Social Engagement and Amyloid-β-Related Cognitive Decline in Cognitively Normal Older Adults.

Objective: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-β, the Alzheimer's disease (AD) pathologic marker.

Methods: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC).

The Impact of a Group-Based Multidisciplinary Rehabilitation Program on the Quality of Life in Patients With Fibromyalgia: Results From the QUALIFIBRO Study.

Background And Objective: Patients with fibromyalgia (FM) have a substantially reduced health-related quality of life (HRQoL). Their management should preferably focus on multidisciplinary nonpharmacological interventions. However, the long-term impact of such multicomponent therapies is not fully established.

Alternative oxidase confers nutritional limitation on Drosophila development.

The mitochondrial alternative oxidase, AOX, present in most eukaryotes apart from vertebrates and insects, catalyzes the direct oxidation of ubiquinol by oxygen, by-passing the terminal proton-motive steps of the respiratory chain. Its physiological role is not fully understood, but it is proposed to buffer stresses in the respiratory chain similar to those encountered in mitochondrial diseases in humans. Previously, we found that the ubiquitous expression of AOX from Ciona intestinalis in Drosophila perturbs the development of flies cultured under low-nutrient conditions (media containing only glucose and yeast).

Subthreshold amyloid and its biological and clinical meaning: Long way ahead.

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), β-amyloid (Aβ), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of Aβ deposition below a threshold indicative of Aβ positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of Aβ and its convergence and divergence with in vivo Aβ imaging.

Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study.

Importance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials.

Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.

A longitudinal model for tau aggregation in Alzheimer's disease based on structural connectivity.

Tau tangles are a pathological hallmark of Alzheimer?s disease (AD) with strong correlations existing between tau aggregation and cognitive decline. Studies in mouse models have shown that the characteristic patterns of tau spatial spread associated with AD progression are determined by neural connectivity rather than physical proximity between different brain regions. We present here a network diffusion model for tau aggregation based on longitudinal tau measures from positron emission tomography (PET) and structural connectivity graphs from diffusion tensor imaging (DTI).

Ultrasound-Guided Approaches to Improve Orthotopic Mouse Xenograft Models for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. While curative approaches for early stage HCC exist, effective treatment options for advanced HCC are lacking. Furthermore, there are no efficient chemopreventive strategies to limit HCC development once cirrhosis is established.

Alzheimer's disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms.

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia).

Recurrent mutations in ALK-negative anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK) or ALK, based on the presence or absence of rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, , exclusively in ALK ALCLs.

Lethal Interaction of Nuclear and Mitochondrial Genotypes in .

, like most animal species, displays considerable genetic variation in both nuclear and mitochondrial DNA (mtDNA). Here we tested whether any of four natural mtDNA variants was able to modify the effect of the phenotypically mild, nuclear mutation, affecting mitochondrial protein synthesis. When combined with , the mtDNA from wild strain KSA2 produced pupal lethality, accompanied by the presence of melanotic nodules in L3 larvae.

Premonitory Symptoms in Episodic and Chronic Migraine From a Pediatric Headache Clinic.

Objective: We evaluated the frequency of six commonly reported adult migraine premonitory symptoms in children and adolescents with episodic and chronic migraine and elicited psychological or behavioral comorbidities that may be associated with these symptoms.

Background: Premonitory symptoms are commonly reported in the adult migraine population; however, little information is available for the pediatric population.

Methods: Data were collected on new patients being evaluated in our multidisciplinary pediatric headache clinic over a six-month time interval.

Water use indicators at farm scale - An agro-hydrological software solution.

The challenge to sustainably intensify agricultural production in farming systems in face of the increasing variability in regional water resources requires concerted action from many stakeholders, locally, regionally and globally. Models, such as the AgroHyd Farmmodel presented here, can provide information on how farm management decisions affect local water resources at various scales for use in multiple assessment frameworks. It is a stand-alone web-based software that connects agricultural and water-related systems, including all water flows related to farming systems.

Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.

We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56-89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ, total-tau (t-tau) and phospho-tau (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays.

Mutating for Good: DNA Damage Responses During Somatic Hypermutation.

Somatic hypermutation (SHM) of immunoglobulin () genes plays a key role in antibody mediated immunity. SHM in B cells provides the molecular basis for affinity maturation of antibodies. In this way SHM is key in optimizing antibody dependent immune responses.

Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred.

The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset.

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults.

Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.

AKT inhibition impairs PCNA ubiquitylation and triggers synthetic lethality in homologous recombination-deficient cells submitted to replication stress.

Translesion DNA synthesis (TLS) and homologous recombination (HR) cooperate during S-phase to safeguard replication forks integrity. Thus, the inhibition of TLS becomes a promising point of therapeutic intervention in HR-deficient cancers, where TLS impairment might trigger synthetic lethality (SL). The main limitation to test this hypothesis is the current lack of selective pharmacological inhibitors of TLS.

Blood-Brain Barrier Leakage and Microvascular Lesions in Cerebral Amyloid Angiopathy.

Background and Purpose- Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions.

RNase H1 promotes replication fork progression through oppositely transcribed regions of mitochondrial DNA.

Mitochondrial DNA (mtDNA) replication uses a simple core machinery similar to those of bacterial viruses and plasmids, but its components are challenging to unravel. Here, we found that, as in mammals, the single gene for RNase H1 () has alternative translational start sites, resulting in two polypeptides, targeted to either mitochondria or the nucleus. RNAi-mediated knockdown did not influence growth or viability of S2 cells, but compromised mtDNA integrity and copy number.

Towards an understanding of C9orf82 protein/CAAP1 function.

C9orf82 protein, or conserved anti-apoptotic protein 1 or caspase activity and apoptosis inhibitor 1 (CAAP1) has been implicated as a negative regulator of the intrinsic apoptosis pathway by modulating caspase expression and activity. In contrast, an independent genome wide screen for factors capable of driving drug resistance to the topoisomerase II (Topo II) poisons doxorubicin and etoposide, implicated a role for the nuclear protein C9orf82 in delaying DSBs repair downstream of Topo II, hereby sensitizing cells to DSB induced apoptosis. To determine its function in a genetically defined setting in vivo and ex vivo, we here employed CRISPR/Cas9 technology in zygotes to generate a C9orf82 knockout mouse model.

Resting-state fMRI in Parkinson's disease patients with cognitive impairment: A meta-analysis.

Background: Cognitive impairment is a common non-motor symptom in Parkinson's disease. So far, the underlying pathophysiology remains unclear. Several alterations in functional network connectivity have been described in Parkinson's disease patients with cognitive impairment which are probably the result of the heterogenous pathophysiology underlying this cognitive decline, including dopaminergic and cholinergic deficits.

STIM1 over-activation generates a multi-systemic phenotype affecting the skeletal muscle, spleen, eye, skin, bones and immune system in mice.

Strict regulation of Ca2+ homeostasis is essential for normal cellular physiology. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling basal Ca2+ levels and intracellular Ca2+ store refilling, and abnormal SOCE severely impacts on human health. Overactive SOCE results in excessive extracellular Ca2+ entry due to dominant STIM1 or ORAI1 mutations and has been associated with tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK).

Regional tau pathology and loneliness in cognitively normal older adults.

Loneliness is a perception of social and emotional isolation that increases in prevalence among older adults during the eighth decade of life. Loneliness has been associated with higher brain amyloid-β deposition, a biologic marker of Alzheimer's disease, in cognitively normal older adults, suggesting a link with preclinical Alzheimer's disease pathophysiology. This study examined whether greater loneliness was associated with tau pathology, the other defining feature of Alzheimer's disease, in 117 cognitively normal older adults.

The impact of amyloid-beta and tau on prospective cognitive decline in older individuals.

Objectives: Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated.

Methods: One hundred thirty-seven older individuals (age = 76.