Historical sedimentary and evolutionary characteristics of POPs and EDCs in typical regions of the three Gorges reservoir, China.

The historical sedimentary and evolutionary characteristics of persistent organic pollutants and endocrine disruptors in typical regions of the Three Gorges Reservoir are scarcely studied. Herein, the 96-year data on contaminated sediment history were reconstructed using Caesium 137 isotope dating. Polychlorinated biphenyl concentrations in the involved sediment cores ranged from non-detected (ND) to 11.39 ng/g. The concentrations of polycyclic aromatic hydrocarbons ranged from ND to 2075.20 ng/g and peaked in the 1970s owing to natural, agricultural and human activities. Further, phthalate esters (PAEs) and heavy metals (HMs) were detected at concentrations ranging from ND to 589.2 ng/g and 12.10-93.67 µg/g, respectively, with highest values recorded in the 1980s owing to rapid industrialisation and insufficient management during China's early reform and development stages. PAE and HM concentrations have increased in recent years, suggesting the need to focus on industrial and agricultural activities that have caused this impact. Although current pollutant concentrations in sediments do not pose a risk to the aquatic ecosystem, they should be continuously monitored.

Sleep CLIP: A Multimodal Sleep Staging Model Based on Sleep Signals and Sleep Staging Labels.

Since the release of the contrastive language-image pre-training (CLIP) model designed by the OpenAI team, it has been applied in several fields owing to its high accuracy. Sleep staging is an important method of diagnosing sleep disorders, and the completion of sleep staging tasks with high accuracy has always remained the main goal of sleep staging algorithm designers. This study is aimed at designing a multimodal model based on the CLIP model that is more suitable for sleep staging tasks using sleep signals and labels. The pre-training efforts of the model involve five different training sets. Finally, the proposed method is tested on two training sets (EDF-39 and EDF-153), with accuracies of 87.3 and 85.4%, respectively.

BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes.

Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.

Exploiting metabolic vulnerabilities in breast cancers with NF1 loss.

Auf der Maur et al.1 identify neurofibromin 1 (NF1) loss as a mechanism of resistance to PI3K inhibitor in breast cancer cells. NF1 loss leads to enhanced glycolysis, which may be targeted with the antioxidant N-acetyl cysteine (NAC).

Case report: Detection of fetal trisomy 9 mosaicism by multiple genetic testing methods: Report of two cases.

Chromosomal mosaicism remains a perpetual diagnostic and clinical dilemma. In the present study, we detected two prenatal trisomy 9 mosaic syndrome cases by using multiple genetic testing methods. The non-invasive prenatal testing (NIPT) results suggested trisomy 9 in two fetuses. Karyotype analysis of amniocytes showed a high level (42%-50%) of mosaicism, and chromosomal microarray analysis (CMA) of uncultured amniocytes showed no copy number variation (CNV) except for large fragment loss of heterozygosity. Ultrasound findings were unmarkable except for small for gestational age. In Case 1, further umbilical blood puncture confirmed 22.4% and 34% trisomy 9 mosaicism by CMA and fluorescent in situ hybridization (FISH) respectively. After comprehensive consideration of the genetic and ultrasound results, the two gravidas decided to receive elective termination and molecular investigations of multiple tissue samples from the aborted fetus and the placenta. The results confirmed the presence of true fetoplacental mosaicism with levels of trisomy 9 mosaicism from 76% to normal in various tissues. These two cases highlight the necessity of genetic counseling for gravidas whose NIPT results highly suggest the risk of chromosome 9 to ascertain the occurrence of mosaicism. In addition, the comprehensive use of multiple genetic techniques and biological samples is recommended for prenatal diagnosis to avoid false-negative results. It should also be noted that ultrasound results of organs with true trisomy 9 mosaicism can be free of structural abnormalities during pregnancy.

Sleep staging classification based on a new parallel fusion method of multiple sources signals.

Objective.In the field of medical informatics, sleep staging is a challenging and time consuming task undertaken by sleep experts. The conventional method for sleep staging is to analyze Polysomnograms (PSGs) recorded in a sleep lab, but the sleep monitoring with polysomnography (PSG) severely degrades the sleep quality. Despite recent significant progress in the development of automatic sleep staging methods, building a good model still remains a big challenge for sleep studies due to the data-variability and data-inefficiency issues. Electrooculograms (EOGs) and electrocardiograms (ECGs) and are much easier to record and may offer an attractive alternative for home sleep monitoring. PSGs from the Sleep Heart Health Study database were used. This study aims to establish an new automatic sleep staging algorithm by using electrooculogram (EOG) and electrocardiogram (ECG).Approach.First, the heart rate variability (HRV) is extracted from EOG with the Weight Calculation Algorithm and an 'NRRD' RR interval detection algorithm. Second, three feature sets were extracted from HRV segments and EOG segments: time-domain features, frequency-domain features and nonlinear-domain features. The frequency domain features and nonlinear-domain features were extracted by using Discrete Wavelet Transform, Autoregressive (AR), and Power Spectral entropy, and Refined Composite Multiscale Dispersion Entropy. Third, a new 'Parallel Fusion Method' (PFM) for sleep stage classification is proposed. Three kinds of feature sets from EOG and HRV segments are fused by using PFM. Fourth, Extreme Gradient Boosting (XGBoost) is employed for sleep staging.Main results.Our experimental results show significant performance improvement on automatic sleep staging on the target domains achieved with the new sleep staging approach. The performance of the proposed method is tested by evaluating the average accuracy, Kappa coefficient. The average accuracy of sleep classification results by using XGBoost classification model with PFM is 83% and the kappa coefficient is 0.7. Experimental results show that the performance of the proposed method is competitive with the most current methods and results, and the recognition rate of S1 stage is significantly improved.Significance.As a consequence, it would enable one to improve the quality of automatic sleep staging models when the EOG and HRV signals are fused, which can be beneficial for monitor sleep quality and keep abreast of health conditions. Besides, our study provides good research ideas and methods for scholars, doctors and individuals.

Whole Exome Sequencing Analysis in Fetal Skeletal Dysplasia Detected by Ultrasonography: An Analysis of 38 Cases.

Background: Skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders that primarily affect bone and cartilage. This study aims to identify the genetic causes for fetal SDs, and evaluates the diagnostic yield of prenatal whole-exome sequencing (WES) for this disorder. Methods: WES was performed on 38 fetuses with sonographically identified SDs and normal results of karyotype and single nucleotide polymorphism (SNP) analysis. Candidate variants were selected by bioinformatics analysis, and verified by Sanger sequencing. Results: WES revealed pathogenic or likely pathogenic variants associated with SDs in 65.79% (25/38) of fetuses, variants of uncertain significance (VUS) in SDs-related genes in 10.53% (4/38) cases, and incidental findings in 31.58% (12/38) fetuses. The SDs-associated variants identified in the present study affected 10 genes, and 35.71% (10/28) of the variants were novel. Conclusion: WES has a high diagnostic rate for prenatal SDs, which improves pregnancy management, prenatal counseling and recurrence risk assessment for future pregnancies. The newly identified variants expanded mutation spectrum of this disorder.

Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients.

Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. Mutation in the NIPBL gene accounts for nearly 60% of the cases. This study reports the clinical and genetic findings of three cases of CdLS from unrelated Chinese families. Clinically, all the three cases were classified as classic CdLS based on the cardinal (distinctive facial features and limb malformations) and suggestive (developmental delay, growth retardation, microcephaly, hirsutism, etc.) manifestations. SNP array detected a novel de novo heterozygous microdeletion of 0.2 Mb [arr[GRCh37]5p13.2(36848530_37052821) × 1] that spans the first 43 exons of NIPBL in the fetus with nuchal translucency thickening in case 1. Whole-exome sequencing in family trios plus Sanger sequencing validation identified a de novo heterozygous NIPBL c.5566G>A (p.R1856G) mutation in the fetus with intrauterine growth retardation in case 2 and a novel de novo heterozygous NIPBL c.448dupA (p.S150Kfs*23) mutation in the proband (an 8-month-old girl) in case 3. The cases presented in this study may serve as references for increasing our understanding of the mutation spectrum of NIPBL in association with CdLS.

The stability of R-spine defines RAF inhibitor resistance: A comprehensive analysis of oncogenic BRAF mutants with in-frame insertion of αC-ß4 loop.

Although targeting BRAF mutants with RAF inhibitors has achieved promising outcomes in cancer therapy, drug resistance remains a remarkable challenge, and underlying molecular mechanisms are not fully understood. Here, we characterized a previously unknown group of oncogenic BRAF mutants with in-frame insertions (LLRins506 or VLRins506) of αC-ß4 loop. Using structure modeling and molecular dynamics simulation, we found that these insertions formed a large hydrophobic network that stabilizes R-spine and thus triggers the catalytic activity of BRAF. Furthermore, these insertions disrupted BRAF dimer interface and impaired dimerization. Unlike BRAF(V600E), these BRAF mutants with low dimer affinity were strongly resistant to all RAF inhibitors in clinic or clinical trials, which arises from their stabilized R-spines. As predicted by molecular docking, the stabilized R-spines in other BRAF mutants also conferred drug resistance. Together, our data indicated that the stability of R-spine but not dimer affinity determines the RAF inhibitor resistance of oncogenic BRAF mutants.

Optimum Strategy for Perforating Distribution of Homogeneous Gas-Liquid Two-Phase Flow in Vertical Gas Wells.

Aiming to optimize the total production of homogeneous gas-liquid two-phase flow in perforated vertical gas wells, a new coupled reservoir-wellbore mathematical model is proposed which consists of the crushed zone damage skin factor, pressure gradient, flow rate, and liquid holdup. An optimum strategy consisting of two optimization problems is developed to study the effect of perforation distribution on the production of vertical wells under a steady-state inflow. Then, these optimization models are applied to infinite and finite conductivity gas wells and the optimal distribution of perforation could be determined. The results show that inflow rate profiles could be improved by optimizing the perforation location for vertical gas wells.

Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism.

BACKGROUND: Emerging studies suggest that low-coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted. METHODS: A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements. RESULTS: Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%. CONCLUSION: In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family.

BACKGROUND: Split hand/foot malformation (SHFM) is a congenital limb developmental disorder, which impairs the fine activities of hand/foot in the affected individuals seriously. SHFM is commonly inherited as an autosomal dominant disease with incomplete penetrance. Chromosomal aberrations such as copy number variations and translocations have been linked to SHFM. This study aimed to identify the genetic cause for three patients with bilateral hand and foot malformation in a Chinese family. METHODS: Karyotyping, single-nucleotide polymorphism (SNP) array, whole exome sequencing, whole genome sequencing, and Sanger sequencing were applied to identify the pathogenic variant. RESULTS: Karyotyping revealed that the three patients had balanced reciprocal translocation, 46, XX, t(3;15) (q29;q22). SNP array identified no pathogenic copy number variation in the proband. Trio-WES (fetus-mother-father) sequencing results revealed no pathogenic variants in the genes related to SHFM. Whole-genome low-coverage mate-pair sequencing (WGL-MPS), breakpoint PCR, and Sanger sequencing identified the breakpoints disrupting TP63 in the patients, but not in healthy family members. CONCLUSION: This study firstly reports that a translocation breakpoint disrupting TP63 contributes to the SHFM in a Chinese family, which expands our knowledge of genetic risk and counseling underlying SHFM. It provides a basis for genetic counseling and prenatal diagnosis (preimplantation genetic diagnosis) for this family.

Drug resistance in targeted cancer therapies with RAF inhibitors.

Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology. Targeting this pathway results in complete or partial regression of most cancers. In recent years, cancer genomic studies have revealed that genetic alterations that aberrantly activate the RAS/RAF/MEK/ERK signaling mainly occur on RAF or upstream, which motivated the extensive development of RAF inhibitors for cancer therapy. Currently, the first-generation RAF inhibitors have been approved for treating late-stage cancers with BRAF(V600E) mutations. Although these inhibitors have achieved promising outcomes in clinical treatments, their efficacy is abolished by quick-rising drug resistance. Moreover, cancers with hyperactive RAS exhibit intrinsic resistance to these drugs. To resolve these problems, the second-generation RAF inhibitors have been designed and are undergoing clinical evaluations. Here, we summarize the recent findings from mechanistic studies on RAF inhibitor resistance and discuss the critical issues in the development of next-generation RAF inhibitors with better therapeutic index, which may provide insights for improving targeted cancer therapy with RAF inhibitors.

[Non-invasive prenatal testing and genetic analysis of a fetus with partial trisomy 21].

OBJECTIVE: To carry out prenatal diagnosis for a fetus with high risk predicted by non-invasive prenatal testing (NIPT). METHODS: Next-generation sequencing (NGS) was used to analyze free fetal DNA (ffDNA) in the maternal plasma. Chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) were used to ascertain copy number variation in the fetus and its parents. RESULTS: SNP-array analysis and chromosomal karyotyping revealed that the fetus had a 15.018 Mb duplication at 4q34.1q35.2 and a 7.678 Mb duplication at 21q11.2q21.1, which were derived from a t(4;21)(q34.1;q21.1) translocation carried by its mother. CONCLUSION: NIPT is capable of detecting submicroscopic chromosomal abnormalities of the fetus. Combined use of genetic techniques, in particular SNP-array, is crucial for the diagnosis of partial trisomy 21q in this case.

[Genetic analysis of a pedigree with MECP duplication syndrome].

OBJECTIVE: To explore the genetic etiology of a pedigree with mental retardation and hypotonia by using chromosome microarray analysis (CMA), low coverage massive parallel copy number variation sequencing (CNV-seq) and quantitative PCR (qPCR). METHODS: Genomic DNA was extracted from peripheral blood samples from two male patients and healthy members from the pedigree. CNV-seq was carried out for one patient. Suspected CNV was verified by qPCR. CNV-seq or single nucleotide polymorphism array (SNP array) were carried out for another patient and his family members. RESULTS: Both patients showed severe hypotonia and global development delay, in particular language delay. CNV-seq and SNP array indicated that both patients had carried a Xq28 duplication, with spanned 0.26 Mb and 0.42 Mb, respectively. Both duplications encompassed the MECP2 gene. CNV-seq analysis of their family members confirmed that the mother and one sister had carried similar duplications, while an elder brother was normal. CONCLUSION: CNV-seq and CMA are rapid and effective tools for the diagnosis of MECP2 duplication syndrome in children with mental retardation, hypotonia and recurrent infections.

Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer.

BACKGROUND: Lysine succinylation is an emerging posttranslational modification that has garnered increased attention recently, but its role in gastric cancer (GC) remains underexplored. METHODS: Proteomic quantification of lysine succinylation was performed in human GC tissues and adjacent normal tissues by mass spectrometry. The mRNA and protein levels of lactate dehydrogenase A (LDHA) in GC and adjacent normal tissues were analyzed by qRT-PCR and western blot, respectively. The expression of K222-succinylated LDHA was measured in GC tissue microarray by the K222 succinylation-specific antibody. The interaction between LDHA and sequestosome 1 (SQSTM1) was measured by co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The binding of carnitine palmitoyltransferase 1A (CPT1A) to LDHA was determined by co-IP. The effect of K222-succinylated LDHA on tumor growth and metastasis was evaluated by in vitro and in vivo experiments. RESULTS: Altogether, 503 lysine succinylation sites in 303 proteins were identified. Lactate dehydrogenase A (LDHA), the key enzyme in Warburg effect, was found highly succinylated at K222 in GC. Intriguingly, this modification did not affect LDHA ubiquitination, but reduced the binding of ubiquitinated LDHA to SQSTM1, thereby decreasing its lysosomal degradation. We demonstrated that CPT1A functions as a lysine succinyltransferase that interacts with and succinylates LDHA. Moreover, high K222-succinylation of LDHA was associated with poor prognosis in patients with GC. Finally, overexpression of a succinylation-mimic mutant of LDHA promoted cell proliferation, invasion, and migration. CONCLUSIONS: Our data revealed a novel lysosomal pathway of LDHA degradation, which is mediated by the binding of K63-ubiquitinated LDHA to SQSTM1. Strikingly, CPT1A succinylates LDHA on K222, which thereby reduces the binding and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation. This study thus uncovers a new role of lysine succinylation and the mechanism underlying LDHA upregulation in GC.

[Xq;Yq translocation in a patient with premature ovarian insufficiency].

OBJECTIVE: To explore the genetic basis for a patient with premature ovarian insufficiency. METHODS: Chromosomal G-banding and C-banding, single nucleotide polymorphism array (SNP-array), fluorescence in situ hybridization (FISH) and Y chromosome microdeletion assay were used for the analysis. RESULTS: With the combined techniques, the patient was found to carry a Xq;Yq translocation, with a karyotype of 46,X,der(X)t(X;Y)(q25;q12).ish der(X)(Tel XYp+,Tel XYq+,Yq12+). CONCLUSION: Unbalanced Xq;Yq translocation probably underlay the premature ovarian insufficiency in this patient.

The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy.

Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

Chromosome-level genome assembly of the East Asian common octopus (Octopus sinensis) using PacBio sequencing and Hi-C technology.

The Cephalopoda are a group of highly diverse marine species in the phylum Mollusca, which are distributed worldwide. They have evolved some vertebrate-like biological traits and exhibit complicated behavioural repertoires. Thus, they are interesting species for studying the mechanisms of evolutionary convergence, innovational functional structures and evolutionary adaptation to a highly active, predatory lifestyle in diverse marine environments. Despite the evolutionary placement and biological significance of cephalopods, genomic data on these organisms remain limited. Here, we assembled a chromosome-level genome of a female East Asian common octopus (Octopus sinensis) by combining Pacific Bioscience (PacBio) single-molecule real-time sequencing, Illumina paired-end sequencing and Hi-C technology. An O. sinensis genome of 2.72 Gb was assembled from a total of 245.01 Gb high-quality PacBio sequences. The assembled genome represents 80.2% completeness (BUSCO) with a contig N50 of 490.36 Kb and a scaffold N50 of 105.89 Mb, showing a considerable improvement compared with other sequenced cephalopod genomes. Hi-C scaffolding of the genome resulted in the construction of 30 pseudochromosomes in Cephalopoda, representing 96.41% of the assembled sequences. The genome contained 42.26% repeat sequences and 5,245 noncoding RNAs. A total of 31,676 protein-coding genes were predicted, of which 82.73% were functionally annotated. The comparative genomic analysis identified 17,020 orthologous gene families, including 819 unique gene families and 629 expanded gene families. This genomic information will be an important molecular resource for further investigation of biological function and evolutionary adaptations in octopuses, and facilitate research into their population genetics and comparative evolution.