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Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 next to basement membrane compounds. Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell-states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we found an expansion of pro-inflammatory Ly6Chighmacrophages in HFpEF, and we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ. Finally, a marker of murine HFpEF fibroblast activation, Angiopoietin-like 4, was elevated in plasma samples of HFpEF patients and associated with disease severity. Taken together, our study provides a comprehensive characterization of molecular fibroblast and macrophage activation patterns in murine HFpEF, as well as the identification of a novel biomarker for disease progression in patients.

Gene regulation plays a critical role in the cellular processes that underlie human health and disease. The regulatory relationship between transcription factors (TFs), key regulators of gene expression, and their target genes, the so called TF regulons, can be coupled with computational algorithms to estimate the activity of TFs. However, to interpret these findings accurately, regulons of high reliability and coverage are needed. In this study, we present and evaluate a collection of regulons created using the CollecTRI meta-resource containing signed TF-gene interactions for 1,183 TFs. In this context, we introduce a workflow to integrate information from multiple resources and assign the sign of regulation to TF-gene interactions that could be applied to other comprehensive knowledge bases. We find that the signed CollecTRI-derived regulons outperform other public collections of regulatory interactions in accurately inferring changes in TF activities in perturbation experiments. Furthermore, we showcase the value of the regulons by investigating hallmarks of TF activity profiles inferred from the transcriptomes of three different cancer types. Overall, the CollecTRI-derived TF regulons enable the accurate and comprehensive estimation of TF activities and thereby help to interpret transcriptomics data.GRAPHICAL ABSTRACT

Single-cell atlases across conditions are essential in the characterization of human disease. In these complex experimental designs, patient samples are profiled across distinct cell-types and clinical conditions to describe disease processes at the cellular level. However, most of the current analysis tools are limited to pairwise cross-condition comparisons, disregarding the multicellular nature of disease processes and the effects of other biological and technical factors in the variation of gene expression. Here we propose a computational framework for an unsupervised analysis of samples from cross-condition single-cell atlases and for the identification of multicellular programs associated with disease. Our strategy, that repurposes multi-omics factor analysis, incorporates the variation of patient samples across cell-types and enables the joint analysis of multiple patient cohorts, facilitating integration of atlases. We applied our analysis to a collection of acute and chronic human heart failure single-cell datasets and described multicellular processes of cardiac remodeling that were conserved in independent spatial and bulk transcriptomics datasets. In sum, our framework serves as an exploratory tool for unsupervised analysis of cross-condition single-cell atlas and allows for the integration of the measurements of patient cohorts across distinct data modalities, facilitating the generation of comprehensive tissue-centric understanding of disease.Graphical Abstract

Existing scholarship documents large worldwide increases in women’s participation in the public sphere over recent decades, for example, in education, politics, and the labor force. Some scholars have argued that these changes follow broader trends in world society, especially its growing liberalism, which increasingly has reconfigured social life around the choices of empowered and rights-bearing individuals, regardless of gender. Very recently, however, a variety of populisms and nationalisms have emerged to present alternatives to liberalism, including in the international arena. We explore here their implications for women’s participation in public life. We use cross-national data to analyze changes in women’s participation in higher education, the polity, and the economy 1970–2017. We find that women’s participation on average continues to expand over this period, but there is evidence of a growing cross-national divergence. In most domains, women’s participation tends to be lower in countries linked to illiberal international organizations, especially in the recent-most period.

Via a cross-national and longitudinal analysis, this study seeks to understand whether and to what extent school textbooks portray children as entities with status and agency. Our core argument is ...

Multiple sclerosis (MS) is a prototypic chronic-inflammatory disease of the central nervous system. After initial lesion formation during active demyelination, inflammation is gradually compartmentalized and restricted to specific tissue areas such as the lesion rim in chronic-active lesions. However, the cell type-specific and spatially restricted drivers of chronic tissue damage and lesion expansion are not well understood. Here, we investigated the properties of subcortical white matter lesions by creating a cell type-specific spatial map of gene expression across various inflammatory lesion stages in MS. An integrated analysis of single-nucleus and spatial transcriptomics data enabled us to uncover patterns of glial, immune and stromal cell subtype diversity, as well as to identify cell-cell communication and signaling signatures across lesion and non-lesion tissue areas in MS. Our results provide insights into the conversion of the tissue microenvironment from a ‘homeostatic’ to a pathogenic or ‘dysfunctional’ state underlying lesion progression in MS. We expect that this study will help identify spatially resolved cell type-specific biomarkers and therapeutic targets for future interventional trials in MS.

We provide here the sub-clustering results for each major cell type forthe manuscript: Kuppe, Ramirez Flores, Li et al. "Spatial multi-omic map of human myocardial infarction", 2022. The cells from snRNA-seq and snATAC-seq were first integrated and then sub-clustering was performed based on the integrated data. We tried our best to annotated the obtained sub-clusters.

Finite Control Set Model Predictive Control (FCS-MPC) is an alternative to conventional linear controllers in power converters due to its attractive properties such as its conceptual simplicity, flexibility, direct consideration of non linearities as well as constraints, and fast control response. This last feature imposes computational constraints and short prediction horizons are therefore needed. In fact, in many applications an horizon one FCS-MPC controller is used. However, using FCS-MPC with a short prediction horizon in topologies that exhibit non-minimum phase behavior such as active-front-end rectifiers, dc-dc boost converters, and Z-source converters, among others, may lead to control issues. This work studies the origin of these control issues using nonlinear control theory considering a dc-dc boost converter as a case study. It is shown that the difficulty to directly control the converter output voltage using short horizon FCS-MPC is the resulting unstable internal dynamic, as the short horizon FCS-MPC controller acts like an input-output linearizing controller. To solve the problem of the unstable internal dynamic, a short horizon FCS-MPC controller based on input-state linearization is proposed allowing correct operation of the system. Experimental results show the feasibility of the proposal.

Small extracellular vesicles (sEVs, "exosomes") in milk have attracted considerable attention for use in delivering therapeutics to diseased tissues because of the following qualities. The production of milk sEVs is scalable, e.g., more than 10

Apis mellifera Royal Jelly (RJ) is a well-known remedy in traditional medicine around the world and its versatile effects range from antibacterial to anti-inflammatory properties and pro-regenerative properties. Several active compounds have been identified, however, the mechanisms of action still remain widely unknown. As a glandular product, RJ has been shown to contain a substantial number of extracellular vesicles (EVs) and in this study, we aimed to investigate the extent of involvement of RJEVs in wound healing associated effects. Molecular analysis of RJEVs verified the presence of important conserved exosomal markers such as CD63 and syntenin, as well as cargo molecules MRJP1, defensin-1 and jellein-3. RJEV internalization analysis demonstrated the involvement of membrane fusion as well as macropinocytosis or clathrin-dependent endocytosis into mammalian cells. Furthermore, RJEVs have demonstrated to modulate MSCs differentiation and secretome, as well as decrease LPS-induced inflammation in RAW 264.7 macrophages by blocking the MAPK pathway. In vivo studies confirmed anti-bacterial effects of RJEVs, and demonstrated an acceleration of wound healing in a splinted mouse model. Summarizing, this study suggests that RJEVs of potentially exosomal origin play a crucial role in the known effects of RJ by modulating the inflammatory phase and cellular response in wound healing.

This paper presents a numerical and experimental evaluation of a new osteosynthesis rib implant. The reported cases are studied using the Finite Element Method (FEM) to compute the implant’s surface strain. The implant was placed to a human morphological rib manufactured in polylactic acid (PLA) by 3D printing. Experimental studies are carried out with a strain gage stuck on the implant’s surface and tested by using a testing machine called Testing Machine for Artificial Rib Impact (TEMARI). The machine was used to emulate the compression force that performs in the chest during deep breathing on humans. The results from numerical analysis and the experimental test show a variation of 4.9% in the compression displacement of the rib, 6.1% in the strain of the left surface of the rib, 1.6% for the strain of the right surface of the rib, and finally 3.1% for the strain in the middle surface of the implant.

We provide here the raw data of visium forthe manuscript: Kuppe, Ramirez Flores, Li et al. "Spatial multi-omic map of human myocardial infarction", 2022

Patellar tendon ruptures are infrequent and potentially disabling injuries. These injuries are usually repaired with transosseous suture tunnels. However, this technique can produce a significant gap formation and prolonged postoperative immobilization. Although several techniques have been described to improve the integrity of the repair, the surgical technique of choice is a matter of debate especially when there is tissue loss due to high-energy trauma. This study aims to evaluate the clinical outcomes of patients with acute patellar tendon ruptures due to high-energy trauma treated with a novel construct configuration that includes a suture anchor and a figure-of-eight augmentation with hamstring autograft with medial and lateral reinforcement. To determine the clinical outcomes the International Knee Documentation Committee (IKDC) score was obtained pre-surgery and at 12 months of follow-up. A total of six patients were recruited, with a median age of 27.5 years, five of these were male. Three lesions were in the proximal pole of the tendon, two mid-substance and one was in the junction with tibial tuberosity. The IKDC clinical score significantly increased from pre-surgery to the 12-month follow-up with a median difference of 32.8 (95% CI, 19.5-42.6, p=0.0313). Likewise, the patients presented a post-surgery quadriceps strength level with a median of 5/5. All patients had full active knee extension with a median of 0-120 degrees. There was no statistical difference in the range of motion comparing the surgical knee to the contralateral knee (p=0.6883). No patient presented any type of reintervention or complication during the follow-up period. The configuration of the construct presented in the technique had not been reported before in the literature and combines the advantages of the use of suture anchors and biological augmentation with lateral and medial reinforcement. This technique may be useful in patients with traumatic injuries with and without loss of tissue. Although it is a small series with concomitant injuries, satisfactory clinical results were presented during follow-up.

The International Association of Universities (IAU) is the only inclusive global university association, its membership barriers are low, yet few universities are members despite considerable benefits. What determines membership in this long-standing international university alliance? Reviewing recent trends toward a more networked, stratified and internationalized global higher education field, we argue that universities with a greater need for legitimation and those ‘born’ into a global era are more likely to become members of an inclusive international network like the IAU. Thus, we expect lower status and younger universities to be more likely to join. We apply regression models to test hypotheses implied by these arguments. Our findings are consistent with these hypotheses, even after controlling for other factors. We discuss these findings using neo-institutional arguments about legitimacy and imprinted logics and suggest potential analytical avenues for further research.

The advent of mass schooling played a pivotal role in European societies of the later nineteenth century, transforming rural peasants into national citizens. The late-twentieth-century global expansion of higher education ushered in new transformations, propelling societal rationalization and organizing, and knitting the world into a more integrated society and economy. We address four key dynamics: (1) Higher education sustains the modern professions and contributes to the rationalization of society and state. (2) The supranational and universalistic orientation of higher education provides elites with shared global cultural frames and identities, facilitating globalization. (3) Consequently, tertiary education provides a foundation for major global movements and sociopolitical change around diverse issues, such as human rights and environmental protection as well as potentially contentious religious and cultural solidarities. (4) Higher education contributes to the reorganization of the economy, creating new monetarized activities and facilitating the reconceptualization of activities distant from material production as economic. In short, many features of the contemporary world arise from the growing legions of people steeped in common forms of higher education. Panel regression models of contemporary cross-national longitudinal data examine these relationships. We find higher-education enrollments are associated with key dimensions of rationalization, globalization, societal mobilization, and expansion of the service economy. Central features of modern society, often seen as natural, in fact hinge on the distinctive form of higher education that has become institutionalized worldwide.

In this study, we analyse data from 176 Chinese universities to examine the use of reputation symbols on official websites. We find that Chinese universities prefer professional and performative symbols more than moral symbols. Reputation symbols are mainly observed in teaching, research, history and strategy categories, whereas their use in internal operations and the external environment is limited. A comparison with samples from the United States and Nordic countries indicates that their universities differ in the use of reputation symbols, with relatively high emphasis on professional and moral symbols, respectively. This difference can be attributed to divergent national cultures, higher education regimes and globalization. Here, we discuss the implications of our findings on reputation management by universities in a globalized world.

Therapeutic promotion of intestinal regeneration holds great promise, but defining the cellular mechanisms that influence tissue regeneration remains an unmet challenge. To gain insight into the process of mucosal healing, we longitudinally examined the immune cell composition during intestinal damage and regeneration. B cells were the dominant cell type in the healing colon, and single-cell RNA sequencing (scRNA-seq) revealed expansion of an IFN-induced B cell subset during experimental mucosal healing that predominantly located in damaged areas and associated with colitis severity. B cell depletion accelerated recovery upon injury, decreased epithelial ulceration, and enhanced gene expression programs associated with tissue remodeling. scRNA-seq from the epithelial and stromal compartments combined with spatial transcriptomics and multiplex immunostaining showed that B cells decreased interactions between stromal and epithelial cells during mucosal healing. Activated B cells disrupted the epithelial-stromal cross talk required for organoid survival. Thus, B cell expansion during injury impairs epithelial-stromal cell interactions required for mucosal healing, with implications for the treatment of IBD.

When a sternum prosthesis is implemented, it must allow the movement of the rib cage. The sternum prosthesis designs that have been developed are completely rigid, this aspect can present discomfort when breathing, as well as fixation problems between the prosthesis and the bone tissue. The aim of this work is to develop a flexible device that allows the movement of the rib cage during breathing. Compliant mechanism design was developed by using the pseudo-rigid body model (PRBM) starting from a 4-bar rigid mechanism. The flexible model was obtained by developing the methodology of replacement from rigid to flexible body. The results show the obtained parameters of the compliant mechanism and the three-dimensional model for subsequent numerical and experimental analysis.

The advancement of technologies to measure highly multiplexed spatial data requires the development of scalable methods that can leverage the spatial information. We present MISTy, a flexible, scalable and explainable machine learning framework for extracting interactions from any spatial omics data. MISTy builds multiple views focusing on different spatial or functional contexts to dissect different effects, such as those from direct neighbours versus those from distant cells. MISTy can be applied to different spatially resolved omics data with dozens to thousands of markers, without the need to perform cell-type annotation. We evaluate the performance of MISTy on an in silico dataset and demonstrate its applicability on three breast cancer datasets, two measured by imaging mass cytometry and one by Visium spatial transcriptomics. We show how we can estimate interactions coming from different spatial contexts that we can relate to tumor progression and clinical features. Our analysis also reveals that the estimated interactions in triple negative breast cancer are associated with clinical outcomes which could improve patient stratification. Finally, we demonstrate the flexibility of MISTy to integrate different kinds of views by modeling activities of pathways estimated from gene expression in a spatial context to analyse intercellular signaling.

Background Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. Methods Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera. Results Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11–30, 41–60, 51–70, and 91–110. Conclusions A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.

This chapter explores cross-national trends in Science, Technology, Engineering, and Math (STEM) degree graduates at the tertiary level from 1998 to 2018 for 143 countries. It focuses on graduation patterns for all tertiary levels precisely because it is a more rigorous measure of the degree to which STEM has opened or failed to open to women. Growth in women’s share of STEM degrees is not mainly a function of increased interest and demand for STEM degrees on the part of women. The association between STEM and male appropriateness may vary across regions, and that may account for why the Middle East and North Africa region (traditional in some respects) may nevertheless be more open to women in STEM. Early policy interventions to boost confidence and interest in students and exposing students to real-life experiences and applications in STEM fields, as well as role models in and outside the classroom, can help attract more young people to STEM fields.

The growing availability of single-cell data has sparked an increased interest in the inference of cell-cell communication from this data. Many tools have been developed for this purpose. Each of them consists of a resource of intercellular interactions prior knowledge and a method to predict potential cell-cell communication events. Yet the impact of the choice of resource and method on the resulting predictions is largely unknown. To shed light on this, we created a framework, available at https://github.com/saezlab/liana/tree/biorxiv-clean, to facilitate a comparative assessment of methods for inferring cell-cell communication from single cell transcriptomics data and then compared 15 resources and 6 methods. We found few unique interactions and a varying degree of overlap among the resources, and observed uneven coverage in terms of pathways and biological categories. We analysed a colorectal cancer single cell RNA-Seq dataset using all possible combinations of methods and resources. We found major differences among the highest ranked intercellular interactions inferred by each method even when using the same resources. The varying predictions lead to fundamentally different biological interpretations, highlighting the need to benchmark resources and methods.

The use of a proper nutrient solution is a key factor in achieving production of vigorous transplants and subsequently obtaining profitable yields. It is true indeed when the grower says: “a good transplant is 50% of the production”. However, management of vegetable transplants' nutrition in Venezuela and in most tropical countries is seldom practiced, or it is carried out empirically, without any planning. The influence of different nutrient solutions on the growth of tomato transplants and leaf nutrient uptake was investigated in an experiment performed at a commercial nursery farm located in Quibor, Lara state, Venezuela. The treatments were: (1) tap water alone (TW); (2) conventional grower nutrient solution (C); (3) wye nutrient solution (W); and (4) W+TW (dW; concentration of 50%), using individual 200-plastic transplant trays filled with a combination of peat and coir (60 and 40%, respectively). It was found that all the transplant growth parameters evaluated (height, number of leaves, leaf area, stem diameter and shoot and root dry weights were significantly higher in W and dW solutions than in the C and control (TW) solutions. Similar responses were observed regarding leaf nutrient uptake. Plant tissues accumulated more nitrogen, phosphorus, potassium, calcium, and magnesium when W and dW were used. The lack of observed differences between C and TW could be associated to some nutrients supplied mainly from peat. Results from the study suggest that introducing new and balanced nutrient solutions is a crucial horticultural practice for the production of vegetable transplants. Besides, further research on integrated and planned transplant fertilization using other nutrient solutions (organic and mineral) and alternative substrates are recommended.

National higher education systems are undergoing profound changes, discussed in many but unrelated studies as outcomes of internationalisation dynamics and institutional isomorphism pressures. We propose to link these studies by emphasising the influence of both internationalisation and isomorphism on the formation of a global educational regime. Through a broad range of indicators, we describe the growth of the discursive, normative, and regulatory dimensions of such a global higher education regime. We find evidence of the following developments: (1) a rapidly growing network of international organisations focused on conferences, initiatives, and programmes supporting a global higher education agenda; (2) a striking increase in the number of international and national accreditation agencies, their mutual cross-national recognition as well as the number of universities that are nationally and internationally accredited; and lastly, (3) parallel increases in regional qualification frameworks and in the implementation of national qualification frameworks. These developments create integration pressures manifest in the mutual recognition of higher education degrees, for which a new generation of regional conventions has emerged worldwide in the past two decades. We discuss these processes and their implications for understanding ‘national’ higher education as well as the threats and limits to the burgeoning higher education regime.

Finite control set model predictive control can be applied to a power converter if there is an accurate existing model of the converter. The best results will be achieved if and only if the parameters and variables that make up the system are properly estimated. If this is not the case, the predictions made using these strategies may be erroneous and cause problems, such as steady-state error with respect to the assigned desired references. This paper presents a predictive control strategy with integral action that compensates for the differences between the estimated model and the inverter with the objective of achieving a zero steady-state error without requiring external loops or state observers. The proposed strategy is tested on a single-phase Z-source inverter so as to evaluate the error in both the ac and dc controlled variables with respect to their references to their cosigns. The experimental results confirm that the proposed strategy achieves a zero error in the steady state while maintaining the fast dynamic response of the classic predictive control.

Aim This clinical report evaluated changes in the mandibular condyles of patients diagnosed with osteoarthritis (OA) at the temporomandibular joint (TMJ), who were treated with a modified dental splint. Materials and methods Four adult patients (age range: 24-47 years) were treated with a dental splint appliance that delivered a low load at the molar region and permitted lateral and protrusive mandibular excursions. An initial magnetic resonance imaging (MRI) scan was performed for diagnosis purpose before treatment. A second MRI scan was conducted after 12 months of treatment to evaluate changes at the TMJ. Results The observations from the MRI results in the four patients showed positive changes at the end of the study period. The results presented here suggest the treatment provided significantly reduced the forces damaging the tissues covering the surface of the mandibular condyle, such as cartilage and cortical bone, which may be the cause of the OA. In that context, it is suggested that that reduction in the overloading of the TMJ produced by the functional dental splint permitted the recovery of those tissues. Conclusion The present results support the idea that the tissues composing the TMJ are viable and may respond to positive stimulus. In that way, this report proposes a way to treat those patients with TMJ OA, who may respond when the treatment aims to reduce the overloading forces affecting the TMJ. Clinical significance This report proposes a noninvasive clinical treatment for patients with TMJ OA, who may respond when the treatment aims to reduce the overloading forces affecting the TMJ.