Piezo1 expression in mature osteocytes is dispensable for the skeletal response to mechanical loading.

Mechanical loading is essential for bone growth and homeostasis, with osteocytes considered the primary mechanosensors. Deleting the mechanosensitive ion channel Piezo1 from Dmp1-Cre-targeted cells, which include both osteoblasts and osteocytes, resulted in reduced bone mass and impaired skeletal responses to mechanical stimuli. To specifically isolate Piezo1's role in osteocytes, we used Sost-Cre mice to generate mice with Piezo1 deletion exclusively in mature osteocytes.

National Institute of Mental Health Support for Cognitive Treatment Development in Schizophrenia: A Narrative Review.

For several decades the National Institute of Mental Health (NIMH) has supported basic and translational research into cognitive impairment in schizophrenia. This article describes the Institute's ongoing commitment to cognitive assessment and intervention research, as reflected by three signature initiatives-Measurement and Treatment Research to Improve Cognition in Schizophrenia; Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia; and Research Domain Criteria-and related funding announcements that span basic experimental studies, efficacy and comparative effectiveness trials, and implementation research designed to promote cognitive healthcare in real-world treatment settings. We discuss how trends in science and public health policy since the early 2000s have influenced NIMH treatment development activities, resulting in greater attention to (1) inclusive teams that reflect end-user perspectives on the utility of proposed studies; (2) measurement of discrete neurocognitive processes to inform targeted interventions; (3) clinical trials that produce useful information about putative illness mechanisms, promising treatment targets, and downstream clinical effects; and (4) "productive urgency" in pursuing feasible and effective cognitive interventions for psychosis.

A missense mouse model for Smith-McCort dysplasia shows bone resorption defects and altered protein glycosylation.

Smith McCort (SMC) dysplasia is a rare, autosomal recessive, osteochondrodysplasia that can be caused by pathogenic variants in either or genes. These genes codes for proteins that are located at the Golgi apparatus and have a role in intracellular vesicle trafficking. We generated mice that carry a disease-causing variant, c.

Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2.

The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation.

Mechanical Analysis of 3 Posterior Fusion Assemblies Intended to Cross the Cervicothoracic Junction.

Study Design: This was a biomechanical comparison study.

Objective: The objective of this study is to evaluate the mechanical properties of 3 posterior spinal fusion assemblies commonly used to cross the cervicothoracic junction.

Summary Of Background: When posterior cervical fusions are extended into the thoracic spine, an instrumentation transition is often utilized.

Transcriptomic analysis of human skin wound healing and rejuvenation following ablative fractional laser treatment.

Ablative fractional laser treatment is considered the gold standard for skin rejuvenation. In order to understand how fractional laser works to rejuvenate skin, we performed microarray profiling on skin biopsies to identify temporal and dose-response changes in gene expression following fractional laser treatment. The backs of 14 women were treated with ablative fractional laser (Fraxel®) and 4 mm punch biopsies were collected from an untreated site and at the treated sites 1, 3, 7, 14, 21 and 28 days after the single treatment.

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with and characterization of clinical candidate PF-06939999.

Combinations of peptides synergistically activate the regenerative capacity of skin cells in vitro.

Objective: To explore synergistic effects related to skin regeneration, peptides with distinct biological mechanisms of action were evaluated in combination with different skin cell lines in the presence or absence of niacinamide (Nam). Furthermore, the synergistic responses of peptide combinations on global gene expression were compared with the changes that occur with fractional laser resurfacing treatment, a gold standard approach for skin rejuvenation, to further define optimal peptide combinations.

Methods: Microarray profiling was used to characterize the biological responses of peptide combinations (+/- Nam) relative to the individual components in epidermal keratinocyte and dermal fibroblast cell lines.

Augmentation of core decompression with synthetic bone graft does not improve mechanical properties of the proximal femur.

Core decompression is a minimally invasive surgical technique used to treat patients with avascular necrosis of the femoral head. The procedure requires an entry hole in the lateral cortex of the femur which potentially leaves patients susceptible to subtrochanteric fractures. The purpose of this study was to determine if filling the core decompression tract with synthetic bone-graft mechanically strengthens the proximal femur.

Geographies of insecure water access and the housing-water nexus in US cities.

Safe, reliable, and equitable water access is critical to human health and livelihoods. In the United States, an estimated 471,000 households or 1.1 million individuals lack a piped water connection and 73% of households are located in cities, close to networked supply.

The vitamin A ester retinyl propionate has a unique metabolic profile and higher retinoid-related bioactivity over retinol and retinyl palmitate in human skin models.

Human skin is exposed daily to environmental stressors, which cause acute damage and inflammation. Over time, this leads to morphological and visual appearance changes associated with premature ageing. Topical vitamin A derivatives such as retinol (ROL), retinyl palmitate (RPalm) and retinyl propionate (RP) have been used to reverse these changes and improve the appearance of skin.

Enhanced retinoid response by a combination of the vitamin A ester retinyl propionate with niacinamide and a flavonoid containing Ceratonia siliqua extract in retinoid responsive in vitro models.

Objectives: Retinoids have been used for decades as efficacious topical agents to treat photoaged skin. The purpose of our present research is to evaluate whether the activity of the vitamin A ester retinyl propionate (RP) can be enhanced by niacinamide (Nam) and a flavonoid containing Ceratonia siliqua (CS) fruit extract in retinoid responsive in vitro models.

Methods: Retinyl propionate was tested alone and in combination with Nam and CS in an RARα reporter cell line for promoter activation and compared to trans-retinoic acid (tRA) activation.

Metabolic dysfunction in human skin: Restoration of mitochondrial integrity and metabolic output by nicotinamide (niacinamide) in primary dermal fibroblasts from older aged donors.

Alterations in metabolism in skin are accelerated by environmental stressors such as solar radiation, leading to premature aging. The impact of aging on mitochondria is of interest given their critical role for metabolic output and the finding that environmental stressors cause lowered energy output, particularly in fibroblasts where damage accumulates. To better understand these metabolic changes with aging, we performed an in-depth profiling of the expression patterns of dermal genes in face, forearm, and buttock biopsies from females of 20-70 years of age that encode for all subunits comprising complexes I-V of the mitochondrial electron transport chain.

A population-based gene expression signature of molecular clock phase from a single epidermal sample.

Background: For circadian medicine to influence health, such as when to take a drug or undergo a procedure, a biomarker of molecular clock phase is required--one that is easily measured and generalizable across a broad population. It is not clear that any circadian biomarker yet satisfies these criteria.

Methods: We analyzed 24-h molecular rhythms in human dermis and epidermis at three distinct body sites, leveraging both longitudinal (n = 20) and population (n = 154) data.

Niacinamide mitigates SASP-related inflammation induced by environmental stressors in human epidermal keratinocytes and skin.

Objective: To evaluate whether niacinamide (Nam) can mitigate production of inflammatory and senescence-related biomarkers induced by environmental stressors.

Methods: Human epidermal keratinocytes were exposed to UVB, urban dust, diesel exhaust and cigarette smoke extract and treated with Nam or vehicle control. Full thickness 3-D skin organotypic models were exposed to a combination of UVB and PM and treated with Nam or vehicle control.

Optimized low pH formulation of niacinamide enhances induction of autophagy marker ATG5 gene expression and protein levels in human epidermal keratinocytes.

Background: Macromolecules in skin cells are damaged when exposed to environmental stressors, leading to disrupted cellular function and homeostasis. While epidermal turnover can eliminate some of this damage, autophagy can rapidly remove these defective components. Niacinamide (Nam) is known to induce autophagy and optimizing formulations to maximize this response could provide improved homeostasis in stressed skin.

Identification of the novel allele, HLA-DPB1*906:01, in a Caucasian individual by next-generation sequencing.

Novel allele HLA-DPB1*906:01 is possibly a recombinant between DPB1*04:02:01:01 and DPB1*06:01:01:01.

Transcriptomic Analysis Links Eosinophilic Esophagitis and Atopic Dermatitis.

Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking. We sought to investigate the mRNA expression profile overlap between EoE, AA, and AD and to identify the involvement of interleukin 13 (IL-13) in modulating gene expression.

Validation of a custom spine biomechanics simulator: A case for standardization.

Mechanical testing machines used in cadaveric spine biomechanics research vary between labs. It is a necessary first step to understand the capabilities and limitations in any testing machine prior to publishing experimental data. In this study, a reproducible protocol that uses a synthetic spine was developed and used to quantify the inherent rotation error and the ability to apply loads in a single physiologic plane (pure-moment) of a custom spine biomechanics simulator.

A Novel External Fixation Technique for Injuries of the Proximal Interphalangeal Joint.

Digital external fixation is often used for the management of complex injuries involving the proximal interphalangeal joint, including pilon fractures of the middle phalanx base and unstable fracture-dislocations. Several dynamic "homemade" constructs have been described which utilize only K-wires and rubber bands and allow early range of motion within the construct. Although these constructs are inexpensive and their application is fairly straightforward, their designs pose a few potential problems when the construct is stressed during rehabilitation efforts.

Identification of a novel allele, HLA-DPB1*417:01:02, in an African American deceased donor.

HLA-DPB1*417:01:02 differs from HLA-DPB1*417:01:01 by a synonymous nucleotide substitution at codon 43.