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Cryoconite holes are the most active and diverse microbial habitats on glacier and ice-sheet surfaces. In this article the authors demonstrate that the shape of cryoconite holes varies depending on ice-surface topography and that this has implications for the carbon cycling regime within. Net ecosystem production is shown to be controlled primarily by sediment thickness within holes. The authors show that irregular hole shapes are indicative of hole migration away from topographic shade, which promotes carbon fixation at the mesoscale on ice surfaces. A cellular automaton is used in conjunction with sediment-delivery experiments to show that migration is the result of simple sediment transfer processes, implying a relationship between ice-surface evolution and cryoconite biogeochemistry that has not previously been examined.

Objective To evaluate gene expression in blood of patients with psoriatic arthritis (PsA) versus healthy controls and identify changes associated with guselkumab treatment. Methods Whole blood transcriptome profiling via paired‐end RNA sequencing was conducted using samples from DISCOVER‐1 and DISCOVER‐2 at baseline (n = 673) and at weeks 4 and 24 from a representative subgroup that received placebo or guselkumab (n = 227 [longitudinal PsA cohort]). Baseline samples were compared with demographically matched healthy controls (n = 21). Guselkumab‐mediated changes in gene expression were assessed in participants from the longitudinal PsA cohort who did versus did not achieve at least 20% improvement in American College of Rheumatology response criteria (ACR20) or at least 75% improvement in Psoriasis Area and Severity Index (PASI75). Differential gene expression was analyzed using edgeR. Results At baseline, 355 upregulated and 314 downregulated genes (PsA‐associated genes) were identified in patients with PsA versus healthy controls. Upregulated genes were related to neutrophil, mononuclear cell, and CD11b+ gene sets. No cell type–specific gene sets were identified among downregulated genes. Most PsA‐associated genes were modulated by guselkumab treatment. At week 24, genes downregulated by guselkumab were enriched with neutrophil, monocyte, eosinophil, and macrophage gene sets; genes upregulated by guselkumab were enriched with B cell, T cell, and natural killer cell gene sets. Reductions in expression of upregulated PsA‐associated gene sets were more pronounced in ACR20 and PASI75 responders than in nonresponders. Conclusion These findings suggest a dysregulation of immune cell profiles in blood from patients in the baseline PsA cohort that approached levels in healthy controls after guselkumab treatment.

Prostate cancer is generally considered an immunologically “cold” tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to “heat up” the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-β type II receptor, bolstering its activity in the TGF-β–rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-β–rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line–derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.

Observed evolution of the total mass distribution with redshift is crucial to testing galaxy evolution theories. To measure the total mass distribution, strong gravitational lenses complement the resolved dynamical observations that are currently limited to z ≲ 0.5. Here we present the lens models for a pilot sample of seven galaxy-scale lenses from the ASTRO3D Galaxy Evolution with Lenses ( AGEL ) survey. The AGEL lenses, modeled using HST/WFC3-F140W images with Gravitational Lens Efficient Explorer ( GLEE ) software, have deflector redshifts in the range 0.3 < z _defl < 0.9. Assuming a power-law density profile with slope γ , we measure the total density profile for the deflector galaxies via lens modeling. We also measure the stellar velocity dispersions ( σ _obs ) for four lenses and obtain σ _obs from SDSS - BOSS for the remaining lenses to test our lens models by comparing observed and model-predicted velocity dispersions. For the seven AGEL lenses, we measure an average density profile slope of −1.95 ± 0.09 and a γ – z relation that does not evolve with redshift at z < 1. Although our result is consistent with some observations and simulations, it differs from other studies at z < 1 that suggest the γ – z relation evolves with redshift. The apparent conflicts among observations and simulations may be due to a combination of (1) systematics in the lensing and dynamical modeling; (2) challenges in comparing observations with simulations; and (3) assuming a simple power law for the total mass distribution. By providing more lenses at z _defl > 0.5, the AGEL survey will provide stronger constraints on whether the mass profiles evolve with redshift as predicted by current theoretical models.

Abstract Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (Mpro also known as 3CLpro) is a primary drug target, due to its essential role in maturation of the viral polyproteins. In this study, we provide crystallographic evidence, along with some binding assay data, that three clinically approved anti hepatitis C virus drugs and two other drug-like compounds covalently bind to the Mpro Cys145 catalytic residue in the active site. Also, molecular docking studies can provide additional insight for the design of new antiviral inhibitors for SARS-CoV-2 using these drugs as lead compounds. One might consider derivatives of these lead compounds with higher affinity to the Mpro as potential COVID-19 therapeutics for further testing and possibly clinical trials.

BackgroundHealthcare simulators have been demonstrated to be a valuable resource for training several technical and nontechnical skills. A gap in the fidelity of tissues has been acknowledged as a barrier to application for current simulators; especially for interventional procedures. Inaccurate or unrealistic mechanical response of a simulated tissue to a given surgical tool motion may result in negative training transfer and/or prevents the "suspension of disbelief" necessary for a trainee to engage in the activity. Thus, where it is relevant to training outcomes, there should be an effort to create healthcare simulators with simulated tissue mechanical responses that match or represent those of biological tissues. Historically, this data is most often gathered from preserved (post mortem) tissue; however, there is a concern that the mechanical properties of preserved tissue, that lacks blood flow, may lack adequate accuracy to provide the necessary training efficacy of simulators.Methods and findingsThis work explores the effect of the "state" of the tissue testing status on liver and peritoneal tissue by using a customized handheld grasper to measure the mechanical responses of representative porcine (Sus domesticus) tissues in n = 5 animals across five test conditions: in vivo, post mortem (in-situ), ex vivo (immediately removed from fresh porcine cadaver), post-refrigeration, and post-freeze-thaw cycle spanning up to 72 hours after death. No statistically significant difference was observed in the mechanical responses due to grasping between in vivo and post-freeze conditions for porcine liver and peritoneum tissue samples (p = 0.05 for derived stiffness at grasping force values F = 5N and 6.5N). Furthermore, variance between in vivo and post-freeze conditions within each animal, was comparable to the variance of the in vivo condition between animals.ConclusionsResults of this study further validate the use of preserved tissue in the design of medical simulators via observing tissue mechanical responses of post-freeze tissue comparable to in vivo tissue. Therefore, the use of thawed preserved tissue for the further study and emulation of mechanical perturbation of the liver and peritoneum can be considered. Further work in this area should investigate these trends further, particularly in regard to other tissues and the potential effects varying preservation methods may yield.

Young workers, those under the age of 25, are considered a vulnerable working population, primarily due to their increased risk of injury. In this study we investigate if young workers may also be at an increased risk for occupational exposure to carcinogens. Using the 2006 and 2016 Canadian Census of Population and previously obtained CAREX Canada data, this study aimed to identify sectors and occupations that have high proportions of young workers and where potential exists for exposure to known and suspected carcinogens. Key groups where young workers are likely at a higher risk for occupational exposure to carcinogens were identified. Our work shows that young workers in construction, outdoor occupations, and farming are key groups that warrant further investigation. These specific groups are highlighted because of the large number of young workers employed in these sectors/situations, the high number of possible carcinogen exposures, and the potential for higher risk behavior patterns that typically occur in these types of jobs. While there is no data available to develop carcinogen exposure estimates specific to young workers, it is our perspective that young workers are likely at a higher risk for occupational exposure to carcinogens. Our findings identify opportunities to improve the occupational health and safety for this vulnerable population, particularly for young construction workers, farm workers, and outdoor workers.

Gravitational lenses can magnify distant galaxies, allowing us to discover and characterize the stellar populations of intrinsically faint, quiescent galaxies that are otherwise extremely difficult to directly observe at high redshift from ground-based telescopes. Here, we present the spectral analysis of two lensed, quiescent galaxies at z ≳ 1 discovered by the ASTRO 3D Galaxy Evolution with Lenses survey: AGEL 1323 ( M _* ∼ 10 ^11.1 M _⊙ , z = 1.016, μ ∼ 14.6) and AGEL 0014 ( M _* ∼ 10 ^11.5 M _⊙ , z = 1.374, μ ∼ 4.3). We measured the age, [Fe/H], and [Mg/Fe] of the two lensed galaxies using deep, rest-frame-optical spectra (S/N ≳40 Å ^−1 ) obtained on the Keck I telescope. The ages of AGEL 1323 and AGEL 0014 are ${5.6}_{-0.8}^{+0.8}$ Gyr and ${3.1}_{-0.3}^{+0.8}$ Gyr, respectively, indicating that most of the stars in the galaxies were formed less than 2 Gyr after the Big Bang. Compared to nearby quiescent galaxies of similar masses, the lensed galaxies have lower [Fe/H] and [Mg/H]. Surprisingly, the two galaxies have comparable [Mg/Fe] to similar-mass galaxies at lower redshifts, despite their old ages. Using a simple analytic chemical evolution model connecting the instantaneously recycled element Mg with the mass-loading factors of outflows averaged over the entire star formation history, we found that the lensed galaxies may have experienced enhanced outflows during their star formation compared to lower-redshift galaxies, which may explain why they quenched early.

Objective: The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death. Methods: Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography–mass spectrometry. Results: High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells. Conclusion: Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents. Keywords: Statins, Dipyridamole, Prostate cancer, Mevalonate pathway, Tumor metabolism, Drug repurposing

We present spectroscopic confirmation of candidate strong gravitational lenses using the Keck Observatory and Very Large Telescope as part of our ASTRO 3D Galaxy Evolution with Lenses ( AGEL ) survey. We confirm that (1) search methods using convolutional neural networks (CNNs) with visual inspection successfully identify strong gravitational lenses and (2) the lenses are at higher redshifts relative to existing surveys due to the combination of deeper and higher-resolution imaging from DECam and spectroscopy spanning optical to near-infrared wavelengths. We measure 104 redshifts in 77 systems selected from a catalog in the DES and DECaLS imaging fields ( r ≤ 22 mag). Combining our results with published redshifts, we present redshifts for 68 lenses and establish that CNN-based searches are highly effective for use in future imaging surveys with a success rate of at least 88% (defined as 68/77). We report 53 strong lenses with spectroscopic redshifts for both the deflector and source ( z _src > z _defl ), and 15 lenses with a spectroscopic redshift for either the deflector ( z _defl > 0.21) or source ( z _src ≥ 1.34). For the 68 lenses, the deflectors and sources have average redshifts and standard deviations of 0.58 ± 0.14 and 1.92 ± 0.59 respectively, and corresponding redshift ranges of z _defl = 0.21–0.89 and z _src = 0.88–3.55. The AGEL systems include 41 deflectors at z _defl ≥ 0.5 that are ideal for follow-up studies to track how mass density profiles evolve with redshift. Our goal with AGEL is to spectroscopically confirm ∼100 strong gravitational lenses that can be observed from both hemispheres throughout the year. The AGEL survey is a resource for refining automated all-sky searches and addressing a range of questions in astrophysics and cosmology.

A 7-year-old boy with a history of spasticity, global developmental delay, and seizures was given the general diagnosis of cerebral palsy at an early age. Chromosomal array analysis performed at an outside center was normal. The patient's family sought neurodevelopmental pediatric care at a new institution following a move out of state. Electroencephalography confirmed abnormal epileptogenic activity. Brain magnetic resonance imaging showed findings consistent with a tubulin gene defect (tubulinopathy) and of focal cortical dysplasia, as well as evidence of a remote occipital lobe injury. This case report describes the various brain magnetic resonance findings suggestive of a tubulin gene defect and raises the possibility of focal cortical dysplasia manifesting as a result of tubulin dysfunction.