Podoplanin Associates with CD44 to Promote Directional Cell Migration

Podoplanin, a cancer-associated glycoprotein, interacts with CD44. Both glycoproteins are coordinately upregulated during tumor progression. Podoplanin–CD44 interaction in the cell membrane occurs mainly in migrating cells, and it seems to be required for podoplanin-mediated cell migration and directionality

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Crustal recycling by subduction erosion in the central Mexican Volcanic Belt

Recycling of upper plate crust in subduction zones, or ‘subduction erosion’, is a major mechanism of crustal destruction at convergent margins. However, assessing the impact of eroded crust on arc magmas is difficult owing to the compositional similarity between the eroded crust, trench sediment and arc crustal basement that may all contribute to arc magma formation. Here we compare Sr–Nd–Pb–Hf and trace element data of crustal input material to Sr–Nd–Pb–Hf–He–O isotope chemistry of a well-characterized series of olivine-phyric, high-Mg# basalts to dacites in the central Mexican Volcanic Belt (MVB). Basaltic to andesitic magmas crystallize high-Ni olivines that have high mantle-like 3He/4He = 7–8 Ra and high crustal δ18Omelt = +6.3–8.5‰ implying their host magmas to be near-primary melts from a mantle infiltrated by slab-derived crustal components. Remarkably, their Hf–Nd isotope and Nd/Hf trace element systematics rule out the trench sediment as the recycled crust end member, and imply that the coastal and offshore granodiorites are the dominant recycled crust component. Sr–Nd–Pb–Hf isotope modeling shows that the granodiorites control the highly to moderately incompatible elements in the calc-alkaline arc magmas, together with lesser additions of Pb- and Sr-rich fluids from subducted mid-oceanic ridge basalt (MORB)-type altered oceanic crust (AOC). Nd–Hf mass balance suggests that the granodiorite exceeds the flux of the trench sediment by at least 9–10 times, corresponding to a flux of ⩾79–88 km3/km/Myr into the subduction zone. At an estimated thickness of 1500–1700 m, the granodiorite may buoyantly rise as bulk ‘slab diapirs’ into the mantle melt region and impose its trace element signature (e.g., Th/La, Nb/Ta) on the prevalent calc-alkaline arc magmas. Deep slab melting and local recycling of other slab components such as oceanic seamounts further diversify the MVB magmas by producing rare, strongly fractionated high-La magmas and a minor population of high-Nb magmas, respectively. Overall, the central MVB magmas inherit their striking geochemical diversity principally from the slab, thus emphasizing the importance of continental crust recycling in modern solid Earth relative to its new formation in modern subduction zones

The life and scientific work of William R. Evitt (1923-2009)

Occasionally (and fortunately), circumstances and timing combine to allow an individual, almost singlehandedly, to generate a paradigm shift in his or her chosen field of inquiry. William R. (‘Bill’) Evitt (1923-2009) was such a person. During his career as a palaeontologist, Bill Evitt made lasting and profound contributions to the study of both dinoflagellates and trilobites. He had a distinguished, long and varied career, researching first trilobites and techniques in palaeontology before moving on to marine palynomorphs. Bill is undoubtedly best known for his work on dinoflagellates, especially their resting cysts. He worked at three major US universities and spent a highly significant period in the oil industry. Bill's early profound interest in the natural sciences was actively encouraged both by his parents and at school. His alma mater was Johns Hopkins University where, commencing in 1940, he studied chemistry and geology as an undergraduate. He quickly developed a strong vocation in the earth sciences, and became fascinated by the fossiliferous Lower Palaeozoic strata of the northwestern United States. Bill commenced a PhD project on silicified Middle Ordovician trilobites from Virginia in 1943. His doctoral research was interrupted by military service during World War II; Bill served as an aerial photograph interpreter in China in 1944 and 1945, and received the Bronze Star for his excellent work. Upon demobilisation from the US Army Air Force, he resumed work on his PhD and was given significant teaching duties at Johns Hopkins, which he thoroughly enjoyed. He accepted his first professional position, as an instructor in sedimentary geology, at the University of Rochester in late 1948. Here Bill supervised his first two graduate students, and shared a great cameraderie with a highly motivated student body which largely comprised World War II veterans. At Rochester, Bill continued his trilobite research, and was the editor of the Journal of Paleontology between 1953 and 1956. Seeking a new challenge, he joined the Carter Oil Company in Tulsa, Oklahoma, during 1956. This brought about an irrevocable realignment of his research interests from trilobites to marine palynology. He undertook basic research on aquatic palynomorphs in a very well-resourced laboratory under the direction of one of his most influential mentors, William S. ‘Bill’ Hoffmeister. Bill Evitt visited the influential European palynologists Georges Deflandre and Alfred Eisenack during late 1959 and, while in Tulsa, first developed several groundbreaking hypotheses. He soon realised that the distinctive morphology of certain fossil dinoflagellates, notably the archaeopyle, meant that they represent the resting cyst stage of the life cycle. The archaeopyle clearly allows the excystment of the cell contents, and comprises one or more plate areas. Bill also concluded that spine-bearing palynomorphs, then called hystrichospheres, could be divided into two groups. The largely Palaeozoic spine-bearing palynomorphs are of uncertain biological affinity, and these were termed acritarchs. Moreover, he determined that unequivocal dinoflagellate cysts are all Mesozoic or younger, and that the fossil record of dinoflagellates is highly selective. Bill was always an academic at heart and he joined Stanford University in 1962, where he remained until retiring in 1988. Bill enjoyed getting back into teaching after his six years in industry. During his 26-year tenure at Stanford, Bill continued to revolutionise our understanding of dinoflagellate cysts. He produced many highly influential papers and two major textbooks. The highlights include defining the acritarchs and comprehensively documenting the archaeopyle, together with highly detailed work on the morphology of Nannoceratopsis and Palaeoperidinium pyrophorum using the scanning electron microscope. Bill supervised 11 graduate students while at Stanford University. He organised the Penrose Conference on Modern and Fossil Dinoflagellates in 1978, which was so successful that similar meetings have been held about every four years since that inaugural symposium. Bill also taught many short courses on dinoflagellate cysts aimed at the professional community. Unlike many eminent geologists, Bill actually retired from actively working in the earth sciences. His full retirement was in 1988; after this he worked on only a small number of dinoflagellate cyst projects, including an extensive paper on the genus Palaeoperidinium

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Autistic-like behavior in a mouse model with impaired ß-neurexin-1 function

Póster presentado en el 15º Congreso de la Sociedad Española de Neurociencia (SENC 2013) celebrado en Oviedo del 25 al 27 de septiembre de 2013.Peer Reviewe

Molecular and behavioral characterization of transgenic mice with impaired beta-neurexin-1 function as a mouse model of autism

Póster presentado en el Workshop "Current Trends in Biomedicina", celebrado en Baeza en octubre de 2013.Synaptic circuitry in the brain is formed early during postnatal development and is continuously remodeled in the adult as a consequence of synaptic activity. Defects in synaptic function lie at the molecular basis of several disorders, including autism spectrum disorders (ASD). ASD are characterized by impairments in verbal and non-verbal communication and social interaction, and restricted and stereotyped patterns of behavior, interests and activities. The identification of mutations in neuroligin, neurexin and SHANK genes in patients with ASD has indicated a role of these proteins in autism. Neurexins are presynaptic partners of several postsynaptic proteins, including neuroligins. The characterization of the functional consequences of autism-associated mutations has led us to suggest a role for synaptic deficits of ß-neurexin-1 as a risk factor for autism (1). To analyze the impact of impaired ß-neurexin-1 function in ASD, we have generated a transgenic mouse line that expresses a mutant ß-neurexin-1 protein (HA-ßNrx1¿C) expected to function in a dominant-negative manner. In TRE-ßNrx1¿C mice, the expression of HA-ßNrx1¿C is controlled by the inducible TRE promoter. Here, we show inducible expression of HA-ßNrx1¿C in postnatal forebrain neurons of double transgenic TRE-HA-ßNrx1¿C; CAMKII¿tTA mice. In immunostaining experiments, HA-ßNrx1¿C is expressed in cortex and striatum. In cortical synaptosomes, HA-ßNrx1¿C is localized at presynaptic fractions, indicating incorporation of the mutant ß-neurexin-1 protein at presynaptic terminals in vivo. Moreover, we have evaluated the behavioral phenotype of TRE-HA-ßNrx1¿C; CamKII-tTA mice compared to control littermate mice and how they can be rescued by turning-off the transgene. The generation of a mouse model with inducible expression of a ß-neurexin-1 dominant negative mutant, such as the one described here, may help answering to what extent behavioral defects due to ß-neurexin-1 dysfunction can be rescued by recovering normal ß-neurexin-1 function. 1. Camacho-Garcia et al. Mutations affecting synaptic levels of neurexin-1ß in autism and mental retardation. Neurobiol. Dis.2012 Jul; 47 (1):135-43.Peer Reviewe

Generation of a transgenic mouse model to inhibit the function of beta-neurexin-1, a gene involved in autism spectrum disorders

Póster presentado en la International Meeting for Autism Research, celebrado en San Sebastián en mayo de 2013.[Background] Synapses are established with precision during brain development and are constantly remodeled as a consequence of synaptic activity in the adult networks. Synaptic dysfunction underlies the molecular basis of several neurodevelopmental disorders, such as autism spectrum disorders (ASD). Trans-synaptic adhesion systems can regulate synaptic function, as they organize pre- and postsynaptic protein complexes. One of these adhesion systems is formed by neurexins and neuroligins. These proteins promote the assembly and maturation of synapses through a bidirectional mechanism. In mammals, neurexins are encoded by three genes with two alternative promoters, which produce the long (alpha-neurexins) and the short (beta-neurexins) isoforms. In addition, alternative splicing in the extracellular domain contributes to generate hundreds of neurexins isoforms. Despite the high heterogeneity of the extracellular region, the cytoplasmic domain is common to all neurexin isoforms and it is thought to regulate intracellular signalling. The relevance of neurexins in neurodevelopmental disorders has been highlighted by the identification of mutations in neurexin genes in ASD. Recently, we have suggested a role for synaptic defects of beta-neurexin-1 as a risk factor for autism and mental retardation.[Objectives] To characterize in cultured neurons the effect of a beta-neurexin-1 dominant negative mutant that lacks the cytoplasmic tail (HA-bNrxDC). To inhibit the function of beta-neurexin-1 in vivo by expressing the HA-bNrxDC mutant. To characterize the behavioral phenotype of a double transgenic mice expressing an inducible form of the HA-bNrx1DC mutant (TRE-HA-bNrx1DC/CamKII-tTA).[Methods] In vitro studies have been performed in hippocampal neurons at 10-14 DIV isolated from 18-19 embryonic day rat brains. For in vivo studies we have generated a transgenic mouse line that expresses a HA-tagged beta-neurexin-1 mutant lacking the cytoplasmic domain (HA-bNrx1DC) under the control of the inducible TRE promoter. The TRE-HA-bNrx1DC transgenic mice have been crossed with CAMKII ¿tTA animals to direct the expression of the mutant protein to glutamatergic terminals in vivo.[Results] Our in vitro results suggest that HA-bNrx1DC mutant can function as a dominant negative mutant as it can be recruited to the membrane of glutamatergic synapses through interaction with neuroligin-1, but it inhibits intracellular signalling mediated by the cytoplasmic tail. In vivo we show expression of HA-bNrx1DC in the cortex and hippocampal formation by immunolocalization. Moreover, we have evaluated the behavioral consequences of the lack of beta-neurexin-1 function in TRE-HA-bNrx1DC/CamKII-tTA double transgenic mice.[Conclusions] Inducible expression of a beta-neurexin-1 dominant negative mutant might have implications in the study of autism, as it may help answering to what extent synaptic and behavioral defects due to beta-neurexin-1 dysfunction can be rescued by resuming normal beta-neurexin-1 function.Peer Reviewe

Papel de la proteína de adhesión sináptica neurexina 1 en autismo

1 página. IX Jornadas Andaluzas Salud Investiga. Cádiz 20-22 octubre, 2010.El Trastorno del Espectro Autista (TEA) es un conjunto de síndromes del desarrollo que se caracterizan por déficit en la interacción social, comunicación restringida y comportamientos estereotipados. Hasta un 70% de los casos están asociados a retraso mental. La mayor parte de los casos de TEA se enmarcan dentro de las enfermedades complejas, causadas por la combinación de alelos de susceptibilidad y factores ambientales. Se han identificado mutaciones y variaciones estructurales en genes que codifican proteínas sinápticas, como las neurexinas, que podrían incrementar el riesgo a desarrollar la enfermedad. Los objetivos de nuestro estudio son entender el mecanismo de acción de neurexina-1 beta (NRXN1β) en el desarrollo del TEA.Peer reviewe

The inactivation of PS activity affects vesicle release at neurexinneuroligin synapsis by abnormal processing of neurexins

Póster presentado en el Workshop "Current Trends in Biomedicina", celebrado en Baeza en octubre de 2013.Peer Reviewe