Complex genetic interactions affect susceptibility to Alzheimer's disease risk in the BIN1 and MS4A6A loci.

Genetics is the second strongest risk factor for Alzheimer's disease (AD) after age. More than 70 loci have been implicated in AD susceptibility so far, and the genetic architecture of AD entails both additive and nonadditive contributions from these loci. To better understand nonadditive impact of single-nucleotide polymorphisms (SNPs) on AD risk, we examined individual, joint, and interacting (SNPxSNP) effects of 139 and 66 SNPs mapped to the BIN1 and MS4A6A AD-associated loci, respectively.

SNP rs6543176 is associated with extreme human longevity but increased risk for cancer.

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk.

BayesAge 2.0: a maximum likelihood algorithm to predict transcriptomic age.

Aging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an upgraded version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data.

Basic Science and Pathogenesis.

Background: The strongest genetic risk factors for AD include the e4 allele of APOE and the R47H point mutation in the TREM2 receptor. TREM2 is required for the induction of a disease-associated microglia (DAM) signature and microglial neurodegenerative phenotype (MGnD) in response to disease pathology, signatures which both include APOE upregulation. There is currently limited information regarding how the TREM2-APOE pathway ultimately contributes to AD risk, and downstream mechanisms of this pathway are unknown.

Basic Science and Pathogenesis.

Background: Traumatic brain injury (TBI) is recognized as one major, potentially modifiable risk factor for neurodegenerative disease (NDD). Autopsy studies describe a range of neuropathologies in a proportion of individuals surviving late after TBI, most frequently the tau associated pathology, chronic traumatic encephalopathy neuropathologic change (CTE-NC). In addition to tau, other NDD pathologies are described.

The ACA Medicaid expansions and abortion rates among young adults.

This paper examines whether the expansion of Medicaid under the Affordable Care Act (ACA), which increases access to contraceptives to low-income childless women and allows them more autonomy to determine the timing of their pregnancies and births, is associated with lower abortion rates during the period 2008-2017. Using state-level data from the Guttmacher Institute and employing a difference-in-differences method, we find that Medicaid expansion is associated with a meaningful reduction in the abortion rate among women ages 18-24, presumably through increased use of contraceptives among low-income young adults. Our estimates imply that Medicaid expansion is associated with a relative decrease in the abortion rate among this age group, approximately 1-2 per 1000 women.

Large language models can segment narrative events similarly to humans.

Humans perceive discrete events such as "restaurant visits" and "train rides" in their continuous experience. One important prerequisite for studying human event perception is the ability of researchers to quantify when one event ends and another begins. Typically, this information is derived by aggregating behavioral annotations from several observers.

Influence of BMI on robotic rectal cancer surgery: a systematic review and meta-analysis.

Obesity presents a significant public health challenge, known to escalate the risk of colorectal cancer twofold. The potential advantages of employing robotic technology in colorectal surgery for obese individuals remain mostly unexplored. A comprehensive search of articles retrieved from Scopus, PubMed, and the Cochrane Library for the duration of January 2014 to March 2024 was performed, without language limitations.

Microfragmented Adipose Tissue Has No Advantage Over Platelet-Rich Plasma and Bone Marrow Aspirate Injections for Symptomatic Knee Osteoarthritis: A Systematic Review and Meta-analysis.

Background: Microfragmented adipose tissue has been proposed for intra-articular treatment of knee osteoarthritis. There are little data comparing the outcomes of treatment between microfragmented adipose tissue and other biological treatments.

Purpose: To perform a systematic review and meta-analysis comparing microfragmented aspirated fat injections to other orthobiologics, hyaluronic acid, and corticosteroid injections for symptomatic knee osteoarthritis.

Cytokine profile of bronchoalveolar lavage in patients with and without checkpoint inhibitor pneumonitis.

Background: Checkpoint inhibitor pneumonitis (CIP) that develops following immune checkpoint inhibitor (ICI) treatment can be difficult to distinguish from other common etiologies of lung inflammation in cancer patients. Here, we evaluate the bronchoalveolar lavage fluid (BAL) for potential biomarkers specific to CIP.

Methods: We conducted a retrospective study of patients who underwent standard of care bronchoscopy to compare the cytokines of interest between patients with and without CIP and with and without immune-mediated pulmonary diseases.

Tissue factor targeted near-infrared photoimmunotherapy: a versatile therapeutic approach for malignancies.

Tissue factor (TF) is a cell surface protein that plays a role in blood clotting but is also commonly expressed in many cancers. Recent research implicated TF in cancer proliferation, metastasis, angiogenesis, and immune escape. Therefore, TF can be considered a viable therapeutic target against cancer.

Computational fluid particle dynamics modeling of tangential flow filtration in perfusion cell culture.

Membrane fouling is a common and complex challenge with cell culture perfusion process in biopharmaceutical manufacturing that can have detrimental effects on the process performance. In this study, we evaluated a method to calculate the hollow fiber membrane resistance at different time points for water and supernatant. In addition, the number of subvisible particles of < 200 nm.

Basic Science and Pathogenesis.

Background: Inclusions of TAR DNA binding protein of 43kDa (TDP-43) constitute the main characteristic pathology in the majority (∼97%) of amyotrophic lateral sclerosis (ALS) cases and approximately 50% of patients with frontotemporal lobar degeneration (FTLD). TDP-43 is a nuclear RNA binding protein; however, in disease, it becomes hyperphosphorylated and/or insoluble, hindering its nuclear function in maintaining RNA homeostasis. Importantly, the incidence of TDP-43 proteinopathy extends to aging brains (LATE) and may be concomitant with Alzheimer's disease (AD) neuropathological changes (LATE/AD) in up to 70% of AD patients.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) identified the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer's disease (AD). ABC proteins transport various molecules across extra and intra-cellular membranes. ABCA7 is part of the ABC1 subfamily and is expressed in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes.

Basic Science and Pathogenesis.

Background: Estrogens, such as 17β-estradiol, are the primary female sex hormones predominantly synthesized by mature ovarian follicular cells. The natural exhaustion of ovarian follicular cells during menopause causes a rapid decline in endogenous estrogen levels. This decline in estrogen levels is associated with an increase in chronic, age-related pathologies, including inflammation in the brain.

Basic Science and Pathogenesis.

Background: Hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated on up to 55 epitopes. Emerging studies suggest that phosphorylation of specific epitopes may alter the role of tau. The role of specific pTau species can be explored through protein interaction ("interactome") studies.

Basic Science and Pathogenesis.

Background: Synucleinopathies lack cures. Antibody therapies targeting α-synuclein aim to inhibit aggregation and enhance degradation, but have limited brain entry because of size (150kDa). Smaller single-domain antibodies (sdAbs, 15kDa) have substantially improved brain uptake.

Basic Science and Pathogenesis.

Background: Microglia are the major innate immune cells of the brain and play diverse roles in brain development and homeostasis. In the context of Alzheimer's disease, microglia acquire new phenotypes that can exert protective or pathogenic roles. Single cell and single nuclei RNA sequencing experiments have defined molecular signatures of different disease-associated microglia states associated with protective or pathogenic functions, but the mechanisms driving these transitions are not known.

Basic Science and Pathogenesis.

Motor proteins play a key role in neuronal functions and morphology that are important for learning and memory. We have previously reported that increased expression KIF11/Kinesin-5 overrides Aß-mediated effects on dendritic spine density and long-term potentiation in a mouse model of Alzheimer's disease (AD), effectively maintaining cognitive function in the face of Aß pathology. Here, we evaluated the association of key AD phenotypes with mRNA expression levels of a select set of Dynein motor proteins METHOD: We utilized measurements of gene expression, AD neuropathology burden, and cognition provided by the ROS/MAP study to determine whether an association exists between AD phenotypes and expression of genes for cytoplasmic and axonemal dynein heavy chains.

Basic Science and Pathogenesis.

Background: Several viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method: Whole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer's Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome-wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source.

Basic Science and Pathogenesis.

Background: Asymptomatic Alzheimer's disease (AsymAD) refers to individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology, including beta-amyloid (Aβ) deposits, neuritic plaques and neurofibrillary tangles upon autopsy. Unlike AD cases, AsymAD exhibits low neuroinflammation and fewer soluble pathological tau species at synaptic levels. However, the link between these observations and the ability to counteract AD pathology is not fully understood.

Basic Science and Pathogenesis.

Background: The TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome-wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD-TDP). However, the causal variant that drives the association has thus far remained elusive.

Basic Science and Pathogenesis.

Background: Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of the cell type-specific transcriptional profiles of tissue specimens. In this study, we compared gene expression in multiple brain cell types in brain tissue from Alzheimer disease (AD) cases with no or other co-existing pathologies including Lewy body disease (LBD) and vascular disease (VaD).

Method: We evaluated differential gene expression measured from single nucleus RNA sequencing (snRNAseq) data generated from the hippocampus region tissue donated by 11 BU ADRC participants with neuropathologically confirmed AD with or without a co-existing pathology (AD-only = 3, AD+VaD = 6, AD+LBD = 2).

Basic Science and Pathogenesis.

Background: Excessive daytime sleepiness is a common and early symptom of Alzheimer's disease (AD). The subcortical wake-promoting neurons in the lateral hypothalamic area, tuberomammillary nucleus (TMN), and locus coeruleus synchronize to maintain wakefulness/arousal. Although significant neuronal decline occurs in wake-promoting regions, the TMN histaminergic neurons remain relatively more intact than orexinergic and nor-adrenergic neurons.