Search Results (27)

Synbiotics can be used to reduce intestinal inflammation and mitigate dysbiosis in dogs with chronic inflammatory enteropathy (CIE). Prior research has not assessed the colonic mucosal ultrastructure of dogs with active CIE treated with synbiotics, nor has it determined a possible association between morphologic injury and signaling pathways. Twenty client-owned dogs diagnosed with CIE were randomized to receive either a hydrolyzed diet (placebo; PL) or a hydrolyzed diet supplemented with synbiotic-IgY (SYN) for 6 weeks. Endoscopic biopsies of the colon were obtained for histopathologic, ultrastructural, and molecular analyses and were compared before and after treatment. Using transmission electron microscopy (TEM), an analysis of the ultrastructural alterations in microvilli length (MVL), mitochondria (MITO), and rough endoplasmic reticulum (ER) was compared between treatment groups. To explore potential signaling pathways that might modulate MITO and ER stress, a transcriptomic analysis was also performed. The degree of mucosal ultrastructural pathology differed among individual dogs before and after treatment. Morphologic alterations in enterocytes, MVL, MITO, and ER were detected without significant differences between PL and SYN dogs prior to treatment. Notable changes in ultrastructural alterations were identified post-treatment, with SYN-treated dogs exhibiting significant improvement in MVL, MITO, and ER injury scores compared to PL-treated dogs. Transcriptomic profiling showed many pathways and key genes to be associated with MITO and ER injury. Multiple signaling pathways and their associated genes with protective effects, including fibroblast growth factor 2 (FGF2), fibroblast growth factor 7 (FGF7), fibroblast growth factor 10 (FGF10), synaptic Ras GTPase activating protein 1 (SynGAP1), RAS guanyl releasing protein 2 (RASGRP2), RAS guanyl releasing protein 3 (RASGRP3), thrombospondin 1 (THBS1), colony stimulating factor 1 (CSF1), colony stimulating factor 3 (CSF3), interleukin 21 receptor (IL21R), collagen type VI alpha 6 chain (COL6A6), ectodysplasin A receptor (EDAR), forkhead box P3 (FoxP3), follistatin (FST), gremlin 1 (GREM1), myocyte enhancer factor 2B (MEF2B), neuregulin 1 (NRG1), collagen type I alpha 1 chain (COL1A1), hepatocyte growth factor (HGF), 5-hydroxytryptamine receptor 7 (HTR7), and platelet derived growth factor receptor beta (PDGFR-β), were upregulated with SYN treatment. Differential gene expression was associated with improved MITO and ER ultrastructural integrity and a reduction in oxidative stress. Conversely, other genes, such as protein kinase cAMP-activated catalytic subunit beta (PRKACB), phospholipase A2 group XIIB (PLA2G12B), calmodulin 1 (CALM1), calmodulin 2 (CALM2), and interleukin-18 (IL18), which have harmful effects, were downregulated following SYN treatment. In dogs treated with PL, genes including PRKACB and CALM2 were upregulated, while other genes, such as FGF2, FGF10, SynGAP1, RASGRP2, RASGRP3, and IL21R, were downregulated. Dogs with CIE have colonic ultrastructural pathology at diagnosis, which improves following synbiotic treatment. Ultrastructural improvement is associated with an upregulation of protective genes and a downregulation of harmful genes that mediate their effects through multiple signaling pathways. Full article

Background/Objectives: Oligodontia, the absence of six or more teeth excluding third molars, is a rare genetic condition, unlike hypodontia (missing one or more teeth), which is a relatively common human disease. Methods: To identify the genetic etiology of nonsyndromic oligodontia (NSO) families, we performed mutational analysis and investigated the functional effects of identified EDAR mutations. Whole-exome sequencing was conducted on recruited families with NSO. Bioinformatic analysis identified mutations in oligodontia-causing candidate genes, which were confirmed by Sanger sequencing and segregation within families. The impact of EDAR mutations on the EDA signaling pathway was assessed using luciferase activity analysis. Results: EDAR mutations were identified in three NSO families. A homozygous missense EDAR mutation (NM_022336.4: c.319A>G p.(Met107Val)) was found in the singleton proband of family 1. The proband of family 2 carried compound heterozygous EDAR mutations: a maternal missense mutation (c.319A>G p.(Met107Val)) and a paternal missense variant (c.1270G>A p.(Val424Met)). The proband of family 3 had heterozygous EDAR mutations: a maternal missense mutation (c.389T>A p.(Ile130Asn)) and paternal intronic variants in cis (c.[357-4G>A;440+50C>T]). Luciferase assays confirmed reduced transcriptional activity for all identified missense mutations, while splicing assays revealed altered splicing patterns. Conclusions: In conclusion, recessive EDAR mutations, including novel ones, were identified in NSO families, and their pathological mechanism was explored through transcriptional activity measurements. Full article

Wastewater treatment plant (WWTP) operations manage massive amounts of data that can be gathered with new Industry 4.0 technologies such as the Internet of Things and Big Data. These data are critical to allow the wastewater treatment industry to improve its operation, control, and maintenance. However, the data available need to be improved and enriched, partly due to their high dimensionality and low reliability, and the lack of appropriate data analysis and processing tools for such systems. This paper presents a visual analytics-based platform for WWTP that allows users to identify relationships among data through data inspection. The results show that the tool developed and implemented for a full-scale WWTP allows operators to construct machine learning (ML) models for water quality and other water treatment process variables. Consequently, analyzing and optimizing plant operation scenarios can enhance key variables, including energy, reagent consumption, and water quality. This improvement facilitates the development of a more sustainable WWTP, contributing to a beneficial environmental impact. Domain experts validated the variables influencing the created ML models and proved their appropriateness. Full article

Skin aging is a multifaceted biological phenomenon influenced by a combination of intrinsic or extrinsic factors. There is an increasing interest in anti-aging materials including components that improve skin wrinkles. Despite the availability of several such wrinkle-improving materials, the demand for ingredients with outstanding efficacy is increasing. Therefore, this study aimed to explore the mechanisms of wrinkle-related genes reported in previous genome-wide association studies (GWASs), identify materials that regulate these genes, and develop an effective anti-wrinkle formula containing the active ingredients that regulate the expression of these genes. We selected two candidate genes, EDAR and BNC2, that are reportedly related to periorbital wrinkles. We investigated their functions in the skin through in vitro experiments using human skin cell lines (keratinocytes and fibroblasts). Moreover, we identified ingredients that regulate the expression of these two genes and confirmed their efficacy through in vitro experiments using the skin cell lines. Finally, we developed a formula containing these ingredients and confirmed that it enhanced dermal collagen in the 3D skin and improved fine wrinkles under the eyes more effectively than retinol in humans, when applied for 8 weeks. Our results are significant and relevant, as we have discovered a special formula for wrinkle improvement with reliable efficacy that surpasses the efficacy of retinol and does not cause side-effects such as skin irritation. Full article

Animal-mediated seed dispersal is very important for plant population regeneration and the stability of forest ecosystems. Seed size and cache density are important factors for seed dispersal, but we still know little about seed size selection at different cache densities. Here, we conducted field experiments in a Larix principis-rupprechtii plantation in the Liupan Mountains in Ningxia province to investigate the effects of tag-marked Quercus wutaishanica seeds of different sizes and cache densities on predation and the scatter-hoarding behavior of rodents. The results showed lower proportions of intact in situ (IIS) and eaten in situ (EIS) large seeds than small seeds at all levels of cache density, with the exception of IIS seeds at a 6.25 seed·m⁻² cache density. A higher proportion of small seeds were eaten after removal (EAR), but a higher proportion of large seeds were scatter-hoarded (SH) by rodents at most cache densities. Furthermore, rodents preferentially removed large seeds farther away for eating or scatter-hoarding. The IIS and EIS proportions of both large and small seeds declined, but the proportion of the two types of seeds that were EAR fluctuated, increasing with increasing cache density. Rodents preferred to increase the proportion of scatter-hoarding of large seeds with increasing cache density, whereas the proportion of scatter-hoarding of small seeds was maximized at a cache density of 6.25 seed·m⁻². Both the eaten distance after removal (EDAR) and scatter-hoarded distance (SHD) increased with increasing cache density. These results suggest that large seeds are more likely to be scatter-hoarded and removed to longer distances than small ones. Rodents tended to reduce the seed proportion of EIS seeds and increased the proportion of seeds EAR and SH, and accordingly increased EDAR and SHD with increasing cache density. This study provides some scientific basis for animal-mediated seed dispersal. Full article

Mutations within the ectodysplasin A (EDA) gene have been associated with congenital hypotrichosis and anodontia (HAD/XHED) in humans, mice, dogs and cattle. We identified a three-generation family of Fleckvieh cattle with male calves exhibiting clinical and histopathological signs consistent with an X-linked recessive HAD (XHED). Whole genome and Sanger sequencing of cDNA showed a perfect association of the missense mutation g.85716041G>A (ss2019497443, rs1114816375) within the EDA gene with all three cases following an X-linked recessive inheritance, but normal EDAR and EDARADD. This mutation causes an exchange of glycine (G) with arginine (R) at amino acid position 227 (p.227G>R) in the second collagen triple helix repeat domain of EDA. The EDA variant was associated with a significant reduction and underdevelopment of hair follicles along with a reduced outgrowth of hairs, a complete loss of seromucous nasolabial and mucous tracheal and bronchial glands and a malformation of and reduction in number of teeth. Thermostability of EDA G227R was reduced, consistent with a relatively mild hair and tooth phenotype. However, incisors and canines were more severely affected in one of the calves, which correlated with the presence of a homozygous missense mutation of RNF111 (g.51306765T>G), a putative candidate gene possibly associated with tooth number in EDA-deficient Fleckvieh calves. Full article

This article investigates the influence of digital influencers on healthy food purchase intention within the context of Instagram. The research model is guided by the theory of source credibility and the elaboration likelihood model. A quantitative approach was employed, and data were collected through an online survey from Instagram users in Portugal (n = 221). A set of ten hypotheses was tested using structural equation modeling (SPSS-AMOS). The findings corroborated that purchase intention of healthy foods is positively influenced by digital influencer perceived credibility, involvement with healthy foods, and attitude toward advertising on Instagram. The findings also confirmed that involvement with healthy foods and with Instagram affect advertising avoidance behavior, and that these three constructs affect attitude toward advertising on Instagram. However, the expected relationship between attitude toward advertising and digital influencer credibility was not confirmed. The study contributes to the literature on influencer marketing, specifically in the context of healthy food, and it provides valuable insights for social media marketers and brand managers interested in adopting influencer marketing to leverage their communication effectiveness. Full article

Cashmere goats play a pivotal role in the animal hair industry and are economically valuable. Cashmere is produced through the periodic growth of secondary hair follicles. To improve their yield of cashmere, the regulatory mechanisms of cashmere follicle growth and development need to be analysed. Therefore, in this study, EDAR gene-targeted cashmere goats were used as an animal model to observe the phenotypic characteristics of abnormal hair growth and development at the top of the head. Transcriptomic and proteomic techniques were used to screen for differentially expressed genes and proteins. In total, 732 differentially expressed genes were identified, including 395 upregulated and 337 downregulated genes. In addition, 140 differentially expressed proteins were identified, including 69 upregulated and 71 downregulated proteins. These results provide a research target for elucidating the mechanism through which EDAR regulates hair follicle growth in cashmere goats. It also enriches the available data on the regulatory network involved in hair follicle growth. Full article

Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders characterized by the abnormal development of ectodermal-derived tissues. They include the involvement of the hair, nails, skin, sweat glands, and teeth. Pathogenic variants in EDA1 (Xq12–13.1; OMIM*300451), EDAR (2q11-q13; OMIM*604095), EDARADD (1q42-q43, OMIM*606603), and WNT10A (2q35; OMIM*606268) genes are responsible for most EDs. Bi-allelic pathogenic variants of WNT10A have been associated with autosomal recessive forms of ED, as well as non-syndromic tooth agenesis (NSTA). The potential phenotypic impact of associated modifier mutations in other ectodysplasin pathway genes has also been pointed out. We present on an 11-year-old Chinese boy with oligodontia, with conical-shaped teeth as the main phenotype, and other very mild ED signs. The genetic study identified the pathogenic variants WNT10A (NM_025216.3): c.310C > T; p. (Arg104Cys) and c.742C > T; p. (Arg248Ter) in compound heterozygosis, confirmed by parental segregation. In addition, the patient had the polymorphism EDAR (NM_022336.4): c.1109T > C, p. (Val370Ala) in homozygosis, named EDAR370. A prominent dental phenotype with minor ectodermal symptoms is very suggestive of WNT10A mutations. In this case, the EDAR370A allele might also attenuate the severity of other ED signs. Full article

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls. Full article

We report on a cohort of 204 children referred between January 2017 and January 2022 to the German Center for Ectodermal Dysplasias, Erlangen. The most frequent reasons for referral were tooth malformations and lack of multiple teeth leading to the suspicion of an ectodermal dysplasia. Many patients also suffered from being unable to perspire. Nail abnormalities, in contrast, represented a much rarer finding, albeit the impact on some individuals was large. As ectodermal dysplasias are congenital genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands, we analyzed congenital nail disorders detected in these patients. Dystrophic or otherwise abnormal nails were evident in 17 of 18 subjects with pathogenic WNT10A or GJB6 variants but in none of 161 children with EDA variants underlying X-linked hypohidrotic ectodermal dysplasia. However, 2 of 17 children who carry mutations in EDAR or EDARADD, two other genes involved in the ectodysplasin A signaling pathway, showed nail abnormalities, such as brittle or hypoplastic nails. TP63 variants were regularly associated with nail disorders. In one girl, anonychia congenita caused by a compound heterozygous variant of the R-spondin-4 gene (RSPO4) was diagnosed. Thus, nail dysplasia is rarer among patients with ectodermal dysplasia than commonly thought. Full article

In our study, a set of lambs with coarse wool type all over their bodies were discovered within a full-sib family during an embryo transfer experiment of merino fine wool sheep. The difference between coarse and fine wool traits were studied from the perspective of RNA modification-N6-methyladenosine. A total of 31,153 peaks were collected, including 15,968 peaks in coarse skin samples and 15,185 peaks in fine skin samples. In addition, 7208 genes were differentially m6A methylated, including 4167 upregulated and 3041 downregulated in coarse skin samples. Four key genes (EDAR, FGF5, TCHH, KRT2) were obtained by comprehensive analysis of the MeRIP-seq and RNA sequence, which are closely related to primary wool follicle morphogenesis and development. The PI3K/AKT pathway was enriched through different m6A-related genes. These results provided new insights to understand the role of epigenetics in wool sheep domestication and breeding. Full article

Prdm1 mutant mice are one of the rare mutant strains that do not develop whisker hair follicles while still displaying a pelage. Here, we show that Prdm1 is expressed at the earliest stage of whisker development in clusters of mesenchymal cells before placode formation. Its conditional knockout in the murine soma leads to the loss of expression of Bmp2, Shh, Bmp4, Krt17, Edar, and Gli1, though leaving the β-catenin-driven first dermal signal intact. Furthermore, we show that Prdm1 expressing cells not only act as a signaling center but also as a multipotent progenitor population contributing to the several lineages of the adult whisker. We confirm by genetic ablation experiments that the absence of macro vibrissae reverberates on the organization of nerve wiring in the mystacial pads and leads to the reorganization of the barrel cortex. We demonstrate that Lef1 acts upstream of Prdm1 and identify a primate-specific deletion of a Lef1 enhancer named Leaf. This loss may have been significant in the evolutionary process, leading to the progressive defunctionalization and disappearance of vibrissae in primates. Full article

Non-syndromic tooth agenesis (ns-TA) is one of the most common dental anomalies characterized by the congenital absence of at least one permanent tooth (excluding third molars). Regarding the essential role of genetic factors in ns-TA aetiology, the present study aimed to identify novel pathogenic variants underlying hypodontia and oligodontia. In a group of 65 ns-TA patients and 127 healthy individuals from the genetically homogenous Polish population, the coding sequences of 423 candidate genes were screened using targeted next-generation sequencing. Pathogenic and likely pathogenic variants were identified in 37 (56.92%) patients, including eight nucleotide alternations of genes not previously implicated in ns-TA (CHD7, CREBBP, EVC, LEF1, ROR2, TBX22 and TP63). However, since only single variants were detected, future research is required to confirm and fully understand their role in the aetiology of ns-TA. Additionally, our results support the importance of already known ns-TA candidate genes (AXIN2, EDA, EDAR, IRF6, LAMA3, LRP6, MSX1, PAX9 and WNT10A) and provide additional evidence that ns-TA might be an oligogenic condition involving the cumulative effect of rare variants in two or more distinct genes. Full article

Pathogenic variants of the gene Eda cause X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by structural abnormalities or lack of ectodermal appendages. Signs of dysplasia are not restricted to derivatives of the ectodermal layer, but mesodermal abnormalities, such as craniofacial dysmorphism, are also frequently observed, suggesting close reciprocal interactions between the ectoderm and mesoderm; however, a causal link has remained unsubstantiated. We investigated the functional impact of defective ectodysplasin A1 (Eda1) signaling on postnatal bone homeostasis in Eda1-deficient Tabby mice. Interestingly, Eda1 was detected in wild-type mouse calvariae throughout postnatal lifetime. In calvariae, bone-lining Osterix (Osx)+ osteoblasts stained positive for Eda1, and osteoclasts were revealed as Eda receptor (Edar)-positive. Moreover, adult Eda1-deficient calvarial bone showed osteopetrosis-like changes with significantly diminished marrow space, which was maintained during adulthood. Concomitantly with osteopetrosis-like changes, Tabby calvarial bone and Tabby bone marrow-derived osteoclasts had far less osteoclastic activity-associated co-enzymes including cathepsin K, Mmp9, Trap, and Tcirg1 (V-type proton ATPase a3 subunit) compared with wild-type calvariae in vivo or osteoclasts in vitro, indicating that Eda1 deficiency may affect the activity of osteoclasts. Finally, we confirmed that nuclear Nfatc1-positive osteoclasts were strongly diminished during mature osteoclastic differentiation under M-CSF and RANKL in the Tabby model, while Fc-EDA treatment of Tabby-derived osteoclasts significantly increased nuclear translocation of Nfatc1. Furthermore, we identified enhanced Nfatc1 and NF-κB transcriptional activity following Fc-EDA treatment in vitro using luciferase assays. Overall, the results indicate that diminished expressions of osteoclastic activity-associated co-enzymes may lead to disturbed bone homeostasis in Tabby calvariae postnatally. Full article