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Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
The permeability and inflammatory tissue reaction to Mucomaix® matrix (MM), a non- cross-linked collagen-based matrix was evaluated in both ex vivo and in vivo settings. Liquid platelet rich fibrin (PRF), a blood concentrate system, was used to assess its capacity to absorb human proteins and interact with blood cells ex vivo. In the in vivo aspect, 12 Wister rats had MM implanted subcutaneously, whereas another 12 rats (control) were sham-operated without biomaterial implantation. On days 3, 15 and 30, explantation was completed (four rats per time-point) to evaluate the tissue reactions to the matrix. Data collected were statistically analyzed using analysis of variance (ANOVA) and Tukey multiple comparisons tests (GraphPad Prism 8). The matrix absorbed the liquid PRF in the ex vivo study. Day 3 post-implantation revealed mild tissue inflammatory reaction with presence of mononuclear cells in the implantation site and on the biomaterial surface (mostly CD68-positive macrophages). The control group at this stage had more mononuclear cells than the test group. From day 15, multinucleated giant cells (MNGCs) were seen in the implantation site and the outer third of the matrix with marked increase on day 30 and spread to the matrix core. The presence of these CD68-positive MNGCs was associated with significant matrix vascularization. The matrix degraded significantly over the study period, but its core was still visible as of day 30 post-implantation. The high permeability and fast degradation properties of MM were highlighted.
Background: Culture-derived mesenchymal stromal cells (MSCs) exhibit variable characteristics when manufactured using different methods and different source materials. The purpose of this study was to assess the impact on MSC characteristics when different laboratories propagated MSCs from cultures initiated with BM aliquots derived from the same donor source material.
Methods and Methods: Five aliquots from each of three different BM donors were distributed to five independent laboratories. Three laboratories plated whole BM and two laboratories a mononuclear BM cell fraction. Four laboratories cultured in media supplemented with fetal bovine serum (FBS) and one laboratory used human platelet lysate (hPL). Initial cell seeding densities (i.e., P0) ranged from 19.7 × 103/cm2–282 × 103/cm2 and for second seeding (i.e., P1) 0.05 × 103–5.1 × 103 cells/cm2. Post-thawed MSCs from each laboratory were analyzed for cell viability, immunophenotype, tri-lineage differentiation, fibroblast colony-forming units (CFU-F), gene expression, and immunosuppressive activity.
Results: Transit times from BM collection to receipt by laboratories located in the United States ranged from 16.0–30.0 h and from 41.5–71.5 h for a laboratory in Asia. Post-thaw culture derived MSCs rom BM #1, #2, and #3 exhibited viabilities that ranged from 74–92%, 61–96%, and 23–90%, respectively. CFU activity from BM #1, #2, and #3 per 200 MSCs plated averaged 45.1 ± 21.4, 49.3 ± 26.8 and 14.9 ± 13.3, respectively. No substantial differences were observed in immunophenotype, and immunosuppressive activities. Global gene expression profiles of MSCs revealed transcriptome differences due to different inter-laboratory methods and to donor source material with the center effects showing greater molecular differences than source material.
Conclusion: Functional and molecular differences exist among MSCs produced by different centers even when the same BM starting material is used to initiate cultures. These results indicated that manufacturing of MSCs by five independent centers contributed more to MSC variability than did the source material of the BM used in this study. Thus, emphasizing the importance of establishing worldwide standards to propagate MSCs for clinical use.
Purpose: In the clinical routine, detection of focal cortical dysplasia (FCD) by visual inspection is challenging. Still, information about the presence and location of FCD is highly relevant for prognostication and treatment decisions. Therefore, this study aimed to develop, describe and test a method for the calculation of synthetic anatomies using multiparametric quantitative MRI (qMRI) data and surface-based analysis, which allows for an improved visualization of FCD.
Materials and Methods: Quantitative T1-, T2- and PD-maps and conventional clinical datasets of patients with FCD and epilepsy were acquired. Tissue segmentation and delineation of the border between white matter and cortex was performed. In order to detect blurring at this border, a surface-based calculation of the standard deviation of each quantitative parameter (T1, T2, and PD) was performed across the cortex and the neighboring white matter for each cortical vertex. The resulting standard deviations combined with measures of the cortical thickness were used to enhance the signal of conventional FLAIR-datasets. The resulting synthetically enhanced FLAIR-anatomies were compared with conventional MRI-data utilizing regions of interest based analysis techniques.
Results: The synthetically enhanced FLAIR-anatomies showed higher signal levels than conventional FLAIR-data at the FCD sites (p = 0.005). In addition, the enhanced FLAIR-anatomies exhibited higher signal levels at the FCD sites than in the corresponding contralateral regions (p = 0.005). However, false positive findings occurred, so careful comparison with conventional datasets is mandatory.
Conclusion: Synthetically enhanced FLAIR-anatomies resulting from surface-based multiparametric qMRI-analyses have the potential to improve the visualization of FCD and, accordingly, the treatment of the respective patients.
Temperature elevations constitute a major threat to plant performance. In recent years, much was learned about the general molecular mode of heat stress reaction of plants. The current research focuses on the integration of the knowledge into more global networks, including the reactions of cellular compartments. For instance, chloroplast function is central for plant growth and survival, and the performance of chloroplasts is tightly linked to the general status of the cell and vice versa. We examined the changes in photosynthesis, chloroplast morphology and proteomic composition posed in Arabidopsis thaliana chloroplasts after a single or repetitive heat stress treatment over a period of two weeks. We observed that the acclimation is potent in the case of repetitive application of heat stress, while a single stress results in lasting alterations. Moreover, the physiological capacity and its adjustment are dependent on the efficiency of the protein translocation process as judged from the analysis of mutants of the two receptor units of the chloroplast translocon, TOC64, and TOC33. In response to repetitive heat stress, plants without TOC33 accumulate Hsp70 proteins and plants without TOC64 have a higher content of proteins involved in thylakoid structure determination when compared to wild-type plants.
A new virus, SARS-CoV-2, emerged in the Chinese city of Wuhan at the end of 2019. Infected persons developed an atypical form of pneumonia, later known as COVID-19. The pathogen created a pandemic, with fatalities throughout the world, and also led to the adoption of restrictive measures which were, until recently, unthinkable, as well as fostering new political conflicts. Even the path of the multilateral order in its current form is at stake. For a take on these issues under international law, the legal regime of the World Health Organization (WHO) and its response to the pandemic provides an insightful access. ...
Since the introduction of rental E-scooters in Germany in mid-June 2019, the safety of this new means of transport has been the subject of extensive public debate. However, valid data on injuries and usage habits are not yet available. This retrospective two-center study included a total of 76 patients who presented to the emergency department following E-scooter-related accidents. The mean age was 34.3 ± 12.4 years and 69.7% of the patients were male. About half of the patients were admitted by ambulance (42.1%). Fractures were found in 48.6% of patients, and 27.6% required surgical treatment due to a fracture. The upper extremities were the most commonly affected body region, followed by injuries to the lower extremity and to the head and face. Only one patient had worn a helmet. In-hospital treatment was necessary for 26.3% of the cases. Patients presented to the emergency department mainly during the weekend and on-call times. This is the first report on E-scooter-related injuries in Germany. Accidents with E-scooters can cause serious injuries and, therefore, represent a further burden to emergency departments. The use of E-scooters appears to be mostly recreational, and the rate of use of protective gear is low.
Transcriptional basis for differential thermosensitivity of seedlings of various tomato genotypes
(2020)
Transcriptional reprograming after the exposure of plants to elevated temperatures is a hallmark of stress response which is required for the manifestation of thermotolerance. Central transcription factors regulate the stress survival and recovery mechanisms and many of the core responses controlled by these factors are well described. In turn, pathways and specific genes contributing to variations in the thermotolerance capacity even among closely related plant genotypes are not well defined. A seedling-based assay was developed to directly compare the growth and transcriptome response to heat stress in four tomato genotypes with contrasting thermotolerance. The conserved and the genotype-specific alterations of mRNA abundance in response to heat stress were monitored after exposure to three different temperatures. The transcripts of the majority of genes behave similarly in all genotypes, including the majority of heat stress transcription factors and heat shock proteins, but also genes involved in photosynthesis and mitochondrial ATP production. In turn, genes involved in hormone and RNA-based regulation, such as auxin- and ethylene-related genes, or transcription factors like HsfA6b, show a differential regulation that associates with the thermotolerance pattern. Our results provide an inventory of genes likely involved in core and genotype-dependent heat stress response mechanisms with putative role in thermotolerance in tomato seedlings.
Did the Federal Reserves’ Quantitative Easing (QE) in the aftermath of the financial crisis have macroeconomic effects? To answer this question, the authors estimate a large-scale DSGE model over the sample from 1998 to 2020, including data of the Fed’s balance sheet. The authors allow for QE to affect the economy via multiple channels that arise from several financial frictions. Their nonlinear Bayesian likelihood approach fully accounts for the zero lower bound on nominal interest rates. They find that between 2009 to 2015, QE increased output by about 1.2 percent. This reflects a net increase in investment of nearly 9 percent, that was accompanied by a 0.7 percent drop in aggregate consumption. Both, government bond and capital asset purchases were effective in improving financing conditions. Especially capital asset purchases significantly facilitated new investment and increased the production capacity. Against the backdrop of a fall in consumption, supply side effects dominated which led to a mild disinflationary effect of about 0.25 percent annually.
Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.
Introduction: The worldwide spread of the novel coronavirus (SARS-CoV2) has prompted numerous countries to restrict public life. Related measures, such as limits on social gatherings, business closures, or lockdowns, are expected to considerably reduce the individual opportunities to move outside the home. As physical activity (PA) and sport participation significantly contribute to health, this study has two objectives. The objectives of this study are to assess changes in PA and well-being since the coronavirus outbreak in affected countries. Additionally, we will evaluate the impact of digital home-based exercise programs on PA as well as physical and mental health outcomes.
Method: A multinational network trial will be conducted with three planned phases (A, B, and C). Part A consists of administering a structured survey. It investigates changes in PA levels and health during the coronavirus outbreak and measures the preferences of the participants regarding online training programs. Part B is a two-armed randomized-controlled trial. Participants assigned to the intervention group (IG) will complete a digital 4-week home exercise training (live streaming via internet) guided by the survey results on content and time of program. The control group (CG) will not receive the program. Part C is 4-week access of both CG and IG to a digital archive of pre-recorded workouts from Part B. Similar to Part A, questionnaires will be used in both Part B and C to estimate the effects of exercise on measures of mental and physical health.
Results and Discussion: The ASAP project will provide valuable insights into the importance of PA during a global pandemic. Our initial survey is the first to determine how governmental confinement measures impact bodily and mental well-being. Based on the results, the intervention studies will be unique to address health problems potentially arising from losses in PA. If proven effective, the newly developed telehealth programs could become a significant and easy-to-distribute factor in combating PA decreases. Results of the study may hence guide policy makers on methods to maintain PA and health when being forced to restrict public life.
Study Register: DRKS00021273.
Dental clinics were suspected to be a hotspot for nosocomial transmission of coronavirus disease 19 (COVID-19), yet there has been no clear recommendation about emergency dental care and appropriate personal protective equipment during pandemics. In this paper, we aim to summarize recommendations for (i) patient risk assessment, (ii) patient triage, and (iii) measures to prevent infection of health professionals and nosocomial transmission in dental clinics. The available evidence was collected by performing searches on PubMed, Embase, and Cochrane databases. We reviewed papers on COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, and related respiratory viral diseases. Legal and ethical frameworks, as well as international (e.g., World Health Organization (WHO)) and national (e.g., public health institutes, dental associations) guidelines were screened to summarize recommendations related to dental emergency care. To assess the patient risk, a questionnaire was developed to classify patients at unknown, high, and very high risk. Patient triage recommendations were summarized in a flow chart that graded the emergency level of treatments (i.e., urgent, as soon as possible, and postpone). Measures to prevent disease transmission based on current evidence were grouped for dental health professionals, dental clinics, and patients. The present recommendations may support health professionals implement preventative measures during the pandemic.
Children are commonly exposed to second-hand smoke (SHS) in the domestic environment or inside vehicles of smokers. Unfortunately, prenatal tobacco smoke (PTS) exposure is still common, too. SHS is hazardous to the health of smokers and non-smokers, but especially to that of children. SHS and PTS increase the risk for children to develop cancers and can trigger or worsen asthma and allergies, modulate the immune status, and is harmful to lung, heart and blood vessels. Smoking during pregnancy can cause pregnancy complications and poor birth outcomes as well as changes in the development of the foetus. Lately, some of the molecular and genetic mechanisms that cause adverse health effects in children have been identified. In this review, some of the current insights are discussed. In this regard, it has been found in children that SHS and PTS exposure is associated with changes in levels of enzymes, hormones, and expression of genes, micro RNAs, and proteins. PTS and SHS exposure are major elicitors of mechanisms of oxidative stress. Genetic predisposition can compound the health effects of PTS and SHS exposure. Epigenetic effects might influence in utero gene expression and disease susceptibility. Hence, the limitation of domestic and public exposure to SHS as well as PTS exposure has to be in the focus of policymakers and the public in order to save the health of children at an early age. Global substantial smoke-free policies, health communication campaigns, and behavioural interventions are useful and should be mandatory.
This article investigates the L1 acquisition of different types of direct objects in European Portuguese (EP). Previous research has revealed that although children have early syntactic and pragmatic knowledge of objects across languages, the adequate use of pronouns and null objects is protracted in the acquisition of EP (Costa et al. 2012). The present study shows that children acquiring the distribution of direct objects are aware of universal pragmatic hierarchies but struggle with the interpretation and feature bundles of null objects. Assuming that arguments are linked to left-peripheral C/edge linkers (Sigurðsson 2011), we argue that children need more time to discover the adult-like feature composition of null objects in EP because they involve phi-silent features. Relative accessibility (Ariel 1991) is universal and available early, whereas the absolute accessibility of null objects, i.e. their feature content, is acquired relatively late.
Objectives: Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Methods: Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for the treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. Results: DRV showed no antiviral activity against SARS-CoV-2 at clinically relevant concentrations (EC50 > 100 μM). Remdesivir, used as a positive control, demonstrated potent antiviral activity (EC50 = 0.38 μM). Conclusions: Overall, the data do not support the use of DRV for the treatment of COVID-19.
A central motivation for the development of x-ray free-electron lasers has been the prospect of time-resolved single-molecule imaging with atomic resolution. Here, we show that x-ray photoelectron diffraction—where a photoelectron emitted after x-ray absorption illuminates the molecular structure from within—can be used to image the increase of the internuclear distance during the x-ray-induced fragmentation of an O2 molecule. By measuring the molecular-frame photoelectron emission patterns for a two-photon sequential K-shell ionization in coincidence with the fragment ions, and by sorting the data as a function of the measured kinetic energy release, we can resolve the elongation of the molecular bond by approximately 1.2 a.u. within the duration of the x-ray pulse. The experiment paves the road toward time-resolved pump-probe photoelectron diffraction imaging at high-repetition-rate x-ray free-electron lasers.
Formation of pathological anti-FVIII antibodies, or “inhibitors,” is the most serious complication of therapeutic FVIII infusions, affecting up to 1/3 of severe Hemophilia A (HA) patients. Inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development vs. immune tolerance, achieved with or without Immune Tolerance Induction (ITI) therapy, are not well-understood. To address these questions, temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) was carried out for HA subjects with and without a current or historic inhibitor using RNA-Seq. PBMCs were isolated from 40 subjects in the following groups: HA with an inhibitor that resolved either following ITI or spontaneously; HA with a current inhibitor; HA with no inhibitor history and non-HA controls. PBMCs were stimulated with 5 nM FVIII and RNA was isolated 4, 16, 24, and 48 h following stimulation. Time-series differential expression analysis was performed and distinct transcriptional signatures were identified for each group, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. Subjects with a current inhibitor showed differential expression of 56 genes and a clustering analysis identified three major temporal profiles. Interestingly, gene ontology enrichments featured innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A, and COLEC12. NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1β and TNFα, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. RNA-Seq results were validated by RT-qPCR, ELISAs, multiplex cytokine analysis, and flow cytometry. The inflammatory status of HA patients suffering from an ongoing inhibitor includes up-regulated innate immune modulators, which may act as ongoing danger signals that influence the responses to, and eventual outcomes of, ITI therapy.
Angesichts des kürzlich von der Bundesregierung verabschiedeten Konjunkturpakets, stellen sich die Autoren des Policy Letters die Frage, ob und inwieweit die angekündigte Mehrwertsteuersenkung sowie der Kinderbonus zur substantiellen Ankurbelung des Binnenkonsums führt. Aus den für das Haushaltskrisenbarometer erhobenen Daten zu Einkommensänderungen sowie Einkommens- und Kündigungserwartungen, können die Ökonomen keine zu erwartende Schwächung der Binnennachfrage ableiten. Der überwiegende Teil der deutschen Wohnbevölkerung scheint kurzfristig nicht davon auszugehen, finanzielle Einbußen aufgrund der Pandemie zu erleiden. Die Erwartungen hinsichtlich der künftigen Einkommensentwicklung haben sich gar über die letzten vier Umfragewellen graduell verbessert. Ferner kann dargelegt werden, dass weder die Konsum- noch die Sparneigung durch die Corona-Krise zum gegenwärtigen Zeitpunkt langfristig stark beeinflusst wird. So geben derzeit lediglich 10 Prozent der Befragten an, größere Anschaffungen angesichts der Pandemie vollständig gestrichen zu haben. Anfang April 2020 lag dieser Wert noch bei 16 Prozent. Die Befragten berichteten in 71 Prozent der Fälle ihre Konsumpläne und in 78 Prozent der Fälle ihre Sparverhalten nicht geändert zu haben. Im Lichte dieser Ergebnisse lassen sich Maßnahmen, die auf eine unspezifische Stimulierung der Binnennachfrage abzielen, nicht substantiell begründen und rechtfertigen.