scholarly journals Post-synaptic scaffold protein TANC2 in psychiatric and somatic disease risk

2021 ◽  
Author(s):  
Lillian Garrett ◽  
Patricia Da Silva-Buttkus ◽  
Birgit Rathkolb ◽  
Raffaele Gerlini ◽  
Lore Becker ◽  
...  
Keyword(s):  
Large Scale ◽  
Disease Risk ◽  
Treatment Options ◽  
Critical Role ◽  
Growth Failure ◽  
Scaffold Protein ◽  
Medical Comorbidity ◽  
Hepatocellular Damage ◽  
Somatic Disease ◽  
Patient Diagnosis

Understanding the shared genetic aetiology of psychiatric and medical comorbidity in neurodevelopmental disorders (NDDs) could improve patient diagnosis, stratification and treatment options. Rare TANC2 (Tetratricopeptide Repeat, Ankyrin Repeat and Coiled-Coil Containing 2) disrupting variants were disease-causing in NDD patients. This post-synaptic scaffold protein, essential for dendrite formation in synaptic plasticity, plays an unclarified but critical role in development. We here report a novel homozygous-viable Tanc2 disrupted function model where mutant mice were hyperactive and had impaired sensorimotor gating consistent with NDD patient psychiatric endophenotypes. Yet, a multi-systemic analysis revealed the pleiotropic effects of Tanc2 outside the brain such as growth failure and hepatocellular damage. This was associated with aberrant liver function including altered hepatocellular metabolism. Integrative analysis indicates that these disrupted Tanc2 systemic effects relate to interaction with Hippo developmental signalling pathway proteins and will increase the risk for comorbid somatic disease. This highlights how NDD gene pleiotropy can augment medical comorbidity susceptibility underscoring the benefit of holistic NDD patient diagnosis and treatment for which large-scale preclinical functional genomics can provide complementary pleiotropic gene function information.

Nursing professionals’ attitudes toward use of physical restraints in Styrian nursing homes Austria

Pflege ◽  
2019 ◽  
Vol 32 (1) ◽  
pp. 57-63
Author(s):  
Hannes Mayerl ◽  
Tanja Trummer ◽  
Erwin Stolz ◽  
Éva Rásky ◽  
Wolfgang Freidl
Keyword(s):  
Nursing Homes ◽  
Large Scale ◽  
Critical Role ◽  
Physical Restraint ◽  
Care Practice ◽  
Physical Restraints ◽  
Convenience Sample ◽  
Restraint Use ◽  
Positive Attitudes ◽  
Nursing Professionals

Abstract. Background: Given that nursing staff play a critical role in the decision regarding use of physical restraints, research has examined nursing professionals’ attitudes toward this practice. Aim: Since nursing professionals’ views on physical restraint use have not yet been examined in Austria to date, we aimed to explore nursing professionals’ attitudes concerning use of physical restraints in nursing homes of Styria (Austria). Method: Data were collected from a convenience sample of nursing professionals (N = 355) within 19 Styrian nursing homes, based on a cross-sectional study design. Attitudes toward the practice of restraint use were assessed by means of the Maastricht Attitude Questionnaire in the German version. Results: The overall results showed rather positive attitudes toward the use of physical restraints, yet the findings regarding the sub-dimensions of the questionnaire were mixed. Although nursing professionals tended to deny “good reasons” for using physical restraints, they evaluated the consequences of physical restraint use rather positive and considered restraint use as an appropriate health care practice. Nursing professionals’ views regarding the consequences of using specific physical restraints further showed that belts were considered as the most restricting and discomforting devices. Conclusions: Overall, Austrian nursing professionals seemed to hold more positive attitudes toward the use of physical restraints than counterparts in other Western European countries. Future nationwide large-scale surveys will be needed to confirm our findings.

scholarly journals Role of the Pharmacist in Managing Treatment-Resistant Depression: A Focus on Ketamine

Pharmacy ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 118
Author(s):  
Linda Xing Yu Liu ◽  
Marina Golts ◽  
Virginia Fernandes
Keyword(s):  
Current Practice ◽  
Quality Care ◽  
Treatment Options ◽  
Critical Role ◽  
Transitions Of Care ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Multiple Treatments ◽  
The Impact

The impact of depression is well described in the literature, and it is most prominent in patients who have trialed multiple treatments. Treatment-resistant depression (TRD) is particularly debilitating, and it is associated with significant morbidity and mortality. Despite this, there seems to be therapeutic inertia in adopting novel therapies in current practice. Ketamine is an N-methyl-D-aspartate receptor antagonist and anesthetic agent which has recently been shown to be effective in the management of TRD when administered intravenously or intranasally. The treatments, however, are not easily accessible due to restrictions in prescribing and dispensing, high costs, and the slow uptake of evidence-based practice involving ketamine within the Canadian healthcare system. Given the limited treatment options for TRD, novel approaches should be considered and adopted into practice, and facilitated by a multi-disciplinary approach. Pharmacists play a critical role in ensuring access to quality care. This includes dissemination of evidence supporting pharmacological treatments and facilitating translation into current practice. Pharmacists are uniquely positioned to collaborate with prescribers and assess novel treatment options, such as ketamine, address modifiable barriers to treatment, and triage access to medications during transitions of care. Extending the reach of these novel psychiatric treatments in both tertiary and primary care settings creates an emerging role for pharmacists in the collaborative effort to better manage treatment-resistant depression.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

scholarly journals Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wen Juan Tu ◽  
Robert D. McCuaig ◽  
Michelle Melino ◽  
Daniel J. Rawle ◽  
Thuy T. Le ◽  
...  
Keyword(s):  
Viral Replication ◽  
Treatment Options ◽  
Critical Role ◽  
Post Exposure Prophylaxis ◽  
Nuclear Entry ◽  
Importin Α ◽  
Active Transcription ◽  
Nuclear Shuttling ◽  
Asymptomatic Phase ◽  
Exposure Prophylaxis

AbstractTreatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

scholarly journals Complex Network Modelling of Origin–Destination Commuting Flows for the COVID-19 Epidemic Spread Analysis in Italian Lombardy Region

2021 ◽  
Vol 11 (10) ◽  
pp. 4381
Author(s):  
Angela Lombardi ◽  
Nicola Amoroso ◽  
Alfonso Monaco ◽  
Sabina Tangaro ◽  
Roberto Bellotti
Keyword(s):  
Urban Areas ◽  
Large Scale ◽  
Critical Role ◽  
Potential Contribution ◽  
Epidemic Spread ◽  
Network Modelling ◽  
Lombardy Region ◽  
Commuting Flows ◽  
Dynamic Growth ◽  
Spread Analysis

Currently the whole world is affected by the COVID-19 disease. Italy was the first country to be seriously affected in Europe, where the first COVID-19 outbreak was localized in the Lombardy region. The further spreading of the cases led to the lockdown of the most affected regions in northern Italy and then the entire country. In this work we investigated an epidemic spread scenario in the Lombardy region by using the origin–destination matrix with information about the commuting flows among 1450 urban areas within the region. We performed a large-scale simulation-based modeling of the epidemic spread over the networks related to three main motivations, i.e., work, study and occasional transfers to quantify the potential contribution of each category of travellers to the spread of the epidemic process. Our findings outline that the three networks are characterised by different weight dynamic growth rates and that the network “work” has a critical role in the diffusion phenomenon showing the greatest contribution to the epidemic spread.

scholarly journals Disease Risk, Spatial Patterns, and Incidence-Severity Relationships of Fusarium Head Blight in No-till Spring Wheat Following Maize or Soybean

Plant Disease ◽  
2015 ◽  
Vol 99 (10) ◽  
pp. 1360-1366 ◽  
Author(s):  
Pierri Spolti ◽  
Denis A. Shah ◽  
José Maurício C. Fernandes ◽  
Gary C. Bergstrom ◽  
Emerson M. Del Ponte
Keyword(s):  
Fusarium Head Blight ◽  
Large Scale ◽  
Disease Risk ◽  
Random Pattern ◽  
Southern Brazil ◽  
Head Blight ◽  
Previous Crop ◽  
Regional Sources ◽  
Epidemiological Surveys ◽  
The Relationship

The first large-scale survey of Fusarium head blight (FHB) in commercial wheat fields in southern Brazil was conducted over three years (2009 to 2011). The objectives were to: (i) evaluate whether increased FHB risk is associated with within-field maize residue; (ii) determine the spatial pattern of FHB incidence; and (iii) quantify the relationship between FHB incidence and severity. FHB was assessed in a total of 160 fields between early milk and dough. Incidence ranged from 1.0 to 89.9% (median = 25%) and severity from 0.02 to 18.6% (median = 1.3%). FHB risk was neither lower nor higher in wheat following maize than in wheat following soybean. Only 18% of fields were classified as having aggregated patterns of FHB-symptomatic spikes. A binary power law description of the variances was consistent with an overall random pattern of the disease. These results conform with the hypothesis that FHB epidemics in southern Brazil are driven by sufficient atmospherically-transported inoculum from regional sources. The incidence-severity relationship was coherent across growing season, growth stage, and previous crop; one common fitted curve described the relationship across all observations. Estimating severity from incidence may be useful in reducing the workload in epidemiological surveys.

A Novel Real-Time Thermal Analysis and Layer Time Control Framework for Large Scale Additive Manufacturing

2020 ◽  
Author(s):  
Sepehr Fathizadan ◽  
Feng Ju ◽  
Kyle Rowe ◽  
Alex Fiechter ◽  
Nils Hofmann
Keyword(s):  
Additive Manufacturing ◽  
Surface Temperature ◽  
Real Time ◽  
Large Scale ◽  
Production Efficiency ◽  
Control Method ◽  
Data Extraction ◽  
Critical Role ◽  
Imaging Data ◽  
Time Data

Abstract Production efficiency and product quality need to be addressed simultaneously to ensure the reliability of large scale additive manufacturing. Specifically, print surface temperature plays a critical role in determining the quality characteristics of the product. Moreover, heat transfer via conduction as a result of spatial correlation between locations on the surface of large and complex geometries necessitates the employment of more robust methodologies to extract and monitor the data. In this paper, we propose a framework for real-time data extraction from thermal images as well as a novel method for controlling layer time during the printing process. A FLIR™ thermal camera captures and stores the stream of images from the print surface temperature while the Thermwood Large Scale Additive Manufacturing (LSAM™) machine is printing components. A set of digital image processing tasks were performed to extract the thermal data. Separate regression models based on real-time thermal imaging data are built on each location on the surface to predict the associated temperatures. Subsequently, a control method is proposed to find the best time for printing the next layer given the predictions. Finally, several scenarios based on the cooling dynamics of surface structure were defined and analyzed, and the results were compared to the current fixed layer time policy. It was concluded that the proposed method can significantly increase the efficiency by reducing the overall printing time while preserving the quality.

Learning Management System for Greater Learner Engagement in Higher Education—A Review

2021 ◽  
pp. 234763112110498
Author(s):  
Parimala Veluvali ◽  
Jayesh Surisetti
Keyword(s):  
Higher Education ◽  
Online Education ◽  
Management System ◽  
Large Scale ◽  
Learning Management System ◽  
Critical Role ◽  
Learner Engagement ◽  
Digital Platforms ◽  
Online Mode ◽  
Learning Management

Online education helped resume learning that had come to a momentary and uncertain pause with the onset of COVID-19 pandemic across the globe. Since then, learning in many educational institutions continued through synchronous and asynchronous modes, with teaching being undertaken remotely on digital platforms. In this large-scale migration towards online mode of curriculum delivery induced by the pandemic, the institutional learning management system (LMS) had a critical role to play in ensuring uninterrupted learning and student engagement. By drawing heavily from extant works, learnings from MOOC platforms, observations from the LMS applications in corporate training, the present article synthesis the extant literature on how the effective use of LMS can make the learning process interactive, student centric, catering to the needs of diverse learners in higher education.

scholarly journals The Arteriovenous Loop: Engineering of Axially Vascularized Tissue

2018 ◽  
Vol 59 (3-4) ◽  
pp. 286-299 ◽  
Author(s):  
Annika Weigand ◽  
Raymund E. Horch ◽  
Anja M. Boos ◽  
Justus P. Beier ◽  
Andreas Arkudas
Keyword(s):  
Tissue Engineering ◽  
Large Scale ◽  
Treatment Options ◽  
Current Treatment ◽  
Loop Model ◽  
Engineering Approach ◽  
In Vivo Tissue Engineering ◽  
Tissue Engineering Approach ◽  
Tissue Defects

Background: Most of the current treatment options for large-scale tissue defects represent a serious burden for the patients, are often not satisfying, and can be associated with significant side effects. Although major achievements have already been made in the field of tissue engineering, the clinical translation in case of extensive tissue defects is only in its early stages. The main challenge and reason for the failure of most tissue engineering approaches is the missing vascularization within large-scale transplants. Summary: The arteriovenous (AV) loop model is an in vivo tissue engineering strategy for generating axially vascularized tissues using the own body as a bioreactor. A superficial artery and vein are anastomosed to create an AV loop. This AV loop is placed into an implantation chamber for prevascularization of the chamber inside, e.g., a scaffold, cells, and growth factors. Subsequently, the generated tissue can be transplanted with its vascular axis into the defect site and anastomosed to the local vasculature. Since the blood supply of the growing tissue is based on the AV loop, it will be immediately perfused with blood in the recipient site leading to optimal healing conditions even in the case of poorly vascularized defects. Using this tissue engineering approach, a multitude of different axially vascularized tissues could be generated, such as bone, skeletal or heart muscle, or lymphatic tissues. Upscaling from the small animal AV loop model into a preclinical large animal model could pave the way for the first successful attempt in clinical application. Key Messages: The AV loop model is a powerful tool for the generation of different axially vascularized replacement tissues. Due to minimal donor site morbidity and the possibility to generate patient-specific tissues variable in type and size, this in vivo tissue engineering approach can be considered as a promising alternative therapy to current treatment options of large-scale defects.

scholarly journals Herbarium specimens reveal substantial and unexpected variation in phenological sensitivity across the eastern United States

2018 ◽  
Vol 374 (1763) ◽  
pp. 20170394 ◽  
Author(s):  
Daniel S. Park ◽  
Ian Breckheimer ◽  
Alex C. Williams ◽  
Edith Law ◽  
Aaron M. Ellison ◽  
...  
Keyword(s):  
United States ◽  
Climatic Change ◽  
Large Scale ◽  
Critical Role ◽  
Flowering Plant ◽  
Reproductive Phenology ◽  
Herbarium Specimens ◽  
Eastern United States ◽  
Regional Patterns ◽  
Continental Scale

Phenology is a key biological trait that can determine an organism's survival and provides one of the clearest indicators of the effects of recent climatic change. Long time-series observations of plant phenology collected at continental scales could clarify latitudinal and regional patterns of plant responses and illuminate drivers of that variation, but few such datasets exist. Here, we use the web tool CrowdCurio to crowdsource phenological data from over 7000 herbarium specimens representing 30 diverse flowering plant species distributed across the eastern United States. Our results, spanning 120 years and generated from over 2000 crowdsourcers, illustrate numerous aspects of continental-scale plant reproductive phenology. First, they support prior studies that found plant reproductive phenology significantly advances in response to warming, especially for early-flowering species. Second, they reveal that fruiting in populations from warmer, lower latitudes is significantly more phenologically sensitive to temperature than that for populations from colder, higher-latitude regions. Last, we found that variation in phenological sensitivities to climate within species between regions was of similar magnitude to variation between species. Overall, our results suggest that phenological responses to anthropogenic climate change will be heterogeneous within communities and across regions, with large amounts of regional variability driven by local adaptation, phenotypic plasticity and differences in species assemblages. As millions of imaged herbarium specimens become available online, they will play an increasingly critical role in revealing large-scale patterns within assemblages and across continents that ultimately can improve forecasts of the impacts of climatic change on the structure and function of ecosystems. This article is part of the theme issue ‘Biological collections for understanding biodiversity in the Anthropocene’.

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