Miracle-dz/UniFAR-FTUs huggingface dataset:
Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty

There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in “paired viewing” experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had “object fields”); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition‐related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.
Predictors of trimodality therapy and trends in therapy for malignant pleural mesothelioma†

OBJECTIVES Malignant pleural mesothelioma is an aggressive and rare malignancy that frequently recurs despite aggressive therapy. We evaluated the frequency of treatment with surgery, radiation or chemotherapy, changes in therapy and survival over time and factors associated with the receipt of trimodality therapy. METHODS The National Cancer Database (NCDB) was used to query patients with histologically proven malignant pleural mesothelioma (2004-14). Treatment over time was evaluated using the Armitage trend test. Factors associated with the receipt of trimodality therapy were analysed using logistic regression. RESULTS Among 20 561 patients, only 4028 (20%) underwent cancer-directed surgery; 533 (2.6%) of whom received trimodality therapy. From 2004 to 2014, the use of surgery with chemotherapy increased 87% (P < 0.01), with no statistically significant change in the use of trimodality therapy. Median survival also increased from 8 months to 11 months (P < 0.01). Patients who were treated at an academic centre or who travel >26 miles for treatment were more likely to undergo trimodality therapy. Additional factors associated with the receipt of trimodality therapy include age less than 70, Charlson comorbidity score of 0 and presence of private insurance. CONCLUSIONS Many malignant pleural mesothelioma patients are not treated with trimodality therapy, with significant variation in treatment patterns. Referrals to high-volume and specialized centres may help offer more therapeutic options and trial or registry enrolment.
Exploration of the anti-enterovirus activity of a series of pleconaril/pirodavir-like compounds

Background The Enterovirus genus of the Picornaviridae is represented by several viral pathogens that are associated with human disease, namely Poliovirus 1, Enterovirus 71 and Rhinoviruses. Enterovirus 71 has been associated with encephalitis, while Rhinoviruses are a major cause of asthma exacerbations and chronic obstructive pulmonary disease. Based on the structure of both pleconaril and pirodavir, we previously synthesized some original compounds as potential inhibitors of Rhinovirus replication. Methods These compounds were explored for in vitro antiviral potential on other human pathogenic Enteroviruses, namely Enterovirus 71 on rhabdo-myosarcoma cells, Coxsackievirus B3 on Vero cells, Poliovirus 1 and Echovirus 11 on BGM cells. Results Activity was confirmed for compound against Rhinovirus 14. Furthermore, few compounds showed a cell-protective effect on Enterovirus 71, presented a marked improvement as compared to the reference drug pleconaril for inhibitory activity on both Enterovirus 71 and Poliovirus 1. The most striking observation was the clear cell protective effect for the set of analogues in a virus-cell-based assay for Echovirus 11 with an effective concentration (EC50) as low as 0.3 µM (Selectivity index or SI = 483), and selectivity indexes greater than 857 (EC50 = 0.6 µM) and 1524 (EC50 = 0.33 µM). Conclusion Some of the evaluated compounds showed potent and selective antiviral activity against several enterovirus species, such as Enterovirus 71 (EV-A), Echovirus 11 (EV-B), and Poliovirus 1 (EV-C). This could be used as a starting point for the development of other pleconaril/pirodavir-like enterovirus inhibitors with broad-spectrum activity and improved effects as compared to the reference drugs.
Genome-wide engineering of an infectious clone of herpes simplex virus type 1 using synthetic genomics assembly methods

Significance Viruses with large DNA genomes, such as herpesviruses, are difficult to manipulate with existing genetic tools. We describe an application of synthetic genomics assembly tools that enables rapid and efficient generation of combinatorial mutations in herpesvirus genomes. The method provides the capacity to design, generate, and test numerous multiloci mutants in parallel, which can help us understand basic virus biology, facilitate vaccine development, and aid development of next-generation virus-based delivery systems. This class of viruses is being used as vectors for therapeutics and vaccines, with an oncolytic herpesvirus approved for the treatment of melanoma. Although such improvements in genome assembly and manipulation raise dual-use concerns, we believe the potential benefits substantially outweigh the risks. Here, we present a transformational approach to genome engineering of herpes simplex virus type 1 (HSV-1), which has a large DNA genome, using synthetic genomics tools. We believe this method will enable more rapid and complex modifications of HSV-1 and other large DNA viruses than previous technologies, facilitating many useful applications. Yeast transformation-associated recombination was used to clone 11 fragments comprising the HSV-1 strain KOS 152 kb genome. Using overlapping sequences between the adjacent pieces, we assembled the fragments into a complete virus genome in yeast, transferred it into an Escherichia coli host, and reconstituted infectious virus following transfection into mammalian cells. The virus derived from this yeast-assembled genome, KOSYA, replicated with kinetics similar to wild-type virus. We demonstrated the utility of this modular assembly technology by making numerous modifications to a single gene, making changes to two genes at the same time and, finally, generating individual and combinatorial deletions to a set of five conserved genes that encode virion structural proteins. While the ability to perform genome-wide editing through assembly methods in large DNA virus genomes raises dual-use concerns, we believe the incremental risks are outweighed by potential benefits. These include enhanced functional studies, generation of oncolytic virus vectors, development of delivery platforms of genes for vaccines or therapy, as well as more rapid development of countermeasures against potential biothreats.
Does a Rehabilitation Program of Aerobic and Progressive Resisted Exercises Influence HIV-Induced Distal Neuropathic Pain?

Objective Distal symmetrical polyneuropathy is a common neurological sequela after HIV, which leads to neuropathic pain and functional limitations. Rehabilitation programs with exercises are used to augment pharmacological therapy to relieve pain but appropriate and effective exercises are unknown. This study explored the safety and effect of moderate-intensity aerobic exercises and progressive resisted exercises for HIV-induced distal symmetrical polyneuropathy neuropathic pain. Design A randomized pretest, posttest of 12 wks of aerobic exercise or progressive resisted exercise compared with a control. Outcome measures were assessed using the subjective periphery neuropathy, brief peripheral neuropathy screening, and numeric pain rating scale. Pain was assessed at baseline, 6 and 12 wks. Data between groups were compared using Kruskal-Wallis, Mann-Whitney U test, and within-groups Friedman and Wilcoxon signed rank tests. Results There were 136 participants (mean [SD] age = 36.79 [8.23] yrs) and the exercise groups completed the protocols without any adverse effects. Pain scores within and between aerobic exercise and progressive resisted exercise groups showed significant improvement (P < 0.05) from baseline to 6 and 12 wks compared with the control (P > 0.05). Conclusions This study supports a rehabilitation program of moderate-intensity aerobic exercise and progressive resisted exercise being safe and effective for reducing neuropathic pain and is beneficial with analgesics for HIV-induced distal symmetrical polyneuropathy.
Is Orthographic Information From Multiple Parafoveal Words Processed in Parallel: An Eye-Tracking Study

In the current study we investigated whether orthographic information available from 1 upcoming parafoveal word influences the processing of another parafoveal word. Across 2 experiments we used the boundary paradigm (Rayner, 1975) to present participants with an identity preview of the 2 words after the boundary (e.g., hot pan), a preview in which 2 letters were transposed between these words (e.g., hop tan), or a preview in which the same 2 letters were substituted (e.g., hob fan). We hypothesized that if these 2 words were processed in parallel in the parafovea then we may observe significant preview benefits for the condition in which the letters were transposed between words relative to the condition in which the letters were substituted. However, no such effect was observed, with participants fixating the words for the same amount of time in both conditions. This was the case both when the transposition was made between the final and first letter of the 2 words (e.g., hop tan as a preview of hot pan; Experiment 1) and when the transposition maintained within word letter position (e.g., pit hop as a preview of hit pop; Experiment 2). The implications of these findings are considered in relation to serial and parallel lexical processing during reading.
Updated Cost-effectiveness Assessments of PCSK9 Inhibitors From the Perspectives of the Health System and Private Payers: Insights Derived From the FOURIER Trial

Importance Preliminary cost-effectiveness analyses of proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) were based on benefits estimated from reductions in low-density lipoprotein cholesterol that occurred in PCSK9i trials with variable results. The recent Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial provides better information about the effectiveness of the drug. Objective To use the trial results to determine the cost-effectiveness of a PCSK9i and statin treatment strategy compared with a statin alone strategy. Design, Setting, and Participants We derived observed rates of events, outcomes, cost of care, and health insurance from existing literature for a theoretical cohort of patients designed to resemble the FOURIER PCSK9i trial population and created a Markov model during the time horizon of a full lifetime. Main Outcomes and Measures We evaluated the incremental cost-effectiveness ratio from a health system perspective, and the return on investment from a private payer perspective. For both measures, we assumed an annual PCSK9i drug price of $14 300, with a lapse in US patent protection that would reduce the price by 43% in year 12. Costs were reported in 2016 US dollars. Results This study modeled 1000 hypothetical patients with attributes similar to those of the FOURIER trial cohort. At the current price, the incremental cost-effectiveness ratio of statin plus PCSK9i therapy was $337 729 per quality-adjusted life-year. Our probabilistic sensitivity analysis found that a statin plus PCSK9i strategy had a low probability (<1%) of being cost effective at the commonly accepted societal threshold of $100 000 per quality-adjusted life-year. Furthermore, PCSK9i produced a negative return on investment of 86% for private payers. In our threshold analysis, the price of PCSK9i would need to drop 62%, to $5459 per year, to reach $100 000 per quality-adjusted life year. Conclusions and Relevance At current prices, the addition of PCSK9i to statin therapy is estimated to provide an additional quality-adjusted life year for $337 729 . Significant discounts are necessary to meet conventional cost-effectiveness standards.
Assessment of the repellent effect of citronella and lemon eucalyptus oil against South African Culicoides species.

The use of insect repellents to reduce the attack rate of Culicoides species (Diptera:Ceratopogonidae) should form part of an integrated control programme to combat Africanhorse sickness and other diseases transmitted by these blood-feeding midges. In the presentstudy the repellent effects of a commercially available mosquito repellent, a combinationof citronella and lemon eucalyptus oils, on Culicoides midges was determined. The numberof midges collected with two 220 V Onderstepoort traps fitted with 8 W 23 cm white lighttubes and baited with peel-stick patches, each containing 40 mg of active ingredient, wascompared with that of two unbaited traps. Two trials were conducted and in each trial thefour traps were rotated in two replicates of a 4 x 4 randomised Latin square design. Althoughmore midges were collected in the baited traps, the mean number in the baited and unbaitedtraps was not significantly different. This mosquito repellent did not influence either thespecies composition or the physiological groups of Culicoides imicola Kieffer. The highermean numbers in the baited traps, although not statistically significant, may indicate that thismosquito repellent might even attract Culicoides midges under certain conditions.
Curing parameters to improve the mechanical properties of stereolithographic printed specimens

Purpose This paper presents findings from a study examining curing procedures to improve the compressive strength and hardness properties of specimens while maintaining surface quality. All specimens were created from a standard grey, acrylic-based photopolymer and fabricated using stereolithography technology. This paper aims to investigate the effects of printing layer thickness and print orientation on specimen compressive strength, as well as the effects of thermal and light curing methods. In addition, the post-print curing depth was investigated. Design/methodology/approach The effects of layer thickness and print orientation were investigated on 10 × 20 mm cylinders by determining the ultimate compressive strength once cured. The compressive strength of cylinders subjected to varying thermal and light settings was also investigated to determine the optimal curing settings. The effective depth of curing was investigated on a 25.4-mm cuboidal specimen, which received both thermal and light curing. Findings To achieve the highest compressive strength, specimens shall be printed with the minimal layer thickness of 25 µm. Increasing temperatures up to 60° C during curing provided a 0.75-MPa increase in compressive strength per degree Celsius. However, increasing temperatures above 60° C only provided a 0.15-MPa increase in compressive strength per degree Celsius. Furthermore, curing temperatures above 110° C resulted in degraded surface quality noted by defects at the layer laminations. Specimens required a minimum light curing exposure time of four hours to reach the maximum cure at which point any increase in exposure time provided no substantial increase in compressive strength. Originality/value This study provides recommendations for printing parameters and curing methods to achieve the optimum mechanical properties of cured stereolithography specimens.
17β‐Oestradiol promotes differentiation of human embryonic stem cells into dopamine neurons via cross‐talk between insulin‐like growth factors‐1 and oestrogen receptor β

Human embryonic stem cells (hESCs) can self‐renew and differentiate into all cell lineages. E2 is known to exhibit positive effects on embryo development. Although the importance of E2 in many physiological processes has been reported, to date few researchers have investigated the effects of E2 on hESCs differentiation. We studied the effects of E2 on dopamine (DA) neuron induction of hESCs and its related signalling pathways using the three‐stage protocol. In our study, 0.1 μM E2 were applied to hESCs‐derived human embryoid bodies (hEBs) and effects of E2 on neural cells differentiation were investigated. Protein and mRNA level assay indicated that E2 up‐regulated the expression of insulin‐like growth factors (IGF)‐1, ectoderm, neural precursor cells (NPC) and DA neuron markers, respectively. The population of hESC‐derived NPCs and DA neurons was increased to 92% and 93% to that of DMSO group, respectively. Furthermore, yield of DA neuron‐secreted tyrosine hydroxylase (TH) and dopamine was also increased. E2‐caused promotion was relieved in single inhibitor (ICI or JB1) group partly, and E2 effects were repressed more stronger in inhibitors combination (ICI plus JB1) group than in single inhibitor group at hEBs, hNPCs and hDA neurons stages. Owing to oestrogen receptors regulate multiple brain functions, when single or two inhibitors were used to treat neural differentiation stage, we found that oestrogen receptor (ER)β but not ERα is strongly repressed at the hNPCs and hDA neurons stage. These findings, for the first time, demonstrate the molecular cascade and related cell biology events involved in E2‐improved hNPC and hDA neuron differentiation through cross‐talk between IGF‐1 and ERβ in vitro.
Universal antiretroviral therapy for HIV-infected children: a review of the benefits and risks to consider during implementation

Background: The 2016 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommended to start all HIV‐infected children on antiretroviral therapy (ART). Here, we explore the possible benefits and risks of implementing universal ART for all HIV‐infected children and adolescents and outline some of the key considerations that led to the 2016 revision of WHO guidelines.
MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox state

Fumagillin and its derivatives are therapeutically useful because they can decrease cancer progression. The specific molecular target of fumagillin is methionine aminopeptidase 2 (MetAP2), one of the two MetAPs present in the cytosol. MetAPs catalyze N-terminal methionine excision (NME), an essential pathway of cotranslational protein maturation. To date, it remains unclear the respective contribution of MetAP1 and MetAP2 to the NME process in vivo and why MetAP2 inhibition causes cell cycle arrest only in a subset of cells. Here, we performed a global characterization of the N-terminal methionine excision pathway and the inhibition of MetAP2 by fumagillin in a number of lines, including cancer cell lines. Large-scale N-terminus profiling in cells responsive and unresponsive to fumagillin treatment revealed that both MetAPs were required in vivo for M[VT]X-targets and, possibly, for lower-level M[G]X-targets. Interestingly, we found that the responsiveness of the cell lines to fumagillin was correlated with the ability of the cells to modulate their glutathione homeostasis. Indeed, alterations to glutathione status were observed in fumagillin-sensitive cells but not in cells unresponsive to this agent. Proteo-transcriptomic analyses revealed that both MetAP1 and MetAP2 accumulated in a cell-specific manner and that cell sensitivity to fumagillin was related to the levels of these MetAPs, particularly MetAP1. We suggest that MetAP1 levels could be routinely checked in several types of tumor and used as a prognostic marker for predicting the response to treatments inhibiting MetAP2.
New public management in Iran’s health complex: a management framework for primary health care system

Background New public management (NPM) was developed as a management reform to improve the efficiency and effectiveness in public organizations, especially in health sector. Using the features of private sector management, the managers of health organizations may try to implement the elements of NPM with the hope to improve the performance of their systems. Aims Our aim in the present study was to identify the elements and infrastructures suitable for implementing NPM in the Iranian health complex. Method In this qualitative study with conventional content analysis approach, we tried to explore the NPM elements and infrastructures in Iranian public health sector. A series of semi-structured interviews (n=48) were conducted in 2016 with a managers in public and private health complex. Three focus group discussions with nine faculty members were also conducted. A data collection form was used to collect the demographic characteristics and perspectives of the participants. Findings From the perspective of managers, managerialism, decentralization, using market mechanism, performance management, customer orientation and performance budgeting were the main elements of NPM in the Iranian context. The most important infrastructures for implementing this reform were as follows: education and training, information technology, the proper use of human resources, decision support systems, top management commitment, organizational culture, flexibility of rules, rehabilitating of the aging infrastructures, and expanding the coverage of services. Conclusion The NPM was generally identified to be an effective replacement for the traditional administration method. These reforms may be helpful in strengthening the public health complex and the management capacity, as well. NPM also seems to be useful in interacting the public health sector with the private sector in terms of personnel and resources, performance, reward structure, and methods of doing business.
Human Antimicrobial Peptides in Bodily Fluids: Current Knowledge and Therapeutic Perspectives in the Postantibiotic Era

Antimicrobial peptides (AMPs) are an integral part of the innate immune defense mechanism of many organisms. Due to the alarming increase of resistance to antimicrobial therapeutics, a growing interest in alternative antimicrobial agents has led to the exploitation of AMPs, both synthetic and isolated from natural sources. Thus, many peptide‐based drugs have been the focus of increasing attention by many researchers not only in identifying novel AMPs, but in defining mechanisms of antimicrobial peptide activity as well. Herein, we review the available strategies for the identification of AMPs in human body fluids and their mechanism(s) of action. In addition, an overview of the distribution of AMPs across different human body fluids is provided, as well as its relation with microorganisms and infectious conditions.