The extracellular matrix dictates regional competence for tumour initiation.

The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2-a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma-affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.

Mutant analysis of Kcng4b reveals how the different functional states of the voltage-gated potassium channel regulate ear development.

The voltage gated (Kv) slow-inactivating delayed rectifier channel regulates the development of hollow organs of the zebrafish. The functional channel consists of the tetramer of electrically active Kcnb1 (Kv2.1) subunits and Kcng4b (Kv6.4) modulatory or electrically silent subunits. The two mutations in zebrafish kcng4b gene - kcng4b-C1 and kcng4b-C2 (Gasanov et al., 2021) - have been studied during ear development using electrophysiology, developmental biology and in silico structural modelling. kcng4b-C1 mutation causes a C-terminal truncation characterized by mild Kcng4b loss-of-function (LOF) manifested by failure of kinocilia to extend and formation of ectopic otoliths. In contrast, the kcng4b-C2-/- mutation causes the C-terminal domain to elongate and the ectopic seventh transmembrane (TM) domain to form, converting the intracellular C-terminus to an extracellular one. Kcng4b-C2 acts as a Kcng4b gain-of-function (GOF) allele. Otoliths fail to develop and kinocilia are reduced in kcng4b-C2-/-. These results show that different mutations of the silent subunit Kcng4 can affect the activity of the Kv channel and cause a wide range of developmental defects.

Non-telecentric photoacoustic microscopy for multi-scale imaging.

Optical-resolution photoacoustic microscopy (OR-PAM) excels in precisely imaging a biological tissue based on absorption contrast. However, existing OR-PAMs are confined by fixed compromises between spatial resolution and field of view (FOV), preventing the integration of large FOV and local high-resolution within one system. Here, we present a non-telecentric OR-PAM (nTC-PAM) that empowers efficient adaptation of FOV and spatial resolution to match the multi-scale requirement of diverse biological imaging. Our method allows for a large-scale transformation in FOV and even surpassing the nominal FOV of the objective with minimal marginal degradation of the lateral resolution. We demonstrate the advantage of nTC-PAM through multi-scale imaging of the leaf phantom, mouse ear, and cortex. The results reveal that nTC-PAM can switch the FOV and spatial resolution to meet the requirements of different biological tissues, such as large-scale imaging of the whole cerebral cortex and high-resolution imaging of microvascular structures in local brain regions.

Miniaturized preamplifier integration in ultrasound transducer design for enhanced photoacoustic imaging.

Photoacoustic imaging (PAI) utilizes the photoacoustic effect to record both vascular and functional characteristics of a biological tissue. Photoacoustic signals have typically low amplitude that cannot be read efficiently by data acquisition systems. This necessitates the use of one or more amplifiers. These amplifiers are somewhat bulky (e.g., the ZFL-500LN+, Mini-Circuits, USA, or 351A-3-50-NI, Analog Modules Inc., USA). Here, we describe the fabrication and development process of a transducer with a built-in low-noise preamplifier that is encased within the transducer housing. This new, to the best of our knowledge, design could be advantageous for applications where a compact transducer + preamplifier is required. We demonstrate the performance of this compact detection unit in a laser scanning photoacoustic microscopy system by imaging a rat ear ex vivo and a rat brain vasculature in vivo.

Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

Preparation of Compound Salvia miltiorrhiza-Blumea balsamifera Nanoemulsion Gel and Its Effect on Hypertrophic Scars in the Rabbit Ear Model.

Hypertrophic scars (HS) still remain an urgent challenge in the medical community. Traditional Chinese medicine (TCM) has unique advantages in the treatment of HS. However, due to the natural barrier of the skin, it is difficult for the natural active components of TCM to more effectively penetrate the skin and exert therapeutic effects. Therefore, the development of an efficient drug delivery system to facilitate enhanced transdermal absorption of TCM becomes imperative for its clinical application. In this study, we designed a compound Salvia miltiorrhiza-Blumea balsamifera nanoemulsion gel (CSB-NEG) and investigated its therapeutic effects on rabbit HS models. The prescription of CSB-NEG was optimized by single-factor, pseudoternary phase diagram, and central composite design experiments. The results showed that the average particle size and PDI of the optimized CSB-NE were 46.0 ± 0.2 nm and 0.222 ± 0.004, respectively, and the encapsulation efficiency of total phenolic acid was 93.37 ± 2.56%. CSB-NEG demonstrated excellent stability and skin permeation in vitro and displayed a significantly enhanced ability to inhibit scar formation compared to the CSB physical mixture in vivo. After 3 weeks of CSB-NEG treatment, the scar appeared to be flat, pink, and flexible. Furthermore, this treatment also resulted in a decrease in the levels of the collagen I/III ratio and TGF-ß1 and Smad2 proteins while simultaneously promoting the growth and remodeling of microvessels. These findings suggest that CSB-NEG has the potential to effectively address the barrier properties of the skin and provide therapeutic benefits for HS, offering a new perspective for the prevention and treatment of HS.

Wideband Absorbance Predicts the Severity of Conductive Hearing Loss in Children With Otitis Media With Effusion.

OBJECTIVES: The objectives of the present study were to investigate the relationship between wideband absorbance (WBA) and air-bone gap (ABG) in children with a conductive hearing loss (CHL) due to otitis media with effusion (OME) and determine the accuracy of WBA to predict the magnitude of ABGs. DESIGN: This was a prospective, cross-sectional study involving a control group of 170 healthy ears from 130 children (mean age 7.7 years) and a CHL cohort of 181 ears from 176 children (mean age 5.9 years) with OME. The CHL cohort was divided into three groups: CHL1, CHL2, and CHL3 defined by mean ABG (averaged across 0.5 to 4 kHz) of 16 to 25 dB, 26 to 35 dB, and 36 to 45 dB, respectively. WBA was measured at frequencies from 0.25 to 8 kHz at ambient pressure. RESULTS: WBA was significantly reduced between 0.25 and 5 kHz for all CHL groups. The difference in WBA at 1 to 4 kHz between the control and CHL groups increased with increasing ABG. The predictive accuracy, as indicated by area under the receiver operating characteristic curve (AUROC) of WBA, increased with increasing ABG. The AUROC for WBA at 1.5 kHz was 0.86 for the CHL1, 0.91 for the CHL2, and 0.93 for the CHL3 group. The AUROCs for WBA averaged across 0.5 to 4 kHz were 0.88, 0.93, and 0.94 for the CHL1, CHL2, and CHL3 groups, respectively. Linear regression analyses showed significant negative correlations between WBA 0.5-4 k and ABG 0.5-4 k . The regression model (ABG 0.5-4 k = 31.83 - 24.08 × WBA 0.5-4 k ) showed that WBA 0.5-4 k predicted ABG 0.5-4 k with high accuracy. Comparison of predicted and actual WBA on a different group of subjects revealed that at an individual level, the model predicted ABG between 16 and 35 with greater precision. CONCLUSIONS: There were significant strong correlations between WBA and ABG such that WBA decreased with increasing ABG. WBA demonstrated good discrimination accuracy with AUROC exceeding 0.88 for the 0.5 to 4 kHz and 1 to 4 kHz frequency bands. The WBA test holds promise for determining the severity of CHL in children with OME.

Changes in Listening Effort Through Pupil Response After Atresioplasty in Children With Congenital Aural Atresia.

OBJECTIVES: This study aimed to determine whether the improvement of hearing by surgical treatment alleviates cognitive demands through pupil response in patients with unilateral congenital aural atresia (CAA). DESIGN: A prospective study was performed on patients with unilateral CAA who were scheduled to undergo primary atresioplasty between November 2017 and May 2020. Pure-tone audiometry, auditory digit span test, Korean Speech Perception in Noise test, pupil measurement during speech tests, and questionnaires (Sound-Spatial-Qualities of Hearing Scale; subjective listening effort rating) were performed before and 6 months after surgery. RESULTS: Of 30 consecutive patients who initially enrolled, only 18 patients (12 males and 6 females) were included in the analysis. When the improvement of the air-bone gap and interaural difference of air conduction within 30 dB was defined as a successful hearing outcome, successful hearing improvement was achieved in 50% of the 18 patients. In pupil measurement, the success group had a significantly smaller mean pupil dilation response than the nonsuccess group at 0 and -3 dB signal to noise ratio (SNR) (all p < 0.01). In addition, significant differences were identified between the two groups for peak dilation and peak latency at all noise levels (all p < 0.01). When analyzing the change in pupil response before and after surgery, the difference in relative mean pupil dilation in the success group was significantly greater than that in the nonsuccess group at -3 dB SNR ( p = 0.02). In addition, the success group showed a significantly greater change in peak latency than the nonsuccess group at the -3 dB SNR ( p < 0.01). The difference in peak dilation tended to be greater in the success group than in the nonsuccess group, but the difference was not statistically significant. CONCLUSIONS: Patients with unilateral CAA who achieved surgically improved hearing had a smaller pupil dilation response than those who did not. These results suggest that successful hearing outcomes after surgery in patients with unilateral CAA may reduce the cognitive effort required to understand speech under difficult listening conditions.

A novel heterozygous variant of the SALL1 gene with atypical Townes-Brocks syndrome phenotypes in Chinese family.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.

HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis.

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.

Treatment of external auditory canal stenosis and atresia after transcanal endoscopic ear surgery.

PURPOSE: To discuss the treatment of external auditory canal stenosis or atresia occurring as a complication of transcanal endoscopic ear surgery. MATERIALS AND METHODS: We retrospectively analyzed the medical records of 11 patients who developed external auditory canal stenosis or atresia after undergoing transcanal endoscopic ear surgery. The 10 patients with stenosis were treated with external auditory canal expansion via drainage tube insertion; 2 of these patients further received local injections of triamcinolone acetonide. One patient with atresia was treated with meatoplasty surgery followed by tube insertion and triamcinolone acetonide injection. RESULTS: The stenosis/atresia improved in all patients, and the external auditory canal was unobstructed without restenosis. CONCLUSIONS: Stenosis/atresia of the external auditory canal after transcanal endoscopic ear surgery should be treated with dilation therapy/meatoplasty in a timely manner to prevent progressive hyperplasia of the scar and regain a normal-sized ear canal.

Hearing rehabilitation in children with malformed ears: The endoscopic-assisted approach for cochlear implantation.

BACKGROUND: Cochlear implantation (CI) in children with malformed ears can be challenging through the standard surgical technique. Several alternative approaches have been described. The endoscopic-assisted approach can be chosen as an effective and safe surgical technique, overcoming the drawbacks of the traditional approach. MATERIAL: We further describe a combined technique based on a limited mastoidectomy with no posterior tympanotomy and an endoscopic transmeatal approach to the round window (RW): the electrode is driven from the mastoid to the middle ear through the attic. RESULTS: The concomitant endoscopic assistance allows for improved surgical vision, reducing the risk of major complications. The main advantages of this technique are related to better visualization of the RW for safe insertion of the electrode; avoidance of damage to the facial nerve (FN), due to direct visualization, and sparing the posterior tympanotomy; avoidance of subtotal petrosectomy, if not necessary. CONCLUSION: The purpose of this article, supported with a video file, is to describe step by step this endoscopic-assisted procedure in a patient with middle ear malformation.

Efficacy of vibrant sound bridge in congenital aural atresia: an updated systematic review.

PURPOSE: The indications of Vibrant Soundbridge (VSB) have been expanded to include patients with conductive and mixed hearing loss due to congenital aural atresia (CAA). However, the current evidence supporting the auditory outcomes of VSB is based mainly on case reports and retrospective chart reviews. Therefore, the present systematic review aims to summarize and critically appraise the current evidence regarding the safety and effectiveness of VSB in children and adult patients with CAA. METHODS: A systematic literature search retrieved studies that evaluated the outcomes of unilateral or bilateral implantation of VSB in patients with CAA. The bibliographic search was conducted in PubMed, Scopus, EBSCO, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from January 2000 to December 2022. RESULTS: Twenty-seven studies were included in the present systematic review. Overall, the speech perception after VSB was good, with a mean word recognition score (WRS) score ranging from 60 to 96.7%. The mean postoperative speech recognition threshold (SRT) after implantation ranged from 20.8 to 50 dB. The effective gain was reported in 15 studies, ranging from 31.3 to 45.5 dB. In terms of user satisfaction with VSB, the included studies showed significant improvements in the patient-reported outcomes, such as the Speech Spatial and Qualities of Hearing scale and Glasgow Hearing Aid Benefit Profile. The VSB implantation was generally safe with low incidence of postoperative complications. CONCLUSION: VSB provides significant benefits to individuals with hearing loss owing to CAA, with very good subjective outcomes and a low risk of complications.

Long-term results and quality of life after vibrant soundbridge implantation (VSBs) in children and adults with aural atresia.

PURPOSE: The aim of this study was to evaluate the long-term effectiveness and acceptance of the active middle ear implant system Vibrant Soundbridge (VSB®, MED-EL, Austria) in patients with aural atresia or aplasia (children and adults). METHODS: Data from 51 patients (mean age 13.9 ± 11.3 years), 42 (79.2%) children and adolescents, and 11 (20.8%) adults) who received a VSB implant between 2009 and 2019 at the Department of Otolaryngology at LMU Clinic Großhadern, Munich were included in the study. Pure-tone audiometry, speech recognition in a quiet environment and in a noisy environment were performed preoperatively, during the first fitting of the audio processor, after 1-3 years, after 3-5 years, and after 5 years (if possible). The follow-up period ranged from 11 to 157 months with a mean of 58.6 months (4.8 years). Furthermore, the benefit of the VSB was evaluated by self-assessment questionnaires (Speech, Spatial, and Qualities of Hearing Scale, respectively, for parents). RESULTS: Significant improvements were observed in hearing and speech comprehension immediately after the initial fitting of the VSB system (mean hearing gain 38.4 ± 9.4 dB HL) and at follow-up intervals (1-3, 3-5 and after 5 years) for children and adults (p < 0.01). The values remained stable over the long-term, indicating a sustained functional gain from the VSB (mean hearing gain 38.9 ± 9.2 dB HL). The results of the self-assessments affirm the positive influence on hearing and speech comprehension with the VSB. With the VSB, there was an improvement of 41.3 ± 13.7% in the Freiburg monosyllable test. CONCLUSION: These results (a stable hearing gain over the long term, a good tolerance of the implant and an improvement in quality of life) affirm the recommendation for using the active middle ear implant VSB as early as permitted for aural atresia and aplasia patients. This study represents the audiometric results with the (to date) largest collective of aural atresia patients and with a long follow-up period.

Question Mark Ear: An Unusual Anomaly and a Novel Surgical Technique for Reconstruction.

The question mark ear is a rare abnormality characterized by a cleft between the helix and the earlobe, resulting in a protrusion of the upper part of the ear. The severity of this ear malformation can range from a minor notch in the helix to a complete separation of the helix and the earlobe. In this study, we present a case of a patient with a moderately severe right-sided unilateral question mark deformity. To address this issue, we utilized a novel technique that involves a combination of a Y-V flap with double opposing Z-plasty. Our clinical study demonstrates that using this technique for reconstructing the deformity yields excellent results in terms of the helical rim and fold contour, utilizing solely the local tissues.

Brain Wearables: Validation Toolkit for Ear-Level EEG Sensors.

EEG-enabled earbuds represent a promising frontier in brain activity monitoring beyond traditional laboratory testing. Their discrete form factor and proximity to the brain make them the ideal candidate for the first generation of discrete non-invasive brain-computer interfaces (BCIs). However, this new technology will require comprehensive characterization before we see widespread consumer and health-related usage. To address this need, we developed a validation toolkit that aims to facilitate and expand the assessment of ear-EEG devices. The first component of this toolkit is a desktop application ("EaR-P Lab") that controls several EEG validation paradigms. This application uses the Lab Streaming Layer (LSL) protocol, making it compatible with most current EEG systems. The second element of the toolkit introduces an adaptation of the phantom evaluation concept to the domain of ear-EEGs. Specifically, it utilizes 3D scans of the test subjects' ears to simulate typical EEG activity around and inside the ear, allowing for controlled assessment of different ear-EEG form factors and sensor configurations. Each of the EEG paradigms were validated using wet-electrode ear-EEG recordings and benchmarked against scalp-EEG measurements. The ear-EEG phantom was successful in acquiring performance metrics for hardware characterization, revealing differences in performance based on electrode location. This information was leveraged to optimize the electrode reference configuration, resulting in increased auditory steady-state response (ASSR) power. Through this work, an ear-EEG evaluation toolkit is made available with the intention to facilitate the systematic assessment of novel ear-EEG devices from hardware to neural signal acquisition.

Human Activity Recognition in a Free-Living Environment Using an Ear-Worn Motion Sensor.

Human activity recognition (HAR) technology enables continuous behavior monitoring, which is particularly valuable in healthcare. This study investigates the viability of using an ear-worn motion sensor for classifying daily activities, including lying, sitting/standing, walking, ascending stairs, descending stairs, and running. Fifty healthy participants (between 20 and 47 years old) engaged in these activities while under monitoring. Various machine learning algorithms, ranging from interpretable shallow models to state-of-the-art deep learning approaches designed for HAR (i.e., DeepConvLSTM and ConvTransformer), were employed for classification. The results demonstrate the ear sensor's efficacy, with deep learning models achieving a 98% accuracy rate of classification. The obtained classification models are agnostic regarding which ear the sensor is worn and robust against moderate variations in sensor orientation (e.g., due to differences in auricle anatomy), meaning no initial calibration of the sensor orientation is required. The study underscores the ear's efficacy as a suitable site for monitoring human daily activity and suggests its potential for combining HAR with in-ear vital sign monitoring. This approach offers a practical method for comprehensive health monitoring by integrating sensors in a single anatomical location. This integration facilitates individualized health assessments, with potential applications in tele-monitoring, personalized health insights, and optimizing athletic training regimes.

Novel GNAI3 mutation in a Chinese family with auriculocondylar syndrome and treatment of severe dentofacial deformities: a 5-year follow-up case report.

BACKGROUND: Auriculocondylar syndrome (ARCND) is an extremely rare autosomal dominant or recessive condition that typically manifests as question mark ears (QMEs), mandibular condyle hypoplasia, and micrognathia. Severe dental and maxillofacial malformations present considerable challenges in patients' lives and clinical treatment. Currently, only a few ARCND cases have been reported worldwide, but most of them are related to genetic mutations, clinical symptoms, and ear correction; there are few reports concerning the treatment of dentofacial deformities. CASE PRESENTATION: Here, we report a rare case of ARCND in a Chinese family. A novel insertional mutation in the guanine nucleotide-binding protein alpha-inhibiting activity polypeptide 3 (GNAI3) was identified in the patient and their brother using whole-exome sequencing. After a multidisciplinary consultation and examination, sequential orthodontic treatment and craniofacial surgery, including distraction osteogenesis and orthognathic surgery, were performed using three-dimensional (3D) digital technology to treat the patient's dentofacial deformity. A good prognosis was achieved at the 5-year follow-up, and the patient returned to normal life. CONCLUSIONS: ARCND is a monogenic and rare condition that can be diagnosed based on its clinical triad of core features. Molecular diagnosis plays a crucial role in the diagnosis of patients with inconspicuous clinical features. We present a novel insertion variation in GNAI3, which was identified in exon 2 of chromosome 110116384 in a Chinese family. Sequential therapy with preoperative orthodontic treatment combined with distraction osteogenesis and orthognathic surgery guided by 3D digital technology may be a practical and effective method for treating ARCND.

Model systems for regeneration: the spiny mouse, Acomys cahirinus.

The spiny mouse, Acomys spp., is a recently described model organism for regeneration studies. For a mammal, it displays surprising powers of regeneration because it does not fibrose (i.e. scar) in response to tissue injury as most other mammals, including humans, do. In this Primer article, we review these regenerative abilities, highlighting the phylogenetic position of the spiny mouse relative to other rodents. We also briefly describe the Acomys tissues that have been used for regeneration studies and the common features of their regeneration compared with the typical mammalian response. Finally, we discuss the contribution that Acomys has made in understanding the general principles of regeneration and elaborate hypotheses as to why this mammal is successful at regenerating.

Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.