Functional Liaison Research Articles

Neurovascular unit dysfunction as a mechanism of seizures and epilepsy during aging.

The term neurovascular unit (NVU) describes the structural and functional liaison between specialized brain endothelium, glial and mural cells, and neurons. Within the NVU, the blood‐brain barrier (BBB) is the microvascular structure regulating neuronal physiology and immune cross‐talk, and its properties adapt to brain aging. Here, we analyze a research framework where NVU dysfunction, caused by acute insults or disease progression in the aging brain, represents a converging mechanism underlying late‐onset seizures or epilepsy and neurological or neurodegenerative sequelae. Furthermore, seizure activity may accelerate brain aging by sustaining regional NVU dysfunction, and a cerebrovascular pathology may link seizures to comorbidities. Next, we focus on NVU diagnostic approaches that could be tailored to seizure conditions in the elderly. We also examine the impending disease‐modifying strategies based on the restoration of the NVU and, more in general, the homeostatic control of anti‐ and pro‐inflammatory players. We conclude with an outlook on current pre‐clinical knowledge gaps and clinical challenges pertinent to seizure onset and conditions in an aging population.

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives.

Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.

The IL1\u03b2-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

BackgroundHypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses.MethodsIn order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation.ResultsWe first determined that IL-1β expression correlates with the levels of HIF-1α as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1α, GPER and the IL-1β/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1β that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1β released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs.ConclusionsOur data shed new light on the role of hypoxia in the activation of the IL-1β/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.

Procaspase-9 induces its cleavage by transnitrosylating XIAP via the Thioredoxin system during cerebral ischemia-reperfusion in rats

Transnitrosylation is an important mechanism by which nitric oxide (NO) modulates cell signaling pathways. For instance, SNO-caspase-3 can transnitrosylate the X-linked inhibitor of apoptosis (XIAP) to enhance apoptosis. XIAP is a potent antagonist of caspase apoptotic activity. Decrease in XIAP activity via nitrosylation results in SNO-XIAP-mediated caspase activation. Considering the functional liaison of procaspase-9 and XIAP, we hypothesized that procaspase-9 nitrosylates XIAP directly. Our data confirmed that cerebral ischemia-reperfusion induced XIAP nitrosylation, procaspase-9 denitrosylation and cleavage. Interestingly, the time courses of the nitrosylation of procaspase-9 and XIAP were negatively correlated, which was more prominent after cerebral ischemia-reperfusion, suggesting a direct interaction. The nitrosylation of XIAP, as well as the denitrosylation and cleavage of procaspase-9, were inhibited by DNCB, TrxR1 AS-ODNs, or TAT-AVPY treatment. Meanwhile, DNCB, TrxR1 AS-ODNs, or TAT-AVPY also inhibited the decrease in hippocampal CA1 neurons induced by ischemia-reperfusion in rats. The denitrosylation and cleavage of procaspase-9 induced by OGD/reoxygenation in SH-SY5Y cells were inhibited when cells were co-transfected with wild-type procaspase-9 and XIAP mutant (C449G). These data suggest that cerebral ischemia-reperfusion induces a transnitrosylation from procaspase-9 to XIAP via the Trx system to consequently cause apoptosis. Additionally, Cys325 is a critical S-nitrosylation site of procaspase-9.

Structural and functional liaisons between transposable elements and satellite DNAs.

Transposable elements (TEs) and satellite DNAs (satDNAs) are typically identified as major repetitive DNA components in eukaryotic genomes. TEs are DNA segments able to move throughout a genome while satDNAs are tandemly repeated sequences organized in long arrays. Both classes of repetitive sequences are extremely diverse, and many TEs and satDNAs exist within a genome. Although they differ in structure, genomic organization, mechanisms of spread, and evolutionary dynamics, TEs and satDNAs can share sequence similarity and organizational patterns, thus indicating that complex mutual relationships can determine their evolution, and ultimately define roles they might have on genome architecture and function. Motivated by accumulating data about sequence elements that incorporate features of both TEs and satDNAs, here we present an overview of their structural and functional liaisons.

Abstract 1285: A functional liaison between E2F and aberrant ETS oncogenes

Abstract Timing, mode and amplitude of gene regulation depend on the tissue specific dynamic composition of transcription factor complexes. Abnormalities of the constituents of the complex are expected to modify the regulatory behavior of the entire module. Here we report a novel E2F-ETS proliferation control module in Ewing's sarcoma. FLI1 and other ETS factors are frequently found to be fused to EWS in this highly aggressive pediatric cancer of the bone. In a genome-wide localization analysis of EWS/FLI1 as well as E2F3 by ChipSeq, two patterns associated with distinct gene sets and modes of regulation were identified and integrated with gene expression data. EWS/FLI1 significantly colocalized with E2F3 to proximal promoters of activated proliferation genes while EWS/FLI1 binding independent of E2F3 occurred predominantly distant to repressed differentiation genes. We find that this key module of the transcription factor network underlying Ewing's sarcoma is of general importance and not limited to this specific ETS driven neoplasm. Recently, prostate cancer was shown to frequently harbor fusions of the ERG gene. Here we demonstrate that the ETS/E2F3 complex is also present in VCap prostate cancer cells, identify a common set of genes responsive to this module and computationally show that this set of core-responders is involved in proliferation control and translation. Acknowledgement: This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1285. doi:1538-7445.AM2012-1285

Fis1, Bap31 and the kiss of death between mitochondria and endoplasmic reticulum

Dynamic structural and functional liaisons between mitochondria and the endoplasmic reticulum (ER) support a wide range of cell functions, including the ability of the cell to kill itself by apoptosis. A new study in this issue of The EMBO Journal sheds light on how these interactions regulate Bax/Bak‐driven cell death within the complex milieu of the cell, suggesting that mitochondria–ER dynamics can involve an unanticipated two‐way communication in cell death, from mitochondria to ER and back again. Much of our knowledge on apoptosis induction in higher organisms, which revolves around mitochondria and proapoptotic Bcl‐2 family members such as Bax or Bak, has derived from reconstitution studies using biochemical and genetically defined systems. These studies revealed step‐wise activation of Bax/Bak in the mitochondrial outer membrane by activator BH3‐only proteins, regulated by prosurvival Bcl‐2 family proteins as well as by sensitizing BH3‐only proteins. In the complex environment of the intact cell, however, where the potential for competing reactions is enormous, the question of efficiencies and specificities takes precedence. As a consequence, there exists a large array of supporting players to ensure rapid and orderly cell demise by the Bax/Bak mechanism. Not surprisingly, many of these supporting roles involve mitochondrial biology—in particular, mitochondrial fusion/fission dynamics as well as the close physical and functional relationship of the mitochondrion with …

ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma–lamin A complexes

As orchestrators of essential cellular processes like proliferation, ERK1/2 mitogen-activated protein kinase signals impact on cell cycle regulation. A-type lamins are major constituents of the nuclear matrix that also control the cell cycle machinery by largely unknown mechanisms. In this paper, we disclose a functional liaison between ERK1/2 and lamin A whereby cell cycle progression is regulated. We demonstrate that lamin A serves as a mutually exclusive dock for ERK1/2 and the retinoblastoma (Rb) protein. Our results reveal that, immediately after their postactivation entrance in the nucleus, ERK1/2 dislodge Rb from its interaction with lamin A, thereby facilitating its rapid phosphorylation and consequently promoting E2F activation and cell cycle entry. Interestingly, these effects are independent of ERK1/2 kinase activity. We also show that cellular transformation and tumor cell proliferation are dependent on the balance between lamin A and nuclear ERK1/2 levels, which determines Rb accessibility for phosphorylation/inactivation.

A liaison model for disassembly-reassembly product ecodesign

This paper focuses on non-destructive disassembly for mechanical products as part of environment friendly manufacturing. An original approach using a clustering method for assembly and the introduction of a mathematical model, describing the fuzzy liaisons between the components, allow us to design the product for disassembly, service, recycling, upgrading and assembly. They also facilitate the determination of the problems related to the automation of assembly and disassembly sequences generation. To do so, the modelling of functional liaisons between parts helps to distinguish a simple contact from an attachment and subsets from subassemblies. Liaisons between components are described by matrices of fuzzy half degrees of liaison. The virtual locking liaisons could be extracted automatically from a B-rep model of a mechanical product on CAD and attachment liaisons are deduced from a fuzzy evaluation of their strength and condition changes.

Characteristics and outcomes of school refusal in Hiroshima, Japan: proposals for network therapy.

The authors conducted a study on children undergoing treatment at major school refusal treatment centers in Hiroshima Prefecture. On the whole, school refusal in the prefecture was found to peak between 13 and 14 years of age. By age group, the main reason for school refusal in elementary school group was parent-child relationship with separation anxiety. Given additional problems such as neglect at home and complicated social situations in their schools, junior high school students were found to present diverse symptoms from introversion and self-analysis to extroversion, neglect of studies, and delinquency. Among high school students, there were more cases suffering withdrawal and schizophrenia spectrum disorders. The major task regarding treatment seems to lie in how to treat complex cases combining different problems. We summarized herein the studies we have carried out and propose a model for a network therapy system based on functional liaisons between treatment centers. With this system, a child psychiatric medical facility plays the part of a liaison center for the overall network system.

Automatic a priori, a posteriori or appropriate determination of subassemblies

In the industrial field, the idea of subassembly must be distinguished from the subset one, when considering subassemblies as the only subsets in which all parts are stable. An original approach using the disassembly method, the logical reverse chronology of assembly, and the introduction of a mathematical model describing the liaisons allow us to determine the problems related to the automation of assembly sequences. To do so, the modelling of functional liaisons between parts helps to distinguish a simple contact from an attachment, and subsets from subassemblies. Liaisons between components are described by matrices of half degrees of liaison. These liaisons are extracted automatically from a B-rep model of a mechanical product on CAD. Subassemblies are determined automatically just in time during the determination of disassembly sequences. A limitation of this approach is that as soon as a relation is no more orthogonal to the basic referential, a new referential has to be introduced. An expert will choose the best sequence between sequences which were generating.

Depressant effect of cooling of the postero-lateral occipital cortex on pupillo-constriction responses evoked from the lateral suprasylvian area in cats

In anesthetized cats, the postero-lateral occipital cortex corresponding to area 20 was temporarily colled. Pupillary constriction responses evoked from the middle part of the ipsilateral lateral suprasylvian area (the PMLS of Palmer et al.) decreased by about 50% in amplitude during cooling. These results demonstrate a functional liaison between area 20 and the PMLS.

Depressant effect of cooling of the postero-lateral occipital cortex on pupillo-constriction responses evoked from the lateral suprasylvian area in cats

In anesthetized cats, the postero-lateral occipital cortex corresponding to area 20 was temporarily cooled. Pupillary constriction responses evoked from the middle part of the ipsilateral lateral suprasylvian area (the PMLS of Palmer et al.) decreased by about 50% in amplitude during cooling. These results demonstrate a functional liaison between area 20 and the PMLS.

Une épreuve collective de rythme — R/H.R.

Our actual tutorials led us to build an Epreuve collective de rythme (Collective Rhythm Test). It is a test of identification and of recognition, after audition, of rhythmical patterns that are intensive and/or temporal, represented graphically, be as are, be in situation of multiple choices. The test applies to subjects, boys and girls, aged 7 to 12 years old. The study of the test permits to bring out the metrical qualities. At the opportunity of this first study, we were able to indicate some new constats as well as already expressed ones in anterior observations ; also, we have formulated some hypothesis on some characteristics of rhythmical patterns and of the rhythmical function, also on the influence of the first one in the rythmical performance. Here are some main statements. If it does not exist any difference between the efficiency of girls and boys, there is a very significant one between the ages (7-8 years old; 9 years old; 10-12 years old). This fact can be observed, also, by some difficulty index progressively more high in one group of age to another, to most of the patterns presented. On the other hand, with the patterns of a bivalent complexity (intensity and duration), we observe one kind uniformity of efficiency between the ages, except if the pattern is very simple, although there is tendency to a better efficiency amongst the oldest ones. Concerning again the characteristics of patterns, it happens that the symétrie or asymétrie quality of the rhythmical pattern does not influence the level of diffi- quality of the rythmical pattern does not influence the level of diffistriking-groups. On the other hand, in the situation of multiple choices, for the recognition of and audible pattern, it appears that some characteristics of the " distractors " render more or less easy the récognitive act. Another observation concerns the spatio-temporal situation, and their number, of the strong intensity of the strikings. The difficulty index of one pattern would be function of these two parameters. Finally, from our study, it is brought out that, if there is a continuum of the rhythmical function, this one presents a character of polyvalency that manifests in the levels of different efficiency at each age. Our test permits to observe three capacities, nevertheless in functional liaison one another: intensive rhythm, temporal rhythm and bivalent (mixed) rhythm. In this manner, we reach a conclusion of Paul Fraisse (28): there are many rhythmical activities that command, for their realisation, some appropriate abilities.