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Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, amongst others, through their main protease (Mpro), which is responsible for the proteolytic cleavage of the largest part of the viral replicase polyproteins pp1a and pp1ab. Additionally, it can cleave cellular substrates, such as innate immune signaling factors, to dampen the immune response. Here, we show that MAVS is cleaved in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV), but not in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This cleavage was independent of cellular negative feedback mechanisms that regulate MAVS activation. Furthermore, MERS-CoV Mpro expression induced MAVS cleavage upon overexpression and suppressed the activation of the interferon-β (IFN-β) and nuclear factor-κB (NF-κB) response. We conclude that we have uncovered a novel mechanism by which MERS-CoV downregulates the innate immune response, which is not observed among other highly pathogenic coronaviruses.

Rationale and Objectives: Thyroid nodules are a common occurrence and up to 30% are indeterminate on Fine Needle Aspiration (FNA) biopsy. Use of machine learning (ML) algorithms as computer aids, i.e., computer-aided diagnosis (CADx), may provide accessible, accurate methods of diagnosing thyroid cancer on ultrasound (US) images of thyroid nodules. We conducted a systematic review to synthesize the current knowledge and potential of ML in assisting physicians in diagnosing indeterminate thyroid nodules. Materials and Methods: We searched PubMed for studies without a year constraint. Inclusion criteria were as follows: (1) publication of the study as a full-text manuscript in a peer-reviewed journal, (2) original work (e.g., not a review). Studies were excluded if they (1) did not perform FNA biopsy, (2) excluded all indeterminate lesions, (3) focused on a non-cancer thyroid pathology, (4) described only non-diagnostic uses of their model(s) (e.g. calcification quantification), or (5) did not use grayscale ultrasound. We used the Joanna Briggs Institute Appraisal Checklist for Diagnostic Test Accuracy Studies to synthesize and present quality data and PRISMA guidelines for reporting. Results: Our search yielded only 6 articles published between 2013 and 2022. All studies used either only fine-needle aspiration (FNA) biopsy or a combination of FNA and surgery as the reference standard. Of these, one study included only indeterminate nodules, while 5 studies included other nodules in categories as well. Results varied greatly and studies were inconsistent in which performance metrics they reported. Physician performances yielded areas under the ROC curve (AUC) ranging from 0.68 to 0.83, while ML models gave AUCs from 0.666 to 0.954. One study showed that their model had a greater AUC than physicians, while another study showed no difference in AUCs of their ML model and physicians. Another study demonstrated that their ML-assisted approach had a greater AUC (0.917) than either an American College of Radiology (ACR) Thyroid Imaging Reporting & Data System (TI-RADS)-only approach (AUC 0.68) or a ML only approach (AUC 0.77). One study measured the performance of ML models without physician comparison, with AUCs ranging from 0.85 to 0.90. One study found no difference between their ML model and molecular testing (AUC 0.88 and 0.81, respectively). Conclusion: The growing field of CADx and increasing availability of commercial models suggests an increasing interest toward utilization of ML-assisted diagnosis in the clinical setting. However, there is a significant lack of research on the role of ML the diagnosis of indeterminate thyroid nodules. Funding: The source of funding for this review was institutional funds from the University of Chicago.

Abstract Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity.

The central premise of this article is that synodality ought to be grounded in the Eucharist. The author explores the implications of this claim in the areas of ecclesiology and ethics. On the side of ecclesiology, the author argues that the Eucharist is the ritual and theological center of a synodal church. In the context of its own life, considered not only at an abstract theological level but at a practical and political level as well, the church cannot be synodal if it is not attentive to its Eucharistic origins. Synodality is the key in which communion is realized. The author discusses this idea in the context of the Eucharist Revival in the United States and in connection to baptism and the ecclesiology of the People of God. On the side of ethics, the author develops an account of synodality as a virtue. Synodality is the virtue that shapes the church and its members in order to realize communion. Its object is the right use of power. An ethics of synodality, the author argues, entails both reform in the church itself and a commitment on the part of the church and its members to a politics of the universal common good and the building of a just social order.

Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011, currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 1012 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic.

Pompe disease is currently treated with enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (GAA). Here, the authors show hepatic-directed gene therapy with AAV vectors enhances GAA bioavailability compared with ERT, resulting in improved rescue of the disease phenotype in mice and broad enzyme distribution in mice and non-human primates.

A review of Lisa Allen, _A Womanist Theology of Worship: Liturgy, Justice, and Communal Righteousness_.

Abstract Background Inversion ankle sprains, or lateral ankle sprains, often result in symptomatic lateral ankle instability, and some patients need lateral ankle ligament reconstruction to reduce pain, improve function, and prevent subsequent injuries. Although anatomically reconstructed ligaments should behave in a biomechanically normal manner, previous studies have not measured the strain patterns of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) after anatomical reconstruction. This study aimed to measure the strain patterns of normal and reconstructed ATFL and CFLs using the miniaturization ligament performance probe (MLPP) system. Methods The MLPP was sutured into the ligamentous bands of the ATFLs and CTLs of three freshly frozen cadaveric lower-extremity specimens. Each ankle was manually moved from 15° dorsiflexion to 30° plantar flexion, and a 1.2-N m force was applied to the ankle and subtalar joint complex. Results The normal and reconstructed ATFLs exhibited maximal strain (100) during supination in three-dimensional motion. Although the normal ATFLs were not strained during pronation, the reconstructed ATFLs demonstrated relative strain values of 16–36. During the axial motion, the normal ATFLs started to gradually tense at 0° plantar flexion, with the strain increasing as the plantar flexion angle increased, to a maximal value (100) at 30° plantar flexion; the reconstructed ATFLs showed similar strain patterns. Further, the normal CFLs exhibited maximal strain (100) during plantar flexion-abduction and relative strain values of 30–52 during dorsiflexion in three-dimensional motion. The reconstructed CFLs exhibited the most strain during dorsiflexion-adduction and demonstrated relative strain values of 29–62 during plantar flexion-abduction. During the axial motion, the normal CFLs started to gradually tense at 20° plantar flexion and 5° dorsiflexion. Conclusion Our results showed that the strain patterns of reconstructed ATFLs and CFLs are not similar to those of normal ATFLs and CFLs.

Abstract. Pancreatic neuroendocrine tumors (PNETs) are a rare group of neoplasms originating from the endocrine pancreas. PNETs are classified as functional or non-functional tumors. PNETs are more often diagnosed at a higher stage with distant metastases or advanced locoregional disease. The majority of individuals with hepatic metastases will ultimately die of liver failure; therefore, the treatment of liver tumor burden is critical to providing a survival impact. While surgical resection remains the only chance of cure for disease confined to the pancreas or for locoregional disease, the treatment of advanced or metastatic PNETs is more complex and often requires a multimodal approach. This review focuses on treatment options for well and moderately differentiated PNETs with metastatic disease to the liver. These include surgery, liver-directed therapies including ablative and intra-arterial therapies, and systemic therapies such as somatostatin analogues, targeted therapies, chemotherapy, and peptide receptor radionuclide therapy. Developing an individualized treatment strategy requires careful assessment of liver tumor burden and predicted biological behavior. Aggressive surgical resection of hepatic metastases secondary to PNET primary tumors is associated with improved survival in multiple retrospective studies. General goals of treatment for metastatic disease include prolonging overall survival and progression free survival, improving quality of life, and control of symptoms.

Abstract Osteoid osteoma is a painful, benign and common bone tumor that is prevalent in young adults. The typical clinical presentation consists of pain that becomes worse at night and is relieved by nonsteroidal anti-inflammatory drugs. The most common imaging finding is a lytic lesion, known as a nidus, with variable intralesional mineralization, accompanied by bone sclerosis, cortical thickening and surrounding bone marrow edema, as well as marked enhancement with intravenous contrast injection. When the lesion is located in typical locations (intracortical bone and the diaphyses of long bones), both characteristic clinical and radiological features are diagnostic. However, osteoid osteoma is a multifaceted pathology that can have unusual presentations, such as intraarticular osteoid osteoma, epiphyseal location, lesions at the extremities and multicentric nidi, and frequently present atypical clinical and radiological manifestations. In addition, many conditions may mimic osteoid osteoma and vice versa, leading to misdiagnosis. Therefore, it is essential to understand these musculoskeletal diseases and their imaging findings to increase diagnostic accuracy, enable early treatment and prevent poor prognosis.

Adeno-associated virus (AAV) vector serotypes vary in their ability to transduce hepatocytes from different species. Chimeric mouse models harboring human hepatocytes have shown translational promise for liver-directed gene therapies. However, many variables that influence human hepatocyte transduction and transgene expression in such models remain poorly defined. Here, we aimed to test whether three experimental conditions influence AAV transgene expression in immunodeficient, fumaryl-acetoactetate-hydrolase-deficient (Fah−/−) chimeric mice repopulated with primary human hepatocytes. We examined the effects of the murine liver injury cycle, human donor variability, and vector doses on hepatocyte transduction with various AAV serotypes expressing a green fluorescent protein (GFP). We determined that the timing of AAV vector challenge in the liver injury cycle resulted in up to 7-fold differences in the percentage of GFP expressing human hepatocytes. The GFP+ hepatocyte frequency varied 7-fold between human donors without, however, changing the relative transduction efficiency between serotypes for an individual donor. There was also a clear relationship between AAV vector doses and human hepatocyte transduction and transgene expression. We conclude that several experimental variables substantially affect human hepatocyte transduction in the Fah−/− chimera model, attention to which may improve reproducibility between findings from different laboratories.

Abstract. There has been a rising trend in the incidence and prevalence of non-functioning pancreatic neuroendocrine tumors (NFPanNETs). While a significant number of the newly diagnosed NFPanNETs are asymptomatic, a majority of patients will present with liver metastasis (LM) at the time of diagnosis. Surgical resection remains the only curative treatment, especially for localized NFPanNETs. While a majority of small NFPanNETs are indolent, some are not. This heterogeneity in tumor biology presents the surgeon with the unique challenge of determining which patient will benefit from surgery, given the morbidity of pancreatic surgery. There has been a recent push for a more aggressive approach to the care of these patients, given the emergence of data supporting such measures. However, the risk of over or under treatment has generated immense debate amongst experts in the field. The heterogeneity of current practice guidelines and institutional practices around the world is a reflection of the disparate opinion on the management of NFPanNET. In this review, we set out to examine the evidence regarding some of the most controversial and challenging aspects of the surgical treatment of NFPanNET. We evaluate the following questions; should patients with small NFPanNETs ≤ 2 cm in size be resected; should patients with metastatic NFPanNETs undergo surgical debulking, and should there be resection of the primary tumor in the setting of non-resectable metastatic disease? Although there are currently no Level 1 data to answer these questions conclusively, we believe that the current literature supports a more aggressive approach to the management of NFPanNET.

Abstract Background There are few reports on the detailed biomechanics of the deltoid ligament, and no studies have measured the biomechanics of each ligamentous band because of the difficulty in inserting sensors into the narrow ligaments. This study aimed to measure the strain pattern of the deltoid ligament bands directly using a Miniaturization Ligament Performance Probe (MLPP) system. Methods The MLPP was sutured into the ligamentous bands of the deltoid ligament in 6 fresh-frozen lower extremity cadaveric specimens. The strain was measured using a round metal disk (clock) fixed on the plantar aspect of the foot. The ankle was manually moved from 15° dorsiflexion to 30° plantar flexion, and a 1.2-N-m force was applied to the ankle and subtalar joint complex. Then the clock was rotated every 30° to measure the strain of each ligamentous band at each endpoint. Results The tibionavicular ligament (TNL) began to tense at 10° plantar flexion, and the tension becomes stronger as the angle increased; the TNL worked most effectively in plantar flex-abduction. The tibiospring ligament (TSL) began to tense gradually at 15° plantar flexion, and the tension became stronger as the angle increased. The TSL worked most effectively in abduction. The tibiocalcaneal ligament (TCL) began to tense gradually at 0° dorsiflexion, and the tension became stronger as the angle increased. The TCL worked most effectively in pronation (dorsiflexion-abduction). The superficial posterior tibiotalar ligament (SPTTL) began to tense gradually at 0° dorsiflexion, and the tension became stronger as the angle increased, with the SPTTL working most effectively in dorsiflexion. Conclusion Our results show the biomechanical function of the superficial deltoid ligament and may contribute to determining which ligament is damaged during assessment in the clinical setting.

Review of Daniel P. Castillo, _An Ecological Theology of Liberation: Salvation and Political Ecology

Background: Human epidermal growth factor receptor-4 (HER4) and yes-associated protein-1 (YAP) are candidate therapeutic targets in oncology. YAP’s transcriptional coactivation function is modulated by the HER4 intracellular domain (HER4-ICD) in vitro , but the clinical relevance of this has not been established. This study investigated the potential for targeting the HER4-YAP pathway in brain metastatic breast cancer. Methods: We performed immuno-phenotypic profiling of pathway markers in a consecutive breast cancer series with 25 years of clinical follow up ( n = 371), and patient-matched breast and metastatic brain tumours ( n = 91; 30 pairs). Results: Membrane localisation of phospho-HER4 [pHER4(Y 1162 )] was infrequent in primary breast cancer, but very frequent in brain metastases (5.9% versus 75% positive), where it was usually co-expressed with pHER3(Y 1289 ) ( p

Abstract Background Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug-free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy. Methods Samples were used from 60 patients from the U-Act-Early study who received tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy, and who achieved sDFR (≥3 months in drug-free remission until the end of the study, n = 37) after therapy was tapered and subsequently stopped, or who were not able to discontinue the therapy as controls (n = 23). Whole blood samples were collected and ribonucleic acid (RNA) was isolated from positive cluster of differentiation 4 (CD4+) and CD14+ cells and analysed using high-throughput sequencing. Weighted gene co-expression network analyses were performed to identify clusters (i.e. modules) of differently expressed genes associated with achieving sDFR and which were subsequently used for pathway analyses. Results Network analyses within CD4+ cells identified two significant modules in the tocilizumab plus methotrexate arm and four modules in the tocilizumab and methotrexate arms, respectively (p ≤ 0.039). Important pathways in the module best correlating with achieving sDFR were in the tocilizumab plus methotrexate arm related to processes involved with transcription and translation; in the tocilizumab arm, pathways were related to migration of white blood cells and G-protein coupled receptors, and in the methotrexate arm pathways were involved with the response to a bacterial or biotic (i.e. biological material)-related stimulus. No relevant networks could be identified in the sequenced CD14+ cells. Conclusions Within networks of co-expressed genes, several pathways were found related to achieving sDFR after initiating therapy with tocilizumab, methotrexate, or the combination. Between the three strategy arms, we identified different networks of predisposing genes which indicates that specific gene expression profiles, depending on the treatment strategy chosen, are associated with a higher chance of achieving sDFR. Trial registration Clinicaltrials.gov, NCT01034137 . Registered on 16 December 2009.

Abstract Recent studies have demonstrated that hyperphosphorylation of tau protein plays a role in neuronal toxicities of α-synuclein (ASYN) in neurodegenerative disease such as familial Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease. Using a transgenic mouse model of Parkinson’s disease (PD) that expresses GFP-ASYN driven by the PDGF-β promoter, we investigated how accumulation of ASYN impacted axonal function. We found that retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF) in DIV7 cultures of E18 cortical neurons was markedly impaired at the embryonic stage, even though hyperphosphorylation of tau was not detectable in these neurons at this stage. Interestingly, we found that overexpressed ASYN interacted with dynein and induced a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7, both key regulators of endocytic processes. Furthermore, expression of ASYN resulted in neuronal atrophy in DIV7 cortical cultures of either from E18 transgenic mouse model or from rat E18 embryos that were transiently transfected with ASYN-GFP for 72 hrs. Our studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models.

The heterogeneity of tumor infiltrating lymphocytes (TILs) is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune-cell subsets in brain metastasis tissues to test immunosuppressive routes involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune-cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and IBA-1, and analyzed an average of 15,000 cells per sample. Classifying tumors as either high (>30%) or low (p < 0.01) as well as in their microenvironment (p < 0.001). Contrastingly, the tumors with high TILs displayed higher levels of microglia, as measured by IBA-1 expression. Low TILs-tumors displayed CD8+ T-cells that co-express VISTA (p < 0.01) significantly more compared to high TILs group, where CD8+cells significantly co-express IBA-11 (p < 0.05). These results were supported by RNA analysis of a publicly available, independent cohort. Our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

El objetivo de este trabajo es identificar y analizar las variables que más influyen en la satisfacción del cliente en los centros deportivos de Barcelona. Los datos fueron recogidos en una encuesta entre los clientes actuales de centros deportivos municipales. Un análisis factorial aplicado a esta información revela cinco dimensiones que subyacen a los múltiples componentes de la oferta de servicios en dichas instalaciones: su calidad, los recursos humanos, la comunicación, el entorno social y la relación calidad-precio. Las variables generadas fueron incorporadas a un modelo de regresión múltiple en el que la variable dependiente fue la satisfacción del cliente. De acuerdo con los resultados las mujeres y los usuarios mayores de 60 años valoran más positivamente el servicio recibido, mientras que a mayor nivel de estudios, más exigentes son los clientes. Finalmente, un gerente debe prestar atención en primer lugar a la calidad de las instalaciones seguido de la comunicación, los recursos humanos, la relación calidad precio y el entorno social, por este orden.

Student dropout is a major concern in studies investigating retention strategies in higher education. This study identifies which variables are important to predict student dropout, using academic data from 3583 first-year students on the Business Administration (BA) degree at the University of Barcelona (Spain). The results indicate that two variables, the percentage of subjects failed and not attended in the first semester, demonstrate significant predictive power. This has been corroborated with an additional sample of 10,784 students from three-degree programs (Law, BA, and Economics) at the Complutense University of Madrid (Spain), to assess the robustness of the results. Three different algorithms have also been utilized: neural networks, random forest, and logit. In the specific case of neural networks, the NeuralSens methodology has been employed, which is based on the use of sensitivities, allowing for its interpretation. The outcomes are highly consistent in all cases: both a simple model (logit) and more sophisticated ones (neural networks and random forest) exhibit high accuracy (correctly predicted values) and sensitivity (correctly predicted dropouts). In test set average values of 77% and 69% have been respectively achieved. In this regard, a noteworthy point is that only academic data from the university itself was used to develop the models. This ensures that there's no dependence on other personal or organizational variables, which can often be difficult to access.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

Context Pancreatic neuroendocrine tumors (PNETs) exhibit a wide range of behavior from localized disease to aggressive metastasis. A comprehensive transcriptomic profile capable of differentiating between these phenotypes remains elusive. Objective Use machine learning to develop predictive models of PNET metastatic potential dependent upon transcriptomic signature. Methods RNA-sequencing data were analyzed from 95 surgically resected primary PNETs in an international cohort. Two cohorts were generated with equally balanced metastatic PNET composition. Machine learning was used to create predictive models distinguishing between localized and metastatic tumors. Models were validated on an independent cohort of 29 formalin-fixed, paraffin-embedded samples using NanoString nCounter®, a clinically available mRNA quantification platform. Results Gene expression analysis identified concordant differentially expressed genes between the 2 cohorts. Gene set enrichment analysis identified additional genes that contributed to enriched biologic pathways in metastatic PNETs. Expression values for these genes were combined with an additional 7 genes known to contribute to PNET oncogenesis and prognosis, including ARX and PDX1. Eight specific genes (AURKA, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1, ZPLD1) were identified as sufficient to classify the metastatic status with high sensitivity (87.5-93.8%) and specificity (78.1-96.9%). These models remained predictive of the metastatic phenotype using NanoString nCounter® on the independent validation cohort, achieving a median area under the receiving operating characteristic curve of 0.886. Conclusion We identified and validated an 8-gene panel predictive of the metastatic phenotype in PNETs, which can be detected using the clinically available NanoString nCounter® system. This panel should be studied prospectively to determine its utility in guiding operative vs nonoperative management. [ABSTRACT FROM AUTHOR]