Miracle-dz/UniFAR-FTUs huggingface dataset:
Nucleic Acid Aptamers as Molecular Tags for Omics Analyses Involving Sequencing

Since the beginning of the $1,000 genome project, sequencing technologies have progressed rapidly and equipments capable of massively parallel sequencing have been developed. These machines can perform 3G DNA sequencing corresponding to the entire human genome within only a few hours. Indeed, using such machines, quantitative analysis methods for multiple types of RNA, even in a single cell, are very close to being developed. This would be useful for transcriptome studies including mRNA, rRNA, tRNA, and other non-coding RNA. However, these methods would not be applicable to proteome and other omics analyses because non-nucleic acid molecules, such as proteins and peptides, do not have nucleotide sequences. If non-nucleic acid molecules could be converted to a nucleotide sequence, analytical methods that use massively parallel sequencing could also be applied to omics analyses for non-nucleic acid molecules. Nucleic acid aptamers (specific binders) can be readily amplified by polymerase reaction and decoded by sequencing. Therefore, it is possible to apply them as molecular tags to quantitative biomolecular analyses and single cell analyses, among others. This chapter focuses on the development of nucleic acid aptamers and the outlook for related technologies.
An explorative multiple case study of subcontracting manufacturing SMEs in Jönköping County

Background – In today ́s globalized environment, a stronger emphasis on moving production to low-cost environments is present. Assembling a complex product usually involves multiple smaller manufacturing firms across the globe. As a result, smaller specialized firms have an important role in the market but are also strongly dependent on the demand for the final product. Hence, their business model can be dependent on a specific patch which inhibit innovation and evidently leaving them vulnerable to changes in the environment. One main challenge for companies ́ business model is the question of continuous flexibility and adaption to an ever changing business context. Purpose The purpose of this thesis is to explore dynamic capabilities as a source of business model innovation in manufacturing subcontractor SMEs in Jönköping County. The studies aim is to explore how these firms develop dynamic capabilities in order to identify and then overcome barriers for business model innovation. Method – Primary data was collected through a multiple case study of three manufacturing companies in Jönköping County. The data was later coded and findings cross-case compared with a lens of dynamic capability view in order to find similarities and dissimilarities. ConclusionThe findings from the three case companies indicates that dynamic capabilities are interdependent to each other, meaning all need to be taken into consideration for continuously successful business model innovation. Disregarding the development of one business model component can restrain others, thereby resulting in inadequate innovations. A sensing capability was identified however yet the abilities to seize and reconfigure opportunities taking the whole BM into consideration were not present for all of the three case companies. By lack of a coherent development of the BM, barriers become present and a sustained competitive advantage is unreachable. All three cases agreed upon the human resource management to be the major challenge for their organization to sustain a healthy growth.
Dissecting Epstein-Barr Virus-Specific T-Cell Responses After Allogeneic EBV-Specific T-Cell Transfer for Central Nervous System Posttransplant Lymphoproliferative Disease

Epstein–Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) with central nervous system (CNS) involvement is a severe complication after solid organ transplantation. Standard treatment with reduction of immunosuppression and anti-CD20 antibody application often fails leading to poor outcome. Here, we report the case of an 11-year-old boy with multilocular EBV-positive CNS PTLD 10 years after liver transplantation. Complete remission was achieved by repeated intravenous and intrathecal anti-CD20 antibody rituximab administration combined with intrathecal chemotherapy (methotrexate, cytarabine, prednisone) over a time period of 3 months. Due to the poor prognosis of CNS PTLD and lack of EBV-specific T-cells (EBV-CTLs) in patient’s blood, we decided to perform EBV-directed T-cell immunotherapy as a consolidating treatment. The patient received five infusions of allogeneic EBV-CTLs from a 5/10 HLA-matched unrelated third-party donor. No relevant acute toxicity was observed. EBV-CTLs became detectable after first injection and increased during the treatment course. Next-generation sequencing (NGS) TCR-profiling verified the persistence and expansion of donor-derived EBV-specific clones. After two transfers, epitope spreading to unrelated EBV antigens occurred suggesting onset of endogenous T-cell production, which was supported by detection of recipient-derived clones in NGS TCR-profiling. Continuous complete remission was confirmed 27 months after initial diagnosis.
Augmented BH 4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells

Objective: Endothelial dysfunction in diabetes is characterized by decreased nitric oxide (NO) bioactivity and increased superoxide (SO) production. Reduced levels of tetrahydrobiopterin (BH4), an essential cofactor of endothelial NO synthase (eNOS), appear to be associated with eNOS enzymatic uncoupling. We sought to investigate whether augmented BH4 biosynthesis in hyperglycemic human aortic endothelial cells (HAEC) by adenovirus-mediated gene transfer of GTP cyclohydrolase I (GTPCH, the rate-limiting enzyme for the de novo BH4 synthesis), would be sufficient to rescue eNOS activity and dimerization. HAEC were cultured in media with low glucose (5 mM) or high glucose (30 mM). Methods: After 5 days, the cells with/without GTPCH gene transfer (AdeGFP as a control) were prepared for assays of (1) NO with electron paramagnetic resonance (EPR); (2) SO with cytochrome c reduction and dihydroethidine (DHE) fluorescence; (3) BH4 with highperformance liquid chromatography (HPLC); (4) eNOS expression and dimerization with immunoblotting. Results:We found that high glucose decreased HAEC NO and increased SO production, in association with reductions in both total biopterin and BH4 levels. High glucose increased total eNOS protein levels in HAEC 1.5-fold, but this was present principally in the monomeric form. GTPCH gene transfer increased cellular biopterin levels and NO production but decreased SO production. Furthermore, augmenting BH4 increased the eNOS dimer:monomer ratio 2.6-fold. Conclusion: This study demonstrates a critical role for BH4 in regulating eNOS function, suggesting that GTPCH is a rational target to augment endothelial BH4 and recover eNOS activity in hyperglycemic endothelial dysfunction states. D 2004 European Society of Cardiology. Published by Elsevier B.V.
Advancing Marine Biological Observations and Data Requirements of the Complementary Essential Ocean Variables (EOVs) and Essential Biodiversity Variables (EBVs) Frameworks

Measurements of the status and trends of key indicators for the ocean and marine life are required to inform policy and management in the context of growing human uses of marine resources, coastal development, and climate change. Two synergistic efforts identify specific priority variables for monitoring: Essential Ocean Variables (EOVs) through the Global Ocean Observing System (GOOS), and Essential Biodiversity Variables (EBVs) from the Group on Earth Observations Biodiversity Observation Network (GEO BON) (see Data Sheet 1 in Supplementary Materials for a glossary of acronyms). Both systems support reporting against internationally agreed conventions and treaties. GOOS, established under the auspices of the Intergovernmental Oceanographic Commission (IOC), plays a leading role in coordinating global monitoring of the ocean and in the definition of EOVs. GEO BON is a global biodiversity observation network that coordinates observations to enhance management of the world's biodiversity and promote both the awareness and accounting of ecosystem services. Convergence and agreement between these two efforts are required to streamline existing and new marine observation programs to advance scientific knowledge effectively and to support the sustainable use and management of ocean spaces and resources. In this context, the Marine Biodiversity Observation Network (MBON), a thematic component of GEO BON, is collaborating with GOOS, the Ocean Biogeographic Information System (OBIS), and the Integrated Marine Biosphere Research (IMBeR) project to ensure that EBVs and EOVs are complementary, representing alternative uses of a common set of scientific measurements. This work is informed by the Joint Technical Commission for Oceanography and Marine Meteorology (JCOMM), an intergovernmental body of technical experts that helps international coordination on best practices for observing, data management and services, combined with capacity development expertise. Characterizing biodiversity and understanding its drivers will require incorporation of observations from traditional and molecular taxonomy, animal tagging and tracking efforts, ocean biogeochemistry, and ocean observatory initiatives including the deep ocean and seafloor. The partnership between large-scale ocean observing and product distribution initiatives (MBON, OBIS, JCOMM, and GOOS) is an expedited, effective way to support international policy-level assessments (e.g., the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services or IPBES), along with the implementation of international development goals (e.g., the United Nations Sustainable Development Goals).
Understanding B‐cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B‐cell immunomics approach

Understanding antibody repertoires and in particular, the properties and fates of B cells expressing potentially pathogenic antibodies is critical to define the mechanisms underlying multiple immunological diseases including autoimmune and allergic conditions as well as transplant rejection. Moreover, an integrated knowledge of the antibody repertoires expressed by B cells and plasma cells (PC) of different functional properties and longevity is essential to develop new therapeutic strategies, better biomarkers for disease segmentation, and new assays to measure restoration of B‐cell tolerance or, at least, of normal B‐cell homeostasis. Reaching these goals, however, will require a more precise phenotypic, functional and molecular definition of B‐cell and PC populations, and a comprehensive analysis of the antigenic reactivity of the antibodies they express. While traditionally hampered by technical and ethical limitations in human experimentation, new technological advances currently enable investigators to address these questions in a comprehensive fashion. In this review, we shall discuss these concepts as they apply to the study of Systemic Lupus Erythematosus.
Disconnected – Impaired Interoceptive Accuracy and Its Association With Self-Perception and Cardiac Vagal Tone in Patients With Dissociative Disorder

Patients suffering from dissociative disorders are characterized by an avoidance of aversive stimuli. This includes the avoidance of emotions and, in particular, bodily perceptions. In the present pilot study, we explored the potential interoceptive accuracy deficit of patients suffering from dissociative disorders in a heartbeat detection task. Moreover, we investigated the impact of facial mirror-confrontation on interoceptive accuracy and the potential association between cardiac vagal tone derived from heart rate variability and interoceptive accuracy. Eighteen patients suffering from dissociative disorders and 18 healthy controls were assessed with the Mental Tracking Paradigm by Schandry for heartbeat detection at baseline and after confrontations exposing them to their own faces in a mirror (2 min each, accompanied by a negative or positive cognition). During the experiment, cardiac vagal tone was assessed. We used Pearson correlations to calculate potential associations between cardiac vagal tone and interoceptive accuracy. Patients performed significantly worse than the healthy controls in the heartbeat detection task at baseline. They displayed no significant increase in interoceptive accuracy following facial mirror-confrontation. In the patient group, higher cardiac vagal tone was associated with a more precise heartbeat detection performance. Dissociative disorder patients showed a considerable deficit in interoceptive accuracy. Our results fit with the assumption that highly dissociative patients tend to tune out the perceiving of bodily signals. To the extent that bodily signal perception may play a causal role in these disorders, therapeutic approaches enhancing interoceptive accuracy and cardiac vagal tone may be considered important and practicable steps to improve the therapy outcome of this patient group.
Explaining socioeconomic inequalities in illicit drug use disorders in Iran

Background: Drug use disorders are one of the major health problems in societies, which cause physical, psychological, and social damages to individuals. Socioeconomic status is often inversely associated with drug use disorders. The present study aimed at determining the effect of socioeconomic inequality on the prevalence of drug use disorders and identifying its determinants in Iran. Methods: Data of 7886 individuals aged 15 to 64 years were collected from Iran Mental Health Survey (IranMHS). Initially, the socioeconomic status of the participants was determined by principal component analysis. Later, socioeconomic inequality was measured using the concentration index, and the factors influencing the gap between the high and low socioeconomic groups were identified using the Oaxaca-Blinder Decomposition. Results: The concentration index for drug use disorders in Iran was -0.29 (standard error= 0.06). The results of decomposition technique revealed that 1.14% and 2.7% of the participants with high and low socioeconomic status were affected by drug use disorders, respectively. In addition, the gap between these 2 groups was found to be 1.65%. Among the studied variables, occupation, marital status, and gender accounted for the highest contribution to inequality, respectively. Conclusion: There is inequality in the prevalence of drug use disorders in Iran; these disorders are more common in lower socioeconomic group. Based on the findings, it is suggested that improvement in the socioeconomic status of the households, especially for males, the divorced or widowed individuals, and the unemployed may lead to a reduction in inequality in drug use disorders.
Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity

The plasma–protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and antitumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T-cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction–decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and colocalization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG–treated gliomas displayed decreased numbers of IL35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control antitumor immunity. Mol Cancer Ther; 17(9); 1961–72. ©2018 AACR.
Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages

Previous genetic studies in mice have shown that functional loss of activin receptor–like kinase 7 (ALK7), a type I transforming growth factor-β receptor, increases lipolysis to resist fat accumulation in adipocytes. Although growth/differentiation factor 3 (GDF3) has been suggested to function as a ligand of ALK7 under nutrient-excess conditions, it is unknown how GDF3 production is regulated. Here, we show that a physiologically low level of insulin converts CD11c− adipose tissue macrophages (ATMs) into GDF3-producing CD11c+ macrophages ex vivo and directs ALK7-dependent accumulation of fat in vivo. Depletion of ATMs by clodronate upregulates adipose lipases and reduces fat mass in ALK7-intact obese mice, but not in their ALK7-deficient counterparts. Furthermore, depletion of ATMs or transplantation of GDF3-deficient bone marrow negates the in vivo effects of insulin on both lipolysis and fat accumulation in ALK7-intact mice. The GDF3-ALK7 axis between ATMs and adipocytes represents a previously unrecognized mechanism by which insulin regulates both fat metabolism and mass.
Allograft Reconstruction of the Extensor Mechanism after Resection of Soft Tissue Sarcoma

Introduction Soft tissue tumors around the knee joint still pose problems for the excision and subsequent reconstruction. Methods In the 6 included patients the soft tissue sarcoma has its base on the anterior surface of the extensor mechanism and expands towards the skin. The entire extensor apparatus (quadriceps tendon, patella, and patellar tendon) was resected and replaced by a fresh-frozen allograft. Results The mean follow-up was 6.7 years (range: 2–12.4 years). In two patients a local recurrence occurred, resulting in a 5-year local recurrence-free rate of 66.7% (95% CI: 19.5%–90.4%). Distant metastases were found in 4 patients resulting in a 5-year metastasis-free rate of 33.3% (95% CI: 4.6%–67.5%). Two patients underwent at least one revision surgery, including one patient in whom the allograft had to be removed. According to the ISOLS function score 24.7 points (range: 19–28 points) were achieved at the last follow-up. The mean active flexion of the knee joint was 82.5° (range: 25–120°) and a mean extension lag of 10° (range: 0–30°) was observed. Conclusions The replacement of the extensor mechanism by an allograft is a reasonable option, allowing wide margins and restoration of active extension in most patients. Trial Registration The presented study is listed on the ISRCTN registry with trial number ISRCTN63060594.
Noninvasive Quantitative Detection Methods of Liver Fat Content in Nonalcoholic Fatty Liver Disease

Abstract Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to NAFLD-related liver cirrhosis and is a main cause of chronic liver diseases. Patients with nonalcoholic steatohepatitis and fibrosis are at a great risk of the progression to cirrhosis or hepatocellular carcinoma, both of which are tightly associated with liver-related mortality. Liver biopsy is still the gold standard for the diagnosis of NAFLD, but some defects, such as serious complications, sampling error and variability in histologic evaluation among pathologists, remain problematic. Therefore, noninvasive, repeatable and accurate diagnostic methods are urgently needed. Ultrasonography is a well-established and lower-cost imaging technique for the diagnosis of hepatic steatosis, especially suitable for population census, but limited by its low sensitivity to diagnose mild steatosis and being highly operator-dependent. Computed tomography also lacks the sensitivity to detect mild steatosis and small changes in fat content, and presents a potential radiation hazard. Controlled attenuation parameter based on the FibroScan® technology is a promising tool for noninvasive semiquantitative assessment of liver fat content, but the accuracy rate depends on the operator’s expertise and is affected by age, width of the intercostal space, skin capsular distance and body mass index. Magnetic resonance imaging and magnetic resonance spectroscopy are regarded as the most accurate quantitative methods for measuring liver fat content in clinical practice, especially for longitudinal follow up of NAFLD patients. In this review, we mainly introduce the current imaging methods that are in use for evaluation of liver fat content and we discuss the advantages and disadvantages of each method.
Diagnosis of Helicobacter pylori Using Invasive and Noninvasive Approaches

Helicobacter pylori (H. pylori) as gram-negative and spiral microorganism is responsible for colonization in the gastric microniche for more than 50% of world population. Recent studies have shown a critical role of H. pylori in the development of peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. Over the past decade, there has been a sharp interest to use noninvasive tests in diagnosis of the H. pylori infection. During the years after discovery by Marshall and Warren, it has been frequently declared that the rapid urease test (RUT) is one of the cheapest and rapid diagnostic approaches used in detecting the infection. Although the specificity and sensitivity are durable for this test, clinical experiences had shown that the ideal results are only achieved only if we take biopsies from both corpus and antrum at the same time. Given the diagnosis of the H. pylori in clinical samples, gastroenterologists are facing a long list of various molecular and nonmolecular tests. We need more in-depth researches and investigations to correctly generalize rapid and accurate molecular tests determining both bacterial identity and antibiotic resistance profile.
Deep Generative Models with Learnable Knowledge Constraints

The broad set of deep generative models (DGMs) has achieved remarkable advances. However, it is often difficult to incorporate rich structured domain knowledge with the end-to-end DGMs. Posterior regularization (PR) offers a principled framework to impose structured constraints on probabilistic models, but has limited applicability to the diverse DGMs that can lack a Bayesian formulation or even explicit density evaluation. PR also requires constraints to be fully specified {\it a priori}, which is impractical or suboptimal for complex knowledge with learnable uncertain parts. In this paper, we establish mathematical correspondence between PR and reinforcement learning (RL), and, based on the connection, expand PR to learn constraints as the extrinsic reward in RL. The resulting algorithm is model-agnostic to apply to any DGMs, and is flexible to adapt arbitrary constraints with the model jointly. Experiments on human image generation and templated sentence generation show models with learned knowledge constraints by our algorithm greatly improve over base generative models.