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Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided. [Display omitted]

The risk of skin injuries in space is increasing with longer space missions and a growing astronaut population. This highlights the importance of understanding the adverse effects of weightlessness on wound healing. The objective of this research was to examine the therapeutic potential of Low-Level Light Therapy (LLLT) on skin healing processes under simulated microgravity (SMG) conditions and uncover the underlying molecular mechanisms, thus providing innovative solutions and a sound theoretical basis for space skin injuries. Hindlimb unloading (HU) mice models were used to simulate weightlessness conditions, with or without a complete management of LLLT for 14 days. A systematic testing consisting of HE, Masson and immunohistochemical staining was performed against the standardized mouse tissue specimens. assessment of cellular biological functions under SMG conditions was carried out in the rotation system of culture (RSOC) using HaCaT and NIH3T3 cell-lines. Under SMG conditions, LLLT significantly reduced skin wound area in HU mice, especially on Days 10 (p < 0.001), accompanied by increased collagen deposition and elevated levels of Ki67 and CD31. Moreover, LLLT showed impressive anti-inflammatory effects represented by the reduced in pro-inflammatory markers including LY6G, F4/80 and CD86, as well as the decreased levels of IL-1β, IL-6 and TNF-α. Conversely, an elevation in the anti-inflammatory marker CD206 was observed. By employing bioinformatics technology, we further found the PI3K/AKT signaling was prominent in the KEGG pathway analysis and CCR2 acted as a hub gene in the interaction network. Therefore, we demonstrated that LLLT could enhance the phosphorylation of PI3K/AKT and reduce CCR2 expression under SMG conditions, while CCR2 knockdown promoted the phosphorylation of PI3K/AKT, suggesting an important role of CCR2/PI3K/AKT signal axis in LLLT-accelerated wound healing under SMG conditions. LLLT induced activation of the PI3K/AKT signaling pathway through suppression of CCR2 expression, which significantly enhanced skin wound healing under SMG conditions.s.

Ciliary dysfunction results in multiorgan developmental diseases, collectively known as ciliopathies. The B9D1-B9D2-MKS1protein complex maintains the gatekeeper function at the ciliary transition zone (TZ). However, the function of B9 proteins and the mechanisms underlying why different variants in the same B9 gene cause different ciliopathies are not fully understood. Here, we investigated the function of B9 proteins and revealed 2 critical functions. First, the B9 complex interacted with and anchored TMEM67 to the TZ membrane. Disruption of the B9-TMEM67 complex reduced posttranslational modifications of axonemal microtubules due to deregulation of tubulin-modifying enzymes within cilia. Second, B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis. In addition, we identified B9D2 variants in a cohort of patients with Joubert syndrome. We found that Joubert syndrome-associated B9D2 variants primarily affected axonemal microtubule modifications without disrupting ciliogenesis, whereas the Meckel syndrome-associated B9D2 variant disrupted both ciliogenesis and axonemal microtubule modifications. Thus, besides its role as a gatekeeper for ciliary membrane proteins, the B9 complex also controls axonemal microtubule posttranslational modifications and early stages of ciliogenesis, providing insights into the distinct pathologies arising from different variants of the same gene.

BackgroundBiallelic pathogenic TULP3 variants have been associated with a novel ciliopathy named hepatorenocardiac degenerative fibrosis, which is characterised by hepatic fibrosis in childhood or early adulthood, fibrocystic kidney disease later in life and hypertrophic cardiomyopathy in the elderly. Its genotype and phenotype spectrum are largely unknown.MethodsPatients presenting with liver diseases between 2015 and 2023 at The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai, and carrying biallelic rare variants of TULP3 were studied. Variants of uncertain significance were evaluated for pathogenicity in vitro.ResultsTwo unrelated children carrying biallelic rare variants in TULP3 were identified. Patient 1 had variants c.666T>G, p. (Tyr222Ter) and c.1291G>C, p. (Gly431Arg). She initially presented with neonatal cholestasis, which rapidly progressed to liver fibrosis, with liver transplantation at 2 years of age. She also had intellectual disability and attention deficit hyperactivity disorder. Patient 2 had variants c.73C>T, p. (Gln25Ter) and c.1211T>G, p. (Met404Arg). He was found to have liver fibrosis, portal hypertension and abnormal cranial imaging at the age of 7.5 years. Both non-sense variants, c.73C>T and c.666T>G, were predicted to result in non-sense-mediated mRNA decay. Missense variant Met404Arg abolished TULP3 expression, while Gly431Arg reduced the localisation of TULP3 in cilia. Both Met404Arg and Gly431Arg impaired ciliogenesis and the trafficking of ARL13B and INPP5E into cilia.ConclusionSevere neonatal cholestasis and/or neurological symptoms may be novel manifestations of disease in patients harbouring compound heterozygous TULP3 variants. Missense variants in TULP3 may impair ciliogenesis or normal cilia function by abolishing the normal expression or localisation of cilia proteins.

Ciliary dysfunction results in multi-organ involved developmental diseases, collectively known as ciliopathies. The B9D1-B9D2-MKS1 protein complex maintains the gatekeeper function at the ciliary transition zone (TZ). However, the function of B9 proteins and the mechanisms underlying why different variants in the same B9 gene cause different ciliopathies are not fully understood. Here, we investigated the function of B9 proteins and revealed two critical functions. First, the B9 complex interacted with and anchored TMEM67 to the TZ membrane. Disruption of the B9-TMEM67 complex reduced posttranslational-modifications of axonemal microtubules due to deregulation of tubulin-modifying enzymes within cilia. Second, B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis. Finally, we identified B9D2 variants in a cohort of patients with Joubert syndrome (JBTS). Consistent with the dual functions, we found that the JBTS-associated B9D2 variants primarily affected axonemal microtubule modifications without disrupting ciliogenesis, whereas the Meckel syndrome (MKS)-associated B9D2 variant disrupted both ciliogenesis and axonemal microtubule modifications. Thus, besides its role as a gatekeeper for ciliary membrane proteins, the B9 complex also controls axonemal microtubule post-translational modifications and early stages of ciliogenesis, providing insights into the distinct pathologies arising from different variants of the same gene.Ciliary dysfunction results in multi-organ involved developmental diseases, collectively known as ciliopathies. The B9D1-B9D2-MKS1 protein complex maintains the gatekeeper function at the ciliary transition zone (TZ). However, the function of B9 proteins and the mechanisms underlying why different variants in the same B9 gene cause different ciliopathies are not fully understood. Here, we investigated the function of B9 proteins and revealed two critical functions. First, the B9 complex interacted with and anchored TMEM67 to the TZ membrane. Disruption of the B9-TMEM67 complex reduced posttranslational-modifications of axonemal microtubules due to deregulation of tubulin-modifying enzymes within cilia. Second, B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis. Finally, we identified B9D2 variants in a cohort of patients with Joubert syndrome (JBTS). Consistent with the dual functions, we found that the JBTS-associated B9D2 variants primarily affected axonemal microtubule modifications without disrupting ciliogenesis, whereas the Meckel syndrome (MKS)-associated B9D2 variant disrupted both ciliogenesis and axonemal microtubule modifications. Thus, besides its role as a gatekeeper for ciliary membrane proteins, the B9 complex also controls axonemal microtubule post-translational modifications and early stages of ciliogenesis, providing insights into the distinct pathologies arising from different variants of the same gene.

The cilium is a slender cellular projection whose membrane transduces signals essential in development and homeostasis. Although assembly of the axonemal core of the organelle is well-studied, the mechanisms that underlie formation of the ∼250 nm diameter ciliary membrane from oppositely curved 50-100 nm diameter pre-ciliary vesicles remain poorly understood. Here we report that during ciliogenesis in the bi-ciliated alga, Chlamydomonas reinhardtii, aminophospholipid flippase 2 (ALA2) is recruited laterally from a reservoir on the plasma membrane onto the nascent ciliary membrane where it transfers conically shaped phosphatidyl ethanolamine (PE) from the outer to the inner leaflet. In cells lacking ALA2, initiation of cilia regeneration after experimentally induced de-ciliation is delayed, PE flipping is impaired, the ciliary membrane becomes distorted, and cilia that do form are shorter than wild type. Our results uncover a membrane topology problem inherent in ciliogenesis and demonstrate that it is resolved by a phospholipid flippase. Membranes of pre-ciliary vesicles reverse curvature to become the ciliary membrane Upon initiation of ciliogenesis, plasma membrane ALA2 transits laterally to cilia The ciliary membranes of ala2 mutants fail to conform to axonemal shape ALA2 flips PE to establish ciliary membrane curvature

Fitouchi et al. illustrate the cognitive and evolutionary foundations of puritanical morality, while leave the emotional foundation unclear. We complement their theory by proposing moral emotions (e.g., guilt and shame) as characteristic emotions underlying puritanical morality. Our proposition is based on the findings that these moral emotions emerge after violations of puritanical norms and promote self-control and cooperation.

Post-surgical treatments of the human throat often require continuous monitoring of diverse vital and muscle activities. However, wireless, continuous monitoring and analysis of these activities directly from the throat skin have not been developed. Here, we report the design and validation of a fully integrated standalone stretchable device platform that provides wireless measurements and machine learning-based analysis of diverse vibrations and muscle electrical activities from the throat. We demonstrate that the modified composite hydrogel with low contact impedance and reduced adhesion provides high-quality long-term monitoring of local muscle electrical signals. We show that the integrated triaxial broad-band accelerometer also measures large body movements and subtle physiological activities/vibrations. We find that the combined data processed by a 2D-like sequential feature extractor with fully connected neurons facilitates the classification of various motion/speech features at a high accuracy of over 90%, which adapts to the data with noise from motion artifacts or the data from new human subjects. The resulting standalone stretchable device with wireless monitoring and machine learning-based processing capabilities paves the way to design and apply wearable skin-interfaced systems for the remote monitoring and treatment evaluation of various diseases. Methods for the wireless, continuous monitoring and analysis of activities directly from the throat skin have not been developed. Here, the authors present a stretchable device platform that provides wireless measurements and machine learning-based analysis of vibrations and muscle electrical activities from the throat.

Atherosclerosis (AS) and arterial infarction currently have a significant impact on human health. Due to their complex pathogenesis and lack of effective treatment approaches, patients worldwide experience high mortality rates. Methyltransferase‐like 3 (METTL3)‐mediated RNA N6‐modification has garnered considerable attention in elucidating the mechanisms underlying the pathogenesis and treatment failure of AS and arterial infarction. However, few reviews have explored the interrelationship between them. Therefore, this review aims to address this literature gap by evaluating all studies reporting on the involvement of METTL3 in AS and arterial infarction, as well as targeting METTL3 for rescuing these diseases. This review suggests that METTL3 serves as a risk factor, diagnostic biomarker and therapeutic target for AS and arterial infarction. Overall, it provides a comprehensive overview of cutting‐edge research on METTL3 in AS and arterial infarction, serving as a convenient reference for researchers in both basic and translational medicine fields.