Rolling back human pluripotent stem cells to an eight-cell embryo-like stage.

After fertilization, the quiescent zygote experiences a burst of genome activation that initiates a short-lived totipotent state. Understanding the process of totipotency in human cells would have broad applications. However, in contrast to in mice1,2, demonstration of the time of zygotic genome activation or the eight-cell (8C) stage in in vitro cultured human cells has not yet been reported, and the study of embryos is limited by ethical and practical considerations. Here we describe a transgene-free, rapid and controllable method for producing 8C-like cells (8CLCs) from human pluripotent stem cells. Single-cell analysis identified key molecular events and gene networks associated with this conversion. Loss-of-function experiments identified fundamental roles for DPPA3, a master regulator of DNA methylation in oocytes3, and TPRX1, a eutherian totipotent cell homeobox (ETCHbox) family transcription factor that is absent in mice4. DPPA3 induces DNA demethylation throughout the 8CLC conversion process, whereas TPRX1 is a key executor of 8CLC gene networks. We further demonstrate that 8CLCs can produce embryonic and extraembryonic lineages in vitro or in vivo in the form of blastoids5 and complex teratomas. Our approach provides a resource to uncover the molecular process of early human embryogenesis.

Supt16 haploinsufficiency causes neurodevelopment disorder by disrupting MAPK pathway in neural stem cells.

Chromatin regulators constitute a fundamental means of transcription regulation, which have been implicated in neurodevelopment and neurodevelopment disorders (NDDs). Supt16, one of candidate genes for NDDs, encodes the large subunit of facilitates chromatin transcription. However, the underlying mechanisms remain poorly understood. Here, Supt16+/- mice was generated, modeling the neurodevelopment disorder. Abnormal cognitive and social behavior was observed in the Supt16  +/- mice. Simultaneously, the number of neurocytes in the cerebral cortex and hippocampus is decreased, which might be resulted from the impairment of mouse neural stem cells (mNSCs) in the SVZ. Supt16 haploinsufficiency affects the proliferation and apoptosis of mNSCs. As the RNA-seq and chromatic immunoprecipitation sequencing assays showed, Supt16 haploinsufficiency disrupts the stemness of mNSCs by inhibiting MAPK signal pathway. Thus, this study demonstrates a critical role of Supt16 gene in the proliferation and apoptosis of mNSCs and provides a novel insight in the pathogenesis of NDDs.

Preoperative peripheral inflammatory markers are predictors of postoperative central diabetes insipidus in craniopharyngioma patients: a retrospective study.

BACKGROUND: Postoperative central diabetes insipidus (CDI) is commonly observed in craniopharyngioma (CP) patients, and the inflammatory response plays an important role in CPs. We aimed to evaluate the predictive value of preoperative peripheral inflammatory markers and their combinations regarding CDI occurrence in CPs. METHODS: The clinical data including preoperative peripheral inflammatory markers of 208 CP patients who underwent surgical treatment were retrospectively collected and analyzed. The preoperative peripheral white blood cells (WBC), neutrophils, lymphocytes, monocytes, platelet (PLT), neutrophil-to-lymphocyte ratio (NLR), derived-NLR (dNLR), monocyte-to-lymphocyte ratio (MLR) and PLT-to-lymphocyte ratio (PLR) were assessed in total 208 CP patients and different age and surgical approach CP patient subgroups. Their predictive values were evaluated by the receiver operator characteristic curve analysis. RESULTS: Preoperative peripheral WBC, neutrophils, NLR, dNLR, MLR, and PLR were positively correlated and lymphocyte was negatively associated with postoperative CDI occurrence in CP patients, especially when WBC ≥ 6.66 × 109/L or lymphocyte ≤ 1.86 × 109/L. Meanwhile, multiple logistic regression analysis showed that WBC > 6.39 × 109/L in the > 18 yrs age patients, WBC > 6.88 × 109/L or lymphocytes ≤ 1.85 × 109/L in the transcranial approach patients were closely associated with the elevated incidence of postoperative CDI. Furthermore, the area under the curve obtained from the receiver operator characteristic curve analysis showed that the best predictors of inflammatory markers were the NLR in total CP patients, the MLR in the ≤ 18 yrs age group and the transsphenoidal group, the NLR in the > 18 yrs age group and the dNLR in the transcranial group. Notably, the combination index NLR + dNLR demonstrated the most valuable predictor in all groups. CONCLUSIONS: Preoperative peripheral inflammatory markers, especially WBC, lymphocytes and NLR + dNLR, are promising predictors of postoperative CDI in CPs.

Trends in statin use for the primary prevention of atherosclerotic cardiovascular disease among US adults by demographic characteristics, 1999-2020.

PURPOSE: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide. Statins, which are effective in preventing ASCVD, are underused, particularly for primary prevention. This study examined trends in statin use for primary ASCVD prevention from 1999 to 2020, focusing on demographic variations. METHODS: Utilizing data from the National Health and Nutrition Examination Survey, the present study includes individuals aged 18 years and older who had a greater than 10% risk of ASCVD over 10 years, and excluded patients with existing ASCVD. Subgroup analyses by demographic categories were performed. We calculated the changes in statin usage and used linear and quadratic tests to assess the linear and nonlinear trends in those changes. RESULTS: A total of 10,037 participants were included. Statin usage increased from 16.16% in 1999 to 36.24% in 2010, and 41.74% in 2020 (quadratic P-value < 0.001). In the 18-44 years age group, statin usage increased from 2.52% in 1999 to 8.14% in 2020 (linear P-value = 0.322), showing no significant linear trend. In the "never-married" group, statin usage increased from 19.16% in 1999 to 30.05% in 2020 (linear P-value = 0.256). CONCLUSION: Statin usage has shown a positive trend among populations requiring primary prevention for ASCVD. Currently, health policies are proving effective. However, the overall statin usage rate remains less than 50%. Additionally, young and never-married individuals should also receive special attention regarding statin usage as primary treatment for ASCVD.

Genome-wide identification of cuticle protein superfamily in Frankliniella occidentalis provide insight into the control of both insect vectors and plant virus.

The structural cuticle proteins (CPs) play important roles in the development and fitness of insects. However, knowledge about CP gene superfamily is limited in virus-transmitting insect vectors, although its importance on transmission of plant virus has been gradually emphasized. In this study, the genome-wide identification of CP superfamily was conducted in western flower thrips Frankliniella occidentalis that is the globally invasive pest and plant virus vector pest. The pest transmits notorious tomato spotted wilt virus (TSWV) around the world, causing large damage to a wide array of plants. One hundred and twenty-eight F. occidentalis CP genes (FoCPs) were annotated in this study and they were classified into 10 distinct families, including 68 CPRs, 16 CPAP1s, 6 CPAP3s, 2 CPCFCs, 10 Tweedles, 4 CPFs, 16 CPLCPs, and 6 CPGs. The comprehensive analysis was performed including phylogenetic relationship, gene location and gene expression profiles during different development stages of F. occidentalis. Transcriptome analysis revealed more than 30% FoCPs were upregulated at least 1.5-fold when F. occidentalis was infected by TSWV, indicating their potential involvement in TSWV interactions. Our study provided an overview of F. occidentalis CP superfamily. The study gave a better understand of CP's role in development and virus transmission, which provided clues for reducing viral damages through silencing CP genes in insect vectors.

Single-cell multi-omics profiling reveals key regulatory mechanisms that poise germinal vesicle oocytes for maturation in pigs.

The molecular mechanisms controlling the transition from meiotic arrest to meiotic resumption in mammalian oocytes have not been fully elucidated. Single-cell omics technology provides a new opportunity to decipher the early molecular events of oocyte growth in mammals. Here we focused on analyzing oocytes that were collected from antral follicles in different diameters of porcine pubertal ovaries, and used single-cell M&T-seq technology to analyze the nuclear DNA methylome and cytoplasmic transcriptome in parallel for 62 oocytes. 10× Genomics single-cell transcriptomic analyses were also performed to explore the bi-directional cell-cell communications within antral follicles. A new pipeline, methyConcerto, was developed to specifically and comprehensively characterize the methylation profile and allele-specific methylation events for a single-cell methylome. We characterized the gene expressions and DNA methylations of individual oocyte in porcine antral follicle, and both active and inactive gene's bodies displayed high methylation levels, thereby enabled defining two distinct types of oocytes. Although the methylation levels of Type II were higher than that of Type I, Type II contained nearly two times more of cytoplasmic transcripts than Type I. Moreover, the imprinting methylation patterns of Type II were more dramatically divergent than Type I, and the gene expressions and DNA methylations of Type II were more similar with that of MII oocytes. The crosstalk between granulosa cells and Type II oocytes was active, and these observations revealed that Type II was more poised for maturation. We further confirmed Insulin Receptor Substrate-1 in insulin signaling pathway is a key regulator on maturation by in vitro maturation experiments. Our study provides new insights into the regulatory mechanisms between meiotic arrest and meiotic resumption in mammalian oocytes. We also provide a new analytical package for future single-cell methylomics study.

[Research on Locating Device for the Entry Point of Intramedullary Nail Based on Inertial Navigation].

Objective: To introduce a locating device for the entry point of intramedullary nail based on the inertial navigation technology, which utilizes multi-dimensional angle information to assist in rapid and accurate positioning of the ideal direction of femoral anterograde intramedullary nails' entry point, and to verify its clinical value through clinical tests. Methods: After matching the locating module with the developing board, which are the two components of the locating device, they were placed on the skin surface of the proximal femur of the affected side. Anteroposterior fluoroscopy was performed. The developing angle corresponding to the ideal direction of entry point was selected based on the X-ray image, and then the yaw angle of the locating module was reset to zero. After resetting, the locating module was combined with the surgical instrument to guide the insertion angle of the guide wire. The ideal direction of entry point was accurately located based on the angle guidance. By setting up an experimental group and a control group for clinical surgical operations, the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss with or without the locating device was recorded. Results: Compared to the control group, the experimental group showed significant improvement in the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss, with a statistically significant difference (P<0.01). Conclusion: The locating device can assist doctors in quickly locating the entry point of intramedullary nail, effectively reducing the fluoroscopy frequency and surgical time by improving the success rate of the guide wire insertion with one shot, improving surgical efficiency, and possessing certain clinical value.

The prognostic value and immune landscaps of m6A/m5C-related lncRNAs signature in the low grade glioma.

BACKGROUND: N6-methyladenosine (m6A) and 5-methylcytosine (m5C) are the main RNA methylation modifications involved in the oncogenesis of cancer. However, it remains obscure whether m6A/m5C-related long non-coding RNAs (lncRNAs) affect the development and progression of low grade gliomas (LGG). METHODS: We summarized 926 LGG tumor samples with RNA-seq data and clinical information from The Cancer Genome Atlas and Chinese Glioma Genome Atlas. 105 normal brain samples with RNA-seq data from the Genotype Tissue Expression project were collected for control. We obtained a molecular classification cluster from the expression pattern of sreened lncRNAs. The least absolute shrinkage and selection operator Cox regression was employed to construct a m6A/m5C-related lncRNAs prognostic signature of LGG. In vitro experiments were employed to validate the biological functions of lncRNAs in our risk model. RESULTS: The expression pattern of 14 sreened highly correlated lncRNAs could cluster samples into two groups, in which various clinicopathological features and the tumor immune microenvironment were significantly distinct. The survival time of cluster 1 was significantly reduced compared with cluster 2. This prognostic signature is based on 8 m6A/m5C-related lncRNAs (GDNF-AS1, HOXA-AS3, LINC00346, LINC00664, LINC00665, MIR155HG, NEAT1, RHPN1-AS1). Patients in the high-risk group harbored shorter survival times. Immunity microenvironment analysis showed B cells, CD4 + T cells, macrophages, and myeloid-derived DC cells were significantly increased in the high-risk group. Patients in high-risk group had the worse overall survival time regardless of followed TMZ therapy or radiotherapy. All observed results from the TCGA-LGG cohort could be validated in CGGA cohort. Afterwards, LINC00664 was found to promote cell viability, invasion and migration ability of glioma cells in vitro. CONCLUSION: Our study elucidated a prognostic prediction model of LGG by 8 m6A/m5C methylated lncRNAs and a critical lncRNA regulation function involved in LGG progression. High-risk patients have shorter survival times and a pro-tumor immune microenvironment.

Reversible Transformation and Distribution Determination of Diverse Pt Single-Atom Species.

In single-atom catalysts (SACs), the complexity of the support anchoring sites creates a vast diversity of single-atom species with varied coordination environments. To date, the quantitative distribution of these diverse single-atom species in a given SAC has remained elusive. Recently, CeO2-supported metal SACs have been extensively studied by modulating their local environments via numerous synthetic strategies. However, owing to the absence of a quantitative description, unraveling the site-specific reactivity and regulating their transformation remain challenging. Here, we show that two distinct Pt/CeO2 SACs can be reversibly generated by oxidative and nonoxidative dispersions, which contain varied Pt1On-Ceδ+ single-atom species despite similar Pt charge states and coordination numbers. By means of Raman spectroscopy and computational studies, we semiquantitatively reveal the distribution of diverse Pt1On-Ceδ+ species in each specific SACs. Remarkably, the minority species of Pt1O4-Ce3+-Ov accounting for only 14.2% affords the highest site-specific reactivity for low-temperature CO oxidation among the other abundant counterparts, i.e., Pt1O4-Ce4+ and Pt1O6-Ce4+. The second nearest oxygen vacancy (Ov) not only acts synergistically with the nearby active metal sites to lower the reaction barrier but also facilitates the dynamic transformation from six-coordinated to four-coordinated sites during cyclic nonoxidative and oxidative dispersions. This work elucidates the quantitative distribution and dynamic transformation of varied single-atom species in a given SAC, offering a more intrinsic descriptor and quantitative measure to depict the inhomogeneity of SACs.

Accurate Identification of Subclones in Tumor Genomes.

Understanding intratumor heterogeneity is critical for studying tumorigenesis and designing personalized treatments. To decompose the mixed cell population in a tumor, subclones are inferred computationally based on variant allele frequency (VAF) from bulk sequencing data. In this study, we showed that sequencing depth, mean VAF, and variance of VAF of a subclone are confounded. Without considering this effect, current methods require deep-sequencing data (>300× depth) to reliably infer subclones. Here, we present a novel algorithm that incorporates depth-variance and mean-variance dependencies in a clustering error model and successfully identifies subclones in tumors sequenced at depths of as low as 30×. We implemented the algorithm as a model-based adaptive grouping of subclones (MAGOS) method. Analyses of computer simulated data and empirical sequencing data showed that MAGOS outperformed existing methods on minimum sequencing depth, decomposition accuracy, and computation efficiency. The most prominent improvements were observed in analyzing tumors sequenced at depths between 30× and 200×, whereas the performance was comparable between MAGOS and existing methods on deeply sequenced tumors. MAGOS supports analysis of single-nucleotide variants and copy number variants from a single sample or multiple samples of a tumor. We applied MAGOS to whole-exome data of late-stage liver cancers and discovered that high subclone count in a tumor was a significant risk factor of poor prognosis. Lastly, our analysis suggested that sequencing multiple samples of the same tumor at standard depth is more cost-effective and robust for subclone characterization than deep sequencing a single sample. MAGOS is available at github (https://github.com/liliulab/magos).

Ultrafast and scalable variant annotation and prioritization with big functional genomics data.

The advances of large-scale genomics studies have enabled compilation of cell type-specific, genome-wide DNA functional elements at high resolution. With the growing volume of functional annotation data and sequencing variants, existing variant annotation algorithms lack the efficiency and scalability to process big genomic data, particularly when annotating whole-genome sequencing variants against a huge database with billions of genomic features. Here, we develop VarNote to rapidly annotate genome-scale variants in large and complex functional annotation resources. Equipped with a novel index system and a parallel random-sweep searching algorithm, VarNote shows substantial performance improvements (two to three orders of magnitude) over existing algorithms at different scales. It supports both region-based and allele-specific annotations and introduces advanced functions for the flexible extraction of annotations. By integrating massive base-wise and context-dependent annotations in the VarNote framework, we introduce three efficient and accurate pipelines to prioritize the causal regulatory variants for common diseases, Mendelian disorders, and cancers.

Cell fate conversion prediction by group sparse optimization method utilizing single-cell and bulk OMICs data.

Cell fate conversion by overexpressing defined factors is a powerful tool in regenerative medicine. However, identifying key factors for cell fate conversion requires laborious experimental efforts; thus, many of such conversions have not been achieved yet. Nevertheless, cell fate conversions found in many published studies were incomplete as the expression of important gene sets could not be manipulated thoroughly. Therefore, the identification of master transcription factors for complete and efficient conversion is crucial to render this technology more applicable clinically. In the past decade, systematic analyses on various single-cell and bulk OMICs data have uncovered numerous gene regulatory mechanisms, and made it possible to predict master gene regulators during cell fate conversion. By virtue of the sparse structure of master transcription factors and the group structure of their simultaneous regulatory effects on the cell fate conversion process, this study introduces a novel computational method predicting master transcription factors based on group sparse optimization technique integrating data from multi-OMICs levels, which can be applicable to both single-cell and bulk OMICs data with a high tolerance of data sparsity. When it is compared with current prediction methods by cross-referencing published and validated master transcription factors, it possesses superior performance. In short, this method facilitates fast identification of key regulators, give raise to the possibility of higher successful conversion rate and in the hope of reducing experimental cost.

Forgetfulness as the primary presenting symptom of type A acute aortic dissection.

Acute aortic dissection (AAD) is the most common lethal disease affecting the aorta. Neurological symptoms have been linked to AAD in some patients. Although aortic dissection patients have previously been shown to present with neurological symptoms, AAD with forgetfulness as the first manifestation is extremely rare. To increase the awareness of AAD among clinicians, we report the first case of a male Chinese patient with AD presenting with forgetfulness as the initial symptom. A 53-year-old man presented to the emergency department with forgetfulness. Based on the concept that "time is brain," stroke was initially considered in the differential diagnosis. The patient underwent emergency coronary angiography and was diagnosed with acute myocardial infarction. After contrast-enhanced computed tomography angiography, the patient was finally diagnosed with AAD. Because valuable time was lost in diagnosis rather than treatment, optimal timing for surgery missed. The patient died following an aortic dissection rupture while waiting for emergency surgery. When forgetfulness cannot be completely accounted for in patients presenting with acute myocardial infarction, AAD should be considered. We believe that this case report contains a worthwhile clinical lesson for clinicians.

Variant Landscape of 15 Genes Involved in Corneal Dystrophies: Report of 30 Families and Comprehensive Analysis of the Literature.

Corneal dystrophies (CDs) represent a group of inherited diseases characterized by the progressive deposit of abnormal materials in the cornea. This study aimed to describe the variant landscape of 15 genes responsible for CDs based on a cohort of Chinese families and a comparative analysis of literature reports. Families with CDs were recruited from our eye clinic. Their genomic DNA was analyzed using exome sequencing. The detected variants were filtered using multi-step bioinformatics and confirmed using Sanger sequencing. Previously reported variants in the literature were summarized and evaluated based on the gnomAD database and in-house exome data. In 30 of 37 families with CDs, 17 pathogenic or likely pathogenic variants were detected in 4 of the 15 genes, including TGFBI, CHST6, SLC4A11, and ZEB1. A comparative analysis of large datasets revealed that 12 of the 586 reported variants are unlikely causative of CDs in monogenic mode, accounting for 61 of 2933 families in the literature. Of the 15 genes, the gene most frequently implicated in CDs was TGFBI (1823/2902, 62.82% of families), followed by CHST6 (483/2902, 16.64%) and SLC4A11 (201/2902, 6.93%). This study presents, for the first time, the landscape of pathogenic and likely pathogenic variants in the 15 genes responsible for CDs. Awareness of frequently misinterpreted variants, such as c.1501C>A, p.(Pro501Thr) in TGFBI, is crucial in the era of genomic medicine.

Supt16 Haploinsufficiency Impairs PI3K/AKT/mTOR/Autophagy Pathway in Human Pluripotent Stem Cells Derived Neural Stem Cells.

The maintenance of neural stem cells (NSCs) plays a critical role in neurodevelopment and has been implicated in neurodevelopmental disorders (NDDs). However, the underlying mechanisms linking defective human neural stem cell self-renewal to NDDs remain undetermined. Our previous study found that Supt16 haploinsufficiency causes cognitive and social behavior deficits by disrupting the stemness maintenance of NSCs in mice. However, its effects and underlying mechanisms have not been elucidated in human neural stem cells (hNSCs). Here, we generated Supt16+/- induced pluripotent stem cells (iPSCs) and induced them into hNSCs. The results revealed that Supt16 heterozygous hNSCs exhibit impaired proliferation, cell cycle arrest, and increased apoptosis. As the RNA-seq analysis showed, Supt16 haploinsufficiency inhibited the PI3K/AKT/mTOR pathway, leading to rising autophagy, and further resulted in the dysregulated expression of multiple proteins related to cell proliferation and apoptotic process. Furthermore, the suppression of Supt16 heterozygous hNSC self-renewal caused by autophagy activation could be rescued by MHY1485 treatment or reproduced in rapamycin-treated hNSCs. Thus, our results showed that Supt16 was essential for hNSC self-renewal and its haploinsufficiency led to cell cycle arrest, impaired cell proliferation, and increased apoptosis of hNSCs by regulating the PI3K/AKT/mTOR/autophagy pathway. These provided a new insight to understand the causality between the Supt16 heterozygous NSCs and NDDs in humans.

New Insight into the Genotype-Phenotype Correlation of PRPH2-Related Diseases Based on a Large Chinese Cohort and Literature Review.

Variants in PRPH2 are a common cause of inherited retinal dystrophies with high genetic and phenotypic heterogeneity. In this study, variants in PRPH2 were selected from in-house exome sequencing data, and all reported PRPH2 variants were evaluated with the assistance of online prediction tools and the comparative validation of large datasets. All variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Individuals with pathogenic or likely pathogenic variants of PRPH2 were confirmed by Sanger sequencing. Clinical characteristics were summarized. Ten pathogenic or likely pathogenic variants of PRPH2 were identified in 14 families. In our cohort, the most frequent variant was p.G305Afs*19, accounting for 33.3% (5/15) of alleles, in contrast to the literature, where p.R172G (11.6%, 119/1028) was the most common variant. Nine in-house families (63.8%) were diagnosed with retinitis pigmentosa (RP), distinct from the phenotypic spectrum in the literature, which shows that RP accounts for 27.9% (283/1013) and macular degeneration is more common (45.2%, 458/1013). Patients carrying missense variants predicted as damaging by all seven prediction tools and absent in the gnomAD database were more likely to develop RP compared to those carrying missense variants predicted as damaging with fewer tools or with more than one allele number in the gnomAD database (p = 0.001). The population-specific genetic and phenotypic spectra of PRPH2 were explored, and novel insight into the genotype-phenotype correlation of PRPH2 was proposed. These findings demonstrated the importance of assessing PRPH2 variants in distinct populations and the value of providing practical suggestions for the genetic interpretation of PRPH2 variants.

Heme is involved in the exogenous ALA-promoted growth and antioxidant defense system of cucumber seedlings under salt stress.

A biosynthetic precursor of tetrapyrrol, 5-aminolevulinic acid (ALA), is widely used in agricultural production, as an exogenous regulatory substance that effectively regulates plant growth. Previous studies have shown that heme and chlorophyll accumulate in plants under salt stress, when treated with exogenous ALA. In this study, we explored the regulatory role of heme in plants, by spraying 25 mg L-1 ALA onto the leaves of cucumber seedlings treated with heme synthesis inhibitor (2,2'-dipyridyl, DPD) and heme scavenger (hemopexin, Hx), under 50 mmol L-1 NaCl stress. The results showed that NaCl alone and DPD + Hx treatments to cucumber seedlings subjected to salt stress adversely affected their growth, by decreasing biomass accumulation, root activity, and root morphology. In addition, these treatments induced an increase in membrane lipid oxidation, as well as enhancement of anti-oxidase activities, proline content, and glutamate betaine. However, exogenous ALA application increased the plant growth and root architecture indices under NaCl stress, owing to a lack of heme in the seedlings. In addition, cucumber seedlings treated with DPD and Hx showed inhibition of growth under salt stress, but exogenous ALA effectively improved cucumber seedling growth as well as the physiological characteristics; moreover, the regulation of ALA in plants was weakened when heme synthesis was inhibited. Heme biosynthesis and metabolism genes, HEMH and HO1, which are involved in the ALA metabolic pathway, were upregulated under salinity conditions, when ferrochelatase activity was inhibited. Application of exogenous ALA increased the heme content in the leaves. Thus, exogenous ALA may supplement the substrates for heme synthesis. These results indicated that heme plays a vital role in the response of plants to salinity stress. In conclusion, heme is involved in ALA-mediated alleviation of damage caused to cucumber seedlings and acts as a positive regulator of plant adaption.

Methods and resources to access mutation-dependent effects on cancer drug treatment.

In clinical cancer treatment, genomic alterations would often affect the response of patients to anticancer drugs. Studies have shown that molecular features of tumors could be biomarkers predictive of sensitivity or resistance to anticancer agents, but the identification of actionable mutations are often constrained by the incomplete understanding of cancer genomes. Recent progresses of next-generation sequencing technology greatly facilitate the extensive molecular characterization of tumors and promote precision medicine in cancers. More and more clinical studies, cancer cell lines studies, CRISPR screening studies as well as patient-derived model studies were performed to identify potential actionable mutations predictive of drug response, which provide rich resources of molecularly and pharmacologically profiled cancer samples at different levels. Such abundance of data also enables the development of various computational models and algorithms to solve the problem of drug sensitivity prediction, biomarker identification and in silico drug prioritization by the integration of multiomics data. Here, we review the recent development of methods and resources that identifies mutation-dependent effects for cancer treatment in clinical studies, functional genomics studies and computational studies and discuss the remaining gaps and future directions in this area.

Torsade de pointes caused by citalopram during the pacemaker battery-depletion phase: A case report.

Drug-induced QT prolongation, primarily antiarrhythmic drugs, is a common cause of torsade de pointes (TdP). Although there have been previous reports of drug-induced TdP in patients, it has not been well documented when caused by citalopram during the pacemaker battery-depletion phase. To improve delirium recognition, we report a case of citalopram-induced TdP during the pacemaker battery-depletion phase. An 84-year-old Chinese female was brought to the hospital presenting recurrent syncope. She lost consciousness and was admitted after her syncope TdP was documented. Her pacemaker was inspected and found to be operating in an extremely ineffective manner. Although she had prolonged QT interval after the pacemaker was replaced, she did not suffer another syncope attack, and ECG monitoring revealed no cardiac arrhythmia or TdP. During her admission, she was treated with citalopram for depression. Citalopram was discontinued when the QT interval shortened progressively. In this study, we described a case of citalopram-induced TdP during the depletion phase of a pacemaker battery. This case should serve as a cautionary lesson to clinicians to avoid using citalopram during the pacemaker battery-depletion phase.

Retrospective Study of 23 Patients with Traumatic Posterolateral Tibial Plateau Fracture Treated in a Single Center Between 2017 and 2019 with Lateral Arthrotomy, Reduction, and Plate Fixation Using the Frosch Approach.

BACKGROUND The Frosch approach is a posterolateral surgical procedure performed with or without osteotomy of the fibula for the treatment of posterolateral tibial plateau fractures (PLFs). This retrospective study from a single center aimed to evaluate 23 patients with PLFs who underwent surgical reduction with the Frosch approach between January 2017 and October 2019. MATERIAL AND METHODS Twenty-three patients, 4 with Schatzker type V and 19 with Schatzker type II fractures were enrolled. Postoperative radiographs were performed regularly to measure the medial proximal tibial angle (MTPA), lateral posterior slope angle (LPSA), medial posterior slope angle (MPSA), and articular step-off to evaluate the fracture reduction. At the last follow-up, the Hospital for Special Surgery (HSS) knee score and knee range of motion (ROM) were used to assess knee function. RESULTS Radiograph examinations indicated excellent reduction and fixation of fractures in all patients. The average HSS scores and ROM of the 23 patients were 88.0±3.5 and 131.8±7.8°, respectively, with an average of 30.5±4.6 months of follow-up. Skin numbness occurred in 3 patients but was recovered within 6 months. One patient sustained superficial wound infection, and another patient had superficial adipose tissue liquefaction necrosis. CONCLUSIONS This experience from a single center demonstrated the advantage of the Frosch approach in visualizing the posterolateral and lateral tibial plateau from a single surgical incision and resulted in excellent postoperative outcomes at follow-up when evaluated by the HSS score, ROM, and radiographic evaluation of the MTPA, LPSA, and MPSA.