In Search of a Unified Theory: An Attempt to Reconcile Gravity and Quantum

Issues around geometry of the universe, density of the universe (Underweight), expansion of the universe and theories held-up by scientists such as Stephen Hawking, John Wheeler, Albert Einstein, etc have been looked into. The equations formulated by these people; that is E =mc2, E = hν and PV = nRT were treated to give meaning under the general truth that the universe has only two entities; MATTER and ENERGY and HEAT and COLD to manipulate them. The Energy x Time oMatter x Space relationships is suggested in this paper in place of, Energy.Matter = Space.Time, which was summarized by Albert Einstein. The three dimensionness of space were incorporated into E = mc2 to give E/N Ξ c3. E = hc/λo which had the notion of space divided by space is re-related to space per time and PV = nRT is revisited until it was modified to be in congruent with the above two fundamental formulations; that is PVΞ KT/N. These new relationships (THEORIES) are in agreement with each other and could be pronounced as “UNITED”

Identification of Cdk8 and Cdkn2d as New Prame-Target Genes in 2C-like Embryonic Stem Cells

Embryonic stem cells (ESCs) present a characteristic pluripotency heterogeneity correspondent to specific metastates. We recently demonstrated that retinoic acid (RA) induces an increase in a specific 2C-like metastate marked by target genes specific to the two-cell embryo stage in preimplantation. Prame (Preferentially expressed antigen in melanoma) is one of the principal actors of the pluripotency stage with a specific role in RA responsiveness. Additionally, PRAME is overexpressed in a variety of cancers, but its molecular functions are poorly understood. To further investigate Prame’s downstream targets, we used a chromatin immunoprecipitation sequencing (ChIP-seq) assay in RA-enriched 2C-like metastates and identified two specific target genes, Cdk8 and Cdkn2d, bound by Prame. These two targets, involved in cancer dedifferentiation and pluripotency, have been further validated in RA-resistant ESCs. Here, we observed for the first time that Prame controls the Cdk8 and Cdkn2d genes in ESCs after RA treatment, shedding light on the regulatory network behind the establishment of naïve pluripotency

CHOP Potentially Co-Operates with FOXO3a in Neuronal Cells to Regulate PUMA and BIM Expression in Response to ER Stress

Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in various neurodegenerative diseases including Parkinson Disease, Alzheimer Disease and Huntington Disease. PUMA (p53 upregulated modulator of apoptosis) and BIM (BCL2 interacting mediator of cell death), pro-apoptotic BH3 domain-only, BCL2 family members, have previously been shown to regulate ER stress-induced cell death, but the upstream signaling pathways that regulate this response in neuronal cells are incompletely defined. Consistent with previous studies, we show that both PUMA and BIM are induced in response to ER stress in neuronal cells and that transcriptional induction of PUMA regulates ER stress-induced cell death, independent of p53. CHOP (C/EBP homologous protein also known as GADD153; gene name Ddit3), a critical initiator of ER stress-induced apoptosis, was found to regulate both PUMA and BIM expression in response to ER stress. We further show that CHOP knockdown prevents perturbations in the AKT (protein kinase B)/FOXO3a (forkhead box, class O, 3a) pathway in response to ER stress. CHOP co-immunoprecipitated with FOXO3a in tunicamycin treated cells, suggesting that CHOP may also regulate other pro-apoptotic signaling cascades culminating in PUMA and BIM activation and cell death. In summary, CHOP regulates the expression of multiple pro-apoptotic BH3-only molecules through multiple mechanisms, making CHOP an important therapeutic target relevant to a number of neurodegenerative conditions

Genetic polymorphisms associated with the inflammatory response in bacterial meningitis

BACKGROUND Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously. METHODS The study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS We did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients. CONCLUSIONS In conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs

ELIXIR-IT HPC@CINECA: high performance computing resources for the bioinformatics community

BACKGROUND: The advent of Next Generation Sequencing (NGS) technologies and the concomitant reduction in sequencing costs allows unprecedented high throughput profiling of biological systems in a cost-efficient manner. Modern biological experiments are increasingly becoming both data and computationally intensive and the wealth of publicly available biological data is introducing bioinformatics into the "Big Data" era. For these reasons, the effective application of High Performance Computing (HPC) architectures is becoming progressively more recognized also by bioinformaticians. Here we describe HPC resources provisioning pilot programs dedicated to bioinformaticians, run by the Italian Node of ELIXIR (ELIXIR-IT) in collaboration with CINECA, the main Italian supercomputing center. RESULTS: Starting from April 2016, CINECA and ELIXIR-IT launched the pilot Call "ELIXIR-IT HPC@CINECA", offering streamlined access to HPC resources for bioinformatics. Resources are made available either through web front-ends to dedicated workflows developed at CINECA or by providing direct access to the High Performance Computing systems through a standard command-line interface tailored for bioinformatics data analysis. This allows to offer to the biomedical research community a production scale environment, continuously updated with the latest available versions of publicly available reference datasets and bioinformatic tools. Currently, 63 research projects have gained access to the HPC@CINECA program, for a total handout of ~ 8 Millions of CPU/hours and, for data storage, ~ 100 TB of permanent and ~ 300 TB of temporary space. CONCLUSIONS: Three years after the beginning of the ELIXIR-IT HPC@CINECA program, we can appreciate its impact over the Italian bioinformatics community and draw some considerations. Several Italian researchers who applied to the program have gained access to one of the top-ranking public scientific supercomputing facilities in Europe. Those investigators had the opportunity to sensibly reduce computational turnaround times in their research projects and to process massive amounts of data, pursuing research approaches that would have been otherwise difficult or impossible to undertake. Moreover, by taking advantage of the wealth of documentation and training material provided by CINECA, participants had the opportunity to improve their skills in the usage of HPC systems and be better positioned to apply to similar EU programs of greater scale, such as PRACE. To illustrate the effective usage and impact of the resources awarded by the program - in different research applications - we report five successful use cases, which have already published their findings in peer-reviewed journals

Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway

Autophagy is a physiological process, important for recycling of macromolecules and maintenance of cellular homeostasis. Defective autophagy is associated with tumorigenesis and has a causative role in chemotherapy resistance in leukemia and in solid cancers. Here, we report that autophagy is regulated by the lysine-specific demethylase LSD1/KDM1A, an epigenetic marker whose overexpression is a feature of malignant neoplasia with an instrumental role in cancer development. In the present study, we determine that two different LSD1 inhibitors (TCP and SP2509) as well as selective ablation of LSD1 expression promote autophagy in neuroblastoma cells. At a mechanistic level, we show that LSD1 binds to the promoter region of Sestrin2 (SESN2), a critical regulator of mTORC1 activity. Pharmacological inhibition of LSD1 triggers SESN2 expression that hampers mTORC1 activity, leading to enhanced autophagy. SESN2 overexpression suffices to promote autophagy in neuroblastoma cells, while loss of SESN2 expression reduces autophagy induced by LSD1 inhibition. Our findings elucidate a mechanism whereby LSD1 controls autophagy in neuroblastoma cells through SESN2 transcription regulation, and we suggest that pharmacological targeting of LSD1 may have effective therapeutic relevance in the control of autophagy in neuroblastoma