Search Results (38)

Background: Gorlin–Goltz syndrome (GGS), also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, is a rare genetic disorder caused by mutations in the PTCH1, PTCH2, or SUFU genes, leading to an increased risk of neoplasms. Craniofacial anomalies are among the most common features of GGS. This paper aimed to highlight the similarities and differences in clinical presentation across different ages and to emphasize the importance of including all family members in the diagnostic process. The diagnosis can often be initiated by a dentist through routine radiographic imaging. Case Presentation: We present a 17-year longitudinal follow-up of a male patient with recurrent multiple odontogenic keratocysts and other manifestations consistent with GGS. Nearly 20 years later, the patient’s mother presented with similar clinical features suggestive of GGS. Diagnostic imaging, including contrast-enhanced computed tomography (CT), cone-beam CT, magnetic resonance imaging, and orthopantomography, was performed, and the diagnosis was confirmed through genetic testing. Interdisciplinary management included age-appropriate surgical and dermatological treatments tailored to lesion severity. Conclusions: Given the frequent involvement of the stomatognathic system in GGS, dentists play a critical role in early detection and referral. Comprehensive family-based screening is essential for timely diagnosis, improved monitoring, and effective management of this multisystem disorder. Full article

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway’s genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation between the expression levels of selected genes of this pathway and the progression-free and overall survival of ovarian cancer patients. Using the database Kaplan–Meier plotter, which includes the gene expression and survival data of 1565 ovarian cancer patients, higher expression levels of the genes SHH, PTCH1, PTCH2, and GLI1 displayed better survival correlations, while GLI, GLI3, and SUFU correlated with adverse outcomes. Further dissection revealed a differential impact of the genes in specific clinical-histopathological categories. Notably, higher expression levels of SUFU were associated with a negative impact on ovarian cancer patients under many clinical–histopathological aspects. These results shed new light on the role of these genes in the chemoresponsiveness of ovarian cancer, especially SUFU, which could be considered a novel indicator for poor prognosis in epithelial ovarian cancer. Full article

OnabotulinumtoxinA is an FDA-approved treatment for adults with overactive bladder (OAB) who have an inadequate response to, or are intolerant of, oral pharmacotherapies including anticholinergics or beta-3 agonists. However, procedural practices of onabotulinumtoxinA intradetrusor injection vary among practitioners and can affect patient experience. To address this, a panel of six high-volume intravesical onabotulinumtoxinA providers with 100 years of combined experience convened to discuss the best office practices when treating patients with OAB. These key best practices include counseling patients on available OAB therapies, including onabotulinumtoxinA, at the initial consultation in accordance with established AUA and SUFU guidelines in a way that is easily understood. An office setting is preferred over a hospital or surgery center when performing the procedure. Staff involvement, from scheduling to post-procedure, is essential for establishing the relationships necessary to optimize patient experience and encourage compliance and retreatment. Experts generally recommend using a viscous lidocaine bladder instillation for an anesthetic 15 min prior to the reconstitution of onabotulinumtoxinA with 5 to 10 mL of normal saline. A range of one to 20 injection sites is acceptable, with a smaller number preferred. Starting in the lower bladder, experts recommend using a slower speed of injection to improve distribution and decrease patient discomfort. Subsequent treatments should be regularly scheduled at six-month intervals with the option of re-treating earlier if symptoms return, but no sooner than 12 weeks. For office intravesical onabotulinumtoxinA procedures, optimization of the patient experience by the physician and their staff, starting with the initial visit through the post-treatment follow-up, is key to long-term patient compliance. Full article

Background: Psychosis, particularly schizophrenia (SZ), is influenced by genetic and environmental factors. The neurodevelopmental hypothesis suggests that genetic factors affect neuronal circuit connectivity during perinatal periods, hence causing the onset of the diseases. In this study, we performed a genome-wide association study (GWAS) in a sample of the first episode of psychosis (FEP). Methods: A sample of 147 individuals diagnosed with non-affective psychosis and 102 controls were recruited and assessed. After venous blood and DNA extraction, the samples were genotyped. Genetic data underwent quality controls, genotype imputation, and a case-control genome-wide association study (GWAS). After the GWAS, results were investigated using an in silico functional mapping and annotation approach. Results: Our GWAS showed the association of 27 variants across 13 chromosomes at genome-wide significance (p < 1 × 10⁻⁷) and a total of 1976 candidate variants across 188 genes at suggestive significance (p < 1 × 10⁻⁵), mostly mapping in non-coding or intergenic regions. Gene-based tests reported the association of the SUFU (p = 4.8 × 10⁻⁷) and NCAN (p = 1.6 × 10⁻⁵) genes. Gene-sets enrichment analyses showed associations in the early stages of life, spanning from 12 to 24 post-conception weeks (p < 1.4 × 10⁻³) and in the late prenatal period (p = 1.4 × 10⁻³), in favor of the neurodevelopmental hypothesis. Moreover, several matches with the GWAS Catalog reported associations with strictly related traits, such as SZ, as well as with autism spectrum disorder, which shares some genetic overlap, and risk factors, such as neuroticism and alcohol dependence. Conclusions: The resulting genetic associations and the consequent functional analysis displayed common genetic liability between the non-affective psychosis, related traits, and risk factors. In sum, our investigation provided novel hints supporting the neurodevelopmental hypothesis in SZ and—in general—in non-affective psychoses. Full article

This study investigated the effects of enzyme-assisted low-temperature cold fermentation on sufu’s microbial diversity, biogenic amine (BA) formation, and physicochemical properties. The results showed that the enzyme-assisted fermentations for both room- and low-temperature groups (RTEF30 and LTEF20, respectively) significantly increased total acid (TA), amino nitrogen (NH3-N), and enzyme activity compared to the non-enzyme fermentation at room-temperature post-fermentation (RTNF30). This indicated that enzyme-assisted fermentation effectively overcame challenges associated with low-temperature fermentation of sufu. BA analysis revealed that the LTEF20 group had the highest total BA (3.7 mg/g) and putrescine (1.8 mg/g) levels compared to other groups. Microbial analysis showed that the LTEF20 group exhibited higher microbial diversity compared to the RTEF30 group. They had the highest levels of Enterobacteriaceae (0.4131) and lactic acid bacteria in the early and late phases (0.5556) among the groups. Correlation analysis revealed significant links between sufu’s physicochemical properties and microbial communities. Notably, putrescine positively correlated with Bifidobacterium, while TA negatively correlated with Enterococcus. These findings suggest that microbial activity alterations, caused by low-temperature cold fermentation, influences sufu’s fermentation process and quality, guiding further studies on the regulation of biogenic amine formation. Full article

Sufu is a traditional Chinese condiment with a distinctive flavor. The umami characteristics are primarily attributed to the hydrolysis of proteins, which produces amino acids and biogenic amines (BAs). Excessive levels of BAs can pose health risks, leading to adverse effects, such as headaches, digestive disorders, and abnormal blood pressure. However, the mechanisms leading to the formation of BAs in fermented bean curd remain insufficiently explored. To explore this phenomenon, an analysis was conducted on the texture, physicochemical properties, and BA content dynamic changes of sufu, fermented with Mucor racemosus, at different intervals, by high-performance liquid chromatography-mass spectrometry (HPLC-MS). During the fermentation process, the total biogenic amines exhibited a downward trend, with levels decreasing from 60.66 to 38.19 mg/kg. Spermidine, spermine, and cadaverine were identified as the main biogenic amines produced during the fermentation process. At 0 h and 24 h, spermidine levels significantly decreased (p < 0.05), but no significant differences were observed at 48 h and 72 h. At 96 h, spermidine levels significantly decreased again (p < 0.05). There was a positive relationship between the bioamines and water content and a negative correlation with soluble protein levels. Additionally, low pH inhibits the formation of BAs, while a soft texture was found to increase their production. The results of this study also confirmed the mechanism of BAs formation. These findings offer valuable insights into the safety and quality control of Mouding sufu by clarifying the BA dynamics during pre-fermentation. Full article

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin–proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway. Full article

Purpose: The study aims to examine the possible correlation between genomic alterations and preoperative olfactory function in patients with olfactory groove meningioma (OGM), due to the frequent presence of olfactory impairment. Methods: We utilised next-generation sequencing to analyse samples from 22 individuals with OGM in order to detect driver mutations. Tumour morphology was assessed using preoperative imaging, whereas olfactory function was examined using Sniffin’ Sticks. Results: In a study of 22 OGM patients, mutations were as follows: 10 with SMO/SUFU, 7 with AKT1, and 5 as wild type. Planum sphenoidale hyperostosis (PSH) was present in 75% of patients, showing significant variation by mutation (p = 0.048). Tumour volumes, averaging 25 cm³, significantly differed among groups. PSH negatively impacted olfaction, notably affecting odour threshold, discrimination, identification, and global olfactory performance score (TDI) (p values ranging from <0.001 to 0.003). Perifocal oedema was associated with lower TDI (p = 0.009) and altered threshold scores (p = 0.038). Age over 65 and female gender were linked to lower thresholds and discrimination scores (p = 0.037 and p = 0.019). Conclusion: The study highlights PSH and perifocal oedema’s significant effect on olfactory function in OGM patients but finds no link between olfactory impairment and tumour mutations, possibly due to the small sample size. This suggests that age and gender affect olfactory impairment. Additional research with a larger group of participants is needed to explore the impact of OGM driver mutations on olfactory performance. Full article

Chinese traditional fermented seasonings, essential to the culinary heritage of China, are produced through fermentation, resulting in a diverse range of unique flavors and aromas. The microorganisms involved in fermentation play significant roles in shaping the quality of these traditional fermented seasonings. The production of traditional fermented seasonings is affected by various biological and abiotic factors, presenting challenges concerning product quality and safety. This review investigates the impact of bioaugmentation technology on key Chinese traditional fermented seasonings, such as vinegar, soy sauce, sufu, doubanjiang, dajiang, and douchi. Additionally, the challenges and constraints linked to the implementation of bioaugmentation technology are discussed. The potential of bioaugmentation is highlighted by its ability to shorten the fermentation time, optimize raw material utilization, improve nutritional value, and enhance the quality parameters of these seasonings. This paper demonstrates an interesting convergence of traditional culinary heritage and contemporary technological advancements. Full article

The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex. Full article

Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide. In detail, basal cell carcinoma (BCC) is the most frequent malignancy in the fair-skinned population. The incidence of BCC remains difficult to assess due to the poor registration practice; however, it has been increasing in the last few years. Approximately, 85% of sporadic BCCs carry mutations in Hedgehog pathway genes, especially in PTCH, SUFU and SMO genes, which lead to the aberrant activation of GLI transcriptional factors, typically silent in cells of adult individuals. The management of advanced BCC (aBCC), both metastatic (mBCC) and locally advanced BCC (laBCC), not candidates for surgical excision or radiotherapy, remains challenging. The discovery of mutations in the Hh signaling pathway has paved the way for the development of Hh pathway inhibiting agents, such as vismodegib and sonidegib, which have represented a breakthrough in the aBCC management. However, the use of these agents is limited by the frequent occurrence of adverse events or the development of drug resistance. In this review, we thoroughly describe the current knowledge regarding the available options for the pharmacological management of aBCCs and provide a forward-looking update on novel therapeutic strategies that could enrich the therapeutic armamentarium of BCC in the near future. Full article

Gamma-aminobutyric acid (GABA) is an important non-proteinogenic amino acid and a potent bioactive compound with many anti-hypertensive and anti-depressant activities. The bioconversion of GABA by glutamic acid decarboxylase (GAD) has been eagerly studied. Herein, novel pyridoxal-5-phosphate monohydrates (PLP)-dependent GAD, which is not quite similar to reporting, was cloned from Latilactobacillus curvatus and efficiently expressed in E. coli. The conveniently purified GAD (designated LcGAD10s) appeared as a single protein on SDS-PAGE with a molecular mass of 52.0 kDa. LcGAD10s exhibited a specific activity of 303.7 U/mg after purification by Ni–IDA affinity chromatography, with optimal activity at 55 °C and pH 5. LcGAD10s displayed excellent temperature (50 °C) and pH (4–8) stability which relative activity above 80% and 70%, respectively. The enzymatic activity was, respectively, increased and depressed by 130%, and 24% in the presence of Mn⁺ and Cu²⁺. Enzyme activity over 90% can be achieved by adding at least 25 mM of PLP. LcGAD10s was able to efficiently transform 15 g/L GABA with a single-factor optimized reaction of pH (5), temperature (50 °C), time (2 h), LcGAD10s dosage (0.4 U) and monosodium glutamate level (5 g/L). Additionally, LcGAD10s can be applied to a tofu fermentation system to achieve GABA conversion and achieved 14.9 mg/g of GABA conversion when added at 2 U/mL, which is higher than most of the commercial sufu and previous application reports, increasing its functional substances. Full article

To study the diversity of microbial flora in Hongqu sufu and analyze the characteristics of special flavor compounds, this study took self-made Hongqu sufu as the research object. Dynamic changes in sufu during fermentation were studied. High-throughput sequencing (HTS) was used to analyze changes in the diversity of fungal and bacterial communities during fermentation. The results showed that at the phylum level, the dominant fungal phyla were identified, Mucormyces and Ascomycetes. The dominant bacterial phyla were Proteobacteria and Firmicutes. At the genus level, the dominant fungal genera were identified as Actinomucor, Monascus, and Aspergillus. The dominant bacterial genera were Pseudomonas, Aneurimibacillus, Sphingobacterium, and Bacillus. Headspace solid-phase microextraction gas chromatography–mass spectrometry (HS-SPME-GC-MS) combined with technology that can dynamically change flavor compounds was explored to investigate the correlation between microbiota and flavor compounds. In different stages of fermentation, 75 main volatile organic compounds were identified, including seven alcohols, four acids, 16 alkanes, 14 olefins, seven kinds of aldehydes, two kinds of ketones, 10 kinds of esters, one kind of phenol, one kind of sulfur-containing compound, one benzene, and 12 other compounds. The correlation analysis between flora and flavor compounds showed that the fungi genera Alternaria and Pichia were significantly correlated with most flavor compounds. Bacteria genera including Weissella, Hafnia-Obesumbacterium, and Leuconostoc had a strong positive correlation with ethyl oleate. Full article

Gray sufu, a traditional fermented food derived from soybeans, undergoes a complex fermentation process. This study aimed to investigate the dynamics of the microbial community during sufu fermentation and its relationship with key quality characteristics. Through systematic sampling of sufu at different phases of fermentation, 143 bacterial genera and 84 fungal genera involved in the process were identified. Among these, Chishuiella, Enterococcus, Lactococcus, and Weissella emerged as the predominant bacterial communities. After seven days of ripening fermentation, Trichosporon supplanted Diutina as the predominant fungus, accounting for more than 84% of all fungi. Using redundancy analysis, significant correlations between microbiota and physicochemical properties were uncovered. Chishuiella and Empedobacter displayed positive relationships with pH, soluble protein, and amino nitrogen content. In addition, five biogenic amines were detected, and it was determined that tyramine accounted for more than 75% of the total biogenic amines in the final gray sufu products. Spearman correlation analysis revealed significant positive relationships between Lactococcus, Enterococcus, Tetragenococcus, Halanaerobium, and Trichosporon and the five biogenic amines examined. These findings shed light on the complex interactions between microorganisms and biogenic amines during the fermentation of gray sufu, thereby facilitating the development of microbial regulation strategies for better quality control. Full article

Transforming growth factor beta (TGF-β) is a key factor mediating the intercellular crosstalk between the hematopoietic stem cells and their microenvironment. Here, we investigated the skeletal phenotype of transgenic mice expressing constitutively active TGF-β receptor type I under the control of Mx1-Cre (Mx1;TβRI^CA mice). μCT analysis showed decreased cortical thickness, and cancellous bone volume in both femurs and mandibles. Histomorphometric analysis confirmed a decrease in cancellous bone volume due to increased osteoclast number and decreased osteoblast number. Primary osteoblasts showed decreased ALP and mineralization. Constitutive TβRI activation increased osteoclast differentiation. qPCR analysis showed that Tnfsf11/Tnfrsf11b ratio, Ctsk, Sufu, and Csf1 were increased whereas Runx2, Ptch1, and Ptch2 were decreased in Mx1;TβRI^CA femurs. Interestingly, Gli1, Wnt3a, Sp7, Alpl, Ptch1, Ptch2, and Shh mRNA expression were reduced whereas Tnfsf11/Tnfrsf11b ratio was increased in Mx1;TβRI^CA mandibles. Similarly, osteoclast-related genes were increased in Mx1;TβRI^CA osteoclasts whereas osteoblast-related genes were reduced in Mx1;TβRI^CA osteoblasts. Western blot analysis indicated that SMAD2 and SMAD3 phosphorylation was increased in Mx1;TβRI^CA osteoblasts, and SMAD3 phosphorylation was increased in Mx1;TβRI^CA osteoclasts. CTSK was increased while RUNX2 and PTCH1 was decreased in Mx1;TβRI^CA mice. Microindentation analysis indicated decreased hardness in Mx1;TβRI^CA mice. Our study indicated that Mx1;TβRI^CA mice were osteopenic by increasing osteoclast number and decreasing osteoblast number, possibly by suppressing Hedgehog signaling pathways. Full article