Total syntheses of conformationally-locked difluorinated pentopyranose analogues and a pentopyranosyl phosphate mimetic

Trifluoroethanol has been elaborated, via a telescoped sequence involving a metalated difluoroenol, a difluoroallylic alcohol, [2,3]-Wittig rearrangement, and ultimately an RCM reaction and requiring minimal intermediate purification, to a number of cyclooctenone intermediates. Epoxidation of these intermediates followed by transannular ring opening or dihydroxylation, then transannular hemiacetalization delivers novel bicyclic analogues of pentopyranoses, which were elaborated (in one case) to an analogue of a glycosyl phosphate

Genomic characterization of pediatric B‐lymphoblastic lymphoma and B‐lymphoblastic leukemia using formalin‐fixed tissues

BackgroundRecurrent genomic changes in B‐lymphoblastic leukemia (B‐ALL) identified by genome‐wide single‐nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B‐lymphoblastic lymphoma (B‐LBL), is limited by the low incidence and lack of fresh tissue for genomic testing.ProcedureWe used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin‐fixed paraffin‐embedded pediatric B‐LBL (n = 23) and B‐ALL (n = 55).ResultsSimilar to B‐ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B‐LBL cases. Eleven of 23 (48%) B‐LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B‐ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B‐LBL, respectively, which was similar to the reported frequency in B‐ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B‐LBL cases, compared with only 1% in B‐ALL samples. None of the B‐LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B‐ALL.ConclusionsOur study demonstrates that the copy number profile of B‐LBL is distinct from B‐ALL, suggesting possible differences in pathogenesis between these closely related diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/1/pbc26363.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/2/pbc26363_am.pd

An L Band Spectrum of the Coldest Brown Dwarf

The coldest brown dwarf, WISE 0855, is the closest known planetary-mass, free-floating object and has a temperature nearly as cold as the solar system gas giants. Like Jupiter, it is predicted to have an atmosphere rich in methane, water, and ammonia, with clouds of volatile ices. WISE 0855 is faint at near-infrared wavelengths and emits almost all its energy in the mid-infrared. Skemer et al. 2016 presented a spectrum of WISE 0855 from 4.5-5.1 micron (M band), revealing water vapor features. Here, we present a spectrum of WISE 0855 in L band, from 3.4-4.14 micron. We present a set of atmosphere models that include a range of compositions (metallicities and C/O ratios) and water ice clouds. Methane absorption is clearly present in the spectrum. The mid-infrared color can be better matched with a methane abundance that is depleted relative to solar abundance. We find that there is evidence for water ice clouds in the M band spectrum, and we find a lack of phosphine spectral features in both the L and M band spectra. We suggest that a deep continuum opacity source may be obscuring the near-infrared flux, possibly a deep phosphorous-bearing cloud, ammonium dihyrogen phosphate. Observations of WISE 0855 provide critical constraints for cold planetary atmospheres, bridging the temperature range between the long-studied solar system planets and accessible exoplanets. JWST will soon revolutionize our understanding of cold brown dwarfs with high-precision spectroscopy across the infrared, allowing us to study their compositions and cloud properties, and to infer their atmospheric dynamics and formation processes.Comment: 19 pages, 21 figures. Accepted for publication in Ap

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

Pathogenesis and treatment of chronic pulmonary disease

Combining sequence-based prediction methods and circular dichroism and infrared spectroscopic data to improve protein secondary structure determinations

<p>Abstract</p> <p>Background</p> <p>A number of sequence-based methods exist for protein secondary structure prediction. Protein secondary structures can also be determined experimentally from circular dichroism, and infrared spectroscopic data using empirical analysis methods. It has been proposed that comparable accuracy can be obtained from sequence-based predictions as from these biophysical measurements. Here we have examined the secondary structure determination accuracies of sequence prediction methods with the empirically determined values from the spectroscopic data on datasets of proteins for which both crystal structures and spectroscopic data are available.</p> <p>Results</p> <p>In this study we show that the sequence prediction methods have accuracies nearly comparable to those of spectroscopic methods. However, we also demonstrate that combining the spectroscopic and sequences techniques produces significant overall improvements in secondary structure determinations. In addition, combining the extra information content available from synchrotron radiation circular dichroism data with sequence methods also shows improvements.</p> <p>Conclusion</p> <p>Combining sequence prediction with experimentally determined spectroscopic methods for protein secondary structure content significantly enhances the accuracy of the overall results obtained.</p

Dialectic tensions in the financial markets: a longitudinal study of pre- and post-crisis regulatory technology

This article presents the findings from a longitudinal research study on regulatory technology in the UK financial services industry. The financial crisis with serious corporate and mutual fund scandals raised the profile of compliance as governmental bodies, institutional and private investors introduced a ‘tsunami’ of financial regulations. Adopting a multi-level analysis, this study examines how regulatory technology was used by financial firms to meet their compliance obligations, pre- and post-crisis. Empirical data collected over 12 years examine the deployment of an investment management system in eight financial firms. Interviews with public regulatory bodies, financial institutions and technology providers reveal a culture of compliance with increased transparency, surveillance and accountability. Findings show that dialectic tensions arise as the pursuit of transparency, surveillance and accountability in compliance mandates is simultaneously rationalized, facilitated and obscured by regulatory technology. Responding to these challenges, regulatory bodies continue to impose revised compliance mandates on financial firms to force them to adapt their financial technologies in an ever-changing multi-jurisdictional regulatory landscape

Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression

BACKGROUND: Sapphyrin analogues and related porphyrin-like species have attracted attention as anticancer agents due to their selective localization in various cancers, including hematologic malignancies, relative to surrounding tissues. Sapphyrins are electron affinic compounds that generate high yields of singlet oxygen formation. Although initially explored in the context of photodynamic therapy, sapphyrins have intrinsic anticancer activity that is independent of their photosensitizing properties. However, the mechanisms for their anticancer activity have not been fully elucidated. RESULTS: We have prepared a series of hydrophilic sapphyrins and evaluated their effect on proliferation, uptake, and cell death in adherent human lung (A549) and prostate (PC3) cancer cell lines and in an A549 xenograft tumor model. PCI-2050, the sapphyrin derivative with the highest in vitro growth inhibitory activity, significantly lowered 5-bromo-2'-deoxyuridine incorporation in S-phase A549 cells by 60% within eight hours and increased levels of reactive oxygen species within four hours. The growth inhibition pattern of PCI-2050 in the National Cancer Institute 60 cell line screen correlated most closely using the COMPARE algorithm with known transcriptional or translational inhibitors. Gene expression analyses conducted on A549 plateau phase cultures treated with PCI-2050 uncovered wide-spread decreases in mRNA levels, which especially affected short-lived transcripts. Intriguingly, PCI-2050 increased the levels of transcripts involved in RNA processing and trafficking, transcriptional regulation, and chromatin remodeling. We propose that these changes reflect the activation of cellular processes aimed at countering the observed wide-spread reductions in transcript levels. In our A549 xenograft model, the two lead compounds, PCI-2050 and PCI-2022, showed similar tumor distributions despite differences in plasma and kidney level profiles. This provides a possible explanation for the better tolerance of PCI-2022 relative to PCI-2050. CONCLUSION: Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression

An L Band Spectrum of the Coldest Brown Dwarf

The coldest brown dwarf, WISE 0855, is the closest known planetary-mass, free-floating object and has a temperature nearly as cold as the solar system gas giants. Like Jupiter, it is predicted to have an atmosphere rich in methane, water, and ammonia, with clouds of volatile ices. WISE 0855 is faint at near-infrared wavelengths and emits almost all its energy in the mid-infrared. Skemer et al. (2016) presented a spectrum of WISE 0855 from 4.5–5.1 µm (M band), revealing water vapor features. Here, we present a spectrum of WISE 0855 in L band, from 3.4–4.14 µm. We present a set of atmosphere models that include a range of compositions (metallicities and C/O ratios) and water ice clouds. Methane absorption is clearly present in the spectrum. The mid-infrared color can be better matched with a methane abundance that is depleted relative to solar abundance. We find that there is evidence for water ice clouds in the M band spectrum, and we find a lack of phosphine spectral features in both the L and M band spectra. We suggest that a deep continuum opacity source may be obscuring the near-infrared flux, possibly a deep phosphorous-bearing cloud, ammonium dihyrogen phosphate. Observations of WISE 0855 provide critical constraints for cold planetary atmospheres, bridging the temperature range between the long-studied solar system planets and accessible exoplanets. JWST will soon revolutionize our understanding of cold brown dwarfs with high-precision spectroscopy across the infrared, allowing us to study their compositions and cloud properties, and to infer their atmospheric dynamics and formation processes

Theta/delta coupling across cortical laminae contributes to semantic cognition

Rhythmic activity in populations of neurons is associated with cognitive and motor function. Our understanding of the neuronal mechanisms underlying these core brain functions has benefitted from demonstrations of cellular, synaptic, and network phenomena, leading to the generation of discrete rhythms at the local network level. However, discrete frequencies of rhythmic activity rarely occur alone. Despite this, little is known about why multiple rhythms are generated together or what mechanisms underlie their interaction to promote brain function. One overarching theory is that different temporal scales of rhythmic activity correspond to communication between brain regions separated by different spatial scales. To test this, we quantified the cross-frequency interactions between two dominant rhythms-theta and delta activity-manifested during magnetoencephalography recordings of subjects performing a word-pair semantic decision task. Semantic processing has been suggested to involve the formation of functional links between anatomically disparate neuronal populations over a range of spatial scales, and a distributed network was manifest in the profile of theta-delta coupling seen. Furthermore, differences in the pattern of theta-delta coupling significantly correlated with semantic outcome. Using an established experimental model of concurrent delta and theta rhythms in neocortex, we show that these outcome-dependent dynamics could be reproduced in a manner determined by the strength of cholinergic neuromodulation. Theta-delta coupling correlated with discrete neuronal activity motifs segregated by the cortical layer, neuronal intrinsic properties, and long-range axonal targets. Thus, the model suggested that local, interlaminar neocortical theta-delta coupling may serve to coordinate both cortico-cortical and cortico-subcortical computations during distributed network activity. NEW & NOTEWORTHY Here, we show, for the first time, that a network of spatially distributed brain regions can be revealed by cross-frequency coupling between delta and theta frequencies in subjects using magnetoencephalography recording during a semantic decision task. A biological model of this cross-frequency coupling suggested an interlaminar, cell-specific division of labor within the neocortex may serve to route the flow of cortico-cortical and cortico-subcortical information to promote such spatially distributed, functional networks