Elastomeric electrolytes for high-energy solid-state lithium batteries.

The use of lithium metal anodes in solid-state batteries has emerged as one of the most promising technologies for replacing conventional lithium-ion batteries1,2. Solid-state electrolytes are a key enabling technology for the safe operation of lithium metal batteries as they suppress the uncontrolled growth of lithium dendrites. However, the mechanical properties and electrochemical performance of current solid-state electrolytes do not meet the requirements for practical applications of lithium metal batteries. Here we report a class of elastomeric solid-state electrolytes with a three-dimensional interconnected plastic crystal phase. The elastomeric electrolytes show a combination of mechanical robustness, high ionic conductivity, low interfacial resistance and high lithium-ion transference number. The in situ-formed elastomer electrolyte on copper foils accommodates volume changes for prolonged lithium plating and stripping processes with a Coulombic efficiency of 100.0 per cent. Moreover, the elastomer electrolytes enable stable operation of the full cells under constrained conditions of a limited lithium source, a thin electrolyte and a high-loading LiNi0.83Mn0.06Co0.11O2 cathode at a high voltage of 4.5 volts at ambient temperature, delivering a high specific energy exceeding 410 watt-hours per kilogram of electrode plus electrolyte. The elastomeric electrolyte system presents a powerful strategy for enabling stable operation of high-energy, solid-state lithium batteries.

Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.

Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.

Functional genomic screens with death rate analyses reveal mechanisms of drug action.

A common approach for understanding how drugs induce their therapeutic effects is to identify the genetic determinants of drug sensitivity. Because 'chemo-genetic profiles' are performed in a pooled format, inference of gene function is subject to several confounding influences related to variation in growth rates between clones. In this study, we developed Method for Evaluating Death Using a Simulation-assisted Approach (MEDUSA), which uses time-resolved measurements, along with model-driven constraints, to reveal the combination of growth and death rates that generated the observed drug response. MEDUSA is uniquely effective at identifying death regulatory genes. We apply MEDUSA to characterize DNA damage-induced lethality in the presence and absence of p53. Loss of p53 switches the mechanism of DNA damage-induced death from apoptosis to a non-apoptotic death that requires high respiration. These findings demonstrate the utility of MEDUSA both for determining the genetic dependencies of lethality and for revealing opportunities to potentiate chemo-efficacy in a cancer-specific manner.

A periplasmic phospholipase that maintains outer membrane lipid asymmetry in Pseudomonas aeruginosa.

The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the inner leaflet is composed of glycerophospholipids. This lipid asymmetry creates mechanical strength, lowers membrane permeability, and is necessary for virulence in many pathogens. Glycerophospholipids that mislocalize to the outer leaflet are removed by the Mla pathway, which consists of the outer membrane channel MlaA, the periplasmic lipid carrier MlaC, and the inner membrane transporter MlaBDEF. The opportunistic pathogen Pseudomonas aeruginosa has two proteins of the MlaA family: PA2800 and PA3239. Here, we show that PA2800 is part of a canonical Mla pathway, while PA3239 functions with the putative lipase PA3238. While loss of either pathway individually has little to no effect on outer membrane integrity, loss of both pathways weakens the outer membrane permeability barrier and increases production of the secondary metabolite pyocyanin. We propose that mislocalized glycerophospholipids are removed from the outer leaflet by PA3239 (renamed MlaZ), transferred to PA3238 (renamed MlaY), and degraded. This pathway streamlines recycling of glycerophospholipid degradation products by removing glycerophospholipids from the outer leaflet prior to degradation.

Threat management priorities for conserving Antarctic biodiversity.

Antarctic terrestrial biodiversity faces multiple threats, from invasive species to climate change. Yet no large-scale assessments of threat management strategies exist. Applying a structured participatory approach, we demonstrate that existing conservation efforts are insufficient in a changing world, estimating that 65% (at best 37%, at worst 97%) of native terrestrial taxa and land-associated seabirds are likely to decline by 2100 under current trajectories. Emperor penguins are identified as the most vulnerable taxon, followed by other seabirds and dry soil nematodes. We find that implementing 10 key threat management strategies in parallel, at an estimated present-day equivalent annual cost of US$23 million, could benefit up to 84% of Antarctic taxa. Climate change is identified as the most pervasive threat to Antarctic biodiversity and influencing global policy to effectively limit climate change is the most beneficial conservation strategy. However, minimising impacts of human activities and improved planning and management of new infrastructure projects are cost-effective and will help to minimise regional threats. Simultaneous global and regional efforts are critical to secure Antarctic biodiversity for future generations.

How well do rudimentary plasticity rules predict adult visual object learning?

A core problem in visual object learning is using a finite number of images of a new object to accurately identify that object in future, novel images. One longstanding, conceptual hypothesis asserts that this core problem is solved by adult brains through two connected mechanisms: 1) the re-representation of incoming retinal images as points in a fixed, multidimensional neural space, and 2) the optimization of linear decision boundaries in that space, via simple plasticity rules applied to a single downstream layer. Though this scheme is biologically plausible, the extent to which it explains learning behavior in humans has been unclear-in part because of a historical lack of image-computable models of the putative neural space, and in part because of a lack of measurements of human learning behaviors in difficult, naturalistic settings. Here, we addressed these gaps by 1) drawing from contemporary, image-computable models of the primate ventral visual stream to create a large set of testable learning models (n = 2,408 models), and 2) using online psychophysics to measure human learning trajectories over a varied set of tasks involving novel 3D objects (n = 371,000 trials), which we then used to develop (and publicly release) empirical benchmarks for comparing learning models to humans. We evaluated each learning model on these benchmarks, and found those based on deep, high-level representations from neural networks were surprisingly aligned with human behavior. While no tested model explained the entirety of replicable human behavior, these results establish that rudimentary plasticity rules, when combined with appropriate visual representations, have high explanatory power in predicting human behavior with respect to this core object learning problem.

Lean body mass in living kidney donors impacts postoperative renal function.

PURPOSE: A living donor kidney transplant is the optimal treatment for chronic renal impairment. Our objective is to assess if lean skeletal muscle mass and donor factors such as body mass index, hypertension, and age impact on renal function following donor nephrectomy. METHODS: Potential donors undergo CT angiography as part of their work-up in our institution. Using dedicated software (Horos®), standardized skeletal muscle area measured at the L3 vertebrae was calculated. When corrected for height, skeletal muscle index can be derived. Skeletal muscle mass index below predefined levels was classified as sarcopenic. The correlation of CT-derived skeletal muscle index and postoperative renal function at 12 months was assessed. Co-variables including donor gender, age, body mass index (BMI), and presence of pre-op hypertension were also assessed for their impact on postoperative renal function. RESULTS: 275 patients who underwent living donor nephrectomy over 10 years were included. Baseline pre-donation glomerular filtration rate (GFR) and renal function at one year post-op were similar between genders. 29% (n = 82) of patients met the criteria for CT-derived sarcopenia. Sarcopenic patients were more likely to have a higher GFR at one year post-op (69.3 vs 63.9 mL/min/1.73 m2, p < 0.001). The main factors impacting better renal function at one year were the presence of sarcopenia and younger age at donation. CONCLUSION: When selecting donors, this study highlights that patients with low skeletal mass are unlikely to underperform in terms of recovery of their renal function postoperatively at one year when compared to patients with normal muscle mass and should not be a barrier to kidney donation.

Mortality, Safety, and Effectiveness of Paclitaxel-Containing Balloons and Stents in the Femoropopliteal Artery: Systematic Review and Meta-Analysis of Randomized Controlled Trials since 2018.

PURPOSE: To provide an updated systematic review and meta-analysis of safety and effectiveness outcomes with paclitaxel-containing devices. MATERIALS AND METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) investigating paclitaxel-containing balloons or stents in the treatment of femoropopliteal disease was performed. Pooled risk ratio (RR) was calculated using the inverse-variance, random-effects model in the assessment of primary patency, all-cause mortality, target limb major amputation, target lesion revascularization (TLR), and thrombosis. RESULTS: In total, 19 RCTs were included comprising 4,284 participants. All-cause mortality rates did not differ significantly between the 2 arms at 12 months (RR, 1.06; 95% confidence interval [CI], 0.66-1.72; P = .80), 24 months (RR, 0.92; 95% CI, 0.56-1.50; P = .73), 36 months (RR, 1.21; 95% CI, 0.65-2.25; P = .55), or 48-60 months (RR, 0.95; 95% CI, 0.66-1.39; P = .81) after intervention. Primary patency was significantly higher at 12 months in the paclitaxel-containing arm: 80.92% (1,438/1,777) versus 57.48% (607/1,056) in the control arm (RR, 1.44; 95% CI, 1.30-1.59; P < .00001). CONCLUSIONS: The present study demonstrates no statistically significant difference in all-cause mortality, target limb major amputation, or thrombosis with paclitaxel drug-eluting therapy to the femoropopliteal region. Additionally, improved and durable patency rates with a statistically significantly lower risk of clinically driven TLR with paclitaxel drug-eluting therapy have been demonstrated.

A Qualitative Systematic Review of Endovascular Management of Renal Artery Aneurysms.

PURPOSE: To perform a qualitative systematic review of endovascular management of renal artery aneurysms (RAAs). MATERIALS AND METHODS: A comprehensive electronic search of PubMed, MEDLINE, Embase, Google Scholar, and Cochrane databases from 2000 to 2022 was performed using the search terms "renal artery," "aneurysm," and "endovascular." Means of outcome measures were calculated with a primary end point focused on RAA-related mortality and rupture. Secondary end points included reintervention rate and renal infarction. RESULTS: Twenty-six, single-center, retrospective, observational studies were included. There were 454 RAAs treated in 427 patients using endovascular techniques. Mean age was 53.8 years, with a female predominance (62%). A variety of endovascular treatments of RAA were used with excellent technical success (96%), renal parenchymal preservation, and a low rate of moderate/severe adverse events (AEs). Primary coil embolization was the most commonly used technique (44.7%). There was an overall AE rate of 22.9%, of which 6.7% were moderate/severe and there was 0% periprocedural mortality. The most common AE was renal infarction (49 patients, 11.5%); however, renal function was preserved in 84% of patients. Nephrectomy rate was 0.4%. Computed tomography (CT) angiography was the most common imaging follow-up modality used in 72% of studies. Only 9 studies (34%) reported anticoagulant use. Although the risk of delayed aneurysm reperfusion warrants clinical and imaging surveillance, relatively few patients (3%) required reintervention in this cohort. CONCLUSIONS: Endovascular management of RAA is a technically feasible treatment option with low rates of AEs and reintervention. The present study highlights the techniques available for interventional radiologists, a need for standardization of AE reporting, anticoagulation therapy, and follow-up imaging.

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

BACKGROUND: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. METHODS: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. RESULTS: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. CONCLUSION: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

Mitochondria of lung venular capillaries mediate lung-liver cross talk in pneumonia.

Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure predisposes to the mortality, but mechanisms are poorly understood. Here, we show that mitochondrial uncoupling protein 2 (UCP2), a component of the mitochondrial inner membrane, plays a role in the barrier failure. Subsequent lung-liver cross talk mediated by neutrophil activation causes liver congestion. We intranasally instilled lipopolysaccharide (LPS). Then, we viewed the lung endothelium by real-time confocal imaging of the isolated, blood-perfused mouse lung. LPS caused alveolar-capillary transfer of reactive oxygen species and mitochondrial depolarization in lung venular capillaries. The mitochondrial depolarization was inhibited by transfection of alveolar Catalase and vascular knockdown of UCP2. LPS instillation caused lung injury as indicated by increases in bronchoalveolar lavage (BAL) protein content and extravascular lung water. LPS or Pseudomonas aeruginosa instillation also caused liver congestion, quantified by liver hemoglobin and plasma aspartate aminotransferase (AST) increases. Genetic inhibition of vascular UCP2 prevented both lung injury and liver congestion. Antibody-mediated neutrophil depletion blocked the liver responses, but not lung injury. Knockdown of lung vascular UCP2 mitigated P. aeruginosa-induced mortality. Together, these data suggest a mechanism in which bacterial pneumonia induces oxidative signaling to lung venular capillaries, known sites of inflammatory signaling in the lung microvasculature, depolarizing venular mitochondria. Successive activation of neutrophils induces liver congestion. We conclude that oxidant-induced UCP2 expression in lung venular capillaries causes a mechanistic sequence leading to liver congestion and mortality. Lung vascular UCP2 may present a therapeutic target in ARDS.NEW & NOTEWORTHY We report that mitochondrial injury in lung venular capillaries underlies barrier failure in pneumonia, and venular capillary uncoupling protein 2 (UCP2) causes neutrophil-mediated liver congestion. Using in situ imaging, we found that epithelial-endothelial transfer of H2O2 activates UCP2, depolarizing mitochondria in venular capillaries. The conceptual advance from our findings is that mitochondrial depolarization in lung capillaries mediates liver cross talk through circulating neutrophils. Pharmacologic blockade of UCP2 could be a therapeutic strategy for lung injury.

Structure-Controlled Carbon Hosts for Dendrite-Free Aqueous Zinc Batteries.

The surging demand for environmental-friendly and safe electrochemical energy storage systems has driven the development of aqueous zinc (Zn)-ion batteries (ZIBs). However, metallic Zn anodes suffer from severe dendrite growth and large volume change, resulting in a limited lifetime for aqueous ZIB applications. Here, it is shown that 3D mesoporous carbon (MC) with controlled carbon and defect configurations can function as a highly reversible and dendrite-free Zn host, enabling the stable operation of aqueous ZIBs. The MC host has a structure-controlled architecture that contains optimal sp2 -carbon and defect sites, which results in an improved initial nucleation energy barrier and promotes uniform Zn deposition. As a consequence, the MC host shows outstanding Zn plating/stripping performance over 1000 cycles at 2 mA cm-2 and over 250 cycles at 6 mA cm-2 in asymmetric cells. Density functional theory calculations further reveal the role of the defective sp2 -carbon surface in Zn adsorption energy. Moreover, a full cell based on Zn@MC900 anode and V2 O5 cathode exhibits remarkable rate performance and cycling stability over 3500 cycles. These results establish a structure-mechanism-performance relationship of the carbon host as a highly reversible Zn anode for the reliable operation of ZIBs.

Radioembolization for Treatment of Hepatocellular Carcinoma: Current Evidence and Patterns of Utilization.

Primary liver malignancy, of which hepatocellular carcinoma (HCC) is the most common type, is the second most common cause of death due to cancer worldwide. Given the historically poor prognosis of liver cancer, there has been major research on its treatment options, with significant advancements over the last decade. Transarterial radioembolization (TARE) is a locoregional treatment option for HCC that involves transarterial delivery of the ß-emitter yttrium-90 via resin or glass microspheres to arterialized tumor vasculature, delivering a tumoricidal dose to the tumor. The recent 2022 update of the Barcelona Clinic Liver Cancer (BCLC) treatment algorithm features a more prominent role for locoregional treatment, including the incorporation of radioembolization for very-early-stage (BCLC-0) and early-stage (BCLC-A) diseases. This review provides a contemporary summary of the evolving role of TARE in treatment of HCC in light of recent and upcoming trials.

Let a hundred flowers bloom: the role of context dependence in creating phenotypic diversity following targeted therapy.

Using a newly developed computational platform, COSPER, Litvin et al. (2015) identify context-dependent interactions between MEK and interferon signaling that underlie sensitivity and resistance to MEK inhibition in melanoma.

Leadership in Interventional Radiology - Fostering a Culture of Excellence.

This invited article reviews the current status of Interventional Radiology (IR), in terms of its status as a speciality, and outlines the conditions needed for IR to function optimally within healthcare settings. Guidance is offered in terms of developing an IR department, ensuring high-quality practice, dealing with administrative and political challenges, dealing with industry and creating a legacy.

Culling of Urban Norway Rats and Carriage of Bartonella spp. Bacteria, Vancouver, British Columbia, Canada.

We investigated the effects of culling on Bartonella spp. bacteria carriage among urban rats in Canada. We found that the odds of Bartonella spp. carriage increased across city blocks except those in which culling occurred. Removing rats may have prevented an increase in Bartonella spp. prevalence, potentially lowering human health risks.

Phase Separation-Controlled Assembly of Hierarchically Porous Aramid Nanofiber Films for High-speed Lithium-Metal Batteries.

The growth of lithium (Li) dendrites reduces the lifespan of Li-metal batteries and causes safety issues. Herein, hierarchically porous aramid nanofiber separators capable of effectively suppressing the Li dendrite growth while maintaining highly stable cycle performances at high charge/discharge rates are reported. A two-step solvent exchange process combined with reprotonation-mediated self-assembly is utilized to control the bimodal porous structure of the separators. In particular, when ethanol and water are used sequentially, aramid nanofibers form hierarchical porous structures containing nanopores in macroporous polymer frameworks to yield a mechanically robust membrane with high porosity of 97% or more. The optimized samples exhibit high ionic conductivities of 1.87-4.04 mS cm-1 and high Li-ion transference numbers of 0.77-0.84 because of the ultrahigh porosity and selective affinity to anions. Li-metal symmetric cells do not show any noticeable presence of dendrites after 100 cycles, and they operate stably for more than 1500 cycles even under extreme conditions with a high current density of >20 mA cm-2 . In addition, the LiFePO4 /Li full cell retains 86.3% of its capacity after 1000 cycles at a charge rate of 30 C.

Carbon Quantum Dot Modified Reduced Graphene Oxide Framework for Improved Alkali Metal Ion Storage Performance.

Organic materials with redox-active oxygen functional groups are of great interest as electrode materials for alkali-ion storage due to their earth-abundant constituents, structural tunability, and enhanced energy storage properties. Herein, a hybrid carbon framework consisting of reduced graphene oxide and oxygen functionalized carbon quantum dots (CQDs) is developed via the one-pot solvothermal reduction method, and a systematic study is undertaken to investigate its redox mechanism and electrochemical properties with Li-, Na-, and K-ions. Due to the incorporation of CQDs, the hybrid cathode delivers consistent improvements in charge storage performance for the alkali-ions and impressive reversible capacity (257 mAh g-1 at 50 mA g-1 ), rate capability (111 mAh g-1 at 1 A g-1 ), and cycling stability (79% retention after 10 000 cycles) with Li-ion. Furthermore, density functional theory calculations uncover the CQD structure-electrochemical reactivity trends for different alkali-ion. The results provide important insights into adopting CQD species for optimal alkali-ion storage.

Drug antagonism and single-agent dominance result from differences in death kinetics.

Cancer treatment generally involves drugs used in combinations. Most previous work has focused on identifying and understanding synergistic drug-drug interactions; however, understanding antagonistic interactions remains an important and understudied issue. To enrich for antagonism and reveal common features of these combinations, we screened all pairwise combinations of drugs characterized as activators of regulated cell death. This network is strongly enriched for antagonism, particularly a form of antagonism that we call 'single-agent dominance'. Single-agent dominance refers to antagonisms in which a two-drug combination phenocopies one of the two agents. Dominance results from differences in cell death onset time, with dominant drugs acting earlier than their suppressed counterparts. We explored mechanisms by which parthanatotic agents dominate apoptotic agents, finding that dominance in this scenario is caused by mutually exclusive and conflicting use of Poly(ADP-ribose) polymerase 1 (PARP1). Taken together, our study reveals death kinetics as a predictive feature of antagonism, due to inhibitory crosstalk between cell death pathways.