Molecular characterization of SARS-CoV-2 nucleocapsid protein.

Corona Virus Disease 2019 (COVID-19) is a highly prevalent and potent infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Until now, the world is still endeavoring to develop new ways to diagnose and treat COVID-19. At present, the clinical prevention and treatment of COVID-19 mainly targets the spike protein on the surface of SRAS-CoV-2. However, with the continuous emergence of SARS-CoV-2 Variants of concern (VOC), targeting the spike protein therapy shows a high degree of limitation. The Nucleocapsid Protein (N protein) of SARS-CoV-2 is highly conserved in virus evolution and is involved in the key process of viral infection and assembly. It is the most expressed viral structural protein after SARS-CoV-2 infection in humans and has high immunogenicity. Therefore, N protein as the key factor of virus infection and replication in basic research and clinical application has great potential research value. This article reviews the research progress on the structure and biological function of SARS-CoV-2 N protein, the diagnosis and drug research of targeting N protein, in order to promote researchers' further understanding of SARS-CoV-2 N protein, and lay a theoretical foundation for the possible outbreak of new and sudden coronavirus infectious diseases in the future.

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.

Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-ß (TGF-ß)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

Copper-Catalyzed [3 + 2] Annulation of O-Acyl Oximes with 4-Sulfonamidophenols for the Synthesis of 5-Sulfonamidoindoles and 2-Amido-5-sulfonamidobenzofuran-3(2H)-ones.

A copper-catalyzed [3 + 2] annulation of O-acyl oximes with 4-sulfonamidophenols is developed. The advantage of this method lies in the concurrent double activation of two substrates to form nucleophilic enamines and electrophilic quinone monoimines. The substituent on the α-carbon of O-acyl oxime determines two different reaction pathways, thereby leading to the selective generation of 5-sulfonamidoindoles and 2-amido-5-sulfonamidobenzofuran-3(2H)-ones.

A panel based on three-miRNAs as diagnostic biomarker for prostate cancer.

Background: Prostate cancer (PCa) is one of the most prevalent malignancies affecting the male life cycle. The incidence and mortality of prostate cancer are also increasing every year. Detection of MicroRNA expression in serum to diagnose prostate cancer and determine prognosis is a very promising non-invasive modality. Materials and method: A total of 224 study participants were included in our study, including 112 prostate cancer patients and 112 healthy adults. The experiment consisted of three main phases, namely, the screening phase, the testing phase, and the validation phase. The expression levels of serum miRNAs in patients and healthy adults were detected using quantitative reverse transcription-polymerase chain reaction. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to evaluate the diagnostic ability, specificity, and sensitivity of the candidate miRNAs. Result: Eventually, three miRNAs most relevant to prostate cancer diagnosis were selected, namely, miR-106b-5p, miR-129-1-3p and miR-381-3p. We used these three miRNAs to construct a diagnostic panel with very high diagnostic potential for prostate cancer, which had an AUC of 0.912 [95% confidence interval (CI): 0.858 to 0.950; p < 0.001; sensitivity = 91.67%; specificity = 79.76%]. In addition, the three target genes (DTNA, GJB1, and TRPC4) we searched for are also expected to be used for prostate cancer diagnosis and treatment in the future.

Testing the accuracy of a four serum microRNA panel for the detection of primary bladder cancer: a discovery and validation study.

BACKGROUND: Bladder cancer (BC) is one of the ten most common cancers worldwide with late detection and early age of diagnosis. There is abundant evidence that early detection and timely intervention can lead to a better prognosis of BC. Substantial evidence has indicated that microRNAs (miRNAs) are specific to different tumour types and are remarkably stable, indicating that serum miRNAs may serve as potential cancer diagnostic markers. This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary BC. METHODS: In this study, 18 miRNAs that were differentially expressed in BC were obtained from the PubMed or Gene Expression Omnibus database. Then, 18 BC-related-miRNAs were verified in screening and validation sets created using 56 (28 primary BC vs. 28 NCs) and 168 (84 primary BC vs. 84 NCs) serum samples, respectively. Quantitative reverse transcription-PCR (qRT-PCR) was performed to verify the identity of the differential miRNAs. A multi-miRNA panel with superior diagnostic performance was constructed. TCGA and KEGG databases were used to conduct the survival analysis and bioinformatics analysis, respectively. RESULTS: Six serum miRNAs (miR-221-5p, miR-181a-5p, miR-98-5p, miR-15a-5p, miR-222-3p, and miR-197-3p) were significantly aberrantly expressed in the BC patients, while four miRNAs from among them (miR-221-5p, miR-181a-5p, miR-15a-5p, miR-222-3p) were assembled into a panel that showed high diagnostic value (AUC = 0.875, 95% CI: 0.815 - 0.921; sensitivity: 82.14%; and specificity: 85.71%) based on the logistic regression analysis. The survival analysis showed that miR-181a-5p was closely associated with BC prognosis (Log-rank p-value < 0.05). CONCLUSION: The combination of the four miRNAs (miR-221-5p, miR-181a-5p, miR-15a-5p and miR-222-3p) may be a novel non-invasive serological biomarker for BC screening.

Early detection and timely intervention can lead to a better prognosis of bladder cancer.This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary bladder cancer.

Specific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory in mice.

Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

Relationship between serum apolipoprotein B and risk of all-cause and cardiovascular disease mortality in individuals with hypertension: a prospective cohort study.

BACKGROUND: Dyslipidemia frequently coexists with hypertension in the population. Apolipoprotein B (ApoB) is increasingly considered a more potent predictor of cardiovascular disease (CVD). Abnormal levels of serum ApoB can potentially impact the mortality risk. METHODS: The prospective cohort study employed data from the National Health and Nutrition Examination Survey (NHANES), which was performed between 2005 and 2016, with follow-ups extended until December 2019. Serum ApoB concentrations were quantified using nephelometry. In line with the NHANES descriptions and recommendations, the reference ranges for ApoB concentrations are 55-140 and 55-125 mg/dL for men and women, respectively. Participants were categorized into low, normal, and high ApoB levels. The low and high groups were combined into the abnormal group. In this study, all-cause mortality (ACM) and CVD mortality (CVM) were the endpoints. Survey-weighted cox hazards models were used for evaluating the correlation between serum ApoB levels and ACM and CVM. A generalized additive model (GAM) was employed to examine the dose-dependent relationship between ApoB levels and mortality risk. RESULTS: After a median of 95 (interquartile range: 62-135) months of follow-up, 986 all-cause and 286 CVD deaths were recorded. The abnormal ApoB group exhibited a trend toward an elevated risk of ACM in relative to the normal group (HR 1.22, 95% CI: 0.96-1.53). The risk of CVM was elevated by 76% in the ApoB abnormal group (HR 1.76, 95% CI: 1.28-2.42). According to the GAM, there existed a nonlinear association between serum ApoB levels and ACM (P = 0.005) and CVM (P = 0.009). CONCLUSIONS: In the US hypertensive population, serum Apo B levels were U-shaped and correlated with ACM and CVM risk, with the lowest risk at 100 mg/dL. Importantly, abnormal Apo B levels were related to an elevated risk of ACM and CVM. These risks were especially high at lower Apo B levels. The obtained findings emphasize the importance of maintaining appropriate Apo B levels to prevent adverse outcomes in hypertensive individuals.

Assessment of new-onset heart failure prediction in a diabetic population using left ventricular global strain: a prospective cohort study based on UK Biobank.

Background: Impaired glucose utilization influences myocardial contractile function. However, the prognostic importance of left ventricular global radial strain (LV-GRS), left ventricular global circumferential strain (LV-GCS), and left ventricular global longitudinal strain (LV-GLS) in predicting new-onset heart failure (HF) in a population with diabetes is unclear. Methods: The study design is prospective cohort from the UK Biobank. Totally 37,899 participants had a complete data of cardiac magnetic resonance (CMR), of which 940 patients with diabetes were included, and all the participants completed follow-up. LV-GRS, LV-GCS, and LV-GLS were measured by completely automated CMR with tissue tagging. Cox proportional hazards regression analysis and C-index was performed to evaluate the association between the strain parameters and the new-onset HF in patients suffering from diabetes. Results: The average age of the 940 participants was 57.67 ± 6.97 years, with males comprising 66.4% of the overall population. With an average follow-up period of 166.82 ± 15.26 months, 35 (3.72%) patients reached the endpoint (emergence of new-onset HF). Significant associations were found for the three strain parameters and the new-onset HF (LV-GRS-hazard ratio [HR]: 0.946, 95% CI: 0.916-0.976; LV-GCS-HR: 1.162, 95% CI: 1.086-1.244; LV-GCS-HR: 1.181, 95% CI: 1.082-1.289). LV-GRS, LV-GCS, and LV-GLS were closely related to the related indicators to HF, and showed a high relationship to new-onset HF in individuals with diabetes at 5 and 10 years: LV-GRS: 0.75 (95% CI, 0.41-0.94) and 0.76 (95% CI, 0.44-0.98), respectively; LV-GCS: 0.80 (95% CI, 0.50-0.96) and 0.75 (95% CI, 0.41-0.98), respectively; LV-GLS: 0.72 (95% CI, 0.40-0.93) and 0.76 (95% CI, 0.48-0.97), respectively. In addition, age, sex, body mass index (BMI), and presence of hypertension or coronary artery disease (CAD) made no impacts on the association between the global strain parameters and the incidence of HF. Conclusion: LV-GRS, LV-GCS, and LV-GLS is significantly related to new-onset HF in patients with diabetes at 5 and 10 years.

Cisplatin-Based Combination Therapy for Enhanced Cancer Treatment.

Cisplatin, a primary chemotherapeutic drug, is of great value in the realm of tumor treatment. However, its clinical efficacy is strictly hindered by issues, such as drug resistance, relapse, poor prognosis, and toxicity to normal tissue. Cisplatin-based combination therapy has garnered increasing attention in both preclinical and clinical cancer research for its ability to overcome resistance, reduce toxicity, and enhance anticancer effects. This review examines three primary co-administration strategies of cisplatin-based drug combinations and their respective advantages and disadvantages. Additionally, seven types of combination therapies involving cisplatin are discussed, focusing on their main therapeutic effects, mechanisms in preclinical research, and clinical applications. This review also discusses future prospects and challenges, aiming to offer guidance for the development of optimal cisplatin-based combination therapy regimens for improved cancer treatment.

A dual-responsive microemulsion with macroscale superlubricity and largely switchable friction.

Although stimuli-responsive microemulsions (MEMs) consisting of water, oil and surfactants have found extensive potential applications in industrial fields, a responsive MEM exhibiting either macroscale superlubricity or two friction states where its coefficient of friction (CoF) can be switched by more than one order of magnitude has not yet been reported. Moreover, although traditional liquid superlubricants can provide ultralow friction and wear, effective control over the friction between two contacting surfaces is crucial for both achieving accurate control of the operation of an instrument and fabricating smart devices. Here we create a thermo- and magneto-responsive MEM capable of providing superlubrication for metallic materials in a broad temperature range from -30 to 20 °C using n-hexane, water, surfactant DDACe ((C12H25)2N+(CH3)2[CeCl4]-) and ethylene glycol. The MEM can abruptly and dramatically switch its CoF by approximately 25 fold based on a thermally reversible MEM-emulsion (EM) transition. Its anti-freezing performance allows it to provide effective lubrication even when the surrounding temperature attains as low as -60 °C. Together with its facile preparation, ultrahigh colloidal stability and magnetically controlled migration, such a novel smart MEM is envisioned to find widespread applications in materials science.

Ultra-sensitive analysis of exhaled biomarkers in ozone-exposed mice via PAI-TOFMS assisted with machine learning algorithms.

Ground-level ozone ranks sixth among common air pollutants. It worsens lung diseases like asthma, emphysema, and chronic bronchitis. Despite recent attention from researchers, the link between exhaled breath and ozone-induced injury remains poorly understood. This study aimed to identify novel exhaled biomarkers in ozone-exposed mice using ultra-sensitive photoinduced associative ionization time-of-flight mass spectrometry and machine learning. Distinct ion peaks for acetonitrile (m/z 42, 60, and 78), butyronitrile (m/z 70, 88, and 106), and hydrogen sulfide (m/z 35) were detected. Integration of tissue characteristics, oxidative stress-related mRNA expression, and exhaled breath condensate free-radical analysis enabled a comprehensive exploration of the relationship between ozone-induced biological responses and potential biomarkers. Under similar exposure levels, C57BL/6 mice exhibited pulmonary injury characterized by significant inflammation, oxidative stress, and cardiac damage. Notably, C57BL/6 mice showed free radical signals, indicating a distinct susceptibility profile. Immunodeficient non-obese diabetic Prkdc-/-/Il2rg-/- (NPI) mice exhibited minimal biological responses to pulmonary injury, with little impact on the heart. These findings suggest a divergence in ozone-induced damage pathways in the two mouse types, leading to alterations in exhaled biomarkers. Integrating biomarker discovery with comprehensive biopathological analysis forms a robust foundation for targeted interventions to manage health risks posed by ozone exposure.

Inhibition of SARS-CoV-2 replication by a ssDNA aptamer targeting the nucleocapsid protein.

The nucleocapsid protein of SARS-CoV-2 plays significant roles in viral assembly, immune evasion, and viral stability. Due to its immunogenicity, high expression levels during COVID-19, and conservation across viral strains, it represents an attractive target for antiviral treatment. In this study, we identified and characterized a single-stranded DNA aptamer, N-Apt17, which effectively disrupts the liquid-liquid phase separation (LLPS) mediated by the N protein. To enhance the aptamer's stability, a circular bivalent form, cb-N-Apt17, was designed and evaluated. Our findings demonstrated that cb-N-Apt17 exhibited improved stability, enhanced binding affinity, and superior inhibition of N protein LLPS; thus, it has the potential inhibition ability on viral replication. These results provide valuable evidence supporting the potential of cb-N-Apt17 as a promising candidate for the development of antiviral therapies against COVID-19.IMPORTANCEVariants of SARS-CoV-2 pose a significant challenge to currently available COVID-19 vaccines and therapies due to the rapid epitope changes observed in the viral spike protein. However, the nucleocapsid (N) protein of SARS-CoV-2, a highly conserved structural protein, offers promising potential as a target for inhibiting viral replication. The N protein forms complexes with genomic RNA, interacts with other viral structural proteins during virion assembly, and plays a critical role in evading host innate immunity by impairing interferon production during viral infection. In this investigation, we discovered a single-stranded DNA aptamer, designated as N-Apt17, exhibiting remarkable affinity and specificity for the N protein. Notably, N-Apt17 disrupts the liquid-liquid phase separation (LLPS) of the N protein. To enhance the stability and molecular recognition capabilities of N-Apt17, we designed a circular bivalent DNA aptamer termed cb-N-Apt17. In both in vivo and in vitro experiments, cb-N-Apt17 exhibited increased stability, enhanced binding affinity, and superior LLPS disrupting ability. Thus, our study provides essential proof-of-principle evidence supporting the further development of cb-N-Apt17 as a therapeutic candidate for COVID-19.

Increased susceptibility to new-onset atrial fibrillation in diabetic women with poor sleep behaviour traits: findings from the prospective cohort study in the UK Biobank.

BACKGROUND: Diabetic individuals often encounter various sleep-related challenges. Although the association between sleep duration and atrial fibrillation (AF) have been explored, the association of other sleep traits with the incidence of AF remains unclear. A comprehensive understanding of these traits is essential for a more accurate assessment of sleep conditions in patients with diabetes and the development of novel AF prevention strategies. METHODS: This study involved 23,785 patients with diabetes without any pre-existing cardiovascular disease, drawn from the UK Biobank. Sleep behaviour traits examined encompassed sleep duration, chronotype, insomnia, snoring and daytime sleepiness. Sleep duration was categorised into three groups: low (≤ 5 h), proper (6-8 h) and long (≥ 9 h). We assessed associations using multivariate Cox proportional risk regression models. Furthermore, four poor sleep behaviours were constructed to evaluate their impact on the risk of new-onset AF. RESULTS: Over a mean follow-up period of 166 months, 2221 (9.3%) new cases of AF were identified. Short (hazard ratio (HR), 1.28; 95% confidence interval (CI) 1.10-1.50) and long sleep durations (HR 1.16; 95% CI 1.03-1.32) consistently exhibited an elevated risk of AF compared to optimal sleep duration. Early chronotype, infrequent insomnia and daytime sleepiness were associated with 11% (HR 0.89; 95% CI 0.82-0.97), 15% (HR 0.85; 95% CI 0.77-0.95) and 12% (HR 0.88; 95% CI 0.81-0.96) reduced risk of new-onset AF, respectively. However, no significant association was found between snoring and the incidence of AF (HR 0.99; 95% CI 0.91-1.07). CONCLUSIONS: In diabetic populations, sleep duration, chronotype, insomnia and daytime sleepiness are strongly associated with AF incidence. An optimal sleep duration of 6-8 h presents the lowest AF risk compared to short or long sleep duration. Additionally, poor sleep patterns present a greater risk of new-onset AF in women than in men.

Highly Interfacial Active Gemini Surfactants as Simple and Versatile Emulsifiers for Stabilizing, Lubricating and Structuring Liquids.

To date, locking the shape of liquids into non-equilibrium states usually relies on jamming nanoparticle surfactants at an oil/water interface. Here we show that a synthetic water-soluble zwitterionic Gemini surfactant can serve as an alternative to nanoparticle surfactants for stabilizing, structuring and additionally lubricating liquids. By having a high binding energy comparable to amphiphilic nanoparticles at the paraffin oil/water interface, the surfactant can attain near-zero interfacial tensions and ultrahigh surface coverages after spontaneous adsorption. Owing to the strong association between neighboring surfactant molecules, closely packed monolayers with high mechanical elasticity can be generated at the oil/water interface, thus allowing the surfactant to produce not only ultra-stable emulsions but also structured liquids with various geometries by using extrusion printing and 3D printing techniques. By undergoing tribochemical reactions at its sulfonic terminus, the surfactant can endow the resultant emulsions with favorable lubricity even under high load-bearing conditions. Our study may provide new insights into creating complex liquid devices and new-generation lubricants capable of combining the characteristics of both liquid and solid lubricants.

Superior predictive value of estimated pulse wave velocity for all-cause and cardiovascular disease mortality risk in U.S. general adults.

BACKGROUND: Estimated pulse wave velocity (ePWV) has been proposed as a potential approach to estimate carotid-femoral pulse wave velocity. However, the potential of ePWV in predicting all-cause mortality (ACM) and cardiovascular disease mortality (CVM) in the general population is unclear. METHODS: We conducted a prospective cohort study using the data of 33,930 adults (age ≥ 20 years) from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 until the end of December 2019. The study outcomes included ACM and CVM. Survey-weighted Cox proportional hazards models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association between ePWV and ACM and CVM. To further investigate whether ePWV was superior to traditional risk factors in predicting ACM and CVM, comparisons between ePWV and the Framingham Risk Score (FRS) and Pooled Cohort Equations (PCE) models were performed. Integrated Discriminant Improvement (IDI) and Net Reclassification Improvement (NRI) were employed to analyze differences in predictive ability between models. RESULTS: The weighted mean age of the 33,930 adults included was 45.2 years, and 50.28% of all participants were men. In the fully adjusted Cox regression model, each 1 m/s increase in ePWV was associated with 50% and 49% increases in the risk of ACM (HR 1.50; 95% CI, 1.45-1.54) and CVM (HR 1.49; 95% CI, 1.41-1.57), respectively. After adjusting for FRS, each 1 m/s increase in ePWV was still associated with 29% (HR 1.29; 95% CI, 1.24-1.34) and 34% (HR 1.34; 95% CI, 1.23-1.45) increases in the risk of ACM and CVM, respectively. The area under the curve (AUC) predicted by ePWV for 10-year ACM and CVM were 0.822 and 0.835, respectively. Compared with the FRS model, the ePWV model improved the predictive value of ACM and CVM by 5.1% and 3.8%, respectively, with no further improvement in event classification. In comparison with the PCE model, the ePWV model's ability to predict 10-year ACM and CVM was improved by 5.1% and 3.5%, and event classification improvement was improved by 34.5% and 37.4%. CONCLUSIONS: In the U.S. adults, ePWV is an independent risk factor for ACM and CVM and is independent of traditional risk factors. In the general population aged 20 to 85 years, ePWV has a robust predictive value for the risk of ACM and CVM, superior to the FRS and PCE models. The predictive power of ePWV likely originates from the traditional risk factors incorporated into its calculation, rather than from an indirect association with measured pulse wave velocity.

Tracking mitochondrial Cu(I) fluctuations through a ratiometric fluorescent probe in AD model cells: Towards understanding how AßOs induce mitochondrial Cu(I) dyshomeostasis.

Mitochondrial copper signaling pathway plays a role in Alzheimer's disease (AD), especially in relevant Amyloid-ß oligomers (AßOs) neurotoxicity and mitochondrial dysfunction. Clarifying the relationship between mitochondrial copper homeostasis and both of mitochondrial dysfunction and AßOs neurotoxicity is important for understanding AD pathogenesis. Herein, we designed and synthesized a ratiometric fluorescent probe CHC-NS4 for Cu(I). CHC-NS4 possesses excellent ratiometric response, high selectivity to Cu(I) and specific ability to target mitochondria. Under mitochondrial dysfunction induced by oligomycin, mitochondrial Cu(I) levels gradually increased, which may be related to inhibition of ATP7A-mediated Cu(I) exportation and/or high expression of COX. On this basis, CHC-NS4 was further utilized to visualize the fluctuations of mitochondrial Cu(I) levels during progression of AD model cells induced by AßOs. It was found that mitochondrial Cu(I) levels were gradually elevated during the AD progression, which depended on not only AßOs concentration but also incubation time. Moreover, endocytosis maybe served as a prime pathway mode for mitochondrial Cu(I) dyshomeostasis induced by AßOs during AD progression. These results have provided a novel inspiration into mitochondrial copper biology in AD pathogenesis.

Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos.

Meiotic recombination is crucial for human genetic diversity and chromosome segregation accuracy. Understanding its variation across individuals and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring recombination landscapes rely either on population genetic patterns of linkage disequilibrium (LD)-capturing a time-averaged view-or on direct detection of crossovers in gametes or multigeneration pedigrees, which limits data set scale and availability. Here, we introduce an approach for inferring sex-specific recombination landscapes using data from preimplantation genetic testing for aneuploidy (PGT-A). This method relies on low-coverage (<0.05×) whole-genome sequencing of in vitro fertilized (IVF) embryo biopsies. To overcome the data sparsity, our method exploits its inherent relatedness structure, knowledge of haplotypes from external population reference panels, and the frequent occurrence of monosomies in embryos, whereby the remaining chromosome is phased by default. Extensive simulations show our method's high accuracy, even at coverages as low as 0.02×. Applying this method to PGT-A data from 18,967 embryos, we mapped 70,660 recombination events with ∼150 kbp resolution, replicating established sex-specific recombination patterns. We observed a reduced total length of the female genetic map in trisomies compared with disomies, as well as chromosome-specific alterations in crossover distributions. Based on haplotype configurations in pericentromeric regions, our data indicate chromosome-specific propensities for different mechanisms of meiotic error. Our results provide a comprehensive view of the role of aberrant meiotic recombination in the origins of human aneuploidies and offer a versatile tool for mapping crossovers in low-coverage sequencing data from multiple siblings.

A genomic mutational constraint map using variation in 76,156 human genomes.

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

Targeting PIM kinases in cancer therapy: An update on pharmacological small-molecule inhibitors.

PIM kinases, a serine/threonine kinase family with three isoforms, has been well-known to participate in multiple physiological processes by phosphorylating various downstream targets. Accumulating evidence has recently unveiled that aberrant upregulation of PIM kinases (PIM1, PIM2, and PIM3) are closely associated with tumor cell proliferation, migration, survival, and even resistance. Inhibiting or silencing of PIM kinases has been reported have remarkable antitumor effects, such as anti-proliferation, pro-apoptosis and resensitivity, indicating the therapeutic potential of PIM kinases as potential druggable targets in many types of human cancers. More recently, several pharmacological small-molecule inhibitors have been preclinically and clinically evaluated and showed their therapeutic potential; however, none of them has been approved for clinical application so far. Thus, in this perspective, we focus on summarizing the oncogenic roles of PIM kinases, key signaling network, and pharmacological small-molecule inhibitors, which will provide a new clue on discovering more candidate antitumor drugs targeting PIM kinases in the future.