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UNLABELLED: Infections caused by antimicrobial-resistant Escherichia coli are the leading cause of death attributed to antimicrobial resistance (AMR) worldwide, and the known AMR mechanisms involve a range of functional proteins. Here, we employed a pan-genome wide association study (GWAS) approach on over 1,000 E. coli isolates from sick dogs collected across the US and Canada and identified a strong statistical association (empirical P < 0.01) of AMR, involving a range of antibiotics to a group 1 capsular (CPS) gene cluster. This cluster included genes under relaxed selection pressure, had several loci missing, and had pseudogenes for other key loci. Furthermore, this cluster is widespread in E. coli and Klebsiella clinical isolates across multiple host species. Earlier studies demonstrated that the octameric CPS polysaccharide export protein Wza can transmit macrolide antibiotics into the E. coli periplasm. We suggest that the CPS in question, and its highly divergent Wza, functions as an antibiotic trap, preventing antimicrobial penetration. We also highlight the high diversity of lineages circulating in dogs across all regions studied, the overlap with human lineages, and regional prevalence of resistance to multiple antimicrobial classes. IMPORTANCE: Much of the human genomic epidemiology data available for E. coli mechanism discovery studies has been heavily biased toward shiga-toxin producing strains from humans and livestock. E. coli occupies many niches and produces a wide variety of other significant pathotypes, including some implicated in chronic disease. We hypothesized that since dogs tend to share similar strains with their owners and are treated with similar antibiotics, their pathogenic isolates will harbor unexplored AMR mechanisms of importance to humans as well as animals. By comparing over 1,000 genomes with in vitro antimicrobial susceptibility data from sick dogs across the US and Canada, we identified a strong multidrug resistance association with an operon that appears to have once conferred a type 1 capsule production system.

Sensory neurons sense pathogenic infiltration to drive innate immune responses, but their role in humoral immunity is unclear. Here, using mouse models of Streptococcus pneumoniae infection and Alternaria alternata asthma, we show that sensory neurons are required for B cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion increases bacterial burden and reduces B cell numbers, IgG release, and neutrophil stimulation. Meanwhile, during A. alternata-induced airway inflammation, sensory neuron depletion decreases B cell population sizes, IgE levels, and asthmatic characteristics. Mechanistically, during bacterial infection, sensory neurons preferentially release vasoactive intestinal polypeptide (VIP). In response to asthma, sensory neurons release substance P. Administration of VIP into sensory neuron-depleted mice suppresses bacterial burden, while VIPR1 deficiency increases infection. Similarly, exogenous substance P delivery aggravates asthma in sensory neuron-depleted mice, while substance P deficiency ameliorates asthma. Our data, thus demonstrate that sensory neurons release select neuropeptides which target B cells dependent on the immunogen.

Abstract Sensory neurons sense pathogenic infiltration to drive innate immune responses, but their role in humoral immunity is unclear. Here, using mouse models of Streptococcus pneumoniae infection and Alternaria alternata asthma, we show that sensory neurons are required for B cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion increases bacterial burden and reduces B cell numbers, IgG release, and neutrophil stimulation. Meanwhile, during A. alternata-induced airway inflammation, sensory neuron depletion decreases B cell population sizes, IgE levels, and asthmatic characteristics. Mechanistically, during bacterial infection, sensory neurons preferentially release vasoactive intestinal polypeptide (VIP). In response to asthma, sensory neurons release substance P. Administration of VIP into sensory neuron-depleted mice suppresses bacterial burden, while VIPR1 deficiency increases infection. Similarly, exogenous substance P delivery aggravates asthma in sensory neuron-depleted mice, while substance P deficiency ameliorates asthma. Our data, thus demonstrate that sensory neurons release select neuropeptides which target B cells dependent on the immunogen.

Lipidomics has unveiled the intricate human lipidome, emphasizing the extensive diversity within lipid classes in mammalian tissues critical for cellular functions. This diversity poses a challenge in maintaining a delicate balance between adaptability to recurring physiological changes and overall stability. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), linked to factors such as obesity and diabetes, stems from a compromise in the structural and functional stability of the liver within the complexities of lipid metabolism. This compromise inaccurately senses an increase in energy status, such as during fasting-feeding cycles or an upsurge in lipogenesis. Serum lipidomic studies have delineated three distinct metabolic phenotypes, or metabotypes in MASLD. MASLD-A is characterized by lower very low-density lipoprotein (VLDL) secretion and triglyceride (TG) levels, associated with a reduced risk of cardiovascular disease (CVD). In contrast, MASLD-C exhibits increased VLDL secretion and TG levels, correlating with elevated CVD risk. An intermediate subtype, with a blend of features, is designated as the MASLD-B metabotype. In this perspective, we examine into recent findings that show the multifaceted regulation of VLDL secretion by S-adenosylmethionine, the primary cellular methyl donor. Furthermore, we explore the differential CVD and hepatic cancer risk across MASLD metabotypes and discuss the context and potential paths forward to gear the findings from genetic studies towards a better understanding of the observed heterogeneity in MASLD.

Abstract Background Outstanding exercise performance has been associated with an exacerbated vagal outflow. Nevertheless, during high-altitude hypobaric-hypoxia (HH), there is a baroreflex-dependent parasympathetic withdrawal and exercise performance deterioration. Notably, vagal control is pivotal in exercise performance, and exogenous oxytocin (OXY) administration has been shown to enhance parasympathetic drive; however, no evidence shows their role in exercise performance during HH. Then, this study aimed to examine the effect of prolonged exogenous oxytocin (OXY) administration on exercise performance during hypobaric hypoxia (HH) in rats. Results A vehicle group (n = 6) and an OXY group (n = 6) performed incremental exercise and baroreflex tests during both normobaric normoxia (NN) and HH (PO2: 100 mmHg, simulated 3,500 m) prior (pre-) and after (post-) 14 days of administration. The results showed that at pre-, there were no significant differences in exercise performance between the two groups, while at post-, the OXY group exhibited similar performance between NN and HH, while the Vehicle group maintained a significant decline in performance at HH compared to NN. At post-, the Vehicle group also demonstrated a reset in the baroreflex and a worse bradycardic response in HH, which was reversed in the OXY group, while the hypoxic ventilatory response was similar in both groups. Conclusion The findings suggest prolonged OXY administration prevents impaired exercise performance and vagal control during short-term HH.

Abstract As more women engage in high-altitude activities, understanding how ovarian hormone fluctuations affect their cardiorespiratory system is essential for optimizing acclimatization to these environments. This study investigates the effects of menstrual cycle (MC) phases on physiological responses at rest, during and after submaximal exercise, at high-altitude (barometric pressure 509 ± 6 mmHg; partial pressure of inspired oxygen 96 ± 1 mmHg; ambient temperature 21 ± 2 °C and relative humidity 27 ± 4%) in 16 eumenorrheic women. Gas exchange, hemodynamic responses, heart rate variability and heart rate recovery (HRR) were monitored at low altitude, and then at 3375 m on the Mont Blanc (following nocturnal exposure) during both the early-follicular (EF) and mid-luteal (ML) phases. Significant differences were observed between low and high-altitude in ventilation, heart rate and cardiac output. Resting ventilation (15.2 ± 1.9 vs. 13.2 ± 2.5 L.min-1; p = 0.039) and tidal volume (812 ± 217 vs. 713 ± 190 mL; p = 0.027) were higher during EF than ML at high-altitude. These differences between EF and ML were no longer evident during exercise, with comparable responses in oxygen uptake kinetics, cycling efficiency and HRR. The MC had negligible effects on physiological responses to high-altitude. An individualized approach, tailored to each woman’s specific responses to hypoxia across the MC, may be more beneficial in optimizing high-altitude sojourns than general guidelines.

Abstract Nucleotide-binding leucine-rich repeat (NLR) disease resistance genes typically confer resistance against races of a single pathogen. Here, we report that Yr87/Lr85, an NLR gene from Aegilops sharonensis and Aegilops longissima, confers resistance against both P. striiformis tritici (Pst) and Puccinia triticina (Pt) that cause stripe and leaf rust, respectively. Yr87/Lr85 confers resistance against Pst and Pt in wheat introgression as well as transgenic lines. Comparative analysis of Yr87/Lr85 and the cloned Triticeae NLR disease resistance genes shows that Yr87/Lr85 contains two distinct LRR domains and that the gene is only found in Ae. sharonensis and Ae. longissima. Allele mining and phylogenetic analysis indicate multiple events of Yr87/Lr85 gene flow between the two species and presence/absence variation explaining the majority of resistance to wheat leaf rust in both species. The confinement of Yr87/Lr85 to Ae. sharonensis and Ae. longissima and the resistance in wheat against Pst and Pt highlight the potential of these species as valuable sources of disease resistance genes for wheat improvement.

Cystoliths are an uncommon manifestation of urolithiasis. They are typically observed in male patients who are over the age of 45. A giant bladder calculus is a stone that is greater than 4 cm in diameter and weighs more than 100 g. We report the case of a 43- year-old female who was admitted to the urology department with dysuria, lower abdominal pain, fever, nausea, and microscopic hematuria. Mild tenderness in the suprapubic region was noted during the patient's physical examination. A hyperdense image measuring 7.2 x 6.4 cm was revealed during an abdominal CT scan, which confirmed the diagnosis. A 280 g stone, measuring 9 x 8 x 4 cm, was extracted through open cystolithotomy. In the female population, bladder calculus formation is uncommon. The standard treatment is open cystolithotomy, and computed tomography is a valuable tool for confirming the diagnosis.

Abstract The relationship between the variations in ovarian hormones (i.e., estrogens and progesterone) and the hypoxic ventilatory response (HVR) remains unclear. HVR is a key adaptive mechanism to high altitude and has been proposed as a predictor for acute mountain sickness (AMS). This study aimed to explore the effects of hormonal changes across the menstrual cycle on HVR. Additionally, it assessed the predictive capacity of HVR for AMS and examined whether a particular menstrual phase could enhance its predictive accuracy. Thirteen eumenorrheic women performed a pure nitrogen breathing test near sea level, measuring HVR and cerebral oxygenation in early follicular, late follicular, and mid-luteal phases. Oxidative stress and ovarian hormone levels were also measured. AMS symptoms were evaluated after spending 14 h, including one overnight, at an altitude of 3,375 m. No differences in HVR, ventilation, peripheral oxygen saturation, or cerebral oxygenation were observed between the three menstrual cycle phases. Moreover, these parameters and the oxidative stress markers did not differ between the women with or without AMS (31% vs 69%), regardless of the menstrual cycle phase. In conclusion, ventilatory responses and cerebral oxygenation in normobaric hypoxia were consistent across the menstrual cycle. Furthermore, these parameters did not differentiate women with or without AMS.

Abstract Background Determining thresholds by measuring blood lactate levels (lactate thresholds) or gas exchange (ventilatory thresholds) that delineate the different exercise intensity domains is crucial for training prescription. This systematic review with meta-analyses aims to assess the overall validity of the first and second heart rate variability - derived threshold (HRVT1 and HRVT2, respectively) by computing global effect sizes for agreement and correlation between HRVTs and reference – lactate and ventilatory (LT-VTs) – thresholds. Furthermore, this review aims to assess the impact of subjects’ characteristics, HRV methods, and study protocols on the agreement and correlation between LT-VTs and HRVTs. Methods Systematic computerised searches for studies determining HRVTs during incremental exercise in humans were conducted. The agreements and correlations meta-analyses were conducted using a random-effect model. Causes of heterogeneity were explored by subgroup analysis and meta-regression with subjects’ characteristics, incremental exercise protocols, and HRV methods variables. The methodological quality was assessed using QUADAS-2 and STARDHRV tools. The risk of bias was assessed by funnel plots, fail-safe N test, Egger’s test of the intercept, and the Begg and Mazumdar rank correlation test. Results Fifty included studies (1160 subjects) assessed 314 agreements (95 for HRVT1, 219 for HRVT2) and 246 correlations (82 for HRVT1, 164 for HRVT2) between LT-VTs and HRVTs. The standardized mean differences were trivial between HRVT1 and LT1-VT1 (SMD = 0.08, 95% CI -0.04–0.19, n = 22) and between HRVT2 and LT2-VT2 (SMD = -0.06, 95% CI -0.15–0.03, n = 42). The correlations were very strong between HRVT1 and LT1-VT1 (r = 0.85, 95% CI 0.75–0.91, n = 22), and between HRVT2 and LT2-VT2 (r = 0.85, 95% CI 0.80–0.89, n = 41). Moreover, subjects’ characteristics, type of ergometer, or initial and incremental workload had no impact on HRVTs determination. Conclusion HRVTs showed trivial differences and very strong correlations with LT-VTs and might thus serve as surrogates. These results emphasize the usefulness of HRVTs as promising, accessible, and cost-effective means for exercise and clinical prescription purposes.

Abstract Carbonate mud is crucial in the global carbon cycle and serves as a key sedimentary archive for paleoclimate reconstruction. Understanding the mechanisms behind its formation is crucial for explaining long-term carbon storage, including atmospheric carbon dioxide transfer to the hydrosphere and variations in mud production over geological timescales. Various mechanisms explain carbonate mud formation in both lake and marine sediments. Using bio-physicochemical methods on deep sediments of Lake Ilay, Jura, France, we propose a model of micrite formation. Our study shows that micrite mineralization occurs in sediments due to the degradation of ooze rich in exopolymeric substances throughout the sediment core’s depth. This mineralization continues as long as exopolymeric substances are present, persisting for at least 2000 years. Cryo-Scanning electron microscope imaging reveals calcite nucleation at degraded exopolymeric substance nodes, advancing with substance degradation and calcium release. These findings provide insights into fossil carbonate mud origins and formation processes.

Ultra-low velocity zones (ULVZs) are anomalous regions on the core–mantle boundary. In the past decade, several ULVZs, and particularly the Hawaiian ULVZ, have been studied using postcursors to core-diffracted S waves (Sdiff), which constrain their shear-wave velocity reduction. Simultaneous observations of P-wave velocity would allow us to better constrain the origin of ULVZs. We present the first observations of core-diffracted P-wave (Pdiff) postcursors likely generated by the Hawaiian ULVZ, at much shorter periods (∼1 s) than those typically associated with Sdiff postcursors (10–20 s). We analyze Sdiff postcursors from previous studies in two different period ranges for comparison. The observed delay times can be explained by a P-wave velocity reduction of 20%–30%. If we assume that the Pdiff postcursor is caused by the presence of a very thin basal layer (with estimated VS reduction of ∼40%), δVP:δVS ranges from 1:1.3 to 1:2. Iron enrichment is able to explain this ratio, whereas partial melt cannot. We also observe an anomalously high slowness for the Pdiff postcursors, which could suggest that the postcursors are not caused by the ULVZ but rather by scattering anomalies at 2400 km depth. We prefer the ULVZ hypothesis.

Lentic waters are biogeochemical reactors, producing and receiving carbon (C) originally fixed by the terrestrial and aquatic biosphere, which is then buried in sediments or respired back to the atmosphere in the forms of carbon dioxide (CO2) and one of the more potent greenhouse gas (GHG) methane (CH4). Additionally, lakes serve as archives of terrestrial and aquatic carbon processes within their sediments, enabling the reconstruction of historical changes spanning thousands of years. These changes encompass alterations in land cover, indicated by pollen records, soil carbon erosion and shifts in lake productivity resulting from changes in land use and climate. Both the burial of C in lakes and the emissions of GHGs are recognised as important components of Earth's climate system, yet they remain poorly understood and constrained due to inadequate quantities and qualities of observations. In the case of GHG emissions from lakes, observations are often sporadic, failing to capture the significant spatial and temporal variations in emissions across diverse lentic systems. To address this challenge, process-based models that incorporate the interconnected biogeochemical processes occurring within lakes and their watersheds would arguably be the best tool to extrapolate from site-level observations to regional and finally global scales, to quantify the anthropogenic impact on these fluxes and to reconstruct long-term shifts in emissions and burial due to changes in land cover and climate. However, the development and evaluation of such models is hampered by the lack of observations in sufficient quality. In this project, we bring together a unique consortium of specialists in aquatic ecology, biogeochemistry, palynology, sedimentology and modelling of terrestrial and aquatic biogeochemistry. This project will put forth a national programme of systematic, long-term observations of lake GHG and C cycling processes of unmet detail, consistency and quality. First, at 40 pilot sites spanning typological and environmental gradients, there will be a comprehensive data acquisition endeavour to evaluate biological processes and mesological factors influencing the sequestration or recycling of organic carbon. This effort will be complemented with a synthesis of existing data (WP1). Second, based on well-dated sediment records, which include both newly-acquired and synthesised existing data, variability of lake C burial and their climate and land-use controls will be reconstructed over the past 150 years (WP2). For 15 of these pilot sites, reconstruction will go back until the mid-Holocene (5,000 years BP), allowing us to shed light on the anthropogenic perturbation of the C cycle in this earlier part of human history, which is commonly excluded from this type of research due to lack of information. The activities of these first two WPs will result in an open-source national database, guaranteeing valorisation of our research far beyond this project. In WP3, we will use the land surface model (LSM) ORCHIDEE C-lateral to assess C cycling in the terrestrial biosphere and the mobilisation of biospheric C into lakes, which is possible due to an explicit representation of soil C leaching and erosion processes and a downscaling scheme permitting us to assess C exports from watersheds at sub-grid scale. While LSMs are used to assess evolution of biospheric C budgets from the beginning of the Industrial Period, we will use it to hindcast the evolution since the mid-Holocene, using lake sediment records for model validation. Moreover, we will develop a new process-based lake C model supported by the database established in WPs 1 and 2, which we will couple to ORCHIDEE C-lateral to simulate lake C burial and GHG emissions in response to climate and processes in the lake watershed. This model set-up will first be used to better constrain contemporary large-scale lake GHG emissions and to disentangle the anthropogenic perturbation of these fluxes from the natural background flux. These estimates will be revolutionary, as they will allow attributing part of lake GHG emissions to anthropogenic emissions for national GHG budget reporting. Then, these models will be emulated to reconstruct evolution of lake GHG budgets and C budgets of the whole lake watershed since the mid-Holocene. While simulations will first be performed at the scales of France and Europe, the development of international partnerships to implement observations from other biomes (WP4) will finally support simulations at the global scale.

Abstract Ethane is the most abundant non-methane hydrocarbon in the troposphere, where it impacts ozone and reactive nitrogen and is a key tracer used for partitioning emitted methane between anthropogenic and natural sources. However, quantification has been challenged by sparse observations. Here, we present a satellite-based measurement of tropospheric ethane and demonstrate its utility for fossil-fuel source quantification. An ethane spectral signal is detectable from space in Cross-track Infrared Sounder (CrIS) radiances, revealing ethane signatures associated with fires and fossil fuel production. We use machine-learning to convert these signals to ethane abundances and validate the results against surface observations (R2 = 0.66, mean CrIS/surface ratio: 0.65). The CrIS data show that the Permian Basin in Texas and New Mexico exhibits the largest persistent ethane enhancements on the planet, with regional emissions underestimated by seven-fold. Correcting this underestimate reveals Permian ethane emissions that represent at least 4-7% of the global fossil-fuel ethane source.

Abstract Background Primaquine (PQ) has activity against mature P. falciparum gametocytes and proven transmission blocking efficacy (TBE) between humans and mosquitoes. WHO formerly recommended a single transmission blocking dose of 0.75 mg/kg but this was little used. Then in 2012, faced with the emergence of artemisinin-resistant P. falciparum (ARPf) in SE Asia, the WHO recommended a lower dose of 0.25 mg/kg to be added to artemisinin-based combination therapy in falciparum-infected patients in low transmission areas. This dose was considered safe in glucose-6-phosphate dehydrogenase deficiency (G6PDd) and not requiring G6PD testing. Subsequent single low-dose primaquine (SLDPQ) studies have demonstrated safety in different G6PD variants. Dosing remains challenging in children under the age of 5 because of the paucity of PQ pharmacokinetic (PK) data. We plan to assess the anti-infectivity efficacy of SLDPQ using an allometrically scaled, weight-based regimen, with a target dose of 0.25 mg/kg, in children with acute uncomplicated falciparum malaria. Methods This study is an open label, randomised 1:1, phase IIb study to assess TBE, tolerability, pharmacokinetics and acceptability of artesunate pyronaridine (ASPYR) administered alone or combined with SLDPQ in 56 Burkinabe children aged ≥ 6 months–

The behavior of ozone gas (O3) in the atmosphere varies according to the region of the globe. Its formation occurs mainly in the tropical stratosphere through the photodissociation of molecular oxygen with the aid of the incidence of ultraviolet solar radiation. Still, the highest concentrations of O3 content are found in high-latitude regions (poles) due to the Brewer–Dobson circulation, a large-scale circulation that takes place from the tropics to the pole in the winter hemisphere. This work presents a multi-instrumental analysis at two Brazilian sites, a subtropical one (Santa Maria – 29.72° S, 53.41° W) and an equatorial one (Natal – 5.4° S, 35.4° W), to investigate ozone distributions in terms of vertical profiles (2002–2020) and total abundance in terms of total columns of ozone (1979–2020). The study is based on the use of ground-based and satellite observations. Ozone profiles over Natal, from the ground up to the mesosphere, are obtained by radiosonde experiments (0–30 km) in the framework of the SHADOZ program and by satellite measurements from the SABER instrument (15–60 km). This enabled the construction of a continuous time series for ozone, including monthly values and climatological trends. There is a good agreement between the two measurements in the common observation layer, mainly for altitudes above 20 km. Below 20 km, SABER ozone profiles showed high variability and overestimated ozone mixing ratios by over 50 %. Dynamic and photochemical effects can interfere with O3 formation and distribution along higher latitudes through the Brewer–Dobson circulation. The measurements of the total ozone columns used are in good agreement with each other (TOMS/OMI × Dobson for Natal and TOMS/OMI × Brewer for Santa Maria) in time and space, in line with previous studies for these latitudes. Wavelet analysis was used over 42 years. The investigation revealed a significant annual cycle in both data series for both sites. The study highlighted that the quasi-biennial oscillation (QBO) plays a significant role in the variability of stratospheric ozone at the two study sites – Natal and Santa Maria. The QBO's contribution was found to be stronger at the Equator (Natal) than at the subtropics (Santa Maria). Additionally, the study showed that the 11-year solar cycle also has a significant impact on ozone variability at both locations. Given the study latitudes, the ozone variations observed at the two sites showed different patterns and amounts. Only a limited number of studies have been conducted on stratospheric ozone in South America, particularly in the region between the Equator and the subtropics. The primary aim of this work is to investigate the behavior of stratospheric ozone at various altitudes and latitudes using ground-based and satellite measurements in terms of vertical profiles and total columns of ozone.

Atmospheric chemistry models generally assume organic aerosol (OA) to be photochemically inert. Recent mechanisms for the oxidation of biogenic isoprene, a major source of secondary organic aerosol (iSOA), produce excessive OA in the absence of subsequent OA reactivity. At the same time, models underestimate atmospheric concentrations of formic and acetic acids for which OA degradation could provide a source. Here we show that the aqueous photooxidation of an isoprene-derived organosulfate (2-methyltriolsulfate or MTS), an important iSOA component, produces formic and acetic acids in high yields and at timescales competitive with deposition. Experimental data are well fit by a kinetic model in which three sequential oxidation reactions of the isoprene organosulfate produce two molar equivalents of formic acid and one of acetic acid. We incorporate this chemistry and that of 2-methyltetrol, another ubiquitous iSOA component, into the GEOS-Chem global atmospheric chemistry model. Simulations show that photooxidation and subsequent revolatilization of this iSOA may account for up to half of total iSOA loss globally, producing 4 Tg a−1 each of formic and acetic acids. This reduces model biases in gas-phase formic acid and total organic aerosol over the Southeast United States in summer by ∼30% and 60% respectively. While our study shows the importance of adding iSOA photochemical sinks into atmospheric models, uncertainties remain that warrant further study. In particular, improved understanding of reaction dependencies on particle characteristics and concentrations of particle-phase OH and other oxidants are needed to better simulate the effects of this chemistry on the atmospheric budgets of organic acids and iSOA.