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Polarimetric multi-offset radio-echo sounding offers improved constraints on englacial thermal conditions, basal properties and ice crystal orientation compared to standard monostatic observations. Nevertheless, such surveys are uncommon in glaciology and are typically limited in offset due to cable losses. In the 2023–24 austral summer, we deployed two radar systems on Eastwind Glacier and the McMurdo Ice Shelf in Antarctica, collecting five polarimetric common-midpoint (CMP) surveys. Using an Autonomous phase-sensitive Radio-Echo Sounder (ApRES), modified with off-the-shelf radio frequency-over-fiber (RFoF) hardware and a low-loss fiber optic link, we detect bed reflections at offsets up to the equivalent of four ice thicknesses, well beyond the theoretical point of total internal reflection. A second, cable-less system built around a software-defined radio (SDR) was deployed simultaneously as an unsynchronized receiver recording the same ApRES transmitter. These co-located datasets demonstrate the potential for cabled radar systems with integrated RFoF technology for extending maximum offsets by overcoming attenuation losses inherent to coaxial cables. Furthermore, we perform polarimetric amplitude-vs-offset analysis to probe glacier dielectric structure. Finally, we present data from deployment of the fiber optic system on Thwaites Glacier, where we detect bed reflections at an offset of 4 km, demonstrating operation on thick ice (~2.2 km).

Patients with cardiogenic shock were assigned to receive milrinone or dobutamine for inotropic support. There was no significant difference between the two groups in the composite primary outcome of in-hospital death from any cause or cardiovascular or renal events.

Understanding the characteristics of the tumor microenvironment (TME) associated with aggressive prostate cancer (PCa) is essential for accurate diagnosis and treatment. We interrogated spatially resolved multi-omics data to find molecular stratifiers of aggressive PCa. We report an aggressive prostate cancer (APC) gene expression signature predictive of increased risk of relapse and metastasis in a cohort of 1,588 patients. Further, we present a chemokine-enriched-gland (CEG) signature specific to non-cancerous prostatic glands from patients with aggressive cancer. The CEG signature is characterized by upregulated expression of pro-inflammatory chemokines, club-like cell enrichment, and immune cell infiltration of surrounding stroma. The activity of both signatures is correlated with reduced citrate and zinc levels and loss of normal prostate secretory gland functions. In summary we report that an increased inflammatory status linked to chemokine production, club-like cell enrichment, and metabolic changes in normal-appearing prostatic glands is associated with the subsequent development of aggressive PCa. Here, the authors identify gene signatures tied to aggressive prostate cancer predicting poor outcomes. Further, they present data showing that early immune and metabolic shifts in normal-looking glands may signal increased relapse and metastasis risk.

Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via av integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the av integrin/TGF-β axis as a potentially useful therapeutic target in GBM.

Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 Å crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor ‘bridges’ the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. Topoisomerase inhibition Enzymes that move along a DNA strand, such as DNA and RNA polymerases, tend to cause the build-up of supercoiling ahead of their motion. Unchecked, this would cause the DNA to become overwound, like a twisted rubber band. Topoisomerases relieve this stress by first cleaving and then re-ligating the DNA. Topoisomerase inhibitors are used as antibacterial and anticancer drugs — for example, antibacterials of the quinolone family have been in clinical use since 1962, but are now compromised by the emergence of multidrug-resistant bacteria. The crystal structure of a type II topoisomerase from Staphylococcus aureus , DNA gyrase, has now been determined in a complex with DNA and with the broad-spectrum antibiotic GSK299423. This is an example of a new class of antibiotics that interact with the same targets as fluoroquinolones, but are structurally and mechanistically distinct from them. The structure reveals a mechanism that circumvents fluoroquinolone resistance and opens up strategies of exploiting alternative inhibition mechanisms for clinically validated targets. Enzymes that move along DNA, such as DNA and RNA polymerases, cause the DNA ahead of them to become supercoiled. This would lead to the DNA becoming overwound, were the stress not relieved by topoisomerases. Topoisomerase inhibitors have been used as antibacterial and anticancer drugs, but the structural basis for their activity has been unclear. Here, the crystal structures are presented of a topoisomerase on DNA, either alone or in the presence of a new type of antibiotic.

Coronary revascularization using imaging guidance is rapidly becoming the standard of care. Intravascular optical coherence tomography uses near-infrared light to obtain high resolution intravascular images. Standard optical coherence tomography imaging technique employs iodinated contrast dye to achieve the required blood clearance during acquisition. We sought to systematically evaluate the technical performance of saline as an alternative to iodinated contrast for intravascular optical coherence tomography assessment. We performed bench top optical coherence tomography analysis on nylon tubing with sequential contrast/saline dilutions to empirically derive adjustment coefficients. We then applied these coefficients in vivo in an established rabbit abdominal stenting model with both saline and contrast optical coherence tomography imaging. In this model, we assessed the impact of saline on both quantitative and qualitative vessel assessment. Nylon tubing assessment demonstrated a linear relationship between saline and contrast for both area and diameter. We then derived adjustment coefficients, allowing for accurate calculation of area and diameter when converting saline into both contrast and reference dimensions. In vivo studies confirmed reduced area with saline versus contrast [7.43 (5.67-8.36) mm.sup.2 versus 8.2 (6.34-9.39) mm.sup.2, p = 0.001] and diameter [3.08 mm versus 3.23 mm, p = 0.001]. Following correction, a strong relationship was achieved in vivo between saline and contrast in both area and diameter without compromising image quality, artefact, or strut assessment. Saline generates reduced dimensions compared to contrast during intravascular optical coherence tomography imaging. The relationship across physiologic coronary diameters is linear and can be corrected with high fidelity. Saline does not adversely impact image quality, artefact, or strut assessment.

The basis for our understanding of quantum magnetism has been the study of elegantly simple model systems. However, even for the antiferromagnetic honeycomb lattice with isotropic spin interactions–one of the simplest model systems–a detailed understanding of quantum effects is still lacking. Here, using inelastic neutron scattering measurements of the honeycomb lattice material YbCl 3 , we elucidate how quantum effects renormalize the single-magnon and multimagnon excitations and how this renormalization can be tuned and ultimately driven to the classical limit by applying a magnetic field. Additionally, our work reveals that the quantum effects tuned by the magnetic field not only renormalize the magnetic excitations but also induce a distinctive sharp feature inside the multimagnon continuum. From a more general perspective, this result demonstrates that structures within magnetic continua can occur over a wide experimental parameter space and can be used as a reliable means of identifying quantum phenomena. The honeycomb lattice is of fundamental importance for understanding quantum spin liquids and frustrated magnetism more generally. Here, the authors use inelastic neutron scattering to investigate the honeycomb antiferromagnet YbCl 3 showing how quantum effects renormalize the single-magnon and multimagnon excitations, shedding further light on the mechanisms of quantum magnetism in honeycomb-lattice compounds.

The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions 1 – 3 . Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)—an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization. High-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO) reveals more than 300 factors that influence genome folding during interphase, including 43 genes that were validated as either increasing or decreasing interactions between topologically associating domains.

Accurately estimating home range and understanding movement behavior can provide important information on ecological processes. Advances in data collection and analysis have improved our ability to estimate home range and movement parameters, both of which have the potential to impact species conservation. Fitting continuous-time movement model to data and incorporating the autocorrelated kernel density estimator (AKDE), we investigated range residency of forty-four jaguars fit with GPS collars across five biomes in Brazil and Argentina. We assessed home range and movement parameters of range resident animals and compared AKDE estimates with kernel density estimates (KDE). We accounted for differential space use and movement among individuals, sex, region, and habitat quality. Thirty-three (80%) of collared jaguars were range resident. Home range estimates using AKDE were 1.02 to 4.80 times larger than KDE estimates that did not consider autocorrelation. Males exhibited larger home ranges, more directional movement paths, and a trend towards larger distances traveled per day. Jaguars with the largest home ranges occupied the Atlantic Forest, a biome with high levels of deforestation and high human population density. Our results fill a gap in the knowledge of the species' ecology with an aim towards better conservation of this endangered/critically endangered carnivore-the top predator in the Neotropics.

A universal pH indicator is used to fabricate a fiber optic ammonia sensor. The advantage of this pH indicator is that it exhibits sensitivity to ammonia over a broad wavelength range. This provides a differential response, with a valley around 500 nm and a peak around 650 nm, which allows us to perform ratiometric measurements. The ratiometric measurements provide not only an enhanced signal, but can also eliminate any external disturbance due to humidity or temperature fluctuations. In addition, the indicator is embedded in a hydrophobic and gas permeable polyurethane film named Tecoflex®. The film provides additional advantages to the sensor, such as operation in dry environments, efficient transport of the element to be measured to the sensitive area of the sensor, and prevent leakage or detachment of the indicator. The combination of the universal pH indicator and Tecoflex® film provides a reliable and robust fiber optic ammonia sensor.