Notes

Proteomic Profiling involving Cranial (Superior) Cervical Ganglia Unveils Beta-Amyloid and also Ubiquitin Proteasome System Perturbations in a Horse Several Method Neuropathy.
The TKSA-MC approach employed here is presented as an efficient computational-based design strategy that can be applied to improve the thermal resistance of enzymes with industrial and biotechnological applications.The formation and disassembly of macromolecular particles is a ubiquitous and essential feature of virtually all living organisms. Additionally, diseases are often associated with the accumulation and propagation of biologically active nanoparticles, like the formation of toxic protein aggregates in protein misfolding diseases and the growth of infectious viral particles. The heterogeneous and dynamic nature of biologically active particles can make them exceedingly challenging to study. The single-particle fluorescence technique known as burst analysis spectroscopy (BAS) was developed to facilitate real-time measurement of macromolecular particle distributions in the submicron range in a minimally perturbing, free-solution environment. Here, we develop a multicolor version of BAS and employ it to examine two problems in macromolecular assembly 1) the extent of DNA packing heterogeneity in bacteriophage viral particles and 2) growth models of non-native protein aggregates. We show that multicolor BAS provides a powerful and flexible approach to studying hidden properties of important biological particles like viruses and protein aggregates.
Autoverification is the process of evaluating and validating laboratory results using predefined computer-based algorithms without human interaction. By using autoverification, all reports are validated according to the standard evaluation criteria with predefined rules, and the number of reports per laboratory specialist is reduced. However, creating and validating these rules are the most demanding steps for setting up an autoverification system. In this study, we aimed to develop a model for helping users establish autoverification rules and evaluate their validity and performance.

The proposed model was established by analyzing white papers, previous study results, and national/international guidelines. An autoverification software (myODS) was developed to create rules according to the model and to evaluate the rules and autoverification rates. The simulation results that were produced by the software were used to demonstrate that the determined framework works as expected. Both autoverification ratesreated according to this model could be used as a starting point for different test groups.
Mutations in the gene encoding the glycogen phosphatase laforin result in the fatal childhood dementia Lafora disease (LD). A cellular hallmark of LD is cytoplasmic, hyper-phosphorylated, glycogen-like aggregates called Lafora bodies (LBs) that form in nearly all tissues and drive disease progression. Additional tools are needed to define the cellular function of laforin, understand the pathological role of laforin in LD, and determine the role of glycogen phosphate in glycogen metabolism. In this work, we present the generation and characterization of laforin nanobodies, with one being a laforin inhibitor.

We identify multiple classes of specific laforin-binding nanobodies and determine their binding epitopes using hydrogen deuterium exchange (HDX) mass spectrometry. Using para-nitrophenyl phosphate (pNPP) and a malachite gold-based assay specific for glucan phosphatase activity, we assess the inhibitory effect of one nanobody on laforin's catalytic activity.

Six families of laforin nanobodies are characterized and their epitopes mapped. One nanobody is identified and characterized that serves as an inhibitor of laforin's phosphatase activity.

The six generated and characterized laforin nanobodies, with one being a laforin inhibitor, are an important set of tools that open new avenues to define unresolved glycogen metabolism questions.
The six generated and characterized laforin nanobodies, with one being a laforin inhibitor, are an important set of tools that open new avenues to define unresolved glycogen metabolism questions.
It is unclear whether vitamin D status is related to cardiovascular risk beyond that explained by conventional risk markers. We examined the relationship between serum 25-hydroxy (OH) vitamin D and incident cardiovascular disease (CVD; heart attack/stroke) after adjusting for individual- and community-level covariates from laboratory, administrative and survey data.

Patients receiving their first 25-OH vitamin D test in Calgary, Alberta from 2009 to 2013 without a past CVD diagnosis but an electrocardiogram and body mass index (BMI) +/- 3months from testing were included. The following was merged to this data first results for laboratory-measured CVD risk markers (lipid profile, fasting plasma glucose, and HbA1c) measured +/- 3months from testing; Census Dissemination Area (CDA)-level indicators of socioeconomic status (SES) in 2011; and CVD diagnoses>3months from testing between 2009 and 2016. Linear and Poisson regression were used to examine associations between 25-OH vitamin D quartile and covariates, and Cox proportional hazard models were used to examine associations with incident CVD before and after adjusting for covariates.

Among 72 348 patients, there were 1898 CVD events over a median of 6.0years. Increasing quartile of 25-OH vitamin D was associated with improved lipid and glycemic profiles (p<0.01), higher proportion of CDA-level indicators of high SES (p<0.01), and a lower risk of CVD (Q4 vs Q1 HR 0.72, 95% CI 0.63-0.81, p for trend<0.01) after adjusting for age, sex and average daily hours of sunlight during month of testing. The association with CVD was unchanged after adjusting for BMI, slightly attenuated after adjusting for SES but completely abolished after adjusting for laboratory-measured cardiovascular risk markers.

Vitamin D status likely offers no additional information on CVD risk over conventional laboratory-measured risk markers.
Vitamin D status likely offers no additional information on CVD risk over conventional laboratory-measured risk markers.Paraoxonase-1 (PON-1), a calcium ion-dependent high-density lipoprotein (HDL)-associated enzyme, has been proposed as a negative acute phase reactant biomarker in animal and human adult studies. The aim of this study was to evaluate the value of PON-1 activity in the diagnosis and monitoring of neonatal sepsis. Serum PON-1 activity, as paraoxonase and arylesterase, was prospectively studied in 48 septic neonates and matched controls. PON-1 activity was decreased at the acute phase of sepsis in comparison with values at recovery and values in controls. Paraoxonase or arylesterase at enrollment correlated significantly with serum Amyloid-A, CRP and IL-6 and could also discriminate septic than non-septic neonates. In conclusion, our results are promising regarding the role of PON-1 as a biomarker of neonatal sepsis. Larger studies are needed to validate the clinical utility of PON-1 in neonatal medicine.Zingiberis Rhizome Carbonisata (ZRC) has been used as a hemostatic agent in traditional Chinese medicine (TCM). However, the underlying molecular mechanism remains unclear. In this study, network pharmacology method was used to predict the potential mechanism of ZRC on hemostasis, based on the structures of the main compounds. Then, iTRAQ-based quantitative proteomics analysis was used for verification of the candidate target proteins and pathways to illustrate the underlying mechanisms. Furthermore, the differentially expressed proteins (DEPs) in the enriched pathways were validated by Enzyme-linked immunosorbent assay. The results showed that the hemostasis mechanism of ZRC may be related to Platelet activation, Rap1 signaling pathway and Complement and coagulation cascades. ML-SI3 research buy And 10 proteins (Fermt3, ACTB, Talin, αIIbβ3, Fga, Fgb, Fgg, FXIIIb, Kng and PLC-β were identified as the target DEPs) are considered as the key factors related to hemostatic efficacy of ZRC. Thus, integrated network pharmacology and quantitative proteomics technology were applied for the effective illuminating the molecular mechanisms of Chinese material medica.Memantine is the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It is also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.The events of the past year have underscored the serious and rapid threat that emerging viruses pose to global health. However, much of the rapid progress in understanding and combating SARS-CoV-2 was made possible because of the decades of important groundwork laid from researchers studying other emergent infectious diseases. The 2021 John Dirks Canada Gairdner Global Health award recognizes the contributions of Joseph Sriyal Malik Peiris and Yi Guan toward understanding the origins and options for control of newly emerging infectious disease outbreaks in Asia, notably zoonotic influenza and severe acute respiratory syndrome (SARS). Cell's Nicole Neuman corresponded with Yi Guan about his path to becoming a viral infection sleuth and the challenges of understanding emerging pathogens and their origins. Excerpts of their exchange are included here.Mary-Claire King's approach to genetics has had a major impact on breast and ovarian cancer and, more recently, mental illnesses including schizophrenia. Science writer Kendall Morgan talked with Mary-Claire, recipient of a 2021 Canada Gairdner International Award, about her life, her lengthy quest to discover the genetic basis of susceptibility to breast cancer, the struggles for women in science, and much more. An edited version of this conversation is presented below.Interdisciplinary work has played a key role in Dr. Elizabeth Eisenhauer's wide-ranging research contributions and leadership in cancer clinical trials, drug delivery, treatment standards, and research and prevention strategy. Cell editor Emma Yee talked with Dr. Eisenhauer, recipient of the 2021 Canada Gairdner Wightman Award, to learn more about the factors that influenced her work in cancer care and the lessons she learned along the way. This conversation is presented below, edited for clarity and length. Note the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) was renamed the Canadian Cancer Trials Group (CCTG) in 2016. In this interview, the two are used interchangeably.
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