Translational potential of astrocytes in brain disorders

Fundamentally, all brain disorders can be broadly defined as the homeostatic failure of this organ. As the brain is composed of many different cells types, including but not limited to neurons and glia, it is only logical that all the cell types/constituents could play a role in health and disease. Yet, for a long time the sole conceptualization of brain pathology was focused on the well-being of neurons. Here, we challenge this neuron-centric view and present neuroglia as a key element in neuropathology, a process that has a toll on astrocytes, which undergo complex morpho-functional changes that can in turn affect the course of the disorder. Such changes can be grossly identified as reactivity, atrophy with loss of function and pathological remodeling. We outline the pathogenic potential of astrocytes in variety of disorders, ranging from neurotrauma, infection, toxic damage, stroke, epilepsy, neurodevelopmental, neurodegenerative and psychiatric disorders, Alexander disease to neoplastic changes seen in gliomas. We hope that in near future we would witness glial-based translational medicine with generation of deliverables for the containment and cure of disorders. We point out that such as a task will require a holistic and multi-disciplinary approach that will take in consideration the concerted operation of all the cell types in the brain

A Bright Submillimeter Source in the Bullet Cluster (1E0657--56) Field Detected with BLAST

We present the 250, 350, and 500 micron detection of bright submillimeter emission in the direction of the Bullet Cluster measured by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST). The 500 micron centroid is coincident with an AzTEC 1.1 mm point-source detection at a position close to the peak lensing magnification produced by the cluster. However, the 250 micron and 350 micron centroids are elongated and shifted toward the south with a differential shift between bands that cannot be explained by pointing uncertainties. We therefore conclude that the BLAST detection is likely contaminated by emission from foreground galaxies associated with the Bullet Cluster. The submillimeter redshift estimate based on 250-1100 micron photometry at the position of the AzTEC source is z_phot = 2.9 (+0.6 -0.3), consistent with the infrared color redshift estimation of the most likely IRAC counterpart. These flux densities indicate an apparent far-infrared luminosity of L_FIR = 2E13 Lsun. When the amplification due to the gravitational lensing of the cluster is removed, the intrinsic far-infrared luminosity of the source is found to be L_FIR <= 10^12 Lsun, consistent with typical luminous infrared galaxies.Comment: Accepted for publication in the Astrophysical Journal. Maps are available at http://blastexperiment.info

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Sélection sexuelle chez une espèce sexuellement dimorphique : l’effet de la taille corporelle sur le succès reproducteur et le sexe-ratio des jeunes chez les kangourous

La sélection sexuelle est responsable de certains des traits les plus extravagants retrouvés dans le règne animal, puisqu’ils confèrent un avantage quant à l’accès aux partenaires sexuels. Notamment, une grande taille corporelle chez les mâles de nombreuses espèces polygynes devrait fournir un avantage reproductif étant donné son association avec un rang de dominance élevé et, ultimement, l'accès aux femelles. Cependant, des résultats récents provenant de multiples espèces remettent en question cette généralisation, suggérant plutôt une faible relation entre la taille des mâles et le succès reproducteur. Cette preuve empirique suggère un besoin de développer une nouvelle théorie afin d’expliquer les variations du succès reproducteur des mâles. Cette thèse s’attaque à ce défi en examinant si et comment la sélection sexuelle agit sur les traits d’une espèce polygyne sexuellement dimorphique. En particulier, j’ai exploré quels facteurs écologiques et démographiques influencent l'association entre la taille corporelle et la dominance ainsi qu’entre la probabilité de reproduction et le succès reproducteur. J’ai également fait le lien entre l'effet de la taille corporelle du père, le sexe de la progéniture et l'allocation maternelle. Pour ce faire, j'ai utilisé une combinaison de données comportementales, morphologiques, spatiales et de reproduction provenant d’individus marqués dans le cadre d'une étude longitudinale à long terme sur les kangourous gris de l'Est (Macropus giganteus). Tout d'abord, je souhaitais comprendre si la taille corporelle est positivement associée au statut de dominance, considérant que le rang individuel est supposé être un facteur décisif pour l’obtention d’un accès prioritaire aux femelles. En analysant le résultat d'environ 2300 interactions agonistiques entre mâles sur six ans (2010-2011 et 2015-2018), le chapitre 2 montre que les mâles kangourous formaient des hiérarchies de dominance annuelles linéaires et stables basées sur la taille corporelle. Le statut de dominance n'était cependant que modérément corrélé au succès reproducteur annuel. Ce résultat suggère fortement que la taille corporelle n'est pas le seul facteur influençant le succès reproducteur de cette espèce, ce qui pourrait indiquer une faible sélection sexuelle sur la taille corporelle. Afin de déterminer quels facteurs, autres que la taille corporelle, pourraient influencer le succès reproducteur, j’ai considéré le fait que si un mâle ne rencontre pas une femelle, il ne peut pas engendrer sa progéniture. Ainsi, j'ai vérifié si les opportunités d’accouplement des mâles pouvaient fixer le nombre maximal de jeunes engendrés par ceux-ci. La plupart des études sur la sélection sexuelle supposent cependant que tous les mâles d'une population ont un accès égal à toutes les femelles de la population. Le chapitre 3 utilise donc des données spatiales récoltées pendant 9 ans (2010-2018) pour montrer que des variables écologiques telles que l'opportunité d'accouplement, quantifiée par le chevauchement spatial entre chaque paire mâle-femelle, le temps passé sur le site de reproduction, ainsi qu’une estimation précise du nombre de compétiteurs influencent les probabilités individuelles de reproduction. Ensuite, j'ai quantifié la sélection sexuelle sur la taille corporelle, sa fluctuation interannuelle et en fonction de l'opportunité d'accouplement et du temps passé sur le site de reproduction, ainsi que la force de l’asymétrie de reproduction. Le chapitre 4 montre que la sélection sexuelle était globalement stabilisatrice et qu'il n'y avait aucune preuve de fluctuation temporelle ou de fluctuation causée par l'opportunité d'accouplement. De plus, le temps passé sur le site de reproduction avait une influence limitée sur la variation de la sélection. Malgré la faible asymétrie de reproduction, la sélection sexuelle agissait fortement sur la taille corporelle. Enfin, j'ai redirigé mon attention vers des résultats récents montrant que les pères peuvent influencer le sexe de leur progéniture et l'allocation maternelle. Le chapitre 5 a donc examiné si la taille corporelle des pères, qui est fortement sélectionnée sexuellement, affectait le sexe-ratio de leur progéniture ou l'allocation maternelle différentielle. Les résultats indiquent que les influences maternelles et paternelles se modulent mutuellement : les mères légères concevaient des fils lorsque le père était lourd, mais, à l’inverse, les mères lourdes concevaient des fils lorsque les pères étaient légers. L'allocation maternelle différentielle était indépendante de la taille du père. J'ai constaté que malgré une hiérarchie sociale linéaire, les mâles les plus dominants ne monopolisaient pas les paternités, possiblement parce qu'ils n'en ont simplement pas l'occasion. Il est important de souligner qu'une forte sélection sexuelle ne conduit pas nécessairement à une variance élevée dans la reproduction actuelle, car les phénotypes sélectionnés déterminent la force de la sélection. En rapportant un rare cas de sélection sexuelle non-linéaire sur la taille corporelle chez une espèce sexuellement dimorphique, cette thèse souligne la nécessité d'étudier simultanément la sélection sexuelle pré- et post-copulatoire. De plus, elle apporte une solide contribution à notre compréhension de la sélection sexuelle en soulignant l'importance de facteurs écologiques et démographiques auparavant sous-estimés, tels que la véritable opportunité d'accouplement, générée par le chevauchement spatial, et le nombre réel de compétiteurs auquel chaque mâle doit faire face.Abstract: Sexual selection is responsible for some of the most extravagant traits found in the animal kingdom, as they confer a fitness advantage in terms of access to mates. Large body size in males of many polygynous species should provide a mating advantage through its association with dominance rank and, ultimately, access to females. Recent evidence from multiple species, however, questions this generalization, suggesting instead a weak relationship between male size and reproductive success. That empirical evidence suggests a need to develop new theory to explain patterns of male reproductive success. This thesis meets this challenge by examining if and how sexual selection acts on a polygynous sexually dimorphic species. I used a combination of behavioral, morphological, spatial, and reproductive data on marked individuals from a long-term longitudinal study of eastern grey kangaroos (Macropus giganteus) to explore which ecological and demographic factors influence the association between body size and dominance, siring chances and reproductive success, and relate the effect of paternal body size to offspring sex and maternal allocation. First, I needed to understand if body size is positively associated with dominance status, as individual rank is assumed to be a decisive factor granting priority access to receptive females. By analyzing the outcome of about 2,300 male-male agonistic interactions across six years (2010-2011 and 2015-2018), chapter 2 shows that kangaroo males formed yearly linear, steep, and stable dominance hierarchies based on body size. Dominance status was, however, only moderately correlated with yearly reproductive success. This finding strongly suggests that body size is not the only factor influencing reproductive success on this species, possibly indicating weak sexual selection on body size. To determine what factors other than body size may influence siring success, I examined if males had an upper reproductive threshold set by their mating opportunity. If a male does not encounter a female, he cannot father her offspring. Most studies of sexual selection, however, assume that all males in a population have equal access to all females. Chapter 3 thus uses spatial data collected over 9 years (2010-2018) to show that ecological variables such as mating opportunity, quantified by the spatial overlap between each male-female pair, residency on the breeding site, and an accurate estimation of the competitive environment influence individual siring chances. Next, I quantified sexual selection on body size, its fluctuation across years and according to mating opportunity and residency, and the strength of reproductive inequality. Chapter 4 shows that sexual selection was overall stabilizing and there was no evidence of temporal fluctuation or fluctuation caused by mating opportunity, and only limited variation caused by differences in residency. Despite weak reproductive inequality, sexual selection acted strongly on body size. Finally, I redirected my attention to recent findings showing that fathers can influence offspring sex and maternal allocation. Chapter 5 thus examined if paternal body size, which is strongly sexually selected, affected offspring sex ratio or maternal differential allocation. The results indicated that maternal and paternal influences modulated each other, as light mothers conceived sons when the father was heavy, conversely, heavy mothers conceived sons when the father was light. Maternal sex-specific allocation was independent of paternal size. I found that despite a stable linear social hierarchy, the most dominant males did not monopolize paternities, possibly because they did not have the opportunity to do so. It is important to emphasize that strong sexual selection does not necessarily lead to contemporary high variance in reproduction, as the phenotypes selected will determine the strength of selection. By reporting a rare occurrence of non-linear sexual selection on body size experienced by a sexually dimorphic species, this thesis underlines the necessity of simultaneous study of pre- and post- copulatory sexual selection. Moreover, it provides a solid contribution to our understanding of sexual selection by highlighting the importance of underrated ecological and demographic factors such true mating opportunity, generated by spatial overlap, and effective number of competitors faced by each male

Euripide, Le Baccanti

Introduzione, traduzione e commento delle Baccanti di Euripid

Fingerprint-Imprinted Polymer: Rational Selection of Peptide Epitope Templates for the Determination of Proteins by Molecularly Imprinted Polymers

The pool of peptides composing a protein allows for its distinctive identification in a process named fingerprint (FP) analysis. Here, the FP concept is used to develop a method for the rational preparation of molecularly imprinted polymers (MIPs) for protein recognition. The fingerprint imprinting (FIP) is based on the following: (1) the in silico cleavage of the protein sequence of interest with specific agents; (2) the screening of all the peptide sequences generated against the UniProtKB database in order to allow for the rational selection of distinctive and unique peptides (named as epitopes) of the target protein; (3) the selected epitopes are synthesized and used as templates for the molecular imprinting process. To prove the principle, NT-proBNP, a marker of the risk of cardiovascular events, was chosen as an example. The in silico analysis of the NT-proBNP sequence allowed us to individuate the peptide candidates, which were next used as templates for the preparation of NT-pro-BNP-specific FIPs and tested for their ability to bind the NT-proBNP peptides in complex samples. Results indicated an imprinting factor, IF, of ∼10, a binding capacity of 0.5–2 mg/g, and the ability to rebind 40% of the template in a complex sample, composed of the whole digests of NT-proBNP