Assisted hatching(AH)is commonly performed before trophectoderm(TE)biopsy for preimplantation genetic testing for aneuploidy(PGT-A),yet whether AH timing influences the detection of chromosomal mosaicism remains uncer...Assisted hatching(AH)is commonly performed before trophectoderm(TE)biopsy for preimplantation genetic testing for aneuploidy(PGT-A),yet whether AH timing influences the detection of chromosomal mosaicism remains uncertain.Beyond timing,procedural choices in PGT-A must balance diagnostic yield against potential harm from additional handling(e.g.,repeat TE biopsy or cryopreservation steps),as underscored by a recent systematic review and meta-analysis[1].展开更多
Primordial germ cells(PGCs)are the precursors of germline that are specified at the embryonic stage.Recent studies reveal that humans employ different mechanisms for PGC specification compared with model organisms suc...Primordial germ cells(PGCs)are the precursors of germline that are specified at the embryonic stage.Recent studies reveal that humans employ different mechanisms for PGC specification compared with model organisms such as mice.Moreover,the specific regulatory machinery remains largely unexplored,mainly due to the inaccessible nature of this complex biological process in humans.Here,we curate and integrate multi-omics data,including 581 RNA-seq,54 ATAC-seq,45 ChIP-seq,and 69 single-cell RNA-seq samples from different stages of human PGC development to recapitulate the precisely controlled and stepwise process,presenting an atlas in the human PGC database(hPGCdb).With these uniformly processed data and integrated analyses,we characterize the potential key transcription factors and regulatory networks governing human germ cell fate.We validate the important roles of some of the key factors in germ cell development by CRISPRi knockdown.We also identify the soma-germline interaction network and discover the involvement of SDC2 and LAMA4 for PGC development,as well as soma-derived NOTCH2 signaling for germ cell differentiation.Taken together,we have built a database for human PGCs(http://43.131.248.15:6882)and demonstrate that hPGCdb enables the identification of the missing pieces of mechanisms governing germline development,including both intrinsic and extrinsic regulatory programs.展开更多
High-throughput technologies in combination with modern exciting advancements in mass spectrometry-based proteomics and data analysis pipelines have empowered comprehensive characterization of disease phenotypes and t...High-throughput technologies in combination with modern exciting advancements in mass spectrometry-based proteomics and data analysis pipelines have empowered comprehensive characterization of disease phenotypes and their mechanistic regulation by dietary agents and bioactive molecules at unprecedented dimensionality and resolution.Extra-ordinary breakthroughs in the field of nutrigenomics have leveraged our understanding altogether to a new level of maturity.Interdisciplinary researchers have extensively analyzed health promoting and pharmacologically significant properties of garlic(Allium sativum).Importantly,garlic and its biologically active chemicals targeted oncogenic signaling cascades.In this mini-review we have attempted to summarize how garlic and its bioactive constituents regulated signal transduction cascades in cell culture studies and tumor-bearing mice.展开更多
Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway.Melatonin has many benefits,such as or...Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway.Melatonin has many benefits,such as organizing circadian rhythms and acting as a powerful hormone.We aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin(mTOR)signaling pathway and the Argyrophilic Nucleolar Regulatory Region(AgNOR),using the Microcomputed Tomography(Micro CT).Ehrlich ascites carcinoma(EAC)cells were administered into the mice by subcutaneous injection.Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days.Volumetric measurements for the taken tumors were made with micro-CT imaging,immunohistochemistry(IHC),real-time polymerase chain reaction(PCR)and AgNOR.Statistically,the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images.In the IHC analysis,the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8(F8)expression were compared with the control group.It was determined that there was a significant decrease(p<0.05).Significant differences were found in the total AgNOR area/nuclear area(TAA/NA)ratio in the treatment groups(p<0.05).Furthermore,there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase(PI3K),AKT Serine/Threonine Kinase(PKB/AKT)genes(p<0.05).Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin;It was observed that 100µg/mL melatonin dose caused an increase in the apoptotic cell death.In this study,we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models.Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and translatability of pre-clinical findings to earlier phases of clinical trials.展开更多
Transforming growth factor （TGF）-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase rec...Transforming growth factor （TGF）-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our under- standing of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.展开更多
AIM:To investigate the expression and potential prognostic role of vascular endothelial growth factor(VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors(GEP-NETs) . METHODS:Microvessel density(MVD) in ...AIM:To investigate the expression and potential prognostic role of vascular endothelial growth factor(VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors(GEP-NETs) . METHODS:Microvessel density(MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry.In addition,tissue levels of endoglin and VEGF were determined in homogenates by ELISA. RESULTS:Endoglin was highly expressed on tumor endothelial cells.CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD(P<0.01) .Two-tofour-fold higher tissue levels of endoglin and VEGF were seen in tumors compared to associated normal tissue. This increased endoglin tissue expression in tumors was significantly related to tumor size(P<0.01) ,presence of metastases(P=0.04) ,and a more advanced tumor stage(P=0.02) ,whereas expression of VEGF was not. CONCLUSION:We suggest that endoglin is a potential marker to indicate and predict metastases,which might be useful in the post-resection therapeutic approach of patients with GEP-NETs.展开更多
Human herpesviruses （HVs） have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system （CNS）. The ability of HVs to enter a state of latency, a defining char- acteris...Human herpesviruses （HVs） have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system （CNS）. The ability of HVs to enter a state of latency, a defining char- acteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease （NDD） patholo- gy by highlighting two prominent members of the HV family, herpes simplex virus 1 （HSV-1） and human herpesvirus 6 （HHV-6）. We （i） introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then （ii） review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer＇s disease （AD） and multiple sclerosis （MS）, respectively. We then （iii） highlight and dis- cuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we （iv） discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.展开更多
RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling c...RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.展开更多
In this study, CeO2 nanostructures were synthesized by a soft chemical method. A hydrothermal treatment was observed to lead to an interesting morphological transformation of the nanoparticles into homogeneous microsp...In this study, CeO2 nanostructures were synthesized by a soft chemical method. A hydrothermal treatment was observed to lead to an interesting morphological transformation of the nanoparticles into homogeneous microspheres composed of nanosheets with an average thickness of 40 nm. Structural analysis revealed the formation of a single-phase cubic fluorite structure of CeO2 for both samples. A Raman spectroscopic study confirmed the XRD results and furthermore indicated the presence of a large number of oxygen vacancies in the nanosheets. These oxygen vacancies led to room-temperature ferromagnetism （RTFM） of the CeO2 nanosheets with enhanced magnetic characteristics. Amazingly, the nanosheets exhibited substantially greater antibacterial activity than the nanoparticles. This greater antibacte- rial activity was attributed to greater exposure of high-surface-energy polar surfaces and to the presence of oxygen vacancies.展开更多
Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral n...Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional recovery.We hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve injury.Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose.While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls.These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration.The animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on March 31,2017.展开更多
4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated tha...4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.展开更多
Here, undoped and Cu doped ZnO nanoparticles(NPs) have been prepared by chemical co-precipitation technique. X-ray diffraction(XRD) results reveal that Cu ions are successfully doped into ZnO matrix without altering i...Here, undoped and Cu doped ZnO nanoparticles(NPs) have been prepared by chemical co-precipitation technique. X-ray diffraction(XRD) results reveal that Cu ions are successfully doped into ZnO matrix without altering its wurtzite phase. The single wurtzite phase of ZnO is retained even for 10 wt% Cu doped ZnO sample. It is observed from the electron microscopy results that higher level of Cu doping varies the morphology of ZnO NPs from spherical to flat NPs. Moreover, the particle size is found to increase with the increase in Cu doping level. Raman spectroscopy results further confirm that Cu dopant has not altered the wurtzite structure of ZnO. Impedance spectroscopy results reveal that the dielectric constant and dielectric loss have increasing trend with Cu doping. Cu doping has been found to slightly decrease the bactericidal potency of ZnO nanoparticles.展开更多
This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in child...This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.展开更多
AIM： To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation.· METHODS： A consanguineous Pakistani fa...AIM： To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation.· METHODS： A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome（USH）. To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat（STR） markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene.· RESULTS： By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them,c.1304AC was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype.This, c.1304 A C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435（p.D435A） of its protein product.Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic.·CONCLUSION：Theidentificationofc.1304ACpathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is thefirst example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.展开更多
Hepatitis C virus is one of the major health problems worldwide. It affects mainly the liver but several extrahepatic manifestations are also accounted. Chronic hepatitis C patients are at an increased risk of develop...Hepatitis C virus is one of the major health problems worldwide. It affects mainly the liver but several extrahepatic manifestations are also accounted. Chronic hepatitis C patients are at an increased risk of developing hepatic steatosis, which share many clinical features with the metabolic syndrome. Hepatic steatosis has also been associated with elevated levels of markers of inflammation such as homocysteine, identified as hyperhomocysteinemia (HHC). HHC due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T polymorphism, was recently associated with coronary heart diseases (CHD) in chronic hepatitis C (CHC) patients. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver metabolism. Deficiencies of micronutrients (folate, vitamin B 6 and possibly vitamin B 12) along with mild hyperhomocysteinemia, perhaps, act synergistically with other classical risk factors to further increase the risk of CHD. Clinical data indicate that HHC is associated with an increased incidence of CHD as well as with the severity of the disease in CHC patients. In conclusion, HHC might be a potential aetiological factor of CHD in CHC patients. The aim of this review is to investigate the progression of coronary heart diseases in chronic hepatitis C patients and correlate with levels of homocysteine in concurrence to genetic defects and nutrient deficiencies. However, future studies need to clarify the mechanistic role of HHC in CHD and CHC as a useful paradigm with most interesting therapeutic implications.展开更多
Cancer is the second deadliest human disease worldwide with high mortality rate.Rehabilitation and treatment of this disease requires precise and automatic assessment of effective drug response and control system.Pred...Cancer is the second deadliest human disease worldwide with high mortality rate.Rehabilitation and treatment of this disease requires precise and automatic assessment of effective drug response and control system.Prediction of treated and untreated cancerous cell line is one of the most challenging problems for precise and targeted drug delivery and response.A novel approach is proposed for prediction of drug treated and untreated cancer cell line automatically by employing modified Deep neural networks.Human hepatocellular carcinoma(HepG2)cells are exposed to anticancer drug functionalized CFO@BTO nanoparticles developed by our lab.Prediction models are developed by modifying ResNet101 and exploiting the transfer learning concept.Last three layers of ResNet101 are re-trained for the identification of drug treated cancer cells.Transfer learning approach in an appropriate choice especially when there is limited amount of annotated data.The proposed technique is validated on acquired 203 fluorescentmicroscopy images of human HepG2 cells treated with drug functionalized cobalt ferrite@barium titanate(CFO@BTO)magnetoelectric nanoparticles in vitro.The developed approach achieved high prediction with accuracy of 97.5%and sensitivity of 100%and outperformed other approaches.The high performance reveals the effectiveness of the approach.It is scalable and fully automatic prediction approach which can be extended for other similar cell diseases such as lung,brain tumor and breast cancer.展开更多
Background: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of ...Background: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-κ B, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-κ B activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. Objectives: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. Methods: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. Results: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6- 2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. Conclusions: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.展开更多
In this paper,we propose bivariate iterated Farlie-Gumbel-Morgenstern(FGM)due to[Huang and Kotz(1984).Correlation structure in iterated Farlie-Gumbel-Morgenstern distributions.Biometrika 71(3),633-636.https://doi.org/...In this paper,we propose bivariate iterated Farlie-Gumbel-Morgenstern(FGM)due to[Huang and Kotz(1984).Correlation structure in iterated Farlie-Gumbel-Morgenstern distributions.Biometrika 71(3),633-636.https://doi.org/10.2307/2336577]with Rayleigh marginals.The dependence stress-strength reliability function is derived with its important reliability characteristics.Estimates of dependence reliability parameters are obtained.We analyse the effects of dependence parameters on the reliability function.We found that the upper bound of the positive correlation coefficient is attaining to 0.41 under a single iteration with Rayleigh marginals.A comprehensive comparison between classical FGM with iterated FGM copulas is graphically examined to assess the over or under estimation of reliability with respect to α and β.We propose a two-phase estimation procedure for estimating the reliability parameters.A Monte-Carlo simulation study is conducted to assess the finite sample behaviour of the proposed reliability estimators.Finally,the proposed estimators are examined and validated with real data sets.展开更多
Oxidative stress is characterized by the deregulation of the redox state in the cells,which plays a role in the initiation of various types of cancers.The activity of galectin-1(Gal-1)depends on the cell redox state a...Oxidative stress is characterized by the deregulation of the redox state in the cells,which plays a role in the initiation of various types of cancers.The activity of galectin-1(Gal-1)depends on the cell redox state and the redox state of the microenvironment.Gal-1 expression has been related to many different tumor types,as it plays important roles in several processes involved in cancer progression,such as apoptosis,cell migration,adhesion,and immune response.The erythroid-2-related factor 2(Nrf2)/Kelch-like ECH-associated protein 1(Keap1)signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress.In this review,we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells,particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway.The emerging evidence concerning the anti-apoptotic effect of Gal-1,together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress,supports the role of Gal-1 in the promotion of tumor cells proliferation,immuno-suppression,and anti-tumor drug resistance,thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression.Overall,a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents.Excitingly,although it is still understudied,the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.展开更多
Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases recep...Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes （DUBs）. In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed.展开更多
文摘Assisted hatching(AH)is commonly performed before trophectoderm(TE)biopsy for preimplantation genetic testing for aneuploidy(PGT-A),yet whether AH timing influences the detection of chromosomal mosaicism remains uncertain.Beyond timing,procedural choices in PGT-A must balance diagnostic yield against potential harm from additional handling(e.g.,repeat TE biopsy or cryopreservation steps),as underscored by a recent systematic review and meta-analysis[1].
基金supported by the National Natural Science Foundation of China awarded to D.C.(32270835)Zhejiang Natural Science Foundation awarded to D.C.(Z22C129553)Dr.Li Dak Sum&Yip Yio Chin Development Fund for Regenerative Medicine,Zhejiang University,awarded to D.C.
文摘Primordial germ cells(PGCs)are the precursors of germline that are specified at the embryonic stage.Recent studies reveal that humans employ different mechanisms for PGC specification compared with model organisms such as mice.Moreover,the specific regulatory machinery remains largely unexplored,mainly due to the inaccessible nature of this complex biological process in humans.Here,we curate and integrate multi-omics data,including 581 RNA-seq,54 ATAC-seq,45 ChIP-seq,and 69 single-cell RNA-seq samples from different stages of human PGC development to recapitulate the precisely controlled and stepwise process,presenting an atlas in the human PGC database(hPGCdb).With these uniformly processed data and integrated analyses,we characterize the potential key transcription factors and regulatory networks governing human germ cell fate.We validate the important roles of some of the key factors in germ cell development by CRISPRi knockdown.We also identify the soma-germline interaction network and discover the involvement of SDC2 and LAMA4 for PGC development,as well as soma-derived NOTCH2 signaling for germ cell differentiation.Taken together,we have built a database for human PGCs(http://43.131.248.15:6882)and demonstrate that hPGCdb enables the identification of the missing pieces of mechanisms governing germline development,including both intrinsic and extrinsic regulatory programs.
基金funded by a grant(UICR202107)from BNUHKBU United International College.
文摘High-throughput technologies in combination with modern exciting advancements in mass spectrometry-based proteomics and data analysis pipelines have empowered comprehensive characterization of disease phenotypes and their mechanistic regulation by dietary agents and bioactive molecules at unprecedented dimensionality and resolution.Extra-ordinary breakthroughs in the field of nutrigenomics have leveraged our understanding altogether to a new level of maturity.Interdisciplinary researchers have extensively analyzed health promoting and pharmacologically significant properties of garlic(Allium sativum).Importantly,garlic and its biologically active chemicals targeted oncogenic signaling cascades.In this mini-review we have attempted to summarize how garlic and its bioactive constituents regulated signal transduction cascades in cell culture studies and tumor-bearing mice.
基金Yozgat Bozok University Scientific Research Projects Coordination Unit(Grant Number:THD-2022-1034).
文摘Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway.Melatonin has many benefits,such as organizing circadian rhythms and acting as a powerful hormone.We aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin(mTOR)signaling pathway and the Argyrophilic Nucleolar Regulatory Region(AgNOR),using the Microcomputed Tomography(Micro CT).Ehrlich ascites carcinoma(EAC)cells were administered into the mice by subcutaneous injection.Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days.Volumetric measurements for the taken tumors were made with micro-CT imaging,immunohistochemistry(IHC),real-time polymerase chain reaction(PCR)and AgNOR.Statistically,the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images.In the IHC analysis,the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8(F8)expression were compared with the control group.It was determined that there was a significant decrease(p<0.05).Significant differences were found in the total AgNOR area/nuclear area(TAA/NA)ratio in the treatment groups(p<0.05).Furthermore,there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase(PI3K),AKT Serine/Threonine Kinase(PKB/AKT)genes(p<0.05).Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin;It was observed that 100µg/mL melatonin dose caused an increase in the apoptotic cell death.In this study,we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models.Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and translatability of pre-clinical findings to earlier phases of clinical trials.
文摘Transforming growth factor （TGF）-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our under- standing of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.
基金Supported by Centre for Biomedical Genetics and Dutch Cancer Society RUL2005-3371(Hawinkels LJAC)
文摘AIM:To investigate the expression and potential prognostic role of vascular endothelial growth factor(VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors(GEP-NETs) . METHODS:Microvessel density(MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry.In addition,tissue levels of endoglin and VEGF were determined in homogenates by ELISA. RESULTS:Endoglin was highly expressed on tumor endothelial cells.CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD(P<0.01) .Two-tofour-fold higher tissue levels of endoglin and VEGF were seen in tumors compared to associated normal tissue. This increased endoglin tissue expression in tumors was significantly related to tumor size(P<0.01) ,presence of metastases(P=0.04) ,and a more advanced tumor stage(P=0.02) ,whereas expression of VEGF was not. CONCLUSION:We suggest that endoglin is a potential marker to indicate and predict metastases,which might be useful in the post-resection therapeutic approach of patients with GEP-NETs.
文摘Human herpesviruses （HVs） have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system （CNS）. The ability of HVs to enter a state of latency, a defining char- acteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease （NDD） patholo- gy by highlighting two prominent members of the HV family, herpes simplex virus 1 （HSV-1） and human herpesvirus 6 （HHV-6）. We （i） introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then （ii） review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer＇s disease （AD） and multiple sclerosis （MS）, respectively. We then （iii） highlight and dis- cuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we （iv） discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.
基金supported in part by the following United States National Institute of Health grants: R01 grants (AR057022 and AR063071), R21 grant (AR059733 to MJH), a P30 Core Center grant (AR061307), and a T32 training grant that supported both AK and TPR (AR053459 to Regis J.O’Keefe and Michael J.Zuscik)
文摘RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.
基金funded by the Higher Education Commission of Pakistan (HEC) IPFP (Grant No. PM-IPFP/HRD/ HEC/2011/3386) to Dr. Javed Iqbal Saggu and funding for HEC Ph.D. Scholar (Tariq Jan) under his supervision
文摘In this study, CeO2 nanostructures were synthesized by a soft chemical method. A hydrothermal treatment was observed to lead to an interesting morphological transformation of the nanoparticles into homogeneous microspheres composed of nanosheets with an average thickness of 40 nm. Structural analysis revealed the formation of a single-phase cubic fluorite structure of CeO2 for both samples. A Raman spectroscopic study confirmed the XRD results and furthermore indicated the presence of a large number of oxygen vacancies in the nanosheets. These oxygen vacancies led to room-temperature ferromagnetism （RTFM） of the CeO2 nanosheets with enhanced magnetic characteristics. Amazingly, the nanosheets exhibited substantially greater antibacterial activity than the nanoparticles. This greater antibacte- rial activity was attributed to greater exposure of high-surface-energy polar surfaces and to the presence of oxygen vacancies.
基金supported by grants from the National Institutes of Health(K08 AR060164-01A)Department of Defense(W81XWH-16-1-0725)to JCE in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers
文摘Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional recovery.We hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve injury.Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose.While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls.These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration.The animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on March 31,2017.
基金supported by grants from the National Institutes of Health(NIHK08 AR060164-01A)+2 种基金the Department of Defense(DoDW81XWH-16-1-0725)to JCEinstitutional support from the University of Rochester and Pennsylvania State University Medical Centers。
文摘4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.
基金funded by the Higher Education Commission, Pakistan (HEC) IPFP (Grant No. PM-IPFP/HRD/HEC/2011/3386)funding for HEC Ph.D. Scholar (Tariq Jan)
文摘Here, undoped and Cu doped ZnO nanoparticles(NPs) have been prepared by chemical co-precipitation technique. X-ray diffraction(XRD) results reveal that Cu ions are successfully doped into ZnO matrix without altering its wurtzite phase. The single wurtzite phase of ZnO is retained even for 10 wt% Cu doped ZnO sample. It is observed from the electron microscopy results that higher level of Cu doping varies the morphology of ZnO NPs from spherical to flat NPs. Moreover, the particle size is found to increase with the increase in Cu doping level. Raman spectroscopy results further confirm that Cu dopant has not altered the wurtzite structure of ZnO. Impedance spectroscopy results reveal that the dielectric constant and dielectric loss have increasing trend with Cu doping. Cu doping has been found to slightly decrease the bactericidal potency of ZnO nanoparticles.
基金supported by the following funding sources:National Institutes of Health,F31-NS078911,https://www.nih.gov(NSH)New York State Department of Health,NYS-DOH-C026877,http://www.stemcell.ny.gov(NSH)+4 种基金New York State Department of Health,NYS-DOH-C029557,http://www.stemcell.ny.gov(MN)New York State Department of Health,NYS-DOH-C026877,http://www.stemcell.ny.gov(CJF)Hunter’s Hope,http://www.huntershope.org/site/Page Server(MN)Children’s Neurobiological Solutions Foundation,http://pediatricbrainfoundation.org(MN)the Legacy of Angels,http://tloaf.org(MN)
文摘This review addresses two puzzling findings related to mutations in galactocerebrosidase （GALC） that cause Krabbe disease （KD）, a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis （MS）, another disease characterized by extensive myelin damage. What explains these correlations？ In studies on cuprizone-induced myelin damage in heterozygous （GALC＋/–） mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC＋/– and wild-type （WT） mice. In contrast, GALC＋/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher （GALC＋/–） mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.
基金Supported by the Kohat University of Science and Technology,Kohat,PakistanInstitute of Biomedical and Genetic Engineering,Islamabad,Pakistan
文摘AIM： To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation.· METHODS： A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome（USH）. To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat（STR） markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene.· RESULTS： By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them,c.1304AC was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype.This, c.1304 A C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435（p.D435A） of its protein product.Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic.·CONCLUSION：Theidentificationofc.1304ACpathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is thefirst example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.
文摘Hepatitis C virus is one of the major health problems worldwide. It affects mainly the liver but several extrahepatic manifestations are also accounted. Chronic hepatitis C patients are at an increased risk of developing hepatic steatosis, which share many clinical features with the metabolic syndrome. Hepatic steatosis has also been associated with elevated levels of markers of inflammation such as homocysteine, identified as hyperhomocysteinemia (HHC). HHC due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T polymorphism, was recently associated with coronary heart diseases (CHD) in chronic hepatitis C (CHC) patients. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver metabolism. Deficiencies of micronutrients (folate, vitamin B 6 and possibly vitamin B 12) along with mild hyperhomocysteinemia, perhaps, act synergistically with other classical risk factors to further increase the risk of CHD. Clinical data indicate that HHC is associated with an increased incidence of CHD as well as with the severity of the disease in CHC patients. In conclusion, HHC might be a potential aetiological factor of CHD in CHC patients. The aim of this review is to investigate the progression of coronary heart diseases in chronic hepatitis C patients and correlate with levels of homocysteine in concurrence to genetic defects and nutrient deficiencies. However, future studies need to clarify the mechanistic role of HHC in CHD and CHC as a useful paradigm with most interesting therapeutic implications.
基金The authors would like to thank the Deanship of Scientific Research at Majmaah University for supporting this work under Project Number No.R-2021-152.
文摘Cancer is the second deadliest human disease worldwide with high mortality rate.Rehabilitation and treatment of this disease requires precise and automatic assessment of effective drug response and control system.Prediction of treated and untreated cancerous cell line is one of the most challenging problems for precise and targeted drug delivery and response.A novel approach is proposed for prediction of drug treated and untreated cancer cell line automatically by employing modified Deep neural networks.Human hepatocellular carcinoma(HepG2)cells are exposed to anticancer drug functionalized CFO@BTO nanoparticles developed by our lab.Prediction models are developed by modifying ResNet101 and exploiting the transfer learning concept.Last three layers of ResNet101 are re-trained for the identification of drug treated cancer cells.Transfer learning approach in an appropriate choice especially when there is limited amount of annotated data.The proposed technique is validated on acquired 203 fluorescentmicroscopy images of human HepG2 cells treated with drug functionalized cobalt ferrite@barium titanate(CFO@BTO)magnetoelectric nanoparticles in vitro.The developed approach achieved high prediction with accuracy of 97.5%and sensitivity of 100%and outperformed other approaches.The high performance reveals the effectiveness of the approach.It is scalable and fully automatic prediction approach which can be extended for other similar cell diseases such as lung,brain tumor and breast cancer.
文摘Background: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-κ B, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-κ B activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. Objectives: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. Methods: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. Results: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6- 2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. Conclusions: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.
文摘In this paper,we propose bivariate iterated Farlie-Gumbel-Morgenstern(FGM)due to[Huang and Kotz(1984).Correlation structure in iterated Farlie-Gumbel-Morgenstern distributions.Biometrika 71(3),633-636.https://doi.org/10.2307/2336577]with Rayleigh marginals.The dependence stress-strength reliability function is derived with its important reliability characteristics.Estimates of dependence reliability parameters are obtained.We analyse the effects of dependence parameters on the reliability function.We found that the upper bound of the positive correlation coefficient is attaining to 0.41 under a single iteration with Rayleigh marginals.A comprehensive comparison between classical FGM with iterated FGM copulas is graphically examined to assess the over or under estimation of reliability with respect to α and β.We propose a two-phase estimation procedure for estimating the reliability parameters.A Monte-Carlo simulation study is conducted to assess the finite sample behaviour of the proposed reliability estimators.Finally,the proposed estimators are examined and validated with real data sets.
文摘Oxidative stress is characterized by the deregulation of the redox state in the cells,which plays a role in the initiation of various types of cancers.The activity of galectin-1(Gal-1)depends on the cell redox state and the redox state of the microenvironment.Gal-1 expression has been related to many different tumor types,as it plays important roles in several processes involved in cancer progression,such as apoptosis,cell migration,adhesion,and immune response.The erythroid-2-related factor 2(Nrf2)/Kelch-like ECH-associated protein 1(Keap1)signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress.In this review,we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells,particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway.The emerging evidence concerning the anti-apoptotic effect of Gal-1,together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress,supports the role of Gal-1 in the promotion of tumor cells proliferation,immuno-suppression,and anti-tumor drug resistance,thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression.Overall,a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents.Excitingly,although it is still understudied,the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.
文摘Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes （DUBs）. In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed.
