The Loss of Hh Responsiveness by a Non-Ciliary Gli2 Variant

Hedgehog signaling is crucial for vertebrate development and physiology. Gli2, the primary effector of Hedgehog signaling, localizes to the tip of the primary cilium, but the importance of its ciliary localization remains unclear. We address the roles of Gli2 ciliary localization by replacing endogenous Gli2 with Gli2ΔCLR, a Gli2 variant not localizing to the cilium. The resulting Gli2ΔCLRKI and Gli2ΔCLRKI;Gli3 double mutants resemble Gli2-null and Gli2;Gli3 double mutants, respectively, suggesting the lack of Gli2ΔCLR activation in development. Significantly, Gli2ΔCLR cannot be activated either by pharmacochemical activation of Smo in vitro or by loss of Ptch1 in vivo. Finally,Gli2ΔCLR exhibits strong transcriptional activator activity in the absence of Sufu, suggesting that the lack of its activation in vivo results from a specific failure in relieving the inhibitory function of Sufu. Our results provide strong evidence that the ciliary localization of Gli2 is crucial for cilium-dependent activation of Hedgehog signaling

A self-adaptive frequency response compensation method for a TIADC system

Time interleaving is one of the most efficient techniques employed in high-speed sampling systems. However, the frequency response mismatch among different channels will create distortion tones that degrade the system performance. In this paper, a selfadaptive frequency response mismatch compensation method is presented, where the design of compensation filter is optimized with a self-adapting strategy. This digital postprocessing technique realizes the compensation of frequency response effectively and also the increase of the digital bandwidth of the acquisition system. MATLAB-based simulation and an actual two-channel acquisition system test verify the effectiveness of the algorithm

Giant electric energy density in epitaxial lead-free thin films with coexistence of ferroelectrics and antiferroelectrics

Ferroelectrics/antiferroelectrics with high dielectric breakdown strength have the potential to store a great amount of electrical energy, attractive for many modern applications in electronic devices and systems. Here we demonstrate that a giant electric energy density (154 J×cm-3, 3 times the highest value of lead-based systems and 5 times the value of the best dielectric/ferroelectric polymer), together with the excellent fatigue-free property, good thermal stability and high efficiency, is realized in pulsed laser deposited (Bi1/2Na1/2)0.9118La0.02Ba0.0582(Ti0.97Zr0.03)O3 (BNLBTZ) epitaxial lead-free relaxor thin films with the coexistence of ferroelectric (FE) and antiferroelectric (AFE) phases. This is endowed by high epitaxial quality, great relaxor dispersion and the coexistence of the FE/AFE phases near the morphotropic phase boundary (MPB). The giant energy storage effect of the BNLBTZ lead-free relaxor thin films may make a great impact on the modern energy storage technology

Ceramides and metabolic profiles of patients with acute coronary disease: a cross-sectional study

Metabolic Syndrome (MS) is a rapidly growing medical problem worldwide and is characterized by a cluster of age-related metabolic risk factors. The presence of MS increases the likelihood of developing atherosclerosis and significantly raises the morbidity/mortality rate of acute coronary syndrome (ACS) patients. Early detection of MS is crucial, and biomarkers, particularly blood-based, play a vital role in this process. This cross-sectional study focused on the investigation of certain plasma ceramides (Cer14:0, Cer16:0, Cer18:0, Cer20:0, Cer22:0, and Cer24:1) as potential blood biomarkers for MS due to their previously documented dysregulated function in MS patients. A total of 695 ACS patients were enrolled, with 286 diagnosed with MS (ACS-MS) and 409 without MS (ACS-nonMS) serving as the control group. Plasma ceramide concentrations were measured by LC-MS/MS assay and analyzed through various statistical methods. The results revealed that Cer18:0, Cer20:0, Cer22:0, and Cer24:1 were significantly correlated with the presence of MS risk factors. Upon further examination, Cer18:0 emerged as a promising biomarker for early MS detection and risk stratification, as its plasma concentration showed a significant sensitivity to minor changes in MS risk status in participants. This cross-sectional observational study was a secondary analysis of a multicenter prospective observational cohort study (Chinese Clinical Trial Registry, https://www.who.int/clinical-trials-registry-platform/network/primary-registries/chinese-clinical-trial-registry-(chictr), ChiCTR-2200056697), conducted from April 2021 to August 2022

Coordinated Translocation of Mammalian Gli Proteins and Suppressor of Fused to the Primary Cilium

Intracellular transduction of Hedgehog (Hh) signals in mammals requires functional primary cilia. The Hh signaling effectors, the Gli family of transcription factors, and their negative regulator, Suppressor of Fused (Sufu), accumulate at the tips of cilia; however, the molecular mechanism regulating this localization remains elusive. In the current study, we show that the ciliary localization of mammalian Gli proteins depends on both their N-terminal domains and a central region lying C-terminal to the zinc-finger DNA-binding domains. Invertebrate Gli homologs Ci and Tra1, when over-expressed in ciliated mouse fibroblasts, fail to localize to the cilia, suggesting the lack of a vertebrate-specific structural feature required for ciliary localization. We further show that activation of protein kinase A (PKA) efficiently inhibits ciliary localization of Gli2 and Gli3, but only moderately affects the ciliary localization of Gli1. Interestingly, variants of Gli2 mimicking the phosphorylated or non-phosphorylated states of Gli2 are both localized to the cilia, and their ciliary localizations are subjected to the inhibitory effect of PKA activation, suggesting a likely indirect mechanism underlying the roles of PKA in Gli ciliary localization. Finally, we show that ciliary localization of Sufu is dependent on ciliary-localized Gli proteins, and is inhibited by PKA activation, suggesting a coordinated mechanism for the ciliary translocation of Sufu and Gli proteins

Recombinant mycobacterium tuberculosis fusion protein for diagnosis of mycobacterium tuberculosis infection: a short-term economic evaluation

ObjectivesRecombinant Mycobacterium tuberculosis fusion protein (EC) was anticipated to be used for the scale-up of clinical application for diagnosis of Mycobacterium tuberculosis infection in China, but it lacked a head-to-head economic evaluation based on the Chinese population. This study aimed to estimate the cost-utility and the cost-effectiveness of both EC and tuberculin pure protein derivative (TB-PPD) for diagnosis of Mycobacterium tuberculosis infection in the short term.MethodsFrom a Chinese societal perspective, both cost-utility analysis and cost-effectiveness analysis were performed to evaluate the economics of EC and TB-PPD for a one-year period based on clinical trials and decision tree model, with quality-adjusted life years (QALYs) as the utility-measured primary outcome and diagnostic performance (including the misdiagnosis rate, the omission diagnostic rate, the number of patients correctly classified, and the number of tuberculosis cases avoided) as the effective-measured secondary outcome. One-way and probabilistic sensitivity analyses were performed to validate the robustness of the base-case analysis, and a scenario analysis was conducted to evaluate the difference in the charging method between EC and TB-PPD.ResultsThe base-case analysis showed that, compared with TB-PPD, EC was the dominant strategy with an incremental cost-utility ratio (ICUR) of saving 192,043.60 CNY per QALY gained, and with an incremental cost-effectiveness ratio (ICER) of saving 7,263.53 CNY per misdiagnosis rate reduction. In addition, there was no statistical difference in terms of the omission diagnostic rate, the number of patients correctly classified, and the number of tuberculosis cases avoided, and EC was a similar cost-saving strategy with a lower test cost (98.00 CNY) than that of TB-PPD (136.78 CNY). The sensitivity analysis showed the robustness of cost-utility and cost-effectiveness analysis, and the scenario analysis indicated cost-utility in EC and cost-effectiveness in TB-PPD.ConclusionThis economic evaluation from a societal perspective showed that, compared to TB-PPD, EC was likely to be a cost-utility and cost-effective intervention in the short term in China

Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture