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Background and aimsJoubert syndrome (JBTS, OMIM # 213300) is a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosing JBTS. It is a clinically and genetically heterogeneous disorder involving mutations in more than 40 ciliopathy-related genes. However, long-term follow-up data are scarce, and further research is needed to determine the abundant phenotypes and genetics of this disorder. The study aimed to summarize clinical manifestations, particular appearance on cranial imaging, genetic data, and prognostic features of patients with JBTS.MethodsA retrospective case review of 36 cases of JBTS from May 1986 to December 2021 was performed. Clinical data of JBTS patients with development retardation and molar tooth sign on cranial imaging as the main features were analyzed. Genetic testing was performed according to consent obtained from patients and their families. The Gesell Developmental Scale was used to evaluate the intelligence level before and after treatment. The children were divided into a purely neurological JBTS (pure JBTS) group and JBTS with multi-organ system involvement group and then followed up every 3–6 months.ResultsWe enrolled 18 males and 18 females. Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness. There was one case co-morbid with Lesch-Nyhan syndrome. Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment. JBTS could also involve the skin. Thirty-one cases (86.11%) showed a typical molar tooth sign, and five cases showed a bat wing sign on cranial imaging. Abnormal video electroencephalogram (VEEG) result was obtained in 7.69% of cases. We found six JBTS-related novel gene loci variants: CPLANE1: c.4189 + 1G > A, c.3101T > C(p.Ile1034Thr), c.3733T > C (p.Cys1245Arg), c.4080G > A(p.Lys1360=); RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys). The CHD7 gene may be potentially related to the occurrence of JBTS. Analysis showed that the prognosis of pure JBTS was better than that of JBTS with neurological and non-neurological involvement after the formal rehabilitation treatment (P

Branched-chain amino acids (BCAAs; a mixture of leucine, valine and isoleucine) have important regulatory effects on glucose and lipid metabolism, protein synthesis and longevity. Many studies have reported that circulating BCAA levels or dietary intake of BCAAs is associated with longevity, sarcopenia, obesity, and diabetes. Among them, the influence of BCAAs on aging and insulin resistance often present different benefits or harmful effects in the elderly and in animals. Considering the nonobvious correlation between circulating BCAA levels and BCAA uptake, as well as the influence of diseases, diet and aging on the body, some of the contradictory conclusions have been drawn. The regulatory mechanism of the remaining contradictory role may be related to endogenous branched-chain amino acid levels, branched-chain amino acid metabolism and mTOR-related autophagy. Furthermore, the recent discovery that insulin resistance may be independent of longevity has expanded the research thinking related to the regulatory mechanism among the three. However, the negative effects of BCAAs on longevity and insulin resistance were mostly observed in high-fat diet-fed subjects or obese individuals, while the effects in other diseases still need to be studied further. In conclusion, there is still no definite conclusion on the specific conditions under which BCAAs and insulin resistance extend life, shorten life, or do not change lifespan, and there is still no credible and comprehensive explanation for the different effects of BCAAs and insulin resistance on lifespan.

Bluetongue virus (BTV), a major threat to livestock, is a multilayered, nonturreted member of the Reoviridae, a family of segmented dsRNA viruses characterized by endogenous RNA transcription through an RNA-dependent RNA polymerase (RdRp). To date, the structure of BTV RdRp has been unknown, limiting our mechanistic understanding of BTV transcription and hindering rational drug design effort targeting this essential enzyme. Here, we report the in situ structures of BTV RdRp VP1 in both the triple-layered virion and double-layered core, as determined by cryo-electron microscopy (cryoEM) and subparticle reconstruction. BTV RdRp has 2 unique motifs not found in other viral RdRps: a fingernail, attached to the conserved fingers subdomain, and a bundle of 3 helices: 1 from the palm subdomain and 2 from the N-terminal domain. BTV RdRp VP1 is anchored to the inner surface of the capsid shell via 5 asymmetrically arranged N termini of the inner capsid shell protein VP3A around the 5-fold axis. The structural changes of RdRp VP1 and associated capsid shell proteins between BTV virions and cores suggest that the detachment of the outer capsid proteins VP2 and VP5 during viral entry induces both global movements of the inner capsid shell and local conformational changes of the N-terminal latch helix (residues 34 to 51) of 1 inner capsid shell protein VP3A, priming RdRp VP1 within the capsid for transcription. Understanding this mechanism in BTV also provides general insights into RdRp activation and regulation during viral entry of other multilayered, nonturreted dsRNA viruses.

Due to their extraordinary properties, particularly the presence of an inherent electric field that effectively suppresses the recombination of photogenerated carriers, Janus two-dimensional (2D) materials exhibit strong light absorption and high solar-to-hydrogen conversion efficiency, making them promising candidates for photocatalytic water splitting applications. In this study, we conducted first-principles calculations to investigate the layers XWZAZ′ (X = S, Se, Te; A = Si, Ge; Z, Z′ = N, P, As; Z ≠ Z′). Out of 36 possible structures, 25 were found to be stable in terms of their dynamic, thermal, and mechanical properties. Among these 25 stable structures, 22 exhibit semiconductor behavior. Notably, 9 of these semiconductor structures demonstrate excellent photocatalytic and light absorption properties. These 9 photocatalysts possess remarkable light absorption rates (∼23%), high solar-to-hydrogen energy conversion efficiencies (38.447%), ultra-high carrier mobilities (101 596.37 cm2 s−1 V−1), and spontaneous hydrogen evolution reaction (HER) capabilities. Furthermore, all 22 semiconductor structures display significant piezoelectric responses both in-plane and out-of-plane, and biaxial strain has a considerable impact on the properties of the 25 stable structures. This study not only provides potential candidate materials for photocatalytic and piezoelectric applications but also offers theoretical guidance for addressing energy crises and environmental pollution challenges. [ABSTRACT FROM AUTHOR]

The hospital admitted a 3‐day‐old female infant presenting with persistent facial cyanosis and hypoxic symptoms, and echocardiography revealed a congenitally unguarded tricuspid valve orifice with an atrial septal defect. After being followed up until the age of one and a half years, the child underwent bidirectional Glenn's surgery and achieved successful survival. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is a growing public health concern affecting millions of people worldwide and causing ocular discomfort and visual disturbance. Developing its therapeutic drugs based on animal models suffer from interspecies differences and poor prediction of human trials. Here, we established long‐term 3D human corneal epithelial organoids, which recapitulated the cell lineages and gene expression signature of the human corneal epithelium. Organoids can be regulated to differentiate ex vivo, but the addition of FGF10 inhibits this process. In the hyperosmolar‐induced DED organoid model, the release of inflammatory factors increased, resulting in damage to the stemness of stem cells and a decrease in functional mucin 1 protein. Furthermore, we found that the organoids could mimic clinical drug treatment responses, suggesting that corneal epithelial organoids are promising candidates for establishing a drug testing platform ex vivo. In summary, we established a functional, long‐term 3D human epithelial organoid that may serve as an ex vivo model for studying the functional regulation and disease modelling. [ABSTRACT FROM AUTHOR]

Summary Class 2 Type V‐A CRISPR‐Cas (Cas12a) nucleases are powerful genome editing tools, particularly effective in A/T‐rich genomic regions, complementing the widely used CRISPR‐Cas9 in plants. To enhance the utility of Cas12a, we investigate three Cas12a orthologs—Mb3Cas12a, PrCas12a, and HkCas12a—in plants. Protospacer adjacent motif (PAM) requirements, editing efficiencies, and editing profiles are compared in rice. Among these orthologs, Mb3Cas12a exhibits high editing efficiency at target sites with a simpler, relaxed TTV PAM which is less restrictive than the canonical TTTV PAM of LbCas12a and AsCas12a. To optimize Mb3Cas12a, we develop an efficient single transcription unit (STU) system by refining the linker between Mb3Cas12a and CRISPR RNA (crRNA), nuclear localization signal (NLS), and direct repeat (DR). This optimized system enables precise genome editing in rice, particularly for fine‐tuning target gene expression by editing promoter regions. Further, we introduced Arginine (R) substitutions at Aspartic acid (D) 172, Asparagine (N) 573, and Lysine (K) 579 of Mb3Cas12a, creating two temperature‐tolerant variants: Mb3Cas12a‐R (D172R) and Mb3Cas12a‐RRR (D172R/N573R/K579R). These variants demonstrate significantly improved editing efficiency at lower temperatures (22 °C and 28 °C) in rice cells, with Mb3Cas12a‐RRR showing the best performance. We extend this approach by developing efficient Mb3Cas12a‐RRR STU systems in maize and tomato, achieving biallelic mutants targeting single or multiple genes in T0 lines cultivated at 28 °C and 25 °C, respectively. This study significantly expands Cas12a's targeting capabilities in plant genome editing, providing valuable tools for future research and practical applications. [ABSTRACT FROM AUTHOR]

Synthetic aperture radar (SAR) simulation is a vital tool for planning SAR missions, interpreting SAR images, and extracting valuable information. SAR imaging is essential for analyzing sea scenes, and the accuracy of sea surface and scattering models is crucial for effective SAR simulations. Traditional methods typically employ empirical formulas to fit sea surface scattering, which are not closely aligned with the principles of electromagnetic scattering. This paper introduces a novel approach by constructing multiple sea surface models based on the Pierson–Moskowitz (P-M) sea spectrum, integrated with the stereo wave observation projection (SWOP) expansion function to thoroughly account for the influence of wave fluctuation characteristics on radar scattering. Utilizing the shooting and bouncing ray-physical optics (SBR-PO) method, which adheres to the principles of electromagnetic scattering, this study not only analyzes sea surface scattering characteristics under various sea conditions but also facilitates the computation of scattering coupling between multiple targets. By constructing detailed scattering distribution data, the method achieves high-precision SAR simulation results. The scattering model developed using the SBR-PO method provides a more nuanced description of sea surface scenes compared to traditional methods, achieving an optimal balance between efficiency and accuracy, thus significantly enhancing sea surface SAR imaging simulations. [ABSTRACT FROM AUTHOR]

Summary: CRISPR‐Cas9 is widely used for genome editing, but its PAM sequence requirements limit its efficiency. In this study, we explore Faecalibaculum rodentium Cas9 (FrCas9) for plant genome editing, especially in rice. FrCas9 recognizes a concise 5′‐NNTA‐3′ PAM, targeting more abundant palindromic TA sites in plant genomes than the 5′‐NGG‐3′ PAM sites of the most popular SpCas9. FrCas9 shows cleavage activities at all tested 5′‐NNTA‐3′ PAM sites with editing outcomes sharing the same characteristics of a typical CRISPR‐Cas9 system. FrCas9 induces high‐efficiency targeted mutagenesis in stable rice lines, readily generating biallelic mutants with expected phenotypes. We augment FrCas9's ability to generate larger deletions through fusion with the exonuclease, TREX2. TREX2‐FrCas9 generates much larger deletions than FrCas9 without compromise in editing efficiency. We demonstrate TREX2‐FrCas9 as an efficient tool for genetic knockout of a microRNA gene. Furthermore, FrCas9‐derived cytosine base editors (CBEs) and adenine base editors (ABE) are developed to produce targeted C‐to‐T and A‐to‐G base edits in rice plants. Whole‐genome sequencing‐based off‐target analysis suggests that FrCas9 is a highly specific nuclease. Expression of TREX2‐FrCas9 in plants, however, causes detectable guide RNA‐independent off‐target mutations, mostly as single nucleotide variants (SNVs). Together, we have established an efficient CRISPR‐FrCas9 system for targeted mutagenesis, large deletions, C‐to‐T base editing, and A‐to‐G base editing in plants. The simple palindromic TA motif in the PAM makes the CRISPR‐FrCas9 system a promising tool for genome editing in plants with an expanded targeting scope. [ABSTRACT FROM AUTHOR]