Mechanisms and functional significance of aberrant seizure-induced hippocampal neurogenesis

Studies of experimental mesial temporal lobe epilepsy (mTLE) indicate that prolonged seizures in the adult not only damage the hippocampal formation but also dramatically stimulate neurogenesis. Endogenous neural progenitor cells (NPCs) located in the adult rodent dentate gyrus and striatal subventricular zone are stimulated by experimental status epilepticus (SE) to generate increased numbers of dentate granule cells (DGCs) and olfactory interneurons, respectively ( Bengzon et al., 1997 ; Parent et al., 1997, 2002 ; Scott et al., 1998 ). In this review, we discuss current knowledge regarding the consequences of seizure activity on NPC proliferation, focusing on the hippocampus, and on the migration and integration of adult-born hippocampal neurons. We also describe the effects of seizure-induced neurogenesis on hippocampal network function and the potential relevance of aberrant neurogenesis to human mTLE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65409/1/j.1528-1167.2008.01634.x.pd

Is neurogenesis reparative after status epilepticus?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65863/1/j.1528-1167.2007.01355.x.pd

ACAP-A/B Are ArfGAP Homologs in Dictyostelium Involved in Sporulation but Not in Chemotaxis

Arfs and Arf GTPase-activating proteins (ArfGAPs) are regulators of membrane trafficking and actin dynamics in mammalian cells. In this study, we identified a primordial Arf, ArfA, and two ArfGAPs (ACAP-A/B) containing BAR, PH, ArfGAP and Ankyrin repeat domains in the eukaryote Dictyostelium discoideum. In vitro, ArfA has similar nucleotide binding properties as mammalian Arfs and, with GTP bound, is a substrate for ACAP-A and B. We also investigated the physiological functions of ACAP-A/B by characterizing cells lacking both ACAP-A and B. Although ACAP-A/B knockout cells showed no defects in cell growth, migration or chemotaxis, they exhibited abnormal actin protrusions and ∼50% reduction in spore yield. We conclude that while ACAP-A/B have a conserved biochemical mechanism and effect on actin organization, their role in migration is not conserved. The absence of an effect on Dictyostelium migration may be due to a specific requirement for ACAPs in mesenchymal migration, which is observed in epithelial cancer cells where most studies of mammalian ArfGAPs were performed

Synthesis of carboxylated derivatives of poly(isobutylene-co-isoprene) by azide–alkyne “click” chemistry

The final publication is available at Springer via https://dx.doi.org/10.1038/s41428-018-0130-yThe synthesis of carboxylated derivatives of poly(isobutylene-co-isoprene) (isobutylene–isoprene rubber, IIR) with substitution levels ranging from 1 to 4 mol% and different spacer lengths was accomplished through azide–alkyne Huisgen cycloaddition. Azido-functionalized IIR was first prepared by reacting brominated IIR with sodium azide to full conversion in a 90:10 tetrahydrofuran/N,N-dimethylacetamide mixture. The click reaction of azido-functionalized IIR with acetylenic acids, which was carried out using the copper(I) bromide/N,N,N′,N″,N″-pentamethyldiethylenetriamine catalyst system in tetrahydrofuran, yielded carboxylated IIRs. The products were characterized by 1H NMR and FT-IR spectroscopy, and their molecular weight was determined by size exclusion chromatography analysis. The conversion to carboxylated groups reached up to 100% as determined by NMR spectroscopy but was highly dependent on the type of solvent and the amounts of catalysts and reactants used in the procedures.ARLANXEO Canada Inc.Natural Sciences and Engineering Research Council (NSERC) of Canad

Decline in age at menarche among Spanish women born from 1925 to 1962

<p>Abstract</p> <p>Background</p> <p>While the timing of reproductive events varies across populations, a downward trend in age at menarche has nevertheless been reported in most of the developed world over the past century. Given the impact of change in age at menarche on health conditions, this study sought to examine secular trends in age at menarche among women living in Navarre (Northern Spain) who participated in a population-based breast cancer screening programme.</p> <p>Methods</p> <p>The study was based on 110545 women born from 1925 to 1962. Trends were tested using a linear regression model, in which year of birth was entered continuously as the predictor and age at menarche (years) as the response variable, using size of town and region of birth as covariates.</p> <p>Results</p> <p>Among women born in Navarre between 1925 and 1962, age at menarche declined steadily from an average of 13.72 years in the 1925-1929 birth-cohorts to 12.83 years in the 1958-1962 birth-cohorts. Controlling for size of town or city of birth, age at menarche declined by an average of 0.132 years every 5 years over the period 1925-1962. This decline was greater in women born in rural versus urban settings. Trends were also different among regions of birth.</p> <p>Conclusion</p> <p>We report a population-based study showing a downward trend in age of onset of menarche among Spanish women born in the period 1925-1962, something that is more pronounced among women born in rural settings and varies geographically.</p

Modeling Cell Gradient Sensing and Migration in Competing Chemoattractant Fields

Directed cell migration mediates physiological and pathological processes. In particular, immune cell trafficking in tissues is crucial for inducing immune responses and is coordinated by multiple environmental cues such as chemoattractant gradients. Although the chemotaxis mechanism has been extensively studied, how cells integrate multiple chemotactic signals for effective trafficking and positioning in tissues is not clearly defined. Results from previous neutrophil chemotaxis experiments and modeling studies suggested that ligand-induced homologous receptor desensitization may provide an important mechanism for cell migration in competing chemoattractant gradients. However, the previous mathematical model is oversimplified to cell gradient sensing in one-dimensional (1-D) environment. To better understand the receptor desensitization mechanism for chemotactic navigation, we further developed the model to test the role of homologous receptor desensitization in regulating both cell gradient sensing and migration in different configurations of chemoattractant fields in two-dimension (2-D). Our results show that cells expressing normal desensitizable receptors preferentially orient and migrate toward the distant gradient in the presence of a second local competing gradient, which are consistent with the experimentally observed preferential migration of cells toward the distant attractant source and confirm the requirement of receptor desensitization for such migratory behaviors. Furthermore, our results are in qualitative agreement with the experimentally observed cell migration patterns in different configurations of competing chemoattractant fields

Ordered Patterns of Cell Shape and Orientational Correlation during Spontaneous Cell Migration

BACKGROUND: In the absence of stimuli, most motile eukaryotic cells move by spontaneously coordinating cell deformation with cell movement in the absence of stimuli. Yet little is known about how cells change their own shape and how cells coordinate the deformation and movement. Here, we investigated the mechanism of spontaneous cell migration by using computational analyses. METHODOLOGY: We observed spontaneously migrating Dictyostelium cells in both a vegetative state (round cell shape and slow motion) and starved one (elongated cell shape and fast motion). We then extracted regular patterns of morphological dynamics and the pattern-dependent systematic coordination with filamentous actin (F-actin) and cell movement by statistical dynamic analyses. CONCLUSIONS/SIGNIFICANCE: We found that Dictyostelium cells in both vegetative and starved states commonly organize their own shape into three ordered patterns, elongation, rotation, and oscillation, in the absence of external stimuli. Further, cells inactivated for PI3-kinase (PI3K) and/or PTEN did not show ordered patterns due to the lack of spatial control in pseudopodial formation in both the vegetative and starved states. We also found that spontaneous polarization was achieved in starved cells by asymmetric localization of PTEN and F-actin. This breaking of the symmetry of protein localization maintained the leading edge and considerably enhanced the persistence of directed migration, and overall random exploration was ensured by switching among the different ordered patterns. Our findings suggest that Dictyostelium cells spontaneously create the ordered patterns of cell shape mediated by PI3K/PTEN/F-actin and control the direction of cell movement by coordination with these patterns even in the absence of external stimuli

Synthetic Activation of Endogenous PI3K and Rac Identifies an AND-Gate Switch for Cell Polarization and Migration

Phosphatidylinositol 3-OH kinase (PI3K) has been widely studied as a principal regulator of cell polarization, migration, and chemotaxis [1], [2], [3], [4]. Surprisingly, recent studies showed that mammalian neutrophils and Dictyostelium discoideum cells can polarize and migrate in the absence of PI3K activity [5], [6], [7]. Here we directly probe the roles of PI3K and its downstream effector, Rac, in HL-60 neutrophils by using a chemical biology approach whereby the endogenously present enzymes are synthetically activated in less than one minute [8], [9], [10]. We show that uniform activation of endogenous PI3K is sufficient to polarize previously unpolarized neutrophils and trigger effective cell migration. After a delay following symmetrical phosphatidylinositol (3,4,5)-triphosphate (PIP3) production, a polarized distribution of PIP3 was induced by positive feedback requiring actin polymerization. Pharmacological studies argue that this process does not require receptor-coupled trimeric G proteins. Contrary to the current working model, rapid activation of endogenous Rac proteins triggered effective actin polymerization but failed to feed back to PI3K to generate PIP3 or induce cell polarization. Thus, the increase in PIP3 concentration at the leading edge is generated by positive feedback with an AND gate logic with a PI3K-Rac-actin polymerization pathway as a first input and a PI3K initiated non-Rac pathway as a second input. This AND-gate control for cell polarization can explain how Rac can be employed for both PI3K-dependent and -independent signaling pathways coexisting in the same cell

Effectiveness of physiotherapy exercise following total knee replacement: Systematic review and meta-analysis

© 2015 Artz et al. Background: Rehabilitation, with an emphasis on physiotherapy and exercise, is widely promoted after total knee replacement. However, provision of services varies in content and duration. The aim of this study is to update the review of Minns Lowe and colleagues 2007 using systematic review and meta-analysis to evaluate the effectiveness of post-discharge physiotherapy exercise in patients with primary total knee replacement. Methods: We searched MEDLINE, Embase, PsycInfo, CINAHL and Cochrane CENTRAL to October 4th 2013 for randomised evaluations of physiotherapy exercise in adults with recent primary knee replacement. Outcomes were: patient-reported pain and function, knee range of motion, and functional performance. Authors were contacted for missing data and outcomes. Risk of bias and heterogeneity were assessed. Data was combined using random effects meta-analysis and reported as standardised mean differences (SMD) or mean differences (MD). Results: Searches identified 18 randomised trials including 1,739 patients with total knee replacement. Interventions compared: physiotherapy exercise and no provision; home and outpatient provision; pool and gym-based provision; walking skills and more general physiotherapy; and general physiotherapy exercise with and without additional balance exercises or ergometer cycling. Compared with controls receiving minimal physiotherapy, patients receiving physiotherapy exercise had improved physical function at 3-4 months, SMD -0.37 (95% CI -0.62, -0.12), and pain, SMD -0.45 (95% CI -0.85, -0.06). Benefit up to 6 months was apparent when considering only higher quality studies. There were no differences for outpatient physiotherapy exercise compared with home-based provision in physical function or pain outcomes. There was a short-term benefit favouring home-based physiotherapy exercise for range of motion flexion. There were no differences in outcomes when the comparator was hydrotherapy, or when additional balancing or cycling components were included. In one study, a walking skills intervention was associated with a long-term improvement in walking performance. However, for all these evaluations studies were under-powered individually and in combination. Conclusion: After recent primary total knee replacement, interventions including physiotherapy and exercise show short-term improvements in physical function. However this conclusion is based on meta-analysis of a few small studies and no long-term benefits of physiotherapy exercise interventions were identified. Future research should target improvements to long-term function, pain and performance outcomes in appropriately powered trials