Conformational dynamics in the disordered region of human CPEB3 linked to memory consolidation.

BACKGROUND: Current understanding of the molecular basis of memory consolidation points to an important function of amyloid formation by neuronal-specific isoforms of the cytoplasmic polyadenylation element binding (CPEB) protein family. In particular, CPEB is thought to promote memory persistence through formation of self-sustaining prion-like amyloid assemblies at synapses, mediated by its intrinsically disordered region (IDR) and leading to permanent physical alterations at the basis of memory persistence. Although the molecular mechanisms by which amyloid formation takes place in CPEB have been described in invertebrates, the way amyloid formation occurs in the human homolog CPEB3 (hCPEB3) remains unclear. Here, we characterize by NMR spectroscopy the atomic level conformation and ps-ms dynamics of the 426-residue IDR of hCPEB3, which has been associated with episodic memory in humans. RESULTS: We show that the 426-residue N-terminal region of hCPEB3 is a dynamic, intrinsically disordered region (IDR) which lacks stable folded structures. The first 29 residues, M1QDDLLMDKSKTQPQPQQQQRQQQQPQP29, adopt a helical + disordered motif, and residues 86-93: P83QQPPPP93, and 166-175: P166PPPAPAPQP175 form polyproline II (PPII) helices. The (VG)5 repeat motif is completely disordered, and residues 200-250 adopt three partially populated α-helices. Residues 345-355, which comprise the nuclear localization signal (NLS), form a modestly populated α-helix which may mediate STAT5B binding. These findings allow us to suggest a model for nascent hCPEB3 structural transitions at single residue resolution, advancing that amyloid breaker residues, like proline, are a key difference between functional versus pathological amyloids. CONCLUSION: Our NMR spectroscopic analysis of hCPEB3 provides insights into the first structural transitions involved in protein-protein and protein-mRNA interactions. The atomic level understanding of these structural transitions involved in hCPEB3 aggregation is a key first step toward understanding memory persistence in humans, as well as sequence features that differentiate beneficial amyloids from pathological ones. AREAS: Biophysics, Structural Biology, Biochemistry & Neurosciences.

S100A7: from mechanism to cancer therapy.

Within the tumor, malignant and stromal cells support each other by secreting a wide variety of growth factors and cytokines, allowing tumor growth and disease progression. The identification and regulation of those key factors in this crosstalk has opened the opportunity to develop new therapeutic strategies that not only act on the tumor cells but also on the stroma. Among these factors, S100A7 protein has gained interest in the last years. With key roles in cell motility its expression correlates with increased tumor growth, angiogenesis and metastatic potential. This work aims to deepen in the role played by extracellular S100A7 in the tumor microenvironment, offering a new integrative insight of its mechanism of action on each cellular compartment (tumor, endothelial, immune and fibroblast). As a result, we demonstrate its implication in cell migration and invasion, and its important contribution to the formation of a proinflammatory and proangiogenic environment that favors tumor progression and metastasis. Furthermore, we define its possible role in the pre-metastatic niche formation. Considering the relevance of S100A7 in cancer progression, we have developed neutralizing monoclonal antibodies, reporting for the first time the proof of principle of this promising therapeutic strategy for cancer treatment.

NFC as a Childhood Obesity Treatment Tool.

Childhood Obesity is associated with a wide range of serious health complications and constitutes an increased risk of premature syndromes, including diabetes or heart diseases. Its treatment seems to be complicated. So, in order to help parents we have developed a system that will try to make easier the process of choosing foodstuff for overweight and obese children at the supermarket. To interact with the system, Near Field Communication mobile phones and tags are used. Those tags would have nutritional information such as energy or fat contain of each product. When the interaction takes place, the system will generate an alert determining if the product is adequate for the user diet or not. Decision will be influenced by specific prescript diets, which would have been previously generated by the system based on user profile parameters. At the same time the diet is established, the shopping list would be generated automatically. Therefore, the user could download and print both things at home easily by the PC application. The system also takes into account physical activity of the user. Children mobile phone includes an accelerometer that will detect and collect user activities in order to modify calorical requirements and, if necessary, to change physical activity too. In the future, it would be possible to extend this project system for adults, managing diets not just for obese and overweight, but also to diabetic or celiac people.

S100P antibody-mediated therapy as a new promising strategy for the treatment of pancreatic cancer.

Despite progresses in diagnosis and treatment, pancreatic cancer continues to have the worst prognosis of all solid malignant tumors. Recent evidences suggest that the metastasis-promoting protein S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression through extracellular functions. Moreover, its expression is strongly correlated with poor prognosis in patients with several types of cancer although the entire molecular mechanism responsible for the diverse biological functions is not fully understood. We showed that extracellular S100P stimulates pancreatic carcinoma BxPC3 cell line by promoting cell proliferation. We also demonstrated that S100P induces, in this cell line, the phosphorylation of IκBα and the secretion of matrix metalloproteinase 9 (MMP-9). In addition, treatment with S100P protected cells from injuries induced by the cytotoxic agent Gemcitabine. On the basis of these results, we developed function-blocking anti-S100P monoclonal antibodies (mAbs) that abolished all of its in vitro activities. Furthermore, in vivo treatment with the candidate 2H8 antibody decreased tumor growth and liver metastasis formation in a subcutaneous and orthotopic BxPC3 tumor model. We conclude here that a therapeutic strategy blocking the extracellular activity of S100P by means of specific mAbs could be an attractive therapeutic approach as a single agent or in combination with target-directed or chemotherapeutic drugs to treat pancreatic cancer.

Efficacy of moxifloxacin in the treatment of bronchial colonisation in COPD.

This study was designed to investigate the efficacy of moxifloxacin for the eradication of bacterial colonisation of the airways in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Out of 119 stable patients with COPD screened, 40 (mean age 69 yrs, mean forced expiratory volume in 1 s 50% predicted) were colonised with potentially pathogenic microorganisms (PPMs) and were included in a randomised, double-blind, placebo-controlled trial with moxifloxacin 400 mg daily for 5 days. Eradication rates were 75% with moxifloxacin and 30% with placebo at 2 weeks (p = 0.01). Bacterial persistence at 8 weeks was still higher (not significantly) in the placebo arm (five (25%) out of 20 versus one (5%) out of 20; p = 0.18). The frequencies of acquisition of a new PPM were high and similar in both treatment groups; consequently, the prevalence of colonisation at 8 weeks was also similar between treatment arms. No difference was found in the number of patients with exacerbations during the 5-month follow-up. Only the acquisition of a new PPM during follow-up showed a statistically significant relationship with occurrence of an exacerbation. Moxifloxacin was effective in eradicating PPMs in patients with positive sputum cultures. However, most patients were recolonised after 8 weeks of follow-up. Acquisition of a new strain of bacteria was associated with an increased risk of developing an exacerbation.

[Fibromuscular dysplasia with moyamoya phenomenon in a patient with Alport's syndrome. A type IV collagen disorder]. / Displasia fibromuscular con fenómeno moyamoya en paciente con síndrome de Alport. Enfermedad del colágeno tipo IV.

INTRODUCTION: Alport's syndrome is a hereditary progressive nephropathy associated with neurosensorial deafness, secondary to mutations of the genes which codify the a chains of collagen IV. In the literature we have found isolated reports of cases with nervous system involvement. CLINICAL CASE: A 37 year old woman was diagnosed as having Alport's syndrome with terminal secondary chronic renal failure and bilateral neurosensorial deafness. She was assessed following repeated transient ischemic attacks of the left hemisphere over the previous three years. Neurological examination was normal. Magnetic resonance showed an ischemic stroke of the left frontal white matter, and on arteriography there was tubular stenosis of the left extracranial internal carotid artery and proximal occlusion of the homolateral anterior and medial cerebral arteries with a compensatory deep vascular network, compatible with fibromuscular dysplasia and secondary moyamoya phenomenon. CONCLUSIONS: Although the association between fibromuscular dysplasia and Alport's syndrome may be casual, we suggest that there may be a common mechanism of pathogenesis in both syndromes, related to the expression of type IV collagen in the vascular basal membranes.

Displasia fibromuscular con fenómeno moyamoya en paciente con síndrome de Alport. Enfermedad del colágeno tipo IV / Fibromuscular dyspasia with moyamoya phenomenon in a patient with alport´s syndrome. A type IV ollagen disorder

Introducción. El síndrome de Alport es una nefropatía progresiva hereditaria asociada a sordera neurosensorial, secundaria a mutaciones en los genes que codifican las cadenas alfa del colágeno IV. En la literatura encontramos casos aislados con afectación del sistema nervioso. Caso clínico. Mujer de 37 años diagnosticada de síndrome de Alport con insuficiencia renal crónica terminal secundaria e hipoacusia neurosensorial bilateral. Fue valorada por accidentes isquémicos transitorios de repetición, hemisféricos izquierdos, en el transcurso de tres años. La exploración neurológica fue normal, mientras que en la resonancia magnética se constata un ictus isquémico en sustancia blanca frontal izquierda, y en la arteriografía una estenosis tubular de la arteria carótida interna izquierda extracraneal y una oclusión proximal de arterias cerebrales anterior y media homolaterales, con red vascular profunda compensadora, compatible con displasia fibromuscular con fenómeno moyamoya secundario. Conclusiones. Aunque esta asociación entre la displasia fibromuscular y el síndrome de Alport puede ser casual, planteamos la posibilidad de que exista un mecanismo común en la patogénesis de ambos síndromes, relacionado con la expresión del colágeno tipo IV en las membranas basales vasculares (AU)

Introduction. Alport’s syndrome is a hereditary progressive nephropathy associated with neurosensorial deafness, secondary to mutations of the genes which codify the a chains of collagen IV. In the literature we have found isolated reports of cases with nervous system involvement. Clinical case. A 37 year old woman was diagnosed as having Alport’s syndrome with terminal secondary chronic renal failure and bilateral neurosensorial deafness. She was assessed following repeated transient ischemic attacks of the left hemisphere over the previous three years. Neurological examination was normal. Magnetic resonance showed an ischemic stroke of the left frontal white matter, and on arteriography there was tubular stenosis of the left extracranial internal carotid artery and proximal occlusion of the homolateral anterior and medial cerebral arteries with a compensatory deep vascular network, compatible with fibromuscular dysplasia and secondary moyamoya phenomenon. Conclusions. Although the association between fibromuscular dysplasia and Alport’s syndrome may be casual, we suggest that there may be a common mechanism of pathogenesis in both syndromes, related to the expression of type IV collagen in the vascular basal membranes (AU)

[The prediction of the degree of metabolic control by minimal technical norms in a diabetes program]. / Predicción del grado de control metabólico por las normas técnicas mínimas en el programa de diabetes.

OBJECTIVE: To assess whether scores on the minimum technical norms (MTN) of the diabetes mellitus programme are of use in determining the level of metabolic control achieved. DESIGN: A retrospective study. SETTING: Two teaching health centres in the city of Santander. PATIENTS AND OTHER PARTICIPANTS: 204 patients, the total chosen by the Santander area management for the 1994 annual evaluation of the Diabetes programme. MEASUREMENTS AND RESULTS: The values reached by the variables of the MTN were measured. For a control criterion we took the value of glycosylated haemoglobin HbA1C or over. 52% of patients fulfilled the criteria of good control, 20% acceptable and 28% bad. CONCLUSIONS: Scoring on the MTN has little value in predicting lower values of HbA1C and is no use in assessing the level of metabolic control achieved by the Diabetes programme. The evaluation of the programme should include results indicators.