Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer's Disease Gene-Dependent Mechanism in Adult Mice.

Background: Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer's disease (AD) and dementia.

Telangiectatic osteosarcoma in four dogs: Cytologic, histopathologic, cytochemical, and immunohistochemical findings.

Telangiectatic osteosarcoma is a rare variant of osteosarcoma histologically and clinically similar to hemangiosarcoma (HSA). This case series describes the imaging and cytologic features of four histologically confirmed telangiectatic osteosarcomas, including the use of cytochemical stains. Alkaline phosphatase (ALP) was applied to Wright-Giemsa-stained cytology slides, and Factor VIII immunohistochemistry was evaluated.

Measurement and assessment of grief in a large international sample.

Background: In 2022, the International Classification of Diseases (ICD-11) and an update of the Diagnostic Statistical Manual of Mental Disorders (DSM 5 TR) were released for implementation worldwide and now include the new Prolonged Grief Disorder (PGD). The newest definition of PGD is based on robust clinical research from the Global North yet until now has not been tested for global applicability.

Methods: The current study assesses the new PGD ICD-11 criteria in a large international sample of 1393 bereaved adults.

Symptom overlap on the srs-2 adult self-report between adults with asd and adults with high anxiety.

Many people diagnosed with autism spectrum disorder (ASD) also experience significant symptoms of anxiety, while many people with anxiety disorders likewise experience social difficulties. These concerns can be difficult to tease apart in general clinical settings. The Social Responsiveness Scale (SRS) is one of the most frequently used measures of dimensional ASD symptoms.

Modeling the cognitive mechanisms linking autism symptoms and anxiety in adults.

Emotional acceptance, alexithymia, and intolerance of uncertainty (IU) contribute to anxiety disorders in neurotypical populations. Their association with anxiety in people diagnosed with autism spectrum disorder (ASD) has not been studied. We aimed to model the contributions of these constructs on the relationship between dimensional measures of autism and anxiety.

Overactive Pattern Separation Memory Associated with Negative Emotionality in Adults Diagnosed with Autism Spectrum Disorder.

Bowler et al. (Journal of Autism and Developmental Disorders 44(9):2355-2362. doi:10.

No dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or G2019S mutant LRRK2 and in human fibroblasts.

Mutations within the LRRK2 gene have been identified in Parkinson's disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2.

Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs.

Background: Peripherally administered oxytocin (OT) has produced antipsychotic drug (APD)-like effects in animal tests that are predictive of APD efficacy. However, these effects have mainly been demonstrated using animal models of schizophrenia-like deficits in prepulse inhibition (PPI) of the startle reflex. Another schizophrenia-relevant abnormality that is the basis of a predictive animal test for APD efficacy is deficient latent inhibition (LI).

Lack of vascular endothelial growth factor receptor-2/Flk1 signaling does not affect substantia nigra development.

Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Lack of hypoxia-inducible factor-1α (HIF1α) impairs midbrain dopaminergic neurogenesis which could be rescued by vascular endothelial growth factor (VEGF) via VEGFR-2 signaling. Here, we conditionally inactivated the VEGFR-2, encoded by the fetal liver kinase 1 (Flk1) gene, in murine NPCs to determine its role in proliferation and survival in vitro as well as survival of dopaminergic neurons in vivo.

Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.

The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from PD patients harboring LRRK2 G2019S and then specifically corrected the mutant LRRK2 allele. We demonstrate that gene correction resulted in phenotypic rescue in differentiated neurons and uncovered expression changes associated with LRRK2 G2019S.

Expression of the stem cell markers nestin and CD133 on circulating melanoma cells.

Different molecular markers have been identified for melanoma-initiating cells including CD133 and nestin. Assuming that metastasis requires a dissemination of tumor-initiating cells, presence of circulating tumor-initiating cells should be associated with worse patient outcome. In this study, 20 ml blood was collected from 32 consecutive patients affected by metastatic melanoma and blood was enriched for circulating melanoma cells (CMCs) by CD45 depletion of the non-melanoma cell fraction.

Genome-wide expression profiling and functional network analysis upon neuroectodermal conversion of human mesenchymal stem cells suggest HIF-1 and miR-124a as important regulators.

Tissue-specific stem cells, such as bone-marrow-derived human mesenchymal stem cells (hMSCs), are thought to be lineage restricted and therefore, could only be differentiated into cell types of the tissue of origin. Several recent studies however have suggested that these types of stem cells might be able to break barriers of germ layer commitment and differentiate in vitro into cells with neuroectodermal properties. We reported earlier about efficient conversion of adult hMSCs into a neural stem cell (NSC)-like population (hmNSCs, for human marrow-derived NSC-like cells) with all major properties of NSCs including functional neuronal differentiation capacity.

Restorative approaches in Parkinson's Disease: which cell type wins the race?

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and is characterized by a continuous and selective loss of dopaminergic neurons in the midbrain with a subsequent reduction of the neurotransmitter dopamine in the striatum. Strategies to overcome limitations of conventional symptomatic treatment have employed cell-based strategies including transplantation of developing neural tissue or neural stem cells (NSCs) into the degenerated host brain. Still there is a tug of war for determining the ideal cell source for transplantation strategies.

Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair.

Mutations in the parkin gene are the most common cause of recessive familial Parkinson disease (PD). Parkin has been initially characterized as an ubiquitin E3 ligase, but the pathological relevance of this activity remains uncertain. Recently, an impressive amount of evidence has accumulated that parkin is involved in the maintenance of mitochondrial function and biogenesis.

Initiation of dopaminergic differentiation of Nurr1(-) mesencephalic precursor cells depends on activation of multiple mitogen-activated protein kinase pathways.

Interleukin-1 (IL-1) plays a pivotal role in terminal dopaminergic differentiation of midbrain-derived neural precursor cells already committed to the mesencephalic dopaminergic phenotype (named mdNPCs for mesencephalic dopaminergic neural precursor cells). Here we characterized the molecular events in long-term expanded rat nuclear receptor related-1(-) (Nurr1(-)) mdNPCs in response to IL-1beta during their terminal dopaminergic specification. We showed that IL-1beta induced a rapid induction of mRNA of dopaminergic key fate-determining transcription factors, such as Nurr1 and Pitx3, and a subsequent increase of tyrosine hydroxylase protein as an early marker for dopaminergic neurons in vitro.

Dopamine D2/D3 receptor stimulation fails to promote dopaminergic neurogenesis of murine and human midbrain-derived neural precursor cells in vitro.

The potential application of neural precursor cells (NPCs) in brain repair of neurodegenerative diseases has placed the factors capable of stimulating neurogenesis under increasing attention. Among these factors are dopamine (DA) D2/D3 receptor agonists, like 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). The purpose of this investigation was to explore proliferating and neurostimulating effects of this drug in murine and human NPCs derived from the fetal midbrain.

Transcription profiling of adult and fetal human neuroprogenitors identifies divergent paths to maintain the neuroprogenitor cell state.

Global gene expression profiling was performed using RNA from adult human hippocampus-derived neuroprogenitor cells (NPCs) and multipotent frontal cortical fetal NPCs compared with adult human mesenchymal stem cells (hMSCs) as a multipotent adult stem cell control, and adult human hippocampal tissue, to define a gene expression pattern that is specific for human NPCs. The results were compared with data from various databases. Hierarchical cluster analysis of all neuroectodermal cell/tissue types revealed a strong relationship of adult hippocampal NPCs with various white matter tissues, whereas fetal NPCs strongly correlate with fetal brain tissue.

Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling.

Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Here, we conditionally inactivated the hypoxia-responsive transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in murine NPCs to determine its role in proliferation, survival, and dopaminergic differentiation in vitro as well as survival of murine dopaminergic neurons in vivo. HIF-1alpha conditional knock-out (HIF-1alpha CKO) mNPCs showed midbrain-specific impairment of survival and proliferation.

Epigenetic conversion of human adult bone mesodermal stromal cells into neuroectodermal cell types for replacement therapy of neurodegenerative disorders.

Tissue-specific stem cells, such as bone marrow-derived mesodermal stromal cells (MSCs), are thought to be lineage restricted and, therefore, could only be differentiated into cell types of the tissue of origin. Several recent studies, however, suggest that these types of stem cells might be able to break barriers of germ layer commitment and differentiate in vitro and/or in vivo into cells of different tissues, such as neuroectodermal cell types. Recently, protocols for high-yield generation of undifferentiated neural stem cell (NSC)-like cells from MSCs of primate and human origin were reported.

Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells.

Neurogenesis in the adult human brain occurs within two principle neurogenic regions, the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. Recent reports demonstrated the isolation of human neuroprogenitor cells (NPCs) from these regions, but due to limited tissue availability the knowledge of their phenotype and differentiation behavior is restricted. Here we characterize the phenotype and differentiation capacity of human adult hippocampal NPCs (hNPCs), derived from patients who underwent epilepsy surgery, on various feeder cells including fetal mixed cortical cultures, mouse embryonic fibroblasts (MEFs) and PA6 stromal cells.

Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons.

Neurogenesis in the adult brain occurs within the two principal neurogenic regions: the hippocampus and the subventricular zone of the lateral ventricles. The occurrence of adult neurogenesis in non-neurogenic regions, including the midbrain, remains controversial, but isolation of neural stem cells (NSCs) from several parts of the adult brain, including the substantia nigra, has been reported. Nevertheless, it is unclear whether adult NSCs do have the capacity to produce functional dopaminergic neurons, the cell type lost in Parkinson's disease.