Effect of microstructure state of titanium alloy Ti-6Al-4V on structure and mechanical properties of joints produced by diffusion bonding process

The studies of diffusion bonded samples of Ti-6Al-4V and Nitinol alloys were carried out considering the titanium alloy in two states: ultra-fine grained and bi-modal microstructures, the last one consisted of small and large a-phase grains. Depending on microstructure and chemical composition of the alloys, the diffusion bonding had been made at temperatures from 600°C to 850°C. The microstructures of joints was studied by scanning electron microscope using detector of backscattering electron diffraction. The shear strengths of joints were measured. It was concluded that the ultra-fine grained Ti-6Al-4V alloy could be applied for joints manufactured at a temperature lower than 750°C. The bi-modal Ti-6Al-4V alloy is an effective material for producing the joints at the temperature larger that 750°

Potential Protective Link Between Type I Diabetes and Parkinson's Disease Risk and Progression

BACKGROUND: Epidemiological studies suggested an association between Parkinson's disease (PD) and type 2 diabetes, but less is known about type 1 diabetes (T1D) and PD. OBJECTIVE: This study sought to explore the association between T1D and PD. METHODS: We used Mendelian randomization, linkage disequilibrium score regression, and multi-tissue transcriptome-wide analysis to examine the association between PD and T1D. RESULTS: Mendelian randomization showed a potentially protective role of T1D for PD risk (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = 0.039), as well as motor (OR, 0.94; 95% CI, 0.88-0.99; P = 0.044) and cognitive progression (OR, 1.50; 95% CI, 1.08-2.09; P = 0.015). We further found a negative genetic correlation between T1D and PD (rg = -0.17; P = 0.016), and we identified eight genes in cross-tissue transcriptome-wide analysis that were associated with both traits. CONCLUSIONS: Our results suggest a potential genetic link between T1D and PD risk and progression. Larger comprehensive epidemiological and genetic studies are required to validate our findings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

The effect of hydrogenation on the fracture of Ti₂AlNb-based alloy during ball milling

In this work we have studied the effect of phase composition and microstructure of a rapidly solidified Ti₂AlNb-based alloy containing hydrogen on deformation of the alloy during ball milling and production of a fine-dispersed powder. Hydrogen is introduced into the alloy up to a concentration of 2.0 wt

SORL1 mutation in a Greek family with Parkinson's disease and dementia

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson’s disease and Parkinson’s disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD

Relevance of biomarkers across different neurodegenerative

Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer’s disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer’s Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care

Multiple Phosphatidylinositol 3-Kinases Regulate Vaccinia Virus Morphogenesis

Poxvirus morphogenesis is a complex process that involves the successive wrapping of the virus in host cell membranes. We screened by plaque assay a focused library of kinase inhibitors for those that caused a reduction in viral growth and identified several compounds that selectively inhibit phosphatidylinositol 3-kinase (PI3K). Previous studies demonstrated that PI3Ks mediate poxviral entry. Using growth curves and electron microscopy in conjunction with inhibitors, we show that that PI3Ks additionally regulate morphogenesis at two distinct steps: immature to mature virion (IMV) transition, and IMV envelopment to form intracellular enveloped virions (IEV). Cells derived from animals lacking the p85 regulatory subunit of Type I PI3Ks (p85α−/−β−/−) presented phenotypes similar to those observed with PI3K inhibitors. In addition, VV appear to redundantly use PI3Ks, as PI3K inhibitors further reduce plaque size and number in p85α−/−β−/− cells. Together, these data provide evidence for a novel regulatory mechanism for virion morphogenesis involving phosphatidylinositol dynamics and may represent a new therapeutic target to contain poxviruses

The Membrane Fusion Step of Vaccinia Virus Entry Is Cooperatively Mediated by Multiple Viral Proteins and Host Cell Components

For many viruses, one or two proteins allow cell attachment and entry, which occurs through the plasma membrane or following endocytosis at low pH. In contrast, vaccinia virus (VACV) enters cells by both neutral and low pH routes; four proteins mediate cell attachment and twelve that are associated in a membrane complex and conserved in all poxviruses are dedicated to entry. The aim of the present study was to determine the roles of cellular and viral proteins in initial stages of entry, specifically fusion of the membranes of the mature virion and cell. For analysis of the role of cellular components, we used well characterized inhibitors and measured binding of a recombinant VACV virion containing Gaussia luciferase fused to a core protein; viral and cellular membrane lipid mixing with a self-quenching fluorescent probe in the virion membrane; and core entry with a recombinant VACV expressing firefly luciferase and electron microscopy. We determined that inhibitors of tyrosine protein kinases, dynamin GTPase and actin dynamics had little effect on binding of virions to cells but impaired membrane fusion, whereas partial cholesterol depletion and inhibitors of endosomal acidification and membrane blebbing had a severe effect at the later stage of core entry. To determine the role of viral proteins, virions lacking individual membrane components were purified from cells infected with members of a panel of ten conditional-lethal inducible mutants. Each of the entry protein-deficient virions had severely reduced infectivity and except for A28, L1 and L5 greatly impaired membrane fusion. In addition, a potent neutralizing L1 monoclonal antibody blocked entry at a post-membrane lipid-mixing step. Taken together, these results suggested a 2-step entry model and implicated an unprecedented number of viral proteins and cellular components involved in signaling and actin rearrangement for initiation of virus-cell membrane fusion during poxvirus entry

Molecular dynamics simulations of the growth of poly(chloro-para-xylylene) films

Parylene C, poly(chloro-para-xylylene) is the most widely used member of the parylene family due to its excellent chemical and physical properties. In this work we analyzed the formation of the parylene C film using molecular mechanics and molecular dynamics methods. A five unit chain is necessary to create a stable hydrophobic cluster and to adhere to a covered surface. Two scenarios were deemed to take place. The obtained results are consistent with a polymer film scaling growth mechanism and contribute to the description of the dynamic growth of the parylene C polymer

Сниженная экспрессия генов нейрогенеза как биомаркер болезни Паркинсона у носителей мутаций в гене GBA: валидация анализа данных транскриптомного исследования

The objective of the study was to validate our previous results obtained during the transcriptome analysis of the primary culture of peripheral blood macrophages in patients with Parkinson's disease associated with mutations in the GBA gene (GBA-PD) in that reduced expression of the neurogenesis genes EGR1 (early growth response protein 1), NR4A2 (nuclear receptor 4A2), JUNB (transcription factor jun-B) in patients with GBA-PD.Methods and materials. The study included 14 patients with GBA-PD, 15 GBA-carriers, 30 patients with Parkinson's disease (PD) and 44 persons of the control group. The assessment of relative mRNA level of neurogenesis genes EGR1, NR4A2, JUNB in peripheral blood mononuclear cells were carried out by real-time quantitative polymerase chain reaction (PCR) using TaqMan fluorescent probes or EvaGreen fluorescent DNA dye.Results. Relative mRNA level of the JUNB gene in peripheral blood mononuclears was decreased in the group of patients with GBA-PD compared to controls (p=0.034). We found out that the relative mRNA level of the NR4A2 gene in peripheral blood mononuclears was increased in the group of patients with GBA-carriers compared to GBA-PD, patients with PD and controls (p=0.0029, p=0.00045, p=0.0024 respectively). There were no statistically significant differences in the mRNA level of the EGR1 gene between all the study groups (p>0.05).Conclusion. GBA-PD is characterized by reduced expression of the JUNB gene compared to control and of the NR4A2 gene compared to GBA-carriers.Цель исследования — проведение валидации результатов, полученных нами ранее в ходе анализа транскриптома первичной культуры макрофагов периферической крови пациентов с болезнью Паркинсона, ассоциированной с мутациями в гене лизосомного фермента глюкоцереброзидазы GBA (GBA-БП), в котором была выявлена сниженная экспрессия генов нейрогенеза EGR1 (early growth response protein 1), NR4A2 (nuclear receptor 4A2), JUNB (transcription factor jun-B) у пациентов с GBA-БП.Методы и материалы. В исследование включены 14 пациентов с GBA-БП, 15 GBA-носителей, 30 пациентов с болезнью Паркинсона (БП) и 44 индивидуума контрольной группы. Оценка относительного уровня мРНК генов нейрогенеза EGR1, NR4A2, JUNB в мононуклеарах периферической крови проводилась методом количественной полимеразной цепной реакции (ПЦР) в режиме реального времени с использованием флюоресцентных зондов TaqMan или флуоресцентного ДНК-красителя EvaGreen.Результаты. Относительный уровень мРНК гена JUNB в мононуклеарах периферической крови был понижен в группе пациентов с GBA-БП по сравнению с контрольной группой (p = 0,034). Также было выявлено, что относительный уровень мРНК гена NR4A2 в мононуклеарах периферической крови был повышен среди GBA-носителей, по сравнению с пациентами с GBA-БП, пациентами с БП и контролем (p = 0,0029, p = 0,00045, p = 0,0024 соответственно). Статистически значимых различий в уровне мРНК гена EGR1 между всеми исследуемых группами выявлено не было (p>0,05).Заключение. GBA-БП характеризуется пониженной экспрессией гена JUNB по сравнению с контролем и гена NR4A2 относительно GBA-носителей

Structural Analysis of Papain-Like NlpC/P60 Superfamily Enzymes with a Circularly Permuted Topology Reveals Potential Lipid Binding Sites

NlpC/P60 superfamily papain-like enzymes play important roles in all kingdoms of life. Two members of this superfamily, LRAT-like and YaeF/YiiX-like families, were predicted to contain a catalytic domain that is circularly permuted such that the catalytic cysteine is located near the C-terminus, instead of at the N-terminus. These permuted enzymes are widespread in virus, pathogenic bacteria, and eukaryotes. We determined the crystal structure of a member of the YaeF/YiiX-like family from Bacillus cereus in complex with lysine. The structure, which adopts a ligand-induced, “closed” conformation, confirms the circular permutation of catalytic residues. A comparative analysis of other related protein structures within the NlpC/P60 superfamily is presented. Permutated NlpC/P60 enzymes contain a similar conserved core and arrangement of catalytic residues, including a Cys/His-containing triad and an additional conserved tyrosine. More surprisingly, permuted enzymes have a hydrophobic S1 binding pocket that is distinct from previously characterized enzymes in the family, indicative of novel substrate specificity. Further analysis of a structural homolog, YiiX (PDB 2if6) identified a fatty acid in the conserved hydrophobic pocket, thus providing additional insights into possible function of these novel enzymes