A Comprehensive Study on Implant Stability Quotient (ISQ) in View of Resonance Frequency and Spectrum Analysis.

PURPOSE: This experimental study investigated how well implant stability quotient (ISQ) represents resonance frequency. Benchtop experiments on standardized samples, mimicking a premolar section of a mandible, were conducted to correlate an ISQ value and a resonance frequency to synthetic bone density and an incremental insertion torque. A frequency spectrum analysis was performed to check the validity of the resonance frequency analysis (RFA). MATERIALS AND METHODS: Branemark Mk III implants with dimensions ∅4 Å~ 11.5 mm were placed in Sawbones test models of five different densities (40, 30, 40/20, 20, 15 PCF). An incremental insertion torque was recorded during implant placement. To perform stability measurements, the test models were clamped partially in a vise (unclamped volume 10 Å~ 20 Å~ 34 mm). A MultiPeg was attached onto the implants, and a Penguin RFA measured ISQ. Simultaneously, motion of the MultiPeg was monitored via a laser Doppler vibrometer and processed by a spectrum analyzer to obtain the resonance frequency. Tightness of the clamp was adjusted to vary the resonance frequency. A statistical analysis produced a linear correlation coefficient 𝑅 among the measured ISQ, resonance frequency, and incremental insertion torque. RESULTS: The resonance frequency had high correlation to the incremental insertion torque (𝑅 = 0.978), confirming the validity of using RFA for this study. Measured ISQ data were scattered and had low correlation to the resonance frequency (𝑅 = 0.214) as well as the incremental insertion torque (𝑅 = -0.386). The spectrum analysis revealed simultaneous presence of multiple resonance frequencies. CONCLUSIONS: For the designed benchtop tests, resonance frequency does indicate implant stability in view of Sawbones density and incremental insertion torque. ISQ measurements, however, do not correlate well to the resonance frequency, and may not reflect the stability when multiple resonance frequencies are present simultaneously.

Spin-Phonon Coupling in Iron-Doped Ultrathin Bismuth Halide Perovskite Derivatives.

Spin in semiconductors facilitates magnetically controlled optoelectronic and spintronic devices. In metal halide perovskites (MHPs), doping magnetic ions is proven to be a simple and efficient approach to introducing a spin magnetic momentum. In this work, we present a facile metal ion doping protocol through the vapor-phase metal halide insertion reaction to the chemical vapor deposition (CVD)-grown ultrathin Cs3BiBr6 perovskites. The Fe-doped bismuth halide (Fe:CBBr) perovskites demonstrate that the iron spins are successfully incorporated into the lattice, as revealed by the spin-phonon coupling below the critical temperature Tc around 50 K observed through temperature-dependent Raman spectroscopy. Furthermore, the phonons exhibit significant softening under an applied magnetic field, possibly originating from magnetostriction and spin exchange interaction. The spin-phonon coupling in Fe:CBBr potentially provides an efficient way to tune the spin and lattice parameters for halide perovskite-based spintronics.

Interfacial Spinel Local Interlocking Strategy Toward Structural Integrity in P3 Oxide Cathodes.

P3-layered transition oxide cathodes have garnered considerable attention owing to their high initial capacity, rapid Na+ kinetics, and less energy consumption during the synthesis process. Despite these merits, their practical application is hindered by the substantial capacity degradation resulting from unfavorable structural transformations, Mn dissolution and migration. In this study, we systematically investigated the failure mechanisms of P3 cathodes, encompassing Mn dissolution, migration, and the irreversible P3-O3' phase transition, culminating in severe structural collapse. To address these challenges, we proposed an interfacial spinel local interlocking strategy utilizing P3/spinel intergrowth oxide as a proof-of-concept material. As a result, P3/spinel intergrowth oxide cathodes demonstrated enhanced cycling performance. The effectiveness of suppressing Mn migration and maintaining local structure of interfacial spinel local interlocking strategy was validated through depth-etching X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and in situ synchrotron-based X-ray diffraction. This interfacial spinel local interlocking engineering strategy presents a promising avenue for the development of advanced cathode materials for sodium-ion batteries.

Spatially Resolved Anion Diffusion and Tunable Waveguides in Bismuth Halide Perovskites.

Bismuth halide perovskites are widely regarded as nontoxic alternatives to lead halide perovskites for optoelectronics and solar energy harvesting applications. With a tailorable composition and intriguing optical properties, bismuth halide perovskites are also promising candidates for tunable photonic devices. However, robust control of the anion composition in bismuth halide perovskites remains elusive. Here, we established chemical vapor deposition and anion exchange protocols to synthesize bismuth halide perovskite nanoflakes with controlled dimensions and variable compositions. In particular, we demonstrated the gradient bromide distribution by controlling the anion exchange and diffusion processes, which is spatially resolved by time-of-flight secondary ion mass spectrometry. Moreover, the optical waveguiding properties of bismuth halide perovskites can be modulated by flake thicknesses and anion compositions. With a unique gradient anion distribution and controllable optical properties, bismuth halide perovskites provide new possibilities for applications in optoelectronic devices and integrated photonics.

Developing an abnormal high-Na-content P2-type layered oxide cathode with near-zero-strain for high-performance sodium-ion batteries.

Layered transition metal oxides (NaxTMO2) possess attractive features such as large specific capacity, high ionic conductivity, and a scalable synthesis process, making them a promising cathode candidate for sodium-ion batteries (SIBs). However, NaxTMO2 suffer from multiple phase transitions and Na+/vacancy ordering upon Na+ insertion/extraction, which is detrimental to their electrochemical performance. Herein, we developed a novel cathode material that exhibits an abnormal P2-type structure at a stoichiometric content of Na up to 1. The cathode material delivers a reversible capacity of 108 mA h g-1 at 0.2C and 97 mA h g-1 at 2C, retaining a capacity retention of 76.15% after 200 cycles within 2.0-4.3 V. In situ diffraction studies demonstrated that this material exhibits an absolute solid-solution reaction with a low volume change of 0.8% during cycling. This near-zero-strain characteristic enables a highly stabilized crystal structure for Na+ storage, contributing to a significant improvement in battery performance. Overall, this work presents a simple yet effective approach to realizing high Na content in P2-type layered oxides, offering new opportunities for high-performance SIB cathode materials.

Iodine-mediated oxidative triple functionalization of indolines with azoles and diazonium salts.

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C-H functionalization to yield the indole derivatives.

Associations between somatic symptoms and remission of major depressive disorder: A longitudinal study in China.

Previous studies have documented negative associations between somatic symptoms and remission of major depressive disorder (MDD). However, the correlations of specific somatic symptoms with remission remain uncertain. We aimed to explore the associations between specific somatic symptoms and remission focusing on sex differences among patients with MDD. We used data from patients with MDD in the Depression Cohort in China. At baseline, total somatic symptoms were evaluated using the 28-item Somatic Symptoms Inventory and were categorized into pain, autonomic, energy, and central nervous system (CNS) symptoms. To measure remission of MDD, depressive symptoms were evaluated using the Patient Health Questionnaire-9 after 3 months of treatment. We ultimately included 634 patients. Compared with quartile 1 of total somatic symptom scores, the full-adjusted ORs (95% CIs) for remission from quartile 2 to quartile 4 were 0.52 (0.30, 0.90), 0.44 (0.23, 0.83), and 0.36 (0.17, 0.75), respectively (P-value for trend = 0.005). The restricted cubic spline showed no non-linear associations between total somatic symptoms with remission (P-value for non-linear = 0.238). Pain, autonomic, and CNS symptoms showed similar results. Sex-stratified analysis showed that total somatic symptoms, pain symptoms, and autonomic symptoms were negatively correlated with remission in females, whereas CNS symptoms were negatively associated with remission in males. Our findings indicate that specific somatic symptoms exert differential effects on remission of MDD. Therapeutic interventions that target pain, autonomic, and CNS symptoms may increase the probability of remission. Furthermore, interventions for somatic symptoms should be tailored by sex, and females deserve more attention.

Re-evaluating a historic cohort of sinonasal and skull base mucoepidermoid carcinoma: an institutional experience.

AIMS: Primary mucoepidermoid carcinomas (MECs) of the sinonasal tract and nasopharynx are rare entities that represent a diagnostic challenge, especially in biopsy samples. Herein, we present a case series of MECs of the sinonasal and skull base and its mimics to evaluate the clinicopathological and molecular characteristics in order to avoid misdiagnosis. METHODS: We reviewed the pathology records of patients diagnosed from 2014 to 2022. Thirty MECs were consecutively diagnosed during that period. RESULTS: Based on morphological and fluorescence in situ hybridization (FISH) analyses, 30 tumors originally diagnosed as MECs were separated into MAML2 fusion-positive (7 cases) and MAML2 fusion-negative groups (23 cases), in which 14 tumors were positive for the EWSR1::ATF1 fusion; these tumors were reclassified to have hyalinizing clear cell carcinoma (HCCC). The remaining nine MAML2 FISH negative cases were reconfirmed as squamous cell carcinoma (SCC, 3 cases) which showed keratinization and high Ki-67 expression; DEK::AFF2 carcinomas (2 cases), in which DEK gene rearrangement was detected by FISH; and MECs as previously described (4 cases) with typical morphological features. Including 7 MAML2 rearrangements tumors, 11 MEC cases had a male-to-female ratio of 4.5:1, and 6 tumors arose from the nasopharyngeal region, while 5 tumors arose from the sinonasal region. The prognosis of this series of salivary gland-type MECs was favorable. CONCLUSIONS: Our study confirmed that HCCC runs the risk of being misdiagnosed as MEC in the sinonasal tract and nasopharynx, particularly with biopsy specimens. Careful histological evaluation with supporting molecular testing can facilitate pathological diagnoses.

Tuning Local Atomic Structures in MoS2 Based Catalysts for Electrochemical Nitrate Reduction.

In recent years, there has been a substantial surge in the investigation of transition-metal dichalcogenides such as MoS2 as a promising electrochemical catalyst. Inspired by denitrification enzymes such as nitrate reductase and nitrite reductase, the electrochemical nitrate reduction catalyzed by MoS2 with varying local atomic structures is reported. It is demonstrated that the hydrothermally synthesized MoS2 containing sulfur vacancies behaves as promising catalysts for electrochemical denitrification. With copper doping at less than 9% atomic ratio, the selectivity of denitrification to dinitrogen in the products can be effectively improved. X-ray absorption characterizations suggest that two sulfur vacancies are associated with one copper dopant in the MoS2 skeleton. DFT calculation confirms that copper dopants replace three adjacent Mo atoms to form a trigonal defect-enriched region, introducing an exposed Mo reaction center that coordinates with Cu atom to increase N2 selectivity. Apart from the higher activity and selectivity, the Cu-doped MoS2 also demonstrates remarkably improved tolerance toward oxygen poisoning at high oxygen concentration. Finally, Cu-doped MoS2 based catalysts exhibit very low specific energy consumption during the electrochemical denitrification process, paving the way for potential scale-up operations.

Associations of rumination with suicidal ideation and suicide attempts amongst individuals with major depressive disorder: A 12-month longitudinal study in China.

BACKGROUND: This study aimed to explore the longitudinal associations of rumination with suicidal ideation and suicide attempts in individuals with major depressive disorder (MDD). METHODS: Participants were derived from the Depression Cohort in China study (DCC). Those who completed at least one follow-up visit during the 12 months were included in the analysis. Dimensions of rumination including brooding and reflection were each measured using five items of the Ruminative Responses Scale. Suicidal ideation was assessed using the Beck Scale for Suicide Ideation. Suicide attempts were also assessed and all were analyzed with generalized estimating equations. RESULTS: Our final sample included 532 participants aged 18 to 59 years (mean [SD], 26.91 [6.94] years) consisting of 148 (27.8%) males and 384 (72.2%) females. After adjusting for temporal trend and potential confounders, individuals with higher levels of reflection were more likely to report suicidal ideation (AOR =1.11, 95% CI:1.01-1.22). However, no statistically significant association was found between brooding and suicidal ideation (AOR =1.06, 95% CI:0.96-1.17). Conversely, individuals with higher levels of brooding were more likely to report suicide attempts (AOR =1.13, 95% CI:1.02-1.24), while no statistically significant association was observed between reflection and suicide attempts (AOR =0.91, 95% CI:0.82-1.01). CONCLUSION: Rumination reflects a disturbance in cognitive emotional processing and manifests in different dimensions. Our findings suggest that high levels of reflection and brooding may be associated with a higher likelihood of having suicidal ideation and suicide attempts, respectively. However, it should be interpreted with caution, given that effect sizes are small.

CSINet: A Cross-Scale Interaction Network for Lightweight Image Super-Resolution.

In recent years, advancements in deep Convolutional Neural Networks (CNNs) have brought about a paradigm shift in the realm of image super-resolution (SR). While augmenting the depth and breadth of CNNs can indeed enhance network performance, it often comes at the expense of heightened computational demands and greater memory usage, which can restrict practical deployment. To mitigate this challenge, we have incorporated a technique called factorized convolution and introduced the efficient Cross-Scale Interaction Block (CSIB). CSIB employs a dual-branch structure, with one branch extracting local features and the other capturing global features. Interaction operations take place in the middle of this dual-branch structure, facilitating the integration of cross-scale contextual information. To further refine the aggregated contextual information, we designed an Efficient Large Kernel Attention (ELKA) using large convolutional kernels and a gating mechanism. By stacking CSIBs, we have created a lightweight cross-scale interaction network for image super-resolution named "CSINet". This innovative approach significantly reduces computational costs while maintaining performance, providing an efficient solution for practical applications. The experimental results convincingly demonstrate that our CSINet surpasses the majority of the state-of-the-art lightweight super-resolution techniques used on widely recognized benchmark datasets. Moreover, our smaller model, CSINet-S, shows an excellent performance record on lightweight super-resolution benchmarks with extremely low parameters and Multi-Adds (e.g., 33.82 dB@Set14 × 2 with only 248 K parameters).

Identifying novel proteins for suicide attempt by integrating proteomes from brain and blood with genome-wide association data.

Genome-wide association studies (GWASs) have identified risk loci for suicide attempt (SA), but deciphering how they confer risk for SA remains largely unknown. This study aims to identify the key proteins and gain insights into SA pathogenesis. We integrated data from the brain proteome (N = 376) and blood proteome (N = 35,559) and combined it with the largest SA GWAS summary statistics to date (N = 518,612). A comprehensive set of methods was employed, including Mendelian randomization (MR), Steiger filtering, Bayesian colocalization, proteome­wide association studies (PWAS), transcript-levels, cell-type specificity, correlation, and protein-protein interaction (PPI) network analysis. Validation was performed using other protein datasets and the SA dataset from FinnGen study. We identified ten proteins (GLRX5, GMPPB, B3GALTL, FUCA2, TTLL12, ADCK1, MMAA, HIBADH, ACP1, DOC2A) associated with SA in brain proteomics. GLRX5, GMPPB, and FUCA2 showed strong colocalization evidence and were supported by PWAS and transcript-level analysis, and were predominantly expressed in glutamatergic neuronal cells. In blood proteomics, one significant protein (PEAR1) and three near-significant proteins (NDE1, EVA1C, B4GALT2) were identified, but lacked colocalization evidence. Moreover, despite the limited correlation between the same protein in brain and blood, the PPI network analysis provided new insights into the interaction between brain and blood in SA. Furthermore, GLRX5 was associated with the GSTP1, the target of Clozapine. The comprehensive analysis provides strong evidence supporting a causal association between three genetically determined brain proteins (GLRX5, GMPPB, and FUCA2) with SA. These findings offer valuable insights into SA's underlying mechanisms and potential therapeutic approaches.

Toward Controlled Synthesis of 2D Crystals by CVD: Learning from the Real-Time Crystal Morphology Evolutions.

The rich morphology of 2D materials grown through chemical vapor deposition (CVD), is a distinctive feature. However, understanding the complex growth of 2D crystals under practical CVD conditions remains a challenge due to various intertwined factors. Real-time monitoring is crucial to providing essential data and enabling the use of advanced tools like machine learning for unraveling these complexities. In this study, we present a custom-built miniaturized CVD system capable of observing and recording 2D MoS2 crystal growth in real time. Image processing converts the real-time footage into digital data, and machine learning algorithms (ML) unveil the significant factors influencing growth. The machine learning model successfully predicts CVD growth parameters for synthesizing ultralarge monolayer MoS2 crystals. It also demonstrates the potential to reverse engineer CVD growth parameters by analyzing the as-grown 2D crystal morphology. This interdisciplinary approach can be integrated to enhance our understanding of controlled 2D crystal synthesis through CVD.

FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype. METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2-knockdown zebrafish, and Fars2-knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification. RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2-deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2-knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis. CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.

First pass effect in patients undergoing endovascular treatment for posterior circulation acute ischemic stroke.

OBJECTIVE: This study aims to investigate the impact of first pass effect (FPE) on outcomes in the posterior circulation acute ischemic stroke (PC-AIS) and the independent predictors of FPE. METHODS: This was a multicenter, retrospective study. PC-AIS patients who underwent endovascular treatment were reviewed. The cohort achieving complete or nearly complete reperfusion (defined as expanded treatment in cerebralischemia [eTICI] ≥ 2c) was categorized into the FPE and multiple pass effect (MPE) groups. FPE was defined as achieving eTICI ≥ 2c with a single pass and without the use of rescue therapy. Modified FPE (mFPE) was defined as meeting the criteria for FPE but with eTICI ≥ 2b. The association of FPE with 90-day clinical outcomes and predictors for FPE were both investigated. RESULTS: The study included a total of 328 patients, with 69 patients (21 %) in the FPE group. For primary outcome, FPE had a significant higher favorable outcome (mRS ≤ 3) rate than MPE (65.2 % vs. 44.8 %, p = 0.003). Similar outcomes were observed in the mFPE. Furthermore, FPE was significantly associated with favorable outcome (adjusted OR 2.23, 95 % CI 1.06-4.73, p = 0.036). Positive predictors for FPE included occlusion in the distal basilar artery, the first-line aspiration or combination, and cardioembolic etiology. Negative predictors for FPE included hypertension and general anesthesia. CONCLUSION: For PC-AIS patients due to large or medium vessel occlusion, FPE is associated with favorable clinical outcomes. The first-line techniques of aspiration or combination, as well as avoiding general anesthesia, contribute to a better realization of FPE.

Pathogenic Somatic Mutation of DICER1 and Clinicopathological Features in Nasal Chondromesenchymal Hamartomas: A Series of Nine Cases.

Nasal chondromesenchymal hamartoma (NCMH) is a rare benign polypoid mesenchymal tumor arising in the nasal cavity and/or paranasal sinuses. Recognizing these sporadic, rare lesions is crucial, as surgical complete removal of the mass is the common treatment approach. This retrospective study analyzed the demographics, symptoms, and imaging data of 9 patients diagnosed with NCMH between January 2017 and June 2023, possibly representing the largest single-center adult case cohort to date. Diagnostic techniques included nasal endoscopy, CT/MRI scan, immunohistological studies, and morphologic comparisons. Pathologic specimens were subjected to Sanger sequencing of exons 24 and 25 of DICER1. The average age of 9 cases was 24.4 years, and the oldest was 55 years. Four of the patients were children, ranging from 1 year old to 11 years old, with an average of 4.5 years. Nasal congestion is the most common registered symptom. Endoscopic findings showed that most patients had smooth pink neoplasms or polypoid masses in the nasal meatus. Radiologic scanning revealed soft-tissue density masses that occupied the nasal cavity. Histologically, the characteristic structure of NCMHs is immature cellular cartilage nodules and mature cartilage nodules distributed in a loose mucoid matrix. Five of the 9 patients had somatic DICER1 missense mutations. Four of the patients with DICER1-mutated NCMH exhibited a p.E1813 missense hotspot mutation. We also report a case of a rare p.P1836H missense mutation. The detected DICER1 somatic mutations provide compelling evidence of an association with the DICER1 tumor family. We emphasize the importance of pathologic consultation and the need for pathologists to accumulate experience in NCMH diagnosis to avoid misdiagnosis.

Nickel Nanoparticles Protruding from Molybdenum Carbide Micropillars with Carbon Layer-Protected Biphasic 0D/1D Heterostructures for Efficient Water Splitting.

It remains a tremendous challenge to achieve high-efficiency bifunctional electrocatalysts for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) for hydrogen production by water splitting. Herein, a novel hybrid of 0D nickel nanoparticles dispersed on the one-dimensional (1D) molybdenum carbide micropillars embedded in the carbon layers (Ni/Mo2C@C) was successfully prepared on nickel foam by a facile pyrolysis strategy. During the synthesis process, the nickel nanoparticles and molybdenum carbide were simultaneously generated under H2 and C2H2 mixed atmospheres and conformally encapsulated in the carbon layers. Benefiting from the distinctive 0D/1D heterostructure and the synergistic effect of the biphasic Mo2C and Ni together with the protective effect of the carbon layer, the reduced activation energy barriers and fast catalytic reaction kinetics can be achieved, resulting in a small overpotential of 96 mV for the HER and 266 mV for the OER at the current density of 10 mA cm-2 together with excellent durability in 1.0 M KOH electrolyte. In addition, using the developed Ni/Mo2C@C as both the cathode and anode, the constructed electrolyzer exhibits a small voltage of 1.55 V for the overall water splitting. The novel designed Ni/Mo2C@C may give inspiration for the development of efficient bifunctional catalysts with low-cost transition metal elements for water splitting.

Prospective prenatal cell-free DNA screening for genetic conditions of heterogenous etiologies.

Prenatal cell-free DNA (cfDNA) screening uses extracellular fetal DNA circulating in the peripheral blood of pregnant women to detect prevalent fetal chromosomal anomalies. However, numerous severe conditions with underlying single-gene defects are not included in current prenatal cfDNA screening. In this prospective, multicenter and observational study, pregnant women at elevated risk for fetal genetic conditions were enrolled for a cfDNA screening test based on coordinative allele-aware target enrichment sequencing. This test encompasses the following three of the most frequent pathogenic genetic variations: aneuploidies, microdeletions and monogenic variants. The cfDNA screening results were compared to invasive prenatal or postnatal diagnostic test results for 1,090 qualified participants. The comprehensive cfDNA screening detected a genetic alteration in 135 pregnancies with 98.5% sensitivity and 99.3% specificity relative to standard diagnostics. Of 876 fetuses with suspected structural anomalies on ultrasound examination, comprehensive cfDNA screening identified 55 (56.1%) aneuploidies, 6 (6.1%) microdeletions and 37 (37.8%) single-gene pathogenic variants. The inclusion of targeted monogenic conditions alongside chromosomal aberrations led to a 60.7% increase (from 61 to 98) in the detection rate. Overall, these data provide preliminary evidence that a comprehensive cfDNA screening test can accurately identify fetal pathogenic variants at both the chromosome and single-gene levels in high-risk pregnancies through a noninvasive approach, which has the potential to improve prenatal evaluation of fetal risks for severe genetic conditions arising from heterogenous molecular etiologies. ClinicalTrials.gov registration: ChiCTR2100045739 .

Cholesterol homeostasis confers glioma malignancy triggered by hnRNPA2B1-dependent regulation of SREBP2 and LDLR.

BACKGROUND: Dysregulation of cholesterol metabolism is a significant characteristic of glioma, yet the underlying mechanisms are largely unknown. N6-methyladenosine (m6A) modification has been implicated in promoting tumor development and progression. The aim of this study was to determine the key m6A regulatory proteins involved in the progression of glioma, which is potentially associated with the reprogramming of cholesterol homeostasis. METHODS: Bioinformatics analysis was performed to determine the association of m6A modification with glioma malignancy from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Glioma stem cell (GSC) self-renewal was determined by tumor sphere formation and bioluminescence image assay. RNA sequencing and lipidomic analysis were performed for cholesterol homeostasis analysis. RNA immunoprecipitation and luciferase reporter assay were performed to determine hnRNPA2B1-dependent regulation of sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR) mRNA. The methylation status of hnRNPA2B1 promoter was determined by bioinformatic analysis and methylation-specific PCR assay. RESULTS: Among the m6A-regulatory proteins, hnRNPA2B1 was demonstrated the most important independent prognostic risk factor for glioma. hnRNPA2B1 ablation exhibited a significant tumor-suppressive effect on glioma cell proliferation, GSC self-renewal and tumorigenesis. hnRNPA2B1 triggers de novo cholesterol synthesis by inducing HMGCR through the stabilization of SREBP2 mRNA. m6A modification of SREBP2 or LDLR mRNA is required for hnRNPA2B1-mediated mRNA stability. The hypomethylation of cg21815882 site on hnRNPA2B1 promoter confers elevated expression of hnRNPA2B1 in glioma tissues. The combination of targeting hnRNPA2B1 and cholesterol metabolism exhibited remarkable antitumor effects, suggesting valuable clinical implications for glioma treatment. CONCLUSIONS: hnRNPA2B1 facilitates cholesterol uptake and de novo synthesis, thereby contributing to glioma stemness and malignancy.

BNC1 deficiency induces mitochondrial dysfunction-triggered spermatogonia apoptosis through the CREB/SIRT1/FOXO3 pathway: the therapeutic potential of nicotinamide riboside and metformin†.

Male infertility is a global health problem that disturbs numerous couples worldwide. Basonuclin 1 (BNC1) is a transcription factor mainly expressed in proliferative keratinocytes and germ cells. A frameshift mutation of BNC1 was identified in a large Chinese primary ovarian insufficiency pedigree. The expression of BNC1 was significantly decreased in the testis biopsies of infertile patients with nonobstructive azoospermia. Previous studies have revealed that mice with BNC1 deficiency are generally subfertile and undergo gradual spermatogenic failure. We observed that apoptosis of spermatogonia is tightly related to spermatogenic failure in mice with a Bnc1 truncation mutation. Such impairment is related to mitochondrial dysfunction causing lower mitochondrial membrane potential and higher reactive oxygen species. We showed that downregulation of CREB/SIRT1/FOXO3 signaling participates in the above impairment. Administration of nicotinamide riboside or metformin reversed mitochondrial dysfunction and inhibited apoptosis in Bnc1-knockdown spermatogonia by stimulating CREB/SIRT1/FOXO3 signaling. Dietary supplementation with nicotinamide riboside or metformin in mutated mice increased SIRT1 signaling, improved the architecture of spermatogenic tubules, inhibited apoptosis of the testis, and improved the fertility of mice with a Bnc1 truncation mutation. Our data establish that oral nicotinamide riboside or metformin can be useful for the treatment of spermatogenic failure induced by Bnc1 mutation.