Miracle-dz/UniFAR-FTUs huggingface dataset:
A new mechanism for reduced sensitivity to demethylation‐inhibitor fungicides in the fungal banana black Sigatoka pathogen Pseudocercospora fijiensis

Summary The Dothideomycete Pseudocercospora fijiensis, previously Mycosphaerella fijiensis, is the causal agent of black Sigatoka, one of the most destructive diseases of bananas and plantains. Disease management depends on fungicide applications, with a major contribution from sterol demethylation‐inhibitors (DMIs). The continued use of DMIs places considerable selection pressure on natural P. fijiensis populations, enabling the selection of novel genotypes with reduced sensitivity. The hitherto explanatory mechanism for this reduced sensitivity was the presence of non‐synonymous point mutations in the target gene Pfcyp51, encoding the sterol 14α‐demethylase enzyme. Here, we demonstrate a second mechanism involved in DMI sensitivity of P. fijiensis. We identified a 19‐bp element in the wild‐type (wt) Pfcyp51 promoter that concatenates in strains with reduced DMI sensitivity. A polymerase chain reaction (PCR) assay identified up to six Pfcyp51 promoter repeats in four field populations of P. fijiensis in Costa Rica. We used transformation experiments to swap the wt promoter of a sensitive field isolate with a promoter from a strain with reduced DMI sensitivity that comprised multiple insertions. Comparative in vivo phenotyping showed a functional and proportional up‐regulation of Pfcyp51, which consequently decreased DMI sensitivity. Our data demonstrate that point mutations in the Pfcyp51 coding domain, as well as promoter inserts, contribute to the reduced DMI sensitivity of P. fijiensis. These results provide new insights into the importance of the appropriate use of DMIs and the need for the discovery of new molecules for black Sigatoka management.
Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs

Cystic fibrosis (CF) patients undergo progressive airway destruction caused in part by chronic neutrophilic inflammation. While opportunistic pathogens infecting CF airways can cause inflammation, we hypothesized that host-derived metabolic and stress signals would also play a role in this process. We show that neutrophils that have entered CF airways have increased phosphorylation of the eukaryotic initiation factor 4E and its partner the 4E-binding protein 1; 2 key effectors in the growth factor- and amino acid-regulated mammalian target of rapamycin (mTOR) pathway. Furthermore CF airway neutrophils display increased phosphorylation of the cAMP response element binding protein (CREB), a major transcriptional coactivator in stress signaling cascades. These active intracellular pathways are associated with increased surface expression of critical adaptor molecules, including the growth factor receptor CD114 and the receptor for advanced glycation end-products (RAGE), a CREB inducer and sensor for host-derived damage-associated molecular patterns (DAMPs). Most CF airway fluids lack any detectable soluble RAGE, an inhibitory decoy receptor for DAMPs. Concomitantly, CF airway fluids displayed high and consequently unopposed levels of S100A12; a potent mucosa- and neutrophil-derived DAMP. CF airway neutrophils also show increased surface levels of 2 critical CREB targets, the purine-recycling enzyme CD39 and the multifunctional, mTOR-inducing CXCR4 receptor. This coordinated set of events occurs in all patients, even in the context of minimal airway inflammation and well-preserved lung function. Taken together, our data demonstrate an early and sustained activation of host-responsive metabolic and stress pathways upon neutrophil entry into CF airways, suggesting potential targets for therapeutic modulation.
Implications of Exchange Rate Objectives under Incomplete Exchange Rate Pass-Through

This paper analyzes the central bank’s optimal objective function in a small open economy model allowing for incomplete exchange rate pass-through. The results indicate that there are welfare gains from different types of monetary policy inertia. The welfare improvements of exchange rate stabilization are, however, dependent on the degree of discretionary stabilization bias. If the stabilization bias has been mitigated through a low weight on output stabilization social welfare can not be improved by inclusion of an explicit exchange rate term in the delegated objective function, irrespective of the degree of pass-through. Welfare can, though, be enhanced by appointing a central banker with greater preference for interest rate smoothing than that of society. The optimal degree of interest rate smoothing is increasing in the degree of pass-through.
A Carboxypeptidase Inhibitor from the Tick Rhipicephalus bursa

A novel proteinaceous metallo-carboxypeptidase inhibitor, named tick carboxypeptidase inhibitor (TCI), was isolated from the ixodid tick Rhipicephalus bursa and N-terminally sequenced. The complete cDNA encoding this protein was cloned from tick mRNA by reverse transcription-PCR and rapid amplification of cDNA ends techniques. The full-length TCI cDNA contains an open reading frame coding for a precursor protein of 97 amino acid residues that consists of a predicted signal peptide of 22 residues and of mature TCI, a 75-residue cysteine-rich protein (12 Cys). The deduced amino acid sequence shows no homology to other known proteins; the C terminus, however, resembles those of other protein metallo-carboxypeptidase inhibitors, suggesting a common mechanism of inhibition. Recombinant TCI expressed in Escherichia coli is fully functional and inhibits carboxypeptidases of the A/B subfamily with equilibrium dissociation constants in the nanomolar range. Structural analyses by circular dichroism and nuclear magnetic resonance indicate that TCI is a protein strongly constrained by disulfide bonds, unusually stable over a wide pH range and highly resistant to denaturing conditions. As a tight binding inhibitor of plasma carboxypeptidase B, also known as thrombin-activatable fibrinolysis inhibitor, recombinant TCI stimulates fibrinolysis in vitro and thus may have potential for applications to prevent or treat thrombotic disorders.
From the margins to mainstream: How providers of autologous ‘stem cell treatments’ legitimise their practice in Australia

This article examines how Australian providers of unproven autologous ‘stem cell treatments’ legitimise these products and their practices. We focus on the strategies employed by providers in their efforts to create and sustain a market for procedures that have yet to be proven safe and clinically efficacious. Drawing on the work of Thomas Gieryn and Pierre Bourdieu and the findings of research involving an analysis of direct-to-consumer online advertising of clinics that sell purported ‘stem cell treatments’ and interviews with clinicians who provide them, we examine the mechanisms by which medical legitimacy for these products is established and defended. We argue that Australian providers employ a number of strategies in order to create medical legitimacy for the use and sale of scientifically unproven therapies. A key strategy employed by providers of stem cell treatments is to use markers of social distinction, drawing strongly on the symbols of science, to confirm their legitimacy and differentiate their own practices from those of other providers, who are posited as operating outside the boundary of accepted practice and hence illegitimate. We argue there is a paradox at the heart of the autologous stem cell treatment market. Providers aim to create legitimacy for their work by emphasising the potential benefits of their ‘treatments’, their expertise and the professionalisation of their practices in an environment where regulators are yet to take a firm stance; they are also required to undertake the challenging task of managing patients’ hopes and expectations that both enable and potentially jeopardise their operations and revenue. We conclude by suggesting that providers’ creation of symbolic capital to establish medical legitimacy is a crucial means by which they seek to bring unproven ‘stem cell treatments’ from the margins of medicine into the mainstream and to portray themselves as medical pioneers rather than medical cowboys who exploit vulnerable patients.
Shotgun proteomic analysis of two Bartonella quintana strains

This study reports the first extensive shotgun analysis of the Bartonella quintana proteome. Proteins extracted from two B. quintana strains, Oklahoma and JK31, were analyzed in triplicate analyses by a bottom‐up approach consisting of tryptic digestion in SDS‐containing buffer, strong cation‐exchange StageTip fractionation, and nano‐LC‐MS/MS analysis. By setting spectral false discovery rate below 0.5%, 548 unique proteins were identified overall, of which 409 protein identifications were shared between the two strains. The data set, which achieves the highest proteome coverage for B. quintana to date, could be exploited for the quantitative analysis of a selected subset of target proteins.
Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Downstream processing and chromatography based analytical methods for production of vaccines, gene therapy vectors, and bacteriophages

Downstream processing of nanoplexes (viruses, virus-like particles, bacteriophages) is characterized by complexity of the starting material, number of purification methods to choose from, regulations that are setting the frame for the final product and analytical methods for upstream and downstream monitoring. This review gives an overview on the nanoplex downstream challenges and chromatography based analytical methods for efficient monitoring of the nanoplex production.
PART OF A SPECIAL ISSUE ON THE PLANT CELL CYCLE Interaction of a 14-3-3 protein with the plant microtubule-associated protein EDE1

†Background and Aims The cell cycle-regulated protein ENDOSPERM DEFECTIVE 1 (EDE1) is a novel plant microtubule-associated protein essential for plant cell division and for microtubule organization in endosperm. EDE1 is only present on microtubules at mitosis and its expression is highly cell cycle regulated both at the protein and the transcript levels. †Methods To search for EDE1-interacting proteins, a yeast two-hybrid screen was used in which EDE1 was fused with GAL4 DNA binding domain and expressed in a yeast strain that was then mated with a strain carrying a cDNA library fused to the GAL4 transactivation domain. Candidate interacting proteins were identified and confirmed in vitro. †Key Results 14-3-3 upsilon was isolated several times from the library screen. In in vitro tests, it also interacted with EDE1: 14-3-3 upsilon most strongly associates with EDE1 in its free form, but also weakly when EDE1 is bound to microtubules. This study shows that EDE1 is a cyclin-dependent kinase substrate but that phosphorylation is not required for interaction with 14-3-3 upsilon. †Conclusions The results suggest that 14-3-3 proteins may play a role in cytoskeletal organization of plant cells. The potential role of this interaction in the dynamics of EDE1 during the cell cycle is discussed.
Biotechnology and Bioengineering

Funding information EMD Millipore Abstract Virus filtration is a robust size‐based technique that can provide the high level of viral clearance required for the production of mammalian‐derived biotherapeutics such as monoclonal antibodies. Several studies have shown that the retention characteristics of some, but not all, virus filters can be significantly affected by membrane fouling, but there have been no direct measurements of how protein fouling might alter the location of virus capture within these membranes. The objective of this study was to directly examine the effect of protein fouling by human immunoglobulin G (IgG) on virus capture within the Viresolve Pro and Viresolve NFP membranes by scanning electron microscopy using different size gold nanoparticles. IgG fouling shifted the capture location of 20 nm gold nanoparticles further upstream within the Viresolve Pro filter due to the constriction and/or blockage of the pores in the virus retentive region of the filter. In contrast, IgG fouling had no measurable effect on the capture of 20 nm nanoparticles in the Viresolve NFP membrane, and IgG fouling had no effect on the capture of larger 40 and 100 nm nanoparticles in either membrane. These results provide important insights into how protein fouling alters the virus retention characteristics of different virus filters.
Multicenter Experience with FRED Jr Flow Re-Direction Endoluminal Device for Intracranial Aneurysms in Small Arteries

The authors assessed the clinical safety and efficacy of the Flow Re-Direction Endoluminal Device Jr (FRED Jr) dedicated to small-vessel diameters between 2.0 and 3.0 mm in 42 patients with 47 aneurysms. The primary efficacy end point of complete or near complete occlusion was reached at 1 month in 27/41 (66%), at 6 months in 21/27 (78%), and at 12 months in 11/11 (100%) aneurysms. BACKGROUND AND PURPOSE: Flow diverters are emerging as an endovascular treatment alternative for proximally located intracranial aneurysms. However, treatment of aneurysms at and beyond the circle of Willis is not well-established. We assessed the clinical safety and efficacy of the Flow Re-Direction Endoluminal Device Jr (FRED Jr) dedicated to small-vessel diameters between 2.0 and 3.0 mm. MATERIALS AND METHODS: This was a multicenter observational clinical study of 42 patients with 47 aneurysms treated by a flow-direction technique with the FRED Jr. The primary end point for clinical safety was the absence of death, major or minor stroke, and TIA. The primary end point for treatment efficacy was complete and near-complete occlusion according to the O'Kelly-Marotta grading scale at follow-up after 1, 6, and 12 months. RESULTS: The FRED Jr deployment was technically successful in all cases. In 39/42 (93%) patients, the primary safety end point was reached; in the 3 remaining patients, 1 disabling ischemic stroke, 1 minor stroke with complete recovery at discharge, and 1 TIA were observed. Two asymptomatic, completely reversible side-branch occlusions occurred. Angiographic (DSA or flat panel CT) and clinical follow-up were available after 1 month in 41/47 (87%), 6 months in 27/47 (57%), and 12 months in 11/47 (23%) aneurysms. The primary efficacy end point was reached at 1 month in 27/41 (66%), at 6 months in 21/27 (78%), and at 12 months in 11/11 (100%) aneurysms. CONCLUSIONS: Deployment of the FRED Jr is safe and effective in the treatment of intracranial aneurysms located in small vessels.
Obstructive Sleep Apnea and Retinal Nerve Fiber Layer Thickness: A Meta-analysis

Study Objectives:The association between obstructive sleep apnea syndrome (OSAS) and retinal nerve fiber layer (RNFL) thickness has been examined in many studies. However, the findings are inconsistent. Our goal is to evaluate the association between OSAS and RNFL thickness by performing a meta-analysis. Methods:We conducted a PubMed database search in November 2014 to identify studies on OSAS and RNFL. Reference lists of retrieved articles were also reviewed. A fixed-effects model was used to compute the summary mean difference (MD). Results:Six studies involving 1034 eyes were included in the meta-analysis. The overall combined MD of RNFL in OSAS patients compared with control participants was −2.03 µm [95% confidence interval (CI), −3.67 to −0.4; P=0.01]. The overall combined MDs of RNFL thickness in relation to moderate OSAS and severe OSAS were −2.49 µm (95% CI: −4.54 to −0.44; P=0.02) and −6.36 µm (95% CI: −8.4 to −4.32; P<0.001). But no significant difference was observed in mild OSAS; the combined MD was −2.05 µm (95% CI: −4.23 to 0.13; P=0.07). Association was also observed in OSAS and RNFL thickness of the inferior quadrant, with a combined MD of −3.31 µm (95% CI: −6.19 to −0.42; P=0.02). Conclusions:This meta-analysis provides evidence that OSAS is associated with RNFL thickness. Furthermore, it was observed that the greater the severity of OSAS, the greater the loss of RNFL. Among the 4 quadrants observed, the most affected quadrant was the inferior quadrant, and the least affected was the temporal quadrant. OSAS may have an impact on changes in RNFL and therefore more attention should be paid to patients with this condition.
Outcome of Splenectomy for Thrombocytopenia Associated With Systemic Lupus Erythematosus

Objective:To determine the efficacy of splenectomy for treating thrombocytopenia associated with systemic lupus erythematosus (SLE). Summary Background Data:The role of splenectomy has been controversial in this patient population. Methods:Between 1975 and 2001, 25 consecutive adults with SLE underwent splenectomy specifically for thrombocytopenia. Surgical indications, operative mortality and morbidity, and hematological outcomes were followed in both the short-term (first 30 days) and the long-term (last recorded platelet count, last contact, or death). Response to splenectomy was rated as: complete (CR: platelets ≥150 × 109/L for at least 4 weeks), partial (PR: platelets 50–149 × 109/L for at least 4 weeks), or none (NR: platelets < 50 × 109/L at all times). Relapse occurred if platelets fell below 50 × 109/L after CR or PR. Results:Indications for splenectomy included: thrombocytopenia refractory to (64%), dependent on (20%), or patient intolerance of (16%) medical treatments. Perioperative mortality was 0% and morbidity was 24%. After a median of 9.5 years, 9 patients (36%) had died, with only 1 death being secondary to bleeding. Early partial or complete response rate to splenectomy was 88%. After a median follow-up of 6.6 years, 16 (64%) patients had sustained complete or partial response without relapse. Eight (32%) of these patients required adjunctive medical therapy, whereas the other 8 (32%) did not. The remaining 9 (36%) patients relapsed, but 5 (20%) of the 9 patients were subsequently salvaged to at least partial response with further treatments. The overall PR or CR to splenectomy combined with medical therapy was 84%. Conclusion:Splenectomy should be considered safe and efficacious for thrombocytopenia associated with SLE.
Lithium chloride inhibits early stages of foot‐and‐mouth disease virus (FMDV) replication in vitro

Foot‐and‐mouth disease virus (FMDV) causes an economically important and highly contagious disease of cloven‐hoofed animals such as cattle, swine, and sheep. FMD vaccine is the traditional way to protect against the disease, which can greatly reduce its occurrence. However, the use of FMD vaccines to protect early infection is limited. Therefore, the alternative strategy of applying antiviral agents is required to control the spread of FMDV in outbreak situations. As previously reported, LiCl has obviously inhibition effects on a variety of viruses such as transmissible gastroenteritis virus (TGEV), infectious bronchitis coronavirus (IBV), and pseudorabies herpesvirus and EV‐A71 virus. In this study, our findings were the first to demonstrate that LiCl inhibition of the FMDV replication. In this study, BHK‐21 cell was dose‐dependent with LiCl at various stages of FMDV. Virus titration assay was calculated by the 50% tissue culture infected dose (TCID50) with the Reed and Muench method. The cytotoxicity assay of LiCl was performed by the CCK8 kit. The expression level of viral mRNA was measured by RT‐qPCR. The results revealed LiCl can inhibit FMDV replication, but it cannot affect FMDV attachment stage and entry stage in the course of FMDV life cycle. Further studies confirmed that the LiCl affect the replication stage of FMDV, especially the early stages of FMDV replication. So LiCl has potential as an effective anti‐FMDV drug. Therefore, LiCl may be an effective drug for the control of FMDV. Based on that, the mechanism of the antiviral effect of LiCl on FMDV infection is need to in‐depth research in vivo.
Effect of intensive counselling on the quality of dietary fats in pregnant women at high risk of gestational diabetes mellitus

As part of a feasibility study to prevent gestational diabetes mellitus (GDM), we evaluated the effect of an intensive dietary therapy on quality of diet, weight gain and birth weight in women at high risk of GDM. Women with risk factors for GDM (n 54) were randomly assigned from April 2005 to May 2006 to a lifestyle intervention group (n 27) including dietary advice six times during pregnancy or to a close follow-up group (n 27) in a community-based setting in Finland. Dietary intake was recorded three times during pregnancy using 4 d food records. The main outcome was the incidence of GDM. The secondary outcomes were the changes in nutrient intake, weight gain and birth weight. Overall, seventeen (65 %) women in the intervention group and eighteen (69 %) women in the close follow-up group returned all three food records. PUFA intake increased (P = 0·008) during pregnancy in the intervention as compared to the close follow-up group. There were no clear differences in the changes of saturated fat or fibre intake between the groups. Intensive dietary education resulted in a somewhat lower weight gain during pregnancy (P = 0·062) and higher birth weights of the infants (P = 0·047) without an effect on macrosomia as compared to the close follow-up group. Individualised counselling by a clinical nutritionist as part of a lifestyle intervention improved the quality of dietary fat intake in pregnant women at high risk of GDM.
Micro-Raman spectroscopy analysis of residual stress in polysilicon MEMS resonators

This paper presents the recent results of utilization of micro-Raman spectroscopy to measure and characterize residual stress in polysilicon doubly-clamped MEMS resonators with small lateral size. Due to imprecise prediction of the magnitude of intrinsic residual stress, detrimental effect of the residual stress severely shifts the resonant frequency of MEMS resonator from the analytical pre-designed value. The stress is not only determined by the fabrication process but also related to the structural dimensions of resonators. In this work, microRaman spectroscopy was used to measure the residual stress of resonators with widths down to 2μm. The results show that the optimized resonator with length shorter than 50μm and width between 3. 2μm and 4. 1μm exhibits minimum residual stress.