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Quarterly published in print and online "Inventi Impact: Genetics (Formerly Inventi Impact: Stem Cell)" publishes high quality unpublished as well as high impact pre-published research and reviews catering to the needs of researchers and professionals. The journal focuses on all aspects of stem and progenitor cell biology. It invites articles related to stem cells, embryonic stem cells, induced pluripotent stem cells, tissue-specific stem cells, stem cell technology, epigenetics, genomics, proteomics, and metabonomics. Articles from cancer stem cells, translational and clinical research and regenerative medicine are also welcome.
A growing body of evidence supports the argument that bone marrow-derived mesenchymal stem cells (MSCs) can differentiate\ninto cardiomyocyte-like cells in an appropriate cellular environment, but the differentiation rate is low. A cocktail method was\ndesigned: we investigated the role of 5-azacytidine (5-aza), salvianolic acid B (SalB), and cardiomyocyte lysis medium (CLM) in\ninducing MSCs to acquire the phenotypical characteristics of cardiomyocytes. The fourth-passage MSCs were treated with 5-aza,\nSalB, CLM, 5-aza+salB, 5-aza+CLM, SalB+CLM, and 5-aza+SalB+CLM for 2 weeks. Immunofluorescence results showed that cTnT\nexpression in the 5-aza+salB+CLM group was stronger than other groups. Real-time qPCR andWestern blotting analyses showed\nthat cTnT, alpha-cardiac actin, mef-2c, Cx43, and GSK-3beta expression increased while beta-catenin expression decreased. The\nsalB+5-aza+CLM group had the most evident effects. SalB combined with 5-aza and CLM improved cardiomyocyte differentiation\nfrom MSCs. In the MSCs differentiation process, theWnt/beta-catenin signaling pathway had been inhibited....
Background: Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated\ngenetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies\nhave been carried out in recent years, but none of these have involved Latin American populations with a high\nlevel of miscegenation, as is seen in the Brazilian population.\nMethods: 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were\nidentified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire.\nFollowing quality control, 1 877 526 autosomal SNPs were tested for association with childhood asthma symptoms\nby logistic regression using an additive genetic model. We complemented the analysis with an estimate of the\nphenotypic variance explained by common genetic variants. Replications were investigated in independent\nMexican and US Latino samples.\nResults: Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the\n14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95 % CI 1.45Ã¢â?¬â??2.18, p-value 2.83 Ã?â?? 10Ã¢Ë?â??8)\nand 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95 % CI 2.02Ã¢â?¬â??4.49, p-value 6.68 Ã?â?? 10Ã¢Ë?â??8 and\nrs8029377, MAF 0.03, OR 2.49, 95 % CI 1.76Ã¢â?¬â??3.53, p-value 2.45 Ã?â?? 10Ã¢Ë?â??7). eQTL analysis suggests that rs1999071 regulates\nthe expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples.\nConclusions: We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood....
Background\nOur laboratory and others reported that the stimulation of specific Toll-like receptors (TLRs) affects the immune modulating responses of human multipotent mesenchymal stromal cells (hMSCs). Toll-like receptors recognize Ã¢â?¬Å?dangerÃ¢â?¬Â signals, and their activation leads to profound cellular and systemic responses that mobilize innate and adaptive host immune cells. The danger signals that trigger TLRs are released following most tissue pathologies. Since danger signals recruit immune cells to sites of injury, we reasoned that hMSCs might be recruited in a similar way. Indeed, we found that hMSCs express several TLRs (e.g., TLR3 and TLR4), and that their migration, invasion, and secretion of immune modulating factors is drastically affected by specific TLR-agonist engagement. In particular, we noted diverse consequences on the hMSCs following stimulation of TLR3 when compared to TLR4 by our low-level, short-term TLR-priming protocol.\n\nPrincipal Findings\nHere we extend our studies on the effect on immune modulation by specific TLR-priming of hMSCs, and based on our findings, propose a new paradigm for hMSCs that takes its cue from the monocyte literature. Specifically, that hMSCs can be polarized by downstream TLR signaling into two homogenously acting phenotypes we classify here as MSC1 and MSC2. This concept came from our observations that TLR4-primed hMSCs, or MSC1, mostly elaborate pro-inflammatory mediators, while TLR3-primed hMSCs, or MSC2, express mostly immunosuppressive ones. Additionally, allogeneic co-cultures of TLR-primed MSCs with peripheral blood mononuclear cells (PBMCs) predictably lead to suppressed T-lymphocyte activation following MSC2 co-culture, and permissive T-lymphocyte activation in co-culture with MSC1.\n\nSignificance\nOur study provides an explanation to some of the conflicting reports on the net effect of TLR stimulation and its downstream consequences on the immune modulating properties of stem cells. We further suggest that MSC polarization provides a convenient way to render these heterogeneous preparations of cells more uniform while introducing a new facet to study, as well as provides an important aspect to consider for the improvement of current stem cell-based therapies....
Background: Gastric cancer (GC) is a common malignant cancer with a poor prognosis. Ferroptosis has been
shown to play crucial roles in GC development. Long non-coding RNAs (lncRNAs) is also associated with tumor
progression in GC. This study aimed to screen the prognostic ferroptosis-related lncRNAs and to construct a
prognostic risk model for GC.
Methods: Ferroptosis-related lncRNAs from The Cancer Genome Atlas (TCGA) GC expression data was downloaded.
First, single factor Cox proportional hazard regression analysis was used to select seven prognostic ferroptosisrelated
lncRNAs from TCGA database. And then, the selected lncRNAs were further included in the multivariate Cox
proportional hazard regression analysis to establish the prognostic model. A nomogram was constructed to predict
individual survival probability. Finally, we performed quantitative reverse transcription polymerase chain reaction
(qRT-PCR) to verify the risk model.
Results: We constructed a prognostic ferroptosis-related lncRNA signature in this study. Kaplan-Meier curve analysis
revealed a significantly better prognosis for the low-risk group than for the high-risk group (P = 2.036e-05).
Multivariate Cox proportional risk regression analysis demonstrated that risk score was an independent prognostic
factor [hazard ratio (HR) = 1.798, 95% confidence interval (CI) =1.410–2.291, P < 0.001]. A nomogram, receiver
operating characteristic curve, and principal component analysis were used to predict individual prognosis. Finally,
the expression levels of AP003392.1, AC245041.2, AP001271.1, and BOLA3-AS1 in GC cell lines and normal cell lines
were tested by qRT-PCR....
Background: The re-sequencing of C. angulata has revealed many polymorphisms in candidate genes related\nto adaptation to abiotic stress that are not present in C. gigas; these genes, therefore, are probably related to\nthe ability of this oyster to retain high concentrations of toxic heavy metals. There is, in addition, an unresolved\ncontroversy as to whether or not C. angulata and C. gigas are the same species or subspecies. Both oysters have 20\nmetacentric chromosomes of similar size that are morphologically indistinguishable. From a genomic perspective,\nas a result of the great variation and selection for heterozygotes in C. gigas, the assembly of its draft genome was\ndifficult: it is fragmented in more than seven thousand scaffolds.\nResults: In this work sixty BAC sequences of C. gigas downloaded from NCBI were assembled in BAC-contigs and\nassigned to BACs that were used as probes for mFISH in C. angulata and C. gigas. In addition, probes of H3, H4\nhistone, 18S and 5S rDNA genes were also used. Hence we obtained markers identifying 8 out the 10 chromosomes\nconstituting the karyotype. Chromosomes 1 and 9 can be distinguished morphologically. The bioinformatic analysis\ncarried out with the BAC-contigs annotated 88 genes. As a result, genes associated with abiotic adaptation, such as\nmetallothioneins, have been positioned in the genome. The gene ontology analysis has also shown many molecular\nfunctions related to metal ion binding, a phenomenon associated with detoxification processes that are characteristic\nin oysters. Hence the provisional integrated map obtained in this study is a useful complementary tool for the study of\noyster genomes.\nConclusions: In this study 8 out of 10 chromosome pairs of Crassostrea angulata/gigas were identified using BAC\nclones as probes. As a result all chromosomes can now be distinguished. Moreover, FISH showed that H3 and H4\nco-localized in two pairs of chromosomes different that those previously escribed. 88 genes were annotated in\nthe BAC-contigs most of them related with Molecular Functions of protein binding, related to the resistance of\nthe species to abiotic stress. An integrated genetic map anchored to the genome has been obtained in which\nthe BAC-contigs structure were not concordant with the gene structure of the C. gigas scaffolds displayed in the\nGenomicus database....
Enrichment of cancer stem cells (CSCs) is thought to be responsible for glioblastomamultiforme (GBM) recurrence after radiation\ntherapy. Simulation results fromour agent-based cellular automatamodel reveal that the enrichment of CSCs may result either from\nan increased symmetric self-renewal division rate of CSCs or a reprogramming of non-stem cancer cells (CCs) to a stem cell state.\nBased on plateau-to-peak ratio of the CSC fraction in the tumor following radiation, a downward trend from peak to subsequent\nplateau (i.e., a plateau-to-peak ratio exceeding 1.0) was found to be inconsistent with increased symmetric division alone and favors\ninstead a strong reprogramming component. The two contributions together are seen to be the product of a dynamic equilibrium\nbetween CSCs and CCs that is highly regulated by the kinetics of single cells, including the potential for CCs to reacquire a stem\ncell state and confer phenotypic plasticity to the population as a whole. We conclude that tumor malignancy can be gauged by a\ndegree of cancer cell plasticity....
Umbilical cord blood banking efforts have increased dramatically in the past two decades in response to increasing demand for\r\nalternative sources of blood stem cells to support patients requiring hematopoietic stem cell transplantation. Transplant centres have\r\naccumulated increasing expertise in their understanding of umbilical cord blood characteristics that are associated with improved\r\noutcome following transplantation. These characteristics and factors can assist transplant centres in selecting cord blood units from\r\nthe worldwide inventory of banked units. Umbilical cord blood banks, therefore, need to remain agile in adjusting the inventory\r\nof the banks to address shifts or changes in the needs of transplant centres. Public umbilical cord blood banks face the challenge of\r\nbuilding inventory while managing limited resources and are faced with decisions regarding which units can be stored and which\r\nunits that have been collected should be discarded or used for other endeavours such as research. To this end, we sought to review\r\nparameters influencing the decision to bank a collected cord blood unit. In this paper, we will address parameters associated with\r\ngraft potency and address other factors that guide the decision to bank collected units....
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Five to ten percent of
patients have monogenic form of the disease, while most of sporadic PD cases are caused by the combination of genetic and
environmental factors. Microtubule-associated protein tau (MAPT) has been appointed as one of the most important risk factors
for several neurodegenerative diseases including PD. MAPT is characterized by an inversion in chromosome 17 resulting in two
distinct haplotypes H1 and H2. Studies described a significant association of MAPT H1j subhaplotype with PD risk, while H2
haplotype was associated with Parkinsonism, particularly to its bradykinetic component. We report here an isolated case
displaying an akinetic-rigid form of PD, with age of onset of 41 years and a good response to levodopa, who developed dementia
gradually during the seven years of disease progression. The patient does not carry the LRRK2 G2019S mutation, copy number
variations, nor pathogenic and rare variants in known genes associated with PD.MAPTsubhaplotype genotyping revealed that the
patient has theH1j/H2 diplotype, his motherH1j/H1j, his two healthy brothersH1j/H1v and his deceased father was by deduction
H1v/H2. The H1j/H2 diplotype was shown in a total of 3 PD patients among 80, who also did not have known PD-causing
mutation and in 1 out of 92 healthy individual controls. The three patients with this diplotype all have a similar clinical phenotype.
Our results suggest that haplotypes H1j and H2 are strong risk factor alleles, and their combination could be responsible for early
onset of PD with dementia....
Background: X chromosome inactivation (XCI) is an important gene regulation mechanism in females to equalize\nthe expression levels of X chromosome between two sexes. Generally, one of two X chromosomes in females is\nrandomly chosen to be inactivated. Nonrandom XCI (XCI skewing) is also observed in females, which has been\nreported to play an important role in many X-linked diseases. However, there is no statistical measure available for\nthe degree of the XCI skewing based on family data in population genetics.\nResults: In this article, we propose a statistical approach to measure the degree of the XCI skewing based on family\ntrios, which is represented by a ratio of two genotypic relative risks in females. The point estimate of the ratio is\nobtained from the maximum likelihood estimates of two genotypic relative risks. When parental genotypes are\nmissing in some family trios, the expectation-conditional-maximization algorithm is adopted to obtain the corresponding\nmaximum likelihood estimates. Further, the confidence interval of the ratio is derived based on the likelihood ratio test.\nSimulation results show that the likelihood-based confidence interval has an accurate coverage probability under the\nsituations considered. Also, we apply our proposed method to the rheumatoid arthritis data from USA for its practical use,\nand find out that a locus, rs2238907, may undergo the XCI skewing against the at-risk allele. But this needs to be further\nconfirmed by molecular genetics.\nConclusions: The proposed statistical measure for the skewness of XCI is applicable to complete family trio data or family\ntrio data with some paternal genotypes missing. The likelihood-based confidence interval has an accurate coverage\nprobability under the situations considered. Therefore, our proposed statistical measure is generally recommended in\npractice for discovering the potential loci which undergo the XCI skewing....
The use of human pluripotent stem cells in basic and translational cardiac research requires efficient differentiation protocols\ntowards cardiomyocytes. In vitro differentiation yields heterogeneous populations of ventricular-, atrial-, and nodal-like cells\nhindering their potential applications in regenerative therapies.We described the effect of the growth factor Activin A during early\nhuman embryonic stem cell fate determination in cardiac differentiation.Addition of high levels ofActivinAduring embryoid body\ncardiac differentiation augmented the generation of endoderm derivatives, which in turn promoted cardiomyocyte differentiation.\nMoreover, a dose-dependent increase in the coreceptor expression of the TGF-...
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