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Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckletype POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling. Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Finally, we demonstrate in a conditional mutant that loss of Spop results in brachydactyly and osteopenia, which can be rescued by reducing the dosage of Gli3. In summary, Spop is an important positive regulator of Ihh signaling and skeletal development.

Two histidine-ligated heme-dependent monooxygenase proteins, TyrH and SfmD, have recently been found to resemble enzymes from the dioxygenase superfamily currently named after tryptophan 2,3-dioxygenase (TDO), that is, the TDO superfamily. These latest findings prompted us to revisit the structure and function of the superfamily. The enzymes in this superfamily share a similar core architecture and a histidine-ligated heme. Their primary functions are to promote O-atom transfer to an aromatic metabolite. TDO and indoleamine 2,3-dioxygenase (IDO), the founding members, promote dioxygenation through a two-step monooxygenation pathway. However, the new members of the superfamily, including PrnB, SfmD, TyrH, and MarE, expand its boundaries and mediate monooxygenation on a broader set of aromatic substrates. We found that the enlarged superfamily contains eight clades of proteins. Overall, this protein group is a more sizeable, structure-based, histidine-ligated heme-dependent, and functionally diverse superfamily for aromatics oxidation. The concept of TDO superfamily or heme-dependent dioxygenase superfamily is no longer appropriate for defining this growing superfamily. Hence, there is a pressing need to redefine it as a heme-dependent aromatic oxygenase (HDAO) superfamily. The revised concept puts HDAO in the context of thiol-ligated heme-based enzymes alongside cytochrome P450 and peroxygenase. It will update what we understand about the choice of heme axial ligand. Hemoproteins may not be as stringent about the type of axial ligand for oxygenation, although thiolate-ligated hemes (P450s and peroxygenases) more frequently catalyze oxygenation reactions. Histidine-ligated hemes found in HDAO enzymes can likewise mediate oxygenation when confronted with a proper substrate.

AbstractMolecular oxygen is utilized in numerous metabolic pathways fundamental for life. Mononuclear nonheme iron-dependent oxygenase enzymes are well known for their involvement in some of these pathways, activating O2 so that oxygen atoms can be incorporated into their primary substrates. These reactions often initiate pathways that allow organisms to use stable organic molecules as sources of carbon and energy for growth. From the myriad of reactions in which these enzymes are involved, this perspective recounts the general mechanisms of aromatic dihydroxylation and oxidative ring cleavage, both of which are ubiquitous chemical reactions found in life-sustaining processes. The organic substrate provides all four electrons required for oxygen activation and insertion in the reactions mediated by extradiol and intradiol ring-cleaving catechol dioxygenases. In contrast, two of the electrons are provided by NADH in the cis-dihydroxylation mechanism of Rieske dioxygenases. The catalytic nonheme Fe center, with the aid of active site residues, facilitates these electron transfers to O2 as key elements of the activation processes. This review discusses some general questions for the catalytic strategies of oxygen activation and insertion into aromatic compounds employed by mononuclear nonheme iron-dependent dioxygenases. These include: (1) how oxygen is activated, (2) whether there are common intermediates before oxygen transfer to the aromatic substrate, and (3) are these key intermediates unique to mononuclear nonheme iron dioxygenases?Graphical Abstract

Background To examine association between gestational weight gain (GWG) in women with gestational diabetes mellitus (GDM) and adverse pregnancy outcomes (APOs). Methods This retrospective cohort study enrolled women with GDM who delivered at 2010–2020 in Changzhou, Jiangsu. Total GWG, rates of GWG in second trimester and third trimesters were stratified into three categories according to IOM guidelines: within, below, and above IOM guidelines. Univariable and multivariable logistic regression analyses were used. Results Overall, 1606 women with GDM fulfilled inclusion criteria. Compared with within IOM guidelines and after adjusting for confounders, total GWG above IOM guidelines in pregnancy was associated with an increased odds of caesarean delivery [adjusted odds ratio (aOR) = 1.34, 95% confidence interval (CI): 1.04–1.72], hypertensive disorders of pregnancy (HDP) (aOR = 2.00, 1.28–3.12), preeclampsia (aOR = 2.06, 1.01–3.12), macrosomia (aOR = 1.55, 1.13–2.13) and large for gestational age (LGA) (aOR = 2.82, 1.94–3.23), and a decreased odds of premature rupture of membrane (PROM) (aOR = 0.46, 0.36–0.60) and preterm birth (aOR = 0.35, 0.26–0.44); total GWG below IOM guidelines in pregnancy was associated with an increased risk of preterm birth (aOR = 1.96, 1.44–2.66), small for gestational age (SGA) (aOR = 1.32, 1.11–1.50) and a decreased odds of macrosomia (aOR = 0.35, 0.23–0.53) and LGA (aOR = 0.54, 0.42–0.72). Further, in both second and third trimesters of pregnancy, rates of GWG above IOM guidelines was found to be associated with a high odds of HDP (aOR = 2.55, 1.86–3.38; aOR = 1.93, 1.08–2.98), preeclampsia (aOR = 2.28, 1.21–3.81; aOR = 2.17, 1.35–4.37), macrosomia (aOR = 1.20, 1.02–1.82; aOR = 2.02, 1.51–2.64) and LGA (aOR = 1.42, 1.24–1.97; aOR = 1.79, 1.51–2.54). Rates of GWG above IOM guidelines in third trimester of pregnancy also increased odds of caesarean delivery (aOR = 1.48, 1.16–2.34) when compared with within IOM guidelines. While rates of GWG below IOM guidelines in both second and third trimesters of pregnancy was associated with a decreased odds of macrosomia (aOR = 0.66, 95% CI: 0.52–0.78; aOR = 0.52, 0.39–0.63) and LGA(aOR = 0.71, 0.51–0.82; aOR = 0.67, 0.55–0.79). In addition, rate of GWG below IOM guidelines in third trimester of pregnancy was associated with an increased odds of preterm birth (aOR = 1.52, 1.12–2.05) and SGA (aOR = 1.21, 1.10–1.69). Conclusion GWG, outside IOM guidelines has increased risks of APOs among women with GDM, implying that careful surveillance for GWG during different stages of pregnancy is warranted.

Gearbox oil temperature is one of the important indicators for gearbox condition monitoring and faults early warning. Accurately predicting the gearbox oil temperature change trend can maintain the gearbox in advance and ensure the safety and reliability of the wind turbine gearbox. The purpose of this article is to analyze the supervisory control and data acquisition (SCADA) data in wind turbines. A method based on multi‐input improved ant lion optimization and support vector regression (M‐IALO‐SVR) proposed, which can accurately predict the gearbox oil temperature. The prediction method is compared with back propagation neural network (BPNN) and ALO‐SVR methods to verify the effectiveness of the M‐IALO‐SVR method. To further analyze the prediction results, the 95% confidence interval processing is performed on the residuals of the prediction model, and then the trends of the mean and standard deviation of the moving window residuals are calculated. Testing SCADA data from a wind farm in northeast China, the test results show that when the gearbox is operating normally, the predicted value of the gearbox oil temperature follows the measured value very well. When the gearbox operates abnormally, its temperature deviates from the normal range, and the statistical characteristics of the residuals also change. According to the trend of the residuals statistical characteristics, the abnormal state of the gearbox can be found in time.

Primary microcephaly is caused by mutations in genes encoding centrosomal proteins including WDR62 and KIF2A. However, mechanisms underlying human microcephaly remain elusive. By creating mutant mice and human cerebral organoids, here we found that WDR62 deletion resulted in a reduction in the size of mouse brains and organoids due to the disruption of neural progenitor cells (NPCs), including outer radial glia (oRG). WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of NPCs. Mechanistically, WDR62 interacts with and promotes CEP170’s localization to the basal body of primary cilium, where CEP170 recruits microtubule-depolymerizing factor KIF2A to disassemble cilium. WDR62 depletion reduced KIF2A’s basal body localization, and enhanced KIF2A expression partially rescued deficits in cilium length and NPC proliferation. Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly. Mutations in WDR62 are the second most common genetic cause of autosomal recessive primary microcephaly, yet the molecular mechanisms underlying this pathogenesis remain unclear. Here, authors demonstrate that WDR62 depletion leads to neural precursor cell depletion and microcephaly via WDR62-CEP170-KIF2A pathway that promotes cilium disassembly.

To enhance the stability, reliability, and efficiency, reduce the operation cycle time, and augment the operation security capability of fully electric and intelligent military special vehicles, a novel segmented pseudo-differential feedback (PDF) control algorithm for the permanent magnet synchronous motors (PMSMs) of special vehicles is introduced. The control algorithm optimizes the differential part of the control system and avoids the direct differential calculation. This enhances the dynamic response and anti-interference capability of the control system, ensuring a rapid and robust performance. At the same time, the control system parameters are determined based on the error and the rate of change of the error in a segmented manner, ensuring precise control of specialized vehicles under various operating conditions. To verify the effectiveness of the proposed control algorithm, a simulation model is established for simulation analysis; an experimental platform is built for experimental verification. Both simulation and experimental results demonstrate that the proposed control algorithm exhibits notable advantages, including a rapid output response, and the absence of overshoot and oscillation. These characteristics effectively enhance the motor efficiency, optimize the output attributes, and elevate the overall operational performance of electric special vehicles.

To reduce the computational burden of 3D finite element analysis for hybrid-flux high-speed switched reluctance motors (HFHSRMs), a quasi-3D parameterized equivalent magnetic network (EMN) is proposed. A parameterized radial–circumferential cross-grid is used to discretize the stator, air-gap, and rotor regions, and axial coupling branches are introduced to represent key 3D flux paths. Rotor rotation and rotor dislocation are implemented through a circumferential node-shift mapping, thereby avoiding topology reconstruction at different rotor positions. Core nonlinearity is incorporated using a piecewise fit of measured B–H data, and sparse-matrix assembly is adopted to improve solution efficiency. Based on the proposed EMN, key electromagnetic quantities are evaluated, including air-gap flux density, static characteristics, and dynamic characteristics. The results are validated against 3D finite element method (FEM) and prototype experiments. In the prototype experiments, the EMN prediction errors of key quantities are within 6%. In addition, computational efficiency is significantly improved compared with the 3D FEM, enabling rapid parameter iteration and early-stage design evaluation for HFHSRMs.

The primary cilium plays critical roles in vertebrate development and physiology, but the mechanisms underlying its biogenesis remain poorly understood. We investigated the molecular function of C2 calcium-dependent domain containing 3 (C2cd3), an essential regulator of primary cilium biogenesis. We show that C2cd3 is localized to the centriolar satellites in a microtubule- and Pcm1-dependent manner; however, C2cd3 is dispensable for centriolar satellite integrity. C2cd3 is also localized to the distal ends of both mother and daughter centrioles and is required for the recruitment of five centriolar distal appendage proteins: Sclt1, Ccdc41, Cep89, Fbf1, and Cep164. Furthermore, loss of C2cd3 results in failure in the recruitment of Ttbk2 to the ciliary basal body as well as the removal of Cp110 from the ciliary basal body, two critical steps in initiating ciliogenesis. C2cd3 is also required for recruiting the intraflagellar transport proteins Ift88 and Ift52 to the mother centriole. Consistent with a role in distal appendage assembly, C2cd3 is essential for ciliary vesicle docking to the mother centriole. Our results suggest that C2cd3 regulates cilium biogenesis by promoting the assembly of centriolar distal appendages critical for docking ciliary vesicles and recruiting other essential ciliogenic proteins.