Expression of the Parkinson’s Disease-Associated Gene Alpha-Synuclein is Regulated by the Neuronal Cell Fate Determinant TRIM32

Alpha-synuclein is an abundant neuronal protein which has been associated with physiological processes like synaptic function, neurogenesis, and neuronal differentiation but also with pathological neurodegeneration. Indeed, alpha-synuclein (snca) is one of the major genes implicated in Parkinson’s disease (PD). However, little is known about the regulation of alpha-synuclein expression. Unveiling the mechanisms that control its regulation is of high importance, as it will enable to further investigate and comprehend the physiological role of alpha-synuclein as well as its potential contribution in the aetiology of PD. Previously, we have shown that the protein TRIM32 regulates fate specification of neural stem cells. Here, we investigated the impact of TRIM32 on snca expression regulation in vitro and in vivo in neural stem cells and neurons. We demonstrated that TRIM32 is positively influencing snca expression in a neuronal cell line, while the absence of TRIM32 is causing deregulated levels of snca transcripts. Finally, we provided evidence that TRIM32 binds to the promoter region of snca, suggesting a novel mechanism of its transcriptional regulation. On the one hand, the presented data link the PD-associated gene alpha-synuclein to the neuronal cell fate determinant TRIM32 and thereby support the concept that PD is a neurodevelopmental disorder. On the other hand, they imply that defects in olfactory bulb adult neurogenesis might contribute to early PD-associated non-motor symptoms like hyposmia.The J. C. S.’s lab is supported by the Boehringer Ingelheim Foundation and the fund “Innovative Medical Research” of the University of Münster Medical School, Schram-Stiftung (T287/21795/2011) by the Fonds National de la Recherche (FNR) Luxembourg (CORE, C13/BM/5791363), a University Luxembourg Internal Research Project (MidNSCs) and the EU Joint Programme - Neurodegenerative Disease Research (JPND) project (supported by the FNR). L.G.C. was supported by a fellowship from the FNR (AFR, Aides à la Formation-Recherche). M.C.M ’s lab is supported by Grant SAF2012-36143 from Spanish Ministerio de Ciencia e and LE310U14 from the Junta de Castilla y Leon. S.F.A holds a predoctoral contract (PIRTU) from Junta de Castilla y Leon

Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent

Background Deoxyribonucleic acid (DNA) vaccines are used for experimental immunotherapy of equine melanoma. The injection of complexed linear DNA encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a clinical study including 27 grey horses. To date, the detailed mechanism of the anti-tumour effect of this treatment is unknown. Results In the present study, the clinical and cellular responses of 24 healthy horses were monitored over 72 h after simultaneous intradermal and intramuscular application of equine IL-12/IL-18 DNA (complexed with a transfection reagent) or comparative substances (transfection reagent only, nonsense DNA, nonsense DNA depleted of CG). Although the strongest effect was observed in horses treated with expressing DNA, horses in all groups treated with DNA showed systemic responses. In these horses treated with DNA, rectal temperatures were elevated after treatment and serum amyloid A increased. Total leukocyte and neutrophil counts increased, while lymphocyte numbers decreased. The secretion of tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) from peripheral mononuclear blood cells ex vivo increased after treatments with DNA, while IL-10 secretion decreased. Horses treated with DNA had significantly higher myeloid cell numbers and chemokine (C-X-C motif) ligand (CXCL)-10 expression in skin samples at the intradermal injection sites compared to horses treated with transfection reagent only, suggesting an inflammatory response to DNA treatment. In horses treated with expressing DNA, however, local CXCL-10 expression was highest and immunohistochemistry revealed more intradermal IL-12-positive cells when compared to the other treatment groups. In contrast to non-grey horses, grey horses showed fewer effects of DNA treatments on blood lymphocyte counts, TNFα secretion and myeloid cell infiltration in the dermis. Conclusion Treatment with complexed linear DNA constructs induced an inflammatory response independent of the coding sequence and of CG motif content. Expressing IL-12/IL-18 DNA locally induces expression of the downstream mediator CXCL-10. The grey horses included appeared to display an attenuated immune response to DNA treatment, although grey horses bearing melanoma responded to this treatment with moderate tumour remission in a preceding study. Whether the different immunological reactivity compared to other horses may contributes to the melanoma susceptibility of grey horses remains to be elucidated

Placental thrombosis in acute phase abortions during experimental Toxoplasma gondii infection in sheep

43 p.After oral administration of ewes during mid gestation with 2000 freshly prepared sporulated oocysts of T. gondii isolate M4, abortions occurred between days 7 and 11 in 91.6% of pregnant and infected ewes. Afterwards, a further infection was carried out at late gestation in another group of sheep with 500 sporulated oocysts. Abortions happened again between days 9 and 11 post infection (pi) in 58.3% of the infected ewes. Classically, abortions in natural and experimental ovine toxoplasmosis usually occur one month after infection. Few experimental studies have reported the so-called acute phase abortions as early as 7 to 14 days after oral inoculation of oocysts, and pyrexia was proposed to be responsible for abortion, although the underline mechanism was not elucidated. In the present study, all placentas analysed from ewes suffering acute phase abortions showed infarcts and thrombosis in the caruncullar villi of the placentomes and ischemic lesions (periventricular leukomalacia) in the brain of some foetuses. The parasite was identified by PCR in samples from some placentomes of only one sheep, and no antigen was detected by immunohistochemical labelling. These findings suggest that the vascular lesions found in the placenta, and the consequent hypoxic damage to the foetus, could be associated to the occurrence of acute phase abortions. Although the pathogenesis of these lesions remains to be determined, the infectious dose or virulence of the isolate may play a role in their developmentS

Knowledge, experience, and potential risks of dating violence among Japanese university students: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The Domestic Violence Prevention Act came into effect in Japan in 2001, but covers only marriage partner violence and post-divorce partner violence, and does not recognize intimate partner violence (IPV). The present study was performed to determine the experience of harassment, both toward and from an intimate partner, and recognition of harassment as IPV among Japanese university students.</p> <p>Methods</p> <p>A self-administered questionnaire survey regarding the experience of harassment involving an intimate partner was conducted as a cross-sectional study among freshman students in a prefectural capital city in Japan.</p> <p>Results</p> <p>A total of 274 students participated in the present study. About half of the subjects (both male and female students) had experience of at least one episode of harassment toward or had been the recipient of harassment from an intimate partner. However, the study participants did not recognize verbal harassment, controlling activities of an intimate partner, and unprotected sexual intercourse as violence. Experience of attending a lecture/seminar about domestic violence and dating violence did not contribute to appropriate help-seeking behavior.</p> <p>Conclusions</p> <p>An educational program regarding harassment and violence prevention and appropriate help-seeking behavior should be provided in early adolescence to avoid IPV among youth.</p

Factors involved in nurses' responses to burnout: a grounded theory study

BACKGROUND: Intense and long-standing problems in burn centers in Tehran have led nurses to burnout. This phenomenon has provoked serious responses and has put the nurses, patients and the organization under pressure. The challenge for managers and nurse executives is to understand the factors which would reduce or increase the nurses' responses to burnout and develop delivery systems that promote positive adaptation and facilitate quality care. This study, as a part of more extensive research, aims to explore and describe the nurses' perceptions of the factors affecting their responses to burnout. METHODS: Grounded theory was used as the method. Thirty- eight participants were recruited. Data were generated by unstructured interviews and 21 sessions of participant observations. Constant comparison was used for data analysis. RESULTS: Nurses' and patients' personal characteristics and social support influenced nurses' responses to burnout. Personal characteristics of the nurses and patients, especially when interacting, had a more powerful effect. They altered emotional, attitudinal, behavioral and organizational responses to burnout and determined the kind of caring behavior. Social support had a palliative effect and altered emotional responses and some aspects of attitudinal responses. CONCLUSIONS: The powerful effect of positive personal characteristics and its sensitivity to long standing and intense organizational pressures suggests approaches to executing stress reduction programs and refreshing the nurses' morale by giving more importance to ethical aspects of caring. Moreover, regarding palliative effect of social support and its importance for the nurses' wellbeing, nurse executives are responsible for promoting a work environment that supports nurses and motivates them

Skin manifestations in COVID-19: prevalence and relationship with disease severity

Background: Data on the clinical patterns and histopathology of SARS-CoV-2 related skin lesions, as well as on their relationship with the severity of COVID-19 are limited. Methods and Materials: Retrospective analysis of a prospectively collected cohort of patients with SARS-CoV-2 infection in a teaching hospital in Barcelona, Spain, from 1 April to 1 May 2020. Clinical, microbiological and therapeutic characteristics, clinicopathological patterns of skin lesions, and direct immunofluorescence and immunohistochemical findings in skin biopsies were analyzed. Results: Fifty-eight out of the 2761 patients (2.1%) either consulting to the emergency room or admitted to the hospital for COVID-19 suspicion during the study period presented COVID-19 related skin lesions. Cutaneous lesions could be categorized into six patterns represented by the acronym "GROUCH": Generalized maculo-papular (20.7%), Grover's disease and other papulo-vesicular eruptions (13.8%), livedo Reticularis (6.9%), Other eruptions (22.4%), Urticarial (6.9%), and CHilblain-like (29.3%). Skin biopsies were performed in 72.4%, including direct immunofluorescence in 71.4% and immunohistochemistry in 28.6%. Patients with chilblain-like lesions exhibited a characteristic histology and were significantly younger and presented lower rates of systemic symptoms, radiological lung infiltrates and analytical abnormalities, and hospital and ICU admission compared to the rest of patients. Conclusion: Cutaneous lesions in patients with COVID-19 appear to be relatively rare and varied. Patients with chilblain-like lesions have a characteristic clinicopathological pattern and a less severe presentation of COVID-19

Self-Reported Health Status in Primary Health Care: The Influence of Immigration and Other Associated Factors

OBJECTIVE: The aims of this study are to compare self-reported health status between Spanish-born and Latin American-born Spanish residents, adjusted by length of residence in the host country; and additionally, to analyse sociodemographic and psychosocial variables associated with a better health status. DESIGN: This is a cross-sectional population based study of Latin American-born (n = 691) and Spanish-born (n = 903) in 15 urban primary health care centres in Madrid (Spain), carried out between 2007 and 2009. The participants provided information, through an interview, about self-reported health status, socioeconomic characteristics, psychosocial factors and migration conditions. Descriptive and multiple logistic regression analyses were conducted. RESULTS: The Spanish-born participants reported a better health status than the Latin America-born participants (79.8% versus 69.3%, p<0.001). Different patterns of self-reported health status were observed depending on the length of residence in the host country. The proportion of immigrants with a better health status is greater in those who have been in Spain for less than five years compared to those who have stayed longer. Better health status is significantly associated with being men, under 34 years old, being Spanish-born, having a monthly incomes of over 1000 euros, and having considerable social support and low stress. CONCLUSIONS: Better self-reported health status is associated with being Spanish-born, men, under 34 years old, having an uppermiddle-socioeconomic status, adequate social support, and low stress. Additionally, length of residence in the host country is seen as a related factor in the self-reported health status of immigrants

Clinical experience with integrase inhibitors in HIV-2-infected individuals in Spain.

Background: HIV-2 is a neglected virus despite estimates of 1–2 million people being infected worldwide. The virus is naturally resistant to some antiretrovirals used to treat HIV-1 and therapeutic options are limited for patients with HIV-2. Methods: In this retrospective observational study, we analysed all HIV-2-infected individuals treated with inte- grase strand transfer inhibitors (INSTIs) recorded in the Spanish HIV-2 cohort. Demographics, treatment modal- ities, laboratory values, quantitative HIV-2 RNA and CD4 counts as well as drug resistance were analysed. Results: From a total of 354 HIV-2-infected patients recruited by the Spanish HIV-2 cohort as of December 2017, INSTIs had been given to 44, in 18 as first-line therapy and in 26 after failing other antiretroviral regimens. After a median follow-up of 13 months of INSTI-based therapy, undetectable viraemia for HIV-2 was achieved in 89% of treatment-naive and in 65.4% of treatment-experienced patients. In parallel, CD4 gains were 82 and 126cells/mm3, respectively. Treatment failure occurred in 15 patients, 2 being treatment-naive and 13 treatment-experienced. INSTI resistance changes were recognized in 12 patients: N155H (5), Q148H/R (3), Y143C/G (3) and R263K (1). Conclusions: Combinations based on INSTIs are effective and safe treatment options for HIV-2-infected individ- uals. However, resistance mutations to INSTIs are selected frequently in failing patients, reducing the already limited treatment options

The granite‑hosted Variscan gold deposit from Santo António mine in the Iberian Massif (Penedono, NW Portugal): constraints from mineral chemistry, fuid inclusions, sulfur and noble gases isotopes

The study area is located in the Central Iberian Zone, a major tectonic unit of the Iberian Massif (Variscan belt). In this region the basement is composed of Cambrian-Ordovician sedimentary and minor volcanic rocks that underwent deformation and metamorphism during the Carboniferous. These metamorphic rocks host ca. 331–308 Ma granitic plutons emplaced during the D2 extensional and D3–D4 contractional deformation phases. The gold-bearing quartz veins from the Santo António mine (Penedono region) occur in granite formed at 310.1 ± 1.1 Ma and post-dated the peak of metamorphism. Gold–silver alloy is included in quartz, but mainly occurs in spaces between grains or micro-fractures within arsenopyrite of all three generations and less in pyrite. Late sulphides and sulphosalts were deposited along fractures mainly in arsenopyrite, and locally surrounding the gold–silver alloy grains. Ferberite, scheelite and stolzite replace arsenopyrite. The abundant aqueous carbonic fluids and the occurrence of a low-salinity fluid and their minimum possible entrapment temperature of 360–380 °C suggest that this gold-forming event began during the waning stages of the Variscan orogeny. The mean δ34S values of arsenopyrite and pyrite are − 4.7‰ and − 3.8‰, respectively. He–Ar–Ne isotopic data suggest a crustal origin. The ascent of the granite magma has provided the heat for remobilization of gold, other metals and metalloids from the metamorphic rocks. This gold-arsenopyrite deposit has thus similar characteristics as other selected gold-arsenopyrite deposits from the Iberian Massif, but it contains tungstates.El área de estudio está ubicada en la Zona Centroibérica, una importante unidad tectónica del Macizo Ibérico (cinturón varisco). En esta región el basamento está compuesto por rocas sedimentarias y volcánicas del Cámbrico-Ordovícico tectonizadas y metamorfzadas durante el Carbonífero. Estas rocas metamórfcas sirven como caja de los plutones graníticos datados en torno a 331–308 Ma y que fueron emplazados durante la fase de deformación extensional D2 y las fases de deformación contraccional D3 y D4. Las venas de cuarzo ricas en oro de la mina de Santo António (región de Penedono) que aparecen en un granito datado a los 310.1 ± 1.1 Ma son posteriores al pico metamórfco regional. La aleación de oro y plata se incluye en el cuarzo, pero se produce principalmente en los espacios entre granos o micro-fracturas dentro de arsenopirita de las tres generaciones y menos en pirita. Los sulfuros y sulfuros tardíos se depositaron a lo largo de las fracturas principalmente en arsenopirita, y alrededor de los granos de aleación de oro y plata. Ferberita, scheelita y la estolzita sustituyen a la arsenopirita. Los abundantes líquidos acuosos carbónicos y la presencia de un fuido de baja salinidad y su posible temperatura de atrapamiento mínima en torno de 360-380 ºC sugieren que este evento de formación de oro comenzó durante las etapas fnales de la orogenia varisca. Los valores medios de S de arsenopirita y pirita son − 4.7 ‰ y − 3.8 ‰, respectivamente. Los datos isotópicos de He–Ar–Ne sugieren que en el origen de los fuidos mineralizados participa la corteza continental. El ascenso del magma granítico ha provisto el calor para la movilización del oro, otros metales y metaloides desde las rocas metamórfcas. Este depósito de oroarsenopirita tiene así características similares a otros yaciamientos con arsenopirita y oro del Macizo Ibérico, pero sin embargo contienen tungstates.This research was financially supported by Fundação para a Ciência e Tecnologia through the projects GOLDGranites, Orogenesis, Long-term strain/stress and Deposition of ore metals—PTDC/GEO-GEO/2446/2012: COMPETE: FCOMP-01-0124-FEDER-029192 and UID/GEO/04035/2013