PS Integrins and Laminins: Key Regulators of Cell Migration during Drosophila Embryogenesis

During embryonic development, there are numerous cases where organ or tissue formation depends upon the migration of primordial cells. In the Drosophila embryo, the visceral mesoderm (vm) acts as a substrate for the migration of several cell populations of epithelial origin, including the endoderm, the trachea and the salivary glands. These migratory processes require both integrins and laminins. The current model is that αPS1βPS (PS1) and/or αPS3βPS (PS3) integrins are required in migrating cells, whereas αPS2βPS (PS2) integrin is required in the vm, where it performs an as yet unidentified function. Here, we show that PS1 integrins are also required for the migration over the vm of cells of mesodermal origin, the caudal visceral mesoderm (CVM). These results support a model in which PS1 might have evolved to acquire the migratory function of integrins, irrespective of the origin of the tissue. This integrin function is highly specific and its specificity resides mainly in the extracellular domain. In addition, we have identified the Laminin α1,2 trimer, as the key extracellular matrix (ECM) component regulating CVM migration. Furthermore, we show that, as it is the case in vertebrates, integrins, and specifically PS2, contributes to CVM movement by participating in the correct assembly of the ECM that serves as tracks for migration

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Integrin-ECM interactions regulate the changes in cell shape driving the morphogenesis of the Drosophila wing epithelium

During development, morphogenesis involves migration and changes in the shape of epithelial sheets, both of which require coordination of cell adhesion. Thus, while modulation of integrin-mediated adhesion to the ECM regulates epithelial motility, cell-cell adhesion via cadherins controls the remodelling of epithelial sheets. We have used the Drosophila wing epithelium to demonstrate that cell-ECM interactions mediated by integrins also regulate the changes in cell shape that underly epithelial morphogenesis. We show that integrins control the transitions from columnar to cuboidal cell shape underlying wing formation, and we demonstrate that eliminating the ECM has the same effect on cell shape as inhibiting integrin function. Furthermore, lack of integrin activity also induces detachment of the basal lamina and failure to assemble the basal matrix. Hence, we propose that integrins control epithelial cell shape by mediating adherence of these cells to the ECM. Finally, we show that the ECM has an instructive rather than a structural role, because inhibition of Raf reverses the cell shape changes caused by perturbing integrins.This work was supported by grants awarded to M.D.M.B.: a Project Grant 054613 from the Wellcome Trust, a Royal Society University Research Fellowship (516002.K5510), a project grant (BMC2001- 2298) from the Spanish Ministery of Science and Technology and a European Molecular Biology Organization Young Investigator Award

Cell consequences of loss of function of the epigenetic factor EHMT1

EHMT1 is an epigenetic factor with histone methyltransferase activity that appears mutated in Kleefstra syndrome, a neurodevelopmental genetic disorder characterized by developmental delay, intellectual disability, and autistic-like features. Despite recent progress in the study of the function of this gene and the molecular etiology of the disease, our knowledge of how EHMT1 haploinsufficiency causes Kleefstra syndrome is still very limited. Here, we show that EHMT1 depletion in RPE1 cells leads to alterations in the morphology and distribution of different subcellular structures, such as the Golgi apparatus, the lysosomes and different cell adhesion components. EHMT1 downregulation also increases centriolar satellites detection, which may indicate a role for EHMT1 in centrosome functioning. Furthermore, the migration process is also altered in EHMT1 depleted cells, which show reduced migration capacity. We consider that the described phenotypes could open new possibilities for understanding the functional impact of EHMT1 haploinsufficiency in Kleefstra syndrome, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in this neurodevelopmental disorder. This knowledge could be relevant not only for the treatment of this syndrome, but also for other neurodevelopmental conditions that could share similar deregulated cellular pathways.This study was funded by the University of Seville (Ayudas a Proyectos Precompetitivos del VI Plan Propio de Investigación granted to S. Rivero)

Uso de heptapéptidos para el control de la hipertensión

La presente invención se refiere a heptapéptidos inhibidores de la enzima conversora de angiotensina (ECA). También se refiere al proceso de producción de los péptidos de la invención mediante estrategias biotecnológicas, por lo que además se refiere al ácido nucleico, al cassette de expresión y al vector que los codifican, así como a la célula hospedadora que los comprende. Así mismo también se refiere al uso de los péptidos para la prevención y/o el tratamiento de la hipertensión así como a la composición farmacéutica que los comprende.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Fundación para la Investigación del Hospital la Fe de ValenciaA1 Solicitud de patente con informe sobre el estado de la técnic

Cerebellin 4, a synaptic protein, enhances inhibitory activity and resistance of neurons to amyloid-ß toxicity

Imbalances between excitatory and inhibitory transmissions in the brain anticipate the neuronal damage and death that occur in the neurodegenerative diseases like Alzheimer's disease (AD). We previously showed that amyloid-β (Aß), a natural peptide involved in the onset and development of AD, counteracts the neurotrophic activity of the nerve growth factor (NGF) by dampening the γ-aminobutyric acid (GABA)ergic connectivity of cultured hippocampal neurons. Neuronal plasticity is partly controlled by the NGF-promoted expression of the homologue of enhancer-of-split 1 (Hes1), a transcription factor that regulates the formation of GABAergic synapses. We now show that Hes1 controls the expression of cerebellin 4 (Cbln4), a member of a small family of secreted synaptic proteins, and we present the evidence that Cbln4 plays an essential role in the formation and maintenance of inhibitory GABAergic connections. Cbln4 immunoreactivity was found in the hippocampus, mostly in the dendrites and somata of pyramidal neurons. In the CA1, the hippocampal region where the first neurons degenerate in AD, Cbln4 immunoreactivity was associated with GABAergic synapses (detected by vesicular inhibitory amino acid transporter [VGAT] immunostaining), which appear to surround and embrace the somata of CA1 pyramidal neurons (basket cells). Moreover, significant decreases of Hes1, Cbln4, and VGAT immunoreactivities and messenger RNA expression were found in the hippocampus of a mouse model of AD. We also found that either the overexpression of Cbln4 in cultured hippocampal neurons or the application of recombinant Cbln4 to the cultures increased the number of GABAergic varicosities, rescuing neurons from Aß-induced death. In contrast, knockdown of Cbln4 gene in cultured neurons was followed by a large reduction of GABAergic connections. Such an effect was reverted by exogenously added Cbln4. These findings suggest a therapeutic potential for Cbln4 in the treatment of AD.P.J. Chacon was supported by the Instituto de Salud Carlos III (Contratos Post-Doctorales Sara Borrell grant no. CD08/00078) and AM by a Proyecto de Excelencia of the Government of Andalusia. This work was financed by the Spanish Ministry of Education and Science (grants BFU2010-20995 and BFU2011-30217-C03-01) and the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (grant P10-CVI-6740)

Heptapéptidos y su uso para el control de la hipertensión

[EN] The present invention relates to angiotensin-converting-enzyme (ACE) inhibitor heptapeptides. The invention also relates to the process for producing the peptides of the invention by means of biotechnological strategies and therefore, furthermore, relates to the nucleic acid, the expression cassette and the vector that encodes said peptides, and also to the host cell that comprises said peptides. Moreover, the invention also relates to the use of the peptides for preventing and/or treating hypertension and also to the pharmaceutical composition that comprises said peptides.[ES] La presente invención se refiere a heptapéptídos inhibidores de la enzima conversora de angiotensina (ECA). También se refiere al proceso de producción de los péptidos de la invención mediante estrategias biotecnológicas, por lo que además se refiere al ácido nucleico, al cassette de expresión y al vector que los codifican, así como a la célula hospedadora que los comprende. Así mismo también se refiere al uso de los péptidos para la prevención y/o el tratamiento de la hipertensión así como a la composición farmacéutica que los comprende.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Fundación para la Investigación del Hospital la Fe de ValenciaA1 Solicitud de patente con informe sobre el estado de la técnic

Fracción de bajo peso molecular de un hidrolizado de lactoferrina para el tratamiento de la hipertensión

[EN] The invention relates to a method for obtaining the lactoferrin hydrolysate fraction with a molecular weight of less than 3000 Da, comprising several peptides. The invention also relates to the lactoferrin hydrolysate fraction that can be obtained by said method and sorne of the peptides that it includes. The invention further relates to the use of said fraction and peptides for producing medicaments for the prevention and/or treatment of hypertension, and food or food supplements.[ES] La invención se refiere a un método para obtener la fracción de paso molecular inferior a 3000 Da de un hidrolizado de lactoferrina, el cual comprende diversos péptidos. La invención también engloba la fracción del hidrolizado de lactoferrina obtenible por dicho método y algunos de los peptidos que incluye, asi como al uso de dicha fracción y péptidos para la elaboración de medicamentos para la prevención y/o el tratamiento de la hipertensión, asi como alimentos o suplementos alimenticios.Peer reviewedConsejo Superior de Investigaciones Científicas, Fundación para la Invetigación del Hospital la Fe de ValenciaA1 Solicitud de patente con informe sobre el estado de la técnic

Clinical Presentation and Short- and Long-term Outcomes in Patients With Isolated Distal Deep Vein Thrombosis vs Proximal Deep Vein Thrombosis in the RIETE Registry

International audienceImportance: Insufficient data exist about the clinical presentation, short-term, and long-term outcomes of patients with isolated distal deep vein thrombosis (IDDVT), that is, thrombosis in infrapopliteal veins without proximal extension or pulmonary embolism (PE).Objective: To determine the clinical characteristics, short-term, and 1-year outcomes in patients with IDDVT and to compare the outcomes in unadjusted and multivariable adjusted analyses with patients who had proximal DVT.Design, setting, and participants: This was a multicenter, international cohort study in participating sites of the Registro Informatizado Enfermedad Tromboembólica (RIETE) registry conducted from March 1, 2001, through February 28, 2021. Patients included in this study had IDDVT. Patients with proximal DVT were identified for comparison. Patients were excluded if they had a history of asymptomatic DVT, upper-extremity DVT, coexisting PE, or COVID-19 infection.Main outcomes and measures: Primary outcomes were 90-day and 1-year mortality, 1-year major bleeding, and 1-year venous thromboembolism (VTE) deterioration, which was defined as subsequent development of proximal DVT or PE.Results: A total of 33 897 patients were identified with isolated DVT (without concomitant PE); 5938 (17.5%) had IDDVT (mean [SD] age, 61 [17] years; 2975 male patients [50.1%]), and 27 959 (82.5%) had proximal DVT (mean [SD] age, 65 [18] years; 14 315 male patients [51.2%]). Compared with individuals with proximal DVT, those with IDDVT had a lower comorbidity burden but were more likely to have had recent surgery or to have received hormonal therapy. Patients with IDDVT had lower risk of 90-day mortality compared with those with proximal DVT (odds ratio [OR], 0.47; 95% CI, 0.40-0.55). Findings were similar in 1-year unadjusted analyses (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59) and adjusted analyses (HR, 0.72; 95% CI, 0.64-0.82). Patients with IDDVT had a lower 1-year hazard of VTE deterioration (HR, 0.83; 95% CI, 0.69-0.99). In 1-year adjusted analyses of patients without an adverse event within the first 3 months, IDDVT was associated with lower risk of VTE deterioration (adjusted HR, 0.48; 95% CI, 0.24-0.97). By 1-year follow-up, symptoms or signs of postthrombotic syndrome were less common in patients with IDDVT (47.6% vs 60.5%).Conclusions and relevance: Results of this cohort study suggest that patients with IDDVT had a less ominous prognosis compared with patients with proximal DVT. Such differences were likely multifactorial, including the differences in demographics, risk factors, comorbidities, particularly for all-cause mortality, and a potential association of thrombus location with VTE deterioration and postthrombotic syndrome. Randomized clinical trials are needed to assess the optimal long-term management of IDDVT