Publications

<title>Abstract</title> Fungal natural products, including polyketides, are a rich source of bioactive molecules. Their biosynthetic enzymes are encoded within biosynthetic gene clusters, which are often activated by specific environmental conditions. As a result, many natural products are not produced under standard laboratory conditions. Heterologous expression bypasses native regulation, enabling a systematic approach for polyketide discovery. The most widely used fungal hosts for natural product production are Saccharomycetales yeasts, and filamentous Eurotiomycetes. Yeasts are highly tractable but have a narrow product scope due to their limited secondary metabolism, while filamentous Eurotiomycetes have a richer secondary metabolism but are more difficult to engineer. In this work, we established two yeasts of the genera <italic>Exophiala </italic>and <italic>Knufia </italic>as novel heterologous hosts for a broad range of polyketides. These hosts combine the genetic tractability of yeast with the metabolic robustness of filamentous fungi. We developed genetic engineering tools for precise gene integration and genome editing, allowing us to heterologously express five fungal polyketide synthases with different domain architectures, including one involved in the biosynthesis of a previously undescribed 2-pyridone. Our findings demonstrate that these novel yeast hosts can efficiently produce complex polyketides, paving the way for systematic polyketide synthase expression and engineering.

<b>BACKGROUND.</b> Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. <b>METHODS.</b> We used stable isotopic labeling with deuterated water (²H₂O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. <b>RESULTS.</b> The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. <b>CONCLUSIONS.</b> This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. <b>TRIAL REGISTRATION.</b> This trial was registered at clinicaltrials.gov (NCT01752426). <b>FUNDING.</b> This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

Introduction: Suboptimal sleep health is highly prevalent and multiple dimensions of poor sleep have been identified as obesity predictors. Prior sleep interventions have not demonstrated a convincing effect on reducing obesity but this may be due to focusing on a single sleep dimension. The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) is an efficacious, individually tailored behavioral intervention aimed at improving multiple dimensions of sleep. However, TranS-C has not been tested in adults with excess weight and suboptimal sleep health. Purpose: This single group, pre-test, post-test pilot study conducted in adults with excess weight and suboptimal sleep health examined the feasibility and impact of a remotely delivered, 8-week TranS-C intervention on a composite sleep health score and individual sleep health dimensions. Methods: The six dimensions of sleep addressed in TranS-C were regularity, satisfaction, alertness, timing, efficiency, and duration. Pre- and post-intervention individual sleep dimensions were assessed using validated questionnaires and Fitbit-derived accelerometry data, with values dichotomized into ‘good’ or ‘poor’ for each sleep dimension. A composite sleep health score was calculated as the count of the ‘good’ individual dimensions (possible range 0-6). Effect sizes were calculated as standardized within-subject mean differences ( d ) to describe the intervention effect on the composite score and individual dimensions. We conducted post-intervention semi-structured interviews and used thematic analysis to analyze the qualitative data. Results: Participants (N = 7) were mostly female (71.4%) and white (71.4%) with a mean age of 41.0 ± 17.2 years and mean body mass index of 33.2 ± 3.8 kg/m 2 . Mean composite sleep health score pre-TranS-C was 3.6 ± 1.3 (range 2-5) compared to a mean post-TranS-C composite sleep health score of 4.7 ± 0.8 (range 4-6) ( d = 1.27). Improvements were seen in all individual dimensions except timing with effect sizes ranging from 0.38 to 1.46. During the semi-structured interviews, participants stated that they found the intervention to be informative, liked receiving the sessions remotely, and thought it improved their sleep. However, participants mentioned that some of the modules were not very helpful because information was repetitive or the information did not apply to them, and they suggested that the intervention be delivered in fewer sessions. Conclusions: TranS-C was acceptable for participants with overweight or obesity and suboptimal sleep health and had a large, positive effect on the composite sleep health score. Future refinement of the intervention will include reducing the number of sessions by identifying the most relevant modules and eliminating repetitive information. Continued refinement of the intervention will focus on the content addressing the timing dimension of sleep.

Efficient vision works maximize accuracy under a latency budget. These works evaluate accuracy offline, one image at a time. However, real-time vision applications like autonomous driving operate in streaming settings, where ground truth changes between inference start and finish. This results in a significant accuracy drop. Therefore, a recent work proposed to maximize accuracy in streaming settings on average. In this paper, we propose to maximize streaming accuracy for every environment context. We posit that scenario difficulty influences the initial (offline) accuracy difference, while obstacle displacement in the scene affects the subsequent accuracy degradation. Our method, Octopus, uses these scenario properties to select configurations that maximize streaming accuracy at test time. Our method improves tracking performance (S-MOTA) by 7.4% over the conventional static approach. Further, performance improvement using our method comes in addition to, and not instead of, advances in offline accuracy.

We present photometric observations of an apparent Type Ia supernova (SN Ia) at a redshift of approximately 1.7, the farthest SN observed to date. The supernova, SN 1997, was discovered in a repeat observation by the Hubble Space Telescope (HST) of the Hubble Deep Field{North (HDF-N), and serendipitously monitored with NICMOS on HST throughout the Thompson et al. GTO campaign. The SN type can be determined from the host galaxy type: an evolved, red elliptical lacking enough recent star formation to provide a significant population of core-collapse supernovae. The classification is further supported by diagnostics available from the observed colors and temporal behavior of the SN, both of which match a typical SN Ia. The photometric record of the SN includes a dozen flux measurements in the I, J, and H bands spanning 35 days in the observed frame. The redshift derived from the SN photometry, z = 1:7 plus or minus 0:1, is in excellent agreement with the redshift estimate of z = 1:65 plus or minus 0:15 derived from the U_300 B_450 V_-606 I_814 J_110 J_125 H_160 H_165 K_s photometry of the galaxy. Optical and near-infrared spectra of the host provide a very tentative spectroscopic redshift of 1.755. Fits to observations of the SN provide constraints for the redshift-distance relation of SNe Ia and a powerful test of the current accelerating Universe hypothesis. The apparent SN brightness is consistent with that expected in the decelerating phase of the preferred cosmological model, Omega_M approximately equal to 1/3; Omega_Lambda approximately equal to 2/3. It is inconsistent with grey dust or simple luminosity evolution, candidate astrophysical effects which could mimic previous evidence for an accelerating Universe from SNe Ia at z approximately equal to 0:5. We consider several sources of potential systematic error including gravitational lensing, supernova misclassification, sample selection bias, and luminosity calibration errors. Currently, none of these effects alone appears likely to challenge our conclusions. Additional SNe Ia at z &amp;gt; 1 will be required to test more exotic alternatives to the accelerating Universe hypothesis and to probe the nature of dark energy.

The atomic-scale restructuring of hex-Pt(100) induced by carbon monoxide with a wide pressure range was studied with a newly designed chamber-in-chamber high-pressure STM and theoretical calculations. Both experimental and DFT calculation results show that CO molecules are bound to Pt nanoclusters through a tilted on-top configuration with a separation of approximately 3.7-4.1 A. The phenomenon of restructuring of metal catalyst surfaces induced by adsorption and, in particular, the formation of small metallic clusters suggests the importance of studying structures of catalyst surfaces under high-pressure conditions for understanding catalytic mechanisms.