Investigating the Behavior of Diffusion Models for Accelerating Electronic Structure Calculations

We present an investigation into diffusion models for molecular generation, with the aim of better understanding how their predictions compare to the results of physics-based calculations. The investigation into these models is driven by their potential to significantly accelerate electronic structure calculations using machine learning, without requiring expensive first-principles datasets for training interatomic potentials. We find that the inference process of a popular diffusion model for de novo molecular generation is divided into an exploration phase, where the model chooses the atomic species, and a relaxation phase, where it adjusts the atomic coordinates to find a low-energy geometry. As training proceeds, we show that the model initially learns about the first-order structure of the potential energy surface, and then later learns about higher-order structure. We also find that the relaxation phase of the diffusion model can be re-purposed to sample the Boltzmann distribution over conformations and to carry out structure relaxations. For structure relaxations, the model finds geometries with ~10x lower energy than those produced by a classical force field for small organic molecules. Initializing a density functional theory (DFT) relaxation at the diffusion-produced structures yields a >2x speedup to the DFT relaxation when compared to initializing at structures relaxed with a classical force field

School Perspectives on Collaborative Inquiry: Lessons Learned From New York City, 2009-2010

The New York City Department of Education has supported collaborative inquiry as a potentially powerful process for helping administrators and teachers use student data to improve instruction and raise student achievement. Beginning with a pilot project in 2006, teams of teachers have learned to work together to diagnose the needs of students who have not been successful in their classrooms and to develop strategies to improve their learning. Collaborative inquiry sits at the heart of the Department\u27s larger Children First initiative and aims to help educators close the achievement gap in their schools. Each year New York City schools have engaged higher proportions of faculty in the inquiry work. The goal is at least 90% participation in collaborative inquiry. The purpose of this research report is to share lessons learned about the conditions, structures, relationships, and leadership practice that support teacher participation in inquiry. The report also presents perceived benefits of collaborative inquiry as reported by school leaders and teachers. Data come from site visits to 13 schools actively engaged in collaborative inquiry. The research team conducted 213 interviews with principals, assistant principals, instructional support staffs, and teachers participating in inquiry and 37 observations of inquiry team meetings

Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model

The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children.; From 17 August 2009 to 20 May 2010, 524 children aged 5-10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio [IRR] = 0.21 [95% CI 0.15, 0.28], p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 [95% CI 0.19, 0.38], p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment (p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes.; These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission.; ClinicalTrials.gov NCT02143934

AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the

Expressions 1998-1999

https://openspace.dmacc.edu/expressions/1018/thumbnail.jp

Highly Pathogenic Avian Influenza Virus A (H7N3) in Domestic Poultry, Saskatchewan, Canada, 2007

Epidemiologic, serologic, and molecular phylogenetic methods were used to investigate an outbreak of highly pathogenic avian influenza on a broiler breeding farm in Saskatchewan, Canada. Results, coupled with data from influenza A virus surveillance of migratory waterfowl in Canada, implicated wild birds as the most probable source of the low pathogenicity precursor virus

Participatory Process for Implementing a Colorectal Cancer Screening Intervention: an Action Plan for Local Sustainability

Background: Rigid protocols can hamper translation of evidence-based interventions from research to real-world settings. This investigation aimed to develop procedures for modifying the study protocol of a community-based participatory research (CBPR) project and to analyze the theoretical constructs that underlie this process. Methods: The research project is a dissemination and implementation study of the Educational Program to Increase Colorectal Cancer Screening (EPICS), an evidence-based intervention targeting African Americans in the United States. The study is being conducted in a partnership with community coalitions in 15 different cities. Each site initially presented unique issues that required modification of the study protocol. Results: In order to honor underlying CBPR theory, it was necessary to negotiate protocol changes with the community coalition at each site, while insuring preservation of the core elements of the intervention. Conclusions: We discuss the ways in which this represents a narrowing of the gap between CBPR and traditional research approaches

Formal support for informal caregivers to older persons with dementia through the course of the disease: an exploratory, cross-sectional study

Background: In European countries, knowledge about availability and utilization of support for informal caregivers caring for older persons (>= 65 years) with dementia (PwD) is lacking. To be able to evaluate and develop the dementia support system for informal caregivers to PwD, a survey of European support systems and professionals involved is needed. The aim of this study was to explore support for informal caregivers to PwD in European countries. We investigated the availability and utilization of support in each of the participating countries, and the professional care providers involved, through the dementia disease. Methods: A mapping system was used in 2010-2011 to gather information about estimations of availability, utilization, and professional providers of support to informal caregivers caring for PwD. Data collected was representing each country as a whole. Results: There was high availability of counselling, caregiver support, and education from the diagnosis to the intermediate stage, with a decrease in the late to end of life stage. Utilization was low, although there was a small increase in the intermediate stage. Day care and respite care were highly available in the diagnosis to the intermediate stage, with a decrease in the late to end of life stage, but both types of care were utilized by few or no caregivers through any of the disease stages. Professionals specialized in dementia (Bachelor to Master's degree) provided counselling and education, whereas caregiver support for informal caregivers and day care, respite care, and respite care at home were provided by professionals with education ranging from upper secondary schooling to a Master's degree. Conclusions: Counselling, caregiver support, and education were highly available in European countries from diagnosis to the intermediate stage of the dementia disease, decreasing in the late/end of life stages but were rarely utilized. Countries with care systems based on national guidelines for dementia care seem to be more aware of the importance of professionals specialized in dementia care when providing support to informal caregivers. Mapping the systems of support for informal caregivers of PwD is a valuable tool for evaluating existing systems, internationally, nationally and locally for policy making

Opsonising antibodies to P. falciparum Merozoites associated with immunity to clinical malaria

Naturally acquired humoral immunity to the malarial parasite Plasmodium falciparum can protect against disease, although the precise mechanisms remain unclear. Although antibody levels can be measured by ELISA, few studies have investigated functional antibody assays in relation to clinical outcomes. In this study we applied a recently developed functional assay of antibody-mediated opsonisation of merozoites, to plasma samples from a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG). Phagocytic activity was quantified by flow cytometry using a standardized and high-throughput protocol, and was subsequently evaluated for association with protection from clinical malaria and high-density parasitemia. Opsonising antibody responses were found to: i) increase with age, ii) be enhanced by concurrent infection, and iii) correlate with protection from clinical episodes and high-density parasitemia. Stronger protective associations were observed in individuals with no detectable parasitemia at baseline. This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria

Rapid copper acquisition by developing murine mesothelioma: Decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an antiangiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes