OBOX regulates mouse zygotic genome activation and early development.

Zygotic genome activation (ZGA) activates the quiescent genome to enable the maternal-to-zygotic transition1,2. However, the identity of transcription factors that underlie mammalian ZGA in vivo remains elusive. Here we show that OBOX, a PRD-like homeobox domain transcription factor family (OBOX1-OBOX8)3-5, are key regulators of mouse ZGA. Mice deficient for maternally transcribed Obox1/2/5/7 and zygotically expressed Obox3/4 had a two-cell to four-cell arrest, accompanied by impaired ZGA. The Obox knockout defects could be rescued by restoring either maternal and zygotic OBOX, which suggests that maternal and zygotic OBOX redundantly support embryonic development. Chromatin-binding analysis showed that Obox knockout preferentially affected OBOX-binding targets. Mechanistically, OBOX facilitated the 'preconfiguration' of RNA polymerase II, as the polymerase relocated from the initial one-cell binding targets to ZGA gene promoters and distal enhancers. Impaired polymerase II preconfiguration in Obox mutants was accompanied by defective ZGA and chromatin accessibility transition, as well as aberrant activation of one-cell polymerase II targets. Finally, ectopic expression of OBOX activated ZGA genes and MERVL repeats in mouse embryonic stem cells. These data thus demonstrate that OBOX regulates mouse ZGA and early embryogenesis.

The landscape of the methodology in drug repurposing using human genomic data: a systematic review.

The process of drug development is expensive and time-consuming. In contrast, drug repurposing can be introduced to clinical practice more quickly and at a reduced cost. Over the last decade, there has been a significant expansion of large biobanks that link genomic data to electronic health record data, public availability of various databases containing biological and clinical information and rapid development of novel methodologies and algorithms in integrating different sources of data. This review aims to provide a thorough summary of different strategies that utilize genomic data to seek drug-repositioning opportunities. We searched MEDLINE and EMBASE databases to identify eligible studies up until 1 May 2023, with a total of 102 studies finally included after two-step parallel screening. We summarized commonly used strategies for drug repurposing, including Mendelian randomization, multi-omic-based and network-based studies and illustrated each strategy with examples, as well as the data sources implemented. By leveraging existing knowledge and infrastructure to expedite the drug discovery process and reduce costs, drug repurposing potentially identifies new therapeutic uses for approved drugs in a more efficient and targeted manner. However, technical challenges when integrating different types of data and biased or incomplete understanding of drug interactions are important hindrances that cannot be disregarded in the pursuit of identifying novel therapeutic applications. This review offers an overview of drug repurposing methodologies, providing valuable insights and guiding future directions for advancing drug repurposing studies.

CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis.

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 (cluster of differentiation 147) in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE-/-) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor-associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest-specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE-/- mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5-dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

Cross-cancer pleiotropic analysis identifies three novel genetic risk loci for colorectal cancer.

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC.

BACKGROUND AND AIMS: Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS: In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.

BACKGROUND: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated. METHODS: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3. RESULTS: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients. CONCLUSIONS: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.

Fecal Microbiota Transplantation for Severe Infant Botulism, China.

Infant botulism in a 4-month-old boy in China who continued to excrete toxins for over a month despite antitoxin therapy was further treated with fecal microbiota transplantation. After treatment, we noted increased gut microbial diversity and altered fecal metabolites, which may help reduce intestinal pH and enhance anti-inflammatory capabilities.

Healthy lifestyle and cancer survival: A multinational cohort study.

Lifestyle factors after a cancer diagnosis could influence the survival of cancer 60 survivors. To examine the independent and joint associations of healthy lifestyle factors with mortality outcomes among cancer survivors, four prospective cohorts (National Health and Nutrition Examination Survey [NHANES], National Health Interview Survey [NHIS], UK Biobank [UKB] and Kailuan study) across three countries. A healthy lifestyle score (HLS) was defined based on five common lifestyle factors (smoking, alcohol drinking, diet, physical activity and body mass index) that related to cancer survival. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of individual lifestyle factors and HLS with all-cause and cancer mortality among cancer survivors. During the follow-up period of 37,095 cancer survivors, 8927 all-cause mortality events were accrued in four cohorts and 4449 cancer death events were documented in the UK and US cohorts. Never smoking (adjusted HR = 0.77, 95% CI: 0.69-0.86), light alcohol consumption (adjusted HR = 0.86, 95% CI: 0.82-0.90), adequate physical activity (adjusted HR = 0.90, 95% CI: 0.85-0.94), a healthy diet (adjusted HR = 0.69, 95% CI: 0.61-0.78) and optimal BMI (adjusted HR = 0.89, 95% CI: 0.85-0.93) were significantly associated with a lower risk of all-cause mortality. In the joint analyses of HLS, the HR of all-cause and cancer mortality for cancer survivors with a favorable HLS (4 and 5 healthy lifestyle factors) were 0.55 (95% CI 0.42-0.64) and 0.57 (95% CI 0.44-0.72), respectively. This multicohort study of cancer survivors from the United States, the United Kingdom and China found that greater adherence to a healthy lifestyle might be beneficial in improving cancer prognosis.

Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation.

BACKGROUND: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. METHODS: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. RESULTS: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10-7) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10-11) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25). CONCLUSION: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.

Silver-Coordinated Watson-Crick Pairing-Driven Three-Dimensional DNA Walker for Locus-Specific Detection of Genomic N6-Methyladenine and N4-Methylcytosine at the Single-Molecule Level.

N6-Methyladenine (6mdA) and N4-methylcytosine (4mdC) are the two most dominant DNA modifications in both prokaryotes and eukaryotes, but standard hybridization-based techniques cannot be applied for the 6mdA/4mdC assay. Herein, we demonstrate the silver-coordinated Watson-Crick pairing-driven three-dimensional (3D) DNA walker for locus-specific detection of genomic 6mdA/4mdC at the single-molecule level. 6mdA-DNA and 4mdC-DNA can selectively hybridize with the binding probes (BP1 and BP2) to form 6mdA-DNA-BP1 and 4mdC-DNA-BP2 duplexes. The 6mdA-C/4mdC-A mismatches cannot be stabilized by AgI, and thus, 18-nt BP1/BP2 cannot be extended by the catalysis of KF exonuclease. Through toehold-mediated strand displacement (TMSD), the signal probe (SP1/SP2) functionalized on the gold nanoparticles (AuNPs) can competitively bind to BP1/BP2 in 6mdA-DNA-BP1/4mdC-DNA-BP2 duplex to obtain SP1-18-nt BP1 and SP2-18-nt BP2 duplexes. The resulting DNA duplexes can act as the substrates of lambda exonuclease, leading to the cleavage of SP1/SP2 and the release of Cy3/Cy5 and 18-nt BP1/BP2. The released 18-nt BP1/BP2 can subsequently serve as the walker DNA, moving along the surface of the AuNP to activate dynamic 3D DNA walking and releasing abundant Cy3/Cy5. The released Cy3/Cy5 can be quantified by single-molecule imaging. This nanosensor exhibits high sensitivity with a limit of detection (LOD) of 9.80 × 10-15 M for 6mdA-DNA and 9.97 × 10-15 M for 4mdC-DNA. It can discriminate 6mdA-/4mdC-DNA from unmodified genomic DNAs, distinguish 0.01% 6mdA-/4mdC-DNA from excess unmethylated DNAs, and quantify 6mdA-/4mdC-DNA at specific sites in genomic DNAs of liver cancer cells and Escherichia coli plasmid cloning vector, providing a new platform for locus-specific analysis of 6mdA/4mdC in genomic DNAs.

Construction of an Enzymatically Controlled DNA Nanomachine for One-Step Imaging of Telomerase in Living Cells.

Telomerase is a basic reverse transcriptase that maintains the telomere length in cells, and accurate and specific sensing of telomerase in living cells is critical for medical diagnostics and disease therapeutics. Herein, we demonstrate for the first time the construction of an enzymatically controlled DNA nanomachine with endogenous apurinic/apyrimidinic endonuclease 1 (APE1) as a driving force for one-step imaging of telomerase in living cells. The DNA nanomachine is designed by rational engineering of substrate probes and reporter probes embedded with an enzyme-activatable site (i.e., AP site) and their subsequent assembly on a gold nanoparticle (AuNP). Upon recognition and cleavage of the AP site in the substrate probe by APE1, the loop of the substrate probe unfolds, exposing telomeric primer (TP) with the 3'-OH end. Subsequently, the TP is elongated by telomerase at the 3'-OH end to generate a long telomeric product. The resultant telomeric product acts as a swing arm that can hybridize with a reporter probe to initiate the APE1-powered walking reaction, ultimately generating a significantly enhanced fluorescence signal. Notably, endogenous APE1 is used as the driving force of the DNA nanomachine, avoiding the introduction of exogenous auxiliary cofactors into the cellular microenvironment. Owing to the high kinetics and high amplification efficiency of the APE1-powered DNA nanomachine, this strategy enables one-step sensitive sensing of telomerase in vitro and in vivo. It can successfully discriminate telomerase activity between cancer cells and normal cells, screen telomerase inhibitors, and monitor the variations of telomerase activity in living cells, offering a prospective platform for molecular diagnostics and drug discovery.

Metal Halide Nanocrystals@Silica Aerogel Composite with Enhanced Dispersion Stability and Light Output for Efficient X-Ray Imaging in Harsh Environment.

Metal halide nanocrystals (MHNCs) embedded in a polymer matrix as flexible X-ray detector screens is an effective strategy with the advantages of low cost, facile preparation, and large area flexibility. However, MHNCs easily aggregate during preparation, recombination, under mechanical force, storage, or high operating temperature. Meanwhile, it shows an unmatched refractive index with polymer, resulting in low light yield. The related stability and properties of the device remain a huge unrevealed challenge. Herein, a composite screen (CZBM@AG-PS) by integrating MHNCs (Cs2ZnBr4: Mn2+ as an example) into silica aerogel (AG) and embedded in polystyrene (PS) is successfully developed. Further characterization points to the high porosity AG template that can effectively improve the dispersion of MHNCs in polymer detector screens, essentially decreasing nonradiative transition, Rayleigh scattering, and performance aging induced by aggregation in harsh environments. Furthermore, the higher light output and lower optical crosstalk are also achieved by a novel light propagation path based on the MHNCs/AG and AG/PS interfaces. Finally, the optimized CZBM@AG-PS screen shows much enhanced light yield, spatial resolution, and temperature stability. Significantly, the strategy is proven universal by the performance tests of other MHNCs embedded composite films for ultra-stable and efficient X-ray imaging.

The Association of the Glymphatic Function with Parkinson's Disease Symptoms: Neuroimaging Evidence from Longitudinal and Cross-Sectional Studies.

OBJECTIVE: Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking. METHODS: In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function. RESULTS: Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aß1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5. INTERPRETATION: The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683.

Investigating the Structure-property Relationships of Two Cd-based Hybrid Multifunctional Compounds with High Tc, Bright Fluorescence and Wide Band-gap.

Organic-inorganic hybrid multifunctional materials have shown significant application in lighting and sensor fields, owing to their prominent performance and diversity structures. Herein, we synthesized two multifunctional compounds: (propyl-quinuclidone)2 CdBr4 (1) and (F-butyl-quinuclidone)2 CdBr4 (2). By introducing light-emitting organic cation with flexible long chain, 1 and 2 exhibit excellent transition properties and bright blue-white fluorescence. Then, combine fluorescence lifetime and first-principal calculation, providing evidence for the electron transfer emission. Subsequently, investigated the impact of substituent carbon chain length (methyl to butyl), structural rigidity (C-C to C-F) and halide framework (Cl to I) on the fluorescence properties. Results indicate that Cd⋅⋅⋅Cd distance and structural rigidity play an important role in fluorescence. Overall, our research provides valuable insight and example for chemical modifications enhance compound performance.

Multiparametric MRI-Based Deep Learning Radiomics Model for Assessing 5-Year Recurrence Risk in Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Accurately assessing 5-year recurrence rates is crucial for managing non-muscle-invasive bladder carcinoma (NMIBC). However, the European Organization for Research and Treatment of Cancer (EORTC) model exhibits poor performance. PURPOSE: To investigate whether integrating multiparametric MRI (mp-MRI) with clinical factors improves NMIBC 5-year recurrence risk assessment. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-one patients (median age, 65 years; age range, 54-73 years; 27 females) underwent mp-MRI between 2011 and 2017, and received ≥5-year follow-ups. They were divided into a training cohort (N = 115) and validation/testing cohorts (N = 38 in each). Recurrence rates were 23.5% (27/115) in the training cohort and 23.7% (9/38) in both validation and testing cohorts. FIELD STRENGTH/SEQUENCE: 3-T, fast spin echo T2-weighted imaging (T2WI), single-shot echo planar diffusion-weighted imaging (DWI), and volumetric spoiled gradient echo dynamic contrast-enhanced (DCE) sequences. ASSESSMENT: Radiomics and deep learning (DL) features were extracted from the combined region of interest (cROI) including intratumoral and peritumoral areas on mp-MRI. Four models were developed, including clinical, cROI-based radiomics, DL, and clinical-radiomics-DL (CRDL) models. STATISTICAL TESTS: Student's t-tests, DeLong's tests with Bonferroni correction, receiver operating characteristics with the area under the curves (AUCs), Cox proportional hazard analyses, Kaplan-Meier plots, SHapley Additive ExPlanations (SHAP) values, and Akaike information criterion for clinical usefulness. A P-value <0.05 was considered statistically significant. RESULTS: The cROI-based CRDL model showed superior performance (AUC 0.909; 95% CI: 0.792-0.985) compared to other models in the testing cohort for assessing 5-year recurrence in NMIBC. It achieved the highest Harrell's concordance index (0.804; 95% CI: 0.749-0.859) for estimating recurrence-free survival. SHAP analysis further highlighted the substantial role (22%) of the radiomics features in NMIBC recurrence assessment. DATA CONCLUSION: Integrating cROI-based radiomics and DL features from preoperative mp-MRI with clinical factors could improve 5-year recurrence risk assessment in NMIBC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Large regions of homozygosity in prenatal diagnosis.

Chromosomal microarrays (CMA) incorporate single nucleotide polymorphisms to enable the detection of regions of homozygosity (ROH). Here, we retrospectively analyzed 6288 prenatal cases who performed CMA to explored the clinical implications of large ROH in prenatal diagnosis. We analyzed cases with ROH larger than 10 megabases and reviewed the ultrasound findings; karyotype results and pregnancy follow-up data. Cases with possible imprinting disorders were assessed by methylation-specific multiplex ligation-dependent probe amplification. In total, we identified 50 cases with large ROH and chromosomes 1 and 2 were the most affected. About 59.18% of the ROH cases had ultrasound abnormalities, with the most common findings being ultrasound soft-marker abnormalities. There were seven fetuses had ROH which covered almost the entire chromosome and four had terminal ROH that involved almost the entire long arm of the chromosomes, which indicated uniparental disomy (UPD), of which 70% showed abnormal ultrasound findings. Ten cases with multiple ROH on different chromosomes indicated the third to fifth degree of consanguinity. In this study, we highlighted the clinical relevance of large ROH related to UPD. The analysis of ROH allowed us to gain further understanding of complex cytogenetic and disease mechanisms in prenatal diagnosis.

Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway.

Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.

Nitric Oxide-Releasing Porous Coating with Antibacterial Activity and Blood Compatibility.

Nitric oxide (NO)-releasing coating is promising to enhance the biocompatibility of medical devices. In this study, polyurethane (PU) and S-nitrosated keratin (KSNO) were dissolved with dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) to prepare a coating solution. This solution is facile to form a porous coating on various substrates based on solvent-evaporation-induced phase separation (SEIPS). The coating could continuously release NO up to 200 h in the presence of ascorbic acid (Asc). In addition, the coating could accelerate endothelialization by promoting the viability of human umbilical vein endothelial cells (HUVECs) while inhibiting the proliferation of human umbilical artery smooth muscle cells (HUASMCs). Furthermore, the coating had good antibacterial activity and blood compatibility. Taken together, this universal coating provides wider potential applications in the field of cardiovascular implants.

Silver/Antimony-Base Multifunctional Double Perovskite with H/F Substitution Enhance Properties.

Two-dimensional double perovskites have experienced rapid development due to their outstanding optoelectronic properties and diverse structural characteristics. However, the synthesis of high-performance multifunctional compounds and the regulation of their properties still lack relevant examples. Herein, we synthesized two multifunctional compounds, (C6H14N)4AgSbBr8 (1) and (F2-C6H12N)4AgSbBr8 (2), which exhibit high solid-state phase transition temperature, bistable dielectric constant switching, second harmonic generation (SHG), and bright emission. Through H/F substitution, the transition temperature increases and achieves a smaller band gap attributed to reduced interlayer spacing. Furthermore, we investigated the broad emission mechanism of the compounds through first-principles calculation and variable-temperature fluorescence, confirming the presence of the STE1 emission. Our work provides insight into the further development of multifunctional compounds and chemical modification that enhances compound properties.

Postpartum romantic attachment and constructiveness: The protective effects of a conflict communication intervention for parents' relationship functioning over one year.

Parent relationship functioning has a well-documented influence on children's early socioemotional development as early as infancy. Postpartum parenting is also a critically vulnerable period for relationships and often results in relationship decline. We investigated the effects of a rigorous, psycho-educational conflict communication intervention for supporting parents' relationship functioning in terms of self-reported romantic attachment and observed conflict constructiveness. Using latent growth curve models, we evaluated the change in romantic attachment and constructiveness among 202 mother-father couples from 6 to 18 months postpartum. We further tested a comparison of the effects of the Conflict Intervention (CI) versus the control group and the Conflict Intervention paired with an additional parent sensitivity intervention (anyCI) versus the control group. Results indicated romantic attachment and observed constructiveness decreased over the 1-year period; this decline was partially mitigated for fathers participating in the intervention(s), wherein fathers who received the Conflict Intervention showed less decline in observed conflict constructiveness over time. Moreover, compared with those in the control condition, mothers who received the Conflict Intervention reported lower attachment security at 18 months postpartum. These results underscore the importance of including perspectives from both mothers and fathers when investigating intervention effects and considering the impact of combining interventions for parents. RESEARCH HIGHLIGHTS: A randomized control trial of a conflict intervention including mothers and fathers demonstrates protective effects for fathers' constructiveness between 6 and 18 months postpartum but was not protective for mothers. Parenting experience, whether parents were transitioning to parenthood or had older children, did not significantly predict romantic attachment or behavioral constructiveness trajectories. Interparental romantic attachment and constructiveness declined only slightly postpartum. Effects of the intervention were reduced when the intervention was combined with a second intervention.