Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20

Background Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson’s disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the “weaver” mouse model of PD. Here, we assessed its potential effects on neurogenesis. Methods We quantified total numbers of dopaminergic neurons in the SNpc of wild-type and “weaver” mice, with or without administration of BNN-20, and we employed BrdU labelling and intracerebroventricular injections of DiI to evaluate the existence of dopaminergic neurogenesis in the SNpc and to assess the origin of newborn dopaminergic neurons. The in vivo experiments were complemented by in vitro proliferation/differentiation assays of adult neural stem cells (NSCs) isolated from the substantia nigra and the subependymal zone (SEZ) stem cell niche to further characterize the effects of BNN-20. Results Our analysis revealed the existence of a low-rate turnover of dopaminergic neurons in the normal SNpc and showed, using three independent lines of experiments (stereologic cell counts, BrdU and DiI tracing), that the administration of BNN-20 leads to increased neurogenesis in the SNpc and to partial reversal of dopaminergic cell loss. The newly born dopaminergic neurons, that are partially originated from the SEZ, follow the typical nigral maturation pathway, expressing the transcription factor FoxA2. Importantly, the pro-cytogenic effects of BNN-20 were very strong in the SNpc, but were absent in other brain areas such as the cortex or the stem cell niche of the hippocampus. Moreover, although the in vitro assays showed that BNN-20 enhances the differentiation of NSCs towards glia and neurons, its in vivo administration stimulated only neurogenesis. Conclusions Our results demonstrate the existence of a neurogenic system in the SNpc that can be manipulated in order to regenerate the depleted dopaminergic cell population in the “weaver” PD mouse model. Microneurotrophin BNN-20 emerges as an excellent candidate for future PD cell replacement therapies, due to its area-specific, pro-neurogenic effects

The seed germination properties of two hyperaccumulator plant species with the potential for Ni agromining

The aim of this study is to investigate the effect of different nickel concentrations and light in combination with storage conditions and storage time on the seed germination ability of two serpentine-endemic nickel hyperaccumulating species (Bornmuellera emarginata and B. tymphaea). The seeds of both species were collected from natural populations in the Pindus Mountain range, Greece in early July and stored in a refrigerator (4°C) and in laboratory conditions (22°C). The seeds were exposed to a range of nickel concentrations typical of non-ultramafic ‒ ultramafic gradient in two light environments (12 h photoperiod and continuous darkness). The nickel concentration only had a significant effect on B. emarginata, decreasing its seed germination rate with increasing Ni concentrations. The storage temperature significantly affected the germination percentage of both species and it was higher at 4°C compared to 22°C. A higher germination rate (> 60%) was observed for 5‒8-month-old seeds, but both species generally showed significantly higher germination rates in the tests conducted seven months after seed ripening in the field. A higher germination rate was observed in a 12-hour photoperiod than in continuous darkness only for B. tymphaea. This study provides guidelines on the germination capacity of two obligate nickel hyperaccumulators with a potential for use in agromining systems

Keep calm and go out : urban nature exposure, mental health, and perceived value during the COVID-19 lockdown

The COVID-19 pandemic has highlighted the importance of incorporating nature-based solutions in urban design, in order to create sustainable and resilient cities. Inspired by these events, the present study aims at exploring the mental health benefits of nature exposure during the outbreak. Secondarily, we investigate changes in use patterns towards urban green spaces (UGS) and urban blue spaces (UBS) and whether extreme conditions, such as these of a lockdown, can lead to an increase in people’s appreciation of urban nature. Through an online survey, we observed that the pandemic resulted in a decrease in the frequency of visitation to UGS/UBS (p < 0.001). Significant differences were found for exercise (p < 0.001) and socialization (p < 0.05) as main drivers for visiting urban nature pre- and post-lockdown. Accordingly, visitation rates for forests (p < 0.05), playgrounds (p < 0.001), and the sea (p < 0.001) differed significantly when comparing the two periods. In people’s perception, UGS/UBS are important for the urban fabric (89%). Our structural equation model indicated that nature exposure had a beneficial effect on participants’ mental health (p < 0.001). Pathways that explain the relationship between nature exposure and post- lockdown value were nature relatedness, motivation, and perceived importance of UGS/UBS. No mediation could be extracted for nature exposure and mental health. Our findings show the positive association between nature exposure and mental health improvement, especially in times of crisis, as well as a shift in the “value domain” towards urban nature

Isolation of neural stem and oligodendrocyte progenitor cells from the brain of live rats

Summary Postnatal brain neural stem and progenitor cells (NSPCs) cluster in anatomically inaccessible stem cell niches, such as the subependymal zone (SEZ). Here, we describe a method for the isolation of NSPCs from live animals, which we term “milking.” The intracerebroventricular injection of a release cocktail, containing neuraminidase, integrin-β1-blocking antibody, and fibroblast growth factor 2, induces the controlled flow of NSPCs in the cerebrospinal fluid, where they are collected via liquid biopsies. Isolated cells retain key in vivo self-renewal properties and their cell-type profile reflects the cell composition of their source area, while the function of the niche is sustained even 8 months post-milking. By changing the target area more caudally, we also isolate oligodendrocyte progenitor cells (OPCs) from the corpus callosum. This novel approach for sampling NSPCs and OPCs paves the way for performing longitudinal studies in experimental animals, for more in vivo relevant cell culture assays, and for future clinical neuro-regenerative applications

Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20.

BACKGROUND: Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson's disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the "weaver" mouse model of PD. Here, we assessed its potential effects on neurogenesis. METHODS: We quantified total numbers of dopaminergic neurons in the SNpc of wild-type and "weaver" mice, with or without administration of BNN-20, and we employed BrdU labelling and intracerebroventricular injections of DiI to evaluate the existence of dopaminergic neurogenesis in the SNpc and to assess the origin of newborn dopaminergic neurons. The in vivo experiments were complemented by in vitro proliferation/differentiation assays of adult neural stem cells (NSCs) isolated from the substantia nigra and the subependymal zone (SEZ) stem cell niche to further characterize the effects of BNN-20. RESULTS: Our analysis revealed the existence of a low-rate turnover of dopaminergic neurons in the normal SNpc and showed, using three independent lines of experiments (stereologic cell counts, BrdU and DiI tracing), that the administration of BNN-20 leads to increased neurogenesis in the SNpc and to partial reversal of dopaminergic cell loss. The newly born dopaminergic neurons, that are partially originated from the SEZ, follow the typical nigral maturation pathway, expressing the transcription factor FoxA2. Importantly, the pro-cytogenic effects of BNN-20 were very strong in the SNpc, but were absent in other brain areas such as the cortex or the stem cell niche of the hippocampus. Moreover, although the in vitro assays showed that BNN-20 enhances the differentiation of NSCs towards glia and neurons, its in vivo administration stimulated only neurogenesis. CONCLUSIONS: Our results demonstrate the existence of a neurogenic system in the SNpc that can be manipulated in order to regenerate the depleted dopaminergic cell population in the "weaver" PD mouse model. Microneurotrophin BNN-20 emerges as an excellent candidate for future PD cell replacement therapies, due to its area-specific, pro-neurogenic effects

Prevalence of hepatitis B and C markers in high-risk hospitalised patients in Crete: a five-year observational study

BACKGROUND: So far the prevalence of viral hepatitis infection in hospitalized patients has not been extensively studied. Therefore we conducted the present five-year observational study to evaluate the prevalence of HBV and HCV infection in high-risk hospitalized patients of Crete, the largest Greek island, Due to the homogeneous population, epidemiological studies can be accurately done. METHODS: The study was carried out in two out of four District General Hospitals, and in the University Hospital of the island. Markers for HBV and HCV were studied and statistically evaluated according to age, sex and geographical area, in a well-defined hospitalized population. RESULTS: The total prevalence of HBsAg and anti-HCV in the three prefectures during the five-year study is 2.66% and 4.75% respectively. Overall the relative risks were higher in males than females for each hepatitis marker (p < 0.001). Higher prevalence of HBcAb was found in the 41–60 years age group for both sexes (males 36.17%, females 27.38%). Peak HBsAg prevalence was found in the age group of 21–40 and 41–60 years for males (5.4%) and females (3.09%) respectively. Anti-HCV prevalence increases with age reaching the highest prevalence in the age group of 41–60 years for males (7.19%) and in the 61–90 years age group for females (7.16%). For both sexes significant differences between the three locations were identified. For HBsAg a higher prevalence in Heraklion (3.96%) compared to Chania (2.30%, males: p < 0.0001, females: p < 0.05) and Rethymnon (1.45%, males: p < 0.01, females: p < 0.0001) was detected. For HCV a significantly higher prevalence in Heraklion (6.54%) compared to Chania (2.39%, males: p < 0.001, females: p < 0.001) but not in Rethymnon (5.15%, NS). A lower prevalence rate of HBcAb in Heraklion compared to Chania (20.07% versus 23.05%, males: p < 0.001, females: p < 0.001) was found. CONCLUSIONS: These results were possibly overestimated, but nevertheless reflect the situation of the general population within the island as shown by our previous publications in other study groups. Moreover they contribute to the mapping of viral hepatitis prevalence in a geographical area of Southern Europe and may be helpful in planning public health interventional strategies

Achaiki Iatriki : official publication of the medical society of western Greece and Peloponnesus

In the current issue, the editorial by Cauchi et al. argues for eco-friendly measures in endoscopy and emphasies the role of healthcare providers in reducing waste. The editorial adeptly employs the three Rs (Reduce, Reuse, Recycle) framework to tackle waste management, offering practical solutions. The editorial by Milionis et al. focuses on the reverse cascade screening for paediatric familial hypercholesterolaemia (FH), which is an upcoming tool for public health. Advantages, practices, and challenges regarding FH are thoroughly discussed. Lastly, the editorial by Fousekis et al. presents the main aspects of a chronic immune-mediated cutaneous disease, dermatitis herpetiformis (DH), which constitutes an extraintestinal manifestation of celiac disease, including its diagnosis, pathogenesis, and management. Moreover, this issue includes three review articles. The review article by Krontira et al. discusses the evolving data on the epidemiology, diagnostic approach and appropriate management of foreign body and caustic substance ingestion, based on updated guidelines published by gastroenterological and endoscopic societies. The review by Halliasos et al. provides data on the clinical presentation, diagnosis, and management of metastatic acute spinal cord compression, focusing on the importance of a multidisciplinary team approach, including spine surgeons, radiation oncologists, medical oncologists, palliative care clinicians, physiotherapists, and psychologists. Lastly, the review by Schinas et al. outlines the potential of immune modulation in the treatment of infections and the need for individualised approaches in the modern world of personalised medicine by examining some of the key strategies and immune-based therapies being developed to combat infectious diseases.peer-reviewe

Heterogeneity of quiescent and active neural stem cells in the postnatal brain

In the postnatal mammalian brain, neurogenic activity is retained in anatomically restricted areas, driven by pools of Neural Stem Cells (NSCs). These cells and their progeny have been studied intensively as potential targets for regenerative treatments, aiming at either their in situmanipulation or their use as sources of cells for transplantation-based strategies. Although their full identity, heterogeneity and differentiation potential remain elusive, due to the absence of specific cell-type markers, our knowledge of their properties is constantly expanding. Here, we focus on the NSC niche that is located at the Subependymal Zone (SEZ/ also known as Subventricular Zone) of the lateral ventricles of the brain. We review, summarize and explain the different faces of the NSC, as they have been described, using a wide range of experimental approaches, over a time-frame of three decades: the primitive, definitive, quiescent or activated NSC. We also review the growing evidence of the existence of latent NSCs outside of niches, in the brain parenchyma, that constitute promising new therapeutic targets, complemented by the novel technologies of in vivo cell reprogramming

Incremental Lagrangian Relaxation Based Discrete Gate Sizing and Threshold Voltage Assignment

Timing closure remains one of the most critical challenges of a physical synthesis flow, especially when the design operates under multiple operating conditions. Even if timing is almost closed at the end of the flow, last-mile placement and routing congestion optimizations may introduce new timing violations. Correcting such violations needs minimally disruptive techniques such as threshold voltage reassignment and gate sizing that affect only marginally the placement and routing of the almost finalized design. To this end, we transform a powerful Lagrangian-relaxation-based optimizer, used for global timing optimization early in the design flow, into a practical incremental timing optimizer that corrects small timing violations with fast runtime and without increasing the area/power of the design. The proposed approach was applied to already optimized designs of the ISPD 2013 benchmarks assuming that they experience new timing violations due to local wire rerouting. Experimental results show that in single corner designs, timing is improved by more than 36% on average, using 45% less runtime. Correspondingly, in a multicorner context, timing is improved by 39% when compared to the fully-fledged version of the timing optimizer

Hydrogeological conditionions of Amyndeon mine: problems during exploitation and overcoming them

The subject of the present doctoral dissertation, which was carried out with the financial support of IKY and DEI, is the investigation of the geological and hydrogeological conditions, prevailing in Amynteon open pit, and the problems arising to the exploitation from the occurrence of ground water. The Amynteon basin is part of the great structural graben element, which extends in a north – south direction between the towns of Bitola in F.Y.R.O.M. to Kozani in Greece. According to the extended hydrological, hydrogeological, hydrochemical research, which took place in Amynteon basin, a lignite deposit of about 200x106 tn of lignite, with a stripping ratio 10.8:1 tn/m3is existing. The Quaternary and Pliocene unconsolidated sediments of the basin fill, contain highly permeable sandy layers above the lignite seams, which can be seen as one main aquifer system and influences the exploitation. The transmissivity T of the aquifer varies from 6,8x10-3 to 2,1x10-5 m2/sec. The storage coefficient S is 1,2 - 12%.The quality of surface water is gradually deteriorating mainly due to the use of fertilizers. The mean annual precipitation is 580 mm, while the infiltration is estimated 12,3%, that is 71,2 mm. Recharge this system of aquifers is both infiltrating rainfall and groundwater flow from Aetos - X. Nero horst, as it was proven after extended piezometric measurements and hydrochemical analyses. The direction of the natural flow, of ground water, is from the periphery of the basin towards the centre of the basin. The main axis of outflow from the basin, that is the trench Chimaditis – Petron, exists there. The aquifer is used mainly for irrigation. There have been recorded 542 irrigation water wells in the basin, from which 37-38x10-6 m3 of ground water are pumped annually. This system of aquifers in the overburden exists independent of a major aquifer in the carstified hardrock formations, in the deep underground of the basin and the surrounding mountain ranges. Ground water problems to be solved in Amynteon mine can be summarized in a simplifying way as achieving, within a period of time, dictated by the mining schedule, a drawdown dictated by geomechanical stability and operational requirements. Aquifers of the overburden must thus fully depleted, within the bounds of the mine. Based on numerical ground water simulations of the Amynteon basin, a dewatering scenario for the Amynteon open lignite mine has been developed. Numerical simulation of the aquifer of overburden revealed that 1200-2600 m3/h must be pumped out, by approximately 20-43 operating gravel packed water wells, for the period 1994-2014.The radius of influence of dewatering wells varies between 100- 400 m. The pumped out water must be distributed to the consumers of the area, that is farmers for the irrigation of their fields, Power Stations and Lignite Mines, in order to eliminate inevitable environmental impacts.Αντικείμενο της διδακτορικής διατριβής είναι η έρευvα των υδρογεωλογικών συνθηκών του ορυχείου Αμυνταίου και ο καθορισμός των απαιτούμεvωv αποστραγγιστικώv έργωv, για την προστασία του λιγνιτωρυχείου. Το κοίτασμα Αμυνταίου ανέρχεται σε 202x 106 tn λιγνίτη με σχέση εκμετάλλευσης 10,8/1 m3/tn. Η έρευvα πραγματοποιήθηκε με την υποστήριξη της ΔΕΗ και την οικονομική ενίσχυση του ΙΚΥ. Τα βασικά ερωτήματα ήταν: Ποιές υδρογεωλογικές συvθήκες επικρατούv στηv λεκάvη του ορυχείου Αμυνταίου. Τι ποσότητες vερού πρέπει vα αvτληθούv προκειμέvου vα υποβιβαστεί η στάθμη του υδροφόρου ορίζοvτα, ώστε vα μηv δημιουργεί προβλήματα στηv εκμετάλλευση. Ποιές είvαι οι επιπτώσεις στο υδατικό περιβάλλοv, από τις αvτλήσεις και ποιά μέτρα μπορούv vα ληφθούv για τοv περιορισμό τωv επιπτώσεωv. Η έρευνα περιελάμβανε: γεωλογική και υδρογεωλογική έρευvα υπαίθρου όρυξη υδρογεωτρήσεων και πιεζομέτρων δοκιμαστικές αντλήσεις και μετρήσεις στάθμης καταγραφή του καθεστώτος εκμετάλλευσης του υδατικού δυvαμικού της λεκάvης υδροχημικές αναλύσεις και επεξεργασία των αποτελεσμάτων κατασκευή του μαθηματικού ομοιώματος της λεκάvης Τα συμπεράσματα της έρευνας είναι: Το κύριο υδροφόρο σύστημα, που επηρεάζει τις εργασίες εκμετάλλευσης, εντοπίζεται σταυπερκείμενα του λιγνίτη στρώματα., που αποτελούνται από εναλλασσόμενες στρώσεις αργίλων, άμμων και κροκαλοπαγών του Αν. Πλειόκαινου-Πλειστόκαινου και Ολόκαινου. Η λιγνιτοφόρος σειρά, που περιλαμβάνει τα λιγνιτικά στρώματα και μαργαϊκές ενστρώσεις (Αν. πλειόκαινο), θεωρείται αδιαπέρατη. Η κύρια τροφοδοσία του υδροφορέα γίvεται από τις βροχοπτώσεις μέσω της κατείσδυσης. Ημέση βροχόπτωση της λεκάνης είναι 580 mm και η κατείσδυση αvέρχεται σε 12,3%. Γίνεται επίσης πλευρική τροφοδοσία από το ΒΔ όριο. Η κατεύθυνση ροής των υπόγειων νερών είναι από τα περιθώρια προς το κέντρο της λεκάνης. Η υδαταγωγιμότητα κυμαίvεται από 6,8x10-3-2,1x10-5 m2/sec και ο συvτελεστής εvαποθήκευσης S 1,2-12%. Ο υδροφορέας υφίσταται εντατική εκμετάλλευση για άρδευση. Εχουν καταγραφεί 542 αρδευτικές υδρογεωτρήσεις, από τις οποίες αντλούνται 37-38x10-6 m3 υπογείων νερώνετησίως. Διαπιστώθηκε η σταδιακή ποιοτική υποβάθμιση τωv επιφαvειακώv vερώv, οφειλόμενη κυρίως σε χρήση λιπασμάτων, με αυξημένες τιμές Cl-, SΟ4 -2 και μόvιμης σκληρότητας.Ο υδροφορέας των υπερκειμένων προσομοιώθηκε με τετραγωvικό κάvvαβο, 500x500 m, που καλύπτει όλη τηv λεκάvη. Οι οριακές συvθήκες, που χρησιμοποιήθηκαv είvαι οι εξής: Το δυτικό όριο, θεωρήθηκε αδιαπέρατο, λόγω της ανάδυσης του κρυσταλλοσχιστώδους υποβάθρου. Το vότιο και το αvατολικό όριο, θεωρήθηκαν αδιαπέρατα, λόγω της ύπαρξης ρηγμάτων. Το βόρειο - αvατολικό όριο θεωρήθηκε όριο σταθερής εκροής. Το βόρειο όριο θεωρήθηκε όριο σταθερού φορτίου. Σύμφωvα με τα αποτελέσματα της προσομοίωσης οι ποσότητες νερού, που πρέπει vα αvτληθούv για την ασφαλή λειτουργία του Ορυχείου, είναι 1200 – 2600 m3/h από 20-43 υδρογεωτρήσεις. Η ακτίνα επίδρασης των υδρογεωτρήσεων αποστράγγισης κυμαίνεται από 100-400 m. Τα φαινόμενα, που αναμένεται να παρατηρηθούν λόγω του συνόλου των αντλήσεων, εάν δεν ληφθούν τα κατάλληλα μέτρα, είναι: Μείωση της παροχής ή αποξήρανση υδρογεωτρήσεων και πηγών Εντονότερη διήθηση νερού από λίμνες ή ποτάμια προς το υπέδαφος. Μείωση της υγρασίας των εδαφών Ρύπανση, των επιφανειακών κυρίως νερών. Με στόχο την μείωση ή αποφυγή των επιπτώσεων, προτείνεται: Αντληση των υπόγειων νερών, πριν αυτά εισέλθουν στο χώρο εκσκαφής Διάθεση των αντλούμενων ποσοτήτων νερού, για κάλυψη αρδευτικών, υδρευτικών καιβιομηχανικών αναγκών. Διοχέτευση των νερών σε τάφρους και υδρογεωτρήσεις για εμπλουτισμό των υπόγειωνυδροφορέων