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Olefin metathesis is a prevailing method for the construction of organic molecules. Recent advancements in olefin metathesis have focused on stereoselective transformations. Ruthenium olefin metathesis catalysts have had a particularly pronounced impact in the area of stereoselective olefin metathesis. The development of three categories of Z-selective olefin metathesis catalysts has made Z-olefins easily accessible to both laboratory and industrial chemists. Further design enhancements to asymmetric olefin metathesis catalysts have streamlined the construction of complex molecules. The understanding gained in these areas has extended to the employment of ruthenium catalysts to stereoretentive olefin metathesis, the first example of a kinetically E-selective process. These advancements, as well as synthetic applications of the newly developed catalysts, are discussed.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Real-time monitoring of volcanic eruptions involving caldera-forming events are rare (see the Perspective by Sigmundsson). Anderson et al. used several types of geophysical observations to track the caldera-forming collapse at the top of Kīlauea Volcano, Hawai'i, during the 2018 eruption. Gansecki et al. used near–real-time lava composition analysis to determine when magma shifted from highly viscous, slow-moving lava to low-viscosity, fast-moving lava. Patrick et al. used a range of geophysical tools to connect processes at the summit to lava rates coming out of far-away fissures. Together, the three studies improve caldera-collapse models and may help improve real-time hazard responses. Science , this issue p. eaaz0147 , p. eaay9070 ; p. eaaz1822 ; see also p. 1200 Geophysical observations track the caldera collapse event during the 2018 Kīlauea volcanic eruption. Caldera-forming eruptions are among Earth’s most hazardous natural phenomena, yet the architecture of subcaldera magma reservoirs and the conditions that trigger collapse are poorly understood. Observations from the formation of a 0.8–cubic kilometer basaltic caldera at Kīlauea Volcano in 2018 included the draining of an active lava lake, which provided a window into pressure decrease in the reservoir. We show that failure began after <4% of magma was withdrawn from a shallow reservoir beneath the volcano’s summit, reducing its internal pressure by ~17 megapascals. Several cubic kilometers of magma were stored in the reservoir, and only a fraction was withdrawn before the end of the eruption. Thus, caldera formation may begin after withdrawal of only small amounts of magma and may end before source reservoirs are completely evacuated.

The evolution of separate sexes is hypothesized to occur through distinct pathways involving few large-effect or many small-effect alleles. However, we lack empirical evidence for how these different genetic architectures shape the transition from quantitative variation in sex expression to distinct male and female phenotypes. To explore these processes, we leveraged the recent transition of Amaranthus tuberculatus to dioecy within a predominantly monoecious genus, along with a sex-phenotyped population genomic dataset, and six newly generated chromosome-level haplotype phased assemblies. We identify a ~3 Mb region strongly associated with sex through complementary SNP genotype and sequence-depth-based analyses. Comparative genomics of these proto-sex chromosomes within the species and across the Amaranthus genus demonstrates remarkable variability in their structure and genic content, including numerous polymorphic inversions. No such inversion underlies the extended linkage we observe associated with sex determination. Instead, we identify a complex presence/absence polymorphism reflecting substantial Y-haplotype variation—structured by ancestry, geography, and habitat—but only partially explaining phenotyped sex. Just over 10% of sexed individuals show phenotype-genotype mismatch in the sex-linked region, and along with observation of leakiness in the phenotypic expression of sex, suggest additional modifiers of sex and dynamic gene content within and between the proto-X and Y. Together, this work reveals a complex genetic architecture of sex determination in A. tuberculatus characterized by the maintenance of substantial haplotype diversity, and variation in the expression of sex.

The 2018 summit and flank eruption of Kīlauea Volcano was one of the largest volcanic events in Hawaiʻi in 200 years. Data suggest that a backup in the magma plumbing system at the long-lived Puʻu ʻŌʻō eruption site caused widespread pressurization in the volcano, driving magma into the lower flank. The eruption evolved, and its impact expanded, as a sequence of cascading events, allowing relatively minor changes at Puʻu ʻŌʻō to cause major destruction and historic changes across the volcano. Eruption forecasting is inherently challenging in cascading scenarios where magmatic systems may prime gradually and trigger on small events.

MicroRNAs inhibit mRNA translation or promote mRNA degradation by binding complementary sequences in 3' untranslated regions of target mRNAs. MicroRNA-21 (miR-21) is upregulated in response to cardiac stress, and its inhibition by a cholesterol-modified antagomir has been reported to prevent cardiac hypertrophy and fibrosis in rodents in response to pressure overload. In contrast, we have shown here that miR-21-null mice are normal and, in response to a variety of cardiac stresses, display cardiac hypertrophy, fibrosis, upregulation of stress-responsive cardiac genes, and loss of cardiac contractility comparable to wild-type littermates. Similarly, inhibition of miR-21 through intravenous delivery of a locked nucleic acid-modified (LNA-modified) antimiR oligonucleotide also failed to block the remodeling response of the heart to stress. We therefore conclude that miR-21 is not essential for pathological cardiac remodeling.

The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y (\"under five\") and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar. Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28-1.08), and for 2006, 0.03 (0.00-0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1-4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period. Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.

Introduction Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). Methods Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. Results Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD ( P  = 0.039), but minimal difference between smokers and non-smokers ( P  = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in α-enolase. Conclusions We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought.

Background Amaranthus tuberculatus (waterhemp) is a troublesome agronomic weed species that is dioecious with an XY sex-determination system. The evolution of the sex-determining region (SDR), the contiguity of the region, genomic landscape, and the expression pattern of genes within the region remain poorly understood. Results We assembled a high-quality, chromosome-level nuclear genome and chloroplast and mitochondrial genomes of a male A. tuberculatus . Combining the genomes with restriction site-associated DNA genome-wide association (RAD-GWA) analysis, comparative genomics, adaptive evolution analysis, and transcriptomic profiling, we identified a ~ 31.8 Mb region on chromosome 1 that is strongly associated with sex. This region is gene-poor, abundant in long terminal repeat (LTR) retrotransposons, and harbors two inversions and a 3.19 Mb haplotype-specific region. Synteny analysis revealed that chromosome 1 likely originated from the fusion of two ancestral chromosomes, and mRNA analysis indicated 76 genes out of the 528 protein-coding genes within the putative SDR of Hap1 were differentially expressed between mature male and female flowers, with several of the genes enriched for Gene Ontology (GO) terms involved in floral development. We further characterized the phosphatidylethanolamine binding protein (PEBP) family in A. tuberculatus and related species to gain insights into FLOWERING LOCUS T diversity, as well as identified nuclear insertions of organellar origin in the species. Conclusion Our results provide insight into the evolution of a sex-associated region in a weedy dioecious species, and the diversity of the PEBP protein family in amaranths. The genomic resources from this study will also be valuable for addressing further questions on adaptive trait evolution within the genus as well as questions surrounding dioecy in this and other plant species.