Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

The Goddard profiling algorithm has evolved from a pseudoparametric algorithm used in the current TRMM operational product (GPROF 2010) to a fully parametric approach used operationally in the GPM era (GPROF 2014). The fully parametric approach uses a Bayesian inversion for all surface types. The algorithm thus abandons rainfall screening procedures and instead uses the full brightness temperature vector to obtain the most likely precipitation state. This paper offers a complete description of the GPROF 2010 and GPROF 2014 algorithms and assesses the sensitivity of the algorithm to assumptions related to channel uncertainty as well as ancillary data. Uncertainties in precipitation are generally less than 1%–2% for realistic assumptions in channel uncertainties. Consistency among different radiometers is extremely good over oceans. Consistency over land is also good if the diurnal cycle is accounted for by sampling GMI product only at the time of day that different sensors operate. While accounting for only a modest amount of the total precipitation, snow-covered surfaces exhibit differences of up to 25% between sensors traceable to the availability of high-frequency (166 and 183 GHz) channels. In general, comparisons against early versions of GPM’s Ku-band radar precipitation estimates are fairly consistent but absolute differences will be more carefully evaluated once GPROF 2014 is upgraded to use the full GPM-combined radar–radiometer product for its a priori database. The combined algorithm represents a physically constructed database that is consistent with both the GPM radars and the GMI observations, and thus it is the ideal basis for a Bayesian approach that can be extended to an arbitrary passive microwave sensor.

Streptococcus agalactiae (group B streptococcus [GBS]) is a Gram-positive bacterium found in the female rectovaginal tract and is capable of producing severe disease in susceptible hosts, including newborns and pregnant women. The vaginal tract is considered a major reservoir for GBS, and maternal vaginal colonization poses a significant risk to the newborn; however, little is known about the specific bacterial factors that promote GBS colonization and persistence in the female reproductive tract. We have developed in vitro models of GBS interaction with the human female cervicovaginal tract using human vaginal and cervical epithelial cell lines. Analysis of isogenic mutant GBS strains deficient in cell surface organelles such as pili and serine-rich repeat (Srr) proteins shows that these factors contribute to host cell attachment. As Srr proteins are heavily glycosylated, we confirmed that carbohydrate moieties contribute to the effective interaction of Srr-1 with vaginal epithelial cells. Antibody inhibition assays identified keratin 4 as a possible host receptor for Srr-1. Our findings were further substantiated in an in vivo mouse model of GBS vaginal colonization, where mice inoculated with an Srr-1-deficient mutant exhibited decreased GBS vaginal persistence compared to those inoculated with the wild-type (WT) parental strain. Furthermore, competition experiments in mice showed that WT GBS exhibited a significant survival advantage over the ⌬pilA or ⌬srr-1 mutant in the vaginal tract. Our results suggest that these GBS surface proteins contribute to vaginal colonization and may offer new insights into the mechanisms of vaginal niche establishment.Group B streptococcus (GBS) is the leading cause of neonatal meningitis and sepsis in the developed world and also causes serious invasive infections in certain adult populations (54). GBS can be isolated from the rectovaginal tracts of up to 30% of women (16,38), and it can be transmitted to infants during birth through the aspiration of vaginal fluids or cross the placental barrier in utero (7,18). GBS neonatal infection is divided into two categories, early-onset (Ͻ7 days old) and late-onset (7 to 90 days old) disease. Due to the serious nature of GBS infection, pregnant women in the United States are routinely screened for GBS vaginal colonization late in the third trimester of pregnancy; a positive test results in the administration of antibiotics during birth to reduce the risk of GBS transfer to the newborn. Despite this intervention, the incidence of early-onset GBS infection in the United States remains at 1 in 3,000 live births, corresponding to approximately 1,200 infected infants per year (54). There is also evidence that infection rates are much higher among some ethnic groups and in infants delivered at Ͻ37 weeks of gestation (42,43,54,62). Additionally, antibiotic prophylaxis does not prevent late-onset disease.Most women are intermittently asymptomatically colonized by GBS in the genitourinary tract (19); however, colonization poses a significant r...

For patients with C. freundii bacteremia, carrying the bla resistance gene was an independent risk factor for 28-day mortality. Carbapenems, fourth-generation cephalosporins, amikacin, and quinolones are still reliable agents for drug-resistant strains.

Abstract-WindSat is a space-based polarimetric microwave radiometer designed to demonstrate the capability to measure the ocean surface wind vector using a radiometer. We describe a nonlinear iterative algorithm for simultaneous retrieval of sea surface temperature, columnar water vapor, columnar cloud liquid water, and the ocean surface wind vector from WindSat measurements. The algorithm uses a physically based forward model function for the WindSat brightness temperatures. Empirical corrections to the physically based model are discussed. We present evaluations of initial retrieval performance using a six-month dataset of WindSat measurements and collocated data from other satellites and a numerical weather model. We focus primarily on the application to wind vector retrievals.