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Huntington's disease (HD) is caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein, with mutant Htt protein subsequently forming aggregates within the brain. Mutant Htt is a current target for novel therapeutic strategies for HD, however, the lack of translation from preclinical research to disease-modifying treatments highlights the need to improve our understanding of the role of Htt protein in the human brain. This study aims to undertake an immunohistochemical screen of 12 candidate antibodies against various sequences along the Htt protein to characterize Htt distribution and expression in post-mortem human brain tissue microarrays (TMAs).Immunohistochemistry was performed on middle temporal gyrus TMAs comprising of up to 28 HD and 27 age-matched control cases, using 12 antibodies specific to various sequences along the Htt protein. From this study, six antibodies directed to the Htt N-terminus successfully immunolabeled human brain tissue. Htt aggregates and Htt protein expression levels for the six successful antibodies were subsequently quantified with a customized automated image analysis pipeline on the TMAs. A 2.5–12 fold increase in the number of Htt aggregates were detected in HD cases using antibodies MAB5374, MW1, and EPR5526, despite no change in overall Htt protein expression compared to control cases, suggesting a redistribution of Htt into aggregates in HD. MAB5374, MW1, and EPR5526 Htt aggregate numbers were positively correlated with CAG repeat length, and negatively correlated with the age of symptom onset in HD. However, the number of Htt aggregates did not correlate with the degree of striatal degeneration or the degree of cortical neuron loss. Together, these results suggest that longer CAG repeat lengths correlate with Htt aggregation in the HD human brain, and greater Htt cortical aggregate deposition is associated with an earlier age of symptom onset in HD. This study also reinforces that antibodies MAB5492, MW8, and 2B7 which have been utilized to characterize Htt in animal models of HD do not specifically immunolabel Htt aggregates in HD human brain tissue exclusively, thereby highlighting the need for validated means of Htt detection to support drug development for HD.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in exon 1 of the huntingtin gene. Emerging evidence shows that additional epigenetic factors can modify disease phenotypes. Harnessing the ability of the epigenome to modify the disease for therapeutic purposes is therefore of interest. Epigenome modifiers, such as histone deacetylase inhibitors (HDACi), have improved pathology in a range of HD models. Yet in clinical trials, HDACi have failed to alleviate HD symptoms in patients. This study investigated potential reasons for the lack of translation of the therapeutic benefits of HDACi from lab to clinic. We analysed histone acetylation patterns of immuno-positive nuclei from brain sections and tissue microarrays from post-mortem human control and HD cases alongside several well-established HD models (OVT73 transgenic HD sheep, YAC128 mice, and an in vitro cell model expressing 97Q mutant huntingtin). Significant increases in histone H4 acetylation were observed in post-mortem HD cases, OVT73 transgenic HD sheep and in vitro models; these changes were absent in YAC128 mice. In addition, nuclear labelling for acetyl-histone H4 levels were inversely proportional to mutant huntingtin aggregate load in HD human cortex. Our data raise concerns regarding the utility of HDACi for the treatment of HD when regions of pathology exhibit already elevated histone acetylation patterns and emphasize the importance of searching for alternative epigenetic targets in future therapeutic strategies aiming to rescue HD phenotypes.

The temperature dependence of the specific heat capacity and change in the thermodynamic functions of strontium-alloyed ultrahigh-purity aluminum base AK1M2 alloy have been studied in “cooling” mode over the 298.15–900 K range. Mathematical models describing the evolution of these properties of the alloys in the abovementioned temperature range with change in alloying addition concentration have been obtained. The heat capacity, enthalpy and entropy of the alloys increase with temperature, decrease with an increase in the alloying addition concentration to 0.5 wt.% and grow with a further increase in the alloying addition concentration. The Gibbs energy of the alloys has an inverse dependence: it decreases with an increase in temperature and grows with an increase in the alloying addition concentration to 0.5 wt.%.

Traditionally regarded to coordinate movement, the cerebellum also exerts non-motor functions including the regulation of cognitive and behavioral processing, suggesting a potential role in neurodegenerative conditions affecting cognition, such as Alzheimer's disease (AD). This study aims to investigate neuropathology and AD-related molecular changes within the neocerebellum using post-mortem human brain tissue microarrays (TMAs).Immunohistochemistry was conducted on neocerebellar paraffin-embedded TMAs from 24 AD and 24 matched control cases, and free-floating neocerebellar sections from 6 AD and 6 controls. Immunoreactivity was compared between control and AD groups for neuropathological hallmarks (amyloid-β, tau, ubiquitin), Purkinje cells (calbindin), microglia (IBA1, HLA-DR), astrocytes (GFAP) basement-membrane associated molecules (fibronectin, collagen IV), endothelial cells (CD31/PECAM-1) and mural cells (PDGFRβ, αSMA).Amyloid-β expression (total immunolabel intensity) and load (area of immunolabel) was increased by >4-fold within the AD cerebellum. Purkinje cell counts, ubiquitin and tau immunoreactivity were unchanged in AD. IBA1 expression and load was increased by 91% and 69%, respectively, in AD, with no change in IBA1-positive cell number. IBA1-positive cell process length and branching was reduced by 22% and 41%, respectively, in AD. HLA-DR and GFAP immunoreactivity was unchanged in AD. HLA-DR-positive cell process length and branching was reduced by 33% and 49%, respectively, in AD. Fibronectin expression was increased by 27% in AD. Collagen IV, PDGFRβ and αSMA immunoreactivity was unchanged in AD. The number of CD31-positive vessels was increased by 98% in AD, suggesting the increase in CD31 expression and load in AD is due to greater vessel number. The PDGFRβ/CD31 load ratio was reduced by 59% in AD.These findings provide evidence of molecular changes affecting microglia and the neurovasculature within the AD neocerebellum. These changes, occurring without overt neuropathology, support the hypothesis of microglial and neurovascular dysfunction as drivers of AD, which has implications on the neocerebellar contribution to AD symptomatology and pathophysiology.

Background: Huntington's disease (HD) is characterised by variable symptoms and neuropathology of the basal ganglia and cortex. Previously, we have shown that the pattern of pyramidal cell loss in 8 different cortical regions correlates with the phenotypic variability in HD. In the primary motor and anterior cingulate cortices, the pattern of interneuron degeneration correlates with pyramidal cell death and variable HD symptom profiles. Objectives: This study aimed to examine the pattern of interneuron degeneration in 3 further regions of the HD cortex (primary sensory, superior frontal, superior parietal cortices) to determine whether HD neuropathogenesis was characterised by a general fundamental pattern of cortical interneuron loss, and explore the relationship between cortical interneuron loss with previously determined pyramidal cell loss and clinical heterogeneity. Methods: Stereological counting was used to quantify 3 sub-populations of calcium-binding protein containing interneurons in 3 cortical human brain regions of 14 HD and 13 control cases as used in our previous studies (Nana et al., 2014; Kim et al., 2014). The HD cases were grouped according to their predominant symptom profile (“motor”, “mood”, “mixed”). Results: The present results demonstrated a heterogeneous loss of interneurons across the 3 cortical regions which, when compared with our previous studies, mirrored the pattern of pyramidal cell loss in the same cortical areas. Most interestingly, the pattern of neuronal loss in these regions correlated with the variable HD symptom profiles. Conclusion: The overall findings in our present and previous cortical studies establish a clear correlative pattern of variable cortical neuronal degeneration in HD pathogenesis, which mirrors the heterogeneity of HD symptom phenotypes.

Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72 -linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)]. Using multiplexed (five-label) fluorescent immunohistochemistry, we mapped the co-localization of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates and p62 in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1 -linked (n = 1), FUS -linked (n = 1), C9orf72 -linked (n = 5) and UBQLN2 -linked (n = 8) cases. We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis and/or frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wild-type ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wild-type to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2 -linked disease. [ABSTRACT FROM AUTHOR]

In breeding programs, direct selection based on crop yields is paradoxical due to its complex polygenically inherited nature, that is impacted by its component traits. To determine the degree of relationship between yield and yield components and other traits in nine barley varieties, a field experiment was carried out at the Regional Agricultural Research Station, Jashore during Rabi 2021-2022. For plant height, disease and insect reaction, and grain yield, substantial heritability together with strong genetic progress as a percentage of mean were detected, indicating a prevalence of additive gene action in the expression of these traits. At both the genotypic and phenotypic levels, the correlation coefficient between grain yield was shown to be positively correlated with plant height and thousand grain weight, indicating that an increase in these traits will boost grain production. Both genotypic and phenotypic analysis of the path coefficient demonstrated that plant height and thousand grain weight had a direct positive impact on grain production, highlighting the significance of these parameters as the primary contributors to yield. For the purpose of genetically improving barley yield, a genotype with a higher extent of these qualities could be chosen as a parent from among genotypes that already exist. [ABSTRACT FROM AUTHOR]

Objective Patient-accessible electronic health records (PAEHR) were implemented in the Stockholm region of Sweden seven years ago. This study examines socio-demographic and psychographic factors associated with reading/not reading these records, as well as the common reasons for such behaviours. Methods Patients or guardians of minors seeking face-to-face or digital primary healthcare in the Stockholm region responded to a questionnaire about whether they were aware that they could read their PAEHR, and if so, if they had read it and reasons for reading or not reading. We conducted a comparative analysis of readers and non-readers and a stepwise multiple logistic regression. Results The majority of participants were aware that they could read the PAEHR (86%) and among those aware, 77% had read it. The odds of reading decreased with increased age, unfavourable opinion of PAEHR, low information literacy and being single. Access to a smartphone increased the probability of reading. Participants who had read their PAEHR had commonly read it to get an overview of their health and care (65%) and to follow up on a healthcare visit (55%). Participants who had not read their PAEHR stated generally that they did not need to (63%) and/or had received sufficient information from their providers (38%). Conclusions While most people were aware they could read the PAEHR and many had read it, a digital divide and several barriers to reading the PAEHR were identified. Efforts to increase PAEHR reading may be targeted at older people, people needing more informal support, those who may be excluded due to limited information literacy, and towards improving the patient portals’ usability.

Abstract Background Smartphone usage is an essential everyday tool in Iran, however problematic use has escalated and become a concern for the Iranian health policy system, particularly during and following the COVID-19 Pandemic. This study’s aim was investigation of the prevalence of smartphone addiction, patterns of use, and the relationship to specific demographic characteristics and associated musculoskeletal disorders during the COVID-19 pandemic. Methods A descriptive-analytical correlational study recruited participants from a population of convenience (n = 2344) who were smartphone owners with > 1 year of use. For demographic information an electronic self-report questionnaire collected age, sex, marital status, usage for daily hours, and patterns. To assess addiction levels, the ‘Smartphone Addiction Scale-short version’ (SAS-SV) patient-reported outcome measure was used (cut-off = 31). For experienced discomfort, the Extended Nordic Musculoskeletal Questionnaire (ENMQ) was used. Results The participants (female = 66.6%, n = 1561, mean age = 29.07 ± 12.34 years, range 6–60 years) smartphone use averaged 5.75 ± 3.44 h/day. The general prevalence of smartphone addiction was 46.16% (females = 46.06%, males = 46.36%; married = 44.5%, single = 47.63%). School students had the greatest addiction (53.2%) and those with a higher education to or above a Master’s degree were the lowest (39.38%). The highest pattern of use was for social networks at 89.1% of participants (female = 88.34%, male = 90.54%). The areas of highest reported discomfort were the eyes (43.5%) and neck (43.3%). A significant correlation was found between smartphone addiction and hours of daily usage, and the amount of usage increased during the COVID-19 pandemic period. Conclusion A high level of smartphone addiction in the Iranian population was found to have occurred during the COVID-19 pandemic. Those most affected were unmarried individuals and school students, with the predominant areas being the eyes and neck. Health decision-makers should consider these findings when developing recommendations and plans for public health, particularly those focused on students.

Abstract Background The use of remote services such as video consultations (VCs) has increased significantly in the wake of the COVID-19 pandemic. In Sweden, private healthcare providers offering VCs have grown substantially since 2016 and have been controversial. Few studies have focused on physicians’ experiences providing care in this context. Our aim was to study physicians’ experiences of VCs, focusing on the work environment, quality of care, and educational needs. Methods Twenty-two semi-structured interviews were performed with physicians working with VCs in Sweden, and analyzed through inductive content analysis. Results We identified five categories; flexibility, social work environment, impact on care and society, continuous learning and career development, and organizational support. Flexibility and accessibility were considered positive features of working digitally by giving physicians control over their time and workplace and increasing patients’ timely access to healthcare. Regarding collegial contact and social activities in a digital context, the majority of the participants did not experience any significant difference compared to the physical context. Access to technical support services, educational support, and collegial support in decision-making, guidance, and consultations were described as well-functioning. Satisfied patients positively impacted the work environment, and participants felt that VCs have a positive socio-economic effect. Continuity of care was considered supported, but patients did not always prioritize this. Privacy risks were considered a challenge, as were poor development of clinical skills due to the low variation of patient cases. Working for an online healthcare provider was contributing to career advancements for junior clinicians. Conclusions Physicians appreciate the flexibility of the digital context and seem satisfied with a work environment where they have a high level of control, but few consider this a full-time career option. The pandemic year 2020 has led to a significant increase in the implementation of VCs in traditional care systems. How this affects the work environment and continuous education needs and career development remains to be seen.