Marked central nervous system pathology in CD59 knockout rats following passive transfer of Neuromyelitis optica immunoglobulin G.

Neuromyelitis optica spectrum disorders (herein called NMO) is an inflammatory demyelinating disease of the central nervous system in which pathogenesis involves complement-dependent cytotoxicity (CDC) produced by immunoglobulin G autoantibodies targeting aquaporin-4 (AQP4-IgG) on astrocytes. We reported evidence previously, using CD59-/- mice, that the membrane-associated complement inhibitor CD59 modulates CDC in NMO (Zhang and Verkman, J. Autoimmun. 53:67-77, 2014). Motivated by the observation that rats, unlike mice, have human-like complement activity, here we generated CD59-/- rats to investigate the role of CD59 in NMO and to create NMO pathology by passive transfer of AQP4-IgG under conditions in which minimal pathology is produced in normal rats. CD59-/- rats generated by CRISPR/Cas9 technology showed no overt phenotype at baseline except for mild hemolysis. CDC assays in astrocyte cultures and cerebellar slices from CD59-/- rats showed much greater sensitivity to AQP4-IgG and complement than those from CD59+/+ rats. Intracerebral administration of AQP4-IgG in CD59-/- rats produced marked NMO pathology, with astrocytopathy, inflammation, deposition of activated complement, and demyelination, whereas identically treated CD59+/+ rats showed minimal pathology. A single, intracisternal injection of AQP4-IgG in CD59-/- rats produced hindlimb paralysis by 3 days, with inflammation and deposition of activated complement in spinal cord, optic nerves and brain periventricular and surface matter, with most marked astrocyte injury in cervical spinal cord. These results implicate an important role of CD59 in modulating NMO pathology in rats and demonstrate amplification of AQP4-IgG-induced NMO disease with CD59 knockout

Spatial optimization for land use allocation: accounting for sustainability concerns

Land-use allocation has long been an important area of research in regional science. Land-use patterns are fundamental to the functions of the biosphere, creating interactions that have substantial impacts on the environment. The spatial arrangement of land uses therefore has implications for activity and travel within a region. Balancing development, economic growth, social interaction, and the protection of the natural environment is at the heart of long-term sustainability. Since land-use patterns are spatially explicit in nature, planning and management necessarily must integrate geographical information system and spatial optimization in meaningful ways if efficiency goals and objectives are to be achieved. This article reviews spatial optimization approaches that have been relied upon to support land-use planning. Characteristics of sustainable land use, particularly compactness, contiguity, and compatibility, are discussed and how spatial optimization techniques have addressed these characteristics are detailed. In particular, objectives and constraints in spatial optimization approaches are examined

Asymptotic integration algorithms for first-order ODEs with application to viscoplasticity

When constructing an algorithm for the numerical integration of a differential equation, one must first convert the known ordinary differential equation (ODE), which is defined at a point, into an ordinary difference equation (O(delta)E), which is defined over an interval. Asymptotic, generalized, midpoint, and trapezoidal, O(delta)E algorithms are derived for a nonlinear first order ODE written in the form of a linear ODE. The asymptotic forward (typically underdamped) and backward (typically overdamped) integrators bound these midpoint and trapezoidal integrators, which tend to cancel out unwanted numerical damping by averaging, in some sense, the forward and backward integrations. Viscoplasticity presents itself as a system of nonlinear, coupled first-ordered ODE's that are mathematically stiff, and therefore, difficult to numerically integrate. They are an excellent application for the asymptotic integrators. Considering a general viscoplastic structure, it is demonstrated that one can either integrate the viscoplastic stresses or their associated eigenstrains

Editor’s Remark

IN 2016, the Center for Research and Reform in Education at Johns Hopkins University, led by Professor Robert Slavin, kicked off an e-newsletter called Best Evidence in Brief (BEiB) which presents the latest empirical studies in education from the world’s top academic journals. Today this effort expands to the UK, Hong Kong, and Spain, including the Institute for Effective in Education of the University of York and the Centre for University and School Partnership Faculty of Education of the Chinese University of Hong Kong, and the La Caixa Foundation. Currently the majority of the selected studies in BEiB are from English-speaking countries. In 2018, the International Research Center for Educational Development and Evaluation at Nan- jing Normal University joined the BEiB family to further promote evidence- based reform in education in the Chinese speaking region. One of the main focuses of the BEiB in China is evidence-based research studies published in Chinese educational academic journals since its launched, the Chinese BEiB has been well-received by the Chinese educational communities.          During the past 40 years, reform and development in China have under- gone earth-shaking changes, including the extensive use of rigorous research methods in research. An increasing number of researchers have applied sophisticated research methods to explore the link between theories and educational reform, and dialectical thinking and scientific thinking. With the exchanges in educational circles from home and abroad, more and more researchers have learned the latest educational methods from Europe and North America. Many young researchers, who have the overseas training, are familiar to those concepts, including research samples, research hypotheses, re- search variables, effect sizes, causal relationships, and related relationships. These are the days that Chinese educational academic journals should pay at-tention to both evidence-based reforms and experimental research results in education. Happily, the proportion of empirical research studies published in Chinese education-related journals is growing

Group II Intron Protein Localization and Insertion Sites Are Affected by Polyphosphate

Mobile group II introns consist of a catalytic intron RNA and an intron-encoded protein with reverse transcriptase activity, which act together in a ribonucleoprotein particle to promote DNA integration during intron mobility. Previously, we found that the Lactococcus lactis Ll.LtrB intron-encoded protein (LtrA) expressed alone or with the intron RNA to form ribonucleoprotein particles localizes to bacterial cellular poles, potentially accounting for the intron's preferential insertion in the oriC and ter regions of the Escherichia coli chromosome. Here, by using cell microarrays and automated fluorescence microscopy to screen a transposon-insertion library, we identified five E. coli genes (gppA, uhpT, wcaK, ynbC, and zntR) whose disruption results in both an increased proportion of cells with more diffuse LtrA localization and a more uniform genomic distribution of Ll.LtrB-insertion sites. Surprisingly, we find that a common factor affecting LtrA localization in these and other disruptants is the accumulation of intracellular polyphosphate, which appears to bind LtrA and other basic proteins and delocalize them away from the poles. Our findings show that the intracellular localization of a group II intron-encoded protein is a major determinant of insertion-site preference. More generally, our results suggest that polyphosphate accumulation may provide a means of localizing proteins to different sites of action during cellular stress or entry into stationary phase, with potentially wide physiological consequences.This work was supported by National Institutes of Health R01 grants GM037949 to AML and GM076536 to EMM, Welch Foundation grants F-1607 to AML and F-1515 to EMM, and a Packard Foundation fellowship to EMM.Cellular and Molecular Biolog

Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation.

The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in Mgp-null lungs. Elevated HGF induced hepatocyte nuclear factor 4 α (Hnf4a), which competed with NK2 homeobox 1 (Nkx2.1) for binding to forkhead box A2 (Foxa2) to drive hepatic differentiation in Mgp-null airway progenitor cells. Limiting endothelial HGF reduced Hnf4a, abolished interference of Hnf4a with Foxa2, and reduced hepatic differentiation in Mgp-null lungs. Together, our results suggest that endothelial-epithelial interactions, maintained by MGP, are essential in pulmonary cell differentiation

How Does a Review Officer and Her Incentivized Contribution Affect the Review System?

Online retail platforms have increasingly employed a new incentive strategy by recruiting review officers and offering monetary rewards for posting incentivized reviews. However, there may be unintended effects of such incentivized reviews on the review system. Using a weekly-product panel dataset, we bridge the causal links between the emergence of incentivized reviews and the reviewers’ subsequent posting behaviors. We show that the emergence of incentivized reviews exerts a positive impact on the reviewers’ overall subsequent contributions. However, we show detrimental effects of incentivized reviews on the subsequent regular (non-incentivized) reviews, reflected in reduced engagement, decreased quality, and usefulness. Our mechanism analyses by separating the title effect and the quality effect show that the positive effect of incentivized reviews can be explained by the observational learning of the high-quality content while the adverse effects may be attributed to the demotivation of regular reviewers in response to the incentivized officer-titles

Location optimization of urban fire stations: access and service coverage

Fire and rescue services are among the most critical public services provided by governments to protect people, property and the environment from fires and other emergencies. Efficient deployment of fire stations is essential to ensure timely response to calls for service. Given the geographic nature of such problems, spatial optimization approaches have long been employed in public facility location modeling along these lines. In particular, median and coverage approaches have been widely adopted to help achieve travel-cost and service-coverage goals, respectively. This paper proposes a bi-objective spatial optimization model that integrates coverage and median goals in the service of demand areas. Based on the properties of derived objective functions, we presented a constraint-based solution procedure to generate the Pareto frontier, enabling the identification of alternative fire station siting scenarios. The developed model is applied to an empirical study that seeks to identify the best fire station locations in Nanjing, China. The results demonstrate the value of spatial optimization in assisting fire station planning and rescue resource deployment, highlighting important policy implications

Gene targeting using randomly inserted group II introns (targetrons) recovered from an Escherichia coli gene disruption library

The Lactococcus lactis Ll.LtrB group II intron retrohomes by reverse-splicing into one strand of a double-stranded DNA target site, while the intron-encoded protein cleaves the opposite strand and uses it to prime reverse transcription of the inserted intron RNA. The protein and intron RNA function in a ribonucleoprotein particle, with much of the DNA target sequence recognized by base-pairing of the intron RNA. Consequently, group II introns can be reprogrammed to insert into specific or random DNA sites by substituting specific or random nucleotide residues in the intron RNA. Here, we show that an Escherichia coli gene disruption library obtained using such randomly inserting Ll.LtrB introns contains most viable E.coli gene disruptions. Further, each inserted intron is targeted to a specific site by its unique base-pairing regions, and in most cases, could be recovered by PCR and used unmodified to obtain the desired single disruptant. Additionally, we identified a subset of introns that insert at sites lacking T+5, a nucleotide residue critical for second-strand cleavage. All such introns tested individually gave the desired specific disruption, some by switching to an alternate retrohoming mechanism targeting single-stranded DNA and using a nascent lagging DNA strand to prime reverse transcription