Merkel cell polyomavirus large T antigen disrupts lysosome clustering by translocating human Vam6p from the cytoplasm to the nucleus

Merkel cell polyomavirus (MCV) has been recently described as the cause for most human Merkel cell carcinomas. MCV is similar to simian virus 40 (SV40) and encodes a nuclear large T (LT) oncoprotein that is usually mutated to eliminate viral replication among tumor-derived MCV. We identified the hVam6p cytoplasmic protein involved in lysosomal processing as a novel interactor with MCV LT but not SV40 LT. hVam6p binds through its clathrin heavy chain homology domain to a unique region of MCV LT adjacent to the retinoblastoma binding site. MCV LT translocates hVam6p to the nucleus, sequestering it from involvement in lysosomal trafficking. A naturally occurring, tumor-derived mutant LT (MCV350) lacking a nuclear localization signal binds hVam6p but fails to inhibit hVam6p-induced lysosomal clustering. MCV has evolved a novel mechanism to target hVam6p that may contribute to viral uncoating or egress through lysosomal processing during virus replication

Corrosion and tribocorrosion behaviour of titanium nitride thin films grown on titanium under different deposition times

Ti and its alloys exhibit combination of unique properties for biomedical applications, however their poor tribo-electrochemical behaviour is a major concern. Therefore, TiN coatings were deposited on cp-Ti (grade 4) by sputtering technique aiming the improvement of its tribocorrosion behaviour. The properties of the coated samples, using different TiN deposition times, were characterized by using grazing incidence X-ray diffraction, FIB-SEM, and nanoindentation. The corrosion behaviour was studied by electrochemical impedance spectroscopy and potentiodynamic polarization in 9 g/L NaCl solution at body temperature. Tribocorrosion tests were employed under open circuit potential by using a ball-on-plate tribometer with 1 N normal load, 3 mm total stroke length, 1 Hz frequency, and 1800 s sliding duration. The results suggested that the TiN coatings deposited during 80 min presented better corrosion and tribocorrosion behaviour as compared to the bare metal and TiN coatings deposited during 30 min.This work is supported by FCT with the reference project UID/EEA/04436/2013, COMPETE 2020 with the code POCI-01-0145-FEDER-006941, and M-ERA-NET/0001/2015 (FAPESP proc. #2015/50.280-5) project. I. Caha grateful for financial support through PhD grant under NORTE-08-5369-FSE-000012 project. The authors would also like to acknowledge Dr. Paulo Ferreira and Dr. Enrique Carbo-Argibay (International Iberian Nanotechnology Laboratory) for the provision of FIB facilities, and Prof. Grata Minas (Universidade do Minho) for the provision of profilometry

Существует ли связь между средним уровнем mIDkIne и прогнозом заболевания COVID-19?

   The objective was aimed to measure plasma midkine (MK)* levels in patients with COVID-19 and assess its clinical significance.   Materials and Methods. 88 patients observed in our hospital with a diagnosis of COVID-19 were included in the study. The patients’ demographic characteristics, clinical, and laboratory data were studied, and the relationship between MK levels, prognosis, and other parameters was investigated.   Results. Of the 88 patients included in the study, 43 (48.9 %) were female and 45 (51.1%) were male. 24 (27%) patients died. The mean age of non-survivors was 70 ± 12.3 years and the survivors were 61.9 ± 18.2 years. Mortality predictors such as D-dimer, ferritin, troponin, LDH, CRP, and procalcitonin were significantly higher in non-survivors than in survivors (p < 0.05). The median MK level (IR) was 152.5 ± 125 pg/ml in all patients, 143 ± 149 pg/ml in survivors, and 165.5 ± 76 pg/ml in non-survivors (p = 0.546). The difference between these two groups was not statistically significant. The area under the ROC curve was found to be 0.542 (95% CI 0.423–0.661, p = 0.546).   Conclusion. MK is not a biomarker that can replace or reinforce known predictors of mortality in COVID-19 patients.   Цель. Исследование направлено на измерение уровня Midkine (MK)* в плазме крови у пациентов с COVID-19 и оценку его клинической значимости.   Материалы и методы. В исследование включены 88 пациентов, наблюдавшихся в клинике с диагнозом COVID-19. Изучены демографические характеристики пациентов, клинические и лабораторные данные, а также исследована взаимосвязь между уровнями MK, прогнозом и другими параметрами.   Результаты. Из 88 пациентов, включенных в исследование, 43 (48,9 %) были женщинами и 45 (51,1 %) – мужчинами. 24 (27 %) пациента умерли. Средний возраст невыживших составил 70 ± 12,3 года, а выживших – 61,9 ± 18,2 года. Предикторы смертности, такие как D-димер, ферритин, тропонин, ЛДГ, СРБ и прокальцитонин, были значительно выше у умерших, чем у выживших (р < 0,05). Медиана уровня МК (IR) составила 152,5 ± 125 пг/мл у всех пациентов, 143 ± 149 пг/мл у выживших и 165,5 ± 76 пг/мл у умерших (р = 0,546). Разница между этими 2 группами была незначима. Было обнаружено, что площадь под кривой ROC составляет 0,542 (95 % ДИ 0,423–0,661, р = 0,546).   Вывод. МК не является биомаркером, который может заменить или усилить известные предикторы смертности у пациентов с COVID-19

Is there an association between mIDkIne levels and the prognosis of COVID-19 disease?

The objective was aimed to measure plasma midkine (MK)* levels in patients with COVID-19 and assess its clinical significance.   Materials and Methods. 88 patients observed in our hospital with a diagnosis of COVID-19 were included in the study. The patients’ demographic characteristics, clinical, and laboratory data were studied, and the relationship between MK levels, prognosis, and other parameters was investigated.   Results. Of the 88 patients included in the study, 43 (48.9 %) were female and 45 (51.1%) were male. 24 (27%) patients died. The mean age of non-survivors was 70 ± 12.3 years and the survivors were 61.9 ± 18.2 years. Mortality predictors such as D-dimer, ferritin, troponin, LDH, CRP, and procalcitonin were significantly higher in non-survivors than in survivors (p < 0.05). The median MK level (IR) was 152.5 ± 125 pg/ml in all patients, 143 ± 149 pg/ml in survivors, and 165.5 ± 76 pg/ml in non-survivors (p = 0.546). The difference between these two groups was not statistically significant. The area under the ROC curve was found to be 0.542 (95% CI 0.423–0.661, p = 0.546).   Conclusion. MK is not a biomarker that can replace or reinforce known predictors of mortality in COVID-19 patients

Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure

Liver cirrhosis is the end stage of all chronic liver diseases and contributes significantly to overall mortality of 2% globally. The age-standardized mortality from liver cirrhosis in Europe is between 10 and 20% and can be explained by not only the development of liver cancer but also the acute deterioration in the patient's overall condition. The development of complications including accumulation of fluid in the abdomen (ascites), bleeding in the gastrointestinal tract (variceal bleeding), bacterial infections, or a decrease in brain function (hepatic encephalopathy) define an acute decompensation that requires therapy and often leads to acute-on-chronic liver failure (ACLF) by different precipitating events. However, due to its complexity and organ-spanning nature, the pathogenesis of ACLF is poorly understood, and the common underlying mechanisms leading to the development of organ dysfunction or failure in ACLF are still elusive. Apart from general intensive care interventions, there are no specific therapy options for ACLF. Liver transplantation is often not possible in these patients due to contraindications and a lack of prioritization. In this review, we describe the framework of the ACLF-I project consortium funded by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) based on existing findings and will provide answers to these open questions.</p

Exposure effects of endotoxin-free titanium-based wear particles to human osteoblasts

Titanium-based materials are widely employed by the biomedical industry in orthopedic and dental implants. However, when placed into the human body, these materials are highly susceptible to degradation processes, such as corrosion, wear, and tribocorrosion. As a consequence, metallic ions or particles (debris) may be released, and although several studies have been conducted in recent years to better understand the effects of their exposure to living cells, a consensual opinion has not yet been obtained. In this work, we produced metallic based wear particles by tribological tests carried out on Ti-6Al-4V and Ti-15Zr-15Mo alloys. They were posteriorly physicochemically characterized according to their crystal structure, size, morphology, and chemical composition and compared to Ti-6Al-4V commercially available particles. Finally, adsorbed endotoxins were removed (by applying a specific thermal treatment) and endotoxin-free particles were used in cell experiments to evaluate effects of their exposure to human osteoblasts (MG-63 and HOb), namely cell viability/metabolism, proinflammatory cytokine production (IL-6 and PGE2), and susceptibility to internalization processes. Our results indicate that tribologically-obtained wear particles exhibit fundamental differences in terms of size (smaller) and morphology (irregular shapes and rough surfaces) when compared to the commercial ones. Consequently, both Ti-6Al-4V and Ti-15Zr-15Mo particles were able to induce more pronounced effects on cell viability (decrease) and cytokine production (increase) than did Ti-6Al-4V commercial particles. Furthermore, both types of wear particles penetrated osteoblast membranes and were internalized by the cells. Influences on cytokine production by endotoxins were also demonstrated.This work was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP (2015/50280-5 and 2017/24300-4), Fundacao para a Ciencia e Tecnologia - FCT (UID/EEA/04436/2013), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - CAPES (Finance Code 0001), FCT/CAPES Joint Research Project (99999.008666/2014-08), FCT COMPETE 2020 (POCI-01-0145-FEDER-006941 and POCI-01-0145-FEDER-007265) and M-ERA-NET (0001/2015)

Case Series of Headache Characteristics in COVID-19: Headache Can Be an Isolated Symptom

Headache was reported in up to one-third of the hospitalized patients; yet, the clinical characteristics of headache associated with coronavirus disease 2019 (COVID-19) have not been defined. This observational case study included patients who were consulted to headache unit due to headache and had COVID-19 illness. Headache features in 13 PCR-confirmed COVID-19 patients with mild symptoms were reported. Headache was the isolated symptom of the COVID-19 in 3 patients and emerged as an early symptom during the disease course in all patients. Patients specified severe, rapid onset, unrelenting headache with migraine-like features, as well as unusual sensory symptoms such as anosmia, and gastrointestinal symptoms such as diarrhea and loss of appetite and weight. Headache lasted up to 3 days in 70\% of the patients and resolved in all patients within 2 weeks. Despite the fact that most of the patients were female and headache characteristics were suggestive of migraine, majority of patients were not suffering from primary headaches. It was concluded that headache could be an isolated symptom of COVID-19, which might possibly be ignored in asymptomatic patients. Headaches associated with COVID-19 included features resembling migraine and/or atypical symptoms including anosmia and diarrhea

Identification and Characterization of Novel Rat Polyomavirus 2 in a Colony of X-SCID Rats by P-PIT assay

ABSTRACT Polyomaviruses (PyVs) are known to infect a wide range of vertebrates and invertebrates and are associated with a broad spectrum of diseases, including cancers, particularly in immune-suppressed hosts. A novel polyomavirus, designated rat polyomavirus 2 (RatPyV2), was identified from a breeding colony of rats having X-linked severe combined immunodeficiency. Using a human panpolyomavirus immunohistochemistry test (P-PIT), RatPyV2 was initially detected in the parotid salivary gland of a colony member. Rolling circle amplification using DNA from harderian and parotid glands identified a novel 5.1-kb polyomavirus genome closely related to human Washington University (WU) and Karolinska Institute (KI) and vole polyomaviruses but notably divergent from Rattus norvegicus PyV1 (RnorPyV1; also designated RatPyV1). Further screening showed RatPyV2 inclusion body infection in the lung epithelium and variably in other respiratory, reproductive, and glandular tissues of 12/12 (100%) rats. IMPORTANCE Although P-PIT was developed to detect diseases associated with known human polyomaviruses, the identification of a new polyomavirus in rats suggests that it may have utility as a broad-based screen for new, as well as known polyomaviruses. Our findings suggest that RatPyV2 may be a commensal infection of laboratory rats that can lead to disseminated disease in T cell immune-deficient rats. Infection of the X-SCID rats with RatPyV2 and Pneumocystis carinii is a potential model for coinfection pathogenesis and treatment options during transplant preclinical studies

Degradation behaviour of Ti-12Nb alloy coated with ZnO/TiN double layer

Ti and its alloys have attracted attention for biomedical applications, but their low tribocorrosion resistance, lack of bioactivity and antimicrobial properties are still major clinical concerns. In this study a ZnO coating, intended to act as an antibacterial agent, was deposited on a Ti-12Nb alloy, which was previously coated with a TiN hard coating, for improving tribocorrosion resistance. The idea behind is the proof-of -concept that ZnO is able to provide interesting tribological properties to the surface, thus inspiring new ZnO-containing surfaces that can combine antimicrobial properties and tribocorrosion resistance. Thus, the corrosion behaviour was studied by open circuit potential, electrochemical impedance spectroscopy, and potentiodynamic polarization tests in phosphate buffered solution at body temperature. The tribocorrosion behaviour was carried out at open circuit potential under 0.5 N of normal load, 1 Hz frequency, during 3600 s sliding in phosphate buffered solution at body temperature. The results indicated that duplex coating sample showed better corrosion resistance and drastically better tribocorrosion resistance compared to uncoated and single TiN coating samples.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação para a Ciência e a TecnologiaCMEMS-Uminho – Center for MicroElectroMechanical Systems Universidade do Minho, AzurémIBTN/Br – Brazilian Branch of the Institute of Biomaterials Tribocorrosion and NanomedicineUNESP—Univ. Estadual Paulista Faculdade de Ciências de Bauru Dep. FísicaUniversidade do Minho Dept. Eng. Mecânica, AzurémDepartment of Materials Science and Engineering Izmir Institute of TechnologyIBTN/Euro – European Branch of the Institute of Biomaterials Tribocorrosion and Nanomedicine Dept. Eng. Mecânica Universidade do Minho, AzurémUNESP—Univ. Estadual Paulista Faculdade de Ciências de Bauru Dep. FísicaFAPESP: 2015/50.280-5CNPq: 308.204/2017-4Fundação para a Ciência e a Tecnologia: M-ERA-NET/0001/2015Fundação para a Ciência e a Tecnologia: UID/EEA/04436/201