Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs.

Neurogenic microRNAs 9/9 and 124 (miR-9/9-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes.

Maternal investment, body condition and calf growth in humpback whales.

Given recent declines in North Pacific humpback whale (Megaptera novaeangliae) reproductive output and calf survival, there is additional urgency to better understand how mother-calf pairs allocate energy resources across their migratory cycle. Here, unoccupied aerial system (UAS; or drone) photogrammetry was used to quantify the body size and condition (BC) of humpback whales on their Hawai'i (HI) breeding and Southeast Alaska (SEAK) feeding grounds. Between 2018 and 2022, we collected 2410 measurements of 1659 individuals.

Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.

Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD.

Evaluation of an 8-week high school science communication course designed to read, write, and present scientific research.

The development of science writing and presentation skills is necessary for a successful science career. Too often these skills are not included in pre- or postsecondary science, technology, engineering, and mathematics (STEM) education, leading to a disconnect between high schoolers' expectations for college preparedness and the skills needed to succeed in college. The Young Scientist Program Summer Focus recruits high school students from historically marginalized backgrounds to participate in 8-week summer internships at Washington University in St.

Endogenous recapitulation of Alzheimer's disease neuropathology through human 3D direct neuronal reprogramming.

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids.

Pregnancy rate and reproductive hormones in humpback whale blubber: Dominant form of progesterone differs during pregnancy.

To better understand reproductive physiology of humpback whales Megaptera novaeangliae that reside in Hawai'i and Alaska, enzyme immunoassays were validated for both progesterone and testosterone in free-ranging and stranded animals (n = 185 biopsies). Concentrations were analyzed between different depths of large segments of blubber taken from skin to muscle layers of stranded female (n = 2, 1 pregnant, 1 non-pregnant) and male (n = 1) whales. Additionally, progesterone metabolites were identified between pregnant (n = 1) and non-pregnant (n = 3) females using high pressure liquid chromatography (HPLC).

Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy.

Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals.

Assessment of QTc and Risk of Torsades de Pointes in Ventricular Conduction Delay and Pacing: A Review of the Literature and Call to Action.

Background: Assessment of the heart rate-corrected QT-interval on the 12-lead electrocardiogram when prescribing medications known to increase the risk of Torsades de Pointes has become a common part of consultation-liaison psychiatry practice.

Objectives: Highlighted by a patient who experienced psychiatric decompensation due to inaccurate interpretation of QTc prolongation in the setting of a wide QRS complex, we aimed to describe the approach to QTc interpretation in patients with ventricular conduction delay.

Methods: We reviewed the current literature on the approach to assessment of prolonged repolarization in patients with ventricular conduction delay due to bundle branch block (BBB) and ventricular pacing.

Need for Integrated Behavior Health Model in Primary Care.

Children and adolescents with clinically concerning behavioral health conditions face several barriers to accessing specialized mental health care. One proposed solution is to improve and expand integrated care provided in the primary health care provider's office. Several strategies can increase pediatrician comfort and willingness to collaborate in diagnosing and treating behavioral health conditions, and increased utilization of new technologies (such as telehealth) are likely to play an increasingly important role in the process.

Generation of Human Neurons by microRNA-Mediated Direct Conversion of Dermal Fibroblasts.

MicroRNAs (miRNAs), miR-9/9, and miR-124 (miR-9/9-124) display fate-reprogramming activities when ectopically expressed in human fibroblasts by erasing the fibroblast identity and evoking a pan-neuronal state. In contrast to induced pluripotent stem cell-derived neurons, miRNA-induced neurons (miNs) retain the biological age of the starting fibroblasts through direct fate conversion and thus provide a human neuron-based platform to study cellular properties inherent in aged neurons and model adult-onset neurodegenerative disorders using patient-derived cells. Furthermore, expression of neuronal subtype-specific transcription factors in conjunction with miR-9/9-124 guides the miNs to distinct neuronal fates, a feature critical for modeling disorders that affect specific neuronal subtypes.

Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs.

Cell-fate conversion generally requires reprogramming effectors to both introduce fate programs of the target cell type and erase the identity of starting cell population. Here, we reveal insights into the activity of microRNAs miR-9/9 and miR-124 (miR-9/9-124) as reprogramming agents that orchestrate direct conversion of human fibroblasts into motor neurons by first eradicating fibroblast identity and promoting uniform transition to a neuronal state in sequence. We identify KLF-family transcription factors as direct target genes for miR-9/9-124 and show their repression is critical for erasing fibroblast fate.

Corticosterone in central North Pacific male humpback whales (Megaptera novaeangliae): Pairing sighting histories with endocrine markers to assess stress.

Developing a better understanding of the stress response is critical to ensuring the health and sustainability of marine mammal populations. However, accurately measuring and interpreting a stress response in free-ranging, large cetaceans is a nascent field. Here, an enzyme immunoassay for corticosterone was validated for use in biopsy samples from male humpback whales (Megaptera novaeangliae).

Comparison of differential accessibility analysis strategies for ATAC-seq data.

ATAC-seq is widely used to measure chromatin accessibility and identify open chromatin regions (OCRs). OCRs usually indicate active regulatory elements in the genome and are directly associated with the gene regulatory network. The identification of differential accessibility regions (DARs) between different biological conditions is critical in determining the differential activity of regulatory elements.

Testosterone trends within and across seasons in male humpback whales (Megaptera novaeangliae) from Hawaii and Alaska.

Understanding reproductive profiles and timing of reproductive events is essential in the management and conservation of humpback whales (Megaptera novaeangliae). Yet compared to other parameters and life history traits, such as abundance, migratory trends, reproductive rates, behavior and communication, relatively little is known about variations in reproductive physiology, especially in males. Here, an enzyme immunoassay (EIA) for testosterone was validated for use in biopsy samples from male humpback whales.

Does obtaining CYP2D6 and CYP2C19 pharmacogenetic testing predict antidepressant response or adverse drug reactions?

Treatment non-response and adverse reactions are common in patients receiving antidepressants. Personalizing psychiatric treatment based on pharmacogenetic testing has been proposed to help clinicians guide antidepressant selection and dosing. This systematic literature review assesses the two most robustly studied drug-metabolizing enzymes, CYP2D6 and CYP2C19, and examines whether obtaining CYP2D6 and CYP2C19 testing can be used to predict antidepressant response or adverse drug reactions in order to improve clinical outcomes.

An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia.

The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL.

Reducing employee injuries through preventing at-risk behaviors.

This article presents the experiences of officials at two medical centers in successfully reducing and preventing employee injuries. Guidance is also provided from psychologists and employee safety experts on ways to approach the problem.

C4B deficiency is not associated with meningitis or bacteremia with encapsulated bacteria.

The two isotypes of the fourth complement component are C4A and C4B. C4B forms ester bonds more efficiently than C4A and so, in theory, is more likely than C4A to bind to polysaccharide capsules of encapsulated bacteria. Two studies have reported homozygous C4B deficiency in patients with meningitis or bacteremia caused by encapsulated organisms.

Transient lymphoblastosis and thrombocytopenia in Gianotti-Crosti syndrome.

Gianotti-Crosti Syndrome, or papular acrodermatitis of childhood, represents a characteristic rash that is irregularly associated with hepatitis B infection. The authors report papular acrodermatitis in a 10-month-old child with leukopenia, thrombocytopenia, circulating lymphoblasts, and acute anicteric hepatitis B. Physical examination revealed a densely distributed papular rash on the patient's extremities and face and neck, but not on his trunk, buttocks, palms, or soles.