Improved mitochondrial function in the heart of sarcolipin-deficient dystrophin and utrophin double knockout mice.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD-cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin null (mdx:utrn-/-) mice in sarcolipin (SLN) heterozygous knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium. Germline reduction of SLN expression in mdx:utrn-/- mice improved cardiac sarco/endoplasmic reticulum (SR) Ca2+ cycling, reduced cardiac fibrosis, and improved cardiac function. At the cellular level, reducing SLN expression prevented mitochondrial Ca2+ overload, reduced mitochondrial membrane potential loss, and improved mitochondrial function. Transmission electron microscopy of myocardial tissues and proteomic analysis of mitochondria-associated membranes show that reducing SLN expression improved mitochondrial structure and SR-mitochondria interactions in dystrophic cardiac myocytes. These findings indicate that SLN upregulation plays a significant role in the pathogenesis of cardiomyopathy and that reducing SLN expression has clinical implications in the treatment of DMD-cardiomyopathy.

Ultrasound manifestations and clinical analysis of 50 cases of heterotopic pregnancy.

OBJECTIVE: To investigate the value of ultrasonography in the diagnosis of heterotopic pregnancy and the follow-up. METHODS: A retrospective analysis of 50 cases of clinically diagnosed heterotopic pregnancy in our hospital was performed, the clinical characteristics and ultrasonographic manifestations of the patients were summarized, the reasons for initial ultrasound missed diagnosis and misdiagnosis were analyzed, and the pregnancy outcomes were followed up. RESULTS: Among the 50 cases, the initial ultrasound diagnoses of intrauterine pregnancy were all gestational sac type, 32 cases of ectopic pregnancy were located in the fallopian tube, and 10 cases were located in the uterine horn, 1 case at cervix, and 1 case at caesarean section scar. Forty-one cases were consistent with surgery and/or pathology, representing initial ultrasound diagnosis coincidence rate of about 82%. Six cases were missed in the initial ultrasound examination (12%), and three cases were misdiagnosed (6%). The maximum diameter of the intrauterine gestational sac was 9-48 mm, the average was about 24.90 ± 9.56 mm, the maximum diameter of the ectopic pregnancy gestational sac or mass was 11-63 mm, and the average was about 31.45 ± 13.82 mm (p < 0.05). Intrauterine pregnancy outcomes were followed up, 45 patients with complete data and 5 patients were lost to follow-up. The follow-up rate was about 90%. CONCLUSION: Combining the patient's medical history and clinical characteristics can reduce missed diagnosis and misdiagnosis of heterotopic pregnancy. Ultrasonography has important value in the assessment of intrauterine pregnancy growth and development, and the integrity of maternal uterus.

Predicting intraoperative hemorrhage during curettage treatment of cesarean scar pregnancy using free-breathing GRASP DCE-MRI.

OBJECTIVE: To explore the feasibility of the golden-angle radial sparse parallel (GRASP) dynamic magnetic resonance imaging (MRI) technique in predicting the intraoperative bleeding risk of scar pregnancy. METHODS: A total of 49 patients with cesarean scar pregnancy (CSP) who underwent curettage and GRASP-MRI imaging were retrospectively selected between January 2021 and July 2022. The pharmacokinetic parameters, including Wash-in, Wash-out, time to peck (TTP), initial area under the curve (iAUC), the transfer rate constant (Ktrans), constant flow rate (Kep), and volume of extracellular space (Ve), were calculated. The amount of intraoperative bleeding was recorded by a gynecologist who performed surgery, after which patients were divided into non-hemorrhage (blood loss ≤ 200 mL) and hemorrhage (blood loss > 200 mL) groups. The measured pharmacokinetic parameters were statistically compared using the t-test or Mann-Whitney U test with a significant level set to be p < 0.05. The receiver operating characteristic (ROC) curve was constructed, and the area under the curve (AUC) was calculated to evaluate each parameter's capability in intraoperative hemorrhage subgroup classification. RESULTS: Twenty patients had intraoperative hemorrhage (blood loss > 200 mL) during curettage. The hemorrhage group had larger Wash-in, iAUC, Ktrans, Ve, and shorter TTP than the non-hemorrhage group (all P > 0.05). Wash-in had the highest AUC value (0.90), while Ktrans had the lowest value (0.67). Wash-out and Kep were not significantly different between the two groups. CONCLUSION: GRASP DCE-MRI has the potential to forecast intraoperative hemorrhage during curettage treatment of CSP, with Wash-in exhibiting the highest predictive performance. This data holds promise for advancing personalized treatment. However, further study is required to compare its effectiveness with other risk factors identified through anatomical MRI and ultrasound.

Carbon nitride quantum dots-modified cobalt phosphate for enhanced photocatalytic H2 evolution.

In the present work, carbon nitride quantum dots (CNQDs)-modified cobalt phosphate (CoPi) composites CNQDs/CoPi-x (x = 1, 2, 3) were prepared at room temperature and characterized by FTIR, XRD, UV-Vis DRS, EIS, SEM, TEM/HR-TEM, XPS, and N2 gas adsorption. The morphologies and surface areas of CNQDs/CoPi-x have no remarkable change after modification of CNQDs, compared with pure CoPi. The obtained CNQDs/CoPi-x shows enhanced activity and stability of photocatalytic H2 evolution compared to pure CoPi using Eosin Y (EY) as a sensitizer and triethanolamine as an electron donor. The CNQDs/CoPi-2 possesses the highest hydrogen evolution rate, 234.5 µmol h-1 g-1 , upon visible light, which outshines that of CoPi by 2.4 times. It was believed that the enhanced photocatalytic performances of the CNQDs/CoPi-2 could result from the boosted electron transfer from radical EY·- to CNQDs/CoPi-2 by the employment of CNQDs; in addition, the visible-light activity of CNQDs contributes to hydrogen evolution. The mechanism of photocatalytic hydrogen production was discussed. This study may contribute toward the development of production of "green hydrogen" using solar.

Triple-Bioinspired Shape Memory Microcavities with Strong and Switchable Adhesion.

Smart adhesives with switchable adhesion have attracted considerable attention for their potential applications in sensors, soft grippers, and robots. In particular, surfaces with controlled adhesion to both solids and liquids have received more attention, because of their wider range of applications. However, surfaces that exhibit controllable adhesion to both solids and liquids often cannot provide sufficient adhesion strength for strong solid adhesion. To overcome this limitation, this study developed a triple-bioinspired shape memory smart adhesive, drawing inspiration from the adhesion structures found in octopus suckers, lotus leaves, and creepers. Our adhesive design incorporates microcavities formed by a shape memory polymer (SMP), which can transition between rubbery and glassy states in response to temperature changes. By leveraging the shape memory effect and the rubber-glass (R-G) phase transition of the SMP, the adhesion of the surface to smooth solids, rough solids, and water droplets could be switched by adjusting the temperature and applied force. Notably, the adhesives designed herein exhibited high adhesion strength (up to 420 kPa) on solids, facilitated by the shape interlocking effect and the negative pressure generated within the microcavities. Furthermore, the programmable transport of solids and liquids can be achieved by utilizing this switchable adhesion. This approach expands the possibilities for designing smart adhesives and holds potential for various applications in different fields.

Coexistence of All-Order Topological States in a Three-Dimensional Phononic Topological Crystalline Insulator.

Classical-wave topological materials lacking intrinsic half-integer spins are less robust while more tunable. Here, we explore a single 3-dimensional phononic topological crystalline insulator that simultaneously exhibits a whole family of first-order quadratic surface, second-order hinge, and third-order corner states within the same bandgap. Such a topological crystalline insulator hosting all-order phases originates from the different topological nature when hierarchically projected onto different facets and lower dimensions, thus free from trivial cladding crystals. Our work offers an ideal platform for either robust wave propagation or localization in on-demand dimensions and may facilitate dimension division multiplexing technology.

Associations between ALDOB polymorphisms and intrahepatic cholestasis of pregnancy susceptibility in the Chinese Han population.

OBJECTIVES: To research the associations between fructose-bisphosphate aldolase B (ALDOB) gene polymorphisms and intrahepatic cholestasis of pregnancy (ICP) risk. MATERIAL AND METHODS: Whole-genome sequencing (WGS) was performed to detect ALDOB polymorphisms. Five web-available tools were employed to predict the effect of the site variant on the protein. Protein structure comparisons between the reference and ALDOB-modified samples were performed by SWISS-MODEL and Chimera 1.14rc, respectively. RESULTS: We identified 28 genetic variants in the ALDOB gene. When the cut-off value of minor allele frequency (MAF) of loci was 0.001 in four databases, five missense variants, including rs747604233, rs759204107, rs758242037, rs371526091 and rs77718928, were reserved for subsequent analysis. These variants were absent from the 1029 control individuals. The influence of all five variants on protein function was predicted to be damaging by the abovementioned five prediction software programs. Bioinformatics analysis demonstrated that these five missense variants were highly conserved among vertebrates. Compared to the wild-type protein structure, all five mutated protein structures showed a slight change in the chemical bond lengths of the enzyme activity domains. The combined clinical data indicate that the variant group had a significantly older age (p = 0.038), a higher level of indirect bilirubin (IDBIL, p = 0.033), and lower counts of white blood cells (WBCs, p = 7.38E-05) and platelets (PLTs, p = 0.018) than the wild-type group. CONCLUSIONS: This is the first study to examine the associations between ALDOB polymorphisms and ICP disease in 249 Chinese patients with ICP. Our present study expands the understanding of the pathogenesis of ICP.

Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice.

The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload. Bcl-xL Ser14 phosphorylation enhances the Ca2+ transient by blocking the inhibitory interaction between Bcl-xL and IP3Rs, thereby promoting Ca2+ release and activation of the calcineurin-NFAT pathway, a Ca2+-dependent mechanism that promotes cardiac hypertrophy. These results suggest that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway.

The growth and developmental of the myodural bridge and its associated structures in the human fetus.

Myodural bridge (MDB) is a dense connective tissue between suboccipital muscle and dura mater. However, there are few reports on the development and maturation of the human MDB. This study aims to explore the developmental relationship between suboccipital muscle and MDB. 30 head and neck specimens from human fetuses (F) ranging from the 12th to 41st week (W) were made into histological sections. The F12W sections showed evidence that the dura mater dominated by fibroblasts, attached to the posterior atlanto-axial membrane (PAAM) which completely sealed the atlanto-axial space. In the F13W stage, myofibrils of the suboccipital muscle fibers increased significantly in number. At the F14W stage, a gap was observed at the caudal end of the PAAM. Numerous myodural bridge-like structures were observed blending into the dura mater through the gap. At the F19W stage, muscle cells mature. Starting at the F21W stage, the MDB were observed as fibroblasts that cross the atlanto-axial interspace and attach to the dura mater. Therefore, the traction generated by the suboccipital muscles seems to promote the maturity of MDB. This study will provide new morphological knowledge to support future research on the function of the human MDB and regulating the development mechanism of MDB.

Diagnostic value of Kaiser score combined with breast vascular assessment from breast MRI for the characterization of breast lesions.

Objectives: The Kaiser scoring system for breast magnetic resonance imaging is a clinical decision-making tool for diagnosing breast lesions. However, the Kaiser score (KS) did not include the evaluation of breast vascularity. Therefore, this study aimed to use KS combined with breast vascular assessment, defined as KS*, and investigate the effectiveness of KS* in differentiating benign from malignant breast lesions. Methods: This retrospective study included 223 patients with suspicious breast lesions and pathologically verified results. The histopathological diagnostic criteria were according to the fifth edition of the WHO classification of breast tumors. The KS* was obtained after a joint evaluation combining the original KS and breast vasculature assessment. The receiver operating characteristic (ROC) curve was used for comparing differences in the diagnostic performance between KS* and KS, and the area under the receiver operating characteristic (AUC) was compared. Results: There were 119 (53.4%) benign and 104 (46.6%) malignant lesions in total. The overall sensitivity, specificity, and accuracy of increased ipsilateral breast vascularity were 69.2%, 76.5%, and 73.1%, respectively. The overall sensitivity, specificity, and accuracy of AVS were 82.7%, 76.5%, and 79.4%, respectively. For all lesions included the AUC of KS* was greater than that of KS (0.877 vs. 0.858, P = 0.016). The largest difference in AUC was observed in the non-mass subgroup (0.793 vs. 0.725, P = 0.029). Conclusion: Ipsilaterally increased breast vascularity and a positive AVS sign were significantly associated with malignancy. KS combined with breast vascular assessment can effectively improve the diagnostic ability of KS for breast lesions, especially for non-mass lesions.

Impact of the bromination of carbazole-based D-π-A organic dyes on their optical and electrochemical properties and visible-light-driven hydrogen evolution.

Brominated dyes, 2C-n (n = 1-5), 3C-4 and 4C-4, were prepared through bromination of three carbazole-based D-π-A dyes, 2C, 3C and 4C with N-bromosuccinimide (NBS). The detailed structures of the brominated dyes were confirmed by 1H NMR spectroscopy and mass spectrometry (MS). The introduction of the Br atom on the 1,8-positon of carbazole moieties led to blueshifted UV-vis and photoluminescence (PL) spectra, increased initial oxidation potentials and enlarged dihedral angles, indicating bromination enhanced non-planarity of the dye molecules. In the hydrogen production experiments, with the increase of the Br content in brominated dyes, the photocatalytic activity increased continuously (except 2C-1). The dye-sensitized Pt/TiO2, 2C-4@T, 3C-4@T and 4C-4@T, exhibited high hydrogen production efficiencies of 655.4, 877.9 and 905.6 µmol h-1 g-1, respectively, which were 4-6-fold higher than those of 2C@T, 3C@T and 4C@T. The enhanced performance of photocatalytic hydrogen evolution was attributed to decreased dye aggregation resulting from the highly non-planar molecular structures of the brominated dyes.

MRI-based scoring model to predict massive hemorrhage during dilatation and curettage in patients with cesarean scar pregnancy.

OBJECTIVE: To construct a scoring model based on MRI signs to predict massive hemorrhage during dilatation and curettage in cesarean scar pregnancy (CSP) patients. MATERIALS AND METHODS: The MRIs of CSP patients admitted to a tertiary referral hospital between February 2020 and July 2022 were retrospectively reviewed. The included patients were randomly assigned to the training and validation cohorts. The univariate and multivariate logistic regression analyses were adopted to identify the independent risk factors for massive hemorrhage (the amount of bleeding ≥ 200 ml) during the dilatation and curettage. A scoring model predicting intraoperative massive hemorrhage was established where each positive independent risk factor was assigned 1 point, and the predictive power of this model was evaluated both in the training and validation cohorts via the receiver operating characteristic curve. RESULTS: A total of 187 CSP patients were enrolled, who were divided into the training cohort (31 in 131 patients had massive hemorrhage) and validation cohort (10 in 56 patients had massive hemorrhage). The independent risk factors for intraoperative massive hemorrhage included cesarean section diverticulum area (OR = 6.957, 95% CI 1.993-21.887; P = 0.001), uterine scar thickness (OR = 5.113, 95% CI 2.086-23.829; P = 0.025) and gestational sac diameter (OR = 3.853, 95% CI 1.103-13.530; P = 0.025). A scoring model with a total point of 3 was developed and the CSP patients were divided into low-risk (Total points < 2) and high-risk groups (Total points ≥ 2) for intraoperative massive hemorrhage accordingly. This model possessed high prediction performance both in the training cohort (area under the curve [AUC] = 0.896, 95% CI 0.830-0.942) and validation cohort (AUC = 0.915, 95% CI 0.785-1.000). CONCLUSION: We first constructed a MRI-based scoring model for predicting intraoperative massive hemorrhage in CSP patients, which could help the decision-making of the patients' therapy strategies. Low-risk patients can be cured by D&C alone to reduce the financial burden, while high-risk patients require more adequate preoperative preparation or consideration of changing surgical approaches to reduce bleeding risk.

Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias.

Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the ß-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pretreatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability, greater plasma membrane depolarization, and Ca2+ overload, which likely caused prolonged action potentials, delayed after depolarizations, and triggered activity. All these cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac-stress-induced arrhythmogenicity.

Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis.

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca2+ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCUfl/fl) and conditional MCU knockout (MCUfl/fl-MCM) mice. LV function was reduced by chronic iron loading in MCUfl/fl mice, but not in MCUfl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCUfl/fl cardiomyocytes, but not in MCUfl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCUfl/fl, but not in MCUfl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCUfl/fl hearts. Isolated cardiomyocytes from MCUfl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca2+ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCUfl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCUfl/fl-MCM hearts nor was there a reduction in Ca2+ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction.

Molecular identification and physiological functional analysis of NtNRT1.1B that mediated nitrate long-distance transport and improved plant growth when overexpressed in tobacco.

Although recent physiological studies demonstrate that flue-cured tobacco preferentially utilizes nitrate ( NO 3 - ) or ammonium nitrate (NH4NO3), and possesses both high- and low-affinity uptake systems for NO 3 - , little is known about the molecular component(s) responsible for acquisition and translocation in this crop. Here we provide experimental data showing that NtNRT1.1B with a 1,785-bp coding sequence exhibited a function in mediating NO 3 - transport associated with tobacco growth on NO 3 - nutrition. Heterologous expression of NtNRT1.1B in the NO 3 - uptake-defective yeast Hp△ynt1 enabled a growth recovery of the mutant on 0.5 mM NO 3 - , suggesting a possible molecular function of NtNRT1.1B in the import of NO 3 - into cells. Transient expression of NtNRT1.1B::green fluorescent protein (GFP) in tobacco leaf cells revealed that NtNRT1.1B targeted mainly the plasma membrane, indicating the possibility of NO 3 - permeation across cell membranes via NtNRT1.1B. Furthermore, promoter activity assays using a GFP marker clearly indicated that NtNRT1.1B transcription in roots may be down-regulated by N starvation and induced by N resupply, including NO 3 - , after 3 days' N depletion. Significantly, constitutive overexpression of NtNRT1.1B could remarkably enhance tobacco growth by showing a higher accumulation of biomass and total N, NO 3 - , and even NH 4 + in plants supplied with NO 3 - ; this NtNRT1.1B-facilitated N acquisition/accumulation could be strengthened by short-term 15N- NO 3 - root influx assays, which showed 15%-20% higher NO 3 - deposition in NtNRT1.1B-overexpressors as well as a high affinity of NtNRT1.1B for NO 3 - at a K m of around 30-45 µM. Together with the detection of NtNRT1.1B promoter activity in the root stele and shoot-stem vascular tissues, and higher NO 3 - in both xylem exudate and the apoplastic washing fluid of NtNRT1.1B-transgenic lines, NtNRT1.1B could be considered as a valuable molecular breeding target aiming at improving crop N-use efficiency by manipulating the absorption and long-distance distribution/transport of nitrate, thus adding a new functional homolog as a nitrate permease to the plant NRT1 family.

Benzoyl isothiocyanate modified surface of silica gel as the extraction material for adsorbing steroid hormones in water.

Steroid hormones have been listed as priority pollutants in the environment, and their detection and pollution control deserve our extensive attention. In this study, a modified silica gel adsorbent material was synthesized by benzoyl isothiocyanate reaction with hydroxyl groups on the silica gel surface. The modified silica gel was used as a solid phase extraction filler for the extraction of steroid hormones from water, which was further analyzed by the HPLC-MS/MS method. The FT-IR, TGA, XPS, and SEM analysis indicated that benzoyl isothiocyanate was successfully grafted on the surface of silica gel to form a bond with an isothioamide group and benzene ring as the tail chain. The modified silica gel synthesized at 40 °C showed excellent adsorption and recovery rates for three steroid hormones in water. Methanol at pH 9.0 was selected as the optimal eluent. The adsorption capacity of the modified silica gel for epiandrosterone, progesterone, and megestrol acetate was 6822 ng mg-1, 13 899 ng mg-1, and 14 301 ng mg-1, respectively. Under optimal conditions, the limit of detection (LOD) and limit of quantification (LOQ) for 3 steroid hormones by modified silica gel extraction with HPLC-MS/MS detection were 0.02-0.88 µg L-1 and 0.06-2.22 µg L-1, respectively. The recovery rate of epiandrosterone, progesterone, and megestrol was between 53.7% and 82.9%, respectively. The modified silica gel has been successfully used to analyze steroid hormones in wastewater and surface water.

Ideal acoustic quantum spin Hall phase in a multi-topology platform.

Fermionic time-reversal symmetry ([Formula: see text])-protected quantum spin Hall (QSH) materials feature gapless helical edge states when adjacent to arbitrary trivial cladding materials. However, due to symmetry reduction at the boundary, bosonic counterparts usually exhibit gaps and thus require additional cladding crystals to maintain robustness, limiting their applications. In this study, we demonstrate an ideal acoustic QSH with gapless behaviour by constructing a global Tf on both the bulk and the boundary based on bilayer structures. Consequently, a pair of helical edge states robustly winds several times in the first Brillouin zone when coupled to resonators, promising broadband topological slow waves. We further reveal that this ideal QSH phase behaves as a topological phase transition plane that bridges trivial and higher-order phases. Our versatile multi-topology platform sheds light on compact topological slow-wave and lasing devices.

Targeted Next-Generation Sequencing for the Diagnosis of Gene Variants in Patients with 46,XY Disorder of Sex Development.

INTRODUCTION: Disorders of sex development (DSDs) are congenital abnormalities in which chromosomal, gonadal, and anatomical sex development are atypical. One of these disorders, 46,XY DSD, is particularly difficult to diagnose and manage because its etiology and clinical phenotypes are highly heterogeneous. METHODS: We used a gene panel containing 141 genes implicated in DSDs to perform targeted next-generation sequencing (NGS) in 50 patients with 46,XY DSD. RESULTS: Gene variants were detected in 23 patients (46%). Among them, 13 patients had previously reported pathogenic or likely pathogenic variants, 9 patients had novel variants, and 1 patient had a previously reported variant of uncertain significance. Three of the novel variants were pathogenic, and the remaining were variants of uncertain significance; therefore, 16 patients had pathogenic or likely pathogenic variants according to ACMG guidelines, and the overall diagnostic rate of 46,XY DSD was 32%. The most common gene variants were SRD5A2 variants, followed by the AR variant. In addition, we analyzed the association between gene variants and clinical phenotypes. Most patients presented with multiple DSD phenotypes (i.e., two or more DSD phenotypes were observed, such as micropenis, hypospadias, and cryptorchidism), but the phenotype with the highest diagnostic rate was micropenis. CONCLUSION: Our results indicate that targeted NGS can effectively detect pathogenic gene variants in patients with 46,XY DSD.

DIA-based proteomics analysis of serum-derived exosomal proteins as potential candidate biomarkers for intrahepatic cholestasis in pregnancy.

BACKGROUND: Data-independent acquisition (DIA) is one of the most powerful and reproducible proteomic technologies for large-scale digital qualitative and quantitative research. The aim of this study was to use proteomic methodologies for the identification of biomarkers that are over or underexpressed in women with intrahepatic cholestasis of pregnancy (ICP) compared with controls and discover a potential biomarker panel for ICP detection. METHODS: The participants included 11 ICP patients and 11 healthy pregnant women as controls. The clinical characteristic data and the laboratory biochemical data were collected at the time of recruitment. Then, a data-independent acquisition (DIA)-based proteomics approach was used to identify differentially expressed proteins (DEPs) in serum exosomes between ICP patients and controls. Finally, bioinformatics analysis was used to identify the relevant processes in which these DEPs were involved. RESULTS: The proteomics results showed that there were 162 DEPs in serum exosomes between pregnant women with ICP and healthy pregnant women, of which 106 were upregulated and 56 were downregulated in ICP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the identified proteins were functionally related to specific cell processes including apoptosis, lipid metabolism, immune response and cell proliferation, and metabolic disorders, suggesting that these may be primary causative factors in ICP pathogenesis. Meanwhile, complement and coagulation cascades may be closely related to the development of ICP. Receiver operating characteristic curve (ROC) analysis showed that the area under the curve values of Elongation factor 1-alpha 1, Beta-2-glycoprotein I, Zinc finger protein 238, CP protein and Ficolin-3 were all approximately 0.9, indicating the promising diagnostic value of these proteins. CONCLUSIONS: This preliminary work provides a better understanding of the proteomic alterations in the serum exosomes of pregnant women with ICP.

A brain structural connectivity biomarker for autism spectrum disorder diagnosis in early childhood.

Background: Autism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers, particularly in young children at the age when symptoms become fully established. Furthermore, such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level. Objective: This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children. Methods: A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) together with symptom severity and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets. Results: Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification achieved very high accuracy of 96.77% in the discovery dataset, and 91.67% and 88.89% in the two independent validation datasets. Conclusions: Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.