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Introducción: El síndrome del músculo piramidal constituye el conjunto de signos y síntomas originados por la compresión del nervio ciático en su salida de la pelvis a través del canal situado entre el músculo piramidal y el gémino superior. Se presenta una serie de casos de pacientes oncológicos con este síndrome con el objetivo de describir el resultado terapéutico de la infiltración con esteroides en el músculo piramidal sin hidrodisección perineural del ciático. Métodos: Se realizó un estudio prospectivo de 10 casos, evaluados entre Febrero de 2014 y Mayo del 2015, en el servicio de dolor y cuidados paliativos del Instituto Oncológico Nacional “Dr. Juan Tanca Marengo”-Solca-Guayaquil. Ingresaron al estudio pacientes con cáncer de cualquier etiología y criterios diagnósticos de síndrome piramidal. Los pacientes fueron tratados con infiltraciones de corticoides sin hidrodisección perineural del ciático, dirigidas por ultrasonido del músculo piramidal afecto y terapia física. Resultados: Se incluyen 10 casos de pacientes con síndrome piramidal (9 mujeres). Con rangos de edad que entre 50 y 70 años. El lado afectado con mayor frecuencia fue el derecho en 5 casos. En 8 casos la Resonancia magnética fue normal y en 2 casos se describió hipertrofia muscular. El procedimiento de infiltración se realizó sin complicaciones y los pacientes recibieron adicionalmente fisioterapia. El EVA inicial fue > 6 en 8 pacientes y 2 casos con EVA de 5. Los pacientes tuvieron una limitación funcional de un 10-20 %. El EVA postbloqueo disminuyó hasta 0-1 en todos los casos. Conclusión: En la presente serie de casos el síndrome piramidal fue controlado satisfactoriamente con infiltración de esteroides sin hidrodisección perineural del ciático y terapia física.

Mount Makiling Forest Reserve (MMFR) supports the water requirements of many towns in its periphery. One of the towns that benefit from the forest reserve is Calamba City, known for its resort-based tourism. The number of resorts in Calamba has significantly increased from 193 in 1998 to 466 in 2014 which has an implication on water consumption on which one of the initial steps in the monitoring aspect is the determination of its spatial distribution. Therefore, this study aims to determine and analyze the spatial distribution of resorts in Calamba City using Geographic Information System (GIS) to generate a distribution map of all the operating resorts showing the hotspots and clustering of resorts. The study recorded 852 resorts in Calamba City. The dense resort areas and the most significant hot spot area are located at Miramonte Village (Purok 6) and Purok 5 of Barangay Pansol. The result indicates a concentration of resorts in certain regions which raised concerns and should further be studied in terms of sustainable water use and environmental impact. The baseline data generated by this study will supplement the existing data of Calamba City on its resorts and help the local government in formulating effective land use and water extraction policies for the resort-based industry for a more sustainable management and conservation.

Abstract Dietary supplementation with triglyceride tributyrin (TBT), a butyrate precursor, has been associated with beneficial effects on fish health and improvements in the ability of carnivorous fish to tolerate higher levels of plant-based protein. In this study, we aimed to investigate the effects of a plant-based diet supplemented with TBT on the structural diversity and putative function of the digesta-associated bacterial communities of rainbow trout (Oncorhynchus mykiss). In addition to this, we also assessed the response of fish gut digestive enzyme activities and chyme metabolic profile in response to TBT supplementation. Our results indicated that TBT had no significant effects on the overall fish gut bacterial communities, digestive enzyme activities or metabolic profile when compared with non-supplemented controls. However, a more in-depth analysis into the most abundant taxa showed that diets at the highest TBT concentrations (0.2% and 0.4%) selectively inhibited members of the Enterobacterales order and reduced the relative abundance of a bacterial population related to Klebsiella pneumoniae, a potential fish pathogen. Furthermore, the predicted functional analysis of the bacterial communities indicated that increased levels of TBT were associated with depleted KEGG pathways related to pathogenesis. The specific effects of TBT on gut bacterial communities observed here are intriguing and encourage further studies to investigate the potential of this triglyceride to promote pathogen suppression in the fish gut environment, namely in the context of aquaculture.

Abstract Background Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. Methods Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. Results In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. Conclusions Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.

Although Gallium Nitride (GaN) Field Effect Transistor (FET) devices have found extensive application in DC-DC converters, their utilization in inverter motor drives remains an evolving area of study. In particular, the intricacies of reverse conduction operation during the dead time, specific to GaN FETs, require in-depth exploration for inverters supplying AC currents to electrical motors. Therefore, this paper undertakes an assessment of reverse conduction during the dead time intervals in low-voltage GaN FETs employed in motor drives applications. This analysis provides correlations between device technology attributes and the variations in AC phase current. To facilitate this investigation, a dedicated numerical tool is developed to evaluate the reverse conduction characteristics of GaN FET and associated power losses. Furthermore, this study includes a comparative analysis of the reverse conduction behavior of GaN FET devices with their low-voltage MOSFET counterparts, taking into account their differing static and dynamic characteristics. As a result, the main contribution of this work is to provide to the inverter designers a comprehensive understanding of dead-time effects in GaN-based inverters, along with guidance on selecting and optimizing dead time intervals within inverter legs for motor control applications employing the latest generation of GaN FET devices.

Reactive oxygen and nitrogen species (ROS and RNS) include two families of molecules that, in recent years, have been shown to be involved in a wide range of biological functions, such as seed and pollen germination, the development and regulation of root architecture, stomatal movement, senescence, flowering, and fruit formation and ripening [...]

El artículo analiza la intervención llevada a cabo en el alcázar del conjunto fortificado de La Guardia, de origen islámico, con sucesivas trasformaciones en época cristiana y en el periodo renacentista, en el que cambia su uso a residencia señorial. Después de un periodo de intervenciones inconexas con criterios dispares, algunas de ellas sin acabar, el castillo se encontraba sin uso y con difícil acceso por sus condiciones de mantenimiento. La intervención se ha basado en la conservación de lo existente, poniendo en valor su compleja estratificación, consecuencia de las diversas mutaciones, añadidos y superposiciones históricas, y a la vez en la adecuación de espacios y recuperación de accesos y recorridos para permitir su uso cultural, compatible con la visita turística.

Abstract Caturoidea is a clade of Mesozoic predatory ray-finned fishes which lived mainly in the Jurassic. The clade has a few records in the earliest Cretaceous and only two in the Triassic. Among the latter, specimen MPCA 632 Caturus sp. doubtfully from continental Early Triassic of Argentina, i.e., outside Europe, was particularly problematic in the light of the known fossil record of the group, which suggested their origin in the Western Tethys. The micropaleontological and geochemical analysis of bulk-rock samples of MPCA 632 allowed us to correct the provenance of the specimen which corresponds to Tithonian marine outcrops of the Vaca Muerta Formation, Neuquén, Argentina. Specimen MPCA 632 is excluded from Caturus and reclassified as Caturoidea sp. MPCA 632 might be a specimen of Catutoichthys olsacheri, the only caturoid known from the Vaca Muerta Formation (Los Catutos Member), but the fossils are not comparable and, thus, this hypothesis needs further study. Additionally, the first-hand study of the type material of the only other alleged Triassic caturoid, Furo insignis, in the Norian of Seefeld, Austria, led to the exclusion of this taxon from the Caturoidea. Consequently, the clade Caturoidea is restricted to the Jurassic–Lowest Cretaceous. After a modest evolution during the Early Jurassic, the group had its initial radiation and westward dispersion across the Hispanic Corridor during the Middle Jurassic and reached its maximal diversity during the Kimmeridgian and Tithonian.

Objetivo: Describir el uso de la terapia de presión negativa con (TPNi) y sin instilación (TPNs) como tratamiento adyuvante en el manejo de infecciones asociadas a dispositivo ortopédico (IADO). Método: Estudio observacional analítico de expedientes de pacientes con IADO manejados con TPNi y TPNs con solución salina al 0.9%, mayores de 18 años, operados en el periodo 2018-2021. Se evaluaron las características clínicas de infección, el agente infeccioso y las variables sociodemográficas. La TPN se realizó con sistema V.A.C.VERAFLO™. Para los análisis se emplearon las pruebas χ2, Fisher y t de Student. Valor estadísticamente aceptado: p < 0.05. Resultados: La muestra fue de 40 pacientes, el 75% masculinos. Fracturas: 42.5% expuestas y 57.5% cerradas. En el 92.5% se aplicó antibiótico profiláctico (30-120 min). Implantes: 35% placas, 12.5% clavo centromedular, 10% prótesis de rodilla y 12.5% cadera. El 47.5% con sangrado < 500 ml. En el 72.5% un tiempo quirúrgico de 2-4 horas. Tiempo de hospitalización previa: TPNs 3 semanas 55.9% y 4 semanas 26.5%; TPNi 3 semanas 50% y 4 semanas 33.3%. Conservación del implante: 73.5% TPNs y 50% TPNi (p = 0.341). Cierre de herida: 91.2% con TPNs y 100% con TPNi (p = 1.000). Conclusiones: El uso de TPNs y TPNi fue útil como tratamiento adyuvante en IADO, y además permitieron conservar el implante y el cierre de la herida en la mayoría de los pacientes.

In higher plants, hydrogen sulfide (H2S) is a recognized signaling molecule that performs multiple regulatory functions. The enzyme L-cysteine desulfhydrase (LCD) catalyzes the conversion of L-cysteine (L-Cys) to pyruvate and ammonium with the concomitant generation of H₂S, and it is considered one of the main sources of H2S in plants. Using non-denaturing polyacrylamide gel electrophoresis (PAGE) in combination with a specific assay for LCD activity, this study aims to identify the potential LCD isozymes in wild-type Arabidopsis thaliana seedlings of 16 days old grown under in vitro conditions, and to evaluate the potential impact of nitric oxide (NO) and H2S on these LCD isozymes. For this purpose, an Atnoa1 mutant characterized to have a low endogenous NO content as well as the exogenous application of H2S were used. Five LCD isozymes were detected, with LCD IV being the isozyme that has the highest activity. However, the LCD V activity was the only one that was positively modulated in the Atnoa1 mutants and by exogenous H2S. To our knowledge, this is the first report showing the different LCD isozymes present in Arabidopsis seedlings and how their activity is affected by NO and H2S content.

Abstract Quantum extreme learning machines (QELMs) aim to efficiently post-process the outcome of fixed — generally uncalibrated — quantum devices to solve tasks such as the estimation of the properties of quantum states. The characterisation of their potential and limitations, which is currently lacking, will enable the full deployment of such approaches to problems of system identification, device performance optimization, and state or process reconstruction. We present a framework to model QELMs, showing that they can be concisely described via single effective measurements, and provide an explicit characterisation of the information exactly retrievable with such protocols. We furthermore find a close analogy between the training process of QELMs and that of reconstructing the effective measurement characterising the given device. Our analysis paves the way to a more thorough understanding of the capabilities and limitations of QELMs, and has the potential to become a powerful measurement paradigm for quantum state estimation that is more resilient to noise and imperfections.

Abstract Background While others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group of seropositive health care workers who were missed by daily symptom screening that was instituted prior to any epidemiologically significant local outbreak. Given that most health care facilities rely on daily symptom screening as the primary method to identify SARS-CoV-2 among health care workers, here, we aim to determine how demographic, occupational, and clinical variables influence SARS-CoV-2 seropositivity among health care workers. Methods We designed a cross-sectional survey of HCWs for SARS-CoV-2 seropositivity conducted from May 15th to June 30th 2020 at a 418-bed academic hospital in Orange County, California. From an eligible population of 5,349 HCWs, study participants were recruited in two ways: an open cohort, and a targeted cohort. The open cohort was open to anyone, whereas the targeted cohort that recruited HCWs previously screened for COVID-19 or work in high-risk units. A total of 1,557 HCWs completed the survey and provided specimens, including 1,044 in the open cohort and 513 in the targeted cohort. Demographic, occupational, and clinical variables were surveyed electronically. SARS-CoV-2 seropositivity was assessed using a coronavirus antigen microarray (CoVAM), which measures antibodies against eleven viral antigens to identify prior infection with 98% specificity and 93% sensitivity. Results Among tested HCWs (n = 1,557), SARS-CoV-2 seropositivity was 10.8%, and risk factors included male gender (OR 1.48, 95% CI 1.05–2.06), exposure to COVID-19 outside of work (2.29, 1.14–4.29), working in food or environmental services (4.85, 1.51–14.85), and working in COVID-19 units (ICU: 2.28, 1.29–3.96; ward: 1.59, 1.01–2.48). Amongst 1,103 HCWs not previously screened, seropositivity was 8.0%, and additional risk factors included younger age (1.57, 1.00-2.45) and working in administration (2.69, 1.10–7.10). Conclusion SARS-CoV-2 seropositivity is significantly higher than reported case counts even among HCWs who are meticulously screened. Seropositive HCWs missed by screening were more likely to be younger, work outside direct patient care, or have exposure outside of work.

Protein persulfidation is a thiol-based oxidative posttranslational modification (oxiPTM) that involves the modification of susceptible cysteine thiol groups present in peptides and proteins through hydrogen sulfide (H2S), thus affecting their function. Using sweet pepper (Capsicum annuum L.) fruits as a model material at different stages of ripening (immature green and ripe red), endogenous persulfidated proteins (persulfidome) were labeled using the dimedone switch method and identified using liquid chromatography and mass spectrometry analysis (LC-MS/MS). A total of 891 persulfidated proteins were found in pepper fruits, either immature green or ripe red. Among these, 370 proteins were exclusively present in green pepper, 237 proteins were exclusively present in red pepper, and 284 proteins were shared between both stages of ripening. A comparative analysis of the pepper persulfidome with that described in Arabidopsis leaves allowed the identification of 25% of common proteins. Among these proteins, glutathione reductase (GR) and leucine aminopeptidase (LAP) were selected to evaluate the effect of persulfidation using an in vitro approach. GR activity was unaffected, whereas LAP activity increased by 3-fold after persulfidation. Furthermore, this effect was reverted through treatment with dithiothreitol (DTT). To our knowledge, this is the first persulfidome described in fruits, which opens new avenues to study H2S metabolism. Additionally, the results obtained lead us to hypothesize that LAP could be involved in glutathione (GSH) recycling in pepper fruits.

Editorial

Abstract Cells have evolved their communication methods to sense their microenvironments and send biological signals. In addition to communication using ligands and receptors, cells use diverse channels including gap junctions to communicate with their immediate neighbors. Current approaches, however, cannot effectively capture the influence of various microenvironments. Here, we propose a novel approach to investigate cell neighbor‐dependent gene expression (CellNeighborEX) in spatial transcriptomics (ST) data. To categorize cells based on their microenvironment, CellNeighborEX uses direct cell location or the mixture of transcriptome from multiple cells depending on ST technologies. For each cell type, CellNeighborEX identifies diverse gene sets associated with partnering cell types, providing further insight. We found that cells express different genes depending on their neighboring cell types in various tissues including mouse embryos, brain, and liver cancer. Those genes are associated with critical biological processes such as development or metastases. We further validated that gene expression is induced by neighboring partners via spatial visualization. The neighbor‐dependent gene expression suggests new potential genes involved in cell–cell interactions beyond what ligand‐receptor co‐expression can discover.

Abstract Background COVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features. Methods We measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients. Results We identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers. Conclusions This study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.

Abstract Background Cone contrast threshold testing (CCT) provides quantitative measurements of color and contrast function to reveal changes in vision quality that are not standard endpoints in clinical trials. We utilize CCT to measure visual function in patients with multiple sclerosis (MS), age-related macular degeneration (AMD), epiretinal membrane (ERM), and retinal vein occlusion (RVO). Methods Retrospective data was gathered from 237 patients of the Gavin Herbert Eye Institute. Subjects included 17 patients with MS, 45 patients with AMD, 41 patients with ERM, 11 patients with RVO, and 123 healthy controls. Patients underwent the primary measurement outcome, CCT testing, as well as Sloan visual acuity test and spectral domain optical coherence tomography during normal care. Results Color and contrast deficits were present in MS patients regardless of history of optic neuritis. AMD with intermediate or worse disease demonstrated reduced CCT scores. All 3 stages of ERM demonstrated cone contrast deficits. Despite restoration of visual acuity, RVO-affected eyes demonstrated poorer CCT performance than unaffected fellow eyes. Conclusions CCT demonstrates color and contrast deficits for multiple retinal diseases with differing pathophysiology. Further prospective studies of CCT in other disease states and with larger samples sizes is warranted.

Abstract Background The opportunistic pathogen Staphylococcus aureus is an asymptomatically carried member of the microbiome of about one third of the human population at any given point in time. Body sites known to harbor S. aureus are the skin, nasopharynx, and gut. In particular, the mechanisms allowing S. aureus to pass the gut epithelial barrier and to invade the bloodstream were so far poorly understood. Therefore, the objective of our present study was to investigate the extent to which genetic differences between enteric S. aureus isolates and isolates that caused serious bloodstream infections contribute to the likelihood of invasive disease. Results Here, we present genome-wide association studies (GWAS) that compare the genome sequences of 69 S. aureus isolates from enteric carriage by healthy volunteers and 95 isolates from bloodstream infections. We complement our GWAS results with a detailed characterization of the cellular and extracellular proteomes of the representative gut and bloodstream isolates, and by assaying the virulence of these isolates with infection models based on human gut epithelial cells, human blood cells, and a small animal infection model. Intriguingly, our results show that enteric and bloodstream isolates with the same sequence type (ST1 or ST5) are very similar to each other at the genomic and proteomic levels. Nonetheless, bloodstream isolates are not necessarily associated with an invasive profile. Furthermore, we show that the main decisive factor preventing infection of gut epithelial cells in vitro is the presence of a tight barrier. Conclusions Our data show that virulence is a highly variable trait, even within a single clone. Importantly, however, there is no evidence that blood stream isolates possess a higher virulence potential than those from the enteric carriage. In fact, some gut isolates from healthy carriers were more virulent than bloodstream isolates. Based on our present observations, we propose that the integrity of the gut epithelial layer, rather than the pathogenic potential of the investigated enteric S. aureus isolates, determines whether staphylococci from the gut microbiome will become invasive pathogens. Video Abstract

Introduction: To understand the sick leave situation and the causes and effects of a temporary loss of capacity to work allows for the strengthening of policies and management in the provision of health services. Objective: To analyze sick leave in Colombia in the 2016–2018 period. Materials and methods: A retrospective cross-sectional observational study and the relative risk was calculated. Sick leave reports were provided by the Ministry of Health and Social Protection. 12,410,837 reports from formal workers between the ages of 18–70 years and had at least one temporary disability were processed. Results: The average age of people with sick leave was 37.11 years, 53% corresponding to females. On average, sick leave was 90.6% and 5.6% for dependent and independent workers, respectively. The principal causes of disability were musculoskeletal diseases and were more likely in men and adults according to RR. Men in comparison to females and adults in comparison to youths are less likely to have sick leave due to respiratory disease. Conclusions: In Colombia, females presented more temporary sick leave, even if males had more days of disability, even though the median was three days in both genders. Youth and adults had more sick leave days.

Adolescent tobacco use (particularly vaping) and co-use of cannabis and tobacco have increased, leading some jurisdictions to implement policies intended to reduce youth access to these products; however, their impacts remain unclear. We examine associations between local policy, density of tobacco, vape, and cannabis retailers around schools, and adolescent use and co-use of tobacco/vape and cannabis.We combined 2018 statewide California (US) data on: (a) jurisdiction-level policies related to tobacco and cannabis retail environments, (b) jurisdiction-level sociodemographic composition, (c) retailer locations (tobacco, vape, and cannabis shops), and (d) survey data on 534,176 middle and high school students (California Healthy Kids Survey). Structural equation models examined how local policies and retailer density near schools are associated with frequency of past 30-day cigarette smoking or vaping, cannabis use, and co-use of tobacco/vape and cannabis, controlling for jurisdiction-, school-, and individual-level confounders.Stricter retail environment policies were associated with lower odds of past-month use of tobacco/vape, cannabis, and co-use of tobacco/vape and cannabis. Stronger tobacco/vape policies were associated with higher tobacco/vape retailer density near schools, while stronger cannabis policies and overall policy strength (tobacco/vape and cannabis combined) were associated with lower cannabis and combined retailer densities (summed tobacco/vape and cannabis), respectively. Tobacco/vape shop density near schools was positively associated with tobacco/vape use odds, as was summed retailer density near schools and co-use of tobacco, cannabis.Considering jurisdiction-level tobacco and cannabis control policies are associated with adolescent use of these substances, policymakers may proactively leverage such policies to curb youth tobacco and cannabis use.

IntroductionIn the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination.MethodsTo characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. ResultsThe primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine based on the original Wuhan strain generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the vaccine strain. Despite waning antibody levels, neutralization activity against the vaccine strain is maintained throughout the 6-month period. DiscussionIn the context of recurrent surges of SARS-CoV-2 infections, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

Copyright of Acta Ortopédica Mexicana is the property of Sociedad Mexicana de Ortopedia, AC and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Acta Ortopédica Mexicana is the property of Sociedad Mexicana de Ortopedia, AC and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The majority of natural products utilized to treat a diverse array of human conditions and diseases are derived from terrestrial sources. In recent years, marine ecosystems have proven to be a valuable resource of diverse natural products that are generated to defend and support their growth. Such marine sources offer a large opportunity for the identification of novel compounds that may guide the future development of new drugs and therapies. Using the National Oceanic and Atmospheric Administration (NOAA) portal, we explore deep-sea coral and sponge species inhabiting a segment of the U.S. Exclusive Economic Zone, specifically off the western coast of Florida. This area spans ~100,000 km2, containing coral and sponge species at sea depths up to 3000 m. Utilizing PubMed, we uncovered current knowledge on and gaps across a subset of these sessile organisms with regards to their natural products and mechanisms of altering cytoskeleton, protein trafficking, and signaling pathways. Since the exploitation of such marine organisms could disrupt the marine ecosystem leading to supply issues that would limit the quantities of bioactive compounds, we surveyed methods and technological advances that are necessary for sustaining the drug discovery pipeline including in vitro aquaculture systems and preserving our natural ecological community in the future. Collectively, our efforts establish the foundation for supporting future research on the identification of marine-based natural products and their mechanism of action to develop novel drugs and therapies for improving treatment regimens of human conditions and diseases.

We provide a new perspective on shadow tomography by demonstrating its deep connections with the general theory of measurement frames. By showing that the formalism of measurement frames offers a natural framework for shadow tomography—in which “classical shadows” correspond to unbiased estimators derived from a suitable dual frame associated with the given measurement—we highlight the intrinsic connection between standard state tomography and shadow tomography. Such a perspective allows us to examine the interplay between measurements, reconstructed observables, and the estimators used to process measurement outcomes, while paving the way to assessing the influence of the input state and the dimension of the underlying space on estimation errors. Our approach generalizes the method described by Huang et al. [H.-Y. Huang et al., Nat. Phys. 16, 1050 (2020)], whose results are recovered in the special case of covariant measurement frames. As an application, we demonstrate that a sought-after target of shadow tomography can be achieved for the entire class of tight rank-1 measurement frames—namely, that it is possible to accurately estimate a finite set of generic rank-1 bounded observables while avoiding the growth of the number of the required samples with the state dimension.

Abstract Risk stratification of COVID‐19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe‐Lose, can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe‐Lose gene expression can outperform conventional methods in predicting outcomes (e.g., death and hospitalization) in COVID‐19 patients. We performed a post‐mortem examination of infected lung tissue in deceased COVID‐19 patients to determine hFwe‐Lose’s biological role in acute lung injury. We then performed an observational study (n = 283) to evaluate whether hFwe‐Lose expression (in nasopharyngeal samples) could accurately predict hospitalization or death in COVID‐19 patients. In COVID‐19 patients with acute lung injury, hFwe‐Lose is highly expressed in the lower respiratory tract and is co‐localized to areas of cell death. In patients presenting in the early phase of COVID‐19 illness, hFwe‐Lose expression accurately predicts subsequent hospitalization or death with positive predictive values of 87.8–100% and a negative predictive value of 64.1–93.2%. hFwe‐Lose outperforms conventional inflammatory biomarkers and patient age and comorbidities, with an area under the receiver operating characteristic curve (AUROC) 0.93–0.97 in predicting hospitalization/death. Specifically, this is significantly higher than the prognostic value of combining biomarkers (serum ferritin, D‐dimer, C‐reactive protein, and neutrophil–lymphocyte ratio), patient age and comorbidities (AUROC of 0.67–0.92). The cell fitness marker, hFwe‐Lose, accurately predicts outcomes in COVID‐19 patients. This finding demonstrates how tissue fitness pathways dictate the response to infection and disease and their utility in managing the current COVID‐19 pandemic.

CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.

Pepper (Capsicum annuum L.) fruit is a horticultural product consumed worldwide which has great nutritional and economic relevance. Besides the phenotypical changes that pepper fruit undergo during ripening, there are many associated modifications at transcriptomic, proteomic, biochemical, and metabolic levels. Nitric oxide (NO) is a recognized signal molecule that can exert regulatory functions in diverse plant processes including fruit ripening, but the relevance of NADPH as a fingerprinting of the crop physiology including ripening has also been proposed. Glucose-6-phosphate dehydrogenase (G6PDH) is the first and rate-limiting enzyme of the oxidative phase of the pentose phosphate pathway (oxiPPP) with the capacity to generate NADPH. Thus far, the available information on G6PDH and other NADPH-generating enzymatic systems in pepper plants, and their expression during the ripening of sweet pepper fruit, is very scarce. Therefore, an analysis at the transcriptomic, molecular and functional levels of the G6PDH system has been accomplished in this work for the first time. Based on a data-mining approach to the pepper genome and fruit transcriptome (RNA-seq), four G6PDH genes were identified in pepper plants and designated CaG6PDH1 to CaG6PDH4, with all of them also being expressed in fruits. While CaG6PDH1 encodes a cytosolic isozyme, the other genes code for plastid isozymes. The time-course expression analysis of these CaG6PDH genes during different fruit ripening stages, including green immature (G), breaking point (BP), and red ripe (R), showed that they were differentially modulated. Thus, while CaG6PDH2 and CaG6PDH4 were upregulated at ripening, CaG6PDH1 was downregulated, and CaG6PDH3 was slightly affected. Exogenous treatment of fruits with NO gas triggered the downregulation of CaG6PDH2, whereas the other genes were positively regulated. In-gel analysis using non-denaturing PAGE of a 50–75% ammonium-sulfate-enriched protein fraction from pepper fruits allowed for identifying two isozymes designated CaG6PDH I and CaG6PDH II, according to their electrophoretic mobility. In order to test the potential modulation of such pepper G6PDH isozymes, in vitro analyses of green pepper fruit samples in the presence of different compounds including NO donors (S-nitrosoglutathione and nitrosocysteine), peroxynitrite (ONOO−), a hydrogen sulfide (H2S) donor (NaHS, sodium hydrosulfide), and reducing agents such as reduced glutathione (GSH) and L-cysteine (L-Cys) were assayed. While peroxynitrite and the reducing compounds provoked a partial inhibition of one or both isoenzymes, NaHS exerted 100% inhibition of the two CaG6PDHs. Taken together these data provide the first data on the modulation of CaG6PDHs at gene and activity levels which occur in pepper fruit during ripening and after NO post-harvest treatment. As a consequence, this phenomenon may influence the NADPH availability for the redox homeostasis of the fruit and balance its active nitro-oxidative metabolism throughout the ripening process.

Cancer is considered one of the main causes of human death worldwide, being characterized by an alteration of the oxidative metabolism. Many natural compounds from plant origin with anti-tumor attributes have been described. Among them, capsaicin, which is the molecule responsible for the pungency in hot pepper fruits, has been reported to show antioxidant, anti-inflammatory, and analgesic activities, as well as anti-proliferative properties against cancer. Thus, in this work, the potential anti-proliferative activity of pepper (Capsicum annuum L.) fruits from diverse varieties with different capsaicin contents (California < Piquillo < Padrón < Alegría riojana) against several tumor cell lines (lung, melanoma, hepatoma, colon, breast, pancreas, and prostate) has been investigated. The results showed that the capsaicin content in pepper fruits did not correspond with their anti-proliferative activity against tumor cell lines. By contrast, the greatest activity was promoted by the pepper tissues which contained the lowest capsaicin amount. This indicates that other compounds different from capsaicin have this anti-tumor potentiality in pepper fruits. Based on this, green fruits from the Alegría riojana variety, which has negligible capsaicin levels, was used to study the effect on the oxidative and redox metabolism of tumor cell lines from liver (Hep-G2) and pancreas (MIA PaCa-2). Different parameters from both lines treated with crude pepper fruit extracts were determined including protein nitration and protein S-nitrosation (two post-translational modifications (PTMs) promoted by nitric oxide), the antioxidant capacity, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), among others. In addition, the activity of the NADPH-generating enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), and NADP-isocitrate dehydrogenase (NADP-ICDH) was followed. Our data revealed that the treatment of both cell lines with pepper fruit extracts altered their antioxidant capacity, enhanced their catalase activity, and considerably reduced the activity of the NADPH-generating enzymes. As a consequence, less H2O2 and NADPH seem to be available to cells, thus avoiding cell proliferation and possibly triggering cell death in both cell lines.

In this study, a new regional Earth system model is developed and applied to the Med-CORDEX (Coordinated Regional Climate Downscaling Experiment) region. The ENEA-REG system is made up of two interchangeable regional climate models as atmospheric components (RegCM, REGional Climate Model, and WRF, Weather Research and Forecasting), a river model (Hydrological Discharge, HD), and an ocean model (Massachusetts Institute of Technology General Circulation Model, MITgcm); processes taking place at the land surface are represented within the atmospheric models with the possibility to use several land surface schemes of different complexity. The coupling between these components is performed through the RegESM driver. Here, we present and describe our regional Earth system model and evaluate its components using a multidecadal hindcast simulation over the period 1980–2013 driven by ERA-Interim reanalysis. We show that the atmospheric components correctly reproduce both large-scale and local features of the Euro-Mediterranean climate, although we found some remarkable biases: in particular, WRF has a significant cold bias during winter over the northeastern bound of the domain and a warm bias in the whole continental Europe during summer, while RegCM overestimates the wind speed over the Mediterranean Sea. Similarly, the ocean component correctly reproduces the analyzed ocean properties with performances comparable to the state-of-art coupled regional models contributing to the Med-CORDEX initiative. Our regional Earth system model allows studying the Euro-Mediterranean climate system and can be applied to both hindcast and scenario simulations.

Availability of detailed short-term forecasts of the ocean main characteristics (circulation and waves) is essential for a correct management of the human activities insisting on coastal areas. These activities include the extraction of renewable energy, which has developed in recent years, and will play an important role in the context of future blue growth. The present work describes the implementation of a new ocean operational system, named MITO, that provides daily 5 days forecasts of the Mediterranean Sea circulation. Distinctive features of this system are the inclusion of the main effects of the tidal forcing, both local and propagating from the Atlantic, and the high spatial detail. The horizontal resolution is of 1/48° (about 2 km) in most of the computational domain, and is smoothly increased (down to few hundred meters) in key passages, such as the Gibraltar Strait and the Turkish Straits, to correctly resolve the complex local dynamics. Initial and boundary conditions for MITO are taken from the reference European operation model of Copernicus, which covers the Mediterranean Sea with a uniform resolution of 1/24°. A thorough validation of the new system is performed, analyzing the forecasts of the year 2020, whose results are compared with in situ and remote observational data (sea surface temperature, altimeter data, temperature and salinity profiles by floats, tide-gauge measurements, available through the Copernicus portal) using the same large-scale metrics applied in the validation of the Copernicus operational model. MITO results are generally found in very good agreement with the observations, despite the fact that the model does not make explicit use of data assimilation. We also give examples of the capability of the model to correctly describe complex local mesoscale dynamics, and point out aspects that need to be improved, which will be addressed in a future upgrade of the operational implementation.

NADPH is an indispensable cofactor in a wide range of physiological processes that is generated by a family of NADPH dehydrogenases, of which the NADP-dependent malic enzyme (NADP-ME) is a member. Pepper (Capsicum annuum L.) fruit is a horticultural product consumed worldwide that has great nutritional and economic relevance. Besides the phenotypical changes that pepper fruit undergoes during ripening, there are many associated modifications at transcriptomic, proteome, biochemical and metabolic levels. Nitric oxide (NO) is a recognized signal molecule with regulatory functions in diverse plant processes. To our knowledge, there is very scarce information about the number of genes encoding for NADP-ME in pepper plants and their expression during the ripening of sweet pepper fruit. Using a data mining approach to evaluate the pepper plant genome and fruit transcriptome (RNA-seq), five NADP-ME genes were identified, and four of them, namely CaNADP-ME2 to CaNADP-ME5, were expressed in fruit. The time course expression analysis of these genes during different fruit ripening stages, including green immature (G), breaking point (BP) and red ripe (R), showed that they were differentially modulated. Thus, while CaNADP-ME3 and CaNADP-ME5 were upregulated, CaNADP-ME2 and CaNADP-ME4 were downregulated. Exogenous NO treatment of fruit triggered the downregulation of CaNADP-ME4. We obtained a 50–75% ammonium–sulfate-enriched protein fraction containing CaNADP-ME enzyme activity, and this was assayed via non-denaturing polyacrylamide gel electrophoresis (PAGE). The results allow us to identify four isozymes designated from CaNADP-ME I to CaNADP-ME IV. Taken together, the data provide new pieces of information on the CaNADP-ME system with the identification of five CaNADP-ME genes and how the four genes expressed in pepper fruits are modulated during ripening and exogenous NO gas treatment.

The class III peroxidases (PODs) catalyze the oxidation of several substrates coupled to the reduction of H2O2 to water, and play important roles in diverse plant processes. The POD family members have been well-studied in several plant species, but little information is available on sweet pepper fruit physiology. Based on the existing pepper genome, a total of 75 CaPOD genes have been identified, but only 10 genes were found in the fruit transcriptome (RNA-Seq). The time-course expression analysis of these genes showed that two were upregulated during fruit ripening, seven were downregulated, and one gene was unaffected. Furthermore, nitric oxide (NO) treatment triggered the upregulation of two CaPOD genes whereas the others were unaffected. Non-denaturing PAGE and in-gel activity staining allowed identifying four CaPOD isozymes (CaPOD I-CaPOD IV) which were differentially modulated during ripening and by NO. In vitro analyses of green fruit samples with peroxynitrite, NO donors, and reducing agents triggered about 100% inhibition of CaPOD IV. These data support the modulation of POD at gene and activity levels, which is in agreement with the nitro-oxidative metabolism of pepper fruit during ripening, and suggest that POD IV is a target for nitration and reducing events that lead to its inhibition.

In a networked control system scenario, the packet dropout is usually modeled by a time-invariant (homogeneous) Markov chain (MC) process. However, from a practical point of view, the probabilities of packet loss can vary in time and/or probability parameter dependency. Therefore, to design a fault detection filter (FDF) implemented in a semi-reliable communication network, it is important to consider the variation in time of the network parameters, by assuming the more accurate scenario provided by a nonhomogeneous jump system. Such a premise can be properly taken into account within the linear parameter varying (LPV) framework. In this sense, this paper proposes a new design method of H∞ gain-scheduled FDF for Markov jump linear systems under the assumption of a nonhomogeneous MC. To illustrate the applicability of the theoretical solution, a numerical simulation is presented.

Peroxisomes are ubiquitous organelles from eukaryotic cells characterized by an active nitro-oxidative metabolism. They have a relevant metabolic plasticity depending on the organism, tissue, developmental stage, or physiological/stress/environmental conditions. Our knowledge of peroxisomal metabolism from fruits is very limited but its proteome is even less known. Using sweet pepper (Capsicum annuum L.) fruits at two ripening stages (immature green and ripe red), it was analyzed the proteomic peroxisomal composition by quantitative isobaric tags for relative and absolute quantitation (iTRAQ)-based protein profiling. For this aim, it was accomplished a comparative analysis of the pepper fruit whole proteome obtained by iTRAQ versus the identified peroxisomal protein profile from Arabidopsis thaliana. This allowed identifying 57 peroxisomal proteins. Among these proteins, 49 were located in the peroxisomal matrix, 36 proteins had a peroxisomal targeting signal type 1 (PTS1), 8 had a PTS type 2, 5 lacked this type of peptide signal, and 8 proteins were associated with the membrane of this organelle. Furthermore, 34 proteins showed significant differences during the ripening of the fruits, 19 being overexpressed and 15 repressed. Based on previous biochemical studies using purified peroxisomes from pepper fruits, it could be said that some of the identified peroxisomal proteins were corroborated as part of the pepper fruit antioxidant metabolism (catalase, superoxide dismutase, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductaseglutathione reductase, 6-phosphogluconate dehydrogenase and NADP-isocitrate dehydrogenase), the β-oxidation pathway (acyl-coenzyme A oxidase, 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase), while other identified proteins could be considered “new” or “unexpected” in fruit peroxisomes like urate oxidase (UO), sulfite oxidase (SO), 5-methyltetrahydropteroyltriglutamate-homocysteine methyltransferase (METE1), 12-oxophytodienoate reductase 3 (OPR3) or 4-coumarate-CoA ligase (4CL), which participate in different metabolic pathways such as purine, sulfur, L-methionine, jasmonic acid (JA) or phenylpropanoid metabolisms. In summary, the present data provide new insights into the complex metabolic machinery of peroxisomes in fruit and open new windows of research into the peroxisomal functions during fruit ripening.

The digital terrain model (DTM), the representation of earth's surface at regularly spaced intervals, is the first input in the computational modelling of atmospheric flows. The ability of computational meshes based on high- (2 m; airborne laser scanning, ASL), medium- (10 m; military maps, Mil) and low-resolution (30 m; Shuttle Radar Topography Mission, SRTM) DTMs to replicate the Perdigão experiment site was appraised in two ways: by their ability to replicate the two main terrain attributes, elevation and slope, and by their effect on the wind flow computational results. The effect on the flow modelling was evaluated by comparing the wind speed, wind direction and turbulent kinetic energy using VENTOS®/2 at three locations, representative of the wind flow in the region. It was found that the SRTM was not an accurate representation of the Perdigão site. A 40 m mesh based on the highest-resolution data yielded an elevation error of less than 1.4 m and an RMSE of less than 2.5 m at five reference points compared to 5.0 m in the case of military maps and 7.6 m in the case of the SRTM. Mesh refinement beyond 40 m yielded no or insignificant changes on the flow field variables, wind speed, wind direction and turbulent kinetic energy. At least 40 m horizontal resolution – threshold resolution – based on topography available from aerial surveys is recommended in computational modelling of the flow over Perdigão.

Small heat shock proteins (sHSPs) are usually upregulated in plants under diverse environmental stresses. These proteins have been suggested to function as molecular chaperones to safeguard other proteins from stress-induced damage. The ripening of pepper (Capsicum annuum L.) fruit involves important phenotypic, physiological, and biochemical changes, which have associated endogenous physiological nitro-oxidative stress, but they can also be significantly affected by environmental conditions, such as temperature. Based on the available pepper genome, a total of 41 sHSP genes were identified in this work, and their distributions in the 12 pepper chromosomes were determined. Among these genes, only 19 sHSP genes were found in the transcriptome (RNA-Seq) of sweet pepper fruits reported previously. This study aims to analyze how these 19 sHSP genes present in the transcriptome of sweet pepper fruits are modulated during ripening and after treatment of fruits with nitric oxide (NO) gas. The time-course expression analysis of these genes during fruit ripening showed that 6 genes were upregulated; another 7 genes were downregulated, whereas 6 genes were not significantly affected. Furthermore, NO treatment triggered the upregulation of 7 sHSP genes and the downregulation of 3 sHSP genes, whereas 9 genes were unchanged. These data indicate the diversification of sHSP genes in pepper plants and, considering that sHSPs are important in stress tolerance, the observed changes in sHSP expression support that pepper fruit ripening has an associated process of physiological nitro-oxidative stress, such as it was previously proposed.

Background: The value of Open Science (OS) for the academic community and society has been becoming more evident recently, especially during the COVID-19 pandemic. Nevertheless, significant challenges regarding its implementation arise that are likely to affect researchers, especially those in early career stages. Hence, monitoring early-career researchers’ views, knowledge, and skills on OS and related policies, is crucial for its advancement. The main aim of this exploratory study was to gain new perspectives regarding the awareness of and attitudes towards OS and related practices having in consideration geographical, economic and research career variables. Methods: The survey was conducted during May-August 2020 as part of a collaboration between Eurodoc and the Open Research Europe project. The data from the survey were analyzed by European region, Gross domestic product, Gross domestic expenditure on research and development as a percentage of gross domestic product, field of study, and career stage. Results: The awareness and positive attitude regarding OS, specifically among early-career researchers, is high in Europe. However, there are significant career stage group differences in views and knowledge about OS. Generally, awareness and positive attitude tend to increase with increasing career seniority. Regarding European regions, we spotted three main groups sharing similar awareness levels and attitudes: researchers in Western Europe - the most informed group towards OS; researchers in northern, central, and southern Europe - a moderately informed group with some minor differences; and researchers in eastern Europe - the least informed group, whose opinions deviate the most. Conclusions: We found that there is an “evolution of needs and focus” regarding scientific publishing: researchers in most European regions are in different stages of transition from the competitive to collaborative levels, while researchers in eastern Europe are largely beginning their transition to the competitive level.

Nitric oxide (•NO) is a free radical which exerts a myriad of functions in the physiology of higher plants either under physiological and environmental stress conditions. NO, and derived molecules designated as reactive nitrogen species (RNS), can mediate posttranslational modifications (PTMs) of proteins which can affect their functionality. Among these NO/RNS-derived PTMs, it can be highlighted S-nitrosation, metal nitrosylation and nitration. This last one involves the addition of a nitro group (-NO2) to some specific amino acids such as tyrosine or tryptophan. An increase in the content of protein nitration has been recognized as a suitable marker of nitro-oxidative stress which is frequently associated with oxidative stress under diverse environmental stress conditions. This mini-review aims to provide a comprehensive overview of protein nitration and its significance in higher plants.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA-NAcc pathway, associated with deficient reward seeking behaviors in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited a social anhedonia-like phenotype in adulthood with decreased direct social approach and time spent with peers in the three-chamber task, and no overt differences in sucrose preference. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may reflect enduring reward deficits.