Miracle-dz/UniFAR-FTUs huggingface dataset:
Transfection efficiency of lipoplexes for site-directed delivery

Targeted gene delivery is a promising strategy to cure disease on its basic level at the site of interest. The ultrastructure, internalization, and transfection efficiency of lipoplexes was investigated. We found that at a charge ratio (ρ) of 4.0 lipoplexes had optimum characteristics for gene delivery in vitro. To decrease the size of lipoplexes, we used a method of continuous-flow microfluidics. PEGylation of lipoplexes did not hinder internalization, but was found to hamper transfection. To discriminate between uptake and transfection efficiency of lipoplexes, we used fluorescence-based approaches: microscopy and FACS. To this end, GFP plasmid was labeled with Alexa 594, and, in parallel experiments, GFP plasmid was combined with rhodamine-labeled lipid. Our studies confirm that cellular uptake does not imply transfection efficiency, and that hurdles in cellular processing have to be taken before targeted gene delivery becomes an established therapeutic option.
On the motion of viscous shocks and the supersensitivity of their steady-state limits

This paper constructs an asymptotic shock-layer solution to the initialboundary-value problem for the partial differential equation e(f(u)ux)x + g(u)ux = ut in a finite spatial domain with nearly-Dirichlet boundary conditions and, to a much lesser extent, for the reaction-diffusion equation e(f(u)ux)x + h(u) = ut. Using an exponentially compressed time scale, it provides a differential equation for the shock layer's motion which displays both the slow convergence of the shock to its steady state and the extreme sensitivity of its location to perturbations in coefficients and/or boundary conditions. The key to the analysis is the appropriate handling of asymptotically exponentially small terms.
Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline

The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4‐ and 1.4‐fold, respectively, whereas peak exposure (Cmax) increased 6.2‐fold and 1.3‐fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1‐mediated hepatic uptake of eluxadoline (during first‐pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3‐mediated basolateral uptake in the proximal renal tubules and MRP2‐mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.
The critical role of IL-6 in the pathogenesis of Takayasu arteritis.

OBJECTIVES To investigate T cell subsets and immune cytokine profiles in untreated Takayasu arteritis (TAK) patients and the underlying immunopathological mechanism. METHODS We enrolled 50 untreated TAK patients and 40 age-matched controls (20 healthy controls, 20 untreated SLE patients). Enzyme-linked immunosorbent assays (ELISAs) were used to define cytokine profiles in all patients, and flow cytometry was performed for 9 TAK patients and 12 healthy controls. Hematoxylin and eosin (Handamp;E) staining and immunohistochemistry (IHC) were performed in aortic tissues of 9 TAK and 9 atherosclerosis patients; clinical data were also collected. RESULTS Circulating CD4(+) T cells were more frequent in TAK patients (p<0.05). Frequencies of Th1, Th2, and Th17 cells were higher, whereas Treg cells were reduced in TAK. Significantly higher levels of IL-6 and lower levels of IFN-γ, IL-4, and IL-17 were detected in TAK patients (p<0.05). By H & E staining, thickened vascular walls with proliferation of collagen fibre were observed in most patients. Inflammatory sites with infiltrating macrophages, lymphocytes, and neutrophils were located in adventitia. IHC revealed T cells (mainly CD4(+) T cells) in vascular lesions. Additionally, IL-6 was positive throughout the vascular wall in most specimens, whereas IFN-γ, IL-12, and IL-17 were detected in inflammatory sites of active patients. IL-6 levels were positively related to ESR, CRP, and Kerr scores (p<0.05). CONCLUSIONS Significantly increased levels of IL-6 were detected in peripheral blood and aortic tissues of untreated patients. IL-6 might be a sensitive biomarker to assess disease activity and could be critical in the immunopathogenesis of TAK.
Function and expression of sulfonylurea, adrenergic, and glucagon‐like peptide 1 receptors in isolated porcine islets

The scarcity of human cadaveric pancreata limits large‐scale application of islet transplantation for patients with diabetes. Islets isolated from pathogen‐free pigs provide an economical and abundant alternative source assuming immunologic barriers are appropriate. Membrane receptors involved in insulin secretion that also have potential as imaging targets were investigated in isolated porcine islets. Quantitative (q)PCR revealed that porcine islets express mRNA transcripts for sulfonylurea receptor 1 (Sur1), inward rectifying potassium channel (Kir6.2, associated with Sur1), glucagon‐like peptide 1 receptor (GLP1R), and adrenergic receptor alpha 2A (ADRα2A). Receptor function was assessed in static incubations with stimulatory glucose concentrations, and in the presence of receptor agonists. Glibenclamide, an anti‐diabetic sulfonylurea, and exendin‐4, a GLP‐1 mimetic, potentiated glucose‐stimulated insulin secretion >2‐fold. Conversely, epinephrine maximally reduced insulin secretion 72 ± 9% (P < 0.05) and had a half maximal inhibitory concentration of 60 nm in porcine islets (95% confidence interval of 45–830 nm). The epinephrine action was inhibited by the ADRα2A antagonist yohimbine. Our findings demonstrate that porcine islets express and are responsive to both stimulatory and inhibitory membrane localized receptors, which can be used as imaging targets after transplantation or to modify insulin secretion.
Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study

Objectives To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. Design Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. Participants 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. Setting Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. Results Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a “way of life” rather than an “illness. ” Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers' familiarity with the patients' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a “chaos narrative” of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. Conclusions Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation.
Effect of Air Injection on the Cloud Cavitation of a Hydrofoil

This paper describes experiments investigating the effects of air injection on the cloud cavitation of an oscillating hydrofoil. The effects of continuous air injection were investigated using two different hydrofoils. Measurements of the acoustic pressure were made on the downstream test section floor and on the surface of one of hydrofoils, and the extent of noise reduction provided by air injection at various volume flow rates was determined. The acoustic surface pressure measurements were also correlated with visual observations made using high speed motion pictures of the cloud cavitation. Thus the effects of continuous air injection on specific cavitation structures could be identified. In addition, the effectiveness of pulsed air injection in achieving greater reductions in cavitation noise at volume flow rates equal to those used in continuous air injection experiments was investigated.
FEED MANUFACTURING CONSIDERATIONS FOR USING DDGS IN POULTRY AND LIVESTOCK DIETS

While not a new ingredient in livestock feed, the volume available and the relative price of DDGS have forced many feed manufacturers into using greater levels than ever before. The use of DDGS has caused feed manufacturing problems at nearly every phase of feed manufacturing. These include railcars that simply won’t unload, feeder screws and supply bins that are wrong for the ingredient, nutrient variation that results in out-of-spec feeds leaving the feed mill, and, of greatest concern, pellet throughput and pellet quality concerns. Nearly all of these problems are the result of the physical properties of DDGS and of the way a particular ethanol facility might manage their byproducts.
Once Bitten , Twice Shy ? The Lasting Impact of IRS Audits on Individual Tax Reporting

This paper studies the impact of tax enforcement activity on subsequent individual taxpaying behavior. We exploit three waves of randomized Internal Revenue Service (IRS) audits of individual income tax filers during the 2006-2009 period to study both the short and long run effects of audits on taxpaying behavior. Rich and confidential IRS data allow us to discover several effects on post-audit taxpaying behavior. First, we find that taxpayers respond to audits by increasing reported taxable income. This impact is stronger but more quickly diminishing for incomes not subject to third-party information. Second, individuals with higher income volatility are found to owe more tax, conceivably because of a larger degree of asymmetric information between the filer and enforcement agency. Finally, we find larger and more persistent responses among those who are less tax literate. Overall, the IRS’s revenue gain from the long-term impact of audits is about twice as large as the revenue gained directly from the audit itself.
Color obsessions and phobias in autism spectrum disorders: The case of J.G.

The current study is the first investigation of color ‘obsessions’ and ‘phobias’ in ASD. We investigate the color perception and cognition of J.G. , a boy with ASD who has a strong obsession with blue, and a strong phobia of other colors. J.G. ’s performance on a series of color tasks (color-entity association; chromatic discrimination; color classification) is compared to 13 children with and without autism who do not have color obsessions or phobias. The findings lead to the formalization of two hypotheses: (i) color obsessions and phobias in individuals with ASD are related to an unusually strong ability to associate colors with entities; (ii) color obsessions are related to hyposensitivity, and color phobias to hypersensitivity, in the affected regions of color space.
How Do You Feel when You Can't Feel Your Body? Interoception, Functional Connectivity and Emotional Processing in Depersonalization-Derealization Disorder

Depersonalization-Derealization Disorder (DD) typically manifests as a disruption of body self-awareness. Interoception −defined as the cognitive processing of body signals− has been extensively considered as a key processing for body self-awareness. In consequence, the purpose of this study was to investigate whether there are systematic differences in interoception between a patient with DD and controls that might explain the disembodiment symptoms suffered in this disease. To assess interoception, we utilized a heartbeat detection task and measures of functional connectivity derived from fMRI networks in interoceptive/exteroceptivo/mind-wandering states. Additionally, we evaluated empathic abilities to test the association between interoception and emotional experience. The results showed patient's impaired performance in the heartbeat detection task when compared to controls. Furthermore, regarding functional connectivity, we found a lower global brain connectivity of the patient relative to controls only in the interoceptive state. He also presented a particular pattern of impairments in affective empathy. To our knowledge, this is the first experimental research that assesses the relationship between interoception and DD combining behavioral and neurobiological measures. Our results suggest that altered neural mechanisms and cognitive processes regarding body signaling might be engaged in DD phenomenology. Moreover, our study contributes experimental data to the comprehension of brain-body interactions and the emergence of self-awareness and emotional feelings.
Sertoli-cell-specific knockout of connexin 43 leads to multiple alterations in testicular gene expression in prepubertal mice

SUMMARY A significant decline in human male reproductive function has been reported for the past 20 years but the molecular mechanisms remain poorly understood. However, recent studies showed that the gap junction protein connexin-43 (CX43; also known as GJA1) might be involved. CX43 is the predominant testicular connexin (CX) in most species, including in humans. Alterations of its expression are associated with different forms of spermatogenic disorders and infertility. Men with impaired spermatogenesis often exhibit a reduction or loss of CX43 expression in germ cells (GCs) and Sertoli cells (SCs). Adult male transgenic mice with a conditional knockout (KO) of the Gja1 gene [referred to here as connexin-43 (Cx43)] in SCs (SCCx43KO) show a comparable testicular phenotype to humans and are infertile. To detect possible signaling pathways and molecular mechanisms leading to the testicular phenotype in adult SCCx43KO mice and to their failure to initiate spermatogenesis, the testicular gene expression of 8-day-old SCCx43KO and wild-type (WT) mice was compared. Microarray analysis revealed that 658 genes were significantly regulated in testes of SCCx43KO mice. Of these genes, 135 were upregulated, whereas 523 genes were downregulated. For selected genes the results of the microarray analysis were confirmed using quantitative real-time PCR and immunostaining. The majority of the downregulated genes are GC-specific and are essential for mitotic and meiotic progression of spermatogenesis, including Stra8, Dazl and members of the DM (dsx and map-3) gene family. Other altered genes can be associated with transcription, metabolism, cell migration and cytoskeleton organization. Our data show that deletion of Cx43 in SCs leads to multiple alterations of gene expression in prepubertal mice and primarily affects GCs. The candidate genes could represent helpful markers for investigators exploring human testicular biopsies from patients showing corresponding spermatogenic deficiencies and for studying the molecular mechanisms of human male sterility.
Event Related Potentials: A Study of the Processing of Gapping Structures in Adolescents

EVENT RELATED POTENTIALS: A STUDY OF THE PROCESSING OF GAPPING STRUCTURES IN ADOLESCENTS Michelle M. Nishida Department of Audiology and Speech-Language Pathology Master of Science Many questions remain unanswered regarding the intricacies of the human brain, especially with regard to the complexities of language processing. One essential component of human sentence processing is the ability to detect, decipher, and recover from errors in the interpretation of both verbal and written language. This process of repair of ungrammatical sentences and revision or reinterpretation of ambiguous sentences has been studied extensively in recent years. A variety of tools have been developed, including the use of event-related potentials (ERPs) in order to assess how language is processed and developed, and to help better identify the nature of these processes. The purpose of this study was to compare event-related potential effects of speech processing of spoken and written sentences containing both incorrect and correct semantic and syntactic information. Specifically, sentences containing correct and incorrect gapping structures, each with a “missing” verb, were presented along with other grammatical and ungrammatical sentences in order to elicit and measure the P300, N400, and P600 amplitudes and latencies. The aim was to determine some of the commonalities and differences in these electrophysiological responses via the auditory and visual modalities. Two experiments were conducted with each participant, one in the auditory modality, and one within the visual using two sets of stimuli. Amplitude and topography differences were noted within and between modalities for each of the components (P300, N400, and P600), as well as between stimulus types. Significant findings suggest that in the adolescent population, incorrect gapping structures are generally processed as semantic errors, as evidenced by the N400 response, followed by the P600 response in both the auditory and visual modalities. The exact nature of the P600 component within gapping structures remains unclear. Of particular interest was the involvement of the occipital area of the brain for the processing of gapping structures. Minimal differences were noted overall between adolescents and the adult populations.
Information Technology Attachment and continuance

An important task in Information Systems research is to understand factors that influence the continuous use of information technology (IT). This study extends the literature by conceptualizing a construct called IT attachment to explain the phenomenon. Drawing upon the attachment theory in developmental and social psychology, it suggests that IT attachment, defined as an affective bond of the IT users to IT, is a determinant of the users’ satisfaction with IT and its continuance intention. Factors that influence the development of IT attachment are also analyzed, including IT confirmation, perceived usefulness, perceived ease of use, and IT playfulness.
Oncolytic Viral Therapy for Mesothelioma

The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1–2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma.
The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response

The unfolded protein response (UPR) is an evolutionarily conserved mechanism by which all eukaryotic cells adapt to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring kinase 1 (IRE1) and PKR-related ER kinase (PERK) are two type I transmembrane ER-localized protein kinase receptors that signal the UPR through a process that involves homodimerization and autophosphorylation. To elucidate the molecular basis of the ER transmembrane signaling event, we determined the x-ray crystal structure of the luminal domain of human IRE1α. The monomer of the luminal domain comprises a unique fold of a triangular assembly of β-sheet clusters. Structural analysis identified an extensive dimerization interface stabilized by hydrogen bonds and hydrophobic interactions. Dimerization creates an MHC-like groove at the interface. However, because this groove is too narrow for peptide binding and the purified luminal domain forms high-affinity dimers in vitro, peptide binding to this groove is not required for dimerization. Consistent with our structural observations, mutations that disrupt the dimerization interface produced IRE1α molecules that failed to either dimerize or activate the UPR upon ER stress. In addition, mutations in a structurally homologous region within PERK also prevented dimerization. Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling.
Corticosterone Concentrations Reflect Parental Expenditure in Contrasting Mating Systems of Two Coucal Species

The period of parental care can be a demanding life-history stage because parents need to find sufficient resources to feed themselves and their offspring. Often, this is reflected by elevated baseline levels of glucocorticoids – hormones that regulate metabolism and energy allocation. During 10 breeding seasons, we studied plasma corticosterone (the major avian glucocorticoid) concentrations as a physiological correlate of parental expenditure in two closely related coucal species with fundamentally different mating systems: the sex-role reversed black coucal (Centropus grillii) with female competition and male-only care and the socially monogamous and biparental white-browed coucal (C. superciliosus). The two species live in the same habitat and share a similar breeding biology. However, female black coucals aggressively defend a territory and produce many eggs for their various male partners, and male black coucals feed their offspring much more frequently and rest less often than female and male white-browed coucals. These differences were reflected in baseline and stress-induced concentrations of corticosterone: male black coucals had higher baseline and stress-induced corticosterone concentrations when they were feeding young than outside a feeding context, and also the concentrations of female black coucals were higher during the main period of breeding when they defended territories and produced multiple clutches. In contrast, baseline and stress-induced concentrations of corticosterone in female and male white-browed coucals did not differ between periods when they were feeding young and periods without dependent offspring. Paradoxically, on an individual basis feeding effort was negatively related to baseline corticosterone in male black coucals and female white-browed coucals. In conclusion, corticosterone concentrations of coucals reflected differences in competition and parental roles and support the notion that a switch from biparental to uniparental care and an increase in mate competition may come at a physiological and energetic cost.