SINEUP Non-coding RNA Targeting GDNF Rescues Motor Deficits and Neurodegeneration in a Mouse Model of Parkinson's Disease.

International audience; Glial cell-derived neurotrophic factor (GDNF) has a potent action in promoting the survival of dopamine (DA) neurons. Several studies indicate that increasing GDNF levels may be beneficial for the treatment of Parkinson's disease (PD) by reducing neurodegeneration of DA neurons. Despite a plethora of preclinical studies showing GDNF efficacy in PD animal models, its application in humans remains questionable for its poor efficacy and side effects due to its uncontrolled, ectopic expression. Here we took advantage of SINEUPs, a new class of antisense long non-coding RNA, that promote translation of partially overlapping sense protein-coding mRNAs with no effects on their mRNA levels. By synthesizing a SINEUP targeting Gdnf mRNA, we were able to increase endogenous GDNF protein levels by about 2-fold. Adeno-associated virus (AAV)9-mediated delivery in the striatum of wild-type (WT) mice led to an increase of endogenous GDNF protein for at least 6 months and the potentiation of the DA system's functions while showing no side effects. Furthermore, SINEUP-GDNF was able to ameliorate motor deficits and neurodegeneration of DA neurons in a PD neurochemical mouse model. Our data indicate that SINEUP-GDNF could represent a new strategy to increase endogenous GDNF protein levels in a more physiological manner for therapeutic treatments of PD

Co-design of sectoral climate services based on seasonal prediction information in the Mediterranean

We present in this contribution the varied experiences gathered in the co-design of a sectoral climate services collection, developed in the framework of the MEDSCOPE project, which have in common the application of seasonal predictions for the Mediterranean geographical and climatic region. Although the region is affected by low seasonal predictability limiting the skill of seasonal forecasting systems, which historically has hindered the development of downstream services, the project was originally conceived to exploit windows of opportunity with enhanced skill for developing and evaluating climate services in various sectors with high societal impact in the region: renewable energy, hydrology, and agriculture and forestry. The project also served as the scientific branch of the WMO-led Mediterranean Climate Outlook Forum (MedCOF) that had as objective -among others- partnership strengthening on climate services between providers and users within the Mediterranean region. The diversity of the MEDSCOPE experiences in co-designing shows the wide range of involvement and engagement of users in this process across the Mediterranean region, which benefits from the existing solid and organized MedCOF community of climate services providers and users. A common issue among the services described here -and also among other prototypes developed in the project- was related with the communication of forecasts uncertainty and skill for efficiently informing decision-making in practice. All MEDSCOPE project prototypes make use of an internally developed software package containing process-based methods for synthesising seasonal forecast data, as well as basic and advanced tools for obtaining tailored products. Another challenge assumed by the project refers to the demonstration of the economic, social, and environmental value of predictions provided by these MEDSCOPE prototypes.The work described in this paper has received funding from the MEDSCOPE project co-funded by the European Commission as part of ERA4CS, an ERA-NET initiated by JPI Climate, grant agreement 690462

Veränderungen im Leukozytenprofil der Dupontlerche ( Chersophilus duponti ) in Spanien und Marokko

[EN] Stress in birds has been widely studied through the measurement of heterophil-to-lymphocyte ratio (H/L ratio). In this study we aimed to assess for the first time the potential variation of stress, measured as H/L ratio, associated to geography (between-country variation) and seasonality (between seasons and within the breeding season), as well as the leukocyte profiles, in the threatened Dupont’s Lark (Chersophilus duponti), using samples from Spain and Morocco. Furthermore, we tested whether variation in H/L ratio was associated with variables such as population density, presence of blood parasites and individual body condition. We found that H/L ratio did not vary between countries, but individuals captured during the breeding season showed higher values of H/L compared to non-breeding ones. Neither male density, nor date within the breeding season had an effect on the H/L ratio. In Spain, individuals with higher body condition showed lower H/L ratio regardless of whether they were malaria-infected. In Morocco, malaria-infected individuals showed higher values of H/L ratio than the non-infected birds. Moreover, we found that our average values of H/L ratio in Morocco were within the ranges of other passerines, but not in Spain. Individuals with higher H/L ratios may be more stressed or present higher capability to face stressful situations. Although H/L ratio is a useful and relatively easy way to obtain measure of stress, the impact that the environment might have on stress and the way it is explained by H/L ratio must be addressed carefully. This study provides new insight for this species’ biology and provides useful reference information to test the status and survival of other populations.[DE] Stress bei Vögeln ist durch die Messung des Verhältnisses von Heterophilen zu T-Lymphozyten (H/L-Verhältnis) umfassend untersucht worden. In dieser Studie wollten wir zum ersten Mal die potentiellen Veränderungen des Stresses in Verbindung mit der Geografie (Unterschiede zwischen einzelnen Ländern) und der Saisonalität (zwischen den Jahreszeiten und innerhalb der Brutsaison), gemessen als H/L-Verhältnis, sowie die Leukozytenprofile bei der bedrohten Dupontlerche (Chersophilus duponti) anhand von Proben aus Spanien und Marokko bewerten. Darüber hinaus haben wir untersucht, ob das H/L-Verhältnis mit Variablen wie der Populationsdichte, dem Vorhandensein von Blutparasiten und der individuellen physischen Verfassung zusammenhängt. Wir stellten fest, dass das H/L-Verhältnis zwischen den einzelnen Ländern nicht variierte, aber die während der Brutzeit gefangenen Tiere höhere H/L-Werte aufwiesen als nicht brütende Tiere. Weder die Dichte an Männchen, noch der Zeitpunkt innerhalb der Brutsaison hatten einen Einfluss auf das H/L-Verhältnis. In Spanien wiesen Tiere mit einer besseren physischen Verfassung ein niedrigeres H/L-Verhältnis auf, unabhängig davon, ob sie mit Malaria infiziert waren. In Marokko zeigten malariainfizierte Vögel höhere Werte des H/L-Verhältnisses als nicht infizierte. Außerdem stellten wir fest, dass unsere Durchschnittswerte für das H/L-Verhältnis in Marokko innerhalb der Werte für andere Sperlingsvögel lagen, nicht aber in Spanien. Tiere mit einem höheren H/L-Verhältnis sind möglicherweise gestresster oder besser in der Lage, mit Stresssituationen umzugehen. Obwohl das H/L-Verhältnis ein nützliches und relativ einfach zu beschaffendes Maß für Stress ist, muss der eventuelle Einfluss der Umwelt auf Stress und die Möglichkeiten, diesen durch das H/L-Verhältnis zu erklären, sorgfältig untersucht werden. Diese Untersuchung bietet neue Einblicke in die Biologie dieser Art und liefert nützliche Referenzinformationen für die Bestimmung des aktuellen Status und für das Überleben anderer Populationen.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.This study was partially funded by the authors, the Spanish Ministry of Environment (MMA; J.J. Areces and B. Heredia), the Spanish Agency for International Cooperation (AECI), and the LIFE Ricoti (LIFE15-NAT-ES-000802), supported by the European Comisison. D.B.R. was supported by FPI-UAM fellowship from the Universidad Autónoma de Madrid (UAM), and the collaboration of the Instituto de Investigación en Recursos Cinegéticos (IREC-CSIC-UCLM). We wish to thank the Servicio de Vida Silvestre of Conselleria D’infraestructures, Territori i Medi Ambient (Generalitat Valenciana) and the Moroccan government for ringing permits and supporting our work. We thank V. Garza, A. Ramírez, R. del pozo, E. Juarez, E.L. García de la Morena, F. Suárez, M. Radi, M. Znari and M. Alouí, and the Colectivo Ornitológico Cigüeña Negra for their help during fieldtrips and arrangements. We also thank two anonymous referees whose helpful comments contributed to improve the paper. This work was approved by the Local Ethical Committee for Animal Experiments of the Autónoma University of Madrid (CEI80-1468-A229).Peer reviewe

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: a voxel-based morphometry approach exploiting Monte Carlo simulations

Purpose: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. Methods: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. Results: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. Conclusions: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan

Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Conclusion: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results.Comment: 142 pages. Accepted by the Astrophysical Journal Supplemen