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Background Circulating serpinB1 levels are increased in obese mice and have been shown to promote β-cell proliferation in several species. However, the data on serum serpinB1 levels in children with obesity are scarce. This study aimed to determine serum serpinB1 levels in children with overweight/obesity, and to study its association with obesity-related parameters. Methods A total of 54 children with overweight/obesity and 36 normal-weight healthy controls aged 6–14 were recruited in this study. Anthropometric parameters, glucolipid metabolic biochemical parameters, sex hormones, and serum serpinB1 levels were measured in all subjects. The association of serum serpinB1 levels with obesity-related parameters and the risk of overweight/obesity were analyzed using correlation analysis and binary regression analysis, respectively. Results The serum serpinB1 level in overweight/obese children was notably greater than in normal-weight controls (2.03 ± 0.70 vs. 1.41 ± 0.58 ng/mL, p  < 0.001). SerpinB1 levels were positively correlated with body mass index (BMI), BMI Z-score, triglyceride (TG), uric acid, fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance (HOMA-IR) levels. Additionally, we found that elevated circulating serpinB1 levels were associated with the increased risk of childhood overweight/obesity even after adjustment for age, gender, and HOMA-IR (odds ratio, 4.132; 95% confidence interval, 1.315–12.983; p  = 0.015). Conclusions Circulating serpinB1 level was significantly increased in children with overweight/obesity and positively associated with obesity-related glucolipid metabolic parameters. These results indicate a close association between serum serpinB1 concentrations and childhood overweight/obesity.

Background Meier–Gorlin syndrome (MGORS) is a rare autosomal inherited form of primordial dwarfism. Pathogenic variants in 13 genes involved in DNA replication initiation have been identified in this disease, but homozygous intronic variants have never been reported. Additionally, whether growth hormone (GH) treatment can increase the height of children with MGORS is unclear. Methods The medical history data of a young girl were collected and reviewed. Whole-exome sequencing (WES) and bioinformatic analysis were performed to identify any variants and predict their pathogenicity. Minigene constructs were generated and transfected into HEK-293T cells for in vitro splicing assays. The literature was reviewed to explore the mutational spectrum and efficacy of GH treatment for this disease. Results A girl with microtia, hypoplastic patellae, and severe growth retardation carried a novel homozygous intronic variant (NM_030928.4: exon 3: c.352–30 A > C) in CDT1 . The variant was predicted to break a branch point and alter splicing, and the minigene assay confirmed abnormal splicing with exon 3 skipping. The patient was treated with GH for 5 years, with an increase in growth velocity from 4.0 cm/year to an average of 6.2 cm/year. A literature review revealed that the most common variant type and inheritance state were missense and compound heterozygous, respectively. Additionally, the vast majority of children with MGORS treated with GH had normal insulin-like growth factor 1 (IGF-1) levels, and half of them responded positively to GH therapy. Conclusions We reported a novel pathogenic homozygous intronic variant (c.352–30 A > C) of CDT1 in a girl with MGORS, and this mutation extended the genetic spectrum of the disease. GH therapy may be beneficial for height outcomes in children with MGORS with normal IGF-1 levels.

High-precision electrostatic accelerometers have achieved remarkable success in satellite Earth gravity field recovery missions. Ultralow-noise inertial sensors play important roles in space gravitational wave detection missions such as the Laser Interferometer Space Antenna (LISA) mission, and key technologies have been verified in the LISA Pathfinder mission. Meanwhile, at Huazhong University of Science and Technology (HUST, China), a space accelerometer and inertial sensor based on capacitive sensors and the electrostatic control technique have also been studied and developed independently for more than 16 years. In this paper, we review the operational principle, application, and requirements of the electrostatic accelerometer and inertial sensor in different space missions. The development and progress of a space electrostatic accelerometer at HUST, including ground investigation and space verification are presented.

Ultra-sensitive inertial sensors are one of the key components in satellite Earth’s gravity field recovery missions and space gravitational wave detection missions. Low-noise capacitive position transducers are crucial to these missions to achieve the scientific goal. However, in actual engineering applications, the sensor head and electronics unit usually place separately in the satellite platform where a connecting cable is needed. In this paper, we focus on the stray-capacitance influences of coaxial cables which are used to connect the mechanical core and the electronics. Specially, for the capacitive transducer with a differential transformer bridge structure usually used in high-precision space inertial sensors, a connecting method of a coaxial cable between the transformer’s secondary winding and front-end circuit’s preamplifier is proposed to transmit the AC modulated analog voltage signal. The measurement and noise models including the stray-capacitance of the coaxial cable under this configuration is analyzed. A prototype system is set up to investigate the influences of the cables experimentally. Three different types and lengths of coaxial cables are chosen in our experiments to compare their performances. The analysis shows that the stray-capacitance will alter the circuit’s resonant frequency which could be adjusted by additional tuning capacitance, then under the optimal resonant condition, the output voltage noises of the preamplifier are measured and the sensitivity coefficients are also calibrated. Meanwhile, the stray-capacitance of the cables is estimated. Finally, the experimental results show that the noise level of this circuit with the selected cables could all achieve 1–2 × 10−7 pF/Hz1/2 at 0.1 Hz.

Background White matter injury (WMI) induced by intrauterine inflammation can cause adverse neurological outcomes. Fibrinogen-like protein 2 (FGL2)/fibroleukin is an important trigger of inflammatory responses and is involved in some cerebral diseases. However, the role of FGL2 in intrauterine inflammation-induced WMI remains unclear. Methods Lipopolysaccharide (LPS) was intraperitoneally injected into wild-type and FGL2 knockout mice to induce intrauterine inflammation. Body weight and brain weight of offspring were monitored. Major basic protein (MBP) expression was evaluated to demonstrate the myelination of offspring. To investigate the regulatory mechanism of FGL2, cytokine expression, microglial polarization, and the activation of mitogen-activated protein kinase (MAPK) signaling pathway in the offspring were analyzed. Results Upon LPS exposure, FGL2 knockout offspring showed a significant increase in body weight loss. MBP reduction induced by LPS was prevented in FGL2 knockout offspring. Expression levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α, and M1 marker CD86 were suppressed, while the expression levels of anti-inflammatory cytokines IL-10 and M2 marker CD206 were increased. FGL2 deficiency significantly inhibited the phosphorylation of p38MAPK and c-Jun N-terminal kinase (JNK) protein. Conclusions FGL2 deficiency can ameliorate WMI induced by intrauterine inflammation, reducing inflammatory cascade and improving hypomyelination, through the regulation of microglial polarization and MAPK signaling pathways. Impact Intrauterine inflammation induces WMI leading to severe neurological sequelae. FGL2 plays an important role in the progression of WMI induced by intrauterine inflammation. FGL2 deficiency can protect against WMI by inhibiting p38 MAPK and JNK phosphorylation, regulating microglia polarization, and reducing inflammation response. FGL2 could be a novel molecular target for protecting against WMI induced by intrauterine inflammation.

It is well-recognized that diabetes represents a powerful independent risk factor for cardiovascular diseases. However, very few studies have investigated the relationship between diabetes and risk of aortic dissection (AD). The aim of this case-control study was to evaluate the association between diabetes and risk of AD in Chinese population. A hospital-based case-control study, consisting of 2160 AD patients and 4320 controls, was conducted in a Chinese population. Demographic, clinical characteristics and risk factors were collected. Diabetes rate of patients with overall AD, Stanford type A AD and type B AD group was compared with that of corresponding matched control groups. Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for relationship between diabetes and AD risk. The prevalence of diabetes was lower in AD cases than that of control subjects, whether it is the overall AD, type A AD or type B AD group (4.7% vs. 10.0%, 2.9% vs. 8.8%, 5.9% vs. 10.9%, all P<0.001). Furthermore, in multivariate model, diabetes was found to be associated with lower AD risk, which not only applies to the overall AD (OR = 0.2, 95%CI: 0.15-0.26), but also type A AD (OR = 0.12, 95% CI: 0.07-0.20) and type B AD (OR = 0.25, 95%CI: 0.18-0.33). We observed the paradoxical inverse relationship between DM and risk of AD in the Chinese population. These results suggest diabetes may play a protective role in the development of AD. However, further studies are needed to enrich related evidence, especially with regard to underlying mechanisms for these trends.

Background ACAN (OMIM 155760) is located on chromosome 15q26 and encodes the production of aggrecan. Aggrecan is a large chondroitin sulfate proteoglycan with a molecular weight of 254 kDa and contains 2530 amino acids. It is a critical structural component of the extracellular matrix of cartilage, including growth plate, articular, and intervertebral disk cartilage. It plays a key role in bone development. Methods Here, we describe two pedigrees with loss‐of‐function variants in ACAN. Whole exome sequencing was performed for the probands from each family. We illustrate the clinical variability associated with ACAN variants. Results The proband of pedigree A manifested short stature, relative macrocephaly, mild flat nasal bridge, low‐set ears, short neck, and short thumbs. The proband of pedigree B had short height, abnormal vertebral development, and central precocious puberty. By trio‐based whole exome sequencing and in silico analyses, we identified two de novo heterozygous variants of ACAN: NM_013227.4: c.116dupT, p.Arg40Glufs*51 and NM_013227.4: c.2367delC, p.Ser790Glnfs*20 (accession number: AC103982.10). Conclusion The clinical manifestations of ACAN gene variants are diverse. ACAN gene variants are important genetic factors for short stature and should be considered as the differential diagnosis of children with idiopathic short stature (ISS). In this manuscript, we describe two pedigrees with novel ACAN gene variants, which were both discovered for the first time. We illustrate the clinical variability associated with ACAN variants.

Voltage-gated potassium （Kv） channels derive their voltage sensitivity from movement of gating charges in volt- age-sensor domains （VSDs）. The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kvl.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and elec- trophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel acti- vators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel.

The frequency domain characteristics of acoustic emission can reflect issues such as rock structure and stress conditions that are difficult to analyze in time domain parameters. Studying the influence of immersion time on the mechanical properties and acoustic emission frequency domain characteristics of muddy mineral rocks is of great significance for comprehensively analyzing rock changes under water–rock coupling conditions. In this study, uniaxial compression tests and acoustic emission tests were conducted on sandstones containing montmorillonite under dry, saturated, and different immersion time conditions, with a focus on analyzing the effect of immersion time on the dominant frequency of rock acoustic emission. The results indicated that immersion time had varying degrees of influence on compressive strength, the distribution characteristics of dominant acoustic emission frequencies, the frequency range of dominant frequencies, and precursor information of instability failure for sandstones. After initial saturation, the strength of the rock sample decreased from 53.52 MPa in the dry state to 49.51 MPa, and it stabilized after 30 days of immersion. Both dry and initially saturated rock samples exhibited three dominant frequency bands. After different immersion days, a dominant frequency band appeared between 95 kHz and 110 kHz. After 5 days of immersion, the dominant frequency band near 0 kHz gradually disappeared. After 60 days of immersion, the dominant frequency band between 35 kHz and 40 kHz gradually disappeared, and with increasing immersion time, the dominant frequency of the acoustic emission signals increased. During the loading process of dry rock samples, the dominant frequency of acoustic emission signals was mainly concentrated between 0 kHz and 310 kHz, while after saturation, the dominant frequencies were all below 180 kHz. The most significant feature before the rupture of dry rock samples was the frequent occurrence of high frequencies and sudden changes in dominant frequencies. Before rupture, the characteristics of precursor events for initially saturated and immersed samples for 5, 10, and 30 days were the appearance and rapid increase in sudden changes in dominant frequencies, as well as an enlargement of the frequency range of dominant frequencies. After 60 days of immersion, the precursor characteristics of rock sample rupture gradually disappeared, and sudden changes in dominant frequencies frequently occurred at various stages of sample loading, making it difficult to accurately predict the rupture of specimens based on these sudden changes.

The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor—gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.