Miracle-dz/UniFAR-FTUs huggingface dataset:
Heterotypic Neuraminidase Antibodies Against Different A(H1N1) Strains are Elicited after Seasonal Influenza Vaccination

Neuraminidase (NA) content is not standardized in current seasonal influenza vaccines; neither anti-NA antibodies (anti-NA Abs) are measured nor is it well-defined as a correlate of humoral protection. In this work, the presence of NA1 antibodies against classical A(H1N1) and A(H1N1) pdm09 subtypes was studied before and after vaccination with seasonal vaccines containing A/California/07/2009 strain (A(H1N1) pdm09 subtype). By Enzyme-Linked Lectin Assay (ELLA; Consortium for the Standardization of Influenza Seroepidemiology), we analyzed serum samples from two different cohorts (adults and elderly). The presence of anti-NA Abs at titers ≥1/40 against classical A(H1N1) and A(H1N1) pdm09 subtypes were frequently found in both age groups, in 81.3% and 96.3% of adults and elderly, respectively. The higher titers of anti-NA Abs (NAI titers) were detected more frequently against classical A(H1N1) strains according to the expected age when the first flu infection takes place. In this way, an Original Antigenic Sin phenomenon related to NA seems to be part of the immune response against flu. Seasonal-vaccination induced homologous seroconversion against NA of A(H1N1) pdm09 subtype in 52.5% and 55.0%, and increased the Geometric Mean Titers (GMTs) in 70.0% and 78.8% of adults and elderly, respectively. Seasonal vaccination also induced a heterotypic anti-NA Abs response against classical A(H1N1) strains (seroconversion at least in 8.8% and 11.3% of adults and elderly, respectively, and an increase in GMTs of at least 28.0% in both age groups). These anti-NA Abs responses occur even though the seasonal vaccine does not contain a standardized amount of NA. This work demonstrates that seasonal vaccines containing the A(H1N1) pdm09 subtype induce a broad antibody response against NA1, that may be a target for future influenza vaccines. Our study is one of the first to analyze the presence of Abs against NA and the response mediated by NAI titers after seasonal influenza vaccination.
Evaluation of Intravenously Delivered Allogeneic Mesenchymal Stem Cells for Treatment of Elbow Osteoarthritis in Dogs: A Pilot Study

Abstract Objectives The aim of this study was to evaluate the safety and collect pilot data measuring clinical effects of intravenously administered, adipose-derived, culture-expanded, allogeneic mesenchymal stem cells in dogs with elbow osteoarthritis. Materials and Methods Dogs (n = 13) with naturally occurring elbow osteoarthritis received three intravenous doses of allogeneic canine mesenchymal stem cells via an open-label clinical trial. Primary outcome measures collected over a 6-month study period included objective gait analysis, accelerometry, owner questionnaires and joint fluid analysis. Results No acute adverse events were observed following repeated intravenous treatment with allogeneic mesenchymal stem cells. A significant improvement in mean client-specific outcome measure (CSOM) activity score and CSOM behaviour score was observed when pre-treatment values were compared with post-treatment values (day >28). In contrast, mean peak vertical force significantly decreased from baseline to post-treatment (>day 28). Weekly activity counts did not show a significant difference between baseline to post-treatment time points. Synovial fluid biomarkers did not change during treatment, and labelled mesenchymal stem cells were rarely detected in synovial fluid samples collected after mesenchymal stem cell administration. Clinical Significance For dogs with naturally occurring elbow osteoarthritis, intravenous administration of mesenchymal stem cells was clinically well tolerated. While some subjective outcome measures showed significant improvements, objective outcome measures did not confirm similar changes. Further research is needed before intravenous mesenchymal stem cells can be recommended as a treatment for elbow osteoarthritis in dogs.
End-of-Life Preparations Among LGBT Older Canadian Adults: The Missing Conversations

LGBT (lesbian, gay, bisexual, and transgender) older adults are more likely than their heterosexual peers to age with limited support in stigmatizing environments often poorly served by traditional social services challenging their preparedness for end of life. Fourteen focus groups and three individual interviews were conducted in five Canadian cities with gay/bisexual men (5 groups; 40 participants), lesbian/bisexual women (5 groups; 29 participants), and transgender persons (3 interviews, 4 groups; 24 participants). Four superordinate themes were identified: (a) motivators and obstacles, (b) relationship concerns, (c) dynamics of LGBT culture and lives, and (d) institutional concerns. Several pressing issues emerged including depression and isolation (more common among gay and bisexual men), financial/class issues (lesbian and bisexual women), and uncomfortable interactions with health-care providers (transgender participants). These findings highlight the challenges and complexities in end-of-life preparation within LGBT communities.
Role of Serotonergic System in the Antidepressant Actions of mGlu2/3 Receptor Antagonists: Similarity to Ketamine

Numerous studies have demonstrated the antidepressant effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists in various rodent models. Importantly, it has been shown that the antidepressant effects of mGlu2/3 receptor antagonists in rodent models are similar to those of ketamine, which exerts rapid and long-lasting antidepressant effects in patients with major depressive disorders, including patients with treatment-resistant depression. In addition, the synaptic mechanisms underlying the effects of mGlu2/3 receptor antagonists are reported to be similar to those underlying the effects of ketamine. The roles of the serotonergic system in the antidepressant effects of mGlu2/3 receptor antagonists have recently been demonstrated. Moreover, it was investigated how mGlu2/3 receptor antagonists interact with the serotonergic system to exert antidepressant effects. Notably, the same neural mechanisms as those underlying the effects of ketamine may be involved in the antidepressant actions of the mGlu2/3 receptor antagonists. In this review, we shall summarize the antidepressant potential of mGlu2/3 receptor antagonists and their mechanisms of action in comparison with those of ketamine. In particular, we shall focus on the roles of the serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists.
Comparing models with one versus multiple myosin-binding sites per actin target zone: The power of simplicity

Mechanokinetic statistical models describe the mechanisms of muscle contraction on the basis of the average behavior of a large ensemble of actin–myosin motors. Such models often assume that myosin II motor domains bind to regularly spaced, discrete target zones along the actin-based thin filaments and develop force in a series of strain-dependent transitions under the turnover of ATP. The simplest models assume that there is just one myosin-binding site per target zone and a uniform spatial distribution of the myosin motor domains in relation to each site. However, most of the recently developed models assume three myosin-binding sites per target zone, and some models include a spatially explicit 3-D treatment of the myofilament lattice and thereby of the geometry of the actin–myosin contact points. Here, I show that the predictions for steady-state contractile behavior of muscle are very similar whether one or three myosin-binding sites per target zone is assumed, provided that the model responses are appropriately scaled to the number of sites. Comparison of the model predictions for isometrically contracting mammalian muscle cells suggests that each target zone contains three or more myosin-binding sites. Finally, I discuss the strengths and weaknesses of one-site spatially inexplicit models in relation to three-site models, including those that take into account the detailed 3-D geometry of the myofilament lattice. The results of this study suggest that single-site models, with reduced computational cost compared with multisite models, are useful for several purposes, e.g., facilitated molecular mechanistic insights.
Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Objective There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC). Design Male Mdr2 −/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/− /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/− -associated intestinal dysbiosis was studied by microbiota transfer experiments. Results Mdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature. Conclusions MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
Elevated Plasma Growth and Differentiation Factor-15 is Associated with Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults.

BACKGROUND Growth and differentiation factor-15 (GDF-15) has been associated with obesity, muscle wasting, and cachexia. The receptor for GDF-15 was recently identified in the brainstem and regulates food intake and metabolism. The relationship of plasma GDF-15 with the age-associated decline of muscle mass and strength, gait speed, and physical performance in adults has not been well characterized. METHODS Plasma GDF-15, grip strength, 6-m gait speed, 400-m walking test time, lower extremity physical performance score, appendicular lean mass, and fat mass were measured in 194 healthy adult participants, 22-93 years, of the Baltimore Longitudinal Study of Aging. RESULTS Plasma GDF-15 concentrations increased with age (P <0.001) and were higher in whites compared with blacks and Asians (P = 0.04). Adults with higher plasma GDF-15 had slower 6-m gait speed, longer 400-m walking time, and lower physical performance score in multivariable analyses adjusting for age and race. Plasma GDF-15 was not associated with grip strength, appendicular lean mass, or fat mass. CONCLUSIONS Elevated plasma GDF-15 is associated with slower gait speed, higher 400-m walking time, and lower physical performance in very healthy community-dwelling adults. The relationship between plasma GDF-15 and sarcopenia-related outcomes may be stronger in the population not selected to be healthy, and this hypothesis should be tested in a representative population.
SmellSpace: An Odor-Based Social Network as a Platform for Collecting Olfactory Perceptual Data

Abstract A common goal in olfaction research is modeling the link between odorant structure and odor perception. Such modeling efforts require large data sets on olfactory perception, yet only a few of these are publicly and freely available. Given that individual odor perception may be informative on personal makeup and interpersonal relationships, we hypothesized that people would gladly provide olfactory perceptual estimates in the context of an odor-based social network. We developed a web-based infrastructure for such a network we called SmellSpace and distributed 10 000 scratch-and-sniff registration booklets each containing a subset of 12 out of 35 microencapsulated odorants. Within ~100 days, we obtained data from ~1000 participants who rated the odorants along 13 verbal descriptors. To verify that these estimates are comparable to lab-collected estimates we tested 26 participants in a controlled lab setting using the same odorants and descriptors. We observed remarkably high overall group correlations between lab and SmellSpace data, implying that this method provides for credible group-representations of odorants. We further estimated the usability of the data by applying to it two previously published models that used odorant structure alone to predict either odorant pleasantness or pairwise odorant perceptual similarity. We observed statistically significant predictions in both cases, thus further implying that the current data may be helpful toward future efforts of modeling olfactory perception from structure. We conclude that an odor-based social network is a potentially useful instrument for collecting extensive data on olfactory perception and here post the complete raw data set from the first ~1000 participants.
Bone Conduction Amplification in Children: Stimulation via a Percutaneous Abutment versus a Transcutaneous Softband

Objectives: Research suggests that the speech perception of children using bone conduction amplification improves if the device is coupled to an implanted abutment rather than to a softband. The purpose of the present study was to determine if the benefit of direct stimulation via an abutment is limited to small improvements in speech perception or if similar or greater benefits occur for other auditory tasks important for learning and communication. Design: Fourteen children (7 to 15 years of age) with bilateral conductive and three children with unilateral conductive or sensorineural hearing loss were enrolled. Each child completed four tasks while using a bone conduction device coupled to an implanted abutment and with the device coupled to a softband. The two devices were worn at the same time and activated one at a time for testing. The children completed four tasks under each coupling condition: (a) a traditional word recognition task, (b) an auditory lexical decision task in which the children repeated aloud, and indicated the category of, real and nonsense words, (c) a nonsense-word detection task which required the children to identify nonsense words within short sentences, and (d) a rapid word learning task in which the children learned to associate nonsense words with novel images. Results: Regression analyses revealed that age, duration of device use, in-situ hearing thresholds, or device output did not account for a significant portion of the variability in performance for any of the four tasks. Repeated-measures analysis of variance revealed significant increases in word recognition with the abutment as well as significantly better performance for the lexical decision and word learning tasks. The data indicated that the children with the poorest performance with the softband tended to benefit most with the abutment. Also, the younger children showed improved performance for more tasks with the abutment than the older children. No difference between coupling conditions was observed for nonsense-word detection. Conclusions: The improved recognition of familiar words, categorization and repetition of nonsense words, and speed of word learning with the abutment suggests that direct stimulation provides a higher-quality signal than indirect stimulation through a softband. Because these processes are important for vocabulary acquisition and language development, children may experience long-term benefits of direct stimulation for academic, social, and vocational purposes in addition to immediate improvement in communication.
Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension.

BACKGROUND & AIMS Mechanical forces contribute to portal hypertension (PHTN) and fibrogenesis. We investigated the mechanisms by which forces are transduced by liver sinusoidal endothelial cells (LSECs) into pressure and matrix changes. METHODS We isolated primary LSECs from mice and induced mechanical stretch with a Flexcell device, to recapitulate the pulsatile forces induced by congestion, and performed microarray and RNA-sequencing analyses to identify gene expression patterns associated with stretch. We also performed studies with C57BL/6 mice (controls), mice with deletion of neutrophil elastase (NE-/-) or peptidyl arginine deiminase type IV (Pad4-/-) (enzymes that formation of neutrophil extracellular traps [NETs]), and mice with LSEC-specific deletion of Notch1 (Notch1iΔEC). We performed partial ligation of the suprahepatic inferior vena cava (pIVCL) to simulate congestive hepatopathy-induced portal hypertension in mice; some mice were given subcutaneous injections of sivelestat or underwent bile-duct ligation. Portal pressure was measured using a digital blood pressure analyzer and we performed intravital imaging of livers of mice. RESULTS Expression of the neutrophil chemoattractant CXCL1 was up-regulated in primary LSECs exposed to mechanical stretch, compared with unexposed cells. Intravital imaging of livers in control mice revealed sinusoidal complexes of neutrophils and platelets and formation of NETs after pIVCL. NE-/- and Pad4-/- mice had lower portal pressure and livers had less fibrin compared with control mice after pIVCL and bile-duct ligation; neutrophil recruitment into sinusoidal lumen of liver might increase portal pressure by promoting sinusoid microthrombi. RNA-sequencing of LSECs identified proteins in mechanosensitive signaling pathways that are altered in response to mechanical stretch, including integrins, Notch1, and calcium signaling pathways. Mechanical stretch of LSECs increased expression of CXCL1 via integrin-dependent activation of transcription factors regulated by Notch and its interaction with the mechanosensitive piezo calcium channel. CONCLUSIONS In studies of LSECs and knockout mice, we identified mechanosensitive angiocrine signals released by LSECs which promote PHTN by recruiting sinusoidal neutrophils and promoting formation of NETs and microthrombi. Strategies to target these pathways might be developed for treatment of PHTN. RNA-sequencing accession number: GSE119547.
Hypoxia Induces Astrocyte-Derived Lipocalin-2 in Ischemic Stroke

Ischemic stroke causes rapid hypoxic damage to the core neural tissue which is followed by graded chronological tissue degeneration in the peri-infarct zone. The latter process is mainly triggered by neuroinflammation, activation of inflammasomes, proinflammatory cytokines, and pyroptosis. Besides microglia, astrocytes play an important role in the fine-tuning of the inflammatory network in the brain. Lipocalin-2 (LCN2) is involved in the control of innate immune responses, regulation of excess iron, and reactive oxygen production. In this study, we analyzed LCN2 expression in hypoxic rat brain tissue after ischemic stroke and in astrocyte cell cultures receiving standardized hypoxic treatment. Whereas no LCN2-positive cells were seen in sham animals, the number of LCN2-positive cells (mainly astrocytes) was significantly increased after stroke. In vitro studies with hypoxic cultured astroglia revealed that LCN2 expression is significantly increased after only 2 h, then further increased, followed by a stepwise decline. The expression pattern of several proinflammatory cytokines mainly followed that profile in wild type (WT) but not in cultured LCN2-deficient astrocytes. Our data revealed that astrocytes are an important source of LCN2 in the peri-infarct region under hypoxic conditions. However, we must also stress that brain-intrinsic LCN2 after the initial hypoxia period might come from other sources such as invaded immune cells and peripheral organs via blood circulation. In any case, secreted LCN2 might have an influence on peripheral organ functions and the innate immune system during brain hypoxia.
Risk Stratification in Differentiated Thyroid Cancer: From Detection to Final Follow-up.

CONTEXT Modern management of differentiated thyroid cancer requires individualized care plans which tailor the intensity of therapy and follow-up to the estimated risks of recurrence and disease-specific mortality. EVIDENCE ACQUISITION This summary is based on the authors' knowledge and extensive clinical experience supplemented by review of published review articles, thyroid cancer management guidelines, published staging systems, and original articles identified through a PubMed search which included terms such as risk stratification, staging, clinical outcomes, and differentiated thyroid cancer. EVIDENCE SYNTHESIS In the past, risk stratification in differentiated thyroid cancer usually referred to a static estimate of disease-specific mortality that was based on a small set of clinicopathological features available within a few weeks of completing initial therapy (thyroidectomy with or without radioactive iodine). Today, risk stratification is a dynamic, active process used to predict the appropriateness for minimalistic initial therapy, disease-specific mortality, risk of recurrence, and the most likely response to initial therapy. Rather than being a static prediction available only after initial therapy, modern risk stratification is a dynamic, iterative process that begins as soon as a suspicious nodule is detected and continues through final follow-up. CONCLUSIONS Dynamic risk assessment should be used to guide all aspects of thyroid cancer management, beginning before a definitive diagnosis is made and continuing through the final follow-up visit.
Comparison of methodologies for the detection of BRAF mutations in bone marrow trephine specimens

Aims BRAF V600E detection assists in the diagnosis of hairy cell leukaemia (HCL); however, testing practices vary. We evaluated the clinical utility of 5 BRAF mutation testing strategies for use on bone marrow trephines (BMT). Methods 11 HCL, 5 HCL ‘mimic’, 2 treated HCL and 10 normal BMT specimens were tested for mutant BRAF, comparing Sanger sequencing, pyrosequencing, amplicon-based next generation sequencing (NGS), automated (Idylla) PCR and immunohistochemistry (IHC). Results PCR and IHC were cheaper and identified V600E in 100 % of HCL cases. Pyrosequencing detected the mutation in 91%, NGS in 55% of cases and Sanger sequencing in 27%. All assays gave wild-type BRAF results in HCL mimics and normal BMT samples. Conclusions PCR and IHC were most sensitive and cost-effective, but these have limited scope for multiplexing and are likely to be replaced by NGS gene panels or whole genome sequencing in the medium to long term.
Investigating GABA concentrations measured with macromolecule suppressed and unsuppressed MEGA‐PRESS MR spectroscopy and their relationship with BOLD responses in the occipital cortex

A combination of magnetic resonance spectroscopy (MRS) and functional (f)MRI is a promising method for studying brain activity. Negative results have, however, produced uncertainty as to the validity of the approach. Using a MEGA‐PRESS sequence adapted to suppress the macromolecule signal (GABA–) has been suggested as a key methodological improvement, but there is some doubt as to the relationship between such estimates and those from the standard sequence (GABA+), making interpretation difficult.