Use of two combination creams for the treatment of ichthyoses and ichthyosiform disorders

Treatment options for ichthyosis and ichthyosiform disorders are limited and often unsatisfactory.Twenty-four patients used combination creams of 2%cholesterol with 2%lovastatin,and 10%glycolic acid with 0.025% tretinoin and 2%ketoconazole daily.At one month(n=20),the average percent reduction in severity scores was 40%,and at three months(n=10),it was 60.3%.Side effects were mainly mild irritation.These findings suggest that these two combination creams could be beneficial in the treatment of ichthyosiform disorders.

Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.

Role of succinate dehydrogenase deficiency and oncometabolites in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.Approximately 85%of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha(PDGFRA).The remaining GISTs,referred to as wild-type(WT)GISTs,are often deficient in succinate dehydrogenase complex(SDH),a key metabolic enzyme complex in the tricarboxylic acid(TCA)cycle and electron transport chain.SDH deficiency leads to the accumulation of succinate,a metabolite produced by the TCA cycle.Succinate inhibitsα-ketoglutarate-dependent dioxygenase family enzymes,which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation,hypoxia responses,and m6A mRNA modification.For this reason,succinate and metabolites with similar structures,such as D-2-hydroxyglutarate and fumarate,are considered oncometabolites.In this article,we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.

Exploring unconventional attributes of red blood cells and their potential applications in biomedicine

We need to talk about red blood cells.Eukaryotic cells are defined as cells containing distinct nuclei and other membranous organelles.However,red blood cells(RBCs)lack a nucleus and organelles—perhaps to limit the generation of reactive oxygen species(Zhang et al.,2011)—and are filled with hemoglobin(Hb).This oxygen carrier is limited to the cytosol by the cell membrane and cytoskeleton,which maintain cellular integrity and deformability as RBCs pass through narrow capillaries(Gratzer,1994)to perform their primary function of gas exchange.

Stem cells in neuroinjury and neurodegenerative disorders: challenges and future neurotherapeutic prospects

The prevalence of neurodegenerative diseases and neural injury disorders is increasing worldwide. Research is now focusing on improving current neurogenesis techniques including neural stem cell therapy and other biochemical drug-based approaches to ameliorate these disorders. Unfortunately, we are still facing many obstacles that are rendering current neurotherapies ineffective in clinical trials for reasons that are yet to be discovered. That is why we should start by fully understanding the complex mechanisms of neurogenesis and the factors that affect it, or else, all our suggested therapies would fail since they would not be targeting the essence of the neurological disorder but rather the symptoms. One possible paradigm shift is to switch from neuroprotectant therapies towards neurodegeneration/neurorestorative approaches. In addition, other and our laboratories are increasingly focusing on combining the use of pharmacological agents（such as Rho-associated kinase（ROCK） inhibitors or other growth factors（such as brain-derived neurotrophic factor（BDNF）） and stem cell treatment to enhance the survivability and/or differentiation capacity of transplanted stem cells in neurotrauma or other neurodegeneration animal models. Ongoing stem cell research is surely on the verge of a breakthrough of multiple effective therapeutic options for neurodegenerative disorders. Once, we fully comprehend the process of neurogenesis and its components, we will fully be capable of manipulating and utilizing it. In this work, we discuss the current knowledge of neuroregenerative therapies and their associated challenges.

Characterization of the Receptor-binding Domain of Ebola Glycoprotein in Viral Entry

Ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. Viral entry/infection is initiated by binding of glycoprotein GP protein on Ebola virion to host cells, followed by fusion of virus-cell membrane also mediated by GP. Using an human immunodeficiency virus (HIV)-based pseudotyping system, the roles of 41 Ebola GP1 residues in the receptor-binding domain in viral entry were studied by alanine scanning substitutions. We identified that four residues appear to be involved in protein folding/structure and four residues are important for viral entry. An improved entry interference assay was developed and used to study the role of these residues that are important for viral entry. It was found that R64 and K95 are involved in receptor binding. In contrast, some residues such as I170 are important for viral entry, but do not play a major role in receptor binding as indicated by entry interference assay and/or protein binding data, suggesting that these residues are involved in post-binding steps of viral entry. Furthermore, our results also suggested that Ebola and Marburg viruses share a common cellular molecule for entry.

The Role of the Charged Residues of the GP2 Helical Regions in Ebola Entry

The glycoprotein(GP) of Ebola is the sole structural protein that forms the spikes on the viral envelope. The GP contains two subunits,GP1 and GP2,linked by a disulfide bond,which are responsible for receptor binding and membrane fusion,respectively. In this study,the full length of GP gene of Ebola Zaire species,2028 base pairs in length,was synthesized using 38 overlapping oligonucleotides by multiple rounds of polymerase chain reaction(PCR) . The synthesized GP gene was shown to be efficiently expressed in mammalian cells. Furthermore,an efficient HIV-based pseudotyping system was developed using the synthetic GP gene,providing a safe approach to dissecting the entry mechanism of Ebola viruses. Using this pseudotyping system and mutational analysis,the role of the charged residues in the GP2 helical regions was examined. It was found that substitutions of the most charged residues in the regions did not adversely affect GP expression,processing,or viral incorporation,however,most of the mutations greatly impaired the ability of GP to mediate efficient viral infection. These results demonstrate that these charged residues of GP2 play an important role in GP-mediated Ebola entry into its host cells. We propose that these charged residues are involved in forming the intermediate conformation(s) of GP in membrane fusion and Ebola entry.

A hypothesis for treating inflammation and oxidative stress with hydrogen sulfide during age-related macular degeneration

Age-related macular degeneration（AMD） is a leading cause of blindness and is becoming a global crisis since affected people will increase to 288 million by 2040.Genetics,age,diabetes,gender,obesity,hypertension,race,hyperopia,iris-color,smoking,sun-light and pyroptosis have varying roles in AMD,but oxidative stress-induced inflammation remains a significant driver of pathobiology.Eye is a unique organ as it contains a remarkable oxygengradient that generates reactive oxygen species（ROS） which upregulates inflammatory pathways.ROS becomes a source of functional and morphological impairments in retinal pigment epithelium（RPE）,endothelial cells and retinal ganglion cells.Reports demonstrated that hydrogen sulfide（H2S） acts as a signaling molecule and that it may treat ailments.Therefore,we propose a novel hypothesis that H2S may restore homeostasis in the eyes thereby reducing damage caused by oxidative injury and inflammation.Since H_2S has been shown to be a powerful antioxidant because of its free-radicals＇ inhibition properties in addition to its beneficial effects in age-relatedconditions,therefore,patients may benefit from H2S salubrious effects not only by minimizing their oxidant and inflammatory injuries to retina but also by lowering retinal glutamate excitotoxicity.

Small regulators making big impacts:regulation of neural stem cells by small non-coding RNAs

Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a major challenge in medicine largely because of the limited regenerative capacity of the adult brain.

TGFβ and Hypoxia Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment

Breast cancers frequently metastasize to bone, a site of hypoxia and high concentrations of active TGFβ. Skeletal metastases involve interactions between tumor and bone cells driven by locally secreted proteins, many

The association of cardiovascular mortality with a first-degree family member history of different cardiovascular diseases

OBJECTIVE To investigate which history of cardiovascular disease[coronary heart disease(CHD),stroke,or peripheral arterial disease]in a first-degree family member predicts cardiovascular mortality.METHODS We studied a prospective cohort(the Lipid Research Clinics Prevalence Study)from ten primary care centers across North America.The primary outcome was cardiovascular mortality,assessed using Cox survival models.RESULTS There were 8,646 participants(mean age:47.4±12.1 years,46%women,52%of participants with hyperlipidemia)who were followed up for a mean duration of 19.4±4.9 years.There were 1,851 deaths(21%),including 852 cardiovascular deaths.A paternal,maternal or sibling history of premature CHD(before 60 years)was present in 26%of participants,of stroke in 27%of participants,and of peripheral arterial disease in 24%of participants.After adjusting for risk factors(age,sex,systolic blood pressure,diastolic blood pressure,body mass index,smoking,fasting glucose,low-density lipoprotein cholesterol and triglycerides),only a paternal history of premature or any CHD,a maternal history of diabetes mellitus or premature or any CHD,and a sibling history of premature CHD,hypertension,or hyperlipidemia were individually predictive of cardiovascular mortality.After adjusting for risk factors and the mentioned familial factors,only paternal and maternal histories of CHD,espe-cially before 60 years,remained predictive of cardiovascular mortality,with a somewhat higher association for a maternal history[adjusted hazard ratio(aHR)=1.99,95%CI:1.36−2.92,P<0.001 for maternal history of premature CHD;aHR=1.52,95%CI:1.10−2.10,P=0.011 for paternal history of premature CHD].Family history of stroke or peripheral arterial disease did not predict cardiovascular mortality.Parental history of premature CHD predicted cardiovascular mortality independently of baseline age(<60 years and≥60 years),hypertension,or hyperlipidemia and carried more important prognostic value in men rather than wo-men.CONCLUSIONS In this study,a parental history of CHD,especially before 60 years,best predicted cardiovascular mortality.This finding could help more accurately identify high-risk patients who would benefit from preventive strategies.

Wilson's disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

AIM To determine the phenotypes and predominant diseasecausing mutations in Lebanese patients with Wilson's disease,as compared to regional non-European data.METHODS The clinical profile of 36 patients diagnosed in Lebanon was studied and their mutations were determined by molecular testing.All patients underwent full physical exam,including ophthalmologic slit-lamp examination ultrasound imaging of the liver,as well as measurement of serum ceruloplasmin and 24-h urinaryCu levels.In addition,genetic screening using PCR followed by sequencing to determine disease-causing mutations and polymorphisms in the ATP7B gene was carried on extracted DNA from patients and immediate family members.Our phenotypic-genotypic findings were then compared to reported mutations in Wilson's disease patients from regional Arab and non-European countries. RESULTS Patients belonged to extended consanguineous families.The majority were homozygous for the disease-causing mutation,with no predominant mutation identified. The most common mutation,detected in 4 out of 13families,involved the ATP hinge region and was present in patients from Lebanon,Egypt,Iran and Turkey.Otherwise,mutations in Lebanese patients and those of the region were scattered over 17 exons of ATP7B.While the homozygous exon 12 mutation Trp939Cys was only detected in patients from Lebanon but none from the regional countries,the worldwide common mutation H1069Q was not present in the Lebanese and was rare in the region.Pure hepatic phenotype was predominant in patients from both Lebanon and the region(25%-65%).Furthermore,the majority of patients,including those who were asymptomatic,had evidence of some hepatic dysfunction.Pure neurologic phenotype was rare. CONCLUSION Findings do not support presence of a founder effect.Clinical and genetic screening is recommended for family members with index patients and unexplained hepatic dysfunction.

Osteogenesis imperfecta mutations in plastin 3 lead to impaired calcium regulation of actin bundling

Mutations in actin-bundling protein plastin 3(PLS3)emerged as a cause of congenital osteoporosis,but neither the role of PLS3 in bone development nor the mechanisms underlying PLS3-dependent osteoporosis are understood.Of the over 20 identified osteoporosis-linked PLS3 mutations,we investigated all five that are expected to produce full-length protein.One of the mutations distorted an actin-binding loop in the second actin-binding domain of PLS3 and abolished F-actin bundling as revealed by cryo-EM reconstruction and protein interaction assays.Surprisingly,the remaining four mutants fully retained F-actin bundling ability.However,they displayed defects in Ca2+sensitivity:two of the mutants lost the ability to be inhibited by Ca2+;while the other two became hypersensitive to Ca2a.Each group of the mutants with similar biochemical properties showed highly characteristic cellular behavior.Wild-type PLS3 was distributed between lamellipodia and focal adhesions.In striking contrast,the Ca2+-hyposensitive mutants were not found at the leading edge but localized exclusively at focal adhesions/stress fibers,which displayed reinforced morphology.Consistently,the Ca2+-hypersensitive PLS3 mutants were restricted to lamellipodia,while chelation of Ca2+caused their redistribution to focal adhesions.Finally,the bundling-deficient mutant failed to co-localize with any F-actin structures in cells despite a preserved F-actin binding through a non-mutation-bearing actin-binding domain.Our findings revealed that severe osteoporosis can be caused by a mutational disruption of the Ca2+-controlled PLS3’s cycling between adhesion complexes and the leading edge.Integration of the structural,biochemical,and cell biology insights enabled us to propose a molecular mechanism of plastin activity regulation by Ca2+.

On the use of residual dipolar couplings in multi-state structure calculation of two-domain proteins

Residual dipolar couplings(RDCs)are powerful nuclear magnetic resonance(NMR)probes for the structure calculation of biomacromolecules.Typically,an alignment tensor that defines the orientation of the entire molecule relative to the magnetic field is determined either before refinement of individual bond vectors or simultaneously with this refinement.For single-domain proteins this approach works well since all bond vectors can be described within the same coordinate frame,which is given by the alignment tensor.However,novel approaches are sought after for systems where no universal alignment tensor can be used.Here,we present an approach that can be applied to two-domain proteins that enables the calculation of multiple states within each domain as well as with respect to the relative positions of the two domains.

Protein-based profiling of the human IgA1 clonal repertoire revealed shared clones of serum polymeric IgA1 and milk secretory IgA1

Human adaptive immunity involves the production and secretion of antibodies by differentiated B cells(ie.,antibody-secreting cells,also called plasma cells)in response to antigens.These secreted antigen-specific antibodies are immunoglobulins that are present at substantial concentrations in blood,mucosal secretions,and breast milk.Structurally,human immunoglobulins consist of two identical heavy(H)chains and two identical light(L)chains that are connected by disulfide bridges to form a homodimer of heterodimers(ie.,H+Ll2).Each heterodimer consists of one H chain linked with one L chain,whereas the homodimer is formed by linking two H chains together.The genes for both the L and H chains are encoded by ligated gene segments that are genetically rearranged during V(D)J recombination,a process that endows each B cell with a unique receptor,giving rise to the enormous diversity of the B-cell antigen receptor repertoire.

Essential functions of iron-requiring proteins n DNA replication, repair and cell cycle contro

Eukaryotic cells contain numerous iron-requiring pro- teins such as iron-sulfur （Fe-S） cluster proteins, hemoproteins and ribonucleotide reductases （RNRs）. These proteins utilize iron as a cofactor and perform key roles in DNA replication, DNA repair, metabolic catalysis, iron regulation and cell cycle progression. Disruption of iron homeostasis always impairs the functions of these iron- requiring proteins and is genetically associated with diseases characterized by DNA repair defects in mam- mals. Organisms have evolved multi-layered mecha- nisms to regulate iron balance to ensure genome stability and cell development. This review briefly pro- vides current perspectives on iron homeostasis in yeast and mammals, and mainly summarizes the most recent understandings on iron-requiring protein functions involved in DNA stability maintenance and cell cycle control.

Iron homeostasis and tumorigenesis： molecular mechanisms and therapeutic opportunities

Excess iron is tightly associated with tumorigenesis in multiple human cancer types through a variety of mechanisms including catalyzing the formation of mutagenic hydroxyl radicals, regulating DNA replica- tion, repair and cell cycle progression, affecting signal transduction in cancer cells, and acting as an essential nutrient for proliferating tumor cells, Thus, multiple therapeutic strategies based on iron deprivation have been developed in cancer therapy, During the past few years, our understanding of genetic association and molecular mechanisms between iron and tumorigenesis has expanded enormously. In this review, we briefly summarize iron homeostasis in mammals, and discuss recent progresses in understanding the aberrant iron metabolism in numerous cancer types, with a focus on studies revealing altered signal transduction in cancer cells.

mRNA vaccines: Past, present, future

mRNA vaccines have emerged as promising alternative platforms to conventional vaccines.Their ease of production,low cost,safety profile and high potency render them ideal candidates for prevention and treatment of infectious diseases,especially in the midst of pandemics.The challenges that face in vitro transcribed RNA were partially amended by addition of tethered adjuvants or co-delivery of naked mRNA with an adjuvanttethered RNA.However,it wasn’t until recently that the progress made in nanotechnology helped enhance mRNA stability and delivery by entrapment in novel delivery systems of which,lipid nanoparticles.The continuous advancement in the fields of nanotechnology and tissue engineering provided novel carriers for mRNA vaccines such as polymeric nanoparticles and scaffolds.Various studies have shown the advantages of adopting mRNA vaccines for viral diseases and cancer in animal and human studies.Self-amplifying mRNA is considered today the next generation of mRNA vaccines and current studies reveal promising outcomes.This review provides a comprehensive overview of mRNA vaccines used in past and present studies,and discusses future directions and challenges in advancing this vaccine platform to widespread clinical use.

Model systems to study the life cycle of human papillomaviruses and HPV-associated cancers

The prevalent human papillomaviruses(HPVs) infect either cutaneous or mucosal epithelium. Active Infections lead to epithelial hyperprolifeation and are usually cleared in healthy individuals within a year. Persistent infections in the anogenital tracts by certain high-risk genotypes such as HPV-16, HPV-18 and closely related types, can progress to high grade dysplasias and carcinomas in women and men, including cervical, vulva, penile and anal cancers. A significant fraction of the head and neck cancers are also caused by HPV-16. The viral oncogenes responsible for neoplastic conversion are E6 and E7 that disrupt the pathways controlled by the two major tumor suppressor genes, p53 and members of p RB family. Because HPV cannot be propagated in conventional submerged monolayer cell cultures, organotypic epithelial raft cultures that generate a stratified and differentiated epithelium have been used to study the viral life cycle. This article describes several systems to examine aspects of the viral productive phase, along with the advantages and limitations. Animal model systems of HPV carcinogenesis are also briefly described.

Ribonucleotide reductase metallocofactor： assembly, maintenance and inhibition

Ribonucleotide rcductase （RNR） supplies cellular deoxyribonucleotidc triphosphates （dNTP） pools by converting ribonucleotides to the corresponding deoxy forms using radical-based chemistry. Eukaryotic RNR comprises a and β subunits： u contains the catalytic and ailosteric sites; β houses a diferric-tyrosyl radical cofactor （FeⅢ2-Y· ） that is required to initiates nucleotide reduction in α. Cells have evolved multi-layered mechanisms to regulate RNR level and activity in order to maintain the adequate sizes and ratios of their dNTP pools to ensure high- fidelity DNA replication and repair. The central role of RNR in nucleotide metabolism also makes it a proven target of chemotherapeutics. In this review, we discuss recent progress in understanding the function and regulation of eukaryofic RNRs, with a focus on studies revealing the cellular machineries involved in RNR metaUocofactor biosynthesis and its implication in RNR-targeting therapeutics.