Unraveling Alpha-Gal Syndrome: A Case Study of a Rare Meat Allergy.

Allergies are a very common pathology and their manifestations consist of a spectrum of presentations, ranging from minimal discomfort like a runny nose to lethal reactions like anaphylaxis and death. Meat allergy is not a very common form of allergy, even though there is a relatively high level of meat consumption. One of the rare forms of non-primate mammalian meat allergy is alpha-gal syndrome (AGS).

Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease.

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al.

Asbestos Exposure and Development of Pulmonary Pleomorphic Carcinoma in a Non-smoker: A Rare Non-small Cell Lung Cancer.

Pulmonary pleomorphic carcinoma (PPC) is a subtype of non-small cell lung cancer that is extremely rare and carries a poor prognosis due to its inadequate response to treatment. Patients that present with PPC often exhibit similar symptoms of other malignancies of the lung, making it hard for clinicians to distinguish between each type. However, cytology and gene mutation testing are two approaches that can aid physicians in an accurate and definitive diagnosis.

Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Glia for the Elucidation of Pathogenic Mechanisms in Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder and a mechanistically complex disease. For the last decade, human models of AD using induced pluripotent stem cells (iPSCs) have emerged as a powerful way to understand disease pathogenesis in relevant human cell types. In this review, we summarize the state of the field and how this technology can apply to studies of both familial and sporadic studies of AD.

Brain organoids, consciousness, ethics and moral status.

Advances in the field of human stem cells are often a source of public and ethical controversy. Researchers must frequently balance diverse societal perspectives on questions of morality with the pursuit of medical therapeutics and innovation. Recent developments in brain organoids make this challenge even more acute.

Amyloidogenic Processing of Amyloid Precursor Protein Drives Stretch-Induced Disruption of Axonal Transport in hiPSC-Derived Neurons.

Traumatic brain injury (TBI) results in disrupted brain function following impact from an external force and is a risk factor for sporadic Alzheimer's disease (AD). Although neurologic symptoms triggered by mild traumatic brain injuries (mTBI), the most common form of TBI, typically resolve rapidly, even an isolated mTBI event can increase the risk to develop AD. Aberrant accumulation of amyloid β peptide (Aβ), a cleaved fragment of amyloid precursor protein (APP), is a key pathologic outcome designating the progression of AD following mTBI and has also been linked to impaired axonal transport.

Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients.

Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways.

The cellular machinery of post-endocytic APP trafficking in Alzheimer's disease: A future target for therapeutic intervention?

Recent data establish multiple defects in endocytic functions as early events initiating various neurodegenerative disorders, including Alzheimer's disease (AD). The genetic landscape resulting from genome-wide association studies (GWAS) reveals changes in post-endocytic trafficking of amyloid precursor protein (APP) in neurons leading to an increase in amyloidogenic processing, deficits in amyloid beta (Aβ) clearance, increases in intracellular Aβ, and other endosomal pathogenic phenotypes. Multiple genetic factors regulate each segment of endosomal and post-endosomal trafficking.

Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization.

Amyloid beta (Aβ) is a major component of amyloid plaques, which are a key pathological hallmark found in the brains of Alzheimer's disease (AD) patients. We show that statins are effective at reducing Aβ in human neurons from nondemented control subjects, as well as subjects with familial AD and sporadic AD. Aβ is derived from amyloid precursor protein (APP) through sequential proteolytic cleavage by BACE1 and γ-secretase.

Amyloid-β-independent regulators of tau pathology in Alzheimer disease.

The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology.

Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells.

In the mammalian genome, the clustered protocadherin (cPCDH) locus provides a paradigm for stochastic gene expression with the potential to generate a unique cPCDH combination in every neuron. Here we report a chromatin-based mechanism that emerges during the transition from the naive to the primed states of cell pluripotency and reduces, by orders of magnitude, the combinatorial potential in the human cPCDH locus. This mechanism selectively increases the frequency of stochastic selection of a small subset of cPCDH genes after neuronal differentiation in monolayers, 10-month-old cortical organoids and engrafted cells in the spinal cords of rats.

Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons.

Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer's disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons and identify cholesteryl esters (CE), the storage product of excess cholesterol, as upstream regulators of Tau early during AD development. Using isogenic induced pluripotent stem cell (iPSC) lines carrying mutations in the cholesterol-binding domain of APP or APP null alleles, we found that while CE also regulate Aβ secretion, the effects of CE on Tau and Aβ are mediated by independent pathways.

Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid-β clearance in human astrocytes.

Mounting evidence suggests that alterations in cholesterol homeostasis are involved in Alzheimer's disease (AD) pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by proteolytic processing of APP have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for cholesterol biosynthesis and regulation in the brain, remains unclear.

Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein.

Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons.

High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) offers the possibility of studying the molecular mechanisms underlying human diseases in cell types difficult to extract from living patients, such as neurons and cardiomyocytes. To date, studies have been published that use small panels of iPSC-derived cell lines to study monogenic diseases. However, to study complex diseases, where the genetic variation underlying the disorder is unknown, a sizable number of patient-specific iPSC lines and controls need to be generated.

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively.

Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations.

We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor.

Mechanical Ventilation Antioxidant Trial.

Background: Many patients each year require prolonged mechanical ventilation. Inflammatory processes may prevent successful weaning, and evidence indicates that mechanical ventilation induces oxidative stress in the diaphragm, resulting in atrophy and contractile dysfunction of diaphragmatic myofibers. Antioxidant supplementation might mitigate the harmful effects of the oxidative stress induced by mechanical ventilation.