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Background: Matrilin-2 is a key extracellular matrix protein involved in peripheral nerve regeneration. We sought to develop a biomimetic scaffold to enhance peripheral nerve regeneration by incorporating matrilin-2 within a chitosan-derived porous scaffold. We hypothesized that the use of such a novel biomaterial delivers microenvironmental cues to facilitate Schwann cell (SC) migration and enhance axonal outgrowth during peripheral nerve regeneration.Materials and Methods: The effect of matrilin-2 on SC migration was evaluated with agarose drop migration assay on matrilin-2 coated dishes. SC adhesion was determined with SCs cultured atop tissue culture dishes coated with matrilin-2. Various formulations of chitosan vs matrilin-2 in scaffold constructs were examined with scanning electron microscopy. The effect of the matrilin-2/chitosan scaffold on SC migration in the collagen conduits was determined by capillary migration assays. Neuronal adhesion and axonal outgrowth were evaluated with three-dimensional (3D) organotypic assay of dorsal root ganglions (DRG). DRG axonal outgrowth within the scaffolds was determined by immunofluorescence staining of neurofilaments.Results: Matrilin-2 induced SC migration and enhanced its adhesion. A formulation of 2% chitosan with matrilin-2 demonstrated an optimal 3D porous architecture for SC interaction. Matrilin-2/chitosan scaffold enabled SCs to migrate against gravity within conduits. Chemical modification of chitosan with lysine (K-chitosan) further improved DRG adhesion and axonal outgrowth than the matrilin-2/chitosan scaffold without lysine modification.Conclusion: We developed a matrilin-2/K-chitosan scaffold to mimic extracellular matrix cues and provide a porous matrix to enhance peripheral nerve regeneration. Taking advantage of matrilin-2’s capability to stimulate SC migration and adhesion, we formulated a porous matrilin-2/chitosan scaffold to support axongal outgrowth. Chemical modification of chitosan with lysine further improved matrilin-2 bioactivity in the 3D scaffold. The 3D porous matrilin-2/K-chitosan scaffolds have high potential for enhancing nerve repair by stimulating SC migration, neuronal adhesion, and axonal outgrowth.

Abstract Background Prescription of testosterone replacement therapy (TRT) has increased in the United States in recent years, and though anabolic steroids have been associated with tendon rupture, there is a paucity of literature evaluating the risk of Achilles tendon injury with TRT. This study aims to evaluate the associative relationship between consistent TRT, Achilles tendon injury, and subsequent surgery. Methods This is a one‐to‐one matched retrospective cohort study utilizing the PearlDiver database. Records were queried for patients aged 35–75 who were prescribed at least 3 consecutive months of TRT between January 1, 2010 and December 31, 2019. Achilles tendon injuries and subsequent surgeries were identified using ICD‐9, ICD‐10, and CPT billing codes. Multivariable logistic regression was used to compare odds of Achilles tendon injury, Achilles tendon surgery, and revision surgery, with a p‐value

The musculoskeletal system (MSKS) is composed of specialized connective tissues including bone, muscle, cartilage, tendon, ligament, and their subtypes. The primary function of the MSKS is to provide protection, structure, mobility, and mechanical properties to the body. In the process of fulfilling these functions, the MSKS is subject to wear and tear during aging and after injury and requires subsequent repair. MSKS diseases are a growing burden due to the increasing population age. The World Health Organization estimates that 1.71 billon people suffer from MSKS diseases worldwide. MSKS diseases usually involve various dysfunctions in bones, muscles, and joints, which often result in pain, disability, and a decrease in quality of life. The most common MSKS diseases are osteoporosis (loss of bone), osteoarthritis (loss of cartilage), and sarcopenia (loss of skeletal muscle). Because of the disease burden and the need for treatment, regenerative drug therapies for MSKS disorders are increasingly in demand. However, the difficulty of effective drug delivery in the MSKS has become a bottleneck for developing MSKS therapeutics. The abundance of extracellular matrix and its small pore size in the MSKS present a formidable barrier to drug delivery. Differences of vascularity among various MSKS tissues pose complications for drug delivery. Novel strategies are necessary to achieve successful drug delivery in different tissues composing the MSKS. Those considerations include the route of administration, mechanics of surrounding fluids, and biomolecular interactions, such as the size and charge of the particles and targeting motifs. This review focuses on recent advances in challenges to deliver drugs to each tissue of the MSKS, current strategies of drug delivery, and future ideas of how to overcome drug delivery challenges in the MSKS.

Abstract Efforts to characterize microbial life across diverse environments have progressed tremendously, yet the microbiome of Earth's largest biomass reservoir—the wood of living trees—has been largely unexplored. Current understanding of the tree microbiome is largely confined to roots and leaves, with little attention given to the endophytic microbiome of wood, even though emergent studies have indicated this zone as a niche for unique taxa, of consequence for ecosystem health and global biogeochemical cycles. The lack of investigation derives partly from the physical recalcitrance of wood, which presents challenges during sampling, homogenization, and the extraction of nucleic acids. In response to these issues, we present an optimized method for processing wood for use in microbial analyses, from sampling through to downstream analyses. Using methane‐cycling taxa as model endophytes, we assess losses in recovery during our method, and determine a limit‐of‐detection of approximately 500 cells per 100 mg of (dry) wood. For all six species evaluated—which represented several diverse taxa of hardwoods and softwoods—PCR inhibition proved minimal, and we expect this method to be applicable for a majority of tree species. The methods presented herein can facilitate future investigation into the wood microbiome and global microbial ecology of methane cycling.

Objectives: Tai Chi (TC) shows some beneficial effects in reducing pain in knee osteoarthritis (OA). However, the selection of criteria TC forms in previous studies were unclear and inconsistent, possibly accounting for the varying outcomes and rendering the training effects suboptimal. We have selected four optimal TC (OTC) forms based on the knee joint load and its association with pain. This pilot study sought to examine the effect of the OTC forms on reducing knee pain in individuals with knee OA. Methods: Fifteen knee OA participants were recruited. Their knee joint pain level was rated by using the Visual Analogue Scale before and after two weeks of OTC training and compared between these two assessments. Results: The two-week OTC training course was well accepted by our participants. The knee OA pain showed a significant reduction (median pain score: 5 ​cm before training and 1 ​cm post-training, Wilcoxon p ​

IntroductionIn recent years, Norway spruce (Picea abies L.) forests in Central Europe have faced escalating threats from bark beetles, primarily Ips typographus (L.), and other species, such as I. duplicatus (Sahlberg). Outbreaks are partially attributed to weakened tree defense resulting from drought periods induced by climate change. This study examines Norway spruce’s physiological and metabolic reactions to acute drought stress during the growing season and evaluates its susceptibility to I. typographus and I. duplicatus.MethodologyIn order to induce drought stress, mature Norway spruces had their roots covered with a roof in April 2021, depriving them of water. Control trees were left with free access to natural rainwater. Over 5 months of the growing season, soil water potential, bark temperature, tree trunk circumference, and sap flow were monitored. Roofed trees and controls were sampled in July, August, and September and analyzed for non-structural carbohydrates and the two classes of defensive compounds, phenolics and terpenes. Furthermore, two different bioassays in tubes and boxes were performed using adult I. typographus and I. duplicatus beetles to assess host choice and acceptance.ResultsRoofed trees exhibited signs of stress as early as July, resulting in decreased tree trunk and a consequent increase in non-structural carbohydrate content. Defensive metabolites remained largely unaffected except for an increase in diterpenes in September. In bioassays, I. typographus preferred boring into the bark of roofed trees in August in tubes and in September in boxes. This increased tree acceptance correlated with increased levels of soluble carbohydrates in the phloem. I. typographus and I. duplicatus beetles showed higher mobility in boxes in August and September on roofed trees but not in July, even though bark surface temperatures were elevated in roof-covered trees during all three bioassay periods.ConclusionThe study revealed rapid physiological responses of trees to acute drought stress, although not many changes were observed in defense traits. Despite the absence of natural bark beetle attacks, drought trees were more accepted by I. typographus than naturally watered trees. This response may indicate the beetles’ preference for trees with phloem of higher nutritional quality induced by the acute drought stress conditions.

The present study aimed to analyze the linear correlation between the production variables of biofuel based on cocoa (Theobroma cacao L.) mucilage in the city of Calceta - Manabí. The issue addressed was the generation of waste from cocoa farming, leading to contamination of aquifers and the land surface. The CCN-51 cocoa variety was used for the research, following the guidelines of the Completely Randomized Design (CRD), with the proportion of yeast (Saccharomyces cerevisiae) as the studied factor, in three quantities: 0.5 kg, 0.1 kg, and 0.025 kg, and two methods of sample dehydration: saline distillation and molecular sieves the interaction between factors generated six treatments, each of which was repeated three times. The study found significant differences in the variables of alcohol content and yield, while there were no differences in pH and ratio/biomass. Treatment T6 was identified as the most feasible for biofuel production, with a pH of 5.86, 83% alcohol content, 76.67 mL ratio/biomass, and 58.10% yield. Regarding the relationship between the production variables, the analysis of linear correlation revealed a strong, directly proportional correlation for all variables, with values ranging from 0.94 to 0.98.

Sugar–sugar glycosyltransferases play important roles in constructing complex and bioactive saponins. Here, we characterized a series of UDP-glycosyltransferases responsible for biosynthesizing the branched sugar chain of bioactive steroidal saponins from a widely known medicinal plant Paris polyphylla var. yunnanensis. Among them, a 2′-O-rhamnosyltransferase and three 6′-O-glucosyltrasferases catalyzed a cascade of glycosylation to produce steroidal diglycosides and triglycosides, respectively. These UDP-glycosyltransferases showed astonishing substrate promiscuity, resulting in the generation of a panel of 24 terpenoid glycosides including 15 previously undescribed compounds. A mutant library containing 44 variants was constructed based on the identification of critical residues by molecular docking simulations and protein model alignments, and a mutant UGT91AH1Y187A with increased catalytic efficiency was obtained. The steroidal saponins exhibited remarkable antifungal activity against four widespread strains of human pathogenic fungi attributed to ergosterol-dependent damage of fungal cell membranes, and 2′-O-rhamnosylation appeared to correlate with strong antifungal effects. The findings elucidated the biosynthetic machinery for their production of steroidal saponins and revealed their potential as new antifungal agents.

Background: Next-generation sequencing (NGS) methods for microbial profiling have increased sensitivity to detect urinary pathogens. Objective: To determine whether NGS microbial profiling can be used to guide antibiotic prophylaxis and reduce infection compared with the standard of care. Design, setting, and participants: A prospective randomized controlled clinical trial of patients undergoing urologic stone interventions at an academic health center from December 2019 to January 2022 was conducted. Urine was collected at the preoperative visit for standard culture and intervention NGS diagnostics. Evaluable patients were culture negative, met 2-wk follow-up, and did not cancel surgery. Of 240 individuals (control = 121, intervention = 119), 83 control and 74 intervention patients were evaluable. Intervention: Microbial findings (paired quantitative polymerase chain reaction and NGS) were sent to an infectious disease pharmacist to recommend prophylactic antimicrobial regimen. Outcome measurements and statistical analysis: The primary outcome was postoperative urinary infection within the follow-up period (Fisher’s exact test). The primary outcome was analyzed by modified intent-to-treat (mITT) and per-protocol analyses. Secondary endpoints considered included positive culture concordance, antibiotic use, and adverse events. Additional post hoc analyses investigated factors contributing to infection (univariate logistic regression). Results and limitations: The intervention significantly reduced postsurgical urinary infection risk by 7.1% (–0.73%, 15%) compared with the standard of care in the mITT analysis (1.4% vs 8.4%, p = 0.045) or by 8.5% (0.88%, 16%) compared with the per-protocol analysis (0% vs 8.5%, p = 0.032). NGS-guided treatment altered the distribution of antibiotics used (p = 0.025), and antibiotics poorly matched with NGS findings were associated with increased infection odds (odds ratio [OR] = 5.9, p = 0.046). Women were at greater odds to develop infection (OR = 10, p = 0.03) and possessed differentiated microbial profiles (p

Abstract Advances in prostate cancer treatment have significantly improved survival, but quality of life for survivors remains an under-studied area of research. Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer and is used as an adjuvant for prolonged periods in many high-risk, localized tumors. More than half of patients treated with ADT experience debilitating cognitive impairments in domains such as spatial learning and working memory. In this study, we investigated the effects of androgen deprivation on hippocampal-mediated cognition in rats. Vortioxetine, a multimodal antidepressant, has been shown to improve cognition in depressed patients. Thus, we also tested the potential efficacy of vortioxetine in restoring impaired cognition after ADT. We further investigated mechanisms that might contribute to these effects, measuring changes in the circuitry and gene expression within the dorsal hippocampus. ADT via surgical castration induced impairments in visuospatial cognition on the novel object location test and attenuated afferent-evoked local field potentials recorded in the CA1 region of the dorsal hippocampus. Chronic dietary administration of vortioxetine effectively reversed these deficits. Castration significantly altered gene expression in the hippocampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that the hippocampus may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients who experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit-level plasticity-related mechanisms compromised by ADT.

The study comprehensively evaluates low-cost CO2 sensors from different price tiers, assessing their performance against a reference-grade instrument and exploring the possibility of calibration using different machine learning techniques. Three sensors (Sunrise AB by Senseair, K30 CO2 by Senseair, and GMP 343 by Vaisala) were tested alongside a reference instrument (Los Gatos precision greenhouse gas analyzer). The results revealed differences in sensor performance, with the higher cost Vaisala sensors exhibiting superior accuracy. Despite its lower price, the Sunrise sensors still demonstrated reasonable accuracy. Meanwhile, the K30 sensor measurements displayed higher variability and noise. Machine learning models, including linear regression, gradient boosting regression, and random forest regression, were employed for sensor calibration. In general, linear regression models performed best for extrapolating data, whereas decision tree-based models were generally more useful in handling non-linear datasets. Notably, a stack ensemble model combining these techniques outperformed the individual models and significantly improved sensor accuracy by approximately 65%. Overall, this study contributes to filling the gap in intercomparing CO2 sensors across different price categories and underscores the potential of machine learning for enhancing sensor accuracy, particularly in low-cost sensor applications.

The Eurasian spruce bark beetle (Ips typographus) is currently the most economically relevant pest of Norway spruce (Picea abies). Ips typographus associates with filamentous fungi that may help it overcome the tree's chemical defenses. However, the involvement of other microbial partners in this pest's ecological success is unclear. To understand the dynamics of the bark beetle-associated microbiota, we characterized the bacterial and fungal communities of wild-collected and lab-reared beetles throughout their development by culture-dependent approaches, meta-barcoding, and quantitative PCR. Gammaproteobacteria dominated the bacterial communities, while the fungal communities were mainly composed of yeasts of the Saccharomycetales order. A stable core of microbes is shared by all life stages, and is distinct from those associated with the surrounding bark, indicating that Ips typographus influences the microbial communities of its environment and offspring. These findings coupled with our observations of maternal behavior, suggest that Ips typographus transfers part of its microbiota to eggs via deposition of an egg plug treated with maternal secretions, and by inducing an increase in abundance of a subset of taxa from the adjacent bark.

Abstract Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging‐associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non‐activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito‐transferred aged CD4+ T cells showed improvements in activation‐induced TCR‐signaling kinetics displaying markers of activation (CD25), increased IL‐2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG‐KO) showed that adoptive transfer of mito‐transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.

With the increasing frequencies of extreme weather events caused by climate change, the risk of forest damage from insect attacks grows. Storms and droughts can damage and weaken trees, reduce tree vigour and defence capacity and thus provide host trees that can be successfully attacked by damaging insects, as often observed in Norway spruce stands attacked by the Eurasian spruce bark beetle Ips typographus. Following storms, partially uprooted trees with grounded crowns suffer reduced water uptake and carbon assimilation, which may lower their vigour and decrease their ability to defend against insect attack. We conducted in situ measurements on windthrown and standing control trees to determine the concentrations of non-structural carbohydrates (NSCs), of phenolic defences and volatile monoterpene emissions. These are the main storage and defence compounds responsible for beetle´s pioneer success and host tree selection. Our results show that while sugar and phenolic concentrations of standing trees remained rather constant over a 4-month period, windthrown trees experienced a decrease of 78% and 37% of sugar and phenolic concentrations, respectively. This strong decline was especially pronounced for fructose (-83%) and glucose (-85%) and for taxifolin (-50.1%). Windthrown trees emitted 25 times greater monoterpene concentrations than standing trees, in particular alpha-pinene (23 times greater), beta-pinene (27 times greater) and 3-carene (90 times greater). We conclude that windthrown trees exhibited reduced resources of anti-herbivore and anti-pathogen defence compounds needed for the response to herbivore attack. The enhanced emission rates of volatile terpenes from windthrown trees may provide olfactory cues during bark beetle early swarming related to altered tree defences. Our results contribute to the knowledge of fallen trees vigour and their defence capacity during the first months after the wind-throw disturbance. Yet, the influence of different emission rates and profiles on bark beetle behaviour and host selection requires further investigation.

El objetivo de esta investigación fue realizar una aplicación que permita la integración de un modelo computacional a una aplicación multiplataforma, para ello se tuvo como datos, la información de un modelo de clasificación de aprendizaje supervisado respecto al levantamiento de información sobre la deserción estudiantil en el contexto del covid-19, esta investigación fue desarrollada en la Escuela Superior Politécnica Agropecuaria de Manabí Manuel Félix López. La metodología que se planteó para el respectivo desarrollo fue Extreme programing (XP). Partiendo de un modelo entrenado, para lo cual se utilizó el framework flask basado en python, luego se procedió a crear un servicio para consumir el modelo, posteriormente se realizaron las respectivas pruebas utilizando postman como cliente web. Se obtuvo como principal resultado dentro de la investigación, que el Framework Flask permitió desarrollar e implementar un API RES de forma mucho más ágil y fácil para el consumo de datos del modelo predictivo.

The plastidic 2-C-methylerythritol 4-phosphate (MEP) pathway supplies the precursors of a large variety of essential plant isoprenoids, but its regulation is still not well understood. Using metabolic control analysis (MCA), we examined the first enzyme of this pathway, 1-deoxyxylulose 5-phosphate synthase (DXS), in multiple grey poplar (Populus × canescens) lines modified in their DXS activity. Single leaves were dynamically labeled with 13CO2 in an illuminated, climate-controlled gas exchange cuvette coupled to a proton transfer reaction mass spectrometer, and the carbon flux through the MEP pathway was calculated. Carbon was rapidly assimilated into MEP pathway intermediates and labeled both the isoprene released and the IDP+DMADP pool by up to 90%. DXS activity was increased by 25% in lines overexpressing the DXS gene and reduced by 50% in RNA interference lines, while the carbon flux in the MEP pathway was 25–35% greater in overexpressing lines and unchanged in RNA interference lines. Isoprene emission was also not altered in these different genetic backgrounds. By correlating absolute flux to DXS activity under different conditions of light and temperature, the flux control coefficient was found to be low. Among isoprenoid end products, isoprene itself was unchanged in DXS transgenic lines, but the levels of the chlorophylls and most carotenoids measured were 20–30% less in RNA interference lines than in overexpression lines. Our data thus demonstrate that DXS in the isoprene-emitting grey poplar plays only a minor part in controlling flux through the MEP pathway.

Abstract Brassicaceae plants have the glucosinolate–myrosinase defense system, jointly active against herbivory. However, constitutive glucosinolate (GLS) defense is observed to occur at levels that do not deter all insects from feeding. That prompts the question of why Brassicaceae plants have not evolved a higher constitutive defense. The answer may lie in the contrasting relationship between plant defense and host plant preference of specialist and generalist herbivores. GLS content increases a plant's susceptibility to specialist insects. In contrast, generalists are deterred by the plant GLSs. Although GLSs can attract the natural enemies (predators and parasitoids) of these herbivores, enemies can reduce herbivore pressure to some extent only. So, plants can be overrun by specialists if GLS content is too high, whereas generalists can invade the plants if it is too low. Therefore, an optimal constitutive plant defense can minimize the overall herbivore pressure. To explain the optimal defense theoretically, we model the contrasting host selection behavior of insect herbivores and the emergence of their natural enemies by non‐autonomous ordinary differential equations, where the independent variable is the plant GLS concentration. From the model, we quantify the optimal amount of GLSs, which minimizes total herbivore (specialists and generalists) pressure. That quite successfully explains the evolution of constitutive defense in plants from the perspective of optimality theory.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

We observed the Seyfert 1 galaxy Mrk 817 during an intensive multiwavelength reverberation mapping campaign for 16 months. Here, we examine the behavior of narrow UV absorption lines seen in the Hubble Space Telescope/Cosmic Origins Spectrograph spectra, both during the campaign and in other epochs extending over 14 yr. We conclude that, while the narrow absorption outflow system (at −3750 km s ^−1 with FWHM = 177 km s ^−1 ) responds to the variations of the UV continuum as modified by the X-ray obscurer, its total column density (log N _H = 19.5 ${}_{-0.13}^{+0.61}$ cm ^−2 ) did not change across all epochs. The adjusted ionization parameter (scaled with respect to the variations in the hydrogen-ionizing continuum flux) is log U _H = −1.0 ${}_{-0.3}^{+0.1}$ . The outflow is located at a distance smaller than 38 pc from the central source, which implies a hydrogen density of n _H > 3000 cm ^−3 . The absorption outflow system only covers the continuum emission source and not the broad emission line region, which suggests that its transverse size is small (< 10 ^16 cm), with potential cloud geometries ranging from spherical to elongated along the line of sight.

We present an intensive multiwavelength monitoring campaign of the quasar PG 1302−102 with Swift and the Las Cumbres Observatory network telescopes. At z ∼ 0.3, it tests the limits of the reverberation mapping (RM) technique in probing the accretion disk around a supermassive black hole (SMBH) and extends the parameter space to high masses and high accretion rates. This is also the first time the RM technique has been applied to test disk structures predicted in the SMBH binary model that has been suggested for this source. PG 1302−102 was observed at a ∼daily cadence for ∼9 months in 14 bands spanning from X-ray to UV and optical wavelengths, and it shows moderate to significant levels of variability correlated between wavelengths. We measure the interband time lags, which are consistent with a τ ∝ λ ^4/3 relation as expected from standard disk reprocessing, albeit with large uncertainties. The disk size implied by the lag spectrum is consistent with the expected disk size for its black hole mass within uncertainties. While the source resembles other reverberation-mapped active galactic nuclei in many respects, and we do not find evidence supporting the prevalent hypothesis that it hosts an SMBH binary, we demonstrate the feasibility of studying SMBH binaries from this novel angle and suggest possibilities for the LSST Deep Drilling Fields.

An intensive reverberation mapping campaign of the Seyfert 1 galaxy Mrk 817 using the Cosmic Origins Spectrograph on the Hubble Space Telescope revealed significant variations in the response of broad UV emission lines to fluctuations in the continuum emission. The response of the prominent UV emission lines changes over an ∼60 day duration, resulting in distinctly different time lags in the various segments of the light curve over the 14 month observing campaign. One-dimensional echo-mapping models fit these variations if a slowly varying background is included for each emission line. These variations are more evident in the C iv light curve, which is the line least affected by intrinsic absorption in Mrk 817 and least blended with neighboring emission lines. We identify five temporal windows with a distinct emission-line response, and measure their corresponding time delays, which range from 2 to 13 days. These temporal windows are plausibly linked to changes in the UV and X-ray obscuration occurring during these same intervals. The shortest time lags occur during periods with diminishing obscuration, whereas the longest lags occur during periods with rising obscuration. We propose that the obscuring outflow shields the broad UV lines from the ionizing continuum. The resulting change in the spectral energy distribution of the ionizing continuum, as seen by clouds at a range of distances from the nucleus, is responsible for the changes in the line response.

IntroductionVarious herbivorous insects prefer toxic plants as their hosts, although this may appear paradoxical. They have evolved specific adaptations (called counter-defenses) against the toxins. For example, the two-component chemical defense system of plants of the Brassicaceae family against herbivores consists of glucosinolates (GLSs) and the activating enzyme myrosinase. GLS hydrolysis by myrosinase leads to isothiocyanates (ITCs), which are toxic and deterrent to many insect herbivores. Two different types of counter-defenses can be distinguished: a preemptive counter-defense that prevents the GLSs from being hydrolyzed to ITCs due to metabolic redirection and direct counter-defense, where the ITCs are formed but then metabolized to non-toxic conjugates. In general, preemptive counter-defense is only a possibility if the plant stores a precursor of the toxin, which is activated upon attack. Preemptive counter-defense is believed to be more efficient due to the lower exposure to ITCs, but this has not been satisfactorily demonstrated experimentally.MethodsHere, we derive on theoretical grounds the conditions under which preemptive counter-defense reduces exposure to ITCs compared to direct counter-defense by studying the dynamics of GLS defense and counter-defense with two separate ordinary differential equation models. We model how herbivory transfers the GLSs to the insect gut with the leaf material. Thereafter, we describe the insects’ exposure to toxins by deriving the dynamics of ITCs in the gut during feeding with the two types of counter-defenses.Results and discussionBy calculating the area under the curve (AUC) of the ITC concentrations, we show, based on empirical data, that herbivores with a preemptive detoxification system are usually less exposed to ITCs. In addition, our models explain how the decline in the level of ITCs is achieved by both counter-defenses, which helps to understand the overall mechanisms and benefits of these techniques. Our results may also apply to plant defenses by inactive toxin precursors other than GLSs as well as to insects that sequester such precursors for their own defense.

Abstract Introduction The discovery of biogenic aldehydes in the postmortem parkinsonian brain and the ability of these aldehydes to modify and cross‐link proteins has called attention to their possible role in Parkinson's disease. For example, many in vitro studies have found that the aldehyde metabolite of dopamine, 3,4‐dihydroxyphenylacetaldehyde (DOPAL), induces the formation of stable, neurotoxic alpha‐synuclein oligomers. Methods To study this in vivo, mice deficient in the two aldehyde dehydrogenase enzymes (Aldh1a1 and Aldh2, DKO) primarily responsible for detoxification of DOPAL in the nigrostriatal pathway were crossed with mice that overexpress human wild‐type alpha‐synuclein. DKO overexpressing human wild‐type alpha‐synuclein (DKO/ASO) offspring were evaluated for impairment on motor tasks associated with Parkinsonism. Results DKO/ASO mice developed severe motor deficits greater than that of mice overexpressing human wild‐type alpha‐synuclein alone. Conclusion These results provide evidence to support the idea that biogenic aldehydes such as DOPAL interact with human wild‐type alpha‐synuclein, directly or indirectly, in vivo to exacerbate locomotor deficits in Parkinson's disease.

Background: Sexually transmitted infections (STIs) are a major health issue, exacerbated by limited financial and infrastructural resources in developing countries. Methods: Prevalence of STIs was assessed in two urban centers of the Dominican Republic (DR) among populations at high risk for STIs: pregnant youth, men who have sex with men (MSM), trans women (TG), batey residents, female sex workers, and people living with human immunodeficiency virus (HIV). We conducted a cross-sectional survey and biological specimen collection to screen for Chlamydia trachomatis, Neisseria gonorrhea, Mycoplasma genitalium, Trichomonas vaginalis (trichomoniasis), Treponema pallidum (syphilis), HIV, hepatitis B and C, and human papillomavirus (HPV) among at-risk populations between 2015 and 2018. Ureaplasma urealyticum testing was also conducted even though it is not considered a STI. A non-probability community sample was recruited. Descriptive statistics examined the prevalence of STIs by population. Results: A total of 1991 subjects participated in the study. The median age was 26 years (range: 18–65). Most participants were female (65.3%), heterosexual (76.7%), and were not partnered (55.7%). Most of the participants reported unprotected vaginal sex in the last 6 months (54%); among MSM and TG almost half of the participants reported unprotected anal sex in the last 6 months and 17.6% reported drug use in the last 6 months. Almost half of the participants (49%) tested positive for one or more STIs. The most prevalent STI was Chlamydia trachomatis (12.8%), and human papillomavirus (11.9%). Among transgender women, 65.3% tested positive for an STI, 64.8% of female sex workers tested positive for an STI, and 53.8% of pregnant adolescents tested positive for an STI. Conclusion: There is a high prevalence of STIs among key and under resourced populations in the DR. Our findings highlight the need to conduct further research to optimize prevention and care strategies for structurally vulnerable and under resourced populations in the DR.

The spurge hawkmoth Hyles euphorbiae (Lepidoptera, Sphingidae) is an insect herbivore feeding exclusively on spurges (Euphorbia). These are toxic due to their secondary metabolites including diterpene esters with numerous harmful biological activities, preventing their use by most herbivores. Extracts of frass from H. euphorbiae and of its main larval food plant in Central Europe, the cypress spurge (Euphorbia cyparissias L.), were analyzed via liquid chromatography using a triple-quadrupole (MS/MS) and a high-resolution–quadrupole time-of-flight mass spectrometer (QTOF-MS). We report for the first time the finding of the tigliane (phorbol ester) phorbol-13-acetate and two 12-O-tetradecanoylphorbol-13-acetate (TPA) isomers of unknown structure (compounds 2 and 3) in E. cyparissias. Our data support the assignment of these two compounds as tiglianes and are therefore referred to by us as “putative tiglianes”. Additionally, the distribution of the three reported compounds within the plant parts (leaves, stem and root) was analyzed to gain first insights into the metabolite conditions H. euphorbiae copes with in nature. Phorbol-13-acetate was detected in the plant’s root only, while the other compounds were observed in all three plant parts, although in different distributions. Moreover, our results indicate that the occurrence of compound 3 rises upon larval feeding. Finally, the presence of the plant-derived putative tiglianes in frass from E. cyparissias leaves feeding larvae is confirmed, corroborating the close plant–herbivore interaction.

Abstract Background Accurate quantification of radioactivity in a source of interest relies on accurate registration between SPECT and anatomical images, and appropriate correction of partial volume effects (PVEs). For small volumes, exact registration between the two imaging modalities and recovery factors used to correct for PVE are unreliable. There is currently no guidance relating to quantification or the associated uncertainty estimation for small volumes. Material and methods A method for quantification of small sources of interest is proposed, which uses multiple oversized volumes of interest. The method was applied to three Na[131I]I activity distributions where a Na[131I]I capsule was situated within a cylindrical phantom containing either zero background, uniform background or non-uniform background and to a scenario with small lesions placed in an anthropomorphic phantom. The Na[131I]I capsule and lesions were quantified using the proposed method and compared with measurements made using two alternative quantification methods. The proposed method was also applied to assess the absorbed dose delivered to a bone metastasis following [131I]mIBG therapy for neuroblastoma including the associated uncertainty estimation. Results The method is accurate across a range of activities and in varied radioactivity distributions. Median percentage errors using the proposed method in no background, uniform backgrounds and non-uniform backgrounds were − 0.4%, − 0.3% and 1.7% with median associated uncertainties of 1.4%, 1.4% and 1.6%, respectively. The technique is more accurate and robust when compared to currently available alternative methods. Conclusions The proposed method provides a reliable and accurate method for quantification of sources of interest, which are less than three times the spatial resolution of the imaging system. The method may be of use in absorbed dose calculation in cases of bone metastasis, lung metastasis or thyroid remnants.

Abstract Background Individuals living with a rheumatic pain condition can face delays in accessing pain clinics, which prevents them from receiving timely treatment. Little is known regarding their specific healthcare utilization in order to alleviate pain while waiting to obtain services in pain clinics. Hence, the aim of this study was to explore the perceptions and experiences of persons living with rheumatic conditions regarding healthcare utilization while waiting to access a pain clinic. Methods In this qualitative descriptive study, semi-structured interviews were conducted with adults living with a painful rheumatic condition that reported either being waiting for admission in a pain clinic, having been referred but then denied pain clinic services, or having received services during the previous six months, in the province of Quebec, Canada. The interviews were transcribed verbatim, and an inductive thematic analysis was performed. Results Twenty-six individuals were interviewed (22 women and 4 men; mean age 54 ± 10 years). Three themes were identified: 1) lacking guidance in identifying solutions to their complex and multidimensional needs, 2) struggling to obtain and maintain services due to systemic access barriers, and 3) displaying resilience through a search for accessible and sustainable self-management strategies. Conclusions The current approaches and structures of health services fail to adequately answer the service needs of individuals experiencing painful rheumatic conditions. Important shifts are required in pain education, in increasing access to multidisciplinary approaches at the primary care level and in breaking down barriers individuals with chronic pain face to receive appropriate and timely care.

To detect new and changing SARS-CoV-2 variants, we investigated candidate Delta–Omicron recombinant genomes from Centers for Disease Control and Prevention national genomic surveillance. Laboratory and bioinformatic investigations identified and validated 9 genetically related SARS-CoV-2 viruses with a hybrid Delta–Omicron spike protein.

Abstract Some COVID-19 patients experience dyspnea without objective impairment of pulmonary or cardiac function. This study determined diaphragm function and its central voluntary activation as a potential correlate with exertional dyspnea after COVID-19 acute respiratory distress syndrome (ARDS) in ten patients and matched controls. One year post discharge, both pulmonary function tests and echocardiography were normal. However, six patients with persisting dyspnea on exertion showed impaired volitional diaphragm function and control based on ultrasound, magnetic stimulation and balloon catheter-based recordings. Diaphragm dysfunction with impaired voluntary activation can be present 1 year after severe COVID-19 ARDS and may relate to exertional dyspnea. This prospective case–control study was registered under the trial registration number NCT04854863 April, 22 2021

The COVID-19 pandemic revolutionized cancer care delivery leading to rapid adoption of digital technology for telehealth in the United States. In this study, we describe telehealth utilization trends across the three largest waves of the pandemic at a safety net academic center. We also provide a perspective on lessons learnt and our vision for cancer care delivery using digital technology in the near future. The integration of interpreter services within the video platform and its integration within the electronic medical record system is crucial for safety net institutes that service a diverse patient population. Pay-parity for telehealth, especially ongoing support for audio-only visits, will be critical in overcoming health disparities for patients without access to smartphone technology. Use of telehealth in clinical trials, widespread adoption of hospital at home programs, electronic consults for rapid access, and structured telehealth slots in clinic templates will be crucial in making cancer care more equitable and efficient.

IntroductionBacterial infections and chronic intestinal inflammations triggered by genetic susceptibility, environment or an imbalance in the intestinal microbiome are usually long-lasting and painful diseases in which the development and maintenance of these various intestinal inflammations is not yet fully understood, research is still needed. This still requires the use of animal models and is subject to the refinement principle of the 3Rs, to minimize suffering or pain perceived by the animals. With regard to this, the present study aimed at the recognition of pain using the mouse grimace scale (MGS) during chronic intestinal colitis due to dextran sodium sulfate (DSS) treatment or after infection with Citrobacter rodentium.MethodsIn this study 56 animals were included which were divided into 2 experimental groups: 1. chronic intestinal inflammation (n = 9) and 2. acute intestinal inflammation (with (n = 23) and without (n = 24) C. rodentium infection). Before the induction of intestinal inflammation in one of the animal models, mice underwent an abdominal surgery and the live MGS from the cage side and a clinical score were assessed before (bsl) and after 2, 4, 6, 8, 24, and 48 hours.ResultsThe highest clinical score as well as the highest live MGS was detected 2 hours after surgery and almost no sign of pain or severity were detected after 24 and 48 hours. Eight weeks after abdominal surgery B6-Il4/Il10-/- mice were treated with DSS to trigger chronic intestinal colitis. During the acute phase as well as the chronic phase of the experiment, the live MGS and a clinical score were evaluated. The clinical score increased after DSS administration due to weight loss of the animals but no change of the live MGS was observed. In the second C57BL/6J mouse model, after infection with C. rodentium the clinical score increased but again, no increased score values in the live MGS was detectable.DiscussionIn conclusion, the live MGS detected post-operative pain, but indicated no pain during DSS-induced colitis or C. rodentium infection. In contrast, clinical scoring and here especially the weight loss revealed a decreased wellbeing due to surgery and intestinal inflammation.

IntroductionThe optimal strategy for differentiated thyroid cancer (DTC) patients treated with radioiodine (RAI) following thyroidectomy remains controversial. Multi-centre clinical studies are essential to identify strategies to improve patient outcomes while minimising treatment-induced toxicity.Materials and MethodsThe INSPIRE clinical trial (ClinicalTrials.gov Identifier: NCT04391244) aims to investigate patient-specific dosimetry for DTC patients and to determine the range of absorbed doses delivered to target and non-target tissues and their relationship with treatment outcome and toxicity.ResultsWe report here initial results of the first 30 patients enrolled onto the INSPIRE trial. A large range of absorbed doses are observed for both thyroid remnants and salivary glands, with median values of 4.8 Gy (Range 0.2 – 242 Gy) and 0.3 Gy (Range 0.1 to 1.7 Gy), respectively.DiscussionThe preliminary study results are encouraging and could help to improve our understanding of absorbed doses to thyroid remnants and normal organs following RAI therapy. Such knowledge could potentially enable patient-specific treatment planning with improved clinical outcomes and quality-of-life of patients.

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed ‘senolytics’. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning. The primary objective of this confirmatory randomized placebo-controlled pilot trial (RCT; NCT02874989) was to report adverse events with D + Q and inform study feasibility for future efficacy trials. Methods: Twelve participants with IPF aged >50 years were blinded and randomized at a 1:1 ratio to either receive three weeks of D + Q (D: 100 mg/d and Q: 1250 mg/d, three consecutive days per week) or matching placebo. Findings: All participants completed the scheduled drug dosing regimen (108/108 doses) and planned assessments (60/60). While the placebo arm reported fewer overall non-serious AEs (65 vs 22), there were no serious adverse events related to D + Q. Most AEs in the D + Q arm are common in IPF patients or anticipated side effects of D. Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6). Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups. Interpretation: Intermittently-dosed D + Q in patients with IPF is feasible and generally well-tolerated. Further prospective studies, such as a larger RCT, are needed to confirm the safety and efficacy of D + Q in patients with IPF. Funding: This work was supported by National Institutes of Health grants R33AG61456 (JLK, TT), Robert and Arlene Kogod (JLK, TT), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT) San Antonio Claude D. Pepper Older Americans Independence Center’s (OAIC) Pilot/Exploratory Studies Core (PESC) Grant (AMN, NM); NIH K01 AG059837 (JNJ), P30 AG021332 (SBK, JNJ); NIH R37 AG013925 (JLK), the Connor Group (JLK), Glenn/AFAR BIG Award (JLK), Robert J. and Theresa W. Ryan (JLK), and the Noaber and Ted Nash Long Life Foundations (JLK).

Abstract Herbivorous insects often possess the ability to detoxify chemical defenses from their host plants. The fall armyworm (Spodoptera frugiperda), which feeds principally on maize, detoxifies the maize benzoxazinoid 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) by stereoselective re-glucosylation using a UDP-glucosyltransferase, SfUGT33F28. SfUGT33F28 activity is induced by feeding on a DIMBOA-containing diet, but how this induction is regulated is unknown. In the present work, we describe the alternative splicing of the SfUGT33F28 transcript. Variant transcripts are differentially expressed in response to DIMBOA, and this transcriptional response is mediated by an insect aryl hydrocarbon receptor. These variants have large deletions leading to the production of truncated proteins that have no intrinsic UGT activity with DIMBOA but interact with the full-length enzyme to raise or lower its activity. Therefore, the formation of SfUGT33F28 splice variants induces DIMBOA-conjugating UGT activity when DIMBOA is present in the insect diet and represses activity in the absence of this plant defense compound.

Outbreaks of the Eurasian spruce bark beetle (Ips typographus) have decimated millions of hectares of conifer forests in Europe in recent years. The ability of these 4.0 to 5.5 mm long insects to kill mature trees over a short period has been sometimes ascribed to two main factors: (1) mass attacks on the host tree to overcome tree defenses and (2) the presence of fungal symbionts that support successful beetle development in the tree. While the role of pheromones in coordinating mass attacks has been well studied, the role of chemical communication in maintaining the fungal symbiosis is poorly understood. Previous evidence indicates that I. typographus can distinguish fungal symbionts of the genera Grosmannia, Endoconidiophora, and Ophiostoma by their de novo synthesized volatile compounds. Here, we hypothesize that the fungal symbionts of this bark beetle species metabolize spruce resin monoterpenes of the beetle's host tree, Norway spruce (Picea abies), and that the volatile products are used as cues by beetles for locating breeding sites with beneficial symbionts. We show that Grosmannia penicillata and other fungal symbionts alter the profile of spruce bark volatiles by converting the major monoterpenes into an attractive blend of oxygenated derivatives. Bornyl acetate was metabolized to camphor, and α- and β-pinene to trans-4-thujanol and other oxygenated products. Electrophysiological measurements showed that I. typographus possesses dedicated olfactory sensory neurons for oxygenated metabolites. Both camphor and trans-4-thujanol attracted beetles at specific doses in walking olfactometer experiments, and the presence of symbiotic fungi enhanced attraction of females to pheromones. Another co-occurring nonbeneficial fungus (Trichoderma sp.) also produced oxygenated monoterpenes, but these were not attractive to I. typographus. Finally, we show that colonization of fungal symbionts on spruce bark diet stimulated beetles to make tunnels into the diet. Collectively, our study suggests that the blends of oxygenated metabolites of conifer monoterpenes produced by fungal symbionts are used by walking bark beetles as attractive or repellent cues to locate breeding or feeding sites containing beneficial microbial symbionts. The oxygenated metabolites may aid beetles in assessing the presence of the fungus, the defense status of the host tree and the density of conspecifics at potential feeding and breeding sites.

IntroductionInsect oviposition can enhance plant defenses and decrease plant quality in response to future feeding damage by hatched larvae. Induced resistance triggered by egg deposition and its negative effect on insect herbivore performance is known for several annual plants but has been much less studied in woody perennials, such as species of the Salicaceae. Here we studied the response of the willow Salix babylonica to oviposition by the specialist willow sawfly Nematus oligospilus and its impact on insect performance.MethodsWe measured the effect of oviposition on larval feeding and pupa formation and evaluated its influence on plant phytohormones and volatile emission profile.ResultsWe showed that oviposition reduced neonate larval growth and increased the proportion of prepupae that delayed their transition to pupae, thus extending the length of the sawfly cocoon phase. Oviposited willows increased jasmonic acid levels and changed their volatile profile through enhanced concentrations of the terpenoids, (E/E)-α-farnesene, (Z)- and (E)-β-ocimene. Volatile profiles were characteristic for each type of insect damage (oviposition vs. feeding), but no priming effect was found.DiscussionWe demonstrated that willows could perceive sawfly oviposition per se as a primary factor activating defense signaling via the jasmonic acid pathway. This induced response ultimately determined changes in pupation dynamics that may affect the whole insect population cycle.

Abstract Most biological sensors preferentially encode changes in a stimulus rather than the steady components. However, intrinsically phasic artificial mechanoreceptors have not yet been described. We constructed a phasic mechanoreceptor by encapsulating carbon nanotube film in a viscoelastic matrix supported by a rigid substrate. When stimulated by a spherical indenter the sensor response resembled the response of fast-adapting mammalian mechanoreceptors. We modelled these sensors from the properties of percolating conductive networks combined with nonlinear contact mechanics and discussed the implications of this finding.

Purpose The aim of this study was to assess the performance of a mobile acoustic Uroflowmetry (UFM) application compared with standard UFM in the pediatric population. Methods A mobile acoustic UFM application represents a noninvasive method to estimate the urine flow rate by recording voiding sounds with a smartphone. Male pediatric patients who were undergoing UFM testing were prospectively recruited, and the voiding sounds were recorded and analyzed. The intraclass correlation coefficient (ICC) was used to compare the maximum flow rate (Qmax), average flow rate (Qavg), voiding time (VT), and voiding volume (VV) as estimated by acoustic UFM with those calculated by standard UFM. Differences in Qmax, Qavg, VT, and VV between the 2 UFM tests were determined using 95% Bland-Altman limits of agreement. Results A total of 16 male patients were evaluated. Their median age was 9 years. With standard UFM, the median Qmax, Qavg, VT, and VV were 18.7 mL/sec, 11.1 mL/sec, 15.2 seconds, and 157.8 mL, respectively. Strong correlations were observed between the 2 methods for Qmax (ICC=0.755, P=0.005), VT (ICC=0.974, P

Abstract The aim of this standard operational procedure is to standardize the methodology employed for the evaluation of pre- and post-treatment absorbed dose calculations in 90Y microsphere liver radioembolization. Basic assumptions include the permanent trapping of microspheres, the local energy deposition method for voxel dosimetry, and the patient–relative calibration method for activity quantification.The identity of 99mTc albumin macro-aggregates (MAA) and 90Y microsphere biodistribution is also assumed. The large observed discrepancies in some patients between 99mTc-MAA predictions and actual 90Y microsphere distributions for lesions is discussed. Absorbed dose predictions to whole non-tumoural liver are considered more reliable and the basic predictors of toxicity. Treatment planning based on mean absorbed dose delivered to the whole non-tumoural liver is advised, except in super-selective treatments. Given the potential mismatch between MAA simulation and actual therapy, absorbed doses should be calculated both pre- and post-therapy. Distinct evaluation between target tumours and non-tumoural tissue, including lungs in cases of lung shunt, are vital for proper optimization of therapy. Dosimetry should be performed first according to a mean absorbed dose approach, with an optional, but important, voxel level evaluation. Fully corrected 99mTc-MAA Single Photon Emission Computed Tomography (SPECT)/computed tomography (CT) and 90Y TOF PET/CT are regarded as optimal acquisition methodologies, but, for institutes where SPECT/CT is not available, non-attenuation corrected 99mTc-MAA SPECT may be used. This offers better planning quality than non dosimetric methods such as Body Surface Area (BSA) or mono-compartmental dosimetry. Quantitative 90Y bremsstrahlung SPECT can be used if dedicated correction methods are available. The proposed methodology is feasible with standard camera software and a spreadsheet. Available commercial or free software can help facilitate the process and improve calculation time.

Abstract Background Optimizing patients’ total hip and knee arthroplasty (THA/TKA) experience is as crucial for providing high quality care as improving safety and clinical effectiveness. Yet, little evidence is available on patient experience in standard-inpatient and enhanced recovery after surgery (ERAS)-outpatient programs. Therefore, this study aimed to gain a more in-depth understanding of the patient experience of ERAS-outpatient programs in comparison to standard-inpatient programs. Methods We conducted a convergent mixed methods study of 48 consecutive patients who experienced both standard-inpatient and ERAS-outpatient THA/TKA contralaterally. A reflective thematic analysis was conducted based on data collected via a questionnaire. Bivariate correlations between the patient experience and patients’ characteristics, clinical outcomes and care components satisfaction were performed. Then, the quantitative and qualitative data were integrated together. Results The theme Support makes the difference for better and for worse was identified by patients as crucial to their experience in both joint replacement programs. On the other hand, patients identified 3 themes distinguishing their ERAS-outpatient from their standard-inpatient experience: 1) Minimizing inconvenience, 2) Home sweet home and 3) Returning to normal function and activities. Potential optimization expressed by patients were to receive more preoperative information, additional postoperative rehabilitation sessions, and ensuring better coherence of care between hospital and home care teams. Weak to moderate positive and statistically significant correlations were found between patients’ THA/TKA experience and satisfaction with pain management, hospital stay, postoperative recovery, home care, and overall results (rs = + [0.36–0.66], p-value

Introducción: La caries dental es una enfermedad que afecta a gran parte de la población mundial por lo que una vacuna para combatirla es el objetivo de este siglo, muchos investigadores están trabajando en vacunas de ADN con adyuvantes como: péptidos sintéticos, con subunidades no tóxicas de E. coli, con liposomas, microcápsulas y micropartículas, vacunas recombinadas; que prometen excelentes resultados en ensayos clínicos. Objetivo: Efectuar una descripción general de la evidencia disponible sobre la efectividad de las vacunas contra la caries dental. Datos: La búsqueda inicial abarcó 1988 artículos, de los cuales se seleccionaron 23 para esta revisión, distribuidos 65.21% en Asia, 26.08% en Norteamérica, el 4.34% en Europa, 4.34% en Sudamérica. Fuentes: Se realizó una extensa búsqueda electrónica en las bases de datos: Pubmed, Proquest, Sage Journals, Ovid, Science Direct, Epistemonikos, Medline, Google Scholar, Cochrane, Scopus, Taylor and Francis online, Web of Science, Base, Springer, Research gate, Healey Library, Lilacs, Redalyc, Scielo, Dialnet Conclusión: existen varias investigaciones realizadas que han brindado “potenciales” vacunas contra la caries dental, han demostrado eficacia inmunitaria mediante ensayos clínicos en ratones de laboratorio arrojando resultados prometedores, gran capacidad de producir respuestas inmunitarias, se ha puesto énfasis especial en la administración intranasal por sus beneficios y mínima citotoxicidad, sin embargo, existe escasa información referente a pruebas en humanos por lo que se debe redirigir esfuerzos y recursos en la búsqueda de la inmunización contra la caries dental. Palabras clave: Dental caries, Dental decay, Anti-caries, Vaccine, Immunization.

Background Studies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.Methods In protocol I, 10 lean, healthy individuals received the following 72-hour i.v. infusions in a randomized crossover design: saline (30 mL/h) plus vehicle; Intralipid (30 mL/h) plus vehicle; or Intralipid (30 mL/h) plus eritoran (12 mg i.v. every 12 hours). In protocol II, also a randomized crossover design, 9 nondiabetic individuals with obesity received eritoran or vehicle for 72 hours. The effect of eritoran was assessed with euglycemic hyperinsulinemic clamps.Results In protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG) concentrations, fasting plasma insulin (FPI) concentrations, and the homeostatic model assessment of insulin resistance (HOMA-IR) index by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations of these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in individuals with obesity and insulin resistance (protocol II).Conclusions Acute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 in metabolic dysfunction in humans.Trial registration ClinicalTrials.gov NCT02321111 and NCT02267317.Funding NIH grants R01DK080157, P30AG044271, P30AG013319, and UL1TR002645.

Summary: Ant-plant defensive mutualism is a widely studied phenomenon, where ants protect their host plants (myrmecophytes) against herbivores in return for the provision of nesting sites and food. However, few studies addressed the influence of ant colonization and herbivory on the plant’s metabolism. We chose the Amazonian plant Tococa quadrialata, living in association with Azteca cf. tonduzi ants for an ant-exclusion study to reveal the chemistry behind this symbiosis. We found that colonized plants did not only benefit from protection but also from increased amino acid and nitrogen content, enabling better performance even in an herbivore-free environment. In contrast, ant-deprived T. quadrialata plants accumulated more ellagitannins, a major class of constitutive defense compounds. Moreover, herbivory-induced jasmonate-mediated defense responses, including the upregulation of signaling and defense genes and the emission of volatiles irrespective of colonization status. Altogether, we show how ant-colonization can influence the general and defense-related metabolism and performance of myrmecophytes.

Abstract Savannas are characterized by the coexistence of grasses and trees. Fires are critical for their coexistence, because they decrease the survival of tree seedlings and saplings and their recruitment to the adult stage. In some humid savannas, perennial grasses inhibit nitrification and trees stimulate nitrification, which likely favors coexistence between trees and grasses. However, fires may influence plant capacity to control nitrogen cycling, which could subsequently influence tree–grass coexistence and savanna nitrogen budget. Therefore, we sampled soil in a humid savanna of Ivory Coast under the dominant nitrification‐inhibiting grass species and the dominant nitrification‐stimulating tree species and under bare soil before and after (i.e., 5 days) fire during the long dry season. We quantified the total microbial and nitrifier abundances and transcriptional activities and the nitrification enzyme activity. Fire decreased soil water content, probably by increasing evaporation and, maybe, by triggering the growth of grasses, and increased soil ammonium availability likely due to ash deposition and increased mineralization. Fire did not impact the total archaeal, bacterial, or fungal abundances, or that of the nitrifiers. Fire did not impact archaeal transcriptional activity and increased bacterial and fungal total transcriptional activities. In contrast, fire decreased the archaeal nitrifier transcriptional activities and the nitrification enzymatic activity, likely due to the often reported resumption of the growth of nitrification‐inhibiting grasses quickly after the fire (and the subsequent increase in root exudation). These results pave the way for a better understanding of the short‐term effects of fire on nitrogen cycling and tree–grass competition for nitrogen.

Plant volatiles play a major role in plant–insect interactions as defense compounds or attractants for insect herbivores. Recent studies have shown that endophytic fungi are also able to produce volatiles and this raises the question of whether these fungal volatiles influence plant–insect interactions. Here, we qualitatively investigated the volatiles released from 13 endophytic fungal species isolated from leaves of mature black poplar (Populus nigra) trees. The volatile blends of these endophytes grown on agar medium consist of typical fungal compounds, including aliphatic alcohols, ketones and esters, the aromatic alcohol 2-phenylethanol and various sesquiterpenes. Some of the compounds were previously reported as constituents of the poplar volatile blend. For one endophyte, a species of Cladosporium, we isolated and characterized two sesquiterpene synthases that can produce a number of mono- and sesquiterpenes like (E)-β-ocimene and (E)-β-caryophyllene, compounds that are dominant components of the herbivore-induced volatile bouquet of black poplar trees. As several of the fungus-derived volatiles like 2-phenylethanol, 3-methyl-1-butanol and the sesquiterpene (E)-β-caryophyllene, are known to play a role in direct and indirect plant defense, the emission of volatiles from endophytic microbial species should be considered in future studies investigating tree-insect interactions.