Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups.

In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si-C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity experiments and fluorophore-release studies on proteins and in zebrafish embryos. By combining tetrazylmethyl derivatives with previously reported tetrazine-responsive 3-isocyanopropyl groups, it was possible to liberate two fluorophores in vertebrates from a single bioorthogonal reaction. This chemistry will open new opportunities towards applications involving multiplexed release schemes and is a valuable asset to the growing toolbox of bioorthogonal dissociative reactions

Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens.

BACKGROUND:Breast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. This demonstrates the need for techniques capable of providing personalized feedback about treatment response at the earliest stages of therapy to identify patients likely to benefit from changing treatment. Diffuse optical spectroscopic imaging (DOSI) has emerged as a promising functional imaging technique for NAC monitoring. DOSI uses non-ionizing near-infrared light to provide non-invasive measures of absolute concentrations of tissue chromophores such as oxyhemoglobin. In 2011, we reported a new DOSI prognostic marker, oxyhemoglobin flare: a transient increase in oxyhemoglobin capable of discriminating NAC responders within the first day of treatment. In this follow-up study, DOSI was used to confirm the presence of the flare as well as to investigate whether DOSI markers of NAC response are regimen dependent. METHODS:This dual-center study examined 54 breast tumors receiving NAC measured with DOSI before therapy and the first week following chemotherapy administration. Patients were treated with either a standard of care maximum tolerated dose (MTD) regimen or an investigational metronomic (MET) regimen. Changes in tumor chromophores were tracked throughout the first week and compared to pathologic response and treatment regimen at specific days utilizing generalized estimating equations (GEE). RESULTS:Within patients receiving MTD therapy, the oxyhemoglobin flare was confirmed as a prognostic DOSI marker for response appearing as soon as day 1 with post hoc GEE analysis demonstrating a difference of 48.77% between responders and non-responders (p < 0.0001). Flare was not observed in patients receiving MET therapy. Within all responding patients, the specific treatment was a significant predictor of day 1 changes in oxyhemoglobin, showing a difference of 39.45% (p = 0.0010) between patients receiving MTD and MET regimens. CONCLUSIONS:DOSI optical biomarkers are differentially sensitive to MTD and MET regimens at early timepoints suggesting the specific treatment regimen should be considered in future DOSI studies. Additionally, DOSI may help to identify regimen-specific responses in a more personalized manner, potentially providing critical feedback necessary to implement adaptive changes to the treatment strategy

Bromocriptine Improves Glucose Tolerance Independent of Circadian Timing, Prolactin, Or the Melanocortin-4 Receptor

Bromocriptine, a dopamine D2 receptor agonist originally used for the treatment of hyperprolactinemia, is largely successful in reducing hyperglycemia and improving glucose tolerance in type 2 diabetics. However, the mechanism behind bromocriptine’s effect on glucose intolerance is unclear. Here, we tested three hypotheses, that bromocriptine may exert its effects on glucose metabolism by 1) decreasing prolactin secretion, 2) indirectly increasing activity of key melanocortin receptors in the central nervous system, or 3) improving/restoring circadian rhythms. Using a diet-induced obese (DIO) mouse model, we established that a 2-wk treatment of bromocriptine is robustly effective at improving glucose tolerance. We then demonstrated that bromocriptine is effective at improving the glucose tolerance of both DIO prolactin-deficient and melanocortin-4 receptor (MC4R)-deficient mice, pointing to bromocriptine’s ability to affect glucose tolerance independently of prolactin or MC4R signaling. Finally, we tested bromocriptine’s dependence on the circadian system by testing its effectiveness in environmental (e.g., repeated shifts to the light-dark cycle) and genetic (e.g., the Clock mutant mouse) models of circadian disruption. In both models of circadian disruption, bromocriptine was effective at improving glucose tolerance, indicating that a functional or well-aligned endogenous clock is not necessary for bromocriptine’s effects on glucose metabolism. Taken together, these results do not support the role of prolactin, MC4R, or the circadian clock as integral to bromocriptine’s underlying mechanism. Instead, we find that bromocriptine is a robust diabetic treatment and resilient to genetically induced obesity, diabetes, and circadian disruption

The Luminosities of Protostars in the Spitzer c2d and Gould Belt Legacy Clouds

Motivated by the long-standing "luminosity problem" in low-mass star formation whereby protostars are underluminous compared to theoretical expectations, we identify 230 protostars in 18 molecular clouds observed by two Spitzer Space Telescope Legacy surveys of nearby star-forming regions. We compile complete spectral energy distributions, calculate Lbol for each source, and study the protostellar luminosity distribution. This distribution extends over three orders of magnitude, from 0.01 Lsun - 69 Lsun, and has a mean and median of 4.3 Lsun and 1.3 Lsun, respectively. The distributions are very similar for Class 0 and Class I sources except for an excess of low luminosity (Lbol < 0.5 Lsun) Class I sources compared to Class 0. 100 out of the 230 protostars (43%) lack any available data in the far-infrared and submillimeter (70 um < wavelength < 850 um) and have Lbol underestimated by factors of 2.5 on average, and up to factors of 8-10 in extreme cases. Correcting these underestimates for each source individually once additional data becomes available will likely increase both the mean and median of the sample by 35% - 40%. We discuss and compare our results to several recent theoretical studies of protostellar luminosities and show that our new results do not invalidate the conclusions of any of these studies. As these studies demonstrate that there is more than one plausible accretion scenario that can match observations, future attention is clearly needed. The better statistics provided by our increased dataset should aid such future work.Comment: Accepted for publication in AJ. 21 pages, 10 figures, 4 table

Young Stellar Objects in the Gould Belt

We present the full catalog of Young Stellar Objects (YSOs) identified in the 18 molecular clouds surveyed by the Spitzer Space Telescope "cores to disks" (c2d) and "Gould Belt" (GB) Legacy surveys. Using standard techniques developed by the c2d project, we identify 3239 candidate YSOs in the 18 clouds, 2966 of which survive visual inspection and form our final catalog of YSOs in the Gould Belt. We compile extinction corrected SEDs for all 2966 YSOs and calculate and tabulate the infrared spectral index, bolometric luminosity, and bolometric temperature for each object. We find that 326 (11%), 210 (7%), 1248 (42%), and 1182 (40%) are classified as Class 0+I, Flat-spectrum, Class II, and Class III, respectively, and show that the Class III sample suffers from an overall contamination rate by background AGB stars between 25% and 90%. Adopting standard assumptions, we derive durations of 0.40-0.78 Myr for Class 0+I YSOs and 0.26-0.50 Myr for Flat-spectrum YSOs, where the ranges encompass uncertainties in the adopted assumptions. Including information from (sub)millimeter wavelengths, one-third of the Class 0+I sample is classified as Class 0, leading to durations of 0.13-0.26 Myr (Class 0) and 0.27-0.52 Myr (Class I). We revisit infrared color-color diagrams used in the literature to classify YSOs and propose minor revisions to classification boundaries in these diagrams. Finally, we show that the bolometric temperature is a poor discriminator between Class II and Class III YSOs.Comment: Accepted for publication in ApJS. 29 pages, 11 figures, 14 tables, 4 appendices. Full versions of data tables (to be published in machine-readable format by ApJS) available at the end of the latex source cod

The Spitzer Survey of Interstellar Clouds in the Gould Belt. VI. The Auriga-California Molecular Cloud observed with IRAC and MIPS

We present observations of the Auriga-California Molecular Cloud (AMC) at 3.6, 4.5, 5.8, 8.0, 24, 70 and 160 micron observed with the IRAC and MIPS detectors as part of the Spitzer Gould Belt Legacy Survey. The total mapped areas are 2.5 sq-deg with IRAC and 10.47 sq-deg with MIPS. This giant molecular cloud is one of two in the nearby Gould Belt of star-forming regions, the other being the Orion A Molecular Cloud (OMC). We compare source counts, colors and magnitudes in our observed region to a subset of the SWIRE data that was processed through our pipeline. Using color-magnitude and color-color diagrams, we find evidence for a substantial population of 166 young stellar objects (YSOs) in the cloud, many of which were previously unknown. Most of this population is concentrated around the LkHalpha 101 cluster and the filament extending from it. We present a quantitative description of the degree of clustering and discuss the fraction of YSOs in the region with disks relative to an estimate of the diskless YSO population. Although the AMC is similar in mass, size and distance to the OMC, it is forming about 15 - 20 times fewer stars.Comment: (30 pages, 17 figures (2 multipage figures), accepted for publication in ApJ

Photocarrier lifetime and transport in silicon supersaturated with sulfur

Doping of silicon-on-insulator layers with sulfur to concentrations far above equilibrium by ion implantation and pulsed laser melting can result in large concentration gradients. Photocarriers generated in and near the impurity gradient can separate into different coplanar transport layers, leading to enhanced photocarrier lifetimes in thin silicon-on-insulator films. The depth from which holes escape the heavily doped region places a lower limit on the minority carrier mobility-lifetime product of 10⁻⁸ cm²/V for heavily sulfur dopedsilicon. We conclude that the cross-section for recombination through S impurities at this concentration is significantly reduced relative to isolated impurities.Research at Rensselaer was supported by the Army Research Office under Contract No. W911NF0910470 and by the NSF REU program at Rensselaer. Research at Harvard was supported by US Army ARDEC under Contract No. W15QKN-07-P-0092. D.R. was supported in part by a National Defense Science and Engineering Graduate fellowship

High optode-density wearable diffuse optical probe for monitoring paced breathing hemodynamics in breast tissue

Significance: Diffuse optical imaging (DOI) provides in vivo quantification of tissue chromophores such as oxy- and deoxyhemoglobin ([Formula: see text] and HHb, respectively). These parameters have been shown to be useful for predicting neoadjuvant treatment response in breast cancer patients. However, most DOI devices designed for the breast are nonportable, making frequent longitudinal monitoring during treatment a challenge. Furthermore, hemodynamics related to the respiratory cycle are currently unexplored in the breast and may have prognostic value. Aim: To design, fabricate, and validate a high optode-density wearable continuous wave diffuse optical probe for the monitoring of breathing hemodynamics in breast tissue. Approach: The probe has a rigid-flex design with 16 dual-wavelength sources and 16 detectors. Performance was characterized on tissue-simulating phantoms, and validation was performed through flow phantom and cuff occlusion measurements. The breasts of [Formula: see text] healthy volunteers were measured while performing a breathing protocol. Results: The probe has 512 unique source–detector (S-D) pairs that span S-D separations of 10 to 54 mm. It exhibited good performance characteristics: [Formula: see text] drift of 0.34%/h, [Formula: see text] precision of 0.063%, and mean [Formula: see text] up to 41 mm S-D separation. Absorption contrast was detected in flow phantoms at depths exceeding 28 mm. A cuff occlusion measurement confirmed the ability of the probe to track expected hemodynamics in vivo. Breast measurements on healthy volunteers during paced breathing revealed median signal-to-motion artifact ratios ranging from 8.1 to 8.7 dB. Median [Formula: see text] and [Formula: see text] amplitudes ranged from 0.39 to [Formula: see text] and 0.08 to [Formula: see text] , respectively. Median oxygen saturations at the respiratory rate ranged from 82% to 87%. Conclusions: A wearable diffuse optical probe has been designed and fabricated for the measurement of breast tissue hemodynamics. This device is capable of quantifying breathing-related hemodynamics in healthy breast tissue