Miracle-dz/UniFAR-FTUs huggingface dataset:
APRIL (TNFSF13) regulates collagen‐induced arthritis, IL‐17 production and Th2 response

A proliferation‐inducing ligand (APRIL or TNFSF13) shares receptors with B‐cell activation factor of the TNF family (BAFF) on B and T cells. Although much is known about the function of APRIL in B cells, its role in T cells remains unclear. Blocking both BAFF and APRIL suggested that BAFF and/or APRIL contributed to collagen‐induced arthritis (CIA); however, the role of APRIL alone in CIA remained unresolved. We show here that, in vitro, our newly generated APRIL−/− mice exhibited increased T‐cell proliferation, enhanced Th2 cytokine production under non‐polarizing conditions, and augmented IL‐13 and IL‐17 production under Th2 polarizing conditions. Upon immunization with OVA and aluminum potassium sulfate, APRIL−/− mice responded with an increased antigen‐specific IgG1 response. We also show that in APRIL−/− mice, the incidence of CIA was significantly reduced compared with WT mice in parallel with diminished levels of antigen‐specific IgG2a autoantibody and IL‐17 production. Our data indicate that APRIL plays an important role in the regulation of cytokine production and that APRIL‐triggered signals contribute to arthritis. Blockade of APRIL thus may be a valuable adjunct in the treatment of rheumatoid arthritis.
Folded Marchand Balun Design and Validation Using Sonnet

The Marchand balun has larger bandwidth than other types of combiners and has been used extensively since its introduction. The Marchand balun has also been extensively used in planar systems in both broadsidecoupled and edgedcoupled configu rations. This paper describes the design and development of two microstrip, folded, edgecoupled Marchand baluns for use as antiphase power combiner. The balun formfactor is thus reduced, m aking the circuit more compact and amenable for use in highdensity printed circuit boards.
ScholarWorks@BGSU ScholarWorks@BGSU

: Surface enhanced Raman spectroscopy (SERS) is frequently associated with “ chemical enhancement ” (CE), which is an e ﬀ ect of the chemical coupling between reporting molecules and surfaces. While SERS technique is mainly attributed to the studies of metallic surfaces, chemical coupling must be present on semiconductor surfaces as well. Here, we examine binding of trans -1,2-two(4-pyridyl) ethylene (BPE) to various crystallographic facets of PbSe semiconductor. The calculated o ﬀ -resonant Raman spectra vary signi ﬁ cantly on di ﬀ erent crystallographic facets of PbSe, correlating with the electronic structure of each type of semiconductor surface. We distinguish situations when the charge transfer is present and when it is not, which raises the question about what exactly should be called the “ chemical enhancement ” . We attempt to clarify this situation by introducing the concept of the “ charge-transfer ” and “ charge-transfer-less ” chemical enhancement. We also demonstrate a transition between these two regimes, which exhibits a nonlinear behavior of the vibrational coupling and a signi ﬁ cantly stronger contribution to the Raman intensity.
Treating Opioid Dependence With Injectable Extended-Release Naltrexone (XR-NTX)

Objectives:Once-monthly intramuscular extended-release naltrexone (XR-NTX) has demonstrated efficacy for the prevention of relapse in opioid dependence, providing an alternative to agonist or partial agonist maintenance (ie, methadone and buprenorphine). The question remains, for whom is this unique treatment most efficacious and can patient-treatment matching factors be identified? Methods:A moderator analysis was conducted on a previously reported 24-week, placebo-controlled, multisite, randomized controlled trial of XR-NTX (n = 126) versus placebo (n = 124) among recently detoxified opioid-dependent adults in Russia, which showed XR-NTX superior to placebo in proportion of opioid abstinent weeks. The moderator analysis examined a dichotomous indicator of good clinical response—achieving at least 90% of weeks abstinent over the 24-week trial. A series of logistic regression models were fit for this outcome as functions of treatment (XR-NTX vs placebo), each baseline moderator variable, and their interactions. The 25 baseline variables included demographics, clinical severity (Addiction Severity Index, SF-36, and Clinical Global Impression-Severity), functioning (EQ-5D), craving, and HIV serostatus (HIV+). Results:More XR-NTX patients achieved 90% abstinence (64/126, 51%) versus placebo (39/124, 31%; P = 0.002). There were no significant interactions between baseline variables and treatment. There was a significant main effect of Clinical Global Impression-Severity score (P = 0.02), such that higher severity score was associated with a lower rate of Good Clinical Response. Conclusions:The absence of significant baseline by treatment interactions indicates that no patient-treatment matching variables could be identified. This suggests that XR-NTX was effective in promoting abstinence from opioids across a range of demographic and severity characteristics.
Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey

abstract Objectives: To estimate the prevalence of dysfunctional breathing in adults with asthma treated in the community. Design: Postal questionnaire survey using Nijmegen questionnaire. Setting: One general practice with 7033 patients. Participants: All adult patients aged 17-65 with diagnosed asthma who were receiving treatment. Main outcome measure: Score23 on Nijmegen questionnaire. Results: 227/307 patients returned completed questionnaires; 219 (71.3%) questionnaires were suitable for analysis. 63 participants scored 23. Those scoring 23 were more likely to be female than male (46/132 (35%) v 17/87 (20%), P=0.016) and were younger (mean (SD) age 44.8 (14.7) v 49.0 (13.8, (P=0.05). Patients at different treatment steps of the British Thoracic Society asthma guidelines were affected equally. Conclusions: About a third of women and a fifth of men had scores suggestive of dysfunctional breathing. Although further studies are needed to confirm the validity of this screening tool and these findings, these prevalences suggest scope for therapeutic intervention and may explain the anecdotal success of the Buteyko method of treating asthma. What is already known on this topic Abnormal breathing patterns may cause characteristic symptoms and impair quality of life Effective interventions exist for dysfunctional breathing Dysfunctional breathing has been described in patients attending hospital respiratory clinics What this study adds 29% of adults treated for asthma in primary care had symptoms suggestive of dysfunctional breathing Affected patients were more likely to be female and younger, but no differences were found with severity of asthma Some patients with asthma may benefit from breathing therapy
Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes

Exosomes are nano-sized extracellular vesicles, released from various cells, which can stimulate or repress responses in targets cells. We recently reported that cultured cardiomyocytes are able to release exosomes and that they, in turn, are involved in facilitating events in target cells by alteration of gene expression. We investigated whether external stimuli of the cardiomyocyte might influence the transcriptional content of the released exosomes. Exosomes were isolated from media collected from cultured cardiomyocytes (HL-1) with or without growth factor treatment (TGF-β2 and PDGF-BB), with a series of differential centrifugations, including preparative ultracentrifugation and separation with a sucrose gradient. The exosomes were characterized with dynamic light scattering (DLS), electron microscopy (EM) and Western blot and analyzed with Illumina whole genome microarray gene expression. The exosomes were rounded in shape and had an average size of 50–90 nm in diameter with no difference between treatment groups. Analysis of the mRNA content in repeated experiments conclusively revealed 505 transcripts in the control group, 562 in the TGF-β2-treated group and 300 in the PDGF-BB-treated group. Common transcripts (217) were found in all 3 groups. We show that the mode of stimulation of parental cells affects the characteristics of exosomes released. Hence, there is a difference in mRNA content between exosomes derived from cultured cardiomyocytes stimulated, or not stimulated, with growth factors. We also conclude that all exosomes contain a basic package consisting of ribosomal transcripts and mRNAs coding for proteins with functions within the energy supply system.
Wnt/β‐Catenin/TCF Pathway Is a Phase‐Dependent Promoter of Colony Formation and Mesendodermal Differentiation During Human Somatic Cell Reprogramming

Somatic cell reprogramming is a biphasic phenomenon that goes through a mesenchymal‐to‐epithelial transition, called initiation phase, followed by a maturation phase wherein reprogramming cells acquire pluripotency. Here, we show that these phases display a differential response to Wnt signaling activation. Wnt signaling increases colony formation by promoting cellular epithelialization during the initiation phase in a TCF7‐dependent manner. However, during maturation phase, it is also responsible for inducing mesendodermal differentiation, which is negatively regulated by TCF7L1. Thus, Wnt signaling inhibition or TCF7L1 overexpression downregulates mesendodermal gene expression without perturbing pluripotency. Together, our results demonstrate that a phase‐specific modulation of Wnt signaling leads to an improved reprogramming efficiency in terms of colony output and pluripotency acquisition. This work provides new insights into the cell context‐dependent roles of Wnt signaling during human somatic cell reprogramming. Stem Cells 2018;36:683–695
Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones

The misfolding of proteins and their accumulation in extracellular tissue compartments as insoluble amyloid or amorphous protein aggregates are a hallmark feature of many debilitating protein deposition diseases such as Alzheimer's disease, prion diseases, and type II diabetes. The plasminogen activation system is best known as an extracellular fibrinolytic system but was previously reported to also be capable of degrading amyloid fibrils. Here we show that amorphous protein aggregates interact with tissue-type plasminogen activator and plasminogen, via an exposed lysine-dependent mechanism, to efficiently generate plasmin. The insoluble aggregate-bound plasmin is shielded from inhibition by α2-antiplasmin and degrades amorphous protein aggregates to release smaller, soluble but relatively hydrophobic fragments of protein (plasmin-generated protein fragments (PGPFs)) that are cytotoxic. In vitro, both endothelial and microglial cells bound and internalized PGPFs before trafficking them to lysosomes. Clusterin and α2-macroglobulin bound to PGPFs to significantly ameliorate their toxicity. On the basis of these findings, we hypothesize that, as part of the in vivo extracellular proteostasis system, the plasminogen activation system may work synergistically with extracellular chaperones to safely clear large and otherwise pathological protein aggregates from the body.
TIMING BEHAVIOR OF THE MAGNETICALLY ACTIVE ROTATION-POWERED PULSAR IN THE SUPERNOVA REMNANT KESTEVEN 75

We report a large spin-up glitch in PSR J1846−0258 which coincided with the onset of magnetar-like behavior on 2006 May 31. We show that the pulsar experienced an unusually large glitch recovery, with a recovery fraction of Q = 8.7 ± 2.5, resulting in a net decrease of the pulse frequency. Such a glitch recovery has never before been observed in a rotation-powered pulsar (RPP); however, similar but smaller glitch over-recovery has been recently reported in the magnetar AXP 4U 0142+61 and may have occurred in SGR 1900+14. We also report a large increase in the timing noise of the source. We discuss the implications of the unusual timing behavior in PSR J1846−0258 on its status as the first identified magnetically active RPP.
Particles as Field Singularities in the Unified Algebraic Dynamics

Nonlinear generalization of Cauchy-Riemann equations to the algebra of biquaternions is considered. In a particular case the latters reduce to the “iversal generating equations” which deal with the 2-spinor and the gauge fields and form the basis of a unified algebraic field theory. For every solution to universal generating equations the components of spinor field satisfy both the eikonal and the wave equations while the strengths of gauge field both Maxwell and Yang-Mills equations. Making use of their specific (“ak”) gauge symmetry, we we reduce universal equations to the equations of shear-free null congruence and, applying the Kerr theorem, integrate them in twistor variables . Particles are considered as bounded singularities of effective metric and electromagnetic fields. For fundamental unisingular solution electric charge of (pointor ring-like) singular source is fixed in magnitude (generally quantized), and related Kerr-Schild metric is of Reisner-Nördstrem or Kerr-Newman type respectively. The value of quadrupole electric moment for the electron is also predicted. Multisingular solutions are presented and briefly discussed.
The Role of Cytotoxic and Regulatory T cells in Relapsed/Refractory Hodgkin Lymphoma

Recent data suggests the presence of cytotoxic (TIA-1 and granzyme B+) and regulatory T-cells (FOXP3+) in classical Hodgkin lymphoma (cHL) tissues has been shown to correlate with poor overall survival in mainly diagnostic biopsies. By tissue microarray analyses, we extend this observation to a cohort of relapsed/refractory cHL tissue biopsies and analyze immunohistochemical expression of FOXP3, TIA-1, and granzyme B in the inflammatory background and the tumor microenvironment. High expression of TIA-1 (>50%) correlated with poor overall survival (P<0.0001), low expression of FOXP3 (<25%) correlated with poor overall survival (P<0.01), and combined high TIA-1 (>50%) and low FOXP3 (<25%) correlated with poor overall survival (P<0.0001). Expression of cytotoxic and regulatory T-cells shows prognostic significance in the relapsed/refractory clinical setting of cHL.
A Monte Carlo Investigation of Partial Least Squares, With Implications for Both Structural and Measurement Models

Partial Least Squares (PLS) is a popular technique with extensive adoption within the Information Systems research community. However, the statistical performance of PLS has not been extensively studied, and recent research has questioned some of its purported advantages. The simulation study reported here analyzed the performance of PLS with regards to the recovery and estimation accuracy of both structural and measurement parameters. Somewhat surprisingly, the effects of estimation bias on the latter and their implications for the evaluation of measurement models have not been the focus of past research. Results show the existence of an important degree of bias in both sets of estimates, and the conflicting effect of increased sample size with additional indicators per composite variable.
Discovery of Regulators of Receptor Internalization with High-Throughput Flow Cytometry

We developed a platform combining fluorogen-activating protein (FAP) technology with high-throughput flow cytometry to detect real-time protein trafficking to and from the plasma membrane in living cells. The hybrid platform facilitates drug discovery for trafficking receptors such as G protein-coupled receptors and was validated with the β2-adrenergic receptor (β2AR) system. When a chemical library containing ∼1200 off-patent drugs was screened against cells expressing FAP-tagged β2ARs, all 33 known β2AR-active ligands in the library were successfully identified, together with a number of compounds that might regulate receptor internalization in a nontraditional manner. Results indicated that the platform identified ligands of target proteins regardless of the associated signaling pathway; therefore, this approach presents opportunities to search for biased receptor modulators and is suitable for screening of multiplexed targets for improved efficiency. The results revealed that ligands may be biased with respect to the rate or duration of receptor internalization and that receptor internalization may be independent of activation of the mitogen-activated protein kinase pathway.
Identifying the synaptic origin of ongoing neuronal oscillations through spatial discrimination of electric fields

Although intracerebral field potential oscillations are commonly used to study information processing during cognition and behavior, the cellular and network processes underlying such events remain unclear. The limited spatial resolution of standard single-point recordings does not clarify whether field oscillations reflect the activity of one or many afferent presynaptic populations. However, multi-site recording devices now provide high-resolution spatial profiles of local field potentials (LFPs) and when coupled to modern mathematical analyses that discriminate signals with distinct but overlapping spatial distributions, they open the door to better understand these potentials. Here we review recent insights that help disentangle certain pathway-specific activities. Accordingly, some oscillatory patterns can now be viewed as a periodic succession of synchronous synaptic currents that reflect the time envelope of spiking activity in given presynaptic populations. These analyses modify our concept of brain rhythms as abstract entities, molding them into mechanistic representations of network activity and allowing us to work in the time domain, reducing the loss of information inherent to data-chopping frequency treatment.
Transplantation of hNT neurons into the ischemic cortex: Cell survival and effect on sensorimotor behavior

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory‐motor function. hNT‐transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors. © 2006 Wiley‐Liss, Inc.
Assessing identity, phenotype, and fate of endothelial progenitor cells.

From the paradigm shifting observations of Harvey, Malpighi, and van Leeuwenhoek, blood vessels have become recognized as distinct and dynamic tissue entities that merge with the heart to form a closed circulatory system.1 Vessel structures are comprised predominantly of a luminal layer of endothelial cells that is surrounded by some form of basement membrane, and mural cells (pericytes or vascular smooth muscle cells) that make up the vessel wall. In larger more complex vessel structures the vessel wall is composed of a complex interwoven matrix with nerve components. Understanding the cellular and molecular basis for the formation, remodeling, repair, and regeneration of the vasculature have been and continue to be popular areas for investigation. The endothelium has become a particularly scrutinized cell population with the recognition that these cells may play important roles in maintaining vascular homeostasis and in the pathogenesis of a variety of diseases.2 Although it has been known for several decades that some shed or extruded endothelial cells enter the circulation as apparent contaminants in the human blood stream,3 only more recent technologies have permitted the identification of not only senescent sloughed endothelial cells,4 but also endothelial progenitor cells (EPCs), which have been purported to represent a normal component of the formed elements of circulating blood5 and play roles in disease pathogenesis.6–9 Most citations refer to an article published in 1997 in which Asahara and colleagues isolated, characterized, and examined the in vivo function of putative EPCs from human peripheral blood as a major impetus for generating interest in the field.10 This seminal article presented some evidence to consider emergence of a new paradigm for the process of neovascularization in the form of postnatal vasculogenesis. Since publication of that article, interest in circulating endothelial cells, and particularly EPCs, has soared, …
Neural Correlates of Auditory Perception in Williams Syndrome: An fMRI Study

Williams syndrome (WS), a neurogenetic developmental disorder, is characterized by a rare fractionation of higher cortical functioning: selective preservation of certain complex faculties (language, music, face processing, and sociability) in contrast to marked and severe deficits in nearly every other cognitive domain (reasoning, spatial ability, motor coordination, arithmetic, problem solving). WS people are also known to suffer from hyperacusis and to experience heightened emotional reactions to music and certain classes of noise. We used functional magnetic resonance imaging to examine the neural basis of auditory processing of music and noise in WS patients and age-matched controls and found strikingly different patterns of neural organization between the groups. Those regions supporting music and noise processing in normal subjects were found not to be consistently activated in the WS participants (e.g., superior temporal and middle temporal gyri). Instead, the WS participants showed significantly reduced activation in the temporal lobes coupled with significantly greater activation in the right amygdala. In addition, WS participants (but not controls) showed a widely distributed network of activation in cortical and subcortical structures, including the brain stem, during music processing. Taken together with previous ERP and cytoarchitectonic studies, this first published report of WS using fMRI provides additional evidence of a different neurofunctional organization in WS people than normal people, which may help to explain their atypical reactions to sound. These results constitute an important first step in drawing out the links between genes, brain, cognition, and behavior in Williams syndrome.