julilili42/papers huggingface dataset:
Refinement of Neurofilament light Dynamics in CSF and Blood for familial Alzheimer’s Disease
2023-12-01

Abstract Background Disease‐modifying therapies for Alzheimer’s Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort. Method Participants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma ( n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI. Result Our results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2). Conclusion Our results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker.
The Role of the Adrenergic System in Neurodegeneration and Oxidative Stress-Induced Damage to the Brain
2023-12-01

Stress is one of the major contributing factors to the development of neurodegenerative diseases and mental disorders. These pathologies are reportedly characterized by progressive loss of neurons and impaired motor and cognitive functions. Changes in stress-induced mechanisms, such as oxidative stress (OS) with corresponding neurotransmitters’ interplay are important for both, the mechanisms of defense and the progression of mental disorders. OS implies an imbalance in the pro-oxidant/antioxidant homeostasis resulting in the generation of aggressive radicals, reactive oxygen species (ROS), and exaggeration of neurodegenerative disease. However, in clinical trials, antioxidants such as alfa-tocopherol have not provided efficacious protection as an alternative therapy for neurodegenerative diseases. Norepinephrine (NE) is the main stress hormone capable of modulating the stress response and providing neuroprotection during neurodegeneration by limiting the production of ROS and stimulating the antioxidative defense, especially against the OH• radical. This in turn leads to the protection of cells from ROS-mediated damage and the improvement of cognitive and behavioral functions. Mounting evidence from preclinical studies in the last decade suggests the α2-adrenoblockers-mediated increase of NE release in the brain to be a promising therapeutic approach in neurodegenerative diseases. In this review, we focus on the role of (1) OS in neurodegenerative diseases; (2) the role of adrenergic receptors (ARs) in disease pathology and mechanisms of defense during neurodegeneration, and (3) the adrenergic signaling system in cognitive functions and neuroprotection provided by NE and α2-adrenoblockers.
Mucosal response of inactivated and recombinant COVID‐19 vaccines in Congolese individuals
2023-12-01

Abstract Background The efficacy of immunization against an airborne pathogen depends in part on its ability to induce antibodies at the major entry site of the virus, the mucosa. Recent studies have revealed that mucosal immunity is poorly activated after vaccination with messenger RNA vaccines, thus failing in blocking virus acquisition upon its site of initial exposure. Little information is available about the induction of mucosal immunity by inactivated and recombinant coronavirus disease 2019 (COVID‐19) vaccines. This study aims to investigate this topic. Methods Saliva and plasma samples from 440 healthy Congolese were collected including (1) fully vaccinated 2 month postvaccination with either an inactivated or a recombinant COVID‐19 vaccine and (2) nonvaccinated control group. Total anti‐severe acute respiratory syndrome coronavirus 2 receptor‐binding domain IgG and IgA antibodies were assessed using in‐house enzyme‐linked immunosorbent assays for both specimens. Findings Altogether, the positivity of IgG was significantly higher in plasma than in saliva samples both in vaccinated and nonvaccinated control groups. Inversely, IgA positivity was slightly higher in saliva than in plasma of vaccinated group. The overall IgG and IgA levels were respectively over 10 3 and 14 times lower in saliva than in plasma samples. We found a strong positive correlation between IgG in saliva and plasma also between IgA in both specimens ( r = .70 for IgG and r = .52 for IgA). Interestingly, contrary to IgG, the level of salivary IgA was not different between seropositive control group and seropositive vaccinated group. No significant difference was observed between recombinant and inactivated COVID‐19 vaccines in total IgG and IgA antibody concentration release 2 months postvaccination both in plasma and saliva. Conclusion Inactivated and recombinant COVID‐19 vaccines in use in the Republic of Congo poorly activated mucosal IgA‐mediated antibody response 2 months postvaccination.
Assets for "Simulation-Based Inference of Surface Accumulation and Basal Melt Rates of an Antarctic Ice shelf from Isochronal Layers"
2023-12-01

&amp;lt;p&amp;gt;Experimental data reported in "Simulation-Based Inference of Surface Accumulation and Basal Melt Rates of an Antarctic Ice shelf from Isochronal Layers".&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;Contains processed simulation data for both synthetic and Ekström Ice Shelf experiments. Selected best layers for each Internal Radar Horizons in the respective simulated datasets are contained in "all_layers_final.p", and the respective mass balance parameters for those simulations in "all_mbs_final.p".&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;Trained Neural Posterior Estimator (NPE) models for each IRH are found in "inference.p" files, and posterior predictive simulations in "post_predictive.p" files for each posterior respectively. Code to visualise and plot this data is found in https://github.com/mackelab/sbi-ice.&amp;lt;/p&amp;gt;
Nation-Building Through Imperial Images Fragility and Charisma of Emperor Meiji’s Public Persona
2023-12-01

This article explores the complex construction of Emperor Meiji’s public image, from a calculated fragility that promoted national unity to the projection of modern imperial charisma. It examines the extensive Meiji period regime of censorship of imperial representations in various forms, such as portraits, photographs, statues, and currency. The fact that the Emperor was forbidden to compose love poetry and the highly selective publication of his poems during his lifetime likewise emphasises the state’s control over the imperial persona and paints a vivid picture of the multifaceted image-crafting efforts surrounding Emperor Meiji.
‘The same contract that is suitable for your Excellency’: Immigration and emulation in the adoption of sharecropping‐cum‐debt arrangements in Brazil (1835‒80)
2023-12-01

Abstract This paper studies the history of contractual choice in coffee plantations of São Paulo, Brazil. It focuses on the consolidation of non‐captive labour markets in the early phases of the transition from slavery in the country, particularly in the 1840s–50s. Vis‐à‐vis the alternatives of fixed rents and fixed payments per time worked or piece rates, the paper examines the rationale for the adoption of sharecropping arrangements with European bonded labourers. New archival evidence suggests that sharecropping had no obvious productivity advantage over alternative labour–rental arrangements in this period, and that the adoption of sharecropping arrangements resulted from the positional advantage of its first proposers, who influenced later choices of contractual design. A credit‐labour tie‐up long outlived the original sharecropping arrangements, in turn allowing for the immigration of poor and credit‐constrained Europeans, paving the way to insert Brazil into the circuits of mass migration without promoting institutional reforms to attract non‐bonded immigrants.
Occupational recognition during the Covid-19 pandemic: differences between occupational groups and the association with compliance with infection control measures
2023-12-01

Abstract This paper examines two research questions. First, we investigate whether specific occupational groups experienced changes in the recognition they received during the Covid-19 crisis. Second, we analyse whether occupational recognition can promote compliance with infection control measures. In addition, we distinguish between a micro-level of job recognition and compliance in the direct working environment on the one hand and a macro-level of recognition of occupational groups and general acceptance of infection control measures on the other. We find that health care occupations and “basic occupations” (essential occupations that do not require formal training) report an increase in recognition received by society during the pandemic, but still perceive the lowest levels of recognition overall. These groups also report lower levels of political recognition and do not feel adequately remunerated. Furthermore, occupational recognition has a positive impact on compliance with infection control measures. We identify institutional trust as the most important mediator. While occupational recognition in the immediate work environment has the greatest impact on micro-level compliance at the workplace, occupational recognition at the macro-level is relevant for accepting closures of public facilities, various restrictions and the intention to get vaccinated.
MYELODYSPLASTIC SYNDROME AND LEUKEMIA IS A SECONDARY EVENT AFTER BONE MARROW FAILURE IN GATA2 HAPLOINSUFFICIENT MICE
2023-12-01

Background and aims: GATA2 is a transcription factor essential for the generation and differentiation of hematopoietic stem and progenitor cells (HSPCs), controlling gene transcription of multiple target genes. In the adult hematopoietic system, GATA2 is crucial for the proliferation and maintenance of HSPCs. Heterozygous germline GATA2 mutations were associated with different syndromes nowadays subsumed as "GATA2 deficiency". The most consistent findings are variable cytopenias, immunodeficiency and an 80% risk of progression to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, the underlying mechanisms remain elusive. With this study we aim to identify the molecular and pathophysiological mechanisms underlying leukemic transformation upon GATA2 deficiency. Methods: To investigate these mechanisms we have modeled GATA2 deficiency in mice. One model made use of aging and serial transplantation of germline GATA2 heterozygous BM, and in the other, we transplanted limited numbers of Vav-CRE;Gata2fl/+HSPCs into lethally irradiated recipients. Results: Serial transplantation of GATA2+/- BM after aging resulted in monocytopenia, B-cell cytopenia as well as reduced HSC fitness. Transplantation of limited numbers of Vav-CRE;Gata2fl/+HSPCs into lethally irradiated WT recipients led to lethal bone marrow failure in approximately 40% of recipients. Histochemical analyses showed bone marrow aplasia in all deceased recipients with significant alterations in B cell and myeloid differentiation. Importantly, 30% of bone marrow failure mice progressed to acute leukemia characterized by both the acquisition of somatic mutations and chromosomal aberrations. Recipients not succumbing to bone marrow failure presented a highly dysplastic normocellular bone marrow, although being phenotypically healthy. Transcriptome analysis showed a marked increase in proliferative signatures and upregulation of G2-M checkpoints in Gata2 haploinsufficient HSCs compared to WT HSCs after transplantation. Furthermore we found, using a human cell model of GATA2 haploinsufficiency, increases in chromosome mis-segregation. Conclusions: Our results suggest that the combination of replicative stress and genomic instability drive bone marrow failure and leukemia in Gata2+/- HSCs. Keywords: GATA2, Mouse model, MDS/AML
Analysis of person recognition deficits in genetic frontotemporal dementia
2023-12-01

Abstract Background Semantic and socioemotional knowledge, including person recognition, can be altered in frontotemporal dementia (FTD), and is often associated with the right temporal lobe variant. Using data from the Genetic FTD Initiative, we investigated person recognition deficits in genetic FTD. Method 901 GENFI participants (279 mutation negative controls, 280 C9orf72 mutation carriers (MCs), 101 MAPT MCs and 241 GRN MCs) were grouped using the Clinical Dementia Rating scale plus National Alzheimer’s Coordinating Centre Frontotemporal Lobar Degeneration (CDR plus NACC FTLD) global score where 0 denotes asymptomatic, 0.5 as prodromal, and 1+ as mild to severe symptoms ( C9orf72 : 135 = 0, 48 = 0.5, 97 = 1+; GRN : 143 = 0, 35 = 0.5, 63 = 1+; MAPT : 50 = 0, 20 = 0.5, 31 = 1+). Person recognition (PR) was assessed using a single question within a structured clinical questionnaire, scoring the ability to recognise people who should be familiar by face or voice to them, with a value between 0 (absent) to 3 (severe), similar to the CDR scale. The percentage of participants with PR deficits was calculated for each group. Logistic regression with bootstrapping compared the PR score between groups with age, gender, and education as covariates. Result 16.1% of C9orf72 MCs (0 = 0.7%, 0.5 = 2.1%, 1+ = 44.3%), 7.5% of GRN (0 = 0.0%, 0.5 = 8.6%, 1+ = 23.8%) and 17.8% of MAPT carriers (0 = 2%, 0.5 = 10%, 1+ = 48.4%) showed PR deficits. Mean (standard deviation) severity in each group was: C9orf72 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.6(0.9); GRN 0 = 0.0(0.0), 0.5 = 0.0(0.1), 1+ = 0.2(0.6); MAPT 0 = 0.0(0.2), 0.5 = 0.1(0.3), 1+ = 0.6(0.8). Each of the symptomatic genetic groups had a significantly greater PR deficit than the control group (p&lt;0.001), with the prodromal MAPT (p = 0.006) and GRN (p&lt;0.001) groups also showing a greater impairment than controls. There was a trend to significance in the C9orf72 asymptomatic and prodromal groups compared with controls (p = 0.058 and p = 0.059 respectively). Symptomatic C9orf72 and MAPT carriers showed greater impairment than the symptomatic GRN carriers (both p = 0.005). Conclusion Person recognition is a key early marker of disease in some individuals with genetic FTD and further imaging analyses will help to reveal the underlying mechanism of this deficit.
The effect of short Aβ(1‐38) peptides on cognitive decline and conversion to AD dementia: longitudinal data using the DELCODE cohort
2023-12-01

Abstract Background The current research consensus is that long Aβ(1‐42) peptides are neurotoxic pathological hallmarks of AD. Interestingly, short Aβ peptides, such as Aβ(1‐38), appear to be less neurotoxic and may counteract AD neuropathology. However, research on Aβ(1‐38) is scarce and their effect on AD pathophysiology in humans in vivo remains unclear. Here, we investigate whether higher relative concentrations of Aβ(1‐38) levels in the cerebrospinal fluid (CSF), compared to Aβ(1‐42) alone, with phospho Tau (pTau) or with both, protect against cognitive decline and risk of conversion to AD dementia. Method Participants with subjective cognitive decline (n = 56), mild cognitive impairment (n = 60) and AD dementia (n = 61) from the DELCODE study with a likely pathological Aβ42/P‐tau ratio of &gt; 9.68 at baseline were included. Cognitive performance was assessed annually for five years with the Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite (i.e., PACC5), which was derived from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Conversion to AD dementia was assessed with the Clinical Dementia Rating (CDR) and NINCDS‐ARDA criteria. CSF was collected at baseline. Data was analysed using statistical model fitting procedures for linear mixed models, i.e., Likelihood Ratio (LR) testing. Additionally, we controlled for baseline diagnostic status and the relative effect of Aβ(1‐42) and pTau. Result Higher Aβ(1‐38) baseline levels were associated with better follow‐up performance on the PACC5 in all three groups across the AD continuum ( p &lt; .001). For the MMSE, only the MCI group showed significantly better follow‐up performance ( p = .003), and a trend was found in the other groups (SCD: p = .090, AD p = .099). Furthermore, higher Aβ(1‐38) baseline levels decreased risk of conversion to AD dementia within three years by 88% ( p = .003) in the SCD and MCI groups. Conclusion Across the AD spectrum, higher Aβ(1‐38) levels protect against cognitive decline and reduce the risk of conversion to AD dementia. This could inform individual risk prediction in memory clinic patients.
Association of low frequency variants with regional cortical grey matter volumes in genetic frontotemporal dementia: Results from GENFI
2023-12-01

Abstract Background Frontotemporal dementia (FTD) is a neurodegenerative condition characterized by heterogeneous clinical, pathological, and genetic features. Mutations in three genes account for the majority of autosomal dominant FTD: GRN , MAPT , and C9orf72 . We tested whether gene‐based aggregate burden of genome‐wide low‐frequency variants contribute to variation in regional cortical and subcortical grey matter volumes in the GENetic Frontotemporal dementia Initiative (GENFI), after controlling for effects of autosomal dominant mutations. Method GENFI recruits symptomatic and presymptomatic participants from families segregating genetic FTD. We included 517 participants with genotype (Neurochip; imputed against TOPMed), and T1w‐MRI brain volumetric data. Gene‐based burden tests that aggregate the number of uncommon/rare variants by gene were used to examine the association of low‐frequency variants (minor allele frequency: 0.000001 to &lt;0.05) with regional cortical and subcortical grey matter volumes, controlling for age, sex, total intracranial volume, mutation status, population stratification, and family membership (kinship matrix). In two separate analyses, we used the following set of annotations to account for (i) loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous, (ii) insertions, deletions, and frameshift mutations (indel‐fs). Result Of the 517 participants (300 women), 307 were mutation carriers (symptomatic = 82). For LOF mutations (731 genes tested; significance threshold: p = 0.05/731 = 6.8×10 −5 ), aggregate burden of variants in BSND were associated with lower volumes in: temporal (p = 6.6×10 −6 ), left insula (p = 5.0×10 −5 ), and ventromedial prefrontal cortical (p = 2.8×10 −5 ) regions. For indel‐fs mutations (826 genes tested; significance threshold: p = 0.05/826 = 6.05×10 −5 ), aggregate burden of variants in: (i) E2F2 was associated with lower volumes in occipital ( p = 8.7×10 −6 ) regions; (ii) TMEM61 was associated with lower volumes in left temporal ( p = 7.8×10 −7 ), and left cingulate regions ( p = 5.5×10 −5 ); (iii) KDM4A‐AS1 was associated with lower volumes in the right temporal ( p = 3.2×10‐7) region. All genes are variably expressed in the brain. Conclusion Identification of deleterious or protective low‐frequency variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication of results followed by functional studies are needed.
Association of low‐frequency and rare variants with cognition in genetic frontotemporal dementia: Results from GENFI
2023-12-01

Abstract Background Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by heterogeneous clinical, pathological, and genetic features. Mutations in three genes account for the majority of autosomal dominant FTD: GRN , MAPT , and C9orf72 . We tested whether gene‐based aggregate burden of genome‐wide low frequency variants contribute to variation in executive function, memory, and language performance in the GENetic Frontotemporal dementia Initiative (GENFI), after controlling for effects of causative mutations. Method GENFI recruits symptomatic and presymptomatic participants from families segregating genetic FTD. We included 565 participants with genotype (Neurochip; imputed against TOPMed), and neuropsychological data. Gene‐based burden tests that aggregate the number of rare alleles by gene, were used to examine the association of low‐frequency variants (minor allele frequency: 0.000001 to &lt;0.05) with factor scores of executive function, memory, and language, controlling for age, sex, education, mutation status, population stratification, and family membership (kinship matrix) in multiple linear regression models. Cognitive factor scores were derived from Confirmatory Factor Analyses. In two separate analyses, we used the following set of annotations to account for (i) loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous, (ii) insertions, deletions, and frameshift mutations (indel‐fs). Result Of the 565 participants (316 women), 307 were mutation carriers (symptomatic = 108). For LOF mutations, aggregate burden of variants in FAM183A reached statistical significance (741 genes tested; significance threshold: p = 0.05/731 = 6.7×10 −5 ) for executive function (standardized β:4.2; p = 6.0×10 −5 ), whereas IPO13 (standardized β: ‐1.7; p = 3.1×10 −5 ) and FAAHP1 (standardized β: ‐1.7; p = 1.8×10 −5 ) were significant for memory. For the indel‐fs mutations, HMGB4 was associated with worse memory function (standardized β: ‐0.95; p = 5.9×10 −6 ). No genes were significantly associated with language. [Gene info: (i) FAM183A‐ codes a ciliary‐base protein ; location1p34.2; associated with autosomal recessive intellectual disability . (ii) IPO13 ‐a nuclear transporter gene; location 1p34.1; associated with Partington syndrome and Agenesis corpus callosum with abnormal genitalia. (iii) HMGB4‐ a transcription regulator gene; location 1p35.1]. Conclusion Identification of low frequency variants contributing to disease phenotypes may help identify genetic modifiers of familial FTD. Replication of results followed by functional studies are required.