Identification of a Putative Network of Actin-Associated Cytoskeletal Proteins in Glomerular Podocytes Defined by Co-Purified mRNAs

The glomerular podocyte is a highly specialized and polarized kidney cell type that contains major processes and foot processes that extend from the cell body. Foot processes from adjacent podocytes form interdigitations with those of adjacent cells, thereby creating an essential intercellular junctional domain of the renal filtration barrier known as the slit diaphragm. Interesting parallels have been drawn between the slit diaphragm and other sites of cell-cell contact by polarized cells. Notably mutations in several genes encoding proteins localized to the foot processes can lead to proteinuria and kidney failure. Mutations in the Wilm's tumor gene (WT1) can also lead to kidney disease and one isoform of WT1, WT1(+KTS), has been proposed to regulate gene expression post-transcriptionally. We originally sought to identify mRNAs associated with WT1(+KTS) through an RNA immunoprecipitation and microarray approach, hypothesizing that the proteins encoded by these mRNAs might be important for podocyte morphology and function. We identified a subset of mRNAs that were remarkably enriched for transcripts encoding actin-binding proteins and other cytoskeletal proteins including several that are localized at or near the slit diaphragm. Interestingly, these mRNAs included those of α-actinin-4 and non-muscle myosin IIA that are mutated in genetic forms of kidney disease. However, isolation of the mRNAs occurred independently of the expression of WT1, suggesting that the identified mRNAs were serendipitously co-purified on the basis of co-association in a common subcellular fraction. Mass spectroscopy revealed that other components of the actin cytoskeleton co-purified with these mRNAs, namely actin, tubulin, and elongation factor 1α. We propose that these mRNAs encode a number of proteins that comprise a highly specialized protein interactome underlying the slit diaphragm. Collectively, these gene products and their interactions may prove to be important for the structural integrity of the actin cytoskeleton in podocytes as well as other polarized cell types

UN Peacekeeping at 75: Achievements, Challenges, and Prospects

This year marks the 75th anniversary of what the UN itself understands to be its first peacekeeping operation. It is therefore an appropriate time to reflect on the track record of UN peacekeeping in its efforts to try to maintain and realize peace and security. Moreover, this milestone invites us to ponder what lies ahead in the realm of peacekeeping. For this reason, this forum article brings together both academics and UN officials to assess the achievements and challenges of UN peacekeeping over the past 75 years. Through a dialogue among peacekeeping scholars and practitioners, we hope to identify current trends and developments in UN peacekeeping, as well as explore priorities for the future to improve the effectiveness of peacekeeping operations in terms of achieving their mandate objectives, such as maintaining peace, protecting civilians, promoting human rights, and facilitating reconciliation. This forum article is structured into six thematic sections, each shedding light on various aspects of UN peacekeeping: (1) foundational principles of UN peacekeeping - namely, consent, impartiality, and the (non-)use of force; (2) protection of civilians; (3) the primacy of politics; (4) early warning; (5) cooperation with regional organizations; and (6) the changing geopolitical landscape in which UN peacekeeping operates

Pigmentary traits, sun exposure, and risk of non-Hodgkin's lymphoma/chronic lymphocytic leukemia: A study within the French E3N prospective cohort.

To investigate whether risk factors for keratinocyte carcinomas (KCs), namely pigmentary traits and sun exposure, are associated with risk of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL). E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Cancer data were collected at baseline and updated every 2-3 years. Hazard Ratios (HRs) and 95% confidence intervals (CIs) for associations between pigmentary traits and sun exposure, and risk of CLL/NHL were estimated using Cox models. With a median follow-up of 24 years, 622 incident cases of CLL/NHL were ascertained among the 92,097 included women. The presence of nevi was associated with CLL/NHL risk: HR for "many or very many nevi" relative to "no nevi": 1.56 [1.15; 2.11]. Such association with number of nevi appears to be mostly limited to risk of CLL: HR for "many or very many nevi": 3.00 [1.38; 6.52]; versus 1.32 [0.94; 1.84] for NHL. Women whose skin was highly sensitive to sunburn also had a higher risk of CLL: HR = 1.96 [1.21; 3.18], while no increase in risk of NHL was observed. Skin or hair color, number of freckles, and average daily ultraviolet (UV) dose during spring and summer in location of residence at birth or at inclusion (kJ/m2 ) were not associated with CLL/NHL risk. Some pigmentary traits (presence of nevi and skin sensitivity), but not sun exposure, were associated with CLL/NHL. These observations suggest that CLL may share some constitutional risk factors with keratinocyte cancers

La vie des sections : II. - Section de jeunes

Lejamble C., Dangel Jacqueline, Guézennec , Geffray Catherine, Perrin Michel, Gelot Huguette, Zussy Bernard. La vie des sections : II. - Section de jeunes. In: Bulletin de l'Association Guillaume Budé, n°3, octobre 1984. pp. 244-259

La vie des sections : II. - Section de jeunes

Lejamble C., Dangel Jacqueline, Guézennec , Geffray Catherine, Perrin Michel, Gelot Huguette, Zussy Bernard. La vie des sections : II. - Section de jeunes. In: Bulletin de l'Association Guillaume Budé, n°3, octobre 1984. pp. 244-259

Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat

BACKGROUND AND AIMS: Neutrophins are involved in somatic and visceral hypersensitivity. The action of nerve growth factor (NGF) on sensory neurones contributes to the development of referred colonic hypersensitivity induced by trinitrobenzene sulfonic acid (TNBS). Based on data on brain derived neurotrophic factor (BDNF) and calcitonin gene related peptide (CGRP) in pain, the aims of the present study were: (1) to investigate the involvement of BDNF and CGRP in this model of referred colonic hypersensitivity, (2) to test the effect of exogenous BDNF and CGRP on the colonic pain threshold, and (3) to investigate the relationship between BDNF, NGF, and CGRP by testing antineurotrophin antibodies or h‐CGRP 8–37 (a CGRP antagonist) on bowel hypersensitivity induced by these peptides. METHODS: Colonic sensitivity was assessed using a colonic distension procedure. RESULTS: Anti‐BDNF antibody and h‐CGRP 8–37 reversed the induced decrease in colonic threshold (33.4 (2.1) and 40.3 (4.1) mm Hg, respectively, compared with a vehicle score of approximately 18 mm Hg; p<0.001). BDNF (1–100 ng/rat intraperitoneally) induced a significant dose dependent decrease in colonic reaction threshold in healthy rats. This effect was reversed by an anti‐BDNF antibody and an anti‐NGF antibody (33.4 (0.6) v 18.7 (0.7) mm Hg (p<0.001), anti‐NGF v vehicle). NGF induced colonic hypersensitivity was reversed by h‐CGRP 8–37 but not by the anti‐BDNF antibody. Finally, antineurotrophin antibody could not reverse CGRP induced colonic hypersensitivity (at a dose of 1 µg/kg intraperitoneally). CONCLUSION: Systemic BDNF, NGF, and CGRP can induce visceral hypersensitivity alone and interactively. This cascade might be involved in TNBS induced referred colonic hypersensitivity in which each of these peptides is involved

Induction of mu opioid and cannabinoid receptors by probiotics: A new mechanism of regulation of visceral pain perception

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Widespread distribution of beta-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol

Sandhoff disease is a severe inherited neurodegenerative disorder resulting from deficiency of the beta-subunit of hexosaminidases A and B, lysosomal hydrolases involved in the degradation of G(M2) ganglioside and related metabolites. Currently, there is no viable treatment for the disease. Here, we show that adenovirus-mediated transfer of the beta-subunit of beta-hexosaminidase restored Hex A and Hex B activity after infection of Sandhoff fibroblasts. Gene transfer following intracerebral injection in a murine model of Sandhoff disease resulted in near-normal level of enzymatic activity in the entire brain at the different doses tested. The addition of hyperosmotic concentrations of mannitol to the adenoviral vector resulted in an enhancement of vector diffusion in the injected hemisphere. Adenoviral-induced lesions were found in brains injected with a high dose of the vector, but were not detected in brains injected with 100-fold lower doses, even in the presence of mannitol. Our data underline the advantage of the adjunction of mannitol to low doses of the adenoviral vector, allowing a high and diffuse transduction efficiency without viral cytotoxicity

Induction of mu opioid and cannabinoid receptors by probiotics: A new mechanism of regulation of visceral pain perception

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