A phosphate starvation response-centered network regulates mycorrhizal symbiosis.

To secure phosphorus (P) from soil, most land plants use a direct phosphate uptake pathway via root hairs and epidermis and an indirect phosphate uptake pathway via mycorrhizal symbiosis. The interaction between these two pathways is unclear. Here, we mapped a network between transcription factors and mycorrhizal symbiosis-related genes using Y1H. Intriguingly, this gene regulatory network is governed by the conserved P-sensing pathway, centered on phosphate starvation response (PHR) transcription factors. PHRs are required for mycorrhizal symbiosis and regulate symbiosis-related genes via the P1BS motif. SPX-domain proteins suppress OsPHR2-mediated induction of symbiosis-related genes and inhibit mycorrhizal infection. In contrast, plants overexpressing OsPHR2 show improved mycorrhizal infection and are partially resistant to P-mediated inhibition of symbiosis. Functional analyses of network nodes revealed co-regulation of hormonal signaling and mycorrhizal symbiosis. This network deciphers extensive regulation of mycorrhizal symbiosis by endogenous and exogenous signals and highlights co-option of the P-sensing pathway for mycorrhizal symbiosis.

The visible gorilla: Unexpected fast-not physically salient-Objects are noticeable.

It is widely believed that observers can fail to notice clearly visible unattended objects, even if they are moving. Here, we created parametric tasks to test this belief and report the results of three high-powered experiments (total n = 4,493) indicating that this effect is strongly modulated by the speed of the unattended object. Specifically, fast-but not slow-objects are readily noticeable, whether they are attended or not. These results suggest that fast motion serves as a potent exogenous cue that overrides task-focused attention, showing that fast speeds, not long exposure duration or physical salience, strongly diminish inattentional blindness effects.

A lateralized alpha-band marker of the interference of exogenous attention over endogenous attention.

Current theories of attention differentiate exogenous from endogenous orienting of visuospatial attention. While both forms of attention orienting engage different functional systems, endogenous and exogenous attention are thought to share resources, as shown by empirical evidence of their functional interactions. The present study aims to uncover the neurobiological basis of how salient events that drive exogenous attention disrupts endogenous attention processes. We hypothesize that interference from exogenous attention over endogenous attention involves alpha-band activity, a neural marker of visuospatial attention. To test this hypothesis, we contrast the effects of endogenous attention across two experimental tasks while we recorded electroencephalography (n = 32, both sexes): a single cueing task where endogenous attention is engaged in isolation, and a double cueing task where endogenous attention is concurrently engaged with exogenous attention. Our results confirm that the concurrent engagement of exogenous attention interferes with endogenous attention processes. We also found that changes in alpha-band activity mediate the relationship between endogenous attention and its effect on task performance, and that the interference of exogenous attention on endogenous attention occurs via the moderation of this indirect effect. Altogether, our results substantiate a model of attention, whereby endogenous and exogenous attentional processes involve the same neurophysiological resources. SIGNIFICANCE STATEMENT: Scientists differentiate top-down from bottom-up visuospatial attention processes. While bottom-up attention is rapidly engaged by emerging demands from the environment, top-down attention in contrast reflects slow voluntary shifts of spatial attention. Several lines of research substantiate the idea that top-down and bottom-up attentional processes involve distinct functional systems. An increasing number of studies, however, argue that both attention systems share brain processing resources. The current study examines how salient visual events that engage bottom-up processes interfere with top-down attentional processes. Using neurophysiological recordings and multivariate pattern classification techniques, the authors show that these patterns of interference occur within the alpha-band of neural activity (8-12 Hz), which implies that bottom-up and top-down attention processes share this narrow-band frequency brain resource. The results further demonstrate that patterns of alpha-band activity explains, in part, the interference between top-down and bottom-up attention at the behavioral level.

Bimetallic Cu@Ru Core-Shell Structures with Ligand Effects for Endo-Exogenous Stimulation-Mediated Dynamic Oncotherapy.

Dynamic therapies, which induce reactive oxygen species (ROS) production in situ through endogenous and exogenous stimulation, are emerging as attractive options for tumor treatment. However, the complexity of the tumor substantially limits the efficacy of individual stimulus-triggered dynamic therapy. Herein, bimetallic copper and ruthenium (Cu@Ru) core-shell nanoparticles are applied for endo-exogenous stimulation-triggered dynamic therapy. The electronic structure of Cu@Ru is regulated through the ligand effects to improve the adsorption level for small molecules, such as water and oxygen. The core-shell heterojunction interface can rapidly separate electron-hole pairs generated by ultrasound and light stimulation, which initiate reactions with adsorbed small molecules, thus enhancing ROS generation. This synergistically complements tumor treatment together with ROS from endogenous stimulation. In vitro and in vivo experiments demonstrate that Cu@Ru nanoparticles can induce tumor cell apoptosis and ferroptosis through generated ROS. This study provides a new paradigm for endo-exogenous stimulation-based synergistic tumor treatment.

Janus Membranes Patch Achieves High-Quality Tendon Repair: Inhibiting Exogenous Healing and Promoting Endogenous Healing.

The imbalance between endogenous and exogenous healing is the fundamental reason for the poor tendon healing. In this study, a Janus patch was developed to promote endogenous healing and inhibit exogenous healing, leading to improved tendon repair. The upper layer of the patch is a poly(dl-lactide-co-glycolide)/polycaprolactone (PLGA/PCL) nanomembrane (PMCP-NM) modified with poly(2-methylacryloxyethyl phosphocholine) (PMPC), which created a lubricated and antifouling surface, preventing cell invasion and mechanical activation. The lower layer is a PLGA/PCL fiber membrane loaded with fibrin (Fb) (Fb-NM), serving as a temporary chemotactic scaffold to regulate the regenerative microenvironment. In vitro, the Janus patch effectively reduced 92.41% cell adhesion and 79.89% motion friction. In vivo, the patch inhibited tendon adhesion through the TGF-ß/Smad signaling pathway and promoted tendon maturation. This Janus patch is expected to provide a practical basis and theoretical guidance for high-quality soft tissue repair.

Lipidomics of homeoviscous adaptation to low temperatures in Staphylococcus aureus utilizing exogenous straight-chain unsaturated fatty acids.

It is well established that Staphylococcus aureus can incorporate exogenous straight-chain unsaturated fatty acids (SCUFAs) into membrane phospho- and glyco-lipids from various sources in supplemented culture media and when growing in vivo during infection. Given the enhancement of membrane fluidity when oleic acid (C18:1Δ9) is incorporated into lipids, we were prompted to examine the effect of medium supplementation with C18:1Δ9 on growth at low temperatures. C18:1Δ9 supported the growth of a cold-sensitive, branched-chain fatty acid (BCFA)-deficient mutant at 12°C. Interestingly, we found similar results in the BCFA-sufficient parental strain, supported by the fact that the incorporation of C18:1Δ9 into the membrane increased membrane fluidity in both strains. We show that the incorporation of C18:1Δ9 and its elongation product C20:1Δ11 into membrane lipids was required for growth stimulation and relied on a functional FakAB incorporation system. Lipidomics analysis of the phosphatidylglycerol and diglycosyldiacylglycerol lipid classes revealed major impacts of C18:1Δ9 and temperature on lipid species. Growth at 12°C in the presence of C18:1Δ9 also led to increased production of the carotenoid pigment staphyloxanthin. The enhancement of growth by C18:1Δ9 is an example of homeoviscous adaptation to low temperatures utilizing an exogenous fatty acid. This may be significant in the growth of S. aureus at low temperatures in foods that commonly contain C18:1Δ9 and other SCUFAs in various forms. IMPORTANCE: We show that Staphylococcus aureus can use its known ability to incorporate exogenous fatty acids to enhance its growth at low temperatures. Individual species of phosphatidylglycerols and diglycosyldiacylglycerols bearing one or two degrees of unsaturation derived from the incorporation of C18:1Δ9 at 12°C are described for the first time. In addition, enhanced production of the carotenoid staphyloxanthin occurs at low temperatures. The studies describe a biochemical reality underlying membrane biophysics. This is an example of homeoviscous adaptation to low temperatures utilizing exogenous fatty acids over the regulation of the biosynthesis of endogenous fatty acids. The studies have likely relevance to food safety in that unsaturated fatty acids may enhance the growth of S. aureus in the food environment.

Iohexol plasma clearance measurement protocol standardization for adults: a consensus paper of the European Kidney Function Consortium.

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.

The impact of single-stranded RNAs on the dimerization of double-stranded RNA-dependent protein kinase PKR.

The RNA-binding protein PKR serves as a crucial antiviral innate immune factor that globally suppresses translation by sensing viral double-stranded RNA (dsRNA) and by phosphorylating the translation initiation factor eIF2α. Recent findings have unveiled that single-stranded RNAs (ssRNAs), including in vitro transcribed (IVT) mRNA, can also bind to and activate PKR. However, the precise mechanism underlying PKR activation by ssRNAs, remains incompletely understood. Here, we developed a NanoLuc Binary Technology (NanoBiT)-based in vitro PKR dimerization assay to assess the impact of ssRNAs on PKR dimerization. Our findings demonstrate that, akin to double-stranded polyinosinic:polycytidylic acid (polyIC), an encephalomyocarditis virus (EMCV) RNA, as well as NanoLuc luciferase (Nluc) mRNA, can induce PKR dimerization. Conversely, homopolymeric RNA lacking secondary structure fails to promote PKR dimerization, underscoring the significance of secondary structure in this process. Furthermore, adenovirus VA RNA 1, another ssRNA, impedes PKR dimerization by competing with Nluc mRNA. Additionally, we observed structured ssRNAs capable of forming G-quadruplexes induce PKR dimerization. Collectively, our results indicate that ssRNAs have the ability to either induce or inhibit PKR dimerization, thus representing potential targets for the development of antiviral and anti-inflammatory agents.

Regulating interparticle proximity in plasmonic nanosphere aggregates to enhance photoacoustic response and photothermal stability.

Designing plasmonic nanoparticles for biomedical photoacoustic (PA) imaging involves tailoring material properties at the nanometer scale. A key in developing plasmonic PA contrast nanoagents is to engineer their enhanced optical responses in the near-infrared wavelength range, as well as heat transfer properties and photostability. This study introduces anisotropic plasmonic nanosphere aggregates with close interparticle proximity as photostable and efficient contrast agent for PA imaging. Silver (Ag), among plasmonic metals, is particularly attractive due to its strongest optical response and highest heat conductivity. Our results demonstrate that close interparticle proximity in silver nanoaggregates (AgNAs), spatially confined within a polymer shell layer, leads to blackbody-like optical absorption, resulting in robust PA signals through efficient pulsed heat generation and transfer. Additionally, our AgNAs exhibit a high photodamage threshold highlighting their potential to outperform conventional plasmonic contrast agents for high-contrast PA imaging over multiple imaging sessions. Furthermore, we demonstrate the capability of the AgNAs for molecular PA cancer imaging in vivo by incorporating a tumor-targeting peptide moiety.

Metal-Organic Framework-Based Nanomaterials for Regulation of the Osteogenic Microenvironment.

As the global population ages, bone diseases have become increasingly prevalent in clinical settings. These conditions often involve detrimental factors such as infection, inflammation, and oxidative stress that disrupt bone homeostasis. Addressing these disorders requires exogenous strategies to regulate the osteogenic microenvironment (OME). The exogenous regulation of OME can be divided into four processes: induction, modulation, protection, and support, each serving a specific purpose. To this end, metal-organic frameworks (MOFs) are an emerging focus in nanomedicine, which show tremendous potential due to their superior delivery capability. MOFs play numerous roles in OME regulation such as metal ion donors, drug carriers, nanozymes, and photosensitizers, which have been extensively explored in recent studies. This review presents a comprehensive introduction to the exogenous regulation of OME by MOF-based nanomaterials. By discussing various functional MOF composites, this work aims to inspire and guide the creation of sophisticated and efficient nanomaterials for bone disease management.

Exogenous putrescine plays a switch-like influence on the pH stress adaptability of biofilm-based activated sludge.

Microbial community adaptability to pH stress plays a crucial role in biofilm formation. This study aims to investigate the regulatory mechanisms of exogenous putrescine on pH stress, as well as enhance understanding and application for the technical measures and molecular mechanisms of biofilm regulation. Findings demonstrated that exogenous putrescine acted as a switch-like distributor affecting microorganism pH stress, thus promoting biofilm formation under acid conditions while inhibiting it under alkaline conditions. As pH decreases, the protonation degree of putrescine increases, making putrescine more readily adsorbed. Protonated exogenous putrescine could increase cell membrane permeability, facilitating its entry into the cell. Subsequently, putrescine consumed intracellular H+ by enhancing the glutamate-based acid resistance strategy and the γ-aminobutyric acid metabolic pathway to reduce acid stress on cells. Furthermore, putrescine stimulated ATPase expression, allowing for better utilization of energy in H+ transmembrane transport and enhancing oxidative phosphorylation activity. However, putrescine protonation was limited under alkaline conditions, and the intracellular H+ consumption further exacerbated alkali stress and inhibits cellular metabolic activity. Exogenous putrescine promoted the proportion of fungi and acidophilic bacteria under acidic stress and alkaliphilic bacteria under alkali stress while having a limited impact on fungi in alkaline biofilms. Increasing Bdellovibrio under alkali conditions with putrescine further aggravated the biofilm decomposition. This research shed light on the unclear relationship between exogenous putrescine, environmental pH, and pH stress adaptability of biofilm. By judiciously employing putrescine, biofilm formation could be controlled to meet the needs of engineering applications with different characteristics.IMPORTANCEThe objective of this study is to unravel the regulatory mechanism by which exogenous putrescine influences biofilm pH stress adaptability and understand the role of environmental pH in this intricate process. Our findings revealed that exogenous putrescine functioned as a switch-like distributor affecting the pH stress adaptability of biofilm-based activated sludge, which promoted energy utilization for growth and reproduction processes under acidic conditions while limiting biofilm development to conserve energy under alkaline conditions. This study not only clarified the previously ambiguous relationship between exogenous putrescine, environmental pH, and biofilm pH stress adaptability but also offered fresh insights into enhancing biofilm stability within extreme environments. Through the modulation of energy utilization, exerting control over biofilm growth and achieving more effective engineering goals could be possible.

A Holistic Framework for the Evaluation of Kidney Function in a Gender-Diverse Landscape.

The most commonly used equations to estimate glomerular filtration rate incorporate a binary male-female sex coefficient, which has important implications for the care of transgender, gender-diverse, and nonbinary (TGD) people. Whether "sex assigned at birth" or a binary "gender identity" is most appropriate for the computation of estimated glomerular filtration rate (eGFR) is unknown. Furthermore, the use of gender-affirming hormone therapy (GAHT) for the development of physical changes to align TGD people with their affirmed gender is increasingly common, and may result in changes in serum creatinine and cystatin C, the biomarkers commonly used to estimate glomerular filtration rate. The paucity of current literature evaluating chronic kidney disease (CKD) prevalence and outcomes in TGD individuals on GAHT makes it difficult to assess any effects of GAHT on kidney function. Whether alterations in serum creatinine reflect changes in glomerular filtration rate or simply changes in muscle mass is unknown. Therefore, we propose a holistic framework to evaluate kidney function in TGD people. The framework focuses on kidney disease prevalence, risk factors, sex hormones, eGFR, other kidney function assessment tools, and the mitigation of health inequities in TGD people.

A novel therapeutic approach to modulate the inflammatory cascade: A timely exogenous local inflammatory response attenuates the sepsis-induced cytokine storm.

BACKGROUND: The emergence of severe sepsis is contingent upon the occurrence of a cytokine storm (CS), a multifaceted process intricately entwined with the temporal dimension, thereby rendering the infection response remarkably intricate. Consequently, it becomes imperative to discern and accurately identify the optimal timing for interventions, predicated upon the dynamic timeline of inflammatory changes. Moreover, the administration of exogenous low-dose pro-inflammatory agents has exhibited the potential to impede the relentless progression of the inflammatory cascade. Hence, the present study aims to scrutinize the impact of exogenous Local Inflammatory Response (eLIR) on the body surface in the context of the inflammatory cascade during sepsis, within a temporal framework, with a particular emphasis on the point of exacerbation of inflammation. METHODS: Rats were induced sterile sepsis by intraperitoneal injection of zymosan (ZY) at an appropriate dosage. The temporal progression of inflammatory changes and eLIR effects were described based on the trend of serum crucial inflammatory cytokines, tring to quest time-point of inflammatory aggravation in sepsis. Then, the varying degrees of surface inflammation caused by eLIR on this time point leading to the final effects on the inflammatory cascade response were explored. In addition, given the authentic pathological progression of sepsis, further observation was conducted on the impact of another intervention timing of eLIR on the inflammatory cascade. The survival rate was measured. Serum and organ related inflammatory cytokines were detected, and organ histopathology was investigated. RESULTS: In present study, a dosage of 600 mg/kg ZY was found to be optimal for the sterile sepsis model. Initiating eLIR 6 h prior to ZY injection, the maximum effect point of eLIR could be precisely align with the inflammatory aggravation point of sterile sepsis. Initiating eLIR at this time, 3 sessions of eLIR were found to be more effective than 1 or 2 sessions in mitigating inflammatory responses during the initial stage of inflammation and the peak of inflammation. Notably, the findings also suggested that this intervention improve survival rate. In addition, the anti-inflammatory efficacy has been substantially diminished by the prompt initiation of 3 sessions of eLIR immediately after ZY injection at the onset of sepsis. Similarly, the current findings did not demonstrate a statistically significant enhancement in survival rates with eLIR at this time point. CONCLUSIONS: Compared with the initial stage of inflammation, low-scale inflammation caused by a certain intensity of eLIR (3 sessions) on the body surface can more effectively pry the inflammation aggravation time-point, thereby shifting the pro-inflammatory to anti-inflammatory milieu, impeding the disproportionate cytokines release in inflammatory diseases, slowing down the inflammatory cascade, and improving the survival rate of sepsis.

Altering the Localization of an Unpaired Spin in a Formal Ni(V) Species.

The participation of both ligand and the metal center in the redox events has been recognized as one of the ways to attain the formal high valent complexes for the late 3d metals, such as Ni and Cu. Such an approach has been employed successfully to stabilize a Ni(III) bisphenoxyl diradical species in which there exist an equilibrium between the ligand and the Ni localized resultant spin. The present work, however, broadens the scope of the previously reported three oxidized equivalent species by conveying the approaches that tend to affect the reported equilibrium in CH3 CN at 233 K. Various spectroscopic characterization revealed that employing exogenous N-donor ligands like 1-methyl imidazole and pyridine favors the formation of the Ni centered localized spin though axial binding. In contrast, due to its steric hinderance, quinoline favors an exclusive ligand localized radical species. DFT studies shed light on the novel intermediates' complex electronic structure. Further, the three oxidized equivalent species with the Ni centered spin was examined for its hydrogen atom abstraction ability stressing their key role in alike reactions.

Establishment of a hydrodynamic delivery system in ducks.

Chronic hepatitis B virus (HBV) poses a significant global health challenge as it can lead to acute or chronic liver disease and hepatocellular carcinoma (HCC). To establish a safety experimental model, a homolog of HBV-duck HBV (DHBV) is often used for HBV research. Hydrodynamic-based gene delivery (HGD) is an efficient method to introduce exogenous genes into the liver, making it suitable for basic research. In this study, a duck HGD system was first constructed by injecting the reporter plasmid pLIVE-SEAP via the ankle vein. The highest expression of SEAP occurred when ducks were injected with 5 µg/mL plasmid pLIVE-SEAP in 10% bodyweight volume of physiological saline for 6 s. To verify the distribution and expression of exogenous genes in multiple tissues, the relative level of foreign gene DNA and ß-galactosidase staining of LacZ were evaluated, which showed the plasmids and their products were located mainly in the liver. Additionally, ß-galactosidase staining and fluorescence imaging indicated the delivered exogenous genes could be expressed in a short time. Further, the application of the duck HGD model on DHBV treatment was investigated by transferring representative anti-HBV genes IFNα and IFNγ into DHBV-infected ducks. Delivery of plasmids expressing IFNα and IFNγ inhibited DHBV infection and we established a novel efficient HGD method in ducks, which could be useful for drug screening of new genes, mRNAs and proteins for anti-HBV treatment.

Ketone monoester attenuates declines in cognitive performance and oxygen saturation during acute severe hypoxic exposure under resting conditions.

Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O2) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single-blind randomized crossover design, 16 male military personnel (age, 25.3 ± 2.4 year, body mass, 86.2 ± 9.3 kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20 min; 0 m; 20.9% O2) and hypoxia (20 min; 6096 m, 9.7% O2) using a reduced O2 breathing device (ROBD). (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-ßHB) ketone monoester (KME; 650 mg/kg, split dose given at 30 min prior to each exposure) or taste-matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R-ßHB and glucose concentrations, cognitive performance and O2 saturation ( S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) were collected throughout. KME ingestion increased blood R-ßHB concentration, which was rapid and sustained (>4 mM 30 min post; P < 0.001) and accompanied by lower blood glucose concentration (∼20 mg/dL; P < 0.01) compared to PLA. Declines in cognitive performance during hypoxic exposure, assessed as cognitive efficiency during a Defense Automated Neurobehavioral Assessment (DANA) code substitution task, were attenuated with KME leading to 6.8 (95% CL: 1.0, 12.6) more correct responses per minute compared to PLA (P = 0.018). The decline in S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ during hypoxic exposure was attenuated (6.40% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ; 95% CL: 0.04, 12.75; P = 0.049) in KME compared to PLA (KME, 76.8 ± 6.4% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ; PLA, 70.4 ± 7.4% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O2 saturation. HIGHLIGHTS: What is the central question of this study? Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute severe hypoxic exposure at rest? What is the main finding and its importance? Acute exogenous ketosis via ingestion of a drink containing the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester prior to acute severe hypoxic exposure attenuated hypoxia-induced declines in blood oxygen saturation and cognitive performance at rest.

Ketone monoester attenuates oxygen desaturation during weighted ruck exercise under acute hypoxic exposure but does not impact cognitive performance.

Acute ingestion of exogenous ketone supplements in the form of a (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-ßHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate-intensity exercise. In a single-blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O2). The R-BD R-ßHB KME (573 mg/kg) or a calorie- and taste-matched placebo (∼50 g maltodextrin) were co-ingested with 40 g of dextrose before exposure to hypoxia. The R-ßHB concentrations were rapidly elevated and sustained (>3 mM; P < 0.001) by KME. The decline in oxygen saturation during hypoxic exposure was attenuated in KME conditions by 2.4%-4.2% (P < 0.05) compared with placebo. Outcomes of cognitive performance tasks, in the form of the Defense Automated Neurobehavioral Assessment (DANA) code substitution task, the Stroop color and word task, and a shooting simulation, did not differ between trials before and during hypoxic exposure. These data suggest that the acute exogenous ketosis induced by KME ingestion can attenuate declining blood oxygen saturation during acute hypoxic exposure both at rest and during moderate-intensity exercise, but this did not translate into differences in cognitive performance before or after exercise in the conditions investigated. HIGHLIGHTS: What is the central question of this study? Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute hypoxic exposure while performing a weighted ruck exercise? What is the main finding and its importance? Acute exogenous ketosis via ingestion of a drink containing the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester prior to acute hypoxic exposure attenuated hypoxia-induced declines in blood oxygen saturation but had no effect on cognitive performance during exercise.

Exploiting relationship directionality to enhance statistical modeling of peer-influence across social networks.

Risky-prescribing is the excessive or inappropriate prescription of drugs that singly or in combination pose significant risks of adverse health outcomes. In the United States, prescribing of opioids and other "risky" drugs is a national public health concern. We use a novel data framework-a directed network connecting physicians who encounter the same patients in a sequence of visits-to investigate if risky-prescribing diffuses across physicians through a process of peer-influence. Using a shared-patient network of 10 661 Ohio-based physicians constructed from Medicare claims data over 2014-2015, we extract information on the order in which patients encountered physicians to derive a directed patient-sharing network. This enables the novel decomposition of peer-effects of a medical practice such as risky-prescribing into directional (outbound and inbound) and bidirectional (mutual) relationship components. Using this framework, we develop models of peer-effects for contagion in risky-prescribing behavior as well as spillover effects. The latter is measured in terms of adverse health events suspected to be related to risky-prescribing in patients of peer-physicians. Estimated peer-effects were strongest when the patient-sharing relationship was mutual as opposed to directional. Using simulations we confirmed that our modeling and estimation strategies allows simultaneous estimation of each type of peer-effect (mutual and directional) with accuracy and precision. We also show that failing to account for these distinct mechanisms (a form of model mis-specification) produces misleading results, demonstrating the importance of retaining directional information in the construction of physician shared-patient networks. These findings suggest network-based interventions for reducing risky-prescribing.

Identification and characterization of STAT family in silver pomfret (Pampus argenteus) involved in different exogenous stresses.

Members of the Signal Transducer and Activator of Transcription (STAT) family function pivotally as transcriptional activators integral to the modulation of inflammatory responses. The aquaculture of silver pomfret is frequently compromised by the imposition of exogenous stressors, which include thermal fluctuations, notably low-temperatures, diminished oxygen levels, and the onslaught of bacterial pathogens. Notwithstanding the critical impact of these stressors, the scientific literature presents a notable gap in our understanding of the STAT pathway's role in the silver pomfret's adaptive response mechanisms. To address this lacuna, we identified stat genes in the silver pomfret-denominated as Pastat1, Pastat2, Pastat3, Pastat4, and Pastat5-through a thorough and systematic bioinformatics analysis. Further scrutiny of the gene configurations and constituent motifs has elucidated that STAT proteins possess analogous structural frameworks and exhibit significant evolutionary preservation. Subsequently, the expression patterns of five stat genes were verified by RT-qPCR in twelve different tissues and four growth periods in healthy fish, showing that the expression of Pastat genes was temporally and spatially specific, with most of the stat genes expressed at higher levels in the spleen, following muscle, gill, and liver. Transcriptomic analysis of exposure to exogenous stressors, specifically formaldehyde and low-temperature conditions, elucidated that Pastat1 and Pastat2 genes exhibited a heightened sensitivity to these environmental challenges. RT-qPCR assays demonstrated a marked alteration in the expression profiles of jak1 and Pastat gene suites in PaS upon prolonged bacterial infection subsequent to these exogenous insults. Moreover, the gene expression of the downstream effectors involved in innate immunity and apoptosis displayed marked deviations. This study additionally elucidated the Pastat gene family's role in modulating the innate immune response and apoptotic regulation within the silver pomfret during exogenous stressors and subsequent pathogenic incursions.

ExpoNano: A Strategy Based on Hyper-Cross-Linked Polymers Achieves Urinary Exposome Assessment for Biomonitoring.

Urinary analysis of exogenous and endogenous molecules constitutes an efficient, noninvasive approach to evaluate human health status. However, the exposome characterization of urinary molecules remains extremely challenging with current techniques. Herein, we develop an ExpoNano strategy based on hyper-cross-linked polymers (HCPs) to achieve ultrahigh-throughput measurement of exo/endogenous molecules in urine. The strategy includes a simple trapping-detrapping procedure (15 min) with HCPs in enzymatically treated urine, followed by mass spectrometer determination. Molecules that can be determined by ExpoNano have a wide range of molecular weight (75-837 Da) and Log Kow (octanol-water partition coefficient; -9.86 to 10.56). The HCPs can be repeatedly used five times without decreasing the trapping efficiency. Application of ExpoNano in a biomonitoring study revealed a total of 63 environmental chemicals detected in >50% of the urine pools collected from Chinese adults living in 13 cities, with a median concentration of 0.026-47 ng/mL, while nontargeted analysis detected an additional 243 exogenous molecules. Targeted and nontargeted analysis also detected 926 endogenous molecules in pooled urine. Collectively, the ExpoNano strategy demonstrates unique advantages over traditional urine analysis approaches, including a wide range of analytes, satisfactory trapping efficiency, high simplicity and reusability, and extremely reduced time demand and financial cost.