The Effects of Molecular Chaperones on Tau Fibril Assembly

The accumulation of microtubule-associated protein tau into fibrillar aggregates is the hallmark of Alzheimer’s disease and other neurodegenerative disorders, collectively referred to as tauopathies. Fibrils can propagate from one cell to the next and spread throughout the brain. However, a study shows that only small aggregates can be taken up by cultured neuronal cells. The mechanisms that lead to the breakage of fibrils into smaller fragments remain unknown. In yeast, the AAA+ chaperone HSP104 processes the reactivation of protein aggregates and is responsible for fragmentation of fibrils. This study focused on investigating the effects of molecular chaperones on tau fibrils and using HSP104 as a model system to test whether we can monitor fibril fracturing. The assays used to detect the chaperone’s actions on tau utilized acrylodan fluorescence, thioflavin T fluorescence, and sedimentation. Tau fibrils were either formed with a cofactor, heparin, to accelerate assembly or without a cofactor. In the process of investigating the effects of HSP104 on tau fibrils, this study established an assay to determine the effects of breakage on the seeding properties of tau fibrils. Our findings demonstrated that the sonication of tau fibrils produces smaller fragments (seeds) that accelerate the conversion of monomeric tau into fibrils. The use of this assay with HSP104 provided evidence that HSP104 inhibits the elongation of tau fibrils. Indeed, HSP104 inhibits the aggregation of soluble tau into aggregates. However, tau fibril breakage and dissociation were not observed with HSP104, either alone or in combination with co-chaperones (HSP70 and HSP40). Our findings provide insights into the seeding properties of tau fibrils, and suggest that fragmentation is a critical part of tau assembly. This knowledge should be valuable for understanding tau fibril aggregation and propagation in the brain, which is necessary to identify new treatments for neurodegenerative diseases.

La tardía emergencia mediática de la vacuna contra la viruela, cobertura de noticias en prensa española (1999-2004)

Introducción. Las discusiones sobre la necesidad de conservación del virus de la viruela en 1999 pusieron de actualidad una enfermedad erradicada veinte años atrás. El escenario de alarma internacional creado tras los incidentes del 11-S en EE.UU vino a resituar a la viruela como potencial candidata para ser utilizada como arma bioterrorista. La consecuencia directa fue la reactivación de una vacuna que permanecía en el olvido y cuyos destinatarios iniciales eran los cuerpos de seguridad estadounidenses. España también se interesó por adquirir la vacuna antivariólica. El objetivo de este estudio es valorar la cobertura mediática que la viruela obtuvo en nuestro país. Métodos. Revisión sistemática en la base documental Dow Jones Factiva de las noticias publicadas durante el periodo 1999-2004 en los cuatro diarios de mayor tirada nacional (ABC, El Mundo, El País y La Vanguardia), utilizando como palabra clave “viruela”. Se efectuó un análisis cuantitativo y cualitativo de los datos obtenidos. Resultados. Se analizaron 416 noticias. El Mundo, con un total de 158 (37.98%), fue el diario con más publicaciones. El mayor número de noticias (152, 36,5%) se editaron en 2003, coincidiendo con la adquisición de vacunas por España. El tipo de mensajes emitidos fue variable a lo largo del sexenio, predominando los relacionados con “diplomacia y política”, “riesgo epidemiológico”, “bioterrorismo” y “vacuna”, concentrados en años diferentes. Conclusiones. La alarma creada en torno a la vacunación antivariólica fue un fenómeno mediático que obedeció a cuestiones de estrategia política más que a un problema real de salud pública.

Biologic therapies and non-melanoma skin cancer rates in three chronic immune-mediated diseases

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Linfoma não Hodgkin da órbita : o sucesso de um caso raro

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

On the periphery of global jihad. The North Caucasus: the illusion of stabilisation. OSW Point of View Number 45, November 2014

The situation in the North Caucasus has stabilised, in comparison with previous years, mainly as regards the activity of the Islamic military underground. This is an effect of ideological changes among the militants which have led to a dilution of the Caucasian armed struggle and its marginalisation in global jihad, since top priority has been granted to the Middle Eastern front. The factors which have contributed to this stabilisation are the organisational crisis in the Caucasus Emirate and the outflux of militants to the Middle East, as well the successful ‘carrot and stick’ policy adopted by Moscow. However, the partial stabilisation in the Caucasus is inherently precarious, being a contingent outcome of the situation rather than the result of systemic change. The region’s pressing problems remain unresolved; and these problems are generating chronic instability and cauing the Caucasus to drift away from Russia in civilisational terms. An economic or political crisis in the Russian Federation may result in the conflicts in the Caucasus unfreezing, including a reactivation of the idea of Chechen independence as well as the idea of the Caucasus Emirate, which is a part of global jihad.

Ramzanistan. Russia's Chechen Problem. OSW POINT OF VIEW Number 54, 2015-08-25

The political activity and growing independence of Chechnya’s leader Ramzan Kadyrov raises questions about his loyalty and the possibility of his openly renouncing his servitude to Moscow. Such a scenario seems unlikely because of the dependence of Kadyrov’s regime on Russia. He is burdened by his republic’s financial dependence, the stain of collaboration and the crimes committed on his own people, and so his regime cannot exist without Moscow’s support. However, Kadyrov’s dependence on Moscow and the apparent stability of the situation in Chechnya do not mean that a lasting peace has been established there. The current plan for governing the republic and the relationship between Moscow and Grozny is a temporary solution, based not on durable solutions, but on the situational convergence of the Kremlin and Kadyrov’s interests. A change of government in the Kremlin, or to an even greater degree a domestic crisis in Russia which weakens its position in the Caucasus, would mean the fall of Kadyrov’s regime, and the reactivation of pro-independence rhetoric in Chechnya.

The Commissioners’ Group on External Action – Key political facilitator. CEPS Special Report No. 125/December 2015

The reactivation of the Commissioners’ Group on External Action (CGEA) is one of the most important institutional initiatives in EU foreign policy-making since the merger of the position of the High Representative for CFSP with that of Vice-President of the Commission and the creation of the European External Action Service. In this report the authors examine the mandate and organisation of the CGEA and note that, in its first year of activity, the Group has injected much-needed political pragmatism into the way the Commission contributes to EU external action, thereby facilitating inter-service cooperation both within the Commission and with the EEAS. They argue that the CGEA has in fact become the logical counterpart to the Foreign Affairs Council, which allows the HRVP to deliver on her duty to assist the Council and the Commission in ensuring a comprehensive approach to EU external action, as indeed consistency in its implementation.

Sandbox experiments on basin inversion: testing the influence of basin orientation and basin fill

Analogue modelling experiments using brittle materials are performed to study the inversion of extensional structures. Asymmetric grabens of two different orientations are first created during a phase of extension and progressively filled. They are subsequently shortened in the same direction. The aim of our experiments is to determine factors affecting the style of deformation during inversion. We specifically investigate variations in thickness and distribution of strong and weak layers constituting the graben fill and in initial basin orientation. The main advantage of our experimental set-up is that we have a complete control on graben location, width, infill and orientation before inversion. The experiments show that shortening results only in limited reactivation of pre-existing normal faults. In general, forward thrusts and backthrusts cut across normal faults into the footwall of the graben. The forward thrusts either propagate parallel to the enveloping surface of faulted blocks or they cut across basin-limiting normal faults at various angles. The graben fill is mechanically extruded by displacement along forward thrusts that accommodate most of the shortening. Both pre-existing faults and weak graben fill act as zones of weakness during inversion and determine the orientation and location of both backthrusts and forward thrusts. The results of our experiments conform well to natural examples of inverted graben structures.

An insight into the breakup of Gondwana: Identifying events through low-temperature thermochronology from the basement rocks of Madagascar

Fission track analysis was applied to the Precambrian suites of Madagascar in order to identify the lower-temperature cooling histories and their relationships to the Phanerozoic events that affected the island. Apatite ages range from 431 to 68 Ma, and zircon ages range from 452 to 238 Ma. Thermochronologically, the island can be divided into a southern, central, and northern region each with a subdivision on an east-west basis. The southern region is sharply separated from the central region by strongly contrasting apparent apatite ages over the northwest-southeast striking Ranotsara Shear Zone (RSZ). The change in apparent ages over the RSZ is indicative of later reactivation along younger brittle faults. The central region has the oldest ages of the island and has a diffuse contact to the third region northward. Along the entire western margin of the Precambrian basement initial Paleozoic exhumation was followed by heating (burial by sediments) during Jurassic and Cretaceous times. A decrease in ages along the eastern margin from 119 to 68 Ma coincides with the predicted positions of the Marion hot spot after effects of erosion are considered. On the other hand, these ages may represent progressive opening of the margin in a southward direction together with associated denudation of the rift shoulder. The eastern part of the central region has remained very stable since at least Devonian times, undergoing only long-term very slow exhumation at rates of 1–5 m/Myr.

(Table T1) Ages of white mica clasts in core samples of ODP Hole 210-1276A

Fifty-seven white mica clasts were separated from five samples taken from near the bases of turbidites ranging in age from early Albian to middle Eocene. Twenty two (39%) of the micas have ages between 260 and 340 Ma and five (9%) have older ages (~400-600 Ma). The former age range is characteristic of the North American Alleghenian orogeny and the Iberian Variscan orogeny. The latter range is characteristic of the North American Acadian orogeny and older basement rocks in the Grand Banks and Newfoundland areas. Both age ranges are present in the middle Eocene sample, but only the younger range occurs in the middle Albian sample. This difference could be a sampling artifact. If this is not the case, then the most likely explanation is that the Acadian-aged micas within the Meguma Zone underlying the Grand Banks were totally reset by Alleghenian reactivation of the zone, a feature which occurs extensively in Nova Scotia. The addition of Acadian-aged micas in the middle Eocene sample may reflect a change in sediment provenance as drainage systems unrelated to rift topography developed. With the exception of one clast dated at 186 Ma, the 12 other micas obtained from the upper Paleocene sample yielded ages between 55 and 74 Ma, with 7 falling within ±2 m.y. of the 57-Ma age of the sample indicated by the biostratigraphic age-depth plot for Site 1276. This, together with the volcaniclastic content of the sample, indicates an input from near-contemporaneous volcanism. The nearest known occurrences of near-contemporaneous late Paleocene volcanism that could have produced white micas are in Greenland and Portugal, some 2000 and 1500 km distant, respectively, from Site 1276 during the Paleocene. However, ages of volcanism in these areas indicate that they could probably not be sources of micas younger than 60 m.y., which suggests some as-yet unknown volcanic source in the North Atlantic area. Accumulation in the Grand Banks area of airborne-transported volcaniclastic material from eruptions of slightly different ages, followed by a single resedimentation event, could account for the spread of dates obtained from the sample. White micas from the lowermost Albian sample show a spread of ages between 37 and 284 Ma that is completely different from the age distribution pattern of the middle Albian and middle Eocene samples. The sample location is between, and at least 25 m above and below, two igneous sills dated at 98 and 105 Ma. The sills have narrow thermal aureoles and ages older than the youngest detrital micas in the sample. It is unlikely, therefore, that the spread of mica ages in the sample is due to partial resetting of ages caused by thermal effects associated with the intrusion of the sills. The resetting may have been associated with a longer lived thermal event.

Neodymium isotopic record of planktonic foraminifera in sediment core MD81-LC21

A well developed sapropel (S5) was deposited in the eastern Mediterranean during the Last Interglacial (Eemian), 124-119 ka. Freshwater contributions to the basin at this time can be traced using the isotopic composition of Nd in planktonic foraminifera. This enables differentiation between radiogenic sources to the south, under the influence of the African monsoon, and unradiogenic sources to the north, relating to the mid-latitude westerlies. Here we compare new Nd data, from a core in the southeast Aegean Sea, with published data from the Ionian and Levantine Seas. Shifts towards more radiogenic Nd in the lower and middle parts of sapropel S5 are most pronounced in the Ionian Sea record, with epsioln-Nd and d18O G. ruber co-varying more closely here than in the Levantine and Aegean Seas. This is consistent with a freshwater source proximal to the Ionian Sea site, likely indicating a substantial reactivation of rivers flowing northward from the central Saharan watershed. The lack, during S5 deposition, of a noticeable shift towards more unradiogenic Nd in the Aegean record would exclude a large influx of water from the northern borders of the eastern Mediterranean during sapropel deposition. These findings support a scenario whereby the Last Interglacial eastern Mediterranean was influenced strongly by the remote effects of an intensified African monsoon, with more local precipitation in the northern borders contributing relatively little to the sea surface composition.

The role of angiogenesis in prostate development and the pathogenesis of prostate cancer

New vessel formation, a highly-regulated, active process commencing in the embryo and evident notably during the pubertal growth spurt, is essential for normal prostate development. Reactivation of this process in response to physiological stimuli, particularly hypoxia in mature tissues, occurs with new vessels forming principally from stromal components. Although angiogenesis is complex, putatively involving a multitude of angiogenic factors and inhibitors, there is powerful evidence of the importance of the VEGF system in the development of both the normal prostate and prostate cancer. Recent advances include an understanding of how castration acts through the VEGF system to inhibit angiogenesis. Stromal-endothelial and epithelial-endothelial interactions are just beginning to be investigated. A better understanding of how physiological angiogenesis is controlled should help to provide further insights into the mechanism of disregulated angiogenesis in tumours. Ultimately, new antiangiogenic agents are likely to find a role in the management of patients with prostate cancer.

Factors affecting the formation of a skin reservoir for topically applied solutes

The reservoir function of the skin is an important determinant of the duration of action of a topical solute. The reservoir can exist in the stratum corneum, in the viable avascular tissue (viable epidermis and supracapillary dermis) and in the dermis. A steroid reservoir in the stratum corneum has been demonstrated by the reactivation of a vasoconstrictor effect by occlusion or application of a placebo cream to the skin some time after the original topical application of steroid. Other solutes have also been reported to show a reservoir effect in the skin after topical application. A simple compartmental model is used to understand why reactivation of vasoconstriction some time after a topical steroid application shows dependency on time, topical solute concentration and the product used to cause reactivation. The model is also used to show which solutes are likely to show a reservoir effect and could be potentially affected by desquamation, especially when the turnover of the skin is abnormally rapid. A similar form of the model can be used to understand the promotion of reservoir function in the viable tissue and in the dermis in terms of effective removal by blood perfusing the tissues. Copyright (C) 2004 S. Karger AG, Basel.

Contemporaneous fluctuations in T cell responses to persistent herpes virus infections

The classical paradigm for T cell dynamics suggests that the resolution of a primary acute virus infection is followed by the generation of a long-lived pool of memory T cells that is thought to be highly stable. Very limited alteration in this repertoire is expected until the immune system is re-challenged by reactivation of latent viruses or by cross-reactive pathogens. Contradicting this view, we show here that the T cell repertoire specific for two different latent herpes viruses in the peripheral blood displayed significant contemporaneous co-fluctuations of virus-specific CD8(+) T cells. The coordinated responses to two different viruses suggest that the fluctuations within the T cell repertoire may be driven by sub-clinical viral reactivation or a more generalized 'bystander' effect. The later contention was supported by the observation that, while absolute number of CD3(+) T cells and their subsets and also the cell surface phenotype of antigen-specific T cells remained relatively constant, a loss of CD62L expression in the total CD8(+) T cell population was coincident with the expansion of tetramer-positive virus-specific T cells. This study demonstrates that the dynamic process of T cell expansion and contractions in persistent viral infections is not limited to the acute phase of infection, but also continues during the latent phase of infection.

RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin

Targeted inhibition of oncogenes in tumor cells is a rational approach toward the development of cancer therapies based on RNA interference (RNAi). Tumors caused by human papillomavirus (HPV) infection are an ideal model system for RNAi-based cancer therapies because the oncogenes that cause cervical cancer, E6 and E7, are expressed only in cancerous cells. We investigated whether targeting HPV E6 and E7 oncogenes yields cancer cells more sensitive to chemotherapy by cisplatin, the chemotherapeutic agent currently used for the treatment of advanced cervical cancer. We have designed siRNAs directed against the HPV E6 oncogene that simultaneously targets both E6 and E7, which results in an 80% reduction in E7 protein and reactivation of the p53 pathway. The loss of E6 and E7 resulted in a reduction in cellular viability concurrent with the induction of cellular senescence. Interference was specific in that no effect on HPV-negative cells was observed. We demonstrate that RNAi against E6 and E7 oncogenes enhances the chemotherapeutic effect of cisplatin in HeLa cells. The IC50 for HeLa cells treated with cisplatin was 9.4 mu M, but after the addition of a lentivirus-delivered shRNA against E6, the IC50 was reduced almost 4-fold to 2.4 mu M. We also observed a decrease in E7 expression with a concurrent increase in p53 protein levels upon cotreatment with shRNA and cisplatin over that seen with individual treatment alone. Our results provide strong evidence that loss of E6 and E7 results in increased sensitivity to cisplatin, probably because of increased p53 levels.