Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction.

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.

Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration.

Tissue regeneration requires inflammatory and reparatory activity of macrophages. Macrophages detect and eliminate the damaged tissue and subsequently promote regeneration. This dichotomy requires the switch of effector functions of macrophages coordinated with other cell types inside the injured tissue. The gene regulatory events supporting the sensory and effector functions of macrophages involved in tissue repair are not well understood. Here we show that the lipid activated transcription factor, PPARγ, is required for proper skeletal muscle regeneration, acting in repair macrophages. PPARγ controls the expression of the transforming growth factor-ß (TGF-ß) family member, GDF3, which in turn regulates the restoration of skeletal muscle integrity by promoting muscle progenitor cell fusion. This work establishes PPARγ as a required metabolic sensor and transcriptional regulator of repair macrophages. Moreover, this work also establishes GDF3 as a secreted extrinsic effector protein acting on myoblasts and serving as an exclusively macrophage-derived regeneration factor in tissue repair.

A Multi-Omics Approach Reveals Features That Permit Robust and Widespread Regulation of IFN-Inducible Antiviral Effectors.

The antiviral state, an initial line of defense against viral infection, is established by a set of IFN-stimulated genes (ISGs) encoding antiviral effector proteins. The effector ISGs are transcriptionally regulated by type I IFNs mainly via activation of IFN-stimulated gene factor 3 (ISGF3). In this study, the regulatory elements of effector ISGs were characterized to determine the (epi)genetic features that enable their robust induction by type I IFNs in multiple cell types. We determined the location of regulatory elements, the DNA motifs, the occupancy of ISGF3 subunits (IRF9, STAT1, and STAT2) and other transcription factors, and the chromatin accessibility of 37 effector ISGs in murine dendritic cells. The IFN-stimulated response element (ISRE) and its tripartite version occurred most frequently in the regulatory elements of effector ISGs than in any other tested ISG subsets. Chromatin accessibility at their promoter regions was similar to most other ISGs but higher than at the promoters of inflammation-related cytokines, which were used as a reference gene set. Most effector ISGs (81.1%) had at least one ISGF3 binding region proximal to the transcription start site (TSS), and only a subset of effector ISGs (24.3%) was associated with three or more ISGF3 binding regions. The IRF9 signals were typically higher, and ISRE motifs were "stronger" (more similar to the canonical sequence) in TSS-proximal versus TSS-distal regulatory regions. Moreover, most TSS-proximal regulatory regions were accessible before stimulation in multiple cell types. Our results indicate that "strong" ISRE motifs and universally accessible promoter regions that permit robust, widespread induction are characteristic features of effector ISGs.

Emerging sensing, imaging, and computational technologies to scale nano-to macroscale rhizosphere dynamics - Review and research perspectives.

The soil region influenced by plant roots, i.e., the rhizosphere, is one of the most complex biological habitats on Earth and significantly impacts global carbon flow and transformation. Understanding the structure and function of the rhizosphere is critically important for maintaining sustainable plant ecosystem services, designing engineered ecosystems for long-term soil carbon storage, and mitigating the effects of climate change. However, studying the biological and ecological processes and interactions in the rhizosphere requires advanced integrated technologies capable of decoding such a complex system at different scales. Here, we review how emerging approaches in sensing, imaging, and computational modeling can advance our understanding of the complex rhizosphere system. Particularly, we provide our perspectives and discuss future directions in developing in situ rhizosphere sensing technologies that could potentially correlate local-scale interactions to ecosystem scale impacts. We first review integrated multimodal imaging techniques for tracking inorganic elements and organic carbon flow at nano- to microscale in the rhizosphere, followed by a discussion on the use of synthetic soil and plant habitats that bridge laboratory-to-field studies on the rhizosphere processes. We then describe applications of genetically encoded biosensors in monitoring nutrient and chemical exchanges in the rhizosphere, and the novel nanotechnology-mediated delivery approaches for introducing biosensors into the root tissues. Next, we review the recent progress and express our vision on field-deployable sensing technologies such as planar optodes for quantifying the distribution of chemical and analyte gradients in the rhizosphere under field conditions. Moreover, we provide perspectives on the challenges of linking complex rhizosphere interactions to ecosystem sensing for detecting biological traits across scales, which arguably requires using the best-available model predictions including the model-experiment and image-based modeling approaches. Experimental platforms relevant to field conditions like SMART (Sensors at Mesoscales with Advanced Remote Telemetry) soils testbed, coupled with ecosystem sensing and predictive models, can be effective tools to explore coupled ecosystem behavior and responses to environmental perturbations. Finally, we envision that with the advent of novel high-resolution imaging capabilities at nano- to macroscale, and remote biosensing technologies, combined with advanced computational models, future studies will lead to detection and upscaling of rhizosphere processes toward ecosystem and global predictions.

Comprehensive Assessment of Labiaplasty Techniques and Tools, Satisfaction Rates, and Risk Factors: A Systematic Review and Meta-analysis.

BACKGROUND: Various surgical techniques have been devised for the surgical cosmetic enhancement of female outer genitalia. The selection of an optimal method should be based on satisfaction rates and safety; however, comprehensive, contemporary systematic assessment of these factors has been limited in the literature. OBJECTIVES: Our aim was to conduct a comprehensive systematic review and meta-analysis to evaluate the overall satisfaction rates and risk factors associated with various labiaplasty techniques and tools. METHODS: The authors performed a systematic literature search in 3 medical databases: PubMed, Elsevier, and Cochrane (Central) with the closing date of October 2023. Original articles with quantitative satisfaction rates and frequencies of the most common complications (hematoma, dehiscence, swelling, bleeding, and infection) were included. RESULTS: Systematic search provided a total of 3954 records. After selection and review of the articles, 86 eligible, peer-reviewed studies were identified, of which 53 provided quantitative data. High overall satisfaction rate was found for all methods (proportion [prop] 94%; confidence interval [CI] 93%-95%), with highest satisfaction for deepithelialization (prop 97%; CI, 85%-99%). Complications were generally rare, with elevated incidences for some techniques (wedge resection: dehiscence, prop, 8%, CI 5%-13%; and composite reduction: swelling, prop 13%, CI 2%-54%). Scalpel technique had significantly higher incidence of complications than laser, namely for bleeding, swelling, and hematoma. CONCLUSIONS: Labiaplasty can be considered a generally effective approach to outer female genitalia beautification, with low associated risks. Surgeons must tailor their approach to the patients' needs and anatomy to achieve maximal satisfaction, given the differences in the frequency of complications for each method.

The Inhibitor Preincubation Effect Is Universal to SLC Transporter Assays and Is Only Partially Eliminated in the Presence of Extracellular Protein.

Variation in the methodology of in vitro transporter inhibition assays causes wide divergence in reported IC50/Ki data. Notably, although potentiation of transporter inhibition by preincubation (PTIP) has been described, current guidelines do not specifically recommend inhibitor preincubation; they only encourage sponsors to follow emerging literature. To clarify how generally preincubation should be considered in transporter inhibition studies and whether PTIP can be solely explained by protein binding of the respective inhibitors, we performed in vitro inhibition assays on solute carrier (SLC) and ATP-binding cassette transporters scarcely or not covered in prior research and examined the effect of extracellular protein in preincubation and washout experiments. In SLC assays without extracellular protein, a 30-minute preincubation caused significant > twofold change of IC50 in 21/33 transporter-inhibitor combinations involving 19 evolutionarily disparate transporters. The preincubation effect correlated with inhibitor properties like protein binding and aqueous solubility. In vesicular transport assays of multidrug resistance protein 1, breast cancer resistance protein, multidrug resistance-associated protein 2, and bile salt export pump, sizable PTIP was observed for only 2/23 combinations, and preincubation was practically inconsequential in breast cancer resistance protein or multidrug resistance protein 1 monolayer assays. In SLC assays, PTIP partly persisted in the presence of 5% albumin, indicating that the absence of extracellular protein does not fully explain PTIP. The presence of protein, however, complicated the interpretation of results. Overall, while preincubating without protein may overpredict inhibitory potency, adding protein compromises clarity, and omitting preincubation altogether may miss clinically relevant inhibitors. Therefore, we propose that protein-free preincubation should be considered in all SLC inhibition assays. ATP-binding cassette transporter inhibition seems less commonly affected by preincubation, but conclusions require further investigation. SIGNIFICANCE STATEMENT: Drugs may inhibit transporter proteins in the body, which may precipitate drug interactions. In vitro transporter inhibition assays help predict such drug interactions. Some inhibitors act more potently when preincubated with the transporter prior to the assay. Here we argue that this effect is not a mere in vitro artifact due to the lack of plasma proteins and should be considered in all uptake inhibition assays to model the worst-case scenario. Preincubation in efflux transporter inhibition assays is likely dispensable.

Minimal Impacts of Microplastics on Soil Physical Properties under Environmentally Relevant Concentrations.

Agricultural soils are a major reservoir of microplastics, and concerns have arisen about the impacts of microplastics on soil properties and functioning. Here, we measured the physical properties of a silt loam in response to the incorporation of polyester fibers and polypropylene granules over a wide range of concentrations. We further elucidated the underlying mechanisms by determining the role of microplastic shape and the baseline effects from the amendment of soil particles. The incorporation of microplastics into soil tended to increase contact angle and saturated hydraulic conductivity and decrease bulk density and water holding capacity, but not affect aggregate stability. Polyester fibers affected soil physical properties more profoundly than polypropylene granules, due to the vastly different shape of fibers from that of soil particles. However, changes in soil properties were gradual, and significant changes did not occur until a high concentration of microplastics was reached (i.e., 0.5% w/w for polyester fibers and 2% w/w for polypropylene granules). Currently, microplastic concentrations in soils not heavily polluted with plastics are far below these concentrations, and results from this study suggest that microplastics at environmentally relevant concentrations have no significant effects on soil physical properties.

Ripples at edges of blooming lilies and torn plastic sheets.

Ripples arise at edges of petals of blooming Lilium casablanca flowers and at edges of torn plastic sheets. In both systems, ripples are a consequence of excess length along the edge of a sheet. Through the use of time-lapse videos of blooming lilies and published images of torn plastic sheets, we find that ripples in both systems are well described by the scaling relationship a∝w(L-w), where a is amplitude, w is wavelength, and L is arc length. A phenomenological relationship previously reported for self-similar ripple patterns, namely ⟨a⟩∝⟨w⟩, can be recovered by assuming that buckling stress is constant. Excess length along petal edges can also influence their overall Gaussian curvature, such that petals invert from a cup shape to a saddle shape upon blooming. Previous simulations of these shape changes have assumed that petal thickness decreases at least quadratically. Here, we evaluate tomograms of several varieties of lily buds and find that this assumption is valid along the short axis of the buds, but not the long axis. A challenge of employing traditional tomography methods to measure petal thickness is that the sample is destroyed; a single bud cannot be followed through the entire blooming process. To address this challenge, we provide proof of principle that the nondestructive, label-free method of x-ray tomography produces high-contrast three-dimensional scans on time scales short enough to follow lily blooming.

Electric field stimulates production of highly conductive microbial OmcZ nanowires.

Multifunctional living materials are attractive due to their powerful ability to self-repair and replicate. However, most natural materials lack electronic functionality. Here we show that an electric field, applied to electricity-producing Geobacter sulfurreducens biofilms, stimulates production of cytochrome OmcZ nanowires with 1,000-fold higher conductivity (30 S cm-1) and threefold higher stiffness (1.5 GPa) than the cytochrome OmcS nanowires that are important in natural environments. Using chemical imaging-based multimodal nanospectroscopy, we correlate protein structure with function and observe pH-induced conformational switching to ß-sheets in individual nanowires, which increases their stiffness and conductivity by 100-fold due to enhanced π-stacking of heme groups; this was further confirmed by computational modeling and bulk spectroscopic studies. These nanowires can transduce mechanical and chemical stimuli into electrical signals to perform sensing, synthesis and energy production. These findings of biologically produced, highly conductive protein nanowires may help to guide the development of seamless, bidirectional interfaces between biological and electronic systems.

Perioperative Factor Concentrate Use is Associated With More Beneficial Outcomes and Reduced Complication Rates Compared With a Pure Blood Product-Based Strategy in Patients Undergoing Elective Cardiac Surgery: A Propensity Score-Matched Cohort Study.

OBJECTIVE: The goal of this study was to compare factor concentrate (FC)-based and blood product-based hemostasis management of coagulopathy in cardiac surgical patients in terms of postoperative bleeding, required blood products, and outcome. DESIGN: Retrospective, propensity score-matched analysis. SETTING: Single, tertiary, academic medical center. PARTICIPANTS: One hundred eighteen matched pairs of 433 consecutive patients scheduled for cardiac surgery in two isolated periods with distinct strategies of hemostasis management. INTERVENTIONS: Patients received either blood product-based (period I) or FC-based (period II) hemostasis management to treat perioperative coagulopathy. MEASUREMENTS AND MAIN RESULTS: Patients treated with FC management experienced less postoperative blood loss (907 v 1,153 mL, p = 0.014) and required less red blood cell and fresh frozen plasma transfusion (2.3 v 3.7 units p < 0.0001, and 2.0 v 3.4 units p < 0.0001, respectively) compared with subjects in the blood product-based management group. The frequency of Stage 3 acute kidney injury and 30-day mortality rate were significantly higher in the blood product-based group than in the FC management group (6.8% v 0.8%, p = 0.016, and 7.2% v 0.8%, p = 0.022, respectively). FC management-related thromboembolic events were not registered. The FC strategy was associated with a 2.19-fold decrease in the odds of massive postoperative bleeding (p < 0.0001), a 2.56-fold decrease in the odds of polytransfusion (p < 0.0001), and a 13.16-fold decrease in the odds of early postoperative death (p = 0.003). CONCLUSIONS: FC-based versus blood product-based management is associated with reduced blood product needs and fewer complications, and was not linked to a higher frequency of thromboembolic events or a decrease in long-term survival in cardiac surgical patients developing perioperative coagulopathy and bleeding.

Understanding the Electronic Structure Evolution of Epitaxial LaNi1-xFexO3 Thin Films for Water Oxidation.

Rare earth nickelates including LaNiO3 are promising catalysts for water electrolysis to produce oxygen gas. Recent studies report that Fe substitution for Ni can significantly enhance the oxygen evolution reaction (OER) activity of LaNiO3. However, the role of Fe in increasing the activity remains ambiguous, with potential origins that are both structural and electronic in nature. On the basis of a series of epitaxial LaNi1-xFexO3 thin films synthesized by molecular beam epitaxy, we report that Fe substitution tunes the Ni oxidation state in LaNi1-xFexO3 and a volcano-like OER trend is observed, with x = 0.375 being the most active. Spectroscopy and ab initio modeling reveal that high-valent Fe3+δ cationic species strongly increase the transition-metal (TM) 3d bandwidth via Ni-O-Fe bridges and enhance TM 3d-O 2p hybridization, boosting the OER activity. These studies deepen our understanding of structural and electronic contributions that give rise to enhanced OER activity in perovskite oxides.

Pseudoaneurysm of the ascending aorta: case report of a donor-derived Pseudomonas infection in a heart transplant recipient.

BACKGROUND: Mycotic aortic pseudoaneurysm is a rare complication after heart transplantation (HTX) with remarkable mortality. Intrathoracic infection is a well-documented predisposing factor for this disease. Staphylococcus aureus, Pseudomonas aeruginosa or Candida species are commonly isolated from resected specimens of the pseudoaneurysms. We demonstrate a unique case of mycotic pseudoaneurysm caused by presumably donor-derived Pseudomonas infection in a heart transplant recipient. CASE PRESENTATION: Our 67-year-old male patient treated with diabetes mellitus underwent HTX. The donor suffered from epiglottic abscess and pneumonia with known microorganisms including Pseudomonas, therefore both the donor and recipient received targeted antimicrobial therapy and prophylaxis. Five months after the uneventful HTX, lab test of the asymptomatic patient showed moderate, increasing C-reactive protein level without obviuos source of infection. Chest computed tomography showed a large (90 mm) saccular dilatation of the tubular portion of ascending aorta. Urgent surgical intervention identified a pseudoaneurysm, histological examinations and cultures of the resected aorta verified Pseudomonas aeruginosa aortitis, while all blood cultures remained negative. Retrospective interrogation of other transplanted organs of the donor supported donor-derived infection as the transport fluid of the right kidney grew Pseudomonas. The patient received 3 weeks of ceftazidime followed by 7 months of oral ciprofloxacin therapy. One year after the operation the patient was asymptomatic with normal inflammatory markers. CONCLUSIONS: Donor-derived infection is a rare but potential cause of aortitis. Early diagnosis, surgical intervention and adjuvant antibiotic therapy seem to be the keys to successful management of mycotic pseudoaneurysms after HTX.

Competitive TcO4-, IO3-, and CrO42- Incorporation into Ettringite.

Ettringite is a naturally occurring mineral found in cementitious matrices that is known for its ability to incorporate environmentally mobile oxyanion contaminants. To better assess this immobilization mechanism for contaminants within cementitious waste forms intended for nuclear waste storage, this work explores how mixed oxyanion contaminants compete for ettringite incorporation and influence the evolving mineralogy. Ettringite was precipitated in the presence of TcO4-, IO3-, and/or CrO42-, known contaminants of concern to nuclear waste treatment, over pre-determined precipitation periods. Solution analyses quantified contaminant removal, and the collected solid was characterized using bulk and microprobe X-ray diffraction coupled with pair distribution function and microprobe X-ray fluorescence analyses. Results suggest that ≥96% IO3- is removed from solution, regardless of ettringite precipitation time or the presence of TcO4- or CrO42-. However, TcO4- removal remained <20%, was not significantly improved with longer ettringite precipitation times, and decreased to zero in the presence of IO3-. When IO3- is co-mingled with CrO42-, calcite and gypsum are formed as secondary mineral phases, which allows for oxyanion partitioning, e.g., IO3- incorporation into ettringite, and CrO42- incorporation into calcite. Results from this work exemplify the importance of competitive immobilization when assessing waste form performance and environmental risk of contaminant release.

A temporal model of territorial defence with antagonistic interactions.

Territorial behaviour is an important part of the lives of many animals. Once a territory has been acquired, an animal may spend its entire life on it, and may have to repeatedly defend it from conspecifics. Some species make great investments in the defence of a territory, and this defence can be costly, in terms of time, energy and risk of injury. Time costs in particular have rarely been explicitly factored into such models. In this paper we consider a model of territorial defence which includes both population dynamic and time delay elements, building upon recent advances in time constraint models. Populations may divide into two distinct types, where one type makes no effort to control territories. We shall call this type nomads, and the other type territorials. Here the territory owners must divide their time between patrolling and foraging, and this balance is their only strategic decision. We show how to find the evolutionarily stable patrolling strategy and the population composition of territorials and nomads, and consider some examples demonstrating key situations. We see that both time constraints and population density pressure are crucial to influencing behaviour. In particular we find cases with both territorial individuals and nomads where a mixed, either pure or both pure patrolling strategies are evolutionarily stable. In different conditions either nomads or territorials can be absent, and indeed for a significant range of parameter combinations the population can exhibit tristability, with three distinct ecologically stable population compositions: with both nomads and territorials, only nomads or only territorials.

Immobilizing Pertechnetate in Ettringite via Sulfate Substitution.

Technetium-99 immobilization in low-temperature nuclear waste forms often relies on additives that reduce environmentally mobile pertechnetate (TcO4-) to insoluble Tc(IV) species. However, this is a short-lived solution unless reducing conditions are maintained over the hazardous life cycle of radioactive wastes (some ∼10,000 years). Considering recent experimental observations, this work explores how rapid formation of ettringite [Ca6Al2(SO4)3(OH)12·26(H2O)], a common mineral formed in cementitious waste forms, may be used to directly immobilize TcO4-. Results from ab initio molecular dynamics (AIMD) simulations and solid-phase characterization techniques, including synchrotron X-ray absorption, fluorescence, and diffraction methods, support successful incorporation of TcO4- into the ettringite crystal structure via sulfate substitution when synthesized by aqueous precipitation methods. One sulfate and one water are replaced with one TcO4- and one OH- during substitution, where Ca2+-coordinated water near the substitution site is deprotonated to form OH- for charge compensation upon TcO4- substitution. Furthermore, AIMD calculations support favorable TcO4- substitution at the SO42- site in ettringite rather than gypsum (CaSO4·2H2O, formed as a secondary mineral phase) by at least 0.76 eV at 298 K. These results are the first of their kind to suggest that ettringite may contribute to TcO4- immobilization and the overall lifetime performance of cementitious waste forms.

The ESS for evolutionary matrix games under time constraints and its relationship with the asymptotically stable rest point of the replicator dynamics.

Recently we interpreted the notion of ESS for matrix games under time constraints and investigated the corresponding state in the polymorphic situation. Now we give two further static (monomorphic) characterizations which are the appropriate analogues of those known for classical evolutionary matrix games. Namely, it is verified that an ESS can be described as a neighbourhood invader strategy independently of the dimension of the strategy space in our non-linear situation too, that is, a strategy is an ESS if and only if it is able to invade and completely replace any monomorphic population which totally consists of individuals following a strategy close to the ESS. With the neighbourhood invader property at hand, we establish a dynamic characterization under the replicator dynamics in two dimensions which corresponds to the strong stability concept for classical evolutionary matrix games. Besides, in some special cases, we also prove the stability of the corresponding rest point in higher dimensions.

Application of entropy and signal energy for ultrasound-based classification of three-dimensional printed polyetherketoneketone components.

This paper describes a preliminary method for the classification of annealed and unannealed polyetherketoneketone (PEKK) components manufactured using a material extrusion three-dimensional (3D) printing process. PEKK is representative of a class of high-performance thermoplastics that are increasingly employed as feedstocks for use in 3D printing. PEKK components may be used continuously at elevated temperatures, are chemically resistant, and able to withstand large mechanical loads. These properties render PEKK suitable as a metal component replacement in aerospace applications, high-temperature industrial applications, and surgical implants. The structure of PEKK is semi-crystalline with the specific crystallinity correlating to the final properties during application, making determination of this property crucial. This study compares three different signal processing techniques intended to distinguish annealed (high crystallinity) from unannealed (low crystallinity) components using backscattered ultrasound. The first is energy-based and is unable to detect annealing. The second two are based on different entropies of the backscattered signal: a limiting form of Renyi's entropy and a limiting form of joint entropy. The joint entropy values for the annealed and unannealed specimens fall into two non-overlapping intervals and have a statistical separation of two standard deviations.

Tilted pillar array fabrication by the combination of proton beam writing and soft lithography for microfluidic cell capture Part 2: Image sequence analysis based evaluation and biological application.

As a continuation of our previously published work, this paper presents a detailed evaluation of a microfabricated cell capture device utilizing a doubly tilted micropillar array. The device was fabricated using a novel hybrid technology based on the combination of proton beam writing and conventional lithography techniques. Tilted pillars offer unique flow characteristics and support enhanced fluidic interaction for improved immunoaffinity based cell capture. The performance of the microdevice was evaluated by an image sequence analysis based in-house developed single-cell tracking system. Individual cell tracking allowed in-depth analysis of the cell-chip surface interaction mechanism from hydrodynamic point of view. Simulation results were validated by using the hybrid device and the optimized surface functionalization procedure. Finally, the cell capture capability of this new generation microdevice was demonstrated by efficiently arresting cells from a HT29 cell-line suspension.

Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair.

Macrophage gene expression determines phagocyte responses and effector functions. Macrophage plasticity has been mainly addressed in in vitro models that do not account for the environmental complexity observed in vivo. In this study, we show that microarray gene expression profiling revealed a highly dynamic landscape of transcriptomic changes of Ly6C(pos)CX3CR1(lo) and Ly6C(neg)CX3CR1(hi) macrophage populations during skeletal muscle regeneration after a sterile damage. Systematic gene expression analysis revealed that the time elapsed, much more than Ly6C status, was correlated with the largest differential gene expression, indicating that the time course of inflammation was the predominant driving force of macrophage gene expression. Moreover, Ly6C(pos)/Ly6C(neg) subsets could not have been aligned to canonical M1/M2 profiles. Instead, a combination of analyses suggested the existence of four main features of muscle-derived macrophages specifying important steps of regeneration: 1) infiltrating Ly6C(pos) macrophages expressed acute-phase proteins and exhibited an inflammatory profile independent of IFN-γ, making them damage-associated macrophages; 2) metabolic changes of macrophages, characterized by a decreased glycolysis and an increased tricarboxylic acid cycle/oxidative pathway, preceded the switch to and sustained their anti-inflammatory profile; 3) Ly6C(neg) macrophages, originating from skewed Ly6C(pos) cells, actively proliferated; and 4) later on, restorative Ly6C(neg) macrophages were characterized by a novel profile, indicative of secretion of molecules involved in intercellular communications, notably matrix-related molecules. These results show the highly dynamic nature of the macrophage response at the molecular level after an acute tissue injury and subsequent repair, and associate a specific signature of macrophages to predictive specialized functions of macrophages at each step of tissue injury/repair.

The ESS and replicator equation in matrix games under time constraints.

Recently, we introduced the class of matrix games under time constraints and characterized the concept of (monomorphic) evolutionarily stable strategy (ESS) in them. We are now interested in how the ESS is related to the existence and stability of equilibria for polymorphic populations. We point out that, although the ESS may no longer be a polymorphic equilibrium, there is a connection between them. Specifically, the polymorphic state at which the average strategy of the active individuals in the population is equal to the ESS is an equilibrium of the polymorphic model. Moreover, in the case when there are only two pure strategies, a polymorphic equilibrium is locally asymptotically stable under the replicator equation for the pure-strategy polymorphic model if and only if it corresponds to an ESS. Finally, we prove that a strict Nash equilibrium is a pure-strategy ESS that is a locally asymptotically stable equilibrium of the replicator equation in n-strategy time-constrained matrix games.