Miracle-dz/UniFAR-FTUs huggingface dataset:
The AKV Murine Leukemia Virus Is Restricted and Hypermutated by Mouse APOBEC3

ABSTRACT APOBEC3 proteins are potent restriction factors against retroviral infection in primates. This restriction is accompanied by hypermutations in the retroviral genome that are attributable to the cytidine deaminase activity of the APOBEC3 proteins. Studies of nucleotide sequence diversity among endogenous gammaretroviruses suggest that the evolution of endogenous retroelements could have been shaped by the mutagenic cytidine deaminase activity of APOBEC3. In mice, however, APOBEC3 appears to restrict exogenous murine retroviruses in the absence of detectable levels of deamination. AKV is an endogenous retrovirus that is involved in causing a high incidence of thymic lymphoma in AKR mice. A comparative analysis of several mouse strains revealed a relatively low level of APOBEC3 expression in AKR mice. Here we show that endogenous mouse APOBEC3 restricts AKV infection and that this restriction likely reflects polymorphisms affecting APOBEC3 abundance rather than differences in the APOBEC3 isoforms expressed. We also observe that restriction of AKV by APOBEC3 is accompanied by G→A hypermutations in the viral genome. Our findings demonstrate that APOBEC3 acts as a restriction factor in rodents affecting the strain tropism of AKV, and they provide good support for the proposal that APOBEC3-mediated hypermutation contributed to the evolution of endogenous rodent retroviral genomes.
Benefit of contrast enhanced ultrasound for detection of ischaemic lesions and arterio venous fistulas in renal transplants - a feasibility study.

PURPOSE To evaluate the benefit of CEUS (contrast enhanced ultrasound) regarding depiction of ischaemic lesions and AVFs (arterio venous fistula) in renal transplants compared to standard ultrasound (US) (grey-scale and color Doppler). MATERIALS AND METHODS In this study 22 patients suspected of having acute vascular complication after renal transplantation were investigated using standard ultrasound (grey-scale US and color Doppler US) and CEUS, respectively. Validity of the respective US-techniques regarding depiction of ischaemic lesions and AVF was compared. Dynamic CTA (computed tomography angiography) served as the standard of reference. RESULTS In 10 renal transplants arterial embolism associated with kidney infarctions were observed. Very good correlation to dynamic CTA was yielded using CEUS, whereas grey scale US and color Doppler US was limited in the accurate depiction of renal infarctions. Additionally CEUS was superior in displaying arteriovenous fistulas compared to standard US. CONCLUSION CEUS as a fast and bedside available imaging modality not associated with dose exposure or renal toxicity facilitates improved detection of ischaemic lesions and AVFs compared to standard US and thus should be considered for short term follow up of renal transplants.
SENP1 regulates PTEN stability to dictate prostate cancer development

SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1a, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis. SENP1 blocks SUMO1-dependent ubiquitylation and degradation of PTEN. In the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol, where binding to ubiquitin-E3 ligase WWP2 occurs. Concurrently, WWP2 is also SUMOylated, which potentiates its interaction with PTEN. Thus, SENP1 directs ubiquitin-E3-substrate association to control PTEN stability. PTEN serves as a barrier for SENP1-mediated prostate carcinogenesis as SENP1-Tg mice develop invasive carcinomas only after PTEN reduction. Hence, SENP1 modulates multiple facets of carcinogenesis and may serve as a target specifically for aggressive PTEN-deficient PCa.
Peptide Vaccination with an Anchor‐Replaced CTL Epitope Protects Against Human Papillomavirus Type 16‐Induced Tumors Expressing the Wild‐Type Epitope

Anchor residues in cytotoxic T-lymphocyte (CTL) epitope-bearing peptides are buried deep in the major histocompatibility complex (MHC) class I antigen-presenting groove and are essential for binding to MHC class I molecules. We investigated whether anchor residue replacement affects the ability of a CTL epitope to be bound and transported by MHC class I molecules and transporter associated with antigen (TAP), respectively, and affects its functionality in vivo. Therefore, both anchor residues, at positions 5 and 9, of the H-2Db-restricted CTL epitope HPV16 E7 49–57 RAHYNIVTF were systematically exchanged for one of the 19 other naturally occurring amino acid (AA). Only replacement at anchor position 9 with residues V, I, L, or M. which are documented Db motif-anchor residues at that position, allowed binding to the MHC class 1 H-2Db molecule as well as transport by TAP with the same efficiency as the wild-type epitope. In B6 mice (H-2b), these anchor-modified peptide epitopes efficiently induced CTL that specifically recognized the wild-type epitope. Conversely, wild-type epitope-induced CTL recognized the V9-, I9-, L9-, and M9-replaced epitopas, respectively. In terms of tumor prelection against a challenge with HPV16-transformed cells, the V9-replaced epitope was as efficient as the wild-type epitope E7 49–57. Taken together, our data demonstrate that specific CTL epitope anchor replacements are allowed with respect to MHC class I binding and TAP transport, as well as with respect to antigenicity and immunogenicity in vivo. The results presented are relevant to CTL epitope-based peptide vaccine development.
Myocardial Gi alpha-protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock.

OBJECTIVE Increased inhibitory G-protein alpha-subunits (Gi alpha) have been reported to be related to adenylyl cyclase desensitization in the failing human heart. In order to investigate whether this cellular alteration occurs already at the stage of hypertensive cardiac hypertrophy or in catecholamine-refractory cardiogenic shock, Gi alpha levels were studied in myocardial samples from patients with hypertensive cardiac hypertrophy, coronary heart disease without heart failure and from patients with cardiogenic shock on high-dose catecholamine therapy as well as from patients without evidence of heart disease. METHODS Gi alpha was quantified with pertussis-toxin-catalyzed 32P-ADP-ribosylation and with a radioimmunoassay in myocardial samples from patients within 16 h of death. The radioimmunoassay was constructed with recombinant G-protein alpha-subunits (rGi alpha 1) from transformed E. coli harbouring the full-length cDNA of Gi alpha 1, iodinated peptide 125I-KENLKDCGLF and immunoprecipitating antiserum (MB 1) raised against the synthetic peptide (KENLKDCGLF) in rabbits. RESULTS Pertussis toxin substrates and immunochemical Gi alpha remained stable up to 80 h following storage at room temperature in myocardium obtained during cardiac transplantation. Gs alpha, adenylyl cyclase, beta-adrenoceptors and inhibitory receptors were not stable and could not be determined. Increases in myocardial Gi alpha of 65-82% of both pertussis toxin substrates and immunologically quantified Gi alpha were observed in hypertensive cardiac hypertrophy. Catecholamine therapy in patients who died of catecholamine-refractory shock increased myocardial Gi alpha by 225% compared to myocardium from patients with coronary heart disease without heart failure and without catecholamine therapy or compared to control myocardium. CONCLUSION These findings provide evidence than an increase in myocardial Gi alpha-proteins could be of relevance in pathological conditions other than chronic heart failure. Since an increase in Gi alpha levels already occurs in hypertensive cardiac hypertrophy, it could play a role in contributing to the development of contractile dysfunction and heart failure in later stages of the syndrome. Finally, an increase in Gi alpha could be one mechanism contributing to catecholamine refractoriness in shock. This could provide a target for pharmacological treatment in this condition.
Effects of amphibian phylogeny, climate and human impact on the occurrence of the amphibian‐killing chytrid fungus

Chytridiomycosis, due to the fungus Batrachochytrium dendrobatidis (Bd), has been associated with the alarming decline and extinction crisis of amphibians worldwide. Because conservation programs are implemented locally, it is essential to understand how the complex interactions among host species, climate and human activities contribute to Bd occurrence at regional scales. Using weighted phylogenetic regressions and model selection, we investigated geographic patterns of Bd occurrence along a latitudinal gradient of 1500 km within a biodiversity hot spot in Chile (1845 individuals sampled from 253 sites and representing 24 species), and its association with climatic, socio‐demographic and economic variables. Analyses show that Bd prevalence decreases with latitude although it has increased by almost 10% between 2008 and 2013, possibly reflecting an ongoing spread of Bd following the introduction of Xenopus laevis. Occurrence of Bd was higher in regions with high gross domestic product (particularly near developed centers) and with a high variability in rainfall regimes, whereas models including other bioclimatic or geographic variables, including temperature, exhibited substantially lower fit and virtually no support based on Akaike weights. In addition, Bd prevalence exhibited a strong phylogenetic signal, with five species having high numbers of infected individuals and higher prevalence than the average of 13.3% across all species. Taken together, our results highlight that Bd in Chile might still be spreading south, facilitated by a subset of species that seem to play an important epidemiological role maintaining this pathogen in the communities, in combination with climatic and human factors affecting the availability and quality of amphibian breeding sites. This information may be employed to design conservation strategies and mitigate the impacts of Bd in the biodiversity hot spot of southern Chile, and similar studies may prove useful to disentangle the role of different factors contributing to the emergence and spread of this catastrophic disease.
ORIGINAL INVESTIGATIONS Pathogenesis and Treatment of Kidney Disease Association of Kidney Function With Coronary Atherosclerosis and Calcification in Autopsy Samples From Japanese Elders: The Hisayama Study

Background: Chronic kidney disease (CKD) is associated with increased risk of coronary heart disease. However, information regarding the histopathologic characteristics of coronary atherosclerosis in individuals with CKD is scarce. This study investigated the relationship between CKD and severity of coronary atherosclerosis in population-based autopsy samples. Study Design: Cross-sectional study. Setting & Participants: 126 individuals randomly selected from 844 consecutive population-based autopsy samples. Predictor: Estimated glomerular filtration rate (eGFR) calculated using the 6-variable Modification of Diet in Renal Disease (MDRD) Study equation. Outcomes: Severity of atherosclerosis in 3 main coronary arteries, including atherosclerotic lesion types defined using the American Heart Association classification; stenosis rates; and coronary calcified lesions. Measurements: The relationship between CKD and severity of coronary atherosclerosis was evaluated using generalized estimating equation methods. Results: Frequencies of advanced atherosclerotic lesions increased gradually as eGFR decreased (33.6%, 41.7%, 52.3%, and 52.8% for eGFRs 60, 45-59, 30-44, and 30 mL/min/1.73 m 2 , respectively; P for trend 0.006). This relationship was substantially unchanged even after adjustment for potential confounding factors (ORs, 1.40 [95% CI, 0.76-2.55], 2.02 [95% CI, 0.99-4.15], and 3.02 [95% CI, 1.22-7.49] for eGFRs of 45-59, 30-44, and 30 mL/min/1.73 m 2 , respectively). Frequencies of calcified lesions of coronary arteries also increased gradually with lower eGFRs (P for trend 0.02). Hypertension and diabetes were associated with increased risk of advanced coronary atherosclerosis and calcification of coronary arteries in individuals with decreased eGFR. Limitations: Cross-sectional study, absence of data for proteinuria, and extremely high proportion of aged people. Conclusions: The autopsy findings presented here suggest that CKD is associated significantly with severity of coronary atherosclerosis. Patients with CKD should be considered a high-risk population for advanced coronary atherosclerosis. Am J Kidney Dis 55:21-30. © 2009 by the National Kidney Foundation, Inc.
In vivo correlates for Streptococcus pneumoniae penicillin resistance in acute otitis media

Eighty-four children suffering from acute otitis media caused by Streptococcus pneumoniae were treated prospectively with cefuroxime axetil suspension (30 mg/kg of body weight twice daily for 8 days). The high incidence of isolates with decreased susceptibilities to penicillin (42 of 84 isolates) allowed us to establish a relationship between clinical success and the penicillin MICs for pneumococcal isolates. It was found that cefuroxime axetil is clinically effective in the treatment of acute otitis media caused by penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae. The results indicate that the risk of treatment failure with cefuroxime axetil was increased in children with otitis media caused by S. pneumoniae when the penicillin MIC were greater than or equal to 2 mg/liter.
Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism.

BACKGROUND Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and secondary HPT. METHODS We undertook a combined analysis of safety data (parathyroidectomy, fracture, hospitalizations, and mortality) from 4 similarly designed randomized, double-blind, placebo-controlled clinical trials enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled secondary HPT (intact PTH > or =300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for hyperphosphatemia and secondary HPT (phosphate binders and vitamin D). Relative risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. Health-related quality-of-life (HRQOL) data were obtained from the Medical Outcomes Study Short Form-36 (SF-36), and the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF). RESULTS Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI 0.01-0.55), fracture (RR 0.46, 95% CI 0.22-0.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.43-0.86) compared with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component Summary score and the specific domains of Bodily Pain and General Health Perception. CONCLUSION Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on important clinical outcomes.
Sexual dysfunction associated with major depressive disorder and antidepressant treatment

Introduction: There is a well-established relationship between sexual functioning and quality of life. Depression can cause sexual dysfunction (SD) and its treatment can often lead to restoration of sexual functioning. Use of antidepressants has also been associated with SD, with implications for treatment compliance and creation of further distress for the patient. Areas covered: This review evaluates available information regarding SD related to both depression and antidepressant treatment, including literature up to June 2014. It includes eligible published studies that investigated antidepressant-associated SD (AASD). Expert opinion: Depression and SD have a bidirectional association. When screening for depression, baseline sexual functioning should be assessed with validated rating scales. If sexual side effects develop with antidepressant treatment, management options include waiting for spontaneous remission, decreasing the medication dose, switching to an alternative drug or adding an augmentation agent or antidote. Research suggests that bupropion and newer antidepressants exhibit a more favorable SD profile compared with other antidepressants, especially selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors. Bupropion, mirtazapine and buspirone have been studied as augmentation agents/antidotes or substitution agents in management of AASD. Future studies validating genetic factors could enable personal genotyping to guide individualized treatment and also facilitate the development of enhanced therapeutic guidelines to avoid or manage AASD.
Multiple Mechanisms Of Early Hyperglycaemic Injury Of The Rat Intestinal Microcirculation

1. Hyperglycaemia in the vast majority of humans with diabetes mellitus is the end result of profound insulin resistance secondary to obesity. For patients in treatment, hyperglycaemia is usually not sustained but, rather, occurs intermittently. In in vivo studies of the rat intestinal microcirculation, endothelial impairment occurs within 30 min at D‐glucose concentrations ≥ 300 mg/dL. Endothelial‐dependent dilation to acetylcholine and constriction to noradrenaline is impaired. Vasodilation to exogenous nitric oxide (NO) remains normal.
Thrombin and Vascular Smooth Muscle Cell Proliferation: Implications for Atherosclerosis and Restenosis

Despite long-standing knowledge about the relationship between thrombosis and atherosclerosis, the specific role of thrombin in modulating atherosclerosis and the response to vascular injury is not well understood. Thrombin receptor stimulation in vitro signals many cellular events that are associated with the response to vascular injury (atherosclerosis) in vivo. Proliferation of smooth muscle cells (SMCs) is an important component of the response to vascular injury. We have previously shown that human alpha-thrombin and the 14-amino acid human thrombin receptor-activating peptide (huTRAP-14) stimulate proliferation of cultured rat aortic SMCs. However, thrombin-induced SMC proliferation demonstrates delayed kinetics relative to platelet-derived growth factor (PDGF-BB, another potent SMC mitogen). Several mechanisms may be responsible for these delayed kinetics in vitro, including production of necessary secondary growth factors and thrombin-induced upregulation of its receptor. In vivo studies have demonstrated that thrombin inhibition limits the response to vascular injury in a hypercholesterolemic rabbit model of focal femoral atherosclerosis. However, this effect does not appear to be mediated by effects on early SMC proliferation. In this discussion, we will address the mechanisms of thrombin-induced SMC proliferation in vitro and apply this knowledge to our understanding of the role of thrombin inhibition in limiting the response to vascular injury in vivo.
Inductive power transfer: Through a bondgraph analogy, an innovative modal approach

There is a wide research interest in the field of design and optimization of inductive power transfer systems due to increasing diffusion of sustainable electric powered transportation systems involving the development of both conventional and autonomous ground, air and marine vehicles. In this work authors, focused their attention on a consolidated toy benchmark (a cylindrical inductive pattern fed by a resonant converter), to introduce, test and validate an innovative approach based on the analogy between electromagnetic systems and mechanical ones. In this way, many key features of resonant inductive power transfer systems should be modelled and understood using methodologies previously developed for the study of mechanical vibrating systems and widely adopted for the optimization and control of suspension systems. In this work an example is validated both on a simplified experimental setup and on the corresponding Finite Element model, showing feasibility and advantages deriving from the proposed approach.
Anthracycline-based Chemotherapy as First-line Treatment in Adults with Malignant Posttransplant Lymphoproliferative Disorder after Solid Organ Transplantation

Background. Recommended first-line treatment for posttransplant lymphoproliferative disorder (PTLD) is reduction in immunosuppressive therapy, irrespective of histopathological type. Second-line treatment with chemotherapy is generally reserved for tumors that fail to respond to reduced immunosuppression. In view of the similarities between monomorphic PTLD and non-Hodgkin's lymphoma in the general population, our policy is to treat monomorphic PTLD with anthracycline-based chemotherapy as first-line treatment. Methods. A retrospective single-center analysis of 18 adults who developed PTLD following liver or kidney transplantation was undertaken, with particular emphasis on tumor histology, treatment received, and clinical outcome. Results. Of the 18 patients with PTLD, 13 had high-grade malignant lymphoma on diagnostic biopsy and received anthracycline-based chemotherapy and reduction in immunosuppression as first-line therapy. Nine (69%) of the 13 patients achieved complete remission and eight (62%) remained in complete remission five years after diagnosis. There was no graft loss from rejection or drug toxicity. Four (22%) patients had polymorphic PTLD on diagnostic biopsy (of which two were re-classified as monomorphic) and one had a low-grade malignant lymphoma. All five patients were treated by reduction in immunosuppression without chemotherapy and were in complete remission at a median of two years after diagnosis. Overall, complete remission was seen in 14 out of 18 patients (78%) at one year following diagnosis. Conclusion. The use of anthracycline-based chemotherapy and reduction of immunosuppression as first-line treatment in adults with monomorphic PTLD is well tolerated and achieves sustained complete remission in around 70% of patients with a low risk of graft loss.
An optimized complex-image prediction model for a closed-form solution of vertical antennas above a dielectric half-space

The electromagnetic modeling of vertical antennas above a dielectric half-space involves the computation of Sommerfeld-type integrals each of which represent he inverse transformation of a slowly-convergent spectral-domain Green's function. It is well known that the numerical evaluation of these integrals is computationally time-expensive. Alternatively, the complex-image technique, proposed in [1], is used in this paper to derive closed-form expressions of the required spatial Green's functions associated with vertical antennas above a dielectric half-space. The accuracy of the complex-image technique is further improved by modifying the amplitudes and locations of the images so that an optimized complex-image prediction model is produced.