Imine Azaenolates: Synthesis, Reactivity, and Outlook

Azaenolates are, quite simply, the aza variant of enolates. Compared to their oxygen counterparts, additional control of the reactivity of azaenolates can be achieved by altering the substituent on the nitrogen atom as well as the metal counterion. Since the seminal examples reported in the early 1960s, azaenolates of various metals have been shown to react with a diverse set of electrophilic partners, including challenging electrophiles such as alkyl fluorides, epoxides, and oxetanes. This review describes in detail the current state of the art of the chemistry of azaenolates derived from imines, with a particular focus on the comparison of the reactivity exhibited with different metal counterions

The role of risk perception and affect in predicting support for conservation policy under rapid ecosystem change

Conservation conflicts are damaging for humans and wildlife, with differences in people's objectives fuelling challenges of managing complex, dynamic systems. We investigate the relative importance of economic, psychological (affect, trust and risk perception) and ecological factors in determining farmers' management preferences, using Greenland barnacle geese (Branta leucopsis) on Islay, Scotland, as a case study. Barnacle geese reduce agricultural productivity on Islay, negatively impacting household economies. Since 1992, farmers have received partial compensation but a new culling scheme has escalated conflict between conservation and agricultural interests. Using a questionnaire, we collected data from 75% of the farmers receiving goose payments. We found that affect was a strong driver of both risk perception and management preferences. However, we revealed complexity in these relationships, with trust and economic factors also influencing decision‐making. Psychological and economic factors surrounding wildlife management must be understood if we are to achieve conservation objectives in human dominated landscapes

Early and late systolic wall stress differentially relate to myocardial contraction and relaxation in middle-aged adults: the Asklepios study

Experimental studies implicate late systolic load as a determinant of impaired left ventricular (LV) relaxation. We aimed to assess the relationship between the myocardial loading sequence and left ventricular (LV) contraction and relaxation. Time-resolved central pressure and time-resolved LV geometry were measured with carotid tonometry and speckle-tracking echocardiography, respectively, for computation of time-resolved ejection-phase myocardial wall stress (EP-MWS) among 1,214 middle-aged adults without manifest cardiovascular disease from the general population. Early diastolic annular velocity, systolic annular velocities were measured with tissue Doppler imaging and segmentaveraged longitudinal strain was measured with speckle-tracking echocardiography. After adjustment for age, gender and potential confounders, late EP-MWS was negatively associated with early diastolic mitral annular velocity (e', standardized β=-0.25; P<0.0001) and mitral inflow propagation velocity (Vpe, standardized β=-0.13; P=0.02). In contrast, early EP-MWS was positively associated with e' (standardized β=0.18; P<0.0001) and Vpe (standardized β=0.22; P<0.0001). A higher late EP-MWS predicted a lower systolic mitral annular velocity (S', standardized β=-0.31; P<0.0001) and lesser myocardial longitudinal strain (standardized β=0.32; P<0.0001), whereas a higher early EP-MWS was associated with a higher S' (standardized β=0.16; P=0.002) and greater longitudinal strain (standardized β=-0.24; P=0.002). The loading sequence remained independently associated with e' after adjustment for S' or systolic longitudinal strain. In the context of available experimental data, our findings support the role of the myocardial loading sequence as a determinant of LV systolic and diastolic function. A loading sequence characterized by prominent late systolic wall stress was associated with lower longitudinal systolic function and diastolic relaxation

A novel leukointegrin, αdβ2, binds preferentially to ICAM-3

AbstractThe leukocyte-restricted β2 (CD18) integrins mediate cell adhesion in a variety of events essential for normal immune function. Despite extensive research in this field, only three members of this Integrin subfamily have been described: C011 a/CD18 (LFA-1), CD11 b/ CD18 (Mac-1), and CD11c/CD18 (p150,95). We have identified a cDNA encoding a fourth a chain, ad, that associates with C018. The ad subunit is more closely related to CD11b and CD11c than to CD11a. This integrin is expressed at moderate levels on myelomonocytic cell lines and subsets of peripheral blood leukocytes, and more strongly on tissue-compartmentalized cells such as foam cells, specialized macrophages found In aortic fatty streaks that may develop into atherosclerotic lesions. The ad/CD18 molecule exhibits preferential recognition of ICAM-3 over ICAM-1

Heritability and genome-wide analyses of problematic peer relationships during childhood and adolescence

Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4–17 years), and a UK twin sample (TEDS, 4–11 years). Longitudinal twin analysis (TEDS; N ≤ 7,366 twin pairs) showed that peer problems in childhood are heritable (4–11 years, 0.60 < twin-h 2 ≤ 0.71) but genetically heterogeneous from age to age (4–11 years, twin-r g = 0.30). GCTA (ALSPAC: N ≤ 5,608, TEDS: N ≤ 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4–12 years, 0.02<GCTA−h2Meta ≤ 0.11) though these influences become stronger in adolescence (13–17 years, 0.14<GCTA−h2ALSPAC ≤ 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC (N ≤ 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P ≤ 0.03). Single variant signals (P ≤ 10−5) were followed up in TEDS (N ≤ 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence

MLPerf Inference Benchmark

Machine-learning (ML) hardware and software system demand is burgeoning. Driven by ML applications, the number of different ML inference systems has exploded. Over 100 organizations are building ML inference chips, and the systems that incorporate existing models span at least three orders of magnitude in power consumption and five orders of magnitude in performance; they range from embedded devices to data-center solutions. Fueling the hardware are a dozen or more software frameworks and libraries. The myriad combinations of ML hardware and ML software make assessing ML-system performance in an architecture-neutral, representative, and reproducible manner challenging. There is a clear need for industry-wide standard ML benchmarking and evaluation criteria. MLPerf Inference answers that call. In this paper, we present our benchmarking method for evaluating ML inference systems. Driven by more than 30 organizations as well as more than 200 ML engineers and practitioners, MLPerf prescribes a set of rules and best practices to ensure comparability across systems with wildly differing architectures. The first call for submissions garnered more than 600 reproducible inference-performance measurements from 14 organizations, representing over 30 systems that showcase a wide range of capabilities. The submissions attest to the benchmark's flexibility and adaptability.Comment: ISCA 202

Deficient Induction Response in a Xenopus Nucleocytoplasmic Hybrid

Defects in induction signaling and response underlie the nucleocytoplasmic incompatibility between two evolutionarily distant frog species, while specific treatments partially restore this response in explants and whole embryos

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

The Genome of a Pathogenic Rhodococcus: Cooptive Virulence Underpinned by Key Gene Acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi