Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

pH, CONDUTIVIDADE ELÉTRICA E POTÁSSIO DO SOLO APÓS TRÊS ANOS DE APLICAÇÕES DE NITROGÊNIO E POTÁSSIO EM AMEIXEIRA, NO MUNICÍPIO DE ARAUCÁRIA – PR

The objective of this research aim was to evaluate after tree years nitrogen and potassium fertilization of plum (Prunus salicina), cv. ‘Reubennel’, this effect in the pH, conductive electric and levels potassium this soil, in the projection ray and middle alley. The experiment was conducted in Araucaria (Brazil) and design was a split-plot in a randomized complete block with three replications. Main plot treatments were potassium rates (55 and 110 kg of K2O ha-1 ano-1), and subplot treatments were the nitrogen rates (40, 80, 120, 160 and 200 kg of N ha-1 ano-1), during the seasons 2003, 2004 and 2005, in the soil type Cambisol not irrigated. The place of collection of the soil under the canopy and in the middle alley, were analyzed was analyzed as split-split plot. Three years of different rates of nitrogen and potassium, was not effect of pH, electrical conductivity and K in the soil. The soil pH ranged from 5.6 to 6.1 until 40 cm depth, was not influenced by N application, due to combined effect of sort-term application, low potential acidification of N source (urea), and residual effect of large application of limestone at orchard establishment. Soil available K was also high and was not influenced by levels K applications during three years. Higher values for soil pH, electric conductivity and K from samples collected canopy compared to middle alley, can explain the results for localized application of limestone and fertilizer on canopy area.O objetivo deste trabalho foi avaliar após três anos de aplicações de adubações potássica e nitrogenada para a cultura da ameixeira (Prunus salicina), cultivar ‘Reubennel’, o efeito no pH, na condutividade elétrica e na concentração de potássio do solo, na projeção da copa e no centro da rua. O experimento foi realizado em Araucária (PR) e teve delineamento experimental em parcela sub-subdividida com três repetições, distribuídos em parcelas sub-subdivididas. Na parcela foi aplicado o potássio (55 e 110 kg de K2O ha-1 ano-1), e na  subparcela o nitrogênio (40, 80, 120, 160 e 200 kg de N ha-1 ano-1), durante as safras de 2003, 2004 e 2005, em solo do tipo Cambissolo não irrigado. O solo foi analisado na projeção da copa e centro da rua como sub-subparcela. Três anos de diferentes doses de adubação nitrogenada e potássica, não apresentaram efeito no pH, na condutividade elétrica e no K do solo. O pH do solo apresentou variação entre 5,6 a 6,1, até 40 cm de profundidade, não sendo alterado pela aplicação de nitrogênio, possivelmente efeito combinado da fonte e do tempo, a baixa capacidade de acidificação da fonte de N utilizada (uréia), e o efeito residual da aplicação do calcário utilizado na implantação do pomar. O K disponível no solo era alto e não foi influenciado pelas doses de K aplicadas durante três anos. Os valores de pH, de condutividade elétrica e de K do solo, maiores na projeção da copa quando comparados ao centro da rua, podem ser explicados pela concentração de fertilizante e calcário na projeção da copa

First report of severe acute respiratory syndrome coronavirus 2 detection in two asymptomatic cats in the state of Pernambuco, Northeastern Brazil

Background and Aim: Despite worldwide case reports, including Brazilian cases, no frequency study on infection of pets by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been conducted to date in Brazil. Accordingly, the present study was aimed to assess dogs and cats belonging to positive owners in Recife, Northeastern Brazil. Materials and Methods: This was a longitudinal prospective study on dogs and cats in the city of Recife whose owners were in isolation at home due to a confirmed laboratory diagnosis of SARS-CoV-2 through reverse-transcriptase polymerase chain reaction (RT-qPCR). Oral and rectal swabs from the pets were tested for the presence of SARS-CoV-2-specific RNA by means of RT-qPCR. Results: Among the pets tested, 0/16 dogs and 2/15 cats were positive for SARS-CoV-2. Interestingly, the two positive cats were owned by two unrelated asymptomatic veterinary students, which, therefore, post a warning to veterinarians worldwide. Conclusion: The findings herein indicate that cats may act as sentinels for human cases, particularly sharing households with asymptomatic human cases. Although with small sampling and convenient recruiting, the presence of infected cats by SARS-CoV-2 was most likely due to close cat-human contact with positive owners, posting a human-animal health threat when pets share the same bed and interact with owners without protection, particularly during owner self-isolation. Thus, infected owners should follow the same human preventive guidelines with their pets to avoid spreading infection

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer : a multicentre pooled analysis of 5161 patients

Background Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. Methods In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I–III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. Findings We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20–80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0–186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41–1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79–2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36–1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73–2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). Interpretation RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Objects of desire rebirth of the arcades : observations and explorations of the commodity fetish

Objects of Desire observes the commodity fetish in art and non-art contexts and examines the performative element of spectatorship and its relationship to both art and consumption. The project seeks an understanding of how notions of commodity fetishism and desire can be used to refigure patterns of audience interaction and engagement in the visual arts. Walter Benjamin's Arcades Project provides the inspiration and focus in my quest to "awaken" audiences from the collective consumer dream, and my art practice incorporates the disjunctions and humour celebrated in the collage and détournement works from Surrealism. My research on commodity examines the social and psychological perspectives of audience behaviour in consumer and art spaces to determine the distinctions between real and actual audiences, and art and non-art contexts. I discuss the mechanics of fetishisation and identify the tensions and collaborations between art and consumerism. Through a series of interactive and site-specific installations, my artworks investigate and build on methods to activate spectatorship and decentre audiences. Objects of Desire explores the dialectics of subject, materials and site, and poetic modes of production to engage knowing and unknowing audiences in an act of desire, and facilitates performance in the collusion of commodity fetishism in the spectacle, known as the visual arts