Extreme shifts in pyrite sulfur isotope compositions reveal the path to bonanza gold.

Pyrite is the most common sulfide mineral in hydrothermal ore-forming systems. The ubiquity and abundance of pyrite, combined with its ability to record and preserve a history of fluid evolution in crustal environments, make it an ideal mineral for studying the genesis of hydrothermal ore deposits, including those that host critical metals. However, with the exception of boiling, few studies have been able to directly link changes in pyrite chemistry to the processes responsible for bonanza-style gold mineralization. Here, we report the results of high-resolution secondary-ion mass spectrometry and electron microprobe analyses conducted on pyrite from the Brucejack epithermal gold deposit, British Columbia. Our δ34S and trace element results reveal that the Brucejack hydrothermal system experienced abrupt fluctuations in fluid chemistry, which preceded and ultimately coincided with the onset of ultra-high-grade mineralization. We argue that these fluctuations, which include the occurrence of extraordinarily negative δ34S values (e.g., -36.1‰) in zones of auriferous, arsenian pyrite, followed by sharp increases of δ34S values in syn-electrum zones of nonarsenian pyrite, were caused by vigorous, fault valve-induced episodic boiling (flashing) and subsequent inundation of the hydrothermal system by seawater. We conclude that the influx of seawater was the essential step to forming bonanza-grade electrum mineralization by triggering, through the addition of cationic flocculants and cooling, the aggregation of colloidal gold suspensions. Moreover, our study demonstrates the efficacy of employing high-resolution, in situ analytical techniques to map out individual ore-forming events in a hydrothermal system.

Disturbance sensitivity shapes patterns of tree species distribution in Afrotropical lowland rainforests more than climate or soil.

Understanding how tropical forests respond to abiotic environmental changes is critical for preserving biodiversity, mitigating climate change, and maintaining ecosystem services in the coming century. To evaluate the relative roles of the abiotic environment and human disturbance on Central African tree community composition, we employ tree inventory data, remotely sensed climatic data, and soil nutrient data collected from 30 1-ha plots distributed across a large-scale observational experiment in forests that had been differently impacted by logging and hunting in northern Republic of Congo. We show that the composition of Afrotropical plant communities at this scale responds to human disturbance more than to climate, with particular sensitivities to hunting and distance to the nearest village (a proxy for other human activities, including tree-cutting and gathering). These findings contrast neotropical predictions, highlighting the unique ecological, evolutionary, and anthropogenic history of Afrotropical forests.

Transient Receptor Potential Canonical 5 (TRPC5): Regulation of Heart Rate and Protection against Pathological Cardiac Hypertrophy.

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.

Sustainable bio-based solid phase extraction adsorbent for the determination of various types of organic compounds.

A sustainable, bio-based, mesoporous material, Starbon A800, was explored for use as an adsorbent in solid phase extraction (SPE). A solution containing seven nitrosamines was first used as a standard to optimise conditions for extraction efficiency with Starbon A800. After optimising conditions, 25 compounds of varying polarity (terpenes, phenolics, pesticides, PAHs, amines, and nitrosamines) were extracted with SPE using either Starbon® A800, C18 or Porous Graphitic Carbon (PGC) as the adsorbent, for comparison purposes. At the same time, 3 different elution solvents (heptane, dichloromethane, and ethanol) were used for each type of adsorbent. Hansen solubility parameters can be used to choose an appropriate elution solvent for the selected SPE adsorbent. The best average SPE recoveries found for the 25 various compounds were 83%, 79%, and 65% using Starbon A800, PGC, and C18 adsorbents respectively and these had dichloromethane as the elution solvent. The identification and quantification of components was carried out using UV-visible spectroscopy, two-dimensional gas chromatography (GCxGC) with time of flight/mass spectrometry (TOF/MS) or a nitrogen chemiluminescence detector (NCD). The optimized method was successfully applied to extract volatile organic compounds from red wine and tap water using Starbon A800. Starbon A800 was shown to be a promising, low-cost, green, scalable, alternative adsorbent for the extraction of various types of organic compounds of a wide range of polarities using SPE.

Imaging mass cytometry analysis of Becker muscular dystrophy muscle samples reveals different stages of muscle degeneration.

Becker muscular dystrophy (BMD) is characterised by fiber loss and expansion of fibrotic and adipose tissue. Several cells interact locally in what is known as the degenerative niche. We analysed muscle biopsies of controls and BMD patients at early, moderate and advanced stages of progression using Hyperion imaging mass cytometry (IMC) by labelling single sections with 17 markers identifying different components of the muscle. We developed a software for analysing IMC images and studied changes in the muscle composition and spatial correlations between markers across disease progression. We found a strong correlation between collagen-I and the area of stroma, collagen-VI, adipose tissue, and M2-macrophages number. There was a negative correlation between the area of collagen-I and the number of satellite cells (SCs), fibres and blood vessels. The comparison between fibrotic and non-fibrotic areas allowed to study the disease process in detail. We found structural differences among non-fibrotic areas from control and patients, being these latter characterized by increase in CTGF and in M2-macrophages and decrease in fibers and blood vessels. IMC enables to study of changes in tissue structure along disease progression, spatio-temporal correlations and opening the door to better understand new potential pathogenic pathways in human samples.

Proposed treatment strategy for reactive hypoglycaemia.

Background/aim: Managing reactive hypoglycaemia (RH) poses challenges due to limited and often ineffective treatment options. We report a case series and draw on this to propose a stepwise treatment approach consisting of lifestyle modifications, metformin, GLP-1 analogues, and the use of flash glucose monitoring technology. Method: A retrospective review was conducted to analyse the management of 11 cases presenting with recurrent RH symptoms. Result: Two patients experienced successful resolution of symptoms through lifestyle modifications. Metformin alone was effective in treating seven out of nine patients who received pharmacological treatment. Two patients with previous upper gastrointestinal surgery showed a partial response to metformin and benefited further from additional long-acting GLP-1 analogue. Pharmacological intervention led to significant reductions in insulin and C-peptide levels in repeat mixed meal tolerance tests (P-values 0.043 for insulin and 0.006 for C-peptide). Finally, flash glucose monitoring technology was useful in early detection and preventing episodes of hypoglycaemia in one of these patients with persistent symptoms. Conclusion: These findings highlight the potential efficacy of escalated treatment strategies for RH, including the use of metformin, GLP-1 analogues, and flash glucose monitoring technology.

Plant evolution: Streptophyte multicellularity, ecology, and the acclimatisation of plants to life on land.

Land plants are celebrated as one of the three great instances of complex multicellularity, but new phylogenomic and phenotypic analyses are revealing deep evolutionary roots of multicellularity among algal relatives, prompting questions about the causal basis of this major evolutionary transition.

Identifying potential high-risk zones for land-derived plastic litter to marine megafauna and key habitats within the North Atlantic.

The pervasive use of plastic in modern society has led to plastic litter becoming ubiquitous within the ocean. Land-based sources of plastic litter are thought to account for the majority of plastic pollution in the marine environment, with plastic bags, bottles, wrappers, food containers and cutlery among the most common items found. In the marine environment, plastic is a transboundary pollutant, with the potential to cause damage far beyond the political borders from where it originated, making the management of this global pollutant particularly complex. In this study, the risks of land-derived plastic litter (LDPL) to major groups of marine megafauna - seabirds, cetaceans, pinnipeds, elasmobranchs, turtles, sirenians, tuna and billfish - and a selection of productive and biodiverse biogenic habitats - coral reefs, mangroves, seagrass, saltmarsh and kelp beds - were analysed using a Spatial Risk Assessment approach. The approach combines metrics for vulnerability (mechanism of harm for megafauna group or habitat), hazard (plastic abundance) and exposure (distribution of group or habitat). Several potential high-risk zones (HRZs) across the North Atlantic were highlighted, including the Azores, the UK, the French and US Atlantic coasts, and the US Gulf of Mexico. Whilst much of the modelled LDPL driving risk in the UK originated from domestic sources, in other HRZs, such as the Azores archipelago and the US Gulf of Mexico, plastic originated almost exclusively from external (non-domestic) sources. LDPL from Caribbean islands - some of the largest generators of marine plastic pollution in the dataset of river plastic emissions used in the study - was noted as a significant input to HRZs across both sides of the Atlantic. These findings highlight the potential of Spatial Risk Assessment analyses to determine the location of HRZs and understand where plastic debris monitoring and management should be prioritised, enabling more efficient deployment of interventions and mitigation measures.

Diverse Fgfr1 signaling pathways and endocytic trafficking regulate early mesoderm development.

The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1 null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth, but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM-interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identify processes regulating early mesoderm development by mechanisms involving both canonical and non-canonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.

Fundamental properties and phosphorus transformation mechanism of soybean straw during microwave hydrothermal conversion process.

Microwave hydrothermal (MHT) conversion is emerging as a promising technology for the disposal and reutilization of biowastes. This study investigated the fundamental properties and phosphorus transformation mechanism of soybean straw during the MHT conversion process. The oxygen-containing functional groups in soybean straw were stripped, and a trend of dehydration was observed as the temperature increased during the MHT process. Cellulose was identified as the major component of the MHT solid products at high temperature. Glucose and glucuronic acid in the MHT liquid products were gradually converted to formic acid and acetic acid with increasing temperature and holding time. The characteristics of the MHT products directly affected the changes in P speciation and transformation. Most of the P was distributed in liquid products and the impact of holding time was not significant on P distribution at low MHT temperature. With the increase in temperature and holding time, P gradually transferred into the solid products. The proportion of organic phosphorus and soluble inorganic phosphorus in soybean straw was high, and it decreased noticeably after the MHT process. The increase in MHT temperature promoted the conversion of OP and AP into IP and NAIP respectively. P K-edge X-ray absorption near edge structure analysis reveals that Ca5(PO4)3(OH) was the major component of soybean straw and more Ca5(PO4)3(OH) was formed at lower MHT temperature. This study provides fundamental knowledge on the property changes of soybean straw and the transformation of phosphorus during MHT conversion process, which is essential for its disposal and further utilization.

Enhanced microwave assisted pyrolysis of waste rice straw through lipid extraction with supercritical carbon dioxide.

A combination of supercritical carbon dioxide (scCO2) extraction and microwave-assisted pyrolysis (MAP) have been investigated for the valorisation of waste rice straw. ScCO2 extraction of rice straw led to a 0.7% dry weight yield of lipophilic molecules, at elevated temperatures of 65 °C and pressures of 400 bar. Lipid compositions (fatty acids, fatty alcohol, fatty aldehydes, steroid ketones, phytosterols, n-alkanes and wax esters) of the waxes obtained by scCO2 were comparable to those obtained Soxhlet extraction using the potentially toxic solvent n-hexane. ScCO2 extraction positively influenced the pyrolysis heating rate, with a rate of 420 K min-1 for particles of 500-2000 µm, compared to 240 K min-1 for the same particle size of untreated straw. Particle size significantly affected cellulose decomposition and the distribution of pyrolysis products (gaseous, liquid and char), highlighting the importance of selecting an adequate physical pre-treatment. TG and DTG of the original rice straw and resulting biochar produced indicated that cellulose was completely decomposed during the MAP. While a rapid pressure change occurred at ∼120 °C (size > 2000 µm) and ∼130 °C (size 500-2000 µm) during MAP and was associated with the production of incondensable gas during cellulose decomposition, this takes place at significantly lower temperatures than those observed with conventional pyrolysis, 320 °C. Wax removal by scCO2 influences the dielectric properties of the straw, enhancing microwave absorption with rapid heating rates and elevated final pyrolysis temperatures, illustrating the benefits of combining these sustainable technologies within a holistic rice straw biorefinery.

Hagfish genome elucidates vertebrate whole-genome duplication events and their evolutionary consequences.

Polyploidy or whole-genome duplication (WGD) is a major event that drastically reshapes genome architecture and is often assumed to be causally associated with organismal innovations and radiations. The 2R hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution. However, the timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved and whether these WGD events underlie vertebrate phenotypic diversification remains elusive. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and 2R occurred in the gnathostome stem-lineage, maximally in the late Cambrian-earliest Ordovician, after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced an additional independent genome triplication. Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only in the gnathostome but not in the cyclostome lineage, calling into question the general expectation that WGDs lead to leaps of bodyplan complexity.

Discovery and validation of genes driving drug-intake and related behavioral traits in mice.

Substance use disorders are heritable disorders characterized by compulsive drug use, the biological mechanisms for which remain largely unknown. Genetic correlations reveal that predisposing drug-naïve phenotypes, including anxiety, depression, novelty preference and sensation seeking, are predictive of drug-use phenotypes, thereby implicating shared genetic mechanisms. High-throughput behavioral screening in knockout (KO) mice allows efficient discovery of the function of genes. We used this strategy in two rounds of candidate prioritization in which we identified 33 drug-use candidate genes based upon predisposing drug-naïve phenotypes and ultimately validated the perturbation of 22 genes as causal drivers of substance intake. We selected 19/221 KO strains (8.5%) that had a difference from control on at least one drug-naïve predictive behavioral phenotype and determined that 15/19 (~80%) affected the consumption or preference for alcohol, methamphetamine or both. No mutant exhibited a difference in nicotine consumption or preference which was possibly confounded with saccharin. In the second round of prioritization, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two-bottle choice and ethanol drinking-in-the-dark protocols. We identified 15/401 KO strains (3.7%, which included one gene from the first cohort) that differed most from controls for the predisposing phenotypes. 8 of 15 gene deletions (53%) affected intake or preference for alcohol, methamphetamine or both. Using multivariate and bioinformatic analyses, we observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction-related processes further.

Detection of Traumatic Ankle Arthrotomies: Computed Tomography Scan Versus Saline Load Test.

OBJECTIVE: Periarticular wounds present a common diagnostic dilemma for emergency providers and orthopedic surgeons because traumatic arthrotomies (TA) often necessitate different management from superficial soft tissue wounds. Historically, TA have been diagnosed with the saline load test (SLT). Computed tomography (CT) scan has been studied as an alternative to SLT in diagnosing TA in several joints, but there are limited data specifically pertaining to the ankle. This study aimed to compare the ability of a CT scan to identify an ankle TA versus a traditional SLT. The hypothesis was that there would be no significant difference between a CT scan and SLT in diagnosing ankle TA in a cadaveric model. METHODS: This cadaveric study used 10 thawed fresh-frozen cadaveric ankles. A baseline CT scan was performed to ensure no intra-articular air existed before simulated TA. After the baseline CT, a 1 cm TA was created in the anterolateral arthroscopy portal site location. The ankles then underwent a postarthrotomy CT scan to evaluate for the presence of intra-articular air. After the CT scan, a 30 mL SLT was performed using the anteromedial portal site location. RESULTS: After arthrotomy, intra-articular air was visualized in 7 of 10 cadavers in the postarthrotomy CT scan. All the ankles had fluid extravasation during the SLT with <10 mL of saline. The sensitivity of the SLT for TA was 100% versus 70% for the CT scan. CONCLUSIONS: The SLT was more sensitive in diagnosing 1-cm ankle TA than a CT scan in a cadaveric model.

Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK.

Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing.

Nitrogen-Doped Starbons®: Methodology Development and Carbon Dioxide Capture Capability.

Five nitrogen sources (glycine, ß-alanine, urea, melamine and nicotinamide) and three heating methods (thermal, monomodal microwave and multimodal microwave) are used to prepare nitrogen-doped Starbons® derived from starch. The materials are initially produced at 250-300 °C (SNx 300y ), then heated in vacuo to 800 °C to produce nitrogen-doped SNx 800y 's. Melamine gives the highest nitrogen incorporation without destroying the Starbon® pore structure and the microwave heating methods give higher nitrogen incorporations than thermal heating. The carbon dioxide adsorption capacities of the nitrogen-doped Starbons® determined gravimetrically, in many cases exceed those of S300 and S800. The carbon dioxide, nitrogen and methane adsorption isotherms of the most promising materials are measured volumetrically. Most of the nitrogen-doped materials show higher carbon dioxide adsorption capacities than S800, but lower methane and nitrogen adsorption capacities. As a result, the nitrogen-doped Starbons® exhibit significantly enhanced carbon dioxide versus nitrogen and methane versus nitrogen selectivities compared to S800.

Traumatic spinal injury patterns of on vs. off-road motorcycle crashes.

OBJECTIVE: Two wheel motorized vehicles used in both street transportation and recreation are a common cause of severe injury in the United States (US). To date, there has been limited data describing the spinal injury patterns among these motorcycle injury patients in the US. The goal of this study is to characterize and compare differences in specific injury patterns of patients sustaining traumatic spinal injuries after motocross (off-road) and street bike (on-road) collisions in the southwestern US at a Level I Trauma Center. METHODS: Trauma registry data was queried for patients sustaining a spinal injury after motorcycle collision from 2010 to 2019 at a single Level I Trauma Center. Computed tomography (CT) scan and magnetic imaging resonance imaging (MRI) reports from initial trauma evaluation were reviewed and data was manually obtained regarding injury morphology and location. RESULTS: A total of 1798 injuries were identified in 549 patients who sustained a motorcycle collision, specifically 67 off-road and 482 on-road motorcycle patients. Off-road motorcycle patients were found to be significantly younger (34.75 vs. 42.66, p = 0.00015). A total of 46.2% of the off-road injuries were determined to be from compression mechanisms, compared to 32.9% in the on-road cohort (p = 0.0027). The on-road cohort was more likely to have an injury classified as insignificant, such as transverse and spinous process fractures (60.1% vs. 42.5%, p = 00.25). There was no significant difference in regards to junctional, mobile, and semirigid spine segments between the two cohorts. CONCLUSIONS: Different fracture patterns were seen between the off-road and on-road motorcycle cohorts. Off road motorcyclists experienced significantly more compression and translational injuries, while on road motorcyclists experienced more frequent insignificant injury patterns. Data on the different fracture patterns may help professionals develop safety equipment for motorcyclists.

Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation.

BACKGROUND: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH. METHODS: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH. RESULTS: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling. CONCLUSIONS: A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.

Mechanistic modeling of climate effects on redistribution and population growth in a community of fish species.

Understanding community responses to climate is critical for anticipating the future impacts of global change. However, despite increased research efforts in this field, models that explicitly include important biological mechanisms are lacking. Quantifying the potential impacts of climate change on species is complicated by the fact that the effects of climate variation may manifest at several points in the biological process. To this end, we extend a dynamic mechanistic model that combines population dynamics, such as species interactions, with species redistribution by allowing climate to affect both processes. We examine their relative contributions in an application to the changing biomass of a community of eight species in the Gulf of Maine using over 30 years of fisheries data from the Northeast Fishery Science Center. Our model suggests that the mechanisms driving biomass trends vary across space, time, and species. Phase space plots demonstrate that failing to account for the dynamic nature of the environmental and biologic system can yield theoretical estimates of population abundances that are not observed in empirical data. The stock assessments used by fisheries managers to set fishing targets and allocate quotas often ignore environmental effects. At the same time, research examining the effects of climate change on fish has largely focused on redistribution. Frameworks that combine multiple biological reactions to climate change are particularly necessary for marine researchers. This work is just one approach to modeling the complexity of natural systems and highlights the need to incorporate multiple and possibly interacting biological processes in future models.

Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer.

BACKGROUND: Systemic immune activation, hallmarked by C-reactive protein (CRP) and interleukin-6 (IL-6), can modulate antitumor immune responses. In this study, we evaluated the role of IL-6 and CRP in the stratification of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We also interrogated the underlying immunosuppressive mechanisms driven by the IL-6/CRP axis. METHODS: In cohort A (n=308), we estimated the association of baseline CRP with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with NSCLC treated with ICIs alone or with chemo-immunotherapy (Chemo-ICI). Baseline tumor bulk RNA sequencing (RNA-seq) of lung adenocarcinomas (LUADs) treated with pembrolizumab (cohort B, n=59) was used to evaluate differential expression of purine metabolism, as well as correlate IL-6 expression with PFS. CODEFACS approach was applied to deconvolve cohort B to characterize the tumor microenvironment by reconstructing the cell-type-specific transcriptome from bulk expression. Using the LUAD cohort from The Cancer Genome Atlas (TCGA) we explored the correlation between IL-6 expression and adenosine gene signatures. In a third cohort (cohort C, n=18), plasma concentrations of CRP, adenosine 2a receptor (A2aR), and IL-6 were measured using ELISA. RESULTS: In cohort A, 67.2% of patients had a baseline CRP≥10 mg/L (CRP-H). Patients with CRP-H achieved shorter OS (8.6 vs 14.8 months; p=0.006), shorter PFS (3.3 vs 6.6 months; p=0.013), and lower ORR (24.7% vs 46.3%; p=0.015). After adjusting for relevant clinical variables, CRP-H was confirmed as an independent predictor of increased risk of death (HR 1.51, 95% CI: 1.09 to 2.11) and lower probability of achieving disease response (OR 0.34, 95% CI: 0.13 to 0.89). In cohort B, RNA-seq analysis demonstrated higher IL-6 expression on tumor cells of non-responders, along with a shorter PFS (p<0.05) and enrichment of the purinergic pathway. Within the TCGA LUAD cohort, tumor IL-6 expression strongly correlated with the adenosine signature (R=0.65; p<2.2e-16). Plasma analysis in cohort C demonstrated that CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs 1.3 ng/mL; p=0.01). CONCLUSIONS: This study demonstrates CRP as a readily available blood-based prognostic biomarker in ICI-treated NSCLC. Additionally, we elucidate a potential link of the CRP/IL-6 axis with the immunosuppressive adenosine signature pathway that could drive inferior outcomes to ICIs in NSCLC and also offer novel therapeutic avenues.