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HIV infection remains a serious global public health problem. Although current drug treatment is effective and can reduce plasma viral loads below the level of detection, it cannot eradicate the virus. The reasons for the low virus persistence despite long-term therapy have not been fully elucidated. In addition, multiple HIV infection, i.e., infection of a cell by multiple viruses, is common and can facilitate viral recombination and mutations, evading the immune system and conferring resistance to drug treatment. The mechanisms for multiple HIV infection formation and their respective contributions remain unclear. To answer these questions, we developed a mathematical modeling framework that encompasses cell-free viral infection and cell-to-cell spread. We fit sub-models that only have one transmission route and the full model containing both to the multi-infection data from HIV-infected patients, and show that the multi-infection data can only be reproduced if these two transmission routes are both considered. Computer simulations with the best-fitting parameter values indicate that cell-to-cell spread leads to the majority of multiple infection and also accounts for the majority of overall infection. Sensitivity analysis shows that cell-to-cell spread has reduced susceptibility to treatment and may explain low HIV persistence. Taken together, this work indicates that cell-to-cell spread plays a crucial role in the development of HIV multi-infection and low HIV persistence despite long-term therapy, and therefore has important implications for understanding HIV pathogenesis and developing more effective treatment strategies to control or even eliminate the disease.

Several hypotheses and conceptual models propose to explain mechanisms mediating riverine fish abundance, but few empirical studies to date have explored their utility in tropical systems. This study assesses key components of previous fish recruitment models by exploring spatiotemporal variation in larval fish assemblages in response to predicted key drivers in a tropical Australian river catchment. Data on larval fish composition and abundance, alongside hydrological, hydraulic, habitat and food variables, were collected monthly to bimonthly over one year at eight sites. Variables which best predicted larval fish abundance and diversity were determined with Boosted Regression Trees. The most commonly important predictors were microfauna abundance, structural habitat complexity and temperature, with high values of each predicting high larval fish abundance and diversity. Maximum larval diversity occurred when discharge was highest because several wet-season spawning taxa occurred alongside aseasonally spawning taxa. These findings support previous generic fish recruitment models, demonstrating the utility of their inclusion in the recent Riverine Recruitment Synthesis Model and the applicability of this model for describing processes important for tropical riverine fish recruitment.

Tetrakis(dithiocarboxylato)molybdenum(IV) complexes of the type Mo(S

El Niño has profound influences on ecosystem dynamics. However, we know little about how it shapes vertebrate faunal community composition over centennial time scales, and this limits our ability to forecast change under projections of future El Niño events. On the basis of correlations between geological records of past El Niño frequency and the species composition of bird and fish remains from a Baja California bone deposit that spans the past 12,000 years, we documented marked faunal restructuring when major El Niño events occurred more than five times per century. This tipping point has implications for the past and future ecology of eastern Pacific coastal environments.

Electrochemical reduction of atmospheric oxygen provides carbon emission-free pathways for the generation of electricity from chemical fuels and for the distributed production of green chemical oxidants like hydrogen peroxide. Recently, organic mixed ionic-electronic conducting polymers (OMIECs) have been reported as a new class of active electrode materials for the oxygen reduction reaction. This work sets out to identify the operative oxygen reduction mechanism of OMIECs through a multi-faceted experimental and theoretical approach. Using a combination of pH-dependent electrochemical characterization, operando UV-Vis and Raman spectroscopy, and ab initio calculations, we find that the n-type OMIEC, p(NDI-T2 P75), displays pH-dependent activity for the selective reduction of oxygen to the 2-electron hydrogen peroxide product. We use microkinetic simulations of the electrochemical behavior to rationalize our experimental observations through a polaron-mediated pathway involving chemical reduction of oxygen to the 1-electron superoxide intermediate followed by pH-dependent catalytic disproportionation to hydrogen peroxide. Finally, this pathway is applied to understand the experimental oxygen reduction reactivity of an expanded set of n- and p-type OMIECs.

Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

BackgroundParalysis after spinal cord injury involves damage to pathways that connect neurons in the brain to peripheral nerves in the limbs. Re-establishing this communication using neural interfaces has the potential to bridge the gap and restore upper extremity function to people with high tetraplegia.ObjectiveWe report a novel approach for restoring upper extremity function using selective peripheral nerve stimulation controlled by intracortical microelectrode recordings from sensorimotor networks, along with restoration of tactile sensation of the hand using intracortical microstimulation.MethodsA right-handed man with motor-complete C3-C4 tetraplegia was enrolled into the clinical trial. Six 64-channel intracortical microelectrode arrays were implanted into left hemisphere regions involved in upper extremity function, including primary motor and sensory cortices, inferior frontal gyrus, and anterior intraparietal area. Nine 16-channel extraneural peripheral nerve electrodes were implanted to allow targeted stimulation of right median, ulnar (2), radial, axillary, musculocutaneous, suprascapular, lateral pectoral, and long thoracic nerves, to produce selective muscle contractions on demand. Proof-of-concept studies were performed to demonstrate feasibility of a bidirectional brain-machine interface to restore function of the participant’s own arm and hand.ResultsMulti-unit neural activity that correlated with intended motor action was successfully recorded from intracortical arrays. Microstimulation of electrodes in somatosensory cortex produced repeatable sensory percepts of individual fingers for restoration of touch sensation. Selective electrical activation of peripheral nerves produced antigravity muscle contractions. The system was well tolerated with no operative complications.ConclusionThe combination of implanted cortical electrodes and nerve cuff electrodes has the potential to allow restoration of motor and sensory functions of the arm and hand after neurological injury.

Purpose: To investigate the potential effects of [1- 13C]lactate RF saturation pulses on [ 13C]bicarbonate detection in hyperpolarized [1- 13C]pyruvate MRI of the brain. Methods: Thirteen healthy rats underwent MRI with hyperpolarized [1- 13C]pyruvate of either the brain (n = 8) or the kidneys, heart, and liver (n = 5). Dynamic, metabolite-selective imaging was used in a cross-over experiment in which [1- 13C]lactate was excited with either 0° or 90° flip angles. The [ 13C]bicarbonate SNR and apparent [1- 13C]pyruvate-to-[ 13C]bicarbonate conversion (k PB) were determined. Furthermore, simulations were performed to identify the SNR optimal flip-angle scheme for detection of [1- 13C]lactate and [ 13C]bicarbonate. Results: In the brain, the [ 13C]bicarbonate SNR was 64% higher when [1- 13C]lactate was not excited (5.8 ± 1.5 vs 3.6 ± 1.3; 1.2 to 3.3–point increase; p = 0.0027). The apparent k PB decreased 25% with [1- 13C]lactate saturation (0.0047 ± 0.0008 s −1 vs 0.0034 ± 0.0006 s −1; 95% confidence interval, 0.0006–0.0019 s −1 increase; p = 0.0049). These effects were not present in the kidneys, heart, or liver. Simulations suggest that the optimal [ 13C]bicarbonate SNR with a TR of 1 s in the brain is obtained with [ 13C]bicarbonate, [1- 13C]lactate, and [1- 13C]pyruvate flip angles of 60°, 15°, and 10°, respectively. Conclusions: Radiofrequency saturation pulses on [1- 13C]lactate limit [ 13C]bicarbonate detection in the brain specifically, which could be due to shuttling of lactate from astrocytes to neurons. Our results have important implications for experimental design in studies in which [ 13C]bicarbonate detection is warranted.

Background: Unfractionated heparin (UFH) remains a frequently utilized agent in the emergency department (ED) for management of acute venous thromboembolism (VTE). While various protocols of UFH dosing have been proposed for patients with obesity, the optimal dosing and monitoring strategy is unclear. Objective: This study aims to compare the time to the first therapeutic anti-Xa level in obese acute VTE patients following the use of either total body weight (TBW) or adjusted body weight-based (AdjBW) dosing of UFH in the ED, and to analyze the impact of different dosing strategies on patient outcomes. Methods: Inclusion criteria included adult patients with a BMI > 30 kg/m2, and suspected VTE managed with UFH per institutional protocol utilizing a bolus dose followed by maintenance infusion and anti-Xa monitoring. The primary outcome was time to the first therapeutic anti-Xa level in the group dosed per TBW compared with the group dosed per AdjBW. Safety outcomes included incidence of bleeding events, protamine administration, and mortality. Results: There were 32 patients included in the study. Patients dosed per TBW achieved a median time to first therapeutic anti-Xa level of 14.5 hours compared with 15 hours in the AdjBW group ( P = .613). The median therapeutic UFH infusion rate was 16 units/kg/hr in the TBW group compared with 13.5 units/kg/hr in the AdjBW group ( P < .001). Safety outcomes were not significantly different between groups. Conclusion: Patients presenting to the ED with acute VTE may be managed with UFH using either a TBW or AdjBW dosing strategy.

Improving signal-to-noise and, thereby, image contrast is one of the key challenges needed to expand the useful applications of mass spectrometry imaging (MSI). Both instrumental and data analysis approaches are of importance. Univariate denoising techniques have been used to improve contrast in MSI images with varying levels of success. Additionally, various multivariate analysis (MVA) methods have proven to be effective for improving image contrast. However, the distribution of important but low intensity ions can be obscured in the MVA analysis, leading to a loss of chemically specific information. In this work we propose inverse maximum signal factors (MSF) denoising as an alternative approach to both denoising and multivariate analysis for MSI imaging. This approach differs from the standard MVA techniques in that the output is denoised images for each original mass peak rather than the frequently difficult to interpret scores and loadings. Five tests have been developed to optimize and validate the resulting denoised images. The algorithm has been tested on a range of simulated data with different levels of noise, correlated noise, varying numbers of underlying components, and nonlinear effects. In the simulations, an excellent correlation between the true images and the denoised images was observed for peaks with an original signal-to-noise ratio as low as 0.1, as long as there was sufficient intensity in the sum of the selected peaks. The power of the approach was then demonstrated on two time-of-flight secondary ion mass spectrometry (ToF-SIMS) images that contained largely uncorrelated noise and a laser post-ionization matrix-assisted laser desorption/ionization mass spectrometry (MALDI-2-MS) image that contained strongly correlated noise. The improvements in signal-to-noise increased with decreasing intensity of the original peaks. A signal-to-noise improvement of as much as two orders of magnitude was achieved for very low intensity peaks. MSF denoising is a powerful addition to the suite of image processing techniques available for studying mass spectrometry images.

T and B cells employ integrin α4β7 to migrate to intestine under homeostatic conditions. Whether those cells differentially rely on α4β7 for homing during inflammatory conditions has not been fully examined. This may have implications for our understanding of the mode of action of anti-integrin therapies in inflammatory bowel disease (IBD). Here, we examined the role of α4β7 integrin during chronic colitis using IL-10−/− mice, β7-deficient IL-10−/−, IgA-deficient IL-10−/− mice, and antibody blockade of MAdCAM-1. We found that α4β7 was predominantly expressed by B cells. β7 deficiency and MAdCAM-1 blockade specifically depleted antibody secreting cells (ASC) (not T cells) from the colonic LP, leading to a fecal pan-immunoglobulin deficit, severe colitis, and alterations of microbiota composition. Colitis was not due to defective regulation, as dendritic cells (DC), regulatory T cells, retinaldehyde dehydrogenase (RALDH) expression, activity, and regulatory T/B-cell cytokines were all comparable between the strains/treatment. Finally, an IgA deficit closely recapitulated the clinical phenotype and altered microbiota composition of β7-deficient IL-10−/− mice. Thus, a luminal IgA deficit contributes to accelerated colitis in the β7-deficient state. Given the critical/nonredundant dependence of IgA ASC on α4β7:MAdCAM-1 for intestinal homing, B cells may represent unappreciated targets of anti-integrin therapies.

Deposition of MoS2 from Mo(S2CMe)4 demonstrates use of dithiocarboxylate ligands for sulfur in single source precursors for TMD materials.

Optical control of spin in semiconductors has been pioneered using nanostructures of III-V and II-VI semiconductors, but the emergence of two-dimensional van der Waals materials offers an alternative low-dimensional platform for spintronic phenomena. Indium selenide (InSe), a group-III monochalcogenide van der Waals material, has shown promise for opto-electronics due to its high electron mobility, tunable direct bandgap, and quantum transport. There are predictions of spin-dependent optical selection rules suggesting potential for all-optical excitation and control of spin in a two-dimensional layered material. Despite these predictions, layer-dependent optical spin phenomena in InSe have yet to be explored. Here, we present measurements of layer-dependent optical spin dynamics in few-layer and bulk InSe. Polarized photoluminescence reveals layer-dependent optical orientation of spin, thereby demonstrating the optical selection rules in few-layer InSe. Spin dynamics are also studied in many-layer InSe using time-resolved Kerr rotation spectroscopy. By applying out-of-plane and in-plane static magnetic fields for polarized emission measurements and Kerr measurements, respectively, the $g$-factor for InSe was extracted. Further investigations are done by calculating precession values using a $\textbf{k} \cdot \textbf{p}$ model, which is supported by \textit{ab-initio} density functional theory. Comparison of predicted precession rates with experimental measurements highlights the importance of excitonic effects in InSe for understanding spin dynamics. Optical orientation of spin is an important prerequisite for opto-spintronic phenomena and devices, and these first demonstrations of layer-dependent optical excitation of spins in InSe lay the foundation for combining layer-dependent spin properties with advantageous electronic properties found in this material., Comment: 11 pages, 6 figures, supplemental material

While SARS-CoV-2 has sporadically infected a wide range of animal species worldwide1, the virus has been repeatedly and frequently detected in white-tailed deer in North America2â€"7. The zoonotic origins of this pandemic virus highlight the need to fill the vast gaps in our knowledge of SARS-CoV-2 ecology and evolution in non-human hosts. Here, we detected SARS-CoV-2 was introduced from humans into white-tailed deer more than 30 times in Ohio, USA during November 2021-March 2022. Subsequently, deer-to-deer transmission persisted for 2-8 months, which disseminated across hundreds of kilometers. We discovered that alpha and delta variants evolved in white-tailed deer at three-times the rate observed in humans. Newly developed Bayesian phylogenetic methods quantified how SARS-CoV-2 evolution is not only faster in white-tailed deer but driven by different mutational biases and selection pressures. White-tailed deer are not just short-term recipients of human viral diversity but serve as reservoirs for alpha and other variants to evolve in new directions after going extinct in humans. The long-term effect of this accelerated evolutionary rate remains to be seen as no critical phenotypic changes were observed in our animal model experiments using viruses isolated from white-tailed deer. Still, SARS-CoV-2 viruses have transmitted in white-tailed deer populations for a relatively short duration, and the risk of future changes may have serious consequences for humans and livestock. ispartof: Res Sq ispartof: location:United States status: Published online

Mechanistic studies of oxide electrocatalysts for heterogeneous water oxidation have been primarily focused on understanding the origins of activity, with fewer studies addressing fundamental properties that influence stability. The main challenge is directly observing and quantifying local structural instability under operating conditions. In this work, we provide a dynamic view of the perovskite stability as a function of time and operational voltage using operando electrochemical atomic force microscopy (EC-AFM). Specifically, we study the degradation pathways of SrIrO3, a highly active electrocatalyst, during the oxygen evolution reaction (OER) by tracking the potential-dependent Sr leaching and perovskite dissolution at the nanometer scale. This material serves as a model system for degradation studies of perovskite AMO3 oxides, exhibiting both A-cation leaching and transition metal (M) dissolution. We show that Sr leaching precedes perovskite dissolution by up to 0.8 V, leading to a wide voltage window of stability where water oxidation occurs on a Sr-depleted surface without significant corrosion. Moreover, we reveal that the stability of the perovskite surface is strongly influenced by the electrolytic environment and that corrosion rates differ dramatically as a function of dissolved Sr concentration. Ultimately, our study demonstrates that the overall stability of perovskite oxides during electrocatalysis can be substantially improved by suppressing A-site leaching.

Layered metal–organic frameworks are promising candidates for new two-dimensional (2D) magnets, as the synthetic programmability of these materials can provide a route to diverse structural and ele...

Lake sediments are important archives of past climate variability and lake responses to climate. In order to accurately infer past climates, it is necessary to understand, and account for, the ecological processes that affect the record of indicators preserved in lake sediment. This is particularly the case with respect to the concentration of carbon and nitrogen (TOC, TN, and calculated C:N), and the stable isotope composition of organic matter preserved in lake sediments. These are common, yet ambiguous, tracers of environmental change. Ideally, palaeoenvironmental reconstructions using the concentration and isotope composition of organic matter should be grounded in a detailed understanding of the sources of the organic material. This study documents the history and evolution of Blue Lake, an environmentally and culturally important oligotrophic, groundwater window lake on North Stradbroke Island, Queensland, Australia. We utilise organic matter δ13C, TOC, TN, and C:N from a 2.4 m sediment core with a basal age of 7.5 cal kyr BP, to investigate changing organic matter sources as a measure of the climate sensitivity of Blue Lake. This interpretation is supported by data from contemporary algae, aquatic and terrestrial plants, and catchment soils. We show that lake nutrient dynamics drove an increase in algal biomass at 4.2 cal kyr BP. This change coincides with a widely documented intensification of the El Nino-Southern Oscillation, which we infer to have influenced lake nutrient concentrations by reducing groundwater throughflow. Climatic changes resulted in marked changes in lake primary productivity, despite relatively little turnover of the lake diatom flora and catchment vegetation. This suggests that south-east Queensland dune lakes are sensitive to climate changes and helps to refine past and future palaeoclimate research using sediments from these lakes. It also indicates that increased nutrient concentrations in Blue Lake may result from projected changes in 21st Century climate.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is one of the most important techniques for chemical imaging of nanomaterials and biological samples with high lateral resolution. However, low ionization efficiency limits the detection of many molecules at low concentrations or in very small volumes. One promising approach to increasing the sensitivity of the technique is by the addition of a matrix that promotes ionization and desorption of important analyte molecules. This approach is known as matrix-enhanced secondary-ion mass spectrometry (ME-SIMS). We have investigated the effect of matrix acidity on molecular ion formation in three different biomolecules. A series of cinnamic acid based matrixes that vary in acidity was employed to systematically investigate the influence of matrix acidity on analyte ion formation. The positive ion signal for all three biomolecules showed a strong increase for more acidic matrixes. The most acidic matrix was then vapor-deposited onto mouse brain sections. This led to significant enhancement of lipid signals from the brain. This work indicates that proton donation plays an important role in the formation of molecular ions in ME-SIMS.

The exotic pet trade has largely shifted from traditional brick-and-mortar shops to online commerce. Understanding the dynamics of online pet trade, including relationships between species characteristics and a species’ relative popularity, can assist in informing trade regulation for conservation and biosecurity. Here, we identified the leading correlates behind the abundance in the Australian trade of parrot (Psittaciformes) and songbird (Passeriformes) species. We examined 14,000 online sales of parrots and songbirds collected from a popular online Australian marketplace in 2019 (representing 235 species) using an automated data collection method. We identified the characteristics that correlated with online species abundance (i.e., popularity); including (i) breeding and handling requirements; (ii) trade and availability; and (iii) appearance and behaviour. We found 55% of parrot species and 64% of songbird species traded online were non-native to Australia (i.e., alien species), most of which (81% and 85% respectively) have an extreme risk of establishing invasive populations. Species abundance of both orders was influenced by cheaper prices, which is associated with a higher invasion risk. Trade in parrots was also correlated with attractive birdsongs, being easy to care for, and a preference for native Australian species. Songbird abundance was correlated with attractive plumage colour and, to a lesser extent, the availability of colour mutations and smaller range sizes. These results, combined with an understanding of consumer behaviour and international trends, may help predict which species will become popular in domestic trade in the future, and identify current and future invasion risks to assist in environmental biosecurity efforts.

Hyperpolarized carbon-13 MRI is a promising technique forin vivometabolic interrogation of alterations between health and disease. This study introduces a model-free formalism for quantifying the metabolic information in hyperpolarized imaging.This study investigated a novel model-free perfusion and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain.Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 ± 2 vs 89 ± 6 mL/100g/min, p < 0.01, respectively) and pigs (139 ± 12 vs 95 ± 5 mL/100g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 ± 5 vs 4 ± 2 %, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 ± 0.007 vs 0.017 ± 0.02 s-1, p = 0.03, respectively) and a decrease in mean transit time (MTT) (31 ± 8 vs 60 ± 2, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.

Background Type 2 diabetes (T2D) is a significant, independent contributor to the development of heart failure (HF), driven by energetic, metabolic, structural and functional myocardial changes. The T2D heart is characterised by over-reliance on fatty acid utilisation, shows reduced glucose oxidation and inhibition of pyruvate dehydrogenase (PDH). This results in a diminished myocardial energy reserve and blunted adenosine triphosphate (ATP) generation as well as cardiac steatosis, contributing to lipotoxicity, and diastolic dysfunction. Purpose We assessed the effects of ninerafaxstat – a novel cardiac mitotrope designed to shift myocardial substrate utilisation in favour of glucose and thus, restore myocardial energy homeostasis – on cardiac metabolism & diastolic function in patients with T2D and obesity. Methods In this open-label, mechanistic phase 2a trial, we enrolled 21 patients with T2D & obesity (HbA1c median 7.0% (IQR 6.6, 7.8), weight 97kg (90, 102)) and subsequently treated them with 200mg ninerafaxstat twice daily for 4 or 8 weeks; (Fig. 1). Cardiac metabolism and function were assessed pre- & post-treatment using magnetic resonance imaging (MRI), 31P-, 1H- and, in a subset of n=9, hyperpolarized [1-13C]pyruvate MR spectroscopy. Results T2D patients at baseline presented with impaired myocardial energetics with a markedly reduced PCr/ATP (1.6 [1.4, 2.1]), myocardial steatosis (myocardial triglycerides 2.2% [1.5, 3.2]) left ventricular (LV) hypertrophy (LV mass 130g [98, 152]), and diastolic dysfunction (peak diastolic strain rate 0.86 1/s [0.82, 1.06]). Ninerafaxstat significantly improved myocardial energetics (PCr/ATP median by 32%, p Conclusions Treatment with ninerafaxstat significantly improves myocardial energetics, reduces myocardial steatosis and improves diastolic function in patients with T2D and obesity. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Imbria Pharmaaceuticals

Conjugated polymers achieve redox activity in electrochemical devices by combining redox-active, electronically conducting backbones with ion-transporting side chains that can be tuned for different electrolytes. In aqueous electrolytes, redox activity can be accomplished by attaching hydrophilic side chains to the polymer backbone, which enables ionic transport and allows volumetric charging of polymer electrodes. While this approach has been beneficial for achieving fast electrochemical charging in aqueous solutions, little is known about the relationship between water uptake by the polymers during electrochemical charging and the stability and redox potentials of the electrodes, particularly for electron-transporting conjugated polymers. We find that excessive water uptake during the electrochemical charging of polymer electrodes harms the reversibility of electrochemical processes and results in irreversible swelling of the polymer. We show that small changes of the side chain composition can significantly increase the reversibility of the redox behavior of the materials in aqueous electrolytes, improving the capacity of the polymer by more than one order of magnitude. Finally, we show that tuning the local environment of the redox-active polymer by attaching hydrophilic side chains can help to reach high fractions of the theoretical capacity for single-phase electrodes in aqueous electrolytes. Our work shows the importance of chemical design strategies for achieving high electrochemical stability for conjugated polymers in aqueous electrolytes.

A central goal of paleoanthropology is understanding the role of ecological change in hominin evolution. Over the past several decades researchers have expanded the hominin fossil record and assembled detailed late Cenozoic paleoclimatic, paleoenvironmental, and paleoecological archives. However, effective use of these data is precluded by the limitations of pattern-matching strategies for inferring causal relationships between ecological and evolutionary change. We examine several obstacles that have hindered progress, and highlight recent research that is addressing them by (i) confronting an incomplete fossil record, (ii) contending with datasets spanning varied spatiotemporal scales, and (iii) using theoretical frameworks to build stronger inferences. Expanding on this work promises to transform challenges into opportunities and set the stage for a new phase of paleoanthropological research.

Objectives To investigate the effect of progressive whole-body hyperthermia on maximal, and rapid voluntary torque production, and their neuromuscular determinants. Design Repeated measures, randomised. Methods Nine participants performed sets of neuromuscular assessments in HOT conditions (∼50 °C, ∼35% relative humidity) at rectal temperatures (Tre) of 37, 38.5 and 39.5 °C and in CON conditions (∼22 °C, ∼35% relative humidity) at a Tre of ∼37 °C and pre-determined comparative time-points. Electrically evoked twitch (single impulse) and octet (8 impulses at 300 Hz) responses were measured at rest. Maximum voluntary torque (MVT), surface electromyography (EMG) normalised to maximal M-wave, and voluntary activation (VA) were measured during 3−5 s isometric maximal voluntary contractions. Rate of torque development (RTD) and normalised EMG were measured during rapid voluntary isometric contractions from rest. Results All neuromuscular variables were unaffected by time in CON. In HOT, MVT, normalised EMG at MVT and VA were lower at 39.5 °C compared to 37 °C (p 0.05), despite lower normalised EMG at Tre 39.5 °C (p Conclusions Hyperthermia reduced late-phase voluntary RTD, likely due to reduced neural drive and the reduction in MVT. In contrast, early- and middle-phase voluntary RTD were unaffected by hyperthermia, likely due to the conflicting effects of reduced neural drive but faster intrinsic contractile properties.

Setting ecologically based water-extraction rules requires an understanding of the relationships between hydrology and the completion of aquatic organism life cycles. Successful reproduction of riverine fishes has been linked to hydrological variation across diverse climatic regions. However, the reproductive ecology for many species in wet–dry tropical northern Australia is poorly understood, and consequently there is little knowledge on how temporal (seasonal) and spatial hydrological variation influences fish reproduction in this region. This study aimed to quantify the hydrology-related reproductive ecologies of freshwater fish across the wet–dry seasonal cycle and between differing hydrological classes in a northern Australian river (Daly River, Northern Territory) subject to increasing interest in water extraction. Sampling of larval and juvenile fish was undertaken over 1 year at eight sites classified into perennial and intermittent flow types. Fish spawning phenologies were developed and spatial–temporal dynamics in larval fish assemblages were investigated using model-based multivariate and univariate analyses. Spawning occurred in all hydrological seasons, with low-flow dry season periods identified as important for many fish taxa. For a different fish assemblage, spawning mostly occurred during high-flow wet season periods. Larval assemblages in the wet season were more diverse than in the dry and wet–dry seasons. Perennial sites maintained higher diversity than intermittent sites year-round; however, larvae were more abundant in intermittent sites for some taxa. Spatial and temporal differences in larval assemblages were largely explained by variation in the occurrence and relative abundance of three aseasonally spawning taxa (Craterocephalus spp., Melanotaenia spp. and Ambassis spp.) and the largely wet-period spawning of Terapontidae spp. These results add to growing evidence of variation in spawning phenologies among fish species and the use of multiple hydrological phases for aseasonal reproduction. The diverse range of hydrological conditions used for spawning and rearing, and the differences between hydrological river classes among taxa, suggests that water-extraction and environmental flow rules should aim to maintain hydrological conditions catchment-wide during both low and high-flow periods to reduce the risk of impacting fish reproduction. In particular, the results suggest that if perennially flowing sites began to flow intermittently, such as through over-extraction of water or due to climate change, less diverse fish assemblages may result. This study expands our understanding of the relationships between hydrology and the reproductive ecology of freshwater fish in wet–dry tropical climates and may inform future ecologically based approaches to setting water-extraction rules.

The ion insertion redox chemistry of manganese dioxide has diverse applications in energy storage, catalysis, and chemical separations. Unique properties derive from the assembly of Mn-O octahedra into polymorphic structures that can host protons and non-protonic cations in interstitial sites. Despite many reports on individual ion-polymorph couples, much less is known about the selectivity of electrochemical ion insertion in MnO2. In this work, we use density functional theory to holistically compare the electrochemistry of AxMnO2 (where A = H+, Li+, Na+, K+, Mg2+, Ca2+, Zn2+ & Al3+) in aqueous and non-aqueous electrolytes. We develop an efficient computational scheme demonstrating that Hubbard-U correction has a greater impact on calculating accurate redox energetics than choice of exchange-correlation functional. Using PBE+U, we find that for non-protonic cations, ion selectivity depends on the oxygen coordination environments inside a polymorph. When H+ is present, however, the driving force to form hydroxyl bonds is usually stronger. In aqueous electrolytes, only three ion-polymorph pairs are thermodynamically stable within water’s voltage stability window (Na+ and K+ in 𝛼-MnO2, and Li+ in λ-MnO2), with all other ion insertion being metastable. We find Al3+ may insert into the 𝛿, R, and λ polymorphs across the full 2-electron redox of MnO2 at high voltage, however, electrolytes for multi-valent ions must be designed to impede formation of insoluble precipitates and facilitate cation desolvation. We also show that small ions co-insert with water in 𝛼-MnO2 to achieve greater coordination by oxygen, while solvation energies and kinetic effects dictate water co-insertion in 𝛿-MnO2. Taken together, these findings explain reports of mixed ion insertion mechanisms in aqueous electrolytes and highlight promising design strategies for safe, high energy density electrochemical energy storage, desalination batteries, and electrocatalysts.

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drive. To assess co-operative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of the collagen-processing enzymes ADAMTS2 and ADAMTS14. While both proteases contributed to collagen-processing, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion. Proteomic analysis revealed enrichment of known, protease-specific substrates following knockdown of either protease. Functional analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in regulating transforming growth factor β availability, acting on protease-specific substrates, SERPINE2 and Fibulin2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncover a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma.

Phreatic explosions at volcanoes are difficult to forecast but can be locally devastating, as illustrated by the deadly 2019 Whakaari (New Zealand) eruption. Quantifying eruption likelihood is essential for risk calculations that underpin volcano access decisions and disaster response. But estimating eruption probabilities is notoriously difficult for sudden onset eruptions. Here, we describe two retrospectively developed models for short-term (48 h) probabilistic forecasting of phreatic eruptions at Whakaari. The models are based on a pseudo-prospective analysis of seven Whakaari eruptions whose precursors were identified by time series feature engineering of continuous seismic data. The first model, an optimized warning system, could anticipate six out of seven eruptions at the cost of 14 warning days each year. While a warning is in effect, the probability of eruption is about 8% in 48 h, which is about 126 times higher than outside the warning. The second model used isotonic calibration to translate the output of the forecast model onto a probability scale. When applied pseudo-prospectively in the 48 h prior to the December 2019 eruption, it indicated an eruption probability up to 400 times higher than the background. Finally, we quantified the accuracy of these seismic data-driven forecasts, alongside an observatory expert elicitation that used multiple data sources. To do this, we used a forecast skill score that was benchmarked against the average rate of eruptions at Whakaari between 2011 and 2019. This exercise highlights the conditions under which the three different forecasting approaches perform well and where potential improvements could be made.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. We therefore set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. We show that this could be due to normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, despite no increase in mitochondrial number. In addition, we found that AICAR prevented excessive myocardial atrophy, and RNAseq analysis showed that this may be due to normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac mass and improve cardiac function.

Recent studies have shown the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and immunotherapy response. A question that remains is whether the ECM is directly educating the immune phenotypes seen in cancer. We identified a tumor-associated macrophage (TAM) population correlated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether ECM was capable of generating the TAM phenotype seen, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissues. ECM educated macrophages have a tissue remodeling and immunoregulatory phenotype, inducing altered T cell function. We conclude that the tumor ECM is directly educating this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

The ion insertion redox chemistry of manganese oxides has diverse applications in energy storage, catalysis, and chemical separations. Unique properties derive from the assembly of Mn-O octahedra into polymorphic structures that can host protons and non-protonic cations in interstitial sites. Despite many experimental reports targeting specific applications, a comprehensive understanding of ion insertion in Mn oxides remains elusive. In this work, we use density functional theory to study the electrochemistry of AxMnO2 (where A = H+, Li+, Na+, K+, Mg2+, Ca2+, Zn2+ & Al3+) in aqueous and non-aqueous electrolytes. We develop an efficient computational scheme demonstrating that Hubbard-U correction has a greater impact on calculating accurate redox energetics than choice of exchange-correlation functional. Using PBE+U, we find that non-protonic cation insertion into MnO2 depends on the oxygen coordination environments inside a polymorph but that when H+ is present, the driving force to form hydroxyl bonds is generally stronger. Only three ion-polymorph pairs are thermodynamically stable within water’s voltage stability window (Na+ and K+ in 𝛼-MnO2, and Li+ in λ-MnO2), with all other aqueous ion insertion relying on metastability. Al3+ insertion into the 𝛿, R, and λ polymorphs may enable the full 2-electron redox of MnO2 at high voltage, but electrolytes must be designed to impede formation of insoluble precipitates and facilitate ion desolvation. We also show that water co-insertion stabilizes small ions in 𝛼-MnO2, while solvation energies and kinetic effects dictate water insertion in 𝛿-MnO2. Taken together, these findings rationalize experimental reports of mixed ion insertion mechanisms in aqueous batteries and highlight promising design strategies for safe, high energy density electrochemical energy storage.

In response to the emerging coronavirus disease 2019 (COVID-19) pandemic in March 2020, the Owen Clinic at UC San Diego Health scaled up telemedicine to ensure the continuity of human immunodeficiency virus primary care. A group of nurse practitioners, physicians, and a physician assistant developed a dedicated COVID-19 telemedicine clinic to provide virtual health care services to patients with or at risk for severe acute respiratory syndrome coronavirus 2 infection. This effort contributed to successful health outcomes for the clinic's 476 patients diagnosed with COVID-19. The Owen Clinic was also the first ambulatory clinic within UC San Diego Health to implement on-site COVID-19 vaccines. Nurse practitioners and a physician assistant spearheaded these 2 clinical initiatives.

Surface patterning of functional materials is a key technology in various fields such as microelectronics, optics, and photonics. In micro- and nanofabrication, polymers are frequently employed either as photoreactive or thermoresponsive resists that enable further fabrication steps, or as functional adlayers in electronic and optical devices. In this article, a method is presented for imprint lithography using low molecular weight arylazoisoxazoles photoswitches instead of polymer resists. These photoswitches exhibit a rapid and reversible solid-to-liquid phase transition upon photo-isomerization at room temperature, making them highly suitable for reversible surface functionalization at ambient conditions. Beyond photo-induced imprint lithography with multiple write-and-erase cycles, prospective applications as patterned matrix for nanoparticles and etch resist on gold surfaces are demonstrated.

Mechanistic studies of oxide electrocatalysts for heterogeneous water oxidation have been primarily focused on understanding the origins of activity, with fewer studies studying fundamental properties influencing stability. The main challenge is directly observing and quantifying local structural instability under operating conditions. In this work, we provide a dynamic view of the perovskite stability as a function of time and operational voltage using operando electrochemical atomic force microscopy (EC-AFM). Specifically, we study the degradation pathways of SrIrO3, a highly active electrocatalyst, during the oxygen evolution reaction (OER) by tracking the potential-dependent Sr leaching and perovskite dissolution at the nanometer scale. This material serves as a model system for degradation studies of perovskite AMO3 oxides, exhibiting both A-cation leaching and transition metal (M) dissolution. We show that Sr leaching precedes perovskite dissolution by up to 0.8 V, leading to a wide voltage window of stability where water oxidation occurs on a Sr-depleted surface without significant corrosion. Moreover, we reveal that the stability of the perovskite surface is strongly influenced by the electrolytic environment and that corrosion rates differ dramatically as a function of dissolved Sr concentration. Ultimately, our study demonstrates the overall stability of perovskite oxides during electrocatalysis can be substantially improved by suppressing A-site leaching.

Biotic homogenization-increasing similarity of species composition among ecological communities-has been linked to anthropogenic processes operating over the last century. Fossil evidence, however, suggests that humans have had impacts on ecosystems for millennia. We quantify biotic homogenization of North American mammalian assemblages during the late Pleistocene through Holocene (similar to 30,000 ybp to recent), a timespan encompassing increased evidence of humans on the landscape (similar to 20,000-14,000 ybp). From similar to 10,000 ybp to recent, assemblages became significantly more homogenous (>100% increase in Jaccard similarity), a pattern that cannot be explained by changes in fossil record sampling. Homogenization was most pronounced among mammals larger than 1 kg and occurred in two phases. The first followed the megafaunal extinction at similar to 10,000 ybp. The second, more rapid phase began during human population growth and early agricultural intensification (similar to 2,000-1,000 ybp). We show that North American ecosystems were homogenizing for millennia, extending human impacts back similar to 10,000 years.

Over the first two decades of the 21st century, many wetlands in eastern Australia exhibited declining water levels, causing concern for communities and environmental managers and raising questions about the roles of climate change and other human activity in these water level declines. In this context we examine the causes of water level variability in four wetlands on North Stradbroke Island (Minjerribah), in the humid subtropics of south-eastern Queensland, Australia, using a combination of hydrological and water isotope monitoring and modelling. North Stradbroke Island has a high concentration of wetlands perched above the regional water table, with cultural and ecological significance, and value for palaeoclimate research. From 2015 to 2019, wetland water depths decreased markedly at all sites, coinciding with increases in oxygen isotope ratios in surface waters. The data indicate that climate, specifically a decrease in precipitation relative to evaporation, was responsible for those declining water levels, and that groundwater extraction did not play a critical role. At two of the sites—both palustrine wetlands—declining surface water levels led to intermittent connectivity with the local perched aquifers. At the other two sites, which are both shallow lakes, the surface waters were constantly fed by perched groundwater. The hydrology of the two lakes was modelled using simple mass balance. However, in order to accurately model lake level change, it was necessary to vary catchment runoff and lake outflow via groundwater through time, highlighting complexity in projecting future hydrological change in these lakes. The long term resilience of these lakes depends on a combination of rainfall regime and the balance between catchment runoff and groundwater throughflow, the future of which is highly uncertain. As a consequence, continued efforts to project future hydroclimate and to model the complex hydrology of subtropical wetlands are essential.

Even as vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expands in the United States, cases will linger among unvaccinated individuals for at least the next year, allowing the spread of the coronavirus to continue in communities across the country. Detecting these infections, particularly asymptomatic ones, is critical to stemming further transmission of the virus in the months ahead. This will require active surveillance efforts in which these undetected cases are proactively sought out rather than waiting for individuals to present to testing sites for diagnosis. However, finding these pockets of asymptomatic cases (i.e., hotspots) is akin to searching for needles in a haystack as choosing where and when to test within communities is hampered by a lack of epidemiological information to guide decision makers’ allocation of these resources. Making sequential decisions with partial information is a classic problem in decision science, the explore v. exploit dilemma. Using methods—bandit algorithms—similar to those used to search for other kinds of lost or hidden objects, from downed aircraft or underground oil deposits, we can address the explore v. exploit tradeoff facing active surveillance efforts and optimize the deployment of mobile testing resources to maximize the yield of new SARS-CoV-2 diagnoses. These bandit algorithms can be implemented easily as a guide to active case finding for SARS-CoV-2. A simple Thompson sampling algorithm and an extension of it to integrate spatial correlation in the data are now embedded in a fully functional prototype of a web app to allow policymakers to use either of these algorithms to target SARS-CoV-2 testing. In this instance, potential testing locations were identified by using mobility data from UberMedia to target high-frequency venues in Columbus, Ohio, as part of a planned feasibility study of the algorithms in the field. However, it is easily adaptable to other jurisdictions, requiring only a set of candidate test locations with point-to-point distances between all locations, whether or not mobility data are integrated into decision making in choosing places to test.