Cytochrome P450-catalyzed insertion of carbenoids into N–H bonds

Expanding nature’s catalytic repertoire to include reactions important in synthetic chemistry will open new opportunities for ‘green’ chemistry and biosynthesis. We demonstrate the first enzyme-catalyzed insertion of carbenoids into N–H bonds. This type of bond disconnection, which has no counterpart in nature, can be mediated by variants of the cytochrome P450 from Bacillus megaterium. The N–H insertion reaction takes place in water, provides the desired products in 26–83% yield, forms the single addition product exclusively, and does not require slow addition of the diazo component

Academic Undermatching of High-Achieving Minority Students: Evidence from Race-Neutral and Holistic Admissions Policies

College is a pathway to social mobility in the United States. Yet too often high-achieving students from low-income and minorities families fail to apply to selective postsecondary institutions. Our study examines the extent to which academic undermatching occurs among high-achieving minority students by analyzing the application choices of students who undergo two distinct admissions policies. We find that minority students eligible for automatic admissions and those who undergo holistic admissions are both less likely to apply to elite flagship universities than white students, despite being equally qualified based on high school performance. Instead, minorities often opt for lower tier universities. </jats:p

Improved Cyclopropanation Activity of Histidine-Ligated Cytochrome P450 Enables the Enantioselective Formal Synthesis of Levomilnacipran

Engineering enzymes capable of modes of activation unprecedented in nature will increase the range of industrially important molecules that can be synthesized through biocatalysis. However, low activity for a new function is often a limitation in adopting enzymes for preparative-scale synthesis, reaction with demanding substrates, or when a natural substrate is also present. By mutating the proximal ligand and other key active-site residues of the cytochrome P450 enzyme from Bacillus megaterium (P450-BM3), a highly active His-ligated variant of P450-BM3 that can be employed for the enantioselective synthesis of the levomilnacipran core was engineered. This enzyme, BM3-Hstar, catalyzes the cyclopropanation of N,N-diethyl-2-phenylacrylamide with an estimated initial rate of over 1000 turnovers per minute and can be used under aerobic conditions. Cyclopropanation activity is highly dependent on the electronic properties of the P450 proximal ligand, which can be used to tune this non-natural enzyme activity

Enteropathogen antibody dynamics and force of infection among children in low-resource settings.

Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG responses to eight enteropathogens (Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni, norovirus) in cohorts from Haiti, Kenya, and Tanzania. We studied antibody dynamics and force of infection across pathogens and cohorts. Enteropathogens shared common seroepidemiologic features that enabled between-pathogen comparisons of transmission. Overall, exposure was intense: for most pathogens the window of primary infection was &lt;3 years old; for highest transmission pathogens primary infection occurred within the first year. Longitudinal profiles demonstrated significant IgG boosting and waning above seropositivity cutoffs, underscoring the value of longitudinal designs to estimate force of infection. Seroprevalence and force of infection were rank-preserving across pathogens, illustrating the measures provide similar information about transmission heterogeneity. Our findings suggest antibody response can be used to measure population-level transmission of diverse enteropathogens in serologic surveillance

Functional characterization of C. elegans Y-box-binding proteins reveals tissue-specific functions and a critical role in the formation of polysomes

The cold shock domain is one of the most highly conserved motifs between bacteria and higher eukaryotes. Y-box-binding proteins represent a subfamily of cold shock domain proteins with pleiotropic functions, ranging from transcription in the nucleus to translation in the cytoplasm. These proteins have been investigated in all major model organisms except Caenorhabditis elegans. In this study, we set out to fill this gap and present a functional characterization of CEYs, the C. elegans Y-box-binding proteins. We find that, similar to other organisms, CEYs are essential for proper gametogenesis. However, we also report a novel function of these proteins in the formation of large polysomes in the soma. In the absence of the somatic CEYs, polysomes are dramatically reduced with a simultaneous increase in monosomes and disomes, which, unexpectedly, has no obvious impact on animal biology. Because transcripts that are enriched in polysomes in wild-type animals tend to be less abundant in the absence of CEYs, our findings suggest that large polysomes might depend on transcript stabilization mediated by CEY protein

Flower colour within communities shifts from overdispersed to clustered along an alpine altitudinal gradient

Altitudinal gradients are interesting models to test the effect of biotic and abiotic drivers of floral colour diversity, since an increase in UV irradiance, decrease of pollinator availability and shifts from bee- to fly-pollination in high relative to low altitudes are expected. We tested the effect of altitude and phylogeny, using several chromatic and achromatic colour properties, UV-reflectance and pollinators’ discrimination capacity (Apis mellifera, Bombus terrestris, Musca do-mestica and Eristalis tenax), to understand the floral colour diversity in an alpine altitudinal gradi-ent. All colour properties were weakly related to phylogeny. We found a shift from overdispersed floral colours and high chromatic contrast with the background (for bees) in the low altitude, to clustered floral colours (UV and green range for bees and flies) and clustered chromatic and achro-matic properties in the high altitude. Different from flies, bees could discriminate floral colours in all altitudinal ranges. Low altitudes are likely to exhibit suitable conditions for more plant species, in-creasing competition for pollinators and floral colour divergence. Conversely, the increase in UV-irradiance in high altitudes may filter plants with specific floral UV-reflectance patterns. Overall, floral colour diversity suggests that both biotic (pollinator fauna) and abiotic (UV-irradiance) drivers shape floral communities, but their importance changes with altitude

A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient after Priming with RRx-001

As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high- and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT, NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status.Peer reviewe