How childhood social isolation causes social dysfunction: deprivation or mismatch?

There is a major gap in our understanding of how childhood social isolation causes adult social dysfunction. To stimulate future developmental mechanistic studies, we present two conceptual models which highlight that isolation can disrupt developmental events that are concurrent (social deprivation model) or subsequent (developmental mismatch model) to adverse experience.

Transcriptional programs mediating neuronal toxicity and altered glial-neuronal signaling in a knock-in tauopathy model.

Missense mutations in the gene encoding the microtubule-associated protein TAU (current and approved symbol is MAPT) cause autosomal dominant forms of frontotemporal dementia. Multiple models of frontotemporal dementia based on transgenic expression of human in experimental model organisms, including , have been described. These models replicate key features of the human disease but do not faithfully recreate the genetic context of the human disorder.

An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration.

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in with human and Alzheimer's disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics in models of Alzheimer's disease and identified Alzheimer's disease human genetic variants that modify expression in disease-vulnerable neurons.

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor-positive Breast Cancer.

Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive.

Transcriptional programs mediating neuronal toxicity and altered glial-neuronal signaling in a knock-in tauopathy model.

Missense mutations in the gene encoding the microtubule-associated protein tau cause autosomal dominant forms of frontotemporal dementia. Multiple models of frontotemporal dementia based on transgenic expression of human tau in experimental model organisms, including , have been described. These models replicate key features of the human disease, but do not faithfully recreate the genetic context of the human disorder.

Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma.

Unlabelled: Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance of CH in newly diagnosed patients, including transplant ineligible patients, and its effect on clonal evolution during multiple myeloma therapy in the era of novel agents, has not been well studied. Using our new algorithm to differentiate tumor and germline mutations from CH, we detected CH in approximately 10% of 986 patients with multiple myeloma from the Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) cohort (40/529 transplanted and 59/457 non-transplanted patients).

Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging.

Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer's disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recover the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants.

Association of Pork Intake with Cognitive Performance in Older Adults Enrolled in the National Health and Nutrition Examination Survey (NHANES), 2011-2014 Data Cycles.

Background: Pork provides higher levels of several nutrients important for cognitive maintenance in older adults. A pilot clinical study suggests the addition of moderate amounts of pork to a Mediterranean-style diet improves cognition in older adults. There is an absence of observational research that isolates effects of pork from other red meats.

A multicomponent complex intervention for supportive follow-up of persons with chronic heart failure: a randomized controlled pilot study (the UTILE project).

Background: Heart failure (HF) is a progressive disease associated with a high burden of symptoms, high morbidity and mortality, and low quality of life (QoL). This study aimed to evaluate the feasibility and potential outcomes of a novel multicomponent complex intervention, to inform a future full-scale randomized controlled trial (RCT) in Switzerland.

Methods: We conducted a pilot RCT at a secondary care hospital for people with HF hospitalized due to decompensated HF or with a history of HF decompensation over the past 6 months.

Consumption Patterns and the Nutritional Contribution of Total, Processed, Fresh, and Fresh-Lean Pork to the U.S. Diet.

Pork has the potential to provide several macro and micronutrients to the diet, as it is a commonly consumed protein in the United States and across many cultures worldwide. There is an absence of clinical and observational studies that isolate the nutritional contribution of various types of pork intake from that of other red and/or processed meats. The objective of this study was to assess consumption patterns and the nutritional contribution of total, processed, fresh, and fresh-lean pork to the diets of participants aged 2+ years enrolled in the National Health and Nutrition Examination Survey (NHANES) 2007-2018 data cycles.

Association of clonal hematopoiesis with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear.

is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing.

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients.

A prefrontal-paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice.

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food.

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.

The Tennessee Men's Health Report Card: A Model for Men's Health Policy Advocacy and Education.

Tennessee is the only state in the United States that has regularly published a document monitoring men's health and assessing men's health disparities. Vanderbilt University, Vanderbilt University Medical Center, the Tennessee Department of Health, Meharry Medical College, Tennessee Men's Health Network, and health providers and advocates across the state have come together to publish a set of indicators as the Tennessee Men's Health Report Card (TMHRC). This article describes the origins, structure, development, and lessons learned from publishing report cards in 2010, 2012, 2014, and 2017.

A dominant-negative effect drives selection of missense mutations in myeloid malignancies.

, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common missense mutations.

Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation.

Immune evasion is a hallmark of cancer and a central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms of immune escape remain unclear. To identify mechanisms of immune evasion, we performed a genetic analysis of serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year after alloHCT.

Focusing of a Rydberg Positronium Beam with an Ellipsoidal Electrostatic Mirror.

Slow atoms in Rydberg states can exhibit specular reflection from a cylindrical surface upon which an azimuthally periodic potential is imposed. We have constructed a concave mirror of this type, in the shape of a truncated oblate ellipsoid of revolution, which has a focal length of (1.50±0.

What Are Effective Program Characteristics of Self-Management Interventions in Patients With Heart Failure? An Individual Patient Data Meta-analysis.

Background: To identify those characteristics of self-management interventions in patients with heart failure (HF) that are effective in influencing health-related quality of life, mortality, and hospitalizations.

Methods And Results: Randomized trials on self-management interventions conducted between January 1985 and June 2013 were identified and individual patient data were requested for meta-analysis. Generalized mixed effects models and Cox proportional hazard models including frailty terms were used to assess the relation between characteristics of interventions and health-related outcomes.

Do Self-Management Interventions Work in Patients With Heart Failure? An Individual Patient Data Meta-Analysis.

Background: Self-management interventions are widely implemented in the care for patients with heart failure (HF). However, trials show inconsistent results, and whether specific patient groups respond differently is unknown. This individual patient data meta-analysis assessed the effectiveness of self-management interventions in patients with HF and whether subgroups of patients respond differently.

The use of Hardy-Weinberg Equilibrium in clonal plant systems.

Traditionally population genetics precludes the use of the same genetic individual more than once in Hardy-Weinberg (HW) based calculations due to the model's explicit assumptions. However, when applied to clonal plant populations this can be difficult to do, and in some circumstances, it may be ecologically informative to use the ramet as the data unit. In fact, ecologists have varied the definition of the individual from a strict adherence to a single data point per genotype to a more inclusive approach of one data point per ramet.