ARHGAP29 promotes keratinocyte proliferation and migration in vitro and is dispensable for in vivo wound healing.

Background: RhoA GTPases play critical roles in actin cytoskeletal remodeling required for controlling a diverse range of cellular functions including cell proliferation, adhesion, migration and changes in cell shape, all required for cutaneous wound healing. RhoA cycles between an active GTP-bound and an inactive GDP-bound form, a process regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). ARHGAP29 is a GAP expressed in skin keratinocytes and is decreased in the absence of interferon regulator factor 6, a critical regulator of cell proliferation, migration, and wound healing.

Beyond Nyquist: A Comparative Analysis of 3D Deep Learning Models Enhancing MRI Resolution.

High-spatial resolution MRI produces abundant structural information, enabling highly accurate clinical diagnosis and image-guided therapeutics. However, the acquisition of high-spatial resolution MRI data typically can come at the expense of less spatial coverage, lower signal-to-noise ratio (SNR), and longer scan time due to physical, physiological and hardware limitations. In order to overcome these limitations, super-resolution MRI deep-learning-based techniques can be utilised.

Development and Characterization of a Novel Composite Hydrogel Biomaterial for Improved Mucoperiosteal Wound Repair.

Mucoperiosteal wound healing, as it occurs after pediatric cleft palate surgery, can be challenging due to the limitations of current treatments such as tissue flaps secured with sutures and fibrin glue. In this study, we characterized the in vitro performance of a novel composite hydrogel biomaterial designed to be employed as an in situ wound filler and enhance mucoperiosteal wound healing. We evaluated a range of photopolymerizable formulations containing methacrylated gelatin (GelMA), glycol chitosan, and bioglass microparticles.

Fully Automated MRI-based Analysis of the Locus Coeruleus in Aging and Alzheimer's Disease Dementia using ELSI-Net.

Introduction: The Locus Coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer's Disease (AD). Magnetic Resonance Imaging based LC features have shown potential to assess LC integrity in vivo.

Methods: We present a Deep Learning based LC segmentation and feature extraction method: ELSI-Net and apply it to healthy aging and AD dementia datasets.

A novel noncanonical function for IRF6 in the recycling of E-cadherin.

Interferon Regulatory Factor 6 (IRF6) is a transcription factor essential for keratinocyte cell-cell adhesions. Previously, we found that recycling of E-cadherin was defective in the absence of IRF6, yet total E-cadherin levels were not altered, suggesting a previously unknown, nontranscriptional function for IRF6. IRF6 protein contains a DNA binding domain (DBD) and a protein binding domain (PBD).

ARHGAP29 is required for keratinocyte proliferation and migration.

Background: RhoA GTPase plays critical roles in actin cytoskeletal remodeling required for controlling a diverse range of cellular functions including cell proliferation, cell adhesions, migration and changes in cell shape. RhoA cycles between an active GTP-bound and an inactive GDP-bound form, a process that is regulated by guanine nucleotide exchange factors (GEFs), and GTPase-activating proteins (GAPs). ARHGAP29 is a GAP expressed in keratinocytes of the skin and is decreased in the absence of Interferon Regulator Factor 6, a critical regulator of cell proliferation and migration.

StRegA: Unsupervised anomaly detection in brain MRIs using a compact context-encoding variational autoencoder.

Expert interpretation of anatomical images of the human brain is the central part of neuroradiology. Several machine learning-based techniques have been proposed to assist in the analysis process. However, the ML models typically need to be trained to perform a specific task, e.

To Stick or Not to Stick: Adhesions in Orofacial Clefts.

Morphogenesis requires a tight coordination between mechanical forces and biochemical signals to inform individual cellular behavior. For these developmental processes to happen correctly the organism requires precise spatial and temporal coordination of the adhesion, migration, growth, differentiation, and apoptosis of cells originating from the three key embryonic layers, namely the ectoderm, mesoderm, and endoderm. The cytoskeleton and its remodeling are essential to organize and amplify many of the signaling pathways required for proper morphogenesis.

Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson's disease using neuromelanin-sensitive MRI.

Purpose: Development and performance measurement of a fully automated pipeline that localizes and segments the locus coeruleus in so-called neuromelanin-sensitive magnetic resonance imaging data for the derivation of quantitative biomarkers of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Methods: We propose a pipeline composed of several 3D-Unet-based convolutional neural networks for iterative multi-scale localization and multi-rater segmentation and non-deep learning-based components for automated biomarker extraction. We trained on the healthy aging cohort and did not carry out any adaption or fine-tuning prior to the application to Parkinson's disease subjects.

IRF6 Regulates the Delivery of E-Cadherin to the Plasma Membrane.

IRF6 is a transcription factor that is required for craniofacial development and epidermal morphogenesis. Specifically, Irf6-deficient mice lack the terminally differentiated epidermal layers, leading to an absence of barrier function. This phenotype also includes intraoral adhesions due to the absence of the oral periderm, leading to the mislocalization of E-cadherin and other cell‒cell adhesion proteins of the oral epithelium.

The Mafb cleft-associated variant H131Q is not required for palatogenesis in the mouse.

Background: Orofacial clefts (OFCs) are common birth defects with complex etiology. Genome wide association studies for OFC have identified SNPs in and near MAFB. MAFB is a transcription factor critical for structural development of digits, kidneys, skin, and brain.

Murine Excisional Wound Healing Model and Histological Morphometric Wound Analysis.

The murine excisional wound model has been used extensively to study each of the sequentially overlapping phases of wound healing: inflammation, proliferation and remodeling. Murine wounds have a histologically well-defined and easily recognizable wound bed over which these different phases of the healing process are measurable. Within the field, it is common to use an arbitrarily defined "middle" of the wound for histological analyses.

Non-random distribution of deleterious mutations in the DNA and protein-binding domains of IRF6 are associated with Van Der Woude syndrome.

Background: The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases.

Interferon regulatory factor 6 is required for proper wound healing in vivo.

Background: Van der Woude syndrome (VWS) is the most common form of syndromic orofacial cleft caused predominantly by mutations in Interferon Regulatory Factor 6 (IRF6). We previously reported that individuals with VWS have increased risk of wound healing complications following cleft repair compared with individuals with nonsyndromic orofacial clefts (nonsyndromic cleft lip and palate-NSCLP). In vitro, absence of IRF6 leads to impaired keratinocyte migration and embryonic wound healing.

A Case Study of Malrotated Kidneys with Asymmetric Multiple Renal Arteries, Variant Venous Drainage, and Unilateral Ureteral Duplication.

Variations in the arterial, venous, and ureteral patterning of the right (r) and left (l) kidneys are common; however, concomitant involvement with all three systems is rare. Specimens that demonstrate anatomic variation across multiple systems provide an opportunity to illustrate links between anatomic concepts, embryologic development, clinical practice, and education. During anatomic study of the abdominal cavity, a total of five major arteries (3l and 2r) emerged from the aortic and common iliac axes in a cadaveric donor.

Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate.

In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome.

ARHGAP29 Mutation Is Associated with Abnormal Oral Epithelial Adhesions.

Nonsyndromic cleft lip and/or palate (NSCL/P) is a prevalent birth defect of complex etiology. Previous studies identified mutations in ARHGAP29 associated with an increased risk for NSCL/P. To investigate the effects of ARHGAP29 in vivo, we generated a novel murine allele by inserting a point mutation identified in a patient with NSCL/P.

Correction: Interferon Regulatory Factor 6 Has a Protective Role in the Host Response to Endotoxic Shock.

[This corrects the article DOI: 10.1371/journal.pone.

Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate.

Background: Recent advances in genomics methodologies, in particular the availability of next-generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only.

Methods: The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions.

Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome.

Objective: Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits.

Interferon Regulatory Factor 6 Has a Protective Role in the Host Response to Endotoxic Shock.

Interferon Regulatory Factor (IRF) 6, a member of the IRF family, is essential for epidermal and orofacial embryonic development. Irf6 is strongly expressed in keratinocytes, in which it regulates epidermal proliferation, differentiation, and migration. A recent role for Irf6 in Toll-like receptor 2-dependent chemokine gene expression was also reported in an epithelial cell line.

Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate.

Non-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome-wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead-like 3) cause Van der Woude syndrome, which includes CL/P.

Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders.

The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively.