The Q336H MAPT mutation linked to Pick's disease leads to increased binding of tau to the microtubule network via altered conformational and phosphorylation effects

Tauopathies are neurodegenerative disorders characterized by Tau aggregation. Genetic studies on familial cases allowed for the discovery of mutations in the MAPT gene that increase Tau propensity to detach from microtubules and to form insoluble cytoplasmic Tau aggregates. Recently, the rare mutation Q336H has been identified to be associated with Pick's disease (PiD) and biochemical analyses demonstrated its ability to increase the microtubules (MTs) polymerization, thus revealing an opposite character compared to other Tau mutations studied so far. Here we investigated the biophysical and molecular properties of Tau(Q336H) in living cells by the employment of the conformational Tau biosensor CST. We found that this mutation alters Tau conformation on microtubules, stabilizes its binding to tubulin, and is associated with a paradoxical lower level of Tau phosphorylation. Moreover, we found that this mutation impacts the cytoskeletal complexity by increasing the tubulin filament length and the number of branches. However, despite these apparently non-pathological traits, we observed the formation of intracellular inclusions confirming that Q336H leads to aggregation. Our results suggest that the Tau aggregation process might be triggered by molecular mechanisms other than Tau destabilization or post-translational modifications which are likely to be detrimental to neuronal function in vivo

Synchronous anal canal cancer and cervical cancer: report of a case and management implication

Background: This is the case report of a synchronous anal canal cancer and cervical cancer in a patient who underwent definitive chemoradiotherapy (CRT) and radical surgery for anal canal and cervical carcinoma, respectively. Case Report: A 55-year-old woman was diagnosed with cT4a cN1 Mx anal canal squamous cell carcinoma and stage IA2 cervical squamous cell carcinoma, based on biopsy and imaging. Definitive CRT consisted of radiotherapy (total dose of 59.4 Gy) and concomitant mitomycin (10 mg/m(2)) and 5-fluorouracil (750 mg/m(2)/5 daily continuous infusion) during the first and last week of radiation. The patient exhibited a complete clinical and radiological response. A radical hysterectomy with pelvic lymphadenectomy was then performed. At the last follow-up (30 months), the patient is still disease-free without any treatment-associated complications. Conclusion: There is limited information in the literature regarding treatment strategy and outcome of patients with synchronous anal canal and cervical cancer. A two-step treatment, including CRT and radical hysterectomy, is likely to be accepted as valid option

XRepo - Towards an information system for prognostics and health management analysis

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Mechanical ventilation parameters in critically ill COVID-19 patients: a scoping review

Background: The mortality of critically ill patients with COVID-19 is high, particularly among those receiving mechanical ventilation (MV). Despite the high number of patients treated worldwide, data on respiratory mechanics are currently scarce and the optimal setting of MV remains to be defined. This scoping review aims to provide an overview of available data about respiratory mechanics, gas exchange and MV settings in patients admitted to intensive care units (ICUs) for COVID-19-associated acute respiratory failure, and to identify knowledge gaps. Main text: PubMed, EMBASE, and MEDLINE databases were searched from inception to October 30, 2020 for studies providing at least one ventilatory parameter collected within 24 h from the ICU admission. The quality of the studies was independently assessed using the Newcastle-Ottawa Quality Assessment Form for Cohort Studies. A total of 26 studies were included for a total of 14,075 patients. At ICU admission, positive end expiratory pressure (PEEP) values ranged from 9 to 16.5 cm of water (cmH2O), suggesting that high levels of PEEP were commonly used for setting MV for these patients. Patients with COVID-19 are severely hypoxemic at ICU admission and show a median ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ranging from 102 to 198 mmHg. Static respiratory system compliance (Crs) values at ICU admission were highly heterogenous, ranging between 24 and 49 ml/cmH2O. Prone positioning and neuromuscular blocking agents were widely used, ranging from 17 to 81 and 22 to 88%, respectively; both rates were higher than previously reported in patients with "classical" acute respiratory distress syndrome (ARDS). Conclusions: Available data show that, in mechanically ventilated patients with COVID-19, respiratory mechanics and MV settings within 24 h from ICU admission are heterogeneous but similar to those reported for "classical" ARDS. However, to date, complete data regarding mechanical properties of respiratory system, optimal setting of MV and the role of rescue treatments for refractory hypoxemia are still lacking in the medical literature

Tau Modulates VGluT1 Expression

Abstract Tau displacement from microtubules is the first step in the onset of tauopathies and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and chromatin-bound fractions. We show that favoring Tau nuclear translocation and accumulation, by Tau overexpression or detachment from MTs, increases the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Remarkably, the P301L mutation, related to frontotemporal dementia FTDP-17, impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration

Smart-working VS office work: how does personal exposure to different air pollutants change?

The COVID-19 pandemic is raging all over the world, with possible structural effects on the work: the smart-working (WFH -Working From Home) role is therefore emphasized by the fact that it could become a traditional way of working in many work sectors. Several scientific papers have recently analyzed the WFH phenomenon under different aspects, but scientific studies have not yet been conducted considering the differences between WFH and WFO (Working From Office), in terms of evaluation of personal exposure assessment to selected airborne pollutants. This study, therefore, aims to evaluate, using portable monitors, the differences in terms of personal exposure to selected airborne pollutants, during different working conditions (WFO vs WFH), over long periods of time (from days to weeks), extending the results to even longer periods (years), to adhere to the approach proposed by the concept of the exposome. The preliminary results of this study refer to three separate phases of the work (i) re-analyses of literature data via Monte Carlo simulation, and assessment of personal exposure to different air pollutants during different working conditions, during (ii) “long term” campaign and (iii) a “short term” monitoring campaign. During the two different measurement campaigns, portable instrumentation was used, because of the ability of these kinds of instruments to obtain data characterized by a high spatial and temperature resolution. The re-elaborations of the data obtained from the literature show how, under different conditions, the exposure concentrations to different PM fractions are statistically lower in WFH working conditions, compared to WFO conditions. These results are in contrast with the preliminary results obtained from exploratory monitoring (both for the “long term” and for the “short term” campaigns). The results obtained from these exploratory monitoring show that the WFH condition has a greater impact on the daily exposure of the monitored subjects, compared to the WFO condition

Monitor and sensors 2.0 for exposure assessment to airborne pollutants

In recent years, the issue of exposure assessment to airborne pollutants has become increasingly popular, both in the occupational and environmental fields. The increasingly stringent national and international air quality standards and exposure limit values both for indoor environments and occupational exposure limit values have been developed with the aim of protecting the health of the general population and workers. On the other hand, this requires a considerable and continuous development of the technologies used to monitor the concentrations of the pollutants to ensure the reliability of the exposure assessment studies. In this regard, one of the most interesting aspects is certainly the development of “new generation” instrumentation for monitoring airborne pollutants (“Next Generation Monitors and Sensors” – NGMS). The main purpose of this work is to analyze the state of the art regarding the afore-mentioned instrumentation, to be able to investigate any practical applications within exposure assessment studies. In this regard, a systematic review of the scientific literature was carried out using three different databases (Scopus, PubMed and Web of Knowledge) and the results were analyzed in terms of the objectives set out above. What emerged is the fact that the use of NGMSs is increasingly growing within the scientific community for exposure assessment studies applied to the occupational and environmental context. The investigated studies have emphasized that NGMSs cannot be considered, in terms of the reliability of the results, to be equal to the reference measurement tools and techniques (i.e., those defined in recognized methods used for regulatory purposes), but they can certainly be integrated into the internal exposure assessment studies to improve their spatial-temporal resolution. These tools have the potential to be easily adapted to different types of studies, are characterized by a small size, which allows them to be worn comfortably without affecting the normal activities of workers or citizens, and by a relatively low cost. Despite this, there is certainly a gap with respect to the reference instrumentation, regarding the measurement performance and quality of the data provided; the objective to be set, however, is not to replace the traditional instrumentation with NGMSs but to integrate and combine the two typologies of instruments to benefit from the strengths of both, therefore, the desirable future developments in this sense has been discussed in this work

Neural stem cells engrafted in the adult brain fuse with endogenous neurons.

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Studies on Air Pollution and Air Quality in Rural and Agricultural Environments: A Systematic Review

Studies on air quality in rural environments are fundamental to obtain first-hand data for the determination of base emissions of air pollutants, to assess the impact of rural-specific airborne pollutants, to model pollutant dispersion, and to develop proper pollution mitigation technologies. The literature lacks a systematic review based on the evaluation of the techniques and methods used for the sampling/monitoring (S/M) of atmospheric pollutants in rural and agricultural settings, which highlights the shortcomings in this field and the need for future studies. This work aims to review the study design applied for on-field monitoring campaigns of airborne pollutants in rural environments and discuss the possible needs and future developments in this field. The results of this literature review, based on the revision of 23 scientific papers, allowed us to determine (i) the basic characteristics related to the study design that should always be reported; (ii) the main techniques and analyses used in exposure assessment studies conducted in this type of setting; and (iii) contextual parameters and descriptors of the S/M site that should be considered to best support the results obtained from the different studies. Future studies carried out to monitor the airborne pollution in rural/agriculture areas should (i) include the use of multiparametric monitors for the contextual measurement of different atmospheric pollutants (as well as meteorological parameters) and (ii) consider the most important boundary information, to better characterize the S/M site