Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Lipopolysaccharide-Induced Depressive-Like Behaviors in Mice: Involvement of p38 and JNK Signaling Pathways

Inflammatory responses induced by peripheral administration of lipopolysaccharide (LPS) triggers depressive-like behavioral syndrome in rodents. Inhibition of phosphodiesterase 4 (PDE4) produces a robust anti-inflammatory effect in inflammatory cells. Unfortunately, archetypal PDE4 inhibitors cause intolerable gastrointestinal side-effects, such as vomiting and nausea. N-isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel, selective PDE4 inhibitor with little, or no, emetic potency. Our previous studies show that FCPR03 is effective in attenuating neuroinflammation in mice treated with LPS. However, whether FCPR03 could exert antidepressant-like effect induced by LPS is largely unknown. In the present study, mice injected intraperitoneally (i.p.) with LPS was established as an in vivo animal model of depression. The antidepressant-like activities of FCPR03 were evaluated using a tail suspension test, forced swimming test, and sucrose preference test. We demonstrated that administration of FCPR03 (1 mg/kg) produced antidepressant-like effects in mice challenged by LPS, as evidenced by decreases in the duration of immobility in the forced swim and tail suspension tests, while no significant changes in locomotor activity were observed. FCPR03 also increased sucrose preference in mice treated with LPS. In addition, treatment with FCPR03 abolished the downregulation of brain-derived neurotrophic factor induced by LPS and decreased the level of corticosterone in plasma. Meanwhile, periphery immune challenge by LPS induced enhanced phosphorylation of p38-mitogen activated protein kinase (p38) and c-Jun N-terminal kinase (JNK) in both the cerebral cortex and hippocampus in mice. Interestingly, treatment with FCPR03 significantly blocked the role of LPS and reduced the levels of phosphorylated p38 and JNK. Collectively, these results indicate that FCPR03 shows antidepressant-like effects in mice challenged by LPS, and the p38/JNK signaling pathway is possibly involved in this process. Our findings suggest that FCPR03 is a potential compound for the prevention or treatment of depression.
Single implants in the aesthetic region preceded by local ridge augmentation; a 10‐year randomized controlled trial

OBJECTIVES The aim of this randomized controlled trial was to assess the 10-year effects of three different augmentation techniques (augmentation with chin bone, augmentation with chin bone plus a membrane and augmentation with a bone substitute plus a membrane) for implant-supported restorations in the maxillary aesthetic region regarding clinical and radiographic parameters, and patient-centred outcomes. MATERIALS AND METHODS Ninety-three patients requesting single tooth replacement and presenting with a horizontal bone deficiency were included. After augmentation, 93 implants were placed. Clinical variables, standardized radiographs and photographs and patient questionnaires were analysed to assess the impact of the various augmentation techniques 1 month (T1 ), 12 months (T12 ) and 120 months (T120 ) after final crown placement. RESULTS 10-years implant survival was 95.7% and did not differ between the groups neither were significant differences observed in the other treatment outcomes assessed. Peri-implant bone loss was low, viz. 0.48 ± 1.19 mm (mesial) and 0.30 ± 1.24 mm (distal) at T120 . Loss of midbuccal marginal gingival level at T120 was 0.32 ± 0.83 mm. Mean overall satisfaction at T120 was 8.6 with 98.6% of the patients satisfied. CONCLUSIONS Clinical, radiographic, aesthetic and patient centred outcomes were very favourable after 10 years and did not differ between the groups with different bone augmentation techniques.
A small non‐coding RNA of the invasion gene island (SPI‐1) represses outer membrane protein synthesis from the Salmonella core genome

The Salmonella pathogenicity island (SPI‐1) encodes ∼35 proteins involved in assembly of a type III secretion system (T3SS) which endows Salmonella with the ability to invade eukaryotic cells. We have discovered a novel SPI‐1 gene, invR, which expresses an abundant small non‐coding RNA (sRNA). The invR gene, which we identified in a global search for new Salmonella sRNA genes, is activated by the major SPI‐1 transcription factor, HilD, under conditions that favour host cell invasion. The RNA chaperone, Hfq, is essential for the in vivo stability of the ∼80 nt InvR RNA. Hfq binds InvR with high affinity in vitro, and InvR co‐immunoprecipitates with FLAG epitope‐tagged Hfq in Salmonella extracts. Surprisingly, deletion/overexpression of invR revealed no phenotype in SPI‐1 regulation. In contrast, we find that InvR represses the synthesis of the abundant OmpD porin encoded by the Salmonella core genome. As invR is conserved in the early branching Salmonella bongori, we speculate that porin repression by InvR may have aided successful establishment of the SPI‐1 T3SS after horizontal acquisition in the Salmonella lineage. This study identifies the first regulatory RNA of an enterobacterial pathogenicity island, and new roles for Hfq and HilD in SPI‐1 gene expression.
Clinical‐scale production of cGMP compliant CD3/CD19 cell‐depleted NK cells in the evolution of NK cell immunotherapy at a single institution

Allogeneic natural killer (NK) cell adoptive immunotherapy is a growing therapeutic option for patients. Clinical‐scale production of NK cells using immunomagnetic selection complies with current good manufacturing practices (cGMPs) and allows for closed‐system, automated purification. We report our experience with CD3/CD19 cell‐depleted (CD3/CD19dep) NK cell production and compare to previous methods of CD3 cell depletion and CD3 cell depletion/CD56 cell enrichment.
Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo

Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor–related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. It does so by triggering α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV). How Dex specifically activates α5 integrin in these GBM lines is unknown. Several chaperone proteins are known to activate integrins, including calreticulin (CALR). We explore the role of CALR as a potential mediator of Dex-dependent induction of α5 integrin activity in primary human GBM cells. We use CALR knock-down and knock-in strategies to explore the effects on FNMA, aggregate compaction, and dispersal velocity in vitro, as well as dispersal ex vivo on extirpated mouse retina and brain slices. We show that Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated FNMA. Overexpression of CALR in GBM cells activates FNMA, increases compaction, and decreases DV in vitro and on explants of mouse retina and brain slices. Our results define a novel interaction between Dex, CALR, and FNMA as inhibitors of GBM dispersal.
Age effects in eating disorder baseline risk factors and prevention intervention effects

OBJECTIVE Examine the impact of age on baseline eating disorder symptoms/risk factors and on the effects of completing three variants of an eating disorder prevention program. METHOD Six hundred and eighty women (60% White) were randomized to clinician-led Body Project groups, peer-led Body Project groups, an Internet-based version of the Body Project (eBodyProject), or educational video control condition. Participants, who were on average 22.2 years old (SD = 7.1, range 17-64, median = 19), were assessed at pretest, posttest, and 6-month follow-up. RESULTS Two of the seven baseline variables were significantly associated with age, indicating that older age was associated with lower reported dieting (r = -.12) and better psychosocial functioning (r = -.13). Interactions indicated that age moderated the intervention effects, such that group-based programs were superior to the Internet-delivered version in terms of eating disorder symptom reductions for women up to age 20, whereas the Internet-delivered program was superior to group-based interventions, particularly in terms of BMI reduction, for women over approximately age 25. None of the four tests examining whether age moderated the effects of delivering Body Project groups by mental health clinicians versus undergraduate peer educators were significant. DISCUSSION Results suggest that group-based versions of the Body Project should be implemented with young women up to the age of 20, as they produce larger eating disorder symptom reductions, whereas the Internet version of the Body Project should be implemented with women aged 25 or older, as it produces superior weight loss/gain prevention effects.
Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata

ABSTRACT Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC90 for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.
The ANK3 gene and facial affect processing: An ERP study

ANK3 is one of the most promising candidate genes for bipolar disorder (BD). A polymorphism (rs10994336) within the ANK3 gene has been associated with BD in at least three genome‐wide association studies of BD [McGuffin et al., 2003; Kieseppä, 2004; Edvardsen et al., 2008]. Because facial affect processing is disrupted in patients with BD, the current study aimed to explore whether the BD risk alleles are associated with the N170, an early event‐related potential (ERP) component related to facial affect processing. We collected data from two independent samples of healthy individuals (Ns = 83 and 82, respectively) to test the association between rs10994336 and an early event‐related potential (ERP) component (N170) that is sensitive to facial affect processing. Repeated‐measures analysis of covariance in both samples consistently revealed significant main effects of rs10994336 genotype (Sample I: F (1, 72) = 7.24, P = 0.009; Sample II: F (1, 69) = 11.81, P = 0.001), but no significant interaction of genotype × electrodes (Ps > 0.05) or genotype × emotional conditions (Ps > 0.05). These results suggested that rs10994336 was linked to early ERP component reflecting facial structural encoding during facial affect processing. These results shed new light on the brain mechanism of this risk SNP and associated disorders such as BD. © 2016 Wiley Periodicals, Inc.
Vitamin D is crucial for maternal care and offspring social behaviour in rats.

Early life vitamin D plays a prominent role in neurodevelopment and subsequent brain function, including schizophrenic-like outcomes and increasing evidence for an association with autism spectrum disorder (ASD). Here, we investigate how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring. Sprague-Dawley rats were placed on either a vitamin D control (2195 IU/kg) or deficient diet (0 IU/kg) for five weeks before timed mating, and diet exposure was maintained until weaning of offspring on postnatal day (PND) 23. MRI scans were conducted to assess brain morphology, and plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure were characterised at PND1, PND12 and 4 months of age. Compared to controls, vitamin D-deficient dams exhibited decreased licking and grooming of their pups but no differences in pup retrieval. Offspring neurodevelopmental markers were unaltered, but vitamin D-deficient pup ultrasonic vocalisations were atypical. As adults, males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours. Accompanying these behavioural changes was an increase in lateral ventricle volume, decreased cortical FOXP2 (a protein implicated in language and communication) and altered neural expression of genes involved in dopamine and glucocorticoid-related pathways. These data highlight that early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry.
Supporting Online Material Materials and Methods Figs. S1 to S10 References Movies S1 to S3 Functional Compartmentalization and Viewpoint Generalization within the Macaque Face-processing System

whereas no labeled cells were detectable in the brain rudiment at this time point (Fig. 4A and fig. S10A). Brain-infiltrating cells appeared only when blood circulation developed, and a significant proportion of Lac-Z + cells appeared associated with blood vessels and infiltrated the brain rudiment in E9.5 conceptus (Fig. 4B and fig. S10B). These results are consistent with prior findings showing that CSF-1R + cells first accumulate in the yolk sac around E8.0 and infiltrate the embryo proper when blood vessels develop around E9.0 (27). To address whether the development of functional blood vessels was required for the recruitment of myeloid precursors into the brain rudiment, we used Ncx-1 –/– animals that lack a heartbeat and functional blood circulation because of a defect in sodium calcium exchanger 1 (28). We found that E9.5 to E10.5 Ncx-1 –/– embryos have yolk sac macrophages levels comparable or higher than control litter-mates (Fig. 4, C and E). In contrast, Ncx-1 –/– embryos have no detectable microglia in the brain, whereas Ncx-1 +/+ control littermates already have a substantial number of microglia in the brain at this time-point (Fig. 4, D and E). Altogether, these results suggest that Runx1 + progenitors migrate from the yolk sac into the brain through blood vessels between E8.5 and E9.5. To examine the contribution of definitive hem-atopoiesis to microglial homeostasis, we injected 4′OHT at E8.5, E9.5, and E10.5. The proportion of eYFP + leukocytes known to derive from definitive hematopoiesis was much higher in mice activated at E8.5 and E9.5 compared with mice activated at E7.25 to E7.5 (up to 40% versus less than 3%, n = 10) (Fig. 3E and fig. S9). In contrast , few eYFP + microglia were detected in the brains of adult mice activated after E8.5 and onward (Fig. 3E). The sharp descending contribution levels between E7.5 and E8.5 argue against the contribution of post-E7.5 Runx1 + anatomic locations to the labeling of the adult microglia lineage. Altogether, these data suggest minimal, if any, contribution of definitive hem-atopoiesis to the development of adult microglia. Our results provide evidence that primitive myeloid precursors give rise to microglia residing in the adult CNS in the steady state. Primitive macrophages differentiate in the yolk sac of mammals , birds, and zebrafish before the onset of blood circulation (14). Studies in zebrafish revealed that yolk sac–derived macrophages spread in the cephalic mesenchyme before invading the brain through …
Linking Plant Specialization to Dependence in Interactions for Seed Set in Pollination Networks

Studies on pollination networks have provided valuable information on the number, frequency, distribution and identity of interactions between plants and pollinators. However, little is still known on the functional effect of these interactions on plant reproductive success. Information on the extent to which plants depend on such interactions will help to make more realistic predictions of the potential impacts of disturbances on plant-pollinator networks. Plant functional dependence on pollinators (all interactions pooled) can be estimated by comparing seed set with and without pollinators (i.e. bagging flowers to exclude them). Our main goal in this study was thus to determine whether plant dependence on current insect interactions is related to plant specialization in a pollination network. We studied two networks from different communities, one in a coastal dune and one in a mountain. For ca. 30% of plant species in each community, we obtained the following specialization measures: (i) linkage level (number of interactions), (ii) diversity of interactions, and (iii) closeness centrality (a measure of how much a species is connected to other plants via shared pollinators). Phylogenetically controlled regression analyses revealed that, for the largest and most diverse coastal community, plants highly dependent on pollinators were the most generalists showing the highest number and diversity of interactions as well as occupying central positions in the network. The mountain community, by contrast, did not show such functional relationship, what might be attributable to their lower flower-resource heterogeneity and diversity of interactions. We conclude that plants with a wide array of pollinator interactions tend to be those that are more strongly dependent upon them for seed production and thus might be those more functionally vulnerable to the loss of network interaction, although these outcomes might be context-dependent.
THE EFFECT OF ALTERNATIVE BLOWING AGENTS ON MICROSTRUCTURE AND MECHANICAL CHARACTERISTICS OF RIGID POLYU-RETHANE FOAM

The influence of alternative blowing agents on the mechanical properties and microstructure of rigid polyurethane (RPU) foam and their relationship were examined. The compression, creep and stress relaxation tests were conducted on RPU foams. For compression test, loading was applied at a rate of 5 mm/min; and for creep tests, a constant stress (0.12 MPa) was applied for 15 min and the strain was recovered for the next 15 min. In stress relaxation experiments the constant strain (3%) was applied for 15 min in the rise and transverse directions. The results of mechanical properties showed that the stiffness of the samples in the rise direction was higher than the transverse direction. Furthermore, the yield strain for all the samples in the transverse direction was higher than the rise direction. Creep and stress relaxation results, showed that the RPU foam in the rise direction exhibited higher creep recovery and lower stress decay than the transverse direction. RPU foam which was blown with n-pentane showed the highest creep recovery and the lowest stress decay, and the foams blown with cyclopentane showed the lowest creep recovery and the highest stress decay at both directions. The microstructures of the foams were studied with an optical microscope. The results of microstructural studies indicated that the RPU foam with the smallest cell size and the narrowest cell size distribution exhibited the highest compressive strength and modulus. RPU foam blown with n-pentane produced the smallest average cell size and narrowest cell size distribution which led to the highest compressive strength and modulus, and the foams blown with cyclopentane produced the largest average cell size and the broadest cell size distribution leading to the lowest compressive strength and modulus.
“Wrong, but Useful”: Negotiating Uncertainty in Infectious Disease Modelling

For infectious disease dynamical models to inform policy for containment of infectious diseases the models must be able to predict; however, it is well recognised that such prediction will never be perfect. Nevertheless, the consensus is that although models are uncertain, some may yet inform effective action. This assumes that the quality of a model can be ascertained in order to evaluate sufficiently model uncertainties, and to decide whether or not, or in what ways or under what conditions, the model should be ‘used’. We examined uncertainty in modelling, utilising a range of data: interviews with scientists, policy-makers and advisors, and analysis of policy documents, scientific publications and reports of major inquiries into key livestock epidemics. We show that the discourse of uncertainty in infectious disease models is multi-layered, flexible, contingent, embedded in context and plays a critical role in negotiating model credibility. We argue that usability and stability of a model is an outcome of the negotiation that occurs within the networks and discourses surrounding it. This negotiation employs a range of discursive devices that renders uncertainty in infectious disease modelling a plastic quality that is amenable to ‘interpretive flexibility’. The utility of models in the face of uncertainty is a function of this flexibility, the negotiation this allows, and the contexts in which model outputs are framed and interpreted in the decision making process. We contend that rather than being based predominantly on beliefs about quality, the usefulness and authority of a model may at times be primarily based on its functional status within the broad social and political environment in which it acts.
Effect of Alloying Elements and Processing Parameters on Mechanical Properties of Austempered Ductile Iron

In the present work, austempering is carried out for three different grades (Unalloyed, copper alloyed and Nickel alloyed) of ductile iron. After that the variation of mechanical properties (Hardness, Tensile strength and Elongation) and microstructure of the austempered ductile iron (ADI) with alloying elements (Copper and Nickel) and austempering process variables (austempering temperature and austempering time) were studied. It is found that, with increasing austempering time hardness, tensile strength and elongation are increasing but with increasing austempering temperature hardness and tensile strength are decreasing and elongation increasing. Austempered ductile iron with alloying element (Cu or Ni) is showing some improved mechanical properties such that: higher strength, hardness and lower elongation, than the unalloyed austempered ductile iron. In Microstructure, higher ferrite fraction is observed for higher austempering time and higher austenite fraction is observed for higher austempering temperature, for all the three grades of austempered ductile iron.