Miracle-dz/UniFAR-FTUs huggingface dataset:
Rational Combination of Parvovirus H1 With CTLA-4 and PD-1 Checkpoint Inhibitors Dampens the Tumor Induced Immune Silencing

The recent therapeutic success of immune checkpoint inhibitors in the treatment of advanced melanoma highlights the potential of cancer immunotherapy. Oncolytic virus-based therapies may further improve the outcome of these cancer patients. A human ex vivo melanoma model was used to investigate the oncolytic parvovirus H-1 (H-1PV) in combination with ipilimumab and/or nivolumab. The effect of this combination on activation of human T lymphocytes was demonstrated. Expression of CTLA-4, PD-1, and PD-L1 immune checkpoint proteins was upregulated in H-1PV-infected melanoma cells. Nevertheless, maturation of antigen presenting cells such as dendritic cells was triggered by H-1PV infected melanoma cells. Combining H-1PV with checkpoint inhibitors, ipilimumab enhanced TNFα release during maturation of dendritic cells; nivolumab increased the amount of IFNγ release. H-1PV mediated reduction of regulatory T cell activity was demonstrated by lower TGF-ß levels. The combination of ipilimumab and nivolumab resulted in a further decline of TGF-ß levels. Similar results were obtained regarding the activation of cytotoxic T cells. H-1PV infection alone and in combination with both checkpoint inhibitors caused strong activation of CTLs, which was reflected by an increased number of CD8+GranB+ cells and increased release of granzyme B, IFNγ, and TNFα. Our data support the concept of a treatment benefit from combining oncolytic H-1PV with the checkpoint inhibitors ipilimumab and nivolumab, with nivolumab inducing stronger effects on cytotoxic T cells, and ipilimumab strengthening T lymphocyte activity.
Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex.
Blind signal extraction of signals with specified frequency band

Blind sources separation, independent component analysis (ICA) and related methods are promising approaches for analysis of biomedical signals, especially for EEG/MEG and fMRI data. However, most of the methods extract all sources simultaneously, so it is time consuming and not reliable especially, when the number of sensors is large (more than 100 sensors) and signals are contaminated by huge noise. The main objective of this paper is to present a new method for extraction of specific source signals using bandpass filters approach. Such a method allows us to extract source signals with specific stochastic properties, e.g., extraction of narrow band sources with specific frequency bandwidth.
25-Hydroxycholesterol suppresses interleukin-1–driven inflammation downstream of type I interferon

Bad cholesterol: Bad for bacteria, too? Why do viral infections, such as the common cold, leave people more susceptible to bacterial pneumonia? One reason is that type I interferons, secreted proteins that initiate antiviral immune responses, suppress other inflammatory molecules that protect against bacterial infection. Reboldi et al. investigated how this suppression occurs on a molecular level in mice. Interferons stimulated expression of a particular enzyme that catalyzes the production of the oxysterol 25-hydroxycholesterol (25-HC). 25-HC inhibits the function of the transcription factor SREBP, which normally drives expression of the gene that encodes interleukin-1, a secreted inflammatory protein with wide-ranging antibacterial functions. Science, this issue p. 679 Antiviral immune responses induce an oxysterol that suppresses interleukin-1–mediated inflammation. Type I interferon (IFN) protects against viruses, yet it also has a poorly understood suppressive influence on inflammation. Here, we report that activated mouse macrophages lacking the IFN-stimulated gene cholesterol 25-hydroxylase (Ch25h) and that are unable to produce the oxysterol 25-hydroxycholesterol (25-HC) overproduce inflammatory interleukin-1 (IL-1) family cytokines. 25-HC acts by antagonizing sterol response element–binding protein (SREBP) processing to reduce Il1b transcription and to broadly repress IL-1–activating inflammasomes. In accord with these dual actions of 25-HC, Ch25h-deficient mice exhibit increased sensitivity to septic shock, exacerbated experimental autoimmune encephalomyelitis, and a stronger ability to repress bacterial growth. These findings identify an oxysterol, 25-HC, as a critical mediator in the negative-feedback pathway of IFN signaling on IL-1 family cytokine production and inflammasome activity.
Phosphorylation of eIF-4E on Ser 209 in response to mitogenic and inflammatory stimuli is faithfully detected by specific antibodies.

Phosphorylation of Ser 209 is thought to modulate the activity of the cap-binding factor eIF-4E which is a crucial component in the initiation complex for cap-dependent translation of mRNA. We report here the full reconstitution of the p38 Map kinase cascade leading to phosphorylation of eIF-4E in vitro and the generation of antibodies specific for phospho-serine 209 in eIF-4E. These antibodies were used to probe the phosphorylation of eIF-4E in mammalian cells stimulated with mitogens and pro-inflammatory cytokines. Treatment of human dermal fibroblasts with FCS led to a transient hyperphosphorylation, followed by hypophosphorylation and return to normal state phosphorylation at 16 h after the initial stimulation. By using a potent small molecular weight inhibitor of Mnk1, the upstream kinase for eIF-4E, we observed a rapid dephosphorylation of eIF-4E within 45 min after addition of the inhibitor, suggesting a high turnover of phosphate on eIF-4E mediated by Mnk1 and a yet unidentified phosphatase.
Advanced Aboveground Spatial Analysis as Proxy for the Competitive Environment Affecting Sapling Development

Tree saplings are exposed to a competitive growth environment in which resources are limited and the ability to adapt determines general vitality and specific growth performance. In this study we analyzed the aboveground spatial neighborhood of oak [Quercus petraea (Matt.) Liebl. ] and beech (Fagus sylvatica L.) saplings growing in Germany, by using hemispherical photography and terrestrial laser scanning as proxy for the competitive pressure saplings were exposed to. The hemispherical images were used to analyze the light availability and the three-dimensional (3D) point clouds from the laser scanning were used to assess the space and forest structure around the saplings. The aim was to increase the precision with which the biomass allocation, growth, and morphology of the saplings could be predicted by including more detailed information of their environment. The predictive strength of the models was especially increased through direct neighborhood variables (e.g., relative space filling), next to the light availability being the most important predictor variable. The biomass allocation patterns within the more light demanding oak were strongly driven by the space availability around the saplings. Diameter and height growth variables of both species reacted significantly to changes in light availability, and partly also to the neighborhood variables. The leaf morphology [as leaf-area ratio (LAR)] was also driven by light availability and decreased with increasing light availability. However, the branch morphology (as mean branch weight) could not be explained for oak and the model outcome for beech was hard to interpret. The results could show that individuals of the same species perform differently under constant light conditions but differing neighborhoods. Assessing the neighborhood of trees with highly precise measurement devices, like terrestrial laser scanners, proved to be useful. However, the primary response to a dense neighborhood seemed to be coping with a reduction of the lateral light availability aboveground, rather than responding to an increase of competition belowground. The results suggest continuing efforts to increase the precision with which plant environments can be described through innovative and efficient methods, like terrestrial laser scanning.
Distribution of Serotonin-Immunoreactive Neurons in the Brain and Gnathal Ganglion of Caterpillar Helicoverpa armigera

Serotonin (5-hydroxytryptamine, 5-HT) is an important biogenic amine that acts as a neural circuit modulator. It is widespread in the central nervous system of insects. However, little is known about the distribution of serotonin in the nervous system of the cotton bollworm Helicoverpa armigera. In the present study, we performed immunohistochemical experiments with anti-serotonin serum to examine the distribution of serotonin in the central nervous system of H. armigera larvae. We found about 40 serotonin-immunoreactive neurons in the brain and about 20 in the gnathal ganglion. Most of these neurons are wide-field neurons giving rise to processes throughout the neuropils of the brain and the gnathal ganglion. In the central brain, serotonin-immunoreactive processes are present bilaterally in the tritocerebrum, the deutocerebrum, and major regions of the protocerebrum, including the central body (CB), lateral accessory lobes (LALs), clamps, crepine, superior protocerebrum, and lateral protocerebrum. The CB, anterior ventrolateral protocerebrum (AVLP), and posterior optic tubercle (POTU) contain extensive serotonin-immunoreactive process terminals. However, the regions of mushroom bodies, the lateral horn, and protocerebral bridges (PBs) are devoid of serotonin-immunoreactivity. In the gnathal ganglion, the serotonin-immunoreactive processes are also widespread throughout the neuropil, and some process projections extend to the tritocerebrum. Our results provide the first comprehensive description of the serotonergic neuronal network in H. armigera larvae, and they reveal the neural architecture and the distribution of neural substances, allowing us to explore the neural mechanisms of behaviors by using electrophysiological and pharmacological approaches on the target regions.
Canine C-reactive Protein Validation of Two Automated Canine-specific C-reactive Protein Assays and Studies on Clinical and Research Applications

C-reactive protein (CRP) is a sensitive and specific marker of systemic inflammation in dogs, valuable for diagnosing and monitoring inflammatory diseases. The use of CRP in canine medicine has however been hampered by the lack of automated assays optimized for measuring CRP in this species. The need for improved CRP assays was the reason for initiating the current project, with the goal to generate automated, canine-specific CRP tests that could reliably measure serum CRP over the whole concentration range expected to occur in dogs. Two different assays were developed for this purpose. One was designed for routine diagnostic testing, and one was a high-sensitivity CRP test intended for research. Method validation studies were performed, demonstrating that both tests met the predefined quality criteria. Using the two novel CRP tests, it was possible to reliably measure serum CRP concentrations in the range of 0.5-1200 mg/l. After successful termination of the validation studies, the CRP assays were used in clinical research studies. C-reactive protein concentrations were measured in dogs with pyometra undergoing ovariohysterectomy, to evaluate how surgical treatment affected degree of systemic inflammation in these patients. Two other studies were performed to evaluate the usefulness of CRP as a diagnostic test. C-reactive protein concentration was found to discriminate well between dogs with suppurative arthritis and dogs with osteoarthritis, whereas measurement of CRP was not efficient for diagnosing late postoperative bacterial infections after orthopaedic surgery because these infections often did not elicit a systemic inflammatory response. In conclusion, two novel automated canine-specific CRP assays were developed and validated with satisfactory results. The tests showed high practicability for measuring CRP in samples from clinical research studies. Availability of these assays will facilitate the use of CRP as a routine diagnostic test in veterinary medicine, and can improve quality in research on canine inflammatory diseases.
Mutations in the Rice OsCHR4 Gene, Encoding a CHD3 Family Chromatin Remodeler, Induce Narrow and Rolled Leaves with Increased Cuticular Wax

Leaf blade width, curvature, and cuticular wax are important agronomic traits of rice. Here, we report the rice Oschr4-5 mutant characterized by pleiotropic phenotypes, including narrow and rolled leaves, enhanced cuticular wax deposition and reduced plant height and tiller number. The reduced leaf width is caused by a reduced number of longitudinal veins and increased auxin content. The cuticular wax content was significantly higher in the Oschr4-5 mutant, resulting in reduced water loss rate and enhanced drought tolerance. Molecular characterization reveals that a single-base deletion results in a frame-shift mutation from the second chromodomain of OsCHR4, a CHD3 (chromodomain helicase DNA-binding) family chromatin remodeler, in the Oschr4-5 mutant. Expressions of seven wax biosynthesis genes (GL1-4, WSL4, OsCER7, LACS2, LACS7, ROC4 and BDG) and four auxin biosynthesis genes (YUC2, YUC3, YUC5 and YUC6) was up-regulated in the Oschr4-5 mutant. Chromatin immunoprecipitation assays revealed that the transcriptionally active histone modification H3K4me3 was increased, whereas the repressive H3K27me3 was reduced in the upregulated genes in the Oschr4-5 mutant. Therefore, OsCHR4 regulates leaf morphogenesis and cuticle wax formation by epigenetic modulation of auxin and wax biosynthetic genes expression.
Association of Serum Uromodulin With ESKD and Kidney Function Decline in the Elderly: The Cardiovascular Health Study.

RATIONALE & OBJECTIVE Uromodulin is released by tubular epithelial cells into the serum and lower levels are associated with more severe interstitial fibrosis and tubular atrophy. Low serum uromodulin (sUMOD) levels are associated with mortality and cardiovascular disease. However, little is known about the association of sUMOD levels with long-term kidney outcomes in older adults, a population with a high prevalence of interstitial fibrosis and tubular atrophy. STUDY DESIGN Case-cohort study and case-control study. SETTING & PARTICIPANTS Random subcohort (n=933) and additional cases of end-stage kidney disease (ESKD) and kidney function decline (≥30% decline in estimated glomerular filtration rate [eGFR]) during follow-up of the Cardiovascular Health Study (CHS). PREDICTOR sUMOD level. OUTCOMES ESKD (n=14) from the random subcohort and all additional ESKD cases from outside the random subcohort (n=39) during follow-up (10 years, case-cohort study); kidney function decline of≥30% eGFR at 9 years of follow-up in individuals with repeated eGFR assessments from the random subcohort (n=56) and additional cases (n=123). 224 participants from the random subcohort served as controls (case-control study). ANALYTICAL APPROACH Modified multivariable Cox regression for ESKD and multivariable logistic regression for kidney function decline. Both analyses adjusted for demographics, eGFR, urinary albumin-creatinine ratio, and other kidney disease progression risk factors. RESULTS Mean age of the random subcohort was 78 years, 40% were men, 15% were black. Mean sUMOD level was 127±64ng/mL and eGFR was 63±19mL/min/1.73m2. In multivariable analysis, each 1-SD higher sUMOD level was associated with 63% lower risk for ESKD (HR, 0.37; 95% CI, 0.14-0.95). In demographic-adjusted analyses of kidney function decline, each 1-SD higher sUMOD level was associated with 25% lower odds of kidney function decline (OR, 0.75; 95% CI, 0.60-0.95); after multivariable adjustment, the association was attenuated and no longer significant (OR, 0.88; 95% CI, 0.68-1.14). LIMITATIONS Possibility of survival bias in the kidney function decline analysis. CONCLUSIONS Higher sUMOD levels may identify elderly persons at reduced risk for ESKD.
Fps1p controls the accumulation and release of the compatible solute glycerol in yeast osmoregulation

The accumulation of compatible solutes, such as glycerol, in the yeast Saccharomyces cerevisiae, is a ubiquitous mechanism in cellular osmoregulation. Here, we demonstrate that yeast cells control glycerol accumulation in part via a regulated, Fps1p‐mediated export of glycerol. Fps1p is a member of the MIP family of channel proteins most closely related to the bacterial glycerol facilitators. The protein is localized in the plasma membrane. The physiological role of Fps1p appears to be glycerol export rather than uptake. Fps1Δ mutants are sensitive to hypo‐osmotic shock, demonstrating that osmolyte export is required for recovery from a sudden drop in external osmolarity. In wild‐type cells, the glycerol transport rate is decreased by hyperosmotic shock and increased by hypo‐osmotic shock on a subminute time scale. This regulation seems to be independent of the known yeast osmosensing HOG and PKC signalling pathways. Mutants lacking the unique hydrophilic N‐terminal domain of Fps1p, or certain parts thereof, fail to reduce the glycerol transport rate after a hyperosmotic shock. Yeast cells carrying these constructs constitutively release glycerol and show a dominant hyperosmosensitivity, but compensate for glycerol loss after prolonged incubation by glycerol overproduction. Fps1p may be an example of a more widespread class of regulators of osmoadaptation, which control the cellular content and release of compatible solutes.
Short Selling Before Initial Public Offerings

This paper shows that the presence of security lending supply before an initial public offering (IPO) reduces the initial stock return following IPO and improves subsequent long-run performance. We use a sample of British firms that go public via a two-stage IPO procedure where a firm becomes publicly traded on the London Stock Exchange in the first stage, and offers new shares to the public in the second stage. Stocks are lendable before the new equity issuance which relaxes the short-sale constraints that investors typically face in a conventional IPO. We find that two-stage offerings with higher security lending supply before offering are associated with lower IPO underpricing and better long-run performance. Our results are consistent with the conjecture that short selling improves the pricing efficiency of the IPO market.
A dynamic trust network based simulation framework for reputation-based service selection

Service-oriented computing is a promising approach to software system construction by selecting and composing autonomous services under the open, dynamic and non-deterministic Internet environment. Appropriate selection of high quality services used in from numerous candidates declaring similar functionalities is crucial to the overall quality of the composed system. As authority centers are not generally available in open environments, reputation-based mechanisms must be adopted to evaluate services. With more and more reputation systems proposed in the literature, there is an increasing need to evaluate and compare them objectively and systematically with a common controlled experiment of trust network environment. In this paper we propose a general simulation framework based on dynamic trust network for this purpose. Especially, the framework is capable to simulate the dynamic evolutions of the trust network, in addition to the static snapshots of the trust relationships. With this framework, some case studies are made to evaluate the effectiveness of several representative reputation mechanisms, and some interesting characters are revealed.
Overcoming adversity among low SES students: a study of strategies for retention

The Bradley Review in 2008 and the Australian government's response echoed policy concerns that young people from low socioeconomic status are underrepresented in tertiary education. In order to address this, responses to both recruitment and retention are necessary. While many studies have looked at reasons for student attrition, few investigated the factors that enabled students from low socio-economic status (SES) backgrounds to stay in university. Over 1,000 domestic undergraduate students at the University of Queensland completed an online survey, in which students from low SES backgrounds were compared with students who were not. It was found that while most students experienced a combination of financial, relationship, mental and physical health stress, students from low SES backgrounds experienced more stressors as well as higher levels of stress. While the majority of respondents were aware of student support services, these did not appear to be a major influencing factor on students' reported decisions to stay at university.
Effect of legume grains as a source of dietary protein on the quality of organic lamb meat.

BACKGROUND This study evaluated the effects on lamb growth, carcass traits and meat quality of replacing conventional soybean meal in the diet with alternative legume grains. RESULTS Twenty-eight male lambs of Comisana breed weighing 16.9 ± 2.7 kg at weaning (66 ± 6 days old) were assigned to one of four diets. Until slaughter at 129 ± 6 days of age, each group received ad libitum pelleted alfalfa hay and concentrates differing in the source of protein: chickpea, faba bean, pea or soybean meal. Lambs fed chickpea showed higher dry matter and protein intakes from concentrate than those fed soybean. Lambs' growth, carcass weight and net dressing percentage did not vary by protein source, although chickpea lambs had more perirenal and pelvic fat than those in the soybean group. Diet did not affect chemical composition, colour, thawing and cooking losses, tenderness, and sensory properties of meat. Chickpea increased trans-vaccenic and linoleic acid, and chickpea and faba bean increased the isomers of conjugated linoleic acid. CONCLUSIONS Legume grains can completely replace soybean meal in concentrate, resulting in lamb carcasses and meat of comparable quality. Chickpea leads to an increase in feed intake of lambs and in fat depots in the carcass, and a more beneficial fatty acid profile.