The BESIII is an electron-positron collision experiment hosted at BEPCII in Beijing and aimed to investigate Tau-Charm physics. Now BESIII has been running for several years and gathered more than ...1PB raw data. In order to analyze these data and perform massive Monte Carlo simulations, a large amount of computing and storage resources is needed. The distributed computing system is based up on DIRAC and it is in production since 2012. It integrates computing and storage resources from different institutes and a variety of resource types such as cluster, grid, cloud or volunteer computing. About 15 sites from BESIII Collaboration from all over the world joined this distributed computing infrastructure, giving a significant contribution to the IHEP computing facility. Nowadays cloud computing is playing a key role in the HEP computing field, due to its scalability and elasticity. Cloud infrastructures take advantages of several tools, such as VMDirac, to manage virtual machines through cloud managers according to the job requirements. With the virtually unlimited resources from commercial clouds, the computing capacity could scale accordingly in order to deal with any burst demands. General computing models have been discussed in the talk and are addressed herewith, with particular focus on the BESIII infrastructure. Moreover new computing tools and upcoming infrastructures will be addressed.
To support equitable and ambitious teaching practices, classroom assessment design must be grounded in a research‐based theory of learning. Compared to other theories, sociocultural theory offers a ...more powerful, integrative account of how motivational aspects of learning—such as self‐regulation, self‐efficacy, sense of belonging, and identity—are completely entwined with cognitive development. Instead of centering assessment within systems that support use of interim and end‐of‐year standardized tests, we argue for a vision of formative assessment based on discipline‐specific tasks and questions that can provide qualitative insights about student experience and thinking, including their identification with disciplinary practices. At the same time, to be consistent with a productive formative assessment culture, grading policies should avoid using points and grades “to motivate” students but should create opportunities for students to use feedback to improve their work. We argue for districts as the locus for the design of such coherent curriculum, instruction, and assessment activity systems because districts have responsibility for curriculum, teacher professional development, and equity; and districts allocate resources for textbooks and assessment.
Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid ...substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher's disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson's disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD. The importance of GCase in PD necessitates preclinical models in which to study GCase-related mechanisms and novel therapeutic approaches, as well as to elucidate the molecular mechanisms leading to enhanced PD risk in GBA1 mutation carriers. The aim of this study was to develop and characterize a novel GBA1 mouse model and to facilitate wide accessibility of the model with phenotypic data. Herein we describe the results of molecular, biochemical, histological, and behavioral phenotyping analyses in a GBA1 D409V knock-in (KI) mouse. This mouse model exhibited significantly decreased GCase activity in liver and brain, with substantial increases in glycosphingolipid substrates in the liver. While no changes in the number of dopamine neurons in the substantia nigra were noted, subtle changes in striatal neurotransmitters were observed in GBA1 D409V KI mice. Alpha-synuclein pathology and inflammation were not observed in the nigrostriatal system of this model. In summary, the GBA1 D409V KI mouse model provides an ideal model for studies aimed at pharmacodynamic assessments of potential therapies aiming to restore GCase.
We study the emergence of collective scattering in the presence of dipole-dipole interactions when we illuminate a cold cloud of rubidium atoms with a near-resonant and weak intensity laser. The size ...of the atomic sample is comparable to the wavelength of light. When we gradually increase the number of atoms from 1 to ~450, we observe a broadening of the line, a small redshift and, consistently with these, a strong suppression of the scattered light with respect to the noninteracting atom case. We compare our data to numerical simulations of the optical response, which include the internal level structure of the atoms.
Atomic compositions and molar extinction coefficients of PbSe semiconductor nanocrystals were determined by atomic absorption spectrometry, UV−vis−NIR spectrophotometry, and transmission electron ...microscopy. The Pb/Se atomic ratio was found to be size-dependent with a systematic excess of Pb atoms in the PbSe nanocrystal system. Experimental results indicated that the individual PbSe nanocrystal was nonstoichiometric, consisting of a PbSe core and an extra layer of Pb atoms. For these nonstoichiometric PbSe semiconductor nanocrystals, we proposed a new computational approach to calculate the total number of Pb and Se atoms in different sized particles. This calculation played a key role on the accurate determination of the strongly size-dependent extinction coefficient, which followed a power law with an exponent of ∼2.5.
Pompe disease is an inherited lysosomal storage disease that results from a deficiency in the enzyme acid α-glucosidase (GAA), and is characterized by progressive accumulation of lysosomal glycogen ...primarily in heart and skeletal muscles. Recombinant human GAA (rhGAA) is the only approved enzyme replacement therapy (ERT) available for the treatment of Pompe disease. Although rhGAA has been shown to slow disease progression and improve some of the pathophysiogical manifestations, the infused enzyme tends to be unstable at neutral pH and body temperature, shows low uptake into some key target tissues, and may elicit immune responses that adversely affect tolerability and efficacy. We hypothesized that co-administration of the orally-available, small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) may improve the pharmacological properties of rhGAA via binding and stabilization. AT2220 co-incubation prevented rhGAA denaturation and loss of activity in vitro at neutral pH and 37°C in both buffer and blood. In addition, oral pre-administration of AT2220 to rats led to a greater than two-fold increase in the circulating half-life of intravenous rhGAA. Importantly, co-administration of AT2220 and rhGAA to GAA knock-out (KO) mice resulted in significantly greater rhGAA levels in plasma, and greater uptake and glycogen reduction in heart and skeletal muscles, compared to administration of rhGAA alone. Collectively, these preclinical data highlight the potentially beneficial effects of AT2220 on rhGAA in vitro and in vivo. As such, a Phase 2 clinical study has been initiated to investigate the effects of co-administered AT2220 on rhGAA in Pompe patients.
Pompe disease is an inherited lysosomal storage disorder that results from a deficiency in acid α-glucosidase (GAA) activity due to mutations in the GAA gene. Pompe disease is characterized by ...accumulation of lysosomal glycogen primarily in heart and skeletal muscles, which leads to progressive muscle weakness. We have shown previously that the small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) binds and stabilizes wild-type as well as multiple mutant forms of GAA, and can lead to higher cellular levels of GAA. In this study, we examined the effect of AT2220 on mutant GAA, in vitro and in vivo, with a primary focus on the endoplasmic reticulum (ER)-retained P545L mutant form of human GAA (P545L GAA). AT2220 increased the specific activity of P545L GAA toward both natural (glycogen) and artificial substrates in vitro. Incubation with AT2220 also increased the ER export, lysosomal delivery, proteolytic processing, and stability of P545L GAA. In a new transgenic mouse model of Pompe disease that expresses human P545L on a Gaa knockout background (Tg/KO) and is characterized by reduced GAA activity and elevated glycogen levels in disease-relevant tissues, daily oral administration of AT2220 for 4 weeks resulted in significant and dose-dependent increases in mature lysosomal GAA isoforms and GAA activity in heart and skeletal muscles. Importantly, oral administration of AT2220 also resulted in significant glycogen reduction in disease-relevant tissues. Compared to daily administration, less-frequent AT2220 administration, including repeated cycles of 4 or 5 days with AT2220 followed by 3 or 2 days without drug, respectively, resulted in even greater glycogen reductions. Collectively, these data indicate that AT2220 increases the specific activity, trafficking, and lysosomal stability of P545L GAA, leads to increased levels of mature GAA in lysosomes, and promotes glycogen reduction in situ. As such, AT2220 may warrant further evaluation as a treatment for Pompe disease.
To evaluate the effectiveness on educational and resource outcomes of blended compared to non-blended learning approaches for participants undertaking accredited life support courses.
This review was ...conducted in adherence with PRISMA standards. We searched EMBASE.com (including all journals listed in Medline), CINAHL and Cochrane from 1 January 2000 to 6 August 2021. Randomised and non-randomised studies were eligible for inclusion. Study screening, data extraction, risk of bias assessment (using RoB2 and ROBINS-I tools), and certainty of evidence evaluation (using GRADE) were all independently performed in duplicate. The systematic review was registered with PROSPERO (CRD42022274392).
From 2,420 studies, we included data from 23 studies covering fourteen basic life support (BLS) with 2,745 participants, eight advanced cardiac life support (ALS) with 33,579 participants, and one Advanced Trauma Life Support (ATLS) with 92 participants. Blended learning is at least as effective as non-blended learning for participant satisfaction, knowledge, skills, and attitudes. There is potential for cost reduction and eventual net profit in using blended learning despite high set up costs. The certainty of evidence was very low due to a high risk of bias and inconsistency. Heterogeneity across studies precluded any meta-analysis.
Blended learning is at least as effective as non-blended learning for accredited BLS, ALS, and ATLS courses. Blended learning is associated with significant long term cost savings and thus provides a more efficient method of teaching. Further research is needed to investigate specific delivery methods and the effect of blended learning on other accredited life support courses.
Background Blood samples from patients with sickle cell disease (SCD) present to transfusion service with numerous antibodies, making the searching for compatible red blood cells (RBC) a challenge. ...To overcome this problem we developed an effective strategy to meet needs of supplying RBC‐compatible units to SCD patients using DNA arrays.
Methods We selected DNA samples from 144 SCD patients with multiple (receiving > 5 units) transfusions previously phenotyped for ABO, Rh(D, C, c, E, e), K1, Fya and Jka. We also selected DNA samples from 948 Brazilian blood donors whose ABO/RhD phenotype matched that of the patients. All samples were analysed by DNA array analysis (HEA BeadchipTM, Bioarray Solutions) to determine polymorphisms associated with antigen expression for 11 blood group systems (Rh, Kell, Kidd, Duffy, MNS, Dombrock, Lutheran, Landsteiner‐Wiener, Diego, Colton, Scianna); and one mutation associated with haemoglobinopathies.
Results Based on genotype results we were able to predict phenotype‐compatible donors needed in order to provide compatible units to this group of patients. Based on their ABO/Rh phenotype we were able to find in this pool of donors compatible units for 134 SCD patients.
Conclusion Blood group genotyping by DNA array contributes to the management of transfusions in SCD patients by facilitating the transfusion support with antigen‐matched blood. It has the potential to improve the life of thousands of SCD‐transfused patients by reducing mortality due to transfusion reactions and immunization.
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