Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.MFS is a systemic disorder of connective tissue caused by mutations in FBN1, the gene encoding fibrillin-1 (1). As a principal component of the extracellular matrix microfibril (2, 3), fibrillin-1 was initially thought to play primarily a structural role in connective tissue. Several lines of evidence support an additional role as a regulator of the cytokine TGF-β (4, 5). Mice homozygous for a hypomorphic Fbn1 allele have impaired pulmonary alveolar septation associated with increased TGF-β signaling that can be prevented by perinatal administration of a polyclonal TGF-β neutralizing antibody (NAb) (5). Similarly, myxomatous

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A database containing microwave single-scattering properties for 11 ice particle shapes is now publicly available and should help practitioners use hitherto difficult-to-assess satellitebased observations of clouds and snowfall.

Direct methods for stereoselective functionalization of C(sp3)–H bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C–H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp3)–CN bond upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90-99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C–H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.

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The direct transformation of C-H bonds into diverse functional groups represents one of the most atom- and step-economical strategies for organic synthesis and has received substantial attention over the last few decades. Despite recent advances, asymmetric C-H bond functionalizations are less developed, especially asymmetric oxidations of sp C-H bonds. Inspired by enzyme (e.g., P450) catalysis, chemists have made great efforts to develop non-enzymatic systems for enantioselective oxidations of sp C-H bonds. However, the involvement of highly reactive radical intermediates makes enantioselective transformations extremely challenging. In this Account, we present our recent studies on the enantioselective induction of prochiral benzylic radicals using a chiral bisoxazoline (Box)/Cu catalytic system. This reaction system was developed on the basis of our extensive studies of copper-catalyzed intermolecular alkene difunctionalizations, such as azidotrifluoromethylations, trifluoromethylcyanations, and trifluoromethylarylations. In these reactions, the proposed catalytic cycle starts from the oxidation of the Cu(I) species by the activated Togni-I reagent (via a Lewis acid/base interaction with a silyl reagent or arylboronic acid) through a single electron transfer process. The generated CF radical can efficiently add to the alkene, and the resultant carbon-centered radical is subsequently trapped by an active Cu(II) species bearing a nucleophile (e.g., an N, CN, or Ar moiety) to form a new C-heteroatom or C-C bond and regenerate the Cu(I) catalyst. Kinetic studies of the trifluoromethylarylation of alkenes support a Cu(I/II/III) catalytic cycle in which the carbon radical reacts with the Cu(II) species to form a highly reactive Cu(III) intermediate and its reductive elimination contributes to the final bond formation. This assumption inspired us to explore asymmetric radical transformations by introducing chiral ligands. Enantioselective cyanations and arylations of benzylic radicals have been demonstrated in the presence of chiral Box/Cu(I) catalysts, and a series of asymmetric difunctionalizations of styrenes have been successfully achieved. In addition, by means of the same benzylic radical trapping process, enantioselective decarboxylative cyanations have been demonstrated using a cooperative photocatalysis and copper catalysis system. Compared with radical addition and decarboxylative processes, hydrogen atom abstraction (HAA) provides direct and facile access to benzylic radicals. By using bisbenzenesulfonimidyl radical for HAA, our group has developed an enantioselective cyanation of benzylic C-H bonds via a copper-catalyzed radical relay, and excellent reactivity and enantioselectivity were achieved in the presence of chiral Box/Cu(I) catalysts. In addition, a regioselective benzylic C-H bond arylation proceeding through a similar process was also developed, providing simple access to 1,1-diarylalkanes. Notably, alkyl arenes were used as the limiting reagent in these reactions, which allowed the late-stage fu...

The tight association between nitrogen status and pathogenesis has been broadly documented in plant–pathogen interactions. However, the interface between primary metabolism and disease responses remains largely unclear. Here, we show that knockout of a single amino acid transporter, LYSINE HISTIDINE TRANSPORTER1 (LHT1), is sufficient for Arabidopsis thaliana plants to confer a broad spectrum of disease resistance in a salicylic acid–dependent manner. We found that redox fine-tuning in photosynthetic cells was causally linked to the lht1 mutant-associated phenotypes. Furthermore, the enhanced resistance in lht1 could be attributed to a specific deficiency of its main physiological substrate, Gln, and not to a general nitrogen deficiency. Thus, by enabling nitrogen metabolism to moderate the cellular redox status, a plant primary metabolite, Gln, plays a crucial role in plant disease resistance.

[1] There has been so far no global estimate of snowfall. CloudSat has, for the first time, provided an opportunity for us to conduct such an estimate. The present study seizes this opportunity and attempts to investigate the global snowfall characteristics using its cloud radar observations. The retrieval methodology developed in this study includes two parts: first, determining whether a radar echo corresponds to snowfall (instead of rainfall), and second, converting radar reflectivity to snowfall rate. The first part is a snow-rain threshold based on multiyear land station and shipboard present weather reports, and the second part is based on backscatter computations of nonspherical ice particles and in situ measured particle size distributions. Using the above retrieval method, global CloudSat data over 1 year were analyzed. The results show the following. (1) In the Southern Hemisphere, there is an almost zonally orientated high snowfall zone centered around 60°S, where both snowfall frequency and rate are high. In the Northern Hemisphere, however, heavy/frequent snowfall areas are mostly locked to geographical locations. (2) Zonally and annually averaged snowfall rate has its maximum value around 2 mm d À1 , which is about one third of the zonally averaged rainfall values found in the tropics, signifying the importance of snowfall in hydrological cycle. (3) Vertical profiles of snowfall rate have the greatest variability in the lowest levels. While near-surface snowfall rate generally increases with cloud top height, there seems to be two prevailing groups of clouds with very different growth rate of snowfall as cloud top height increases. (4) The characteristics of the vertical distribution of snowfall rate are quite similar for over-ocean and over-land snow clouds, except that over-land snow clouds seem to be somewhat shallower than those over ocean.