ApoE Receptor 2 Regulates Synapse and Dendritic Spine Formation

Apolipoprotein E receptor 2 (ApoEr2) is a postsynaptic protein involved in long-term potentiation (LTP), learning, and memory through unknown mechanisms. We examined the biological effects of ApoEr2 on synapse and dendritic spine formation-processes critical for learning and memory.In a heterologous co-culture synapse assay, overexpression of ApoEr2 in COS7 cells significantly increased colocalization with synaptophysin in primary hippocampal neurons, suggesting that ApoEr2 promotes interaction with presynaptic structures. In primary neuronal cultures, overexpression of ApoEr2 increased dendritic spine density. Consistent with our in vitro findings, ApoEr2 knockout mice had decreased dendritic spine density in cortical layers II/III at 1 month of age. We also tested whether the interaction between ApoEr2 and its cytoplasmic adaptor proteins, specifically X11α and PSD-95, affected synapse and dendritic spine formation. X11α decreased cell surface levels of ApoEr2 along with synapse and dendritic spine density. In contrast, PSD-95 increased cell surface levels of ApoEr2 as well as synapse and dendritic spine density.These results suggest that ApoEr2 plays important roles in structure and function of CNS synapses and dendritic spines, and that these roles are modulated by cytoplasmic adaptor proteins X11α and PSD-95

Comparison of the force exerted by hippocampal and DRG growth cones

Mechanical properties such as force generation are fundamental for neuronal motility, development and regeneration. We used optical tweezers to compare the force exerted by growth cones (GCs) of neurons from the Peripheral Nervous System (PNS), such as Dorsal Root Ganglia (DRG) neurons, and from the Central Nervous System (CNS) such as hippocampal neurons. Developing GCs from dissociated DRG and hippocampal neurons were obtained from P1-P2 and P10-P12 rats. Comparing their morphology, we observed that the area of GCs of hippocampal neurons was 8-10 \ub5m(2) and did not vary between P1-P2 and P10-P12 rats, but GCs of DRG neurons were larger and their area increased from P1-P2 to P10-P12 by 2-4 times. The force exerted by DRG filopodia was in the order of 1-2 pN and never exceeded 5 pN, while hippocampal filopodia exerted a larger force, often in the order of 5 pN. Hippocampal and DRG lamellipodia exerted lateral forces up to 20 pN, but lamellipodia of DRG neurons could exert a vertical force larger than that of hippocampal neurons. Force-velocity relationships (Fv) in both types of neurons had the same qualitative behaviour, consistent with a common autocatalytic model of force generation. These results indicate that molecular mechanisms of force generation of GC from CNS and PNS neurons are similar but the amplitude of generated force is influenced by their cytoskeletal properties

Transboundary water interaction III: contest and compliance

This paper serves international water conflict resolution efforts by examining the ways that states contest hegemonic transboundary water arrangements. The conceptual framework of dynamic transboundary water interaction that it presents integrates theories about change and counter-hegemony to ascertain coercive, leverage, and liberating mechanisms through which contest and transformation of an arrangement occur. While the mechanisms can be active through sociopolitical processes either of compliance or of contest of the arrangement, most transboundary water interaction is found to contain elements of both. The role of power asymmetry is interpreted through classification of intervention strategies that seek to either influence or challenge the arrangements. Coexisting contest and compliance serve to explain in part the stasis on the Jordan and Ganges rivers (where the non-hegemons have in effect consented to the arrangement), as well as the changes on the Tigris and Mekong rivers, and even more rapid changes on the Amu Darya and Nile rivers (where the non-hegemons have confronted power asymmetry through influence and challenge). The framework also stresses how transboundary water events that may appear isolated are more accurately read within the many sociopolitical processes and arrangements they are shaped by. By clarifying the typically murky dynamics of interstate relations over transboundary waters, furthermore, the framework exposes a new suite of entry points for hydro-diplomatic initiatives

The pancreatic zymogen granule membrane protein, GP2, binds Escherichia coli type 1 Fimbriae

<p>Abstract</p> <p>Background</p> <p>GP2 is the major membrane protein present in the pancreatic zymogen granule, and is cleaved and released into the pancreatic duct along with exocrine secretions. The function of GP2 is unknown. GP2's amino acid sequence is most similar to that of uromodulin, which is secreted by the kidney. Recent studies have demonstrated uromodulin binding to bacterial Type 1 fimbria. The fimbriae serve as adhesins to host receptors. The present study examines whether GP2 also shares similar binding properties to bacteria with Type 1 fimbria. Commensal and pathogenic bacteria, including E. coli and Salmonella, express type 1 fimbria.</p> <p>Methods</p> <p>An <it>in vitro </it>binding assay was used to assay the binding of recombinant GP2 to defined strains of <it>E. coli </it>that differ in their expression of Type 1 fimbria or its subunit protein, FimH. Studies were also performed to determine whether GP2 binding is dependent on the presence of mannose residues, which is a known determinant for FimH binding.</p> <p>Results</p> <p>GP2 binds <it>E. coli </it>that express Type 1 fimbria. Binding is dependent on GP2 glycosylation, and specifically the presence of mannose residues.</p> <p>Conclusion</p> <p>GP2 binds to Type 1 fimbria, a bacterial adhesin that is commonly expressed by members of the <it>Enterobacteriacae </it>family.</p

Nephrolithiasis related to inborn metabolic diseases

Nephrolithiasis associated with inborn metabolic diseases is a very rare condition with some common characteristics: early onset of symptoms, family history, associated tubular impairment, bilateral, multiple and recurrent stones, and association with nephrocalcinosis. The prognosis of such diseases may lead to life threatening conditions, not only because of unabated kidney damage but also because of progressive extra-renal involvement, either in a systemic form (e.g. primary hyperoxaluria type 1, requiring combined liver and kidney transplantation), or in a neurological form (Lesch–Nyhan syndrome leading to auto-mutilation and disability, phosphoribosyl pyrophosphate synthetase superactivity, which is associated with mental retardation). Patients with other inborn metabolic diseases present only with recurrent stone formation, such as cystinuria, adenine phosphoribosyl-transferase deficiency, xanthine deficiency. Finally, nephrolithiasis may be secondarily part of some other metabolic diseases, such as glycogen storage disease type 1 or inborn errors of metabolism leading to Fanconi syndrome (nephropathic cystinosis, tyrosinaemia type 1, fructose intolerance, Wilson disease, respiratory chain disorders, etc.). The diagnosis is based on highly specific investigations, including crystal identification, biochemical analyses and DNA study. The treatment of nephrolithiasis requires hydration as well as specific measures. Compliance is a major issue regarding the progression of renal damage, but the overall outcome mainly depends on extra-renal involvement in relation to the metabolic defect

Sudden cardiac death and pump failure death prediction in chronic heart failure by combining ECG and clinical markers in an integrated risk model

BACKGROUND: Sudden cardiac death (SCD) and pump failure death (PFD) are common endpoints in chronic heart failure (CHF) patients, but prevention strategies are different. Currently used tools to specifically predict these endpoints are limited. We developed risk models to specifically assess SCD and PFD risk in CHF by combining ECG markers and clinical variables. METHODS: The relation of clinical and ECG markers with SCD and PFD risk was assessed in 597 patients enrolled in the MUSIC (MUerte Súbita en Insuficiencia Cardiaca) study. ECG indices included: turbulence slope (TS), reflecting autonomic dysfunction; T-wave alternans (TWA), reflecting ventricular repolarization instability; and T-peak-to-end restitution (ΔαTpe) and T-wave morphology restitution (TMR), both reflecting changes in dispersion of repolarization due to heart rate changes. Standard clinical indices were also included. RESULTS: The indices with the greatest SCD prognostic impact were gender, New York Heart Association (NYHA) class, left ventricular ejection fraction, TWA, ΔαTpe and TMR. For PFD, the indices were diabetes, NYHA class, ΔαTpe and TS. Using a model with only clinical variables, the hazard ratios (HRs) for SCD and PFD for patients in the high-risk group (fifth quintile of risk score) with respect to patients in the low-risk group (first and second quintiles of risk score) were both greater than 4. HRs for SCD and PFD increased to 9 and 11 when using a model including only ECG markers, and to 14 and 13, when combining clinical and ECG markers. CONCLUSION: The inclusion of ECG markers capturing complementary pro-arrhythmic and pump failure mechanisms into risk models based only on standard clinical variables substantially improves prediction of SCD and PFD in CHF patients

Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells

Response of Sunflower (Helianthus annuus L.) Leaf Surface Defenses to Exogenous Methyl Jasmonate

Helianthus annuus, the common sunflower, produces a complex array of secondary compounds that are secreted into glandular trichomes, specialized structures found on leaf surfaces and anther appendages of flowers. The primary components of these trichome secretions are sesquiterpene lactones (STL), a diverse class of compounds produced abundantly by the plant family Compositae and believed to contribute to plant defense against herbivory. We treated wild and cultivated H. annuus accessions with exogenous methyl jasmonate, a plant hormone that mediates plant defense against insect herbivores and certain classes of fungal pathogens. The wild sunflower produced a higher density of glandular trichomes on its leaves than the cultivar. Comparison of the profiles of glandular trichome extracts obtained by liquid chromatography–mass spectroscopy (LC-MS) showed that wild and cultivated H. annuus were qualitatively similar in surface chemistry, although differing in the relative size and proportion of various compounds detected. Despite observing consistent transcriptional responses to methyl jasmonate treatment, we detected no significant effect on glandular trichome density or LC-MS profile in cultivated or wild sunflower, with wild sunflower exhibiting a declining trend in overall STL production and foliar glandular trichome density of jasmonate-treated plants. These results suggest that glandular trichomes and associated compounds may act as constitutive defenses or require greater levels of stimulus for induction than the observed transcriptional responses to exogenous jasmonate. Reduced defense investment in domesticated lines is consistent with predicted tradeoffs caused by selection for increased yield; future research will focus on the development of genetic resources to explicitly test the ecological roles of glandular trichomes and associated effects on plant growth and fitness

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method: We used an established mouse model of maternal immune activation (MIA) by the viral mimic Polyl:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results: Polyl:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life. © 2009 Li et al.published_or_final_versio