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Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.

Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define their interactomes is lacking. Here, we demonstrate that genetic incorporation of the photo-crosslinking noncanonical amino acid AbK into SEP transgenes allows for the facile identification of SEP cellular interaction partners using affinity-based methods. From a survey of seven SEPs, we report the discovery of short ORF-encoded histone binding protein (SEHBP), a conserved microprotein that interacts with chromatin-associated proteins, localizes to discrete genomic loci, and induces a robust transcriptional program when overexpressed in human cells. This work affords a straightforward method to help define the physiological roles of SEPs and demonstrates its utility by identifying SEHBP as a short ORF-encoded transcription factor.

Land surface albedo is a key parameter controlling the local energy budget, and altering the albedo of built surfaces has been proposed as a tool to mitigate high near‐surface temperatures in the urban heat island. However, most research on albedo in urban landscapes has used coarse‐resolution data, and few studies have attempted to relate albedo to other urban land cover characteristics. This study provides an empirical description of urban summertime albedo using 30 m remote sensing measurements in the metropolitan area around Boston, Massachusetts, relating albedo to metrics of impervious cover fraction, tree canopy coverage, population density, and land surface temperature (LST). At 30 m spatial resolution, median albedo over the study area (excluding open water) was 0.152 (0.112–0.187). Trends of lower albedo with increasing urbanization metrics and temperature emerged only after aggregating data to 500 m or the boundaries of individual towns, at which scale a −0.01 change in albedo was associated with a 29 (25–35)% decrease in canopy cover, a 27 (24–30)% increase in impervious cover, and an increase in population from 11 to 386 km−2. The most intensively urbanized towns in the region showed albedo up to 0.035 lower than the least urbanized towns, and mean mid‐morning LST 12.6°C higher. Trends in albedo derived from 500 m Moderate Resolution Imaging Spectroradiometer (MODIS) measurements were comparable, but indicated a strong contribution of open water at this coarser resolution. These results reveal linkages between albedo and urban land cover character, and offer empirical context for climate resilient planning and future landscape functional changes with urbanization. Key Points Albedo is a factor in urban surface energy balance, but has not been measured at high resolution or related to land cover characteristics Combining data from Landsat and MODIS, we find albedo declined about 3% from the least to most developed areas across the Boston region Trends between albedo and land cover were sensitive to the influence of low‐albedo open water, and spatial scale of the analysis

Models for light dark matter particles with masses below 1 GeV/c 2 are a natural and well-motivated alternative to so-far unobserved weakly interacting massive particles. Gram-scale cryogenic calorimeters provide the required detector performance to detect these particles and extend the direct dark matter search program of CRESST. A prototype 0.5 g sapphire detector developed for the ν -cleus experiment has achieved an energy threshold of E t h = ( 19.7 ± 0.9 )  eV. This is one order of magnitude lower than for previous devices and independent of the type of particle interaction. The result presented here is obtained in a setup above ground without significant shielding against ambient and cosmogenic radiation. Although operated in a high-background environment, the detector probes a new range of light-mass dark matter particles previously not accessible by direct searches. We report the first limit on the spin-independent dark matter particle-nucleon cross section for masses between 140 and 500 MeV/c 2 .

The CRESST-II experiment uses cryogenic detectors to search for nuclear recoil events induced by the elastic scattering of dark matter particles in CaWO 4  crystals. Given the low energy threshold of our detectors in combination with light target nuclei, low mass dark matter particles can be probed with high sensitivity. In this letter we present the results from data of a single detector module corresponding to 52 kg live days. A blind analysis is carried out. With an energy threshold for nuclear recoils of 307 eV we substantially enhance the sensitivity for light dark matter. Thereby, we extend the reach of direct dark matter experiments to the sub- GeV/ c 2  region and demonstrate that the energy threshold is the key parameter in the search for low mass dark matter particles.

Models for light dark matter particles with masses below 1 GeV/c [Formula omitted] are a natural and well-motivated alternative to so-far unobserved weakly interacting massive particles. Gram-scale cryogenic calorimeters provide the required detector performance to detect these particles and extend the direct dark matter search program of CRESST. A prototype 0.5 g sapphire detector developed for the [Formula omitted]-cleus experiment has achieved an energy threshold of [Formula omitted] eV. This is one order of magnitude lower than for previous devices and independent of the type of particle interaction. The result presented here is obtained in a setup above ground without significant shielding against ambient and cosmogenic radiation. Although operated in a high-background environment, the detector probes a new range of light-mass dark matter particles previously not accessible by direct searches. We report the first limit on the spin-independent dark matter particle-nucleon cross section for masses between 140 and 500 MeV/c [Formula omitted].

IntroductionWe previously demonstrated that the difference between 11 PM and 8 AM TSH response to protirelin (TRH) tests on the same day (∆∆TSH test) is an improved measure in detecting hypothalamic-pituitary-thyroid (HPT) axis dysregulation in depression. This chronobiological index is normalized after successful antidepressant treatment.ObjectivesThe present study aimed at assessing the effects of repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) on the HPT axis activity in treatment resistant depressed inpatients (TRDs) (defined as having at least 2 treatment failures).MethodsThe ∆∆TSH test was performed in 13 TRDs and 14 healthy hospitalized control subjects (HCs). To be enrolled in this study, patients had to show reduced ∆∆TSH values (i.e., < 2.5 mU/L) at baseline (BL). After 20 sessions of rTMS (using daily theta-burst stimulation; 100% resting motor threshold; number of pulses/session: 900), the ∆∆TSH test was repeated in all inpatients. The 17-item Hamilton depression rating scale (HAM-D) was used to assess the severity of depression. Remission was defined by a final HAM-D score ≤ 8.ResultsCompared to BL, HAM-D scores decreased and ∆∆ TSH values increased after 20 sessions of rTMS (both p< 0.05 by T-test). There was a relationship between the reduction in HAM-D scores from BL to endpoint and the increase in ∆∆TSH values (rho = - 0.64; n = 13; p = 0.018). At endpoint, 7 patients showed ∆∆TSH normalization (among them 6 were remitters), while 6 patients did not normalize their ∆∆TSH (all were non-remitters) (p < 0.005 by Fisher Exact test).ConclusionsOur results suggest that after 20 sessions of rTMS, chronobiological restoration of the HPT axis activity is associated with clinical remission. Further investigation of the specific effects of rTMS on the HPT axis activity in TRDs is warranted.Disclosure of InterestNone Declared

The CRESST-II cryogenic dark matter search aims for the detection of WIMPs via elastic scattering off nuclei in CaWO 4 crystals. We present results from a low-threshold analysis of a single upgraded detector module. This module efficiently vetoes low energy backgrounds induced by α -decays on inner surfaces of the detector. With an exposure of 29.35 kg live days collected in 2013 we set a limit on spin-independent WIMP-nucleon scattering which probes a new region of parameter space for WIMP masses below 3 GeV/c 2 , previously not covered in direct detection searches. A possible excess over background discussed for the previous CRESST-II phase 1 (from 2009 to 2011) is not confirmed.

In recent times, the sensitivity of low-mass direct dark matter searches has been limited by unknown low energy backgrounds close to the energy threshold of the experiments known as the low energy excess (LEE). The CRESST experiment utilises advanced cryogenic detectors constructed with different types of crystals equipped with Transition Edge Sensors (TESs) to measure signals of nuclear recoils induced by the scattering of dark matter particles in the detector. In CRESST, this low energy background manifests itself as a steeply rising population of events below 200 eV. A novel detector design named doubleTES using two identical TESs on the target crystal was studied to investigate the hypothesis that the events are sensor-related. We present the first results from two such modules, demonstrating their ability to differentiate between events originating from the crystal’s bulk and those occurring in the sensor or in its close proximity.

Diamond operated as a cryogenic calorimeter is an excellent target for direct detection of low-mass dark matter candidates. Following the realization of the first low-threshold cryogenic detector that uses diamond as absorber for astroparticle physics applications, we now present the resulting exclusion limits on the elastic spin-independent interaction cross-section of dark matter with diamond. We measured two 0.175 g CVD (Chemical Vapor Deposition) diamond samples, each instrumented with a Transition Edge Sensor made of Tungsten (W-TES). Thanks to the energy threshold of just 16.8 eV of one of the two detectors, we set exclusion limits on the elastic spin-independent interaction of dark matter particles with carbon nuclei down to dark matter masses as low as 0.122 GeV/c 2 . This work shows the scientific potential of cryogenic detectors made from diamond and lays the foundation for the use of this material as target for direct detection dark matter experiments.