RNA binding properties of the US11 protein from four primate simplexviruses

<p>Abstract</p> <p>Background</p> <p>The protein encoded by the Us11 gene of herpes simplex viruses is a dsRNA binding protein which inhibits protein kinase R activity, thereby preventing the interferon-induced shut down of protein synthesis following viral infection. Us11 protein is not essential for infectivity <it>in vitro </it>and in mice in herpes simplex virus type 1 (HSV1), however this virus has a second, and apparently more important, inhibitor of PKR activity, the γ₁34.5 protein. Recently sequenced simian simplexviruses SA8, HVP2 and B virus do not have an ORF corresponding to the γ₁34.5 protein, yet they have similar, or greater, infectivity as HSV1 and HSV2.</p> <p>Methods</p> <p>We have expressed the US11 proteins of the simplexviruses HSV1, HSV2, HVP2 and B virus and measured their abilities to bind dsRNA, in order to investigate possible differences that could complement the absence of the γ₁34.5 protein. We employed a filter binding technique that allows binding of the Us11 protein under condition of excess dsRNA substrate and therefore a measurement of the true Kd value of Us11-dsRNA binding.</p> <p>Results and Conclusions</p> <p>The results show a Kd of binding in the range of 0.89 nM to 1.82 nM, with no significant difference among the four Us11 proteins.</p

Complete genome sequence of cercopithecine herpesvirus 2 (SA8) and comparison with other simplexviruses

AbstractWe have obtained the complete sequence of the herpesvirus simian agent 8 (SA8; cercopithecine herpesvirus 2) a baboon simplexvirus closely related to the monkey B virus and herpes simplex virus types 1 and 2. The genome of SA8 is 150,715 bp long, with an overall G/C content of 76%, the highest among the simplexviruses sequenced so far. The sequencing has confirmed that the genomic arrangement of SA8 is similar to that of other simplexviruses: unique long and unique short regions bordered by two sets of inverted repeats. All genes identified in SA8 are homologous and collinear with those of the monkey B virus, including the lack of the RL1 open reading frame, a gene responsible for neurovirulence in human herpes simplex viruses. This latter finding supports the hypothesis that a different pathogenetic mechanism may have developed in human simplexviruses, after their divergence from monkey simplexviruses

SEGUIMIENTO ORIENTACIÓN Y APOYO DEL AVANCE ACADÉMICO DE LOS ALUMNOS: UNA ESTRATEGIA INSTITUCIONAL PARA GENERAR CALIDAD.

La Facultad de Ciencias Exactas, Físicas y Naturales de la Universidad Nacional de Córdoba, basándose en una nueva filosofía de gestión de los procesos de enseñanza y aprendizaje ha generado modalidades de acción hacia el logro de calidad. Una de las estrategias que se han puesto en marcha es la creación de una Comisión de Seguimiento, Orientación y Apoyo del Avance Académico de los Alumnos. Esta instancia, dependiente de la Pro-Secretaría de Evaluación Institucional, forma parte de un programa más ambicioso y se articula con una batería de estrategias afines, entre otras: con un sistema de control de gestión docente, un gabinete psicopedagógico y un proyecto de tutoría a alumnos. En esta ponencia se sintetizan los fundamentos, procedimientos y resultados parciales del trabajo de la Comisión. El mismo abarca, a la fecha, cinco líneas: Estudio de Cohortes, Eficacia, Índices de Resultado, Ciclo de Nivelación y Experiencia de los Estudiantes ante el Primer Año de Carrera. Se considera que constituyen una tentativa válida para la búsqueda continua de calidad y que pueden aportar al campo de la evaluación, la investigación y la acreditación de la educación superior

Neither hereditary periodic fever nor periodic fever, aphthae, pharingitis, adenitis: Undifferentiated periodic fever in a tertiary pediatric center

AIM: To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever (UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up. METHODS: Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever (HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis (PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV (NM_000243.2), MVK (NM_000431.3), TNFRSF1A (NM_001065.3), NLRP3 (NM_001079821.2), NLRP12 (NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases. RESULTS: Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients (10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo (IQR 4-24). Patients with UPF had a higher frequency of aphthae (52.2% vs 0%, P = 0.0026) and musculoskeletal pain (65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis (52.2% vs 10.7%, P < 0.0001), musculoskeletal pain (65.2% vs 8,0%, P < 0.0001), and abdominal pain (52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis (56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF (91.3%) received steroids, being effective in 16; 13 (56.2%) were given colchicine, which was effective in 6. Symptoms resolution occurred in 2 patients with UPF at last follow-up. Classification according to the PRINTO-Eurofever score did not correlate with treatment response and prognosis. CONCLUSION: UPF is not a rare diagnosis among patients with periodic fever. Clinical presentation place UPF half way on a clinical spectrum between PFAPA and HPF. The PRINTO-Eurofever score is not useful to predict clinical outcome and treatment response in these patients

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis

Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study

Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS

Stakeholder perspectives to improve risk management in European farming systems

The challenges faced by agricultural systems call for an advance in risk management (RM) assessments. This research identifies and discusses potential improvements to RM across 11 European Union (EU) farming systems (FS). The paper proposes a comprehensive, participatory approach that accounts for multi-stakeholder perspectives relying on 11 focus groups for brainstorming and gathering suggestions to improve RM. Data analysis is based on content analysis and coding of suggested improvements, and their assessment through the lenses of main challenges faced, farms’ flexibility, and dependence on subsidies. First, the results show that necessary improvements differ depending on whether they have their origin in sudden shocks or long-term pressures. Second, farm dependence on direct payments determines a stronger need to improve financial instruments, whereas farm flexibility suggests a need for more accessible and tailored tools for low-flexibility FS, and increased know-what and know-how for high-flexibility FS. Third, our findings indicate a potential for extending stakeholder involvement in RM to new or unconventional roles. Underlying specific improvements, the paper suggests and discusses three main avenues to improve RM as a whole: i) a developed learning and knowledge network; ii) new forms of collaboration; and iii) integrated financial and policy instruments

Effects of continuous positive airway pressure on comprehensive geriatric assessment and cognitive function in elderly patients with obstructive sleep apnea syndrome

Obstructive sleep apnea syndrome (OSAS) can lead to cognitive impairment and depression affecting memory, attention, and executive functions. Continuous positive airway pressure (CPAP) treatment seems to be able to revert changes in brain networks and neuropsychological tests correlated to OSAS. The aim of the present study was to evaluate the effects of a 6-month treatment with CPAP on functional, humoral and cognitive parameters in a cohort of elderly OSAS patients with several comorbidities. We enrolled 360 elderly patients suffering from moderate to severe OSAS and indication for nocturnal CPAP. At baseline the Comprehensive Geriatric Assessment (CGA) revealed a borderline Mini-Mental State Examination (MMSE) score that improved after 6-month treatment with CPAP (25.3 +/- 1.6 vs 26 +/- 1.5; p &lt; 0.0001), as well as the Montreal Cognitive Assessment (MoCA) showed a mild improvement (24.4 +/- 2.3 vs 26.2 +/- 1.7; p &lt; 0.0001). Moreover, functionality activities increased after treatment, as documented by a short physical performance battery (SPPB) (6.3 +/- 1.5 vs 6.9 +/- 1.4; p &lt; 0.0001). Reduction of the Geriatric Depression Scale (GDS) from 6.0 +/- 2.5 to 4.6 +/- 2.2 (p &lt; 0.0001) was also detected. Changes of homeostasis model assessment (HOMA) index, oxygen desaturation index (ODI), sleep-time spent with saturation below 90% (TC90), peripheral arterial oxyhaemoglobin saturation (SpO(2)), apnea-hypopnea index (AHI) and estimation of glomerular filtration rate (eGFR), contributed, respectively, to 27.9%, 9.0%, 2.8%, 2.3%, 1.7% and 0.9% of MMSE variability for a total of 44.6% of MMSE variations. GDS score changes were due to the improvement of AHI, ODI and TC90, respectively, for 19.2%, 4.9%, 4.2% of the GDS variability, cumulative responsible for 28.3% of GDS modifications. The present real-world study shows that CPAP treatment is able to improve cognition and depressive symptoms in OSAS elderly patients

A complicated case of pulmonary embolism in a patient with renal failure

We describe a case of pulmonary embolism with instable hemodynamics in a patient with renal failure; the case is complicated by heparin-induced thrombocytopenia (HIT). Renal failure has a high prevalence in hospitalized patients and is a restriction on administration of low molecular weight heparins (LMWH) and fondaparinux. HIT is a potentially life-threatening complication, therefore a precocious diagnosis is essential. Therapy consists in the immediate stop of heparin’s administration and in the administration of non-heparin antithrombotic drugs