0, P < 0.001), use of vibrating hand tools (OR 2.2, P = 0.025), and low level of decision authority (OR 1.4, P = 0.042). CONCLUSION: Personal and work-related physical and psychosocial factors were strongly associated with clinically diagnosed upper-extremity musculoskeletal disorders

Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis

Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen