Calcium signaling and network activity : mathematical modeling and molecular mechanisms

The calcium (Ca2+) ion is a versatile second messenger present in all cells. It is involved in such diverse processes as cell division, differentiation, vesicle transport and muscle contraction. Its widespread applicability is partially explained by its wide temporal and spatial dynamics. By varying in time, oscillations arise and enable frequency modulation. Likewise, by varying in space, waves are formed and enable cross talk in-between cells in networks. In here, I present novel data on the mechanism behind Ca2+ signaling both in the form of oscillations and in the form of intercellular networks. The investigation are performed both from a theoretical point of view using mathematical modeling simulated in silico and from a molecular point of view in wet-lab experiments in vitro and in vivo. To be more specific, in Paper I, I present a method with software to identify functional networks in groups of cells and ways of analyzing them. In Paper II, this method is used to identify so-called small-world networks with scale-free properties in spontaneously active neural progenitor cells. These network formations are dependent on gap junctions and critically regulate proliferation both in neural progenitors derived from embryonic stem cells and in embryonic mouse brains. In Paper III, I present a model for the generation of spontaneous Ca2+ oscillations in neural progenitors. The essence of this model is that the spontaneous Ca2+ and electrical activity is driven by functional pacemaker cells expressing slightly more voltage-gated Ca2+ channels than the cells connected to them with gap junctions. Interestingly, one type of channel involved in this pacemaker activity is encoded by the mental disorder susceptibility gene Cacna1c. Transgenic mice lacking Cacna1c expression in the forebrain exhibit signs of increased anxiety as well as changes in brain anatomy. Finally in Paper IV, I describe a method of finding genes dependent on the frequency of Ca2+ oscillations. Cells stably expressing the light-sensitive protein melanopsin are exposed to light, after which the cellular content is collected and analyzed with RT-qPCR, RNA sequencing and phosphoproteomics. Hereby, a large network of genes and proteins dependent on frequency is identified. In conclusion, the research described below deepens our understanding on Ca2+ oscillations and network activity, using both mathematical modeling and wet-lab molecular biology experiments

Cognitive Outcome in Adolescents and Young Adults after Repeat Courses of Antenatal Corticosteroids

ObjectiveTo investigate whether repeat courses of antenatal corticosteroids have long-term effects on cognitive and psychological functioning.Study designIn a prospective cohort study, 58 adolescents and young adults (36 males) who had been exposed to 2-9 weekly courses of betamethasone in utero were assessed with neuropsychological tests and behavior self-reports. Unexposed subjects (n = 44, 25 males) matched for age, sex, and gestational age at birth served as a comparison group. In addition, individuals exposed in utero to a single course (n = 25, 14 males) were included for dose-response analysis. Group differences were investigated using multilevel linear modeling.ResultsMean scores obtained in 2 measures of attention and speed were significantly lower in subjects exposed to 2 or more antenatal corticosteroids courses (Symbol Search, P = .009; Digit Span Forward, P = .02), but these were not dose-dependent. Exposure to repeat courses of antenatal corticosteroids was not associated with general deficits in higher cognitive functions, self-reported attention, adaptability, or overall psychological function.ConclusionsAlthough this study indicates that repeat exposure to antenatal corticosteroids may have an impact on aspects of executive functioning, it does not provide support for the prevailing concern that such fetal exposure will have a major adverse impact on cognitive functions and psychological health later in life

Palladium dispersion effects on wet methane oxidation kinetics

The catalytic activity for dry and wet methane oxidation over a series of palladium–alumina catalysts with palladium loadings from 0.23 to 3.6 wt% Pd and systematically varied PdO dispersions from 8.1 to 39% was evaluated by flow reactor measurements and compared with multiscale simulations. The catalysts were prepared by industrially relevant incipient wetness impregnation followed by controlled calcination to provide similar active surface area with a realistic contact between active PdO nanoparticles and the alumina support. Kinetic analysis reveals that in wet conditions, the apparent activation energy for methane oxidation decreases as the PdO particle size increases as opposed to dry conditions where it increases. Active sites at the rim of the PdO particles in contact with the alumina support seem to contribute more to the overall activity under dry conditions but are more sensitive to wet conditions than PdO sites farther away from the rim. This sensitivity is likely due to more severe blocking by hydroxyl groups formed by water dissociation and reversed spillover. Simulations support that PdO bound hydroxyls well may form under the present reaction conditions. It is envisaged that the design of palladium–alumina catalysts for high methane turn-over frequency should target high but not too high PdO dispersion, i.e., the PdO particles should not be smaller than about 2 nm, as to balance water tolerance and palladium utilisation

Hampered PdO Redox Dynamics by Water Suppresses Lean Methane Oxidation over Realistic Palladium Catalysts

By use of operando spectroscopies under cycling reaction conditions, water is shown to hamper the redox dynamics of realistic palladium oxide nanoparticles dispersed onto alumina and hydrophobic zeolite supports thereby lowering the activity for total oxidation of methane. Water adsorption forms hydroxyl ad-species that block the methane and oxygen dissociation and seem to prevent lattice oxygen to take part in the methane oxidation. The main catalytic action is thus proposed to shift from the Mars-van Krevelen mechanism in dry conditions to a slower route that relies on Langmuir-Hinshelwood type of steps in wet conditions. This key finding has clear implications on catalyst design for low-temperature gas combustion emission control

Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder

The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium’s mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder

Cerebrospinal fluid proteomic study of two bipolar disorder cohorts

The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder

CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture

Inflammation-induced release of prostaglandin E-2 (PGE(2)) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE(2). This alters neural network activity in the preBotzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R(+/+) cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.Peer reviewe

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment

How are individuals with Multiple Sclerosis affected by fatigue?

BAKGRUND Multipel skleros (MS) är en neurologisk sjukdom som drabbar centrala nervsystemet. Sjukdomen bryter vanligtvis ut i 20-40 årsåldern och ger neurologiska symtom ex. domningar. MS är än så länge obotlig, men sedan i början av 2000-talet finns effektiva bromsmediciner. Fatigue är ett engelskt ord som beskriver den sjukliga trötthet som kan uppträda vid exempelvis MS. SYFTE Att undersöka hur symtomet fatigue vid MS-sjukdom påverkar personernas liv och vilka strategier de använder sig av för att hantera vardagen. METOD Uppsatsen bygger på en allmän litteraturstudie gjord på 15 vetenskapliga artiklar. Data har analyserats med hjälp av Evans metod (2002) som är en form av innehållsanalys som lämpar sig särskilt väl för litteraturstudier. Artiklarna analyseras med hjälp av begreppen coping och KASAM (känsla av sammanhang). RESULTAT Resultatet är uppbyggt på två huvudteman och tio subteman. Konsekvenser beskriver hur studiedeltagarna påverkades i sin vardag av fatigue och vilka förändringar de har behövt göra i exempelvis sitt arbetsliv. Strategier presenterar vilka strategier studiedeltagarna använde sig av för att hantera sina nya livsförutsättningar. Många studiedeltagare berättar om sina familjer och sociala nätverk och betydelsen av deras stöd. Vidare berättar studiedeltagarna om hur de lärt känna sig själva och hur fatigue drabbar just dem och därför har de kunnat hantera situationen. SLUTSATS Fatigue är ett livsomvälvande symtom som ger fysiska, psykiska och sociala konsekvenser. Studiedeltagarnas egna strategier har haft stor betydelse för att minska det personliga lidandet och bevara livskvalitet och en känsla av sammanhang. På grund av symtomets osynlighet är det som sjuksköterska viktigt att förstå innebörden av fatigue och hur det påverkar patientens liv och på vilka sätt patienter hanterar fatigue

Links San Antonio Papers

Letter from Geraldine Smedler to the San Antonio chapter of The Links, Inc. inviting them to attend and support a fashion show, pageant, and fund raiser hosted by the San Antonio chapter of the Alpha Kappa Alpha Sorority. Included is a blank form for buying advertisements in the event's program