Passive Immunotherapy in Alzheimer’s Disease

The development of therapeutics for the treatment of Alzheimer’s disease (AD) has been challenged with a myriad of obstacles: an evolving and incomplete understanding of disease etiology and progression, challenges with early diagnosis, multifactorial genetic and environmental factors that contribute to patient variability, and the cost of conducting lengthy clinical trials. One approach that has garnered a significant amount of attention and resources for its potential as a disease modifying approach is passive immunotherapy directed at clearing amyloid-β (Aβ) species, a pathological hallmark of Alzheimer’s disease. While passive immunotherapeutic trials directed at Aβ have not yet demonstrated clinical benefit, they have prompted important advances in the application and understanding of biomarkers, patient selection, novel functional readouts, and safety monitoring. Application of these lessons has enabled more recent clinical trials to incorporate better trial designs and refine inclusion criteria to optimize patient population enrollment. In addition, new passive immunotherapy targets emerging in the clinic have emerged, as well as novel technologies to enhance future antibody therapeutics. Taken together, the advances in research and clinical science have prepared the passive immunotherapy field to advance emerging promising disease modifying treatments in AD

Diversity of filamentous fungi in Cerrado soil under native vegetation

Soil is a habitat intrinsic to the development of the biodiversity of microorganisms, including fungi. The municipality of Tangará da Serra - MT is located in the Cerrado region of Brazil. Considering the limited knowledge of fungal biodiversity in this region, the aim of this research was to isolate and identify filamentous fungi from the soil through seasonal surveys in three areas of native vegetation of the cerrado. Three samples were collected during the rainy period and three in the dry period. The samples were collected at a depth of 20 cm of soil, each point was composed 25 grams of soil, and each sample was subjected to serial dilution technique, inoculated in dishes, placed in a bacteriological 28ºC incubator for five days. Were isolated from 136 specimens (25 Mycelia sterilia) dispersed in 17 genera, equivalent to 02 Ascomycota, 04 Zygomycota and 11 Deuteromycota these subdivided into 10 genera of Hyphomycetes and 01 genera of Coelomycetes. The highest abundance occurred in the rainy season (69 specimens) in relation to drought (67 specimens) and richness higher was observed in the dry season (12 genera) in analogy to the rainy season (11 genera).(Diversidade de fungos filamentosos no solo do Cerrado sob vegetação nativa). O solo é um habitat intrínseco para o desenvolvimento da biodiversidade de microrganismos, destacando-se os fungos. O município de Tangará da Serra, MT, está localizado na região de cerrado brasileiro, desta forma, considerando o escasso conhecimento da biodiversidade fúngica nesta região, o presente trabalho objetivou isolar e identificar fungos filamentosos do solo, através de levantamentos sazonais em três áreas de vegetação nativa de cerrado. Foram coletadas três amostras no período chuvoso e três no período de estiagem. As sub-amostras foram coletadas a uma profundidade de 0 a 20 cm do solo, cada amostra correspondia a 25 gramas de solo, posteriormente submetidas à técnica de diluição seriada, inoculada em placas e incubadas em estufa bacteriológica a 28 ºC durante cinco dias. Foram isolados 136 espécimes (25 Mycelia sterilia) disseminados em 17 gêneros, sendo 02 Ascomycota, 04 Zygomycota e 11 Deuteromycota estes subdivididos em 10 gêneros de Hyphomycetes e 01 gênero de Coelomycetes. A maior abundância ocorreu no período chuvoso (69 UFC) em relação a estiagem (67 UFC) e a maior riqueza foi observada na estiagem (12 gêneros) em analogia  ao período chuvoso (11 gêneros)

The ESPRI project: astrometric exoplanet search with PRIMA I. Instrument description and performance of first light observations

The ESPRI project relies on the astrometric capabilities offered by the PRIMA facility of the Very Large Telescope Interferometer for the discovery and study of planetary systems. Our survey consists of obtaining high-precision astrometry for a large sample of stars over several years and to detect their barycentric motions due to orbiting planets. We present the operation principle, the instrument's implementation, and the results of a first series of test observations. A comprehensive overview of the instrument infrastructure is given and the observation strategy for dual-field relative astrometry is presented. The differential delay lines, a key component of the PRIMA facility which was delivered by the ESPRI consortium, are described and their performance within the facility is discussed. Observations of bright visual binaries are used to test the observation procedures and to establish the instrument's astrometric precision and accuracy. The data reduction strategy for astrometry and the necessary corrections to the raw data are presented. Adaptive optics observations with NACO are used as an independent verification of PRIMA astrometric observations. The PRIMA facility was used to carry out tests of astrometric observations. The astrometric performance in terms of precision is limited by the atmospheric turbulence at a level close to the theoretical expectations and a precision of 30 micro-arcseconds was achieved. In contrast, the astrometric accuracy is insufficient for the goals of the ESPRI project and is currently limited by systematic errors that originate in the part of the interferometer beamtrain which is not monitored by the internal metrology system. Our observations led to the definition of corrective actions required to make the facility ready for carrying out the ESPRI search for extrasolar planets.Comment: 32 pages, 39 figures, Accepted for publication in Astronomy and Astrophysic

C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.

Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synaptic terminal, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in vitro. This study provides a new view on the binding of alpha-synuclein to synaptic vesicles, which might also affect our understanding of synucleinopathies

β-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil

Five restriction site polymorphisms in the β-globin gene cluster (HincII-5‘ ε, HindIII-G γ, HindIII-A γ, HincII- ψβ1 and HincII-3‘ ψβ1) were analyzed in three populations (n = 114) from Reconcavo Baiano, State of Bahia, Brazil. The groups included two urban populations from the towns of Cachoeira and Maragojipe and one rural Afro-descendant population, known as the “quilombo community”, from Cachoeira municipality. The number of haplotypes found in the populations ranged from 10 to 13, which indicated higher diversity than in the parental populations. The haplotypes 2 (+ - - - -), 3 (- - - - +), 4 (- + - - +) and 6 (- + + - +) on the βA chromosomes were the most common, and two haplotypes, 9 (- + + + +) and 14 (+ + - - +), were found exclusively in the Maragojipe population. The other haplotypes (1, 5, 9, 11, 12, 13, 14 and 16) had lower frequencies. Restriction site analysis and the derived haplotypes indicated homogeneity among the populations. Thirty-two individuals with hemoglobinopathies (17 sickle cell disease, 12 HbSC disease and 3 HbCC disease) were also analyzed. The haplotype frequencies of these patients differed significantly from those of the general population. In the sickle cell disease subgroup, the predominant haplotypes were BEN (Benin) and CAR (Central African Republic), with frequencies of 52.9% and 32.4%, respectively. The high frequency of the BEN haplotype agreed with the historical origin of the afro-descendant population in the state of Bahia. However, this frequency differed from that of Salvador, the state capital, where the CAR and BEN haplotypes have similar frequencies, probably as a consequence of domestic slave trade and subsequent internal migrations to other regions of Brazil

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

BackgroundIn Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function.Methods/designA prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation.DiscussionWe anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD.Clinical trail registrationTRN NCT03043768

Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson's Disease

Abstract The misfolding of intrinsically disordered proteins such as a-synuclein, tau and the Ab peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets a-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of a-synuclein-mediated dysfunction, including rescue of a-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of a-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting a-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions

CMS physics technical design report : Addendum on high density QCD with heavy ions

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