Comprehensive Insights into the Health Effects of Selenium Exposure and Supplementation Among the Chinese Community Middle-Aged and Elderly: a Combined Retrospective Cohort Study and Intervention Study.

Selenium (Se) is an essential trace element for maintaining human health, for example, plays a crucial role in preventing aging-related diseases. However, most studies on the health effects of Se among the community middle-aged and elderly have been observational or the health indices were single, and the related study among the Chinese population is limited. Additionally, China is recognized as among the countries facing a significant deficiency in Se, and Se contents in the human body may decrease with age. Therefore, a two-step study was conducted to explore the health effects of Se exposure and supplementation among such populations in China. Firstly, a retrospective cohort study was conducted to compare the health outcomes between such populations residing in Se-rich regions and non-Se-rich regions, involving a total of 102 subjects, with 51 residing in Se-rich regions and 51 in non-Se-rich regions. The hair-Se (H-Se) contents, serum-Se (S-Se) contents, and total cholesterol of subjects from Se-rich regions were significantly higher than their counterparts. Notably, significant positive associations were observed between S-Se and lipids. Secondly, a before-after self-control Se supplementation study among subjects residing in non-Se-rich regions was conducted. A total of 40 subjects administered Se tablets orally for 30 days, with Se of 120 µg/day. The results showed significant increases in H-Se and S-Se. Se supplementation also exhibited positive effects on alanine aminotransferase, homocysteine, and fasting glucose; however, high-density lipoprotein cholesterol significantly decreased. Overall, the community middle-aged and elderly residing in Se-rich regions or receiving quantitative Se supplementation could effectively improve Se contents in bodies and certain health indices, excluding lipids. These improvements encompass liver function, cardiovascular health, and glucose metabolism. These findings enhance our understanding of how Se impacts the health of the middle-aged and elderly, emphasizing the significance of targeted interventions for such populations in non-Se-rich regions. Trial registration: ChiCTR2000040987 ( https://www.chictr.org.cn ).

Corrigendum: Quantitative proteomics on the cerebrospinal fluid of hydrocephalus in neonatal bacterial meningitis.

[This corrects the article DOI: 10.3389/fped.2022.972032.].

A de novo mutation of ADAMTS8 in a patient with Wiedemann-Steiner syndrome.

BACKGROUND: Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant disorder caused by mutations in the KMT2A gene and is usually characterized by hairy elbows, short stature, developmental delay, intellectual disability and obvious facial dysmorphism. CASE PRESENTATION: Here, we report a 5-year-old girl with clinical features similar to WDSTS, including postnatal growth delay, retarded intellectual development, and ocular hypertelorism. Through whole-exome sequencing (WES), a frameshift variant of KMT2A was found in the patient but not in her parents' genomic DNA. By bioinformatics analysis, the KMT2A variant was demonstrated to be the top candidate pathogenic variant for the clinical phenotype consistent with WDSTS. Moreover, a duplication of exon 1 in ADAMTS8 (belonging to the zinc metalloproteinase family) was found in the genomic DNA of this patient, which may be responsible for the characteristics that are different from those of WDSTS, including early teething, rapid tooth replacement, and dysplastic enamel. CONCLUSIONS: From the above results, we propose that in our patient, the frameshift variant in KMT2A is the main reason for the WDSTS phenotype, and the unreported mutation in ADAMTS8 may be the candidate reason for other characteristics that are different from those of WDSTS. Therefore, this study not only provides a new KMT2A variant associated with WDSTS but is also a reminder that combined mutations may be present in a case with more characteristics than those seen in WDSTS.

Associations of micronutrients exposure with cadmium body burden among population: A systematic review.

BACKGROUND: The absorption and accumulation of cadmium (Cd) within the human body can be influenced by the status of certain micronutrients, while available evidence for the association between micronutrient exposure and Cd body burden remains fragmented and inconsistent. To address this issue, this article reviews and synthesizes epidemiological studies that examine the association between micronutrient exposure and Cd burden in humans, to elucidate the potential association between micronutrient exposure and Cd body burden. METHODS: We conducted a systematic review of epidemiologic studies reporting the association between micronutrient status and Cd body burden among the population. Relevant articles were selected based on predetermined criteria from PubMed, Web of Science, and Scopus databases published from 2000 to 2021. The exposures that were evaluated included micronutrients (zinc, selenium, iron, calcium, and vitamins) status or intakes of them. The outcome of interest was the Cd body burden as indicated by blood Cd or urinary Cd levels. The quality of included studies was assessed using The Joanna Briggs Institute critical appraisal tool. We extracted data from each article, including study design, study site, study population, micronutrient status, Cd body burden, and the correlations between micronutrient status and Cd body burden. RESULTS: Our systematic search yielded 1660 articles. Of these, forty-four were selected for inclusion based on prespecified criteria. These selected articles evaluated the relationship between Cd body burden and seven different micronutrients, namely, selenium (Se), zinc (Zn), calcium (Ca), iron (Fe), vitamin A, vitamin B12, and vitamin D. The majority of studies (n = 41) were observational, while only three were randomized controlled trials. Among the seventeen studies assessing Zn status, ten reported a negative association between serum Zn levels or intake and urinary and blood Cd levels. Results were inconsistent among the ten studies examining the association between Se levels and Cd body burden. Six studies showed that Cd in blood and urine was negatively correlated with serum ferritin (SF), a biomarker of body Fe status. Two studies reported a negative correlation between Ca and blood Cd. CONCLUSIONS: This synthesis of available evidence suggests that certain micronutrients, especially Zn and Fe, may play a role in reducing the Cd body burden among populations. The evidence strongly supports a negative association between Zn, Fe, and Cd body burden, whereas evidence for Se, Ca and vitamins is insufficient to draw definitive conclusions regarding their relationship with Cd body burden. In addition, observational studies limit the ability to infer a causal relationship between micronutrients and Cd body burden, highlighting the need for additional intervention studies. Our review may inform nutrient supplementation guidance, control of Cd body burden, and future research to mitigate the adverse health effects of Cd in the context of global Cd pollution.

The clinical spectrum of a nonsense mutation in KAT6A: a case report.

KAT6A syndrome is an autosomal dominant genetic disorder associated with intellectual disability due to mutations in the lysine acetyltransferase 6A (KAT6A) gene. There are some differences in phenotype between KAT6A gene variants. This current case report describes a 1-month-old male infant that had a nonsense mutation in the KAT6A gene. Neither of his parents had the mutation. The proband had feeding difficulties and a physical examination revealed the following: moderate dysphagia, hypoplastic laryngeal cartilage, poor audio-visual response, poor head-up ability, no active grasping awareness, microcephaly, high arched palate and he was significantly behind other children of the same age. Echocardiography showed that the foramen ovale was not closed. He was diagnosed with atrial septal defect (ASD) when 2 years old. The patient received ASD repair at 32 months of age. Head colour Doppler ultrasonography and brain magnetic resonance imaging showed cysts in the right ventricle and choroid plexus, which returned to normal at 2 years of age. This current case demonstrates that immediate surgery should be considered in newborns with KAT6A syndrome presenting with a heart malformation. A new KAT6A syndrome phenotype is described in this current case report, which requires early diagnosis and treatment.

Quantitative proteomics on the cerebrospinal fluid of hydrocephalus in neonatal bacterial meningitis.

Objective: Hydrocephalus in bacterial meningitis (BM) is a devastating infectious neurological disease and the proteins and pathways involved in its pathophysiology are not fully understood. Materials and methods: Label-free quantitative (LFQ) proteomics analyses was used to identify differentially expressed proteins (DEPs) in cerebrospinal fluid (CSF) samples from infants with hydrocephalus and bacterial meningitis (HBM group, N = 8), infants with bacterial meningitis (BM group, N = 9); and healthy infants (N group, N = 11). Bioinformatics analysis was subsequently performed to investigate Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched signaling pathways of these DEPs. Six proteins (AZU1, COX4I1, EDF1, KRT31, MMP12, and PRG2) were selected for further validation via enzyme-linked immunosorbent assay (ELISA). Results: Compared with BM group and N group, HBM group had a higher whole CSF protein level (5.6 ± 2.7 vs. 1.7 ± 1.0 vs. 1.2 ± 0.5 g/l) and lower whole CSF glucose level (0.8 ± 0.6 vs. 1.8 ± 0.7 vs. 3.3 ± 0.8 mmol/l) (both P < 0.05). Over 300 DEPs were differentially expressed in HBM group compared with BM group and BM compared with N group, of which 78% were common to both. Cluster analysis indicated that the levels of 226 proteins were increased in BM group compared with N group and were decreased in HBM group compared with BM group. Bioinformatics analysis indicated the involvement of the cell adhesion, immune response and extracellular exosome signaling were significantly enriched in HBM compared with BM group and BM compared with N group. 267 DEPs were identified between HBM group with N group, KEGG analysis indicated that DEPs mainly involved in filament cytoskeleton and immune response. The ELISA results further verified that the expression levels of AZU1 were significantly different from among three groups (both P < 0.05). Conclusion: This is the first reported characterization of quantitative proteomics from the CSF of infants with HBM. Our study also demonstrated that AZU1 could be a potential biomarker for the diagnosis of hydrocephalus in bacterial meningitis.

A novel UBE2A splice site variant causing intellectual disability type Nascimento.

X-linked intellectual disability type Nascimento (XLID) is a rare disease caused by variants in the ubiquitin-conjugating enzyme E2A gene (UBE2A). Patients with XLID have similar phenotypes, including speech impairments, severe intellectual disability, hearing loss, wide facies, synophrys, generalized hirsutism, and urogenital abnormalities. Till date, only two splice-site variants of the UBE2A gene have been observed in patients with X-linked ID type Nascimento. Here, we report the case of a Chinese boy with a syndrome clinically similar to XLID with speech impairment, severe intellectual disability, and moderate hearing loss. However, different characteristics were also present in the patient, including an inability to maintain his head in an upright posture. Both of the patient's palms have a single transverse palmar crease. Subsequent whole-exome sequencing revealed a novel splice site variant in UBE2A (c.241 + 1 G > A). Our study not only expands the variant spectrum and clinical characteristics of UBE2A deficiency syndrome but also provides clinical evidence for genetic diagnoses.

Neomodified Koyanagi technique for severe hypospadias with one-stage sealed Y-shaped penis foreskin vascular protection surgery.

Proximal hypospadias defects represent the most challenging aspect of maintaining blood supply to the flap, which eventually leads to a high rate of complications. We modified a sealed Y-shaped penis foreskin vascular protection technique, which can repair the urethra in a single stage. The inner plate of the foreskin was cut along the coronal sulcus, and both sides of the urethral plate were cut as deep as Buck's fascia. The "Y"-shaped foreskin flaps on both sides of the mouth that are continuous with the urethral plate were sutured to form a new urethral skin tube. The urethral skin tube was turned to the ventral side, and the foreskin was reshaped and sutured. A total of 89 children had their urinary catheters removed 4 weeks after the operation. All children were evaluated at least once a year for 3 consecutive years. There were 11 patients with urine leakage that occurred after the operation. These children, diagnosed with urine leakage, underwent successful repair after the leakage occurred. There were no urethral strictures after the operation. The one-time success rate of this operation was 87.6% (78/89), and the incidence of urethral fistula was 12.6% (11/89). The results showed that sealed Y-shaped penis foreskin vascular protection surgery was safer and had a higher operation rate than the traditional hypospadias repair technique. Modifying Koyanagi repair by our improved Koyanagi hypospadias repair is an excellent technique with relatively low complication rates.

Bohring-Opitz syndrome caused by a novel ASXL1 mutation (c.3762delT) in an IVF baby: A case report.

RATIONALE: Bohring-Opitz syndrome is a severe congenital disorder associated with a de novo mutation in the additional sex combs-like 1 (ASXL1) gene, and it is characterized by symptoms that include developmental delay and musculoskeletal and neurological features. PATIENT CONCERNS: The patient was a girl, an in vitro fertilization (IVF) baby, with delayed motor development, drooling, short stature, slow growth, low muscle tone, image diagnosis of hypoplasia of the corpus callosum, delayed tooth eruption, high palatal arch, adduction of the thumb, drooling, not chewing, excessive joint activity, and ligament relaxation. DIAGNOSIS: Whole-exome sequencing analysis detected 1 novel disruptive frameshift mutation in ASXL1 in the proband but wild-type ASXL1 in both parents. INTERVENTIONS: Approximately 1 year of rehabilitation training, which included exercise therapy, toy imitation operation, cognition of daily objects, daily living skills training, gesture language training, oral muscle training, and hand movement training. OUTCOMES: After approximately 1 year of training, the patient was 3 years old and able to eat normally without drooling. She was able to grasp objects and pick them up after they fell. She was able to grasp small objects and actively played with toys. In addition, she was able to crawl on the floor (at slow speed, with poor initiative), stand with assistance, and walk with assistance; she was unstable when standing unassisted (standing unassisted for 8 seconds at most during training). LESSON: ASXL1 c.3762delT is a novel mutation that may be caused by IVF. This finding suggests that appropriate gene mutation detection approaches may be necessary for IVF technology.

The Use of CRISPR/Cas9 as a Tool to Study Human Infectious Viruses.

Clustered regularly interspaced short palindromic repeats (CRISPR) systems are a set of versatile gene-editing toolkit that perform diverse revolutionary functions in various fields of application such as agricultural practices, food industry, biotechnology, biomedicine, and clinical research. Specially, as a novel antiviral method of choice, CRISPR/Cas9 system has been extensively and effectively exploited to fight against human infectious viruses. Infectious diseases including human immunodeficiency virus (HIV), hepatitis B virus (HBV), human papillomavirus (HPV), and other viruses are still global threats with persistent potential to probably cause pandemics. To facilitate virus removals, the CRISPR/Cas9 system has already been customized to confer new antiviral capabilities into host animals either by modifying host genome or by directly targeting viral inherent factors in the form of DNA. Although several limitations and difficulties still need to be conquered, this technology holds great promises in the treatment of human viral infectious diseases. In this review, we will first present a brief biological feature of CRISPR/Cas9 systems, which includes a description of CRISPR/Cas9 structure and composition; thereafter, we will focus on the investigations and applications that employ CRISPR/Cas9 system to combat several human infectious viruses and discuss challenges and future perspectives of using this new platform in the preclinical and clinical settings as an antiviral strategy.

Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration.

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic ß-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that p21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic ß-catenin at Ser 675 and increases its stability at disassembled sarcomeres. Myocardial-specific induction of the phospho-mimetic ß-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to injury. Conversely, inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylated ß-catenin (pS675-ß-catenin) and attenuates CM sarcomere disorganization and dedifferentiation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-ß-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.

The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase.

Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in gridlock (grl; also known as hey2), encoding a Hairy-related basic helix-loop-helix transcriptional repressor, enhance CM proliferation and reduce fibrosis following damage. In contrast, myocardial grl induction blunts CM dedifferentiation and regenerative responses to heart injury. RNA sequencing analyses uncover Smyd2 lysine methyltransferase (KMT) as a key transcriptional target repressed by Grl. Reduction in Grl protein levels triggered by injury induces smyd2 expression at the wound myocardium, enhancing CM proliferation. We show that Smyd2 functions as a methyltransferase and modulates the Stat3 methylation and phosphorylation activity. Inhibition of the KMT activity of Smyd2 reduces phosphorylated Stat3 at cardiac wounds, suppressing the elevated CM proliferation in injured grl mutant hearts. Our findings establish an injury-specific transcriptional repression program in governing CM renewal during heart regeneration, providing a potential strategy whereby silencing Grl repression at local regions might empower regeneration capacity to the injured mammalian heart.

Wnt2bb Induces Cardiomyocyte Proliferation in Zebrafish Hearts via the jnk1/c-jun/creb1 Pathway.

Previous studies have demonstrated that inhibition of canonical Wnt signaling promotes zebrafish heart regeneration and that treatment of injured heart tissue with the Wnt activator 6-bromo-indirubin-3-oxime (BIO) can impede cardiomyocyte proliferation. However, the mechanism by which Wnt signaling regulates downstream gene expression following heart injury remains unknown. In this study, we have demonstrated that inhibition of injury-induced myocardial wnt2bb and jnk1/creb1/c-jun signaling impedes heart repair following apex resection. The expression of jnk1, creb1, and c-jun were inhibited in wnt2bb dominant negative (dn) mutant hearts and elevated in wnt2bb-overexpresssing hearts following ventricular amputation. The overexpression of creb1 sufficiently rescued the dn-wnt2bb-induced phenotype of reduced nkx2.5 expression and attenuated heart regeneration. In addition, wnt2bb/jnk1/c-jun/creb1 signaling was increased in Tg(hsp70l:dkk1) transgenic fish, whereas it was inhibited in Tg(hsp70l:wnt8) transgenic fish, indicating that canonical Wnt and non-canonical Wnt antagonize each other to regulate heart regeneration. Overall, the results of our study demonstrate that the wnt2bb-mediated jnk1/c-jun/creb1 non-canonical Wnt pathway regulates cardiomyocyte proliferation.

Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair.

There are intense interests in discovering proregenerative medicine leads that can promote cardiac differentiation and regeneration, as well as repair damaged heart tissues. We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects. Two related compounds with novel structures, named as Cardiomogen 1 and 2 (CDMG1 and CDMG2), were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population. We find that Cardiomogen acts as a Wnt inhibitor by targeting ß-catenin and reducing Tcf/Lef-mediated transcription in cultured cells. CDMG treatment of amputated zebrafish hearts reduces nuclear ß-catenin in injured heart tissue, increases cardiomyocyte (CM) proliferation, and expedites wound healing, thus accelerating cardiac muscle regeneration. Importantly, Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial infarction. Injured hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue, which are in part attributable to the ß-catenin reduction. Our findings indicate Cardiomogen as a Wnt inhibitor in enhancing injury-induced CM proliferation and heart regeneration, highlighting the values of embryo-based small molecule screens in discovery of effective and safe medicine leads.

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair.

Upon arterial injury, endothelial denudation leads to platelet activation and delivery of multiple agents (e.g., TXA2, PDGF), promoting VSMC dedifferentiation and proliferation (intimal hyperplasia) during injury repair. The process of resolution of vessel injury repair, and prevention of excessive repair (switching VSMCs back to a differentiated quiescent state), is poorly understood. We now report that internalization of APs by VSMCs promotes resolution of arterial injury by switching on VSMC quiescence. Ex vivo and in vivo studies using lineage tracing reporter mice (PF4-cre × mT/mG) demonstrated uptake of GFP-labeled platelets (mG) by mTomato red-labeled VSMCs (mT) upon arterial wire injury. Genome-wide miRNA sequencing of VSMCs cocultured with APs identified significant increases in platelet-derived miR-223. miR-223 appears to directly target PDGFRß (in VSMCs), reversing the injury-induced dedifferentiation. Upon arterial injury, platelet miR-223-KO mice exhibited increased intimal hyperplasia, whereas miR-223 mimics reduced intimal hyperplasia. Diabetic mice with reduced expression of miR-223 exhibited enhanced VSMC dedifferentiation and proliferation and increased intimal hyperplasia. Our results suggest that horizontal transfer of platelet-derived miRNAs into VSMCs provides a novel mechanism for regulating VSMC phenotypic switching. Platelets thus play a dual role in vascular injury repair, initiating an immediate repair process and, concurrently, a delayed process to prevent excessive repair.

Cardiotoxicity and Mechanism of Particulate Matter 2.5 (PM2.5) Exposure in Offspring Rats During Pregnancy.

BACKGROUND The aim of this study was to investigate the cardiotoxicity and mechanism of particulate matter 2.5 (PM2.5) exposure on offspring rats during pregnancy. MATERIAL AND METHODS Wistar rats were used to establish a PM2.5 exposure animal model during pregnancy, and they were divided into a control group, a low-dose group, a middle-dose group, and a high-dose group according to PM2.5 exposure dose. The pathological changes of heart tissue, the rate of myocardial cell apoptosis, the levels of LDH, AST, and CM-KB in serum, and the difference in mitochondrial fusion genes (OPA1 and Mfn1) and mitochondrial genes (Drp1 and Fis1) were compared among groups. RESULTS The arrangement of myocardial fibers in offspring mice of PM2.5 exposure groups became disordered, the shape of some cardiomyocytes became irregular, and some staining darker nuclei appeared. The apoptotic rates of myocardium in offspring rats exposed to PM2.5 were (12.61±0.93)% in the low-dose group, (25.14±1.53)% in the middle-dose group, and (30.13±1.50)% in the high-dose group, which were all significantly higher than in the control group (9.12±0.80)% (P<0.05). The levels of LDH, AST, and CM-KB and the expression of OPA1, Mfn1, Drp1, and Fis1 in offspring mice of PM2.5 exposure groups increased with the increase of PM2.5 exposure dose, and were significantly higher than that of the control group (P<0.05). CONCLUSIONS The mitochondria of the offspring mice were damaged due to the abnormal expression of mitochondrial fusion/splicing gene by PM2.5 exposure during pregnancy, and the hearts of offspring mice were damaged due to damaged mitochondria.

A cross-sectional study on the prevalence and associated risk factors for workplace violence against Chinese nurses.

OBJECTIVES: The purpose of the present study was to explore the characteristics of workplace violence that Chinese nurses at tertiary and county-level hospitals encountered in the 12 months from December 2014 to January 2016, to identify and analyse risk factors for workplace violence, and to establish the basis for future preventive strategies. DESIGN: A cross-sectional study. SETTING: A total of 44 tertiary hospitals and 90 county-level hospitals in 16 provinces (municipalities or autonomous regions) in China. METHODS: We used stratified random sampling to collect data from December 2014 to January 2016. We distributed 21 360 questionnaires, and 15 970 participants provided valid data (effective response rate=74.77%). We conducted binary logistic regression analyses on the risk factors for workplace violence among the nurses in our sample and analysed the reasons for aggression. RESULTS: The prevalence of workplace violence was 65.8%; of this, 64.9% was verbal violence, and physical violence and sexual harassment accounted for 11.8% and 3.9%, respectively. Frequent workplace violence occurred primarily in emergency and paediatric departments. Respondents reported that patients' relatives were the main perpetrators in tertiary and county-level hospitals. Logistic regression analysis showed that respondents' age, department, years of experience and direct contact with patients were common risk factors at different levels of hospitals. CONCLUSIONS: Workplace violence is frequent in China's tertiary and county-level hospitals; its occurrence is especially frequent in the emergency and paediatric departments. It is necessary to cope with workplace violence by developing effective control strategies at individual, hospital and national levels.

Rac1-PAK2 pathway is essential for zebrafish heart regeneration.

P-21 activated kinases, or PAKs, are serine-threonine kinases that play important roles in diverse heart functions include heart development, cardiovascular development and function in a range of models; however, the mechanisms by which PAKs mediate heart regeneration are unknown. Here, we demonstrate that PAK2 and PAK4 expression is induced in cardiomyocytes and vessels, respectively, following zebrafish heart injury. Inhibition of PAK2 and PAK4 using a specific small molecule inhibitor impedes cardiomyocyte proliferation/dedifferentiation and cardiovascular regeneration, respectively. Cdc42 is specifically expressed in the ventricle and may function upstream of PAK2 but not PAK4 under normal conditions and that cardiomyocyte proliferentation during heart regeneration relies on Rac1-mediated activation of Pak2. Our results indicate that PAKs play a key role in heart regeneration.

Genome-wide prediction of cancer driver genes based on SNP and cancer SNV data.

Identifying cancer driver genes and exploring their functions are essential and the most urgent need in basic cancer research. Developing efficient methods to differentiate between driver and passenger somatic mutations revealed from large-scale cancer genome sequencing data is critical to cancer driver gene discovery. Here, we compared distinct features of SNP with SNV data in detail and found that the weighted ratio of SNV to SNP (termed as WVPR) is an excellent indicator for cancer driver genes. The power of WVPR was validated by accurate predictions of known drivers. We ranked most of human genes by WVPR and did functional analyses on the list. The results demonstrate that driver genes are usually highly enriched in chromatin organization related genes/pathways. And some protein complexes, such as histone acetyltransferase, histone methyltransferase, telomerase, centrosome, sin3 and U12-type spliceosomal complexes, are hot spots of driver mutations. Furthermore, this study identified many new potential driver genes (e.g. NTRK3 and ZIC4) and pathways including oxidative phosphorylation pathway, which were not deemed by previous methods. Taken together, our study not only developed a method to identify cancer driver genes/pathways but also provided new insights into molecular mechanisms of cancer development.