Miracle-dz/UniFAR-FTUs huggingface dataset:
Neurovirulence and Immunogenicity of Attenuated Recombinant Vesicular Stomatitis Viruses in Nonhuman Primates

ABSTRACT In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. IMPORTANCE The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans.
The role of apoptosis in acute lung injury

ObjectiveTo discuss current aspects of our understanding of the role of apoptosis in lung injury. Data SourcesReview of English language literature. Data SummaryApoptosis is a process that produces timely death in senescent cells. Apoptosis is important in developmental biology and in remodeling of tissues during repair. Many apoptosis pathways converge in intracellular protease cascades that lead to DNA cleavage and cell death. Apoptosis pathways can be triggered by surface receptors, which interact with soluble proteins or membrane-bound proteins, such as Fas ligand. Fas ligand accumulates in soluble form at sites of tissue inflammation and has the potential to initiate apoptosis of leukocytes, epithelial cells, and other parenchymal cells. Dysregulation of apoptosis pathways could contribute to the epithelial injury that is characteristic of acute lung injury in humans. The effects of Fas ligand are modulated by factors in lung fluids, such as cytokines (e.g., transforming growth factor-&bgr;, surfactant protein A, and angiotensin II) and a specific Fas ligand decoy receptor (DcR3). ConclusionStrategies to block apoptosis pathways could be useful in limiting some forms of acute lung injury in humans.
Indexing and Active Fund Management: International Evidence

We examine the relation between indexing and active management in the mutual fund industry worldwide. Explicit indexing and closet indexing by active funds are associated with countries’ regulatory and financial market environments. We find that actively managed funds are more active and charge lower fees when they face more competitive pressure from low-cost explicitly indexed funds. A quasi-natural experiment using the exogenous variation in indexed funds generated by the passage of pension laws supports a causal interpretation of the results. Moreover, the average alpha generated by active management is higher in countries with more explicit indexing and lower in countries with more closet indexing. Overall, our evidence suggests that explicit indexing improves competition in the mutual fund industry.
Prevalence of leg weakness in broiler chickens and its relationship with genotype

A method for measuring the prevalence of leg weakness by assessing the walking ability of broilers was developed. Walking ability was divided into six categories, from completely normal to immobile. The method was found to give consistent results when performed by the same people. In a survey of commercial, intensively reared broilers, 90 per cent had a detectable gait abnormality and 26 per cent suffered an abnormality of sufficient severity for their welfare to be considered compromised. The prevalence of leg weakness in free range broilers, and three commercial breeds of broilers was determined. The results indicated that genetic factors were an important cause of leg weakness in broilers and also identified a possible relationship between liveweight and leg weakness.
Acute Myeloid Leukemia: Clinical Spectrum of 125 Patients.

BACKGROUND Acute myeloid leukemia is an acquired clonal heterogeneous stem cell disorder. Hence, various parameters are sought out to categorize this disease into subtypes, so that as a consequence specific treatment modalities can be offered. Conventionally, the practically used method for classification utilizes French American British (FAB) criteria based on morphology and cytochemistry. The aim of present study was to determine the current spectrum of AML sub types in patients in Karachi. MATERIALS AND METHODS This single centre cross sectional study was conducted at Liaquat National Hospital, Karachi, extending from January 2010 to December 2014. Data were retrieved from archives were analyzed with SPSS version 22. RESULTS A total of 125 patients were diagnosed at our institution with de novo AML during five years period, 76 males and 49 females. Median age was 34.5 years. AML-M1 was the predominant FAB subtype (23.2%) followed by M2 (18.4%), M3 and M4 (16% each), M0 (14.4%), M5 (7.2%), M6 (3.2%) and M7 (1.6%). CONCLUSIONS AML in Pakistani patients is seen in a relatively young population. The most common FAB subtype observed in our study was acute myeloblastic leukemia, without maturation (M1).
How is respiratory rhythm generated?

The time course of respiratory activity, e.g., the the abrupt transitions between the inspiratory (1) and expiratory (E) phases, can be explained by several types of interaction between brainstem respiratory neurons. 1) Reciprocal inhibition: Inhibition of E neurons by I neurons, and of I neurons by E neurons, has been demonstrated, a mechanism that prevents occurrence of activity in one set of populations during the period of activity of another set of populations. 2) Recurrent inhibition: During each respiratory phase, activity in recurrent loops gradually rises to levels sufficient to inhibit ongoing activity and produce abrupt phase-switching. a) I leads to E phase-switching: By use of lung inflation tests, several categories of I neurons in the region of the ventrolateral nucleus of tractus solitarius (NTS) have been specified; in particular, a population of late-I neurons has been found that may function to terminate the I phase. b) E leads to I phase-switching: Several populations of medullary neurons (early-E, late-E, and EI) have been found with responses to lung inflation that suggest that they may play a role in determining E phase duration and E leads to I switching; in particular, a population of early-E neurons in the NTS has been found whose discharge properties suggest that they may function to delay the onset of the succeeding I phase. 3) Recurrent excitation: There is evidence for the existence of recurrent excitatory actions among I neurons that may produce the augmenting pattern of I neurons' discharges.
Translational research: The CD34+ cell is crucial for large-volume bone regeneration from the milieu of bone marrow progenitor cells in craniomandibular reconstruction.

PURPOSE This study investigated the role of the bone marrow-derived CD34+ cell in a milieu of osteoprogenitor cells, bone marrow plasma cell adhesion molecules, recombinant human bone morphogenetic protein (rhBMP), and a matrix of crushed cancellous allogeneic bone in the clinical regeneration of functionally useful bone in craniomandibular reconstructions. The history and current concepts of bone marrow hematopoietic stem cells and mesenchymal stem cells are reviewed as they relate to bone regeneration in large continuity defects of the mandible. MATERIALS AND METHODS Patients with 6- to 8-cm continuity defects of the mandible with retained proximal and distal segments were randomized into two groups. Group A received an in situ tissue-engineered graft containing 54 ± 38 CD34+ cells/mL along with 54 ± 38 CD44+, CD90+, and CD105+ cells/mL together with rhBMP-2 in an absorbable collagen sponge (1 mg/cm of defect) and crushed cancellous allogeneic bone. Group B received the same graft, except the CD34+ cell concentration was 1,012 ± 752 cells/mL. The results were analyzed clinically, radiographic bone density was measured in Hounsfield units (HU), and specimens were analyzed histomorphometrically. RESULTS Forty patients participated (22 men and 12 women; mean age, 57 years). Eight of 20 group A patients (40%) achieved the primary endpoint of mature bone regeneration, whereas all 20 group B patients (100%) achieved the primary endpoint. CD34+ cell counts above 200/mL were associated with achievement of the primary endpoint. Bone density was lower in group A (424 ± 115 HU) than in group B (731 ± 98 HU). Group A bone showed a mean trabecular bone area of 36% ± 10%, versus 67% ± 13% for group B. CONCLUSIONS The CD34+ cell functions as a central signaling cell to mesenchymal stem cells and osteoprogenitor cells in bone regeneration. The mechanism of bone marrow-supported grafts requires a complete milieu to regenerate large quantities of functionally useful bone. CD34+ cell counts in a concentration of at least 200/mL in composite grafts are directly correlated to clinically successful bone regeneration.
The impact of response distortion on preemployment personality testing and hiring decisions.

Response distortion (RD), or faking, among job applicants completing personality inventories has been a concern for selection specialists. In a field study using the NEO Personality Inventory, Revised, the authors show that RD is significantly greater among job applicants than among job incumbents, that there are significant individual differences in RD, and that RD among job applicants can have a significant effect on who is hired. These results are discussed in the context of recent studies suggesting that RD has little effect on the predictive validity of personality inventories. The authors conclude that future research, rather than focusing on predictive validity, should focus instead on the effect of RD on construct validity and hiring decisions. Personality assessment as a preemployment screening procedure is receiving renewed interest from researchers and practitioners. A number of quantitative reviews have demonstrated that personality inventories can be useful predictors of job performance, particularly if specific, job-relevant personality constructs are used to predict specific criteria (Barrick & Mount, 1991; Hough, Eaton, Dunnette, Kamp, & McCloy, 1990; Ones, Viswesvaran, & Schmidt, 1993; Tett, Jackson, & Rothstein, 1991). These findings have led to a resurgence of interest in personality testing as an employee-selection tool. Yet this trend is not without controversy. One major debate concerns the effect of response distortion on personality inventory scores. What is clear from the existing research is that people completing personality inventories
The emergence of untrained mands and tacts in children with autism.

Despite Skinner's (1957) assertion that verbal operants are initially functionally independent, recent studies have suggested that in some cases the acquisition of one verbal operant (e.g., mand) gives rise to the other (e.g., tact) without explicit training. The present study aimed to evaluate the functional independence of mands and tacts during instruction with children with autism. Four boys with autism (3 to 6 years old) were taught to construct two 4-piece structures. Two participants were taught directly to mand, whereas the other 2 were taught to tact the names of the pieces. The effects of training were evaluated in a multiple probe design across verbal operants and tasks. Three of the 4 participants demonstrated an immediate transfer of control from 1 verbal operant to the other. These results were consistent with previous research with typically developing young children.
The Caspase-Related Protease Separase (EXTRA SPINDLE POLES) Regulates Cell Polarity and Cytokinesis in Arabidopsis[C][W]

Separase is responsible for segregation of daughter chromatids during cell division in all eukaryotes. Here it is reported that in addition to regulating chromatid segregation, the plant homolog of separase regulates vesicle trafficking essential for the cytokinesis and establishment of cell polarity during tissue and organ patterning. Vesicle trafficking plays an important role in cell division, establishment of cell polarity, and translation of environmental cues to developmental responses. However, the molecular mechanisms regulating vesicle trafficking remain poorly understood. Here, we report that the evolutionarily conserved caspase-related protease separase (EXTRA SPINDLE POLES [ESP]) is required for the establishment of cell polarity and cytokinesis in Arabidopsis thaliana. At the cellular level, separase colocalizes with microtubules and RabA2a (for RAS GENES FROM RAT BRAINA2a) GTPase-positive structures. Separase facilitates polar targeting of the auxin efflux carrier PIN-FORMED2 (PIN2) to the rootward side of the root cortex cells. Plants with the radially swollen4 (rsw4) allele with compromised separase activity, in addition to mitotic failure, display isotropic cell growth, perturbation of auxin gradient formation, slower gravitropic response in roots, and cytokinetic failure. Measurements of the dynamics of vesicle markers on the cell plate revealed an overall reduction of the delivery rates of KNOLLE and RabA2a GTPase in separase-deficient roots. Furthermore, dissociation of the clathrin light chain, a protein that plays major role in the formation of coated vesicles, was slower in rsw4 than in the control. Our results demonstrate that separase is a key regulator of vesicle trafficking, which is indispensable for cytokinesis and the establishment of cell polarity.
Absorption and intensity-dependent photoluminescence measurements on CdSe quantum dots: assignment of the first electronic transitions

CdSe is used as a prototype to show the implications of valence-band degeneracy for the optical properties of strongly quantum-confined nanocrystals. Absorption spectra and photoluminescence spectra obtained under intermediate and strong pulsed excitation show the presence of new structures. The energy levels for the electron and the hole are calculated with the spherical confinement, the nonparabolicity of the conduction band, and the valence band degeneracy taken into account. The oscillator strengths of the dipole-allowed transitions are also calculated. This model is found to be in good agreement with the experimental observations, which originate mainly from the quantization of the energy spectrum of holes with due account given to valence-band degeneracy.
Negative feedback and adaptive resistance to the targeted therapy of cancer.

UNLABELLED Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling. SIGNIFICANCE Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance.
Towards a sustainable use of water at home: understanding how much, where and why?

This paper presents the findings which have arisen from a literature review carried out at the beginning of a three year CONACYT sponsored PhD project, investigating water-related activities in the home and the growing need to understand user behaviour when consuming water. It illustrates how habits and routines emerge and develop. It then considers how perceptions of consumption and hygiene influence domestic water use, reflecting on how social, psychological and technological aspects influence domestic water use. The paper concludes by identifying a number of research questions which will be investigated through the remainder of the project.
Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases.

BACKGROUND Chronic kidney disease (CKD) caused by idiopathic glomerular diseases usually is progressive. Inhibition of the renin-angiotensin system (RAS) retards, but does not abrogate, CKD progression. Statins and spironolactone may decrease the rate of CKD progression independently or in addition to RAS inhibition. STUDY DESIGN Randomized open-label study. SETTING & PARTICIPANTS We recruited 128 patients (82 men and 46 women) with a clinical diagnosis of idiopathic chronic glomerulonephritis and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) (range, 36-102 mL/min/1.73 m(2)), and urine protein-creatinine ratio ranging from 1.1-5.2 g/g. INTERVENTION Intensive therapy (a combination of RAS inhibitors [angiotensin-converting enzyme [ACE] inhibitors plus angiotensin receptor blockers [ARBs] plus a high-dose statin and spironolactone) versus conventional therapy (a regimen based on ACE inhibitors with a low-dose statin). OUTCOMES Changes in eGFR, proteinuria, and adverse events after 3 years of therapy. RESULTS With intensive therapy, urine protein-creatinine ratio decreased from 2.65 (range, 1.1-5.2) to 0.45 (0.14-1.51) g/g (P < 0.001) and eGFR did not significantly change over time (64.6 +/- 2.1 vs 62.9 +/- 2.9 mL/min/1.73 m(2)). With conventional therapy, urine protein-creatinine ratio decreased from 2.60 (range, 1.32-5.4) to 1.23 (0.36-3.42) g/g (P < 0.001) and eGFR decreased from 62.5 +/- 1.7 to 55.8 +/- 1.9 mL/min/1.73 m(2) (P < 0.001). Comparison of the decreases in proteinuria and GFR between intensive versus conventional therapy was significantly different starting in the 1st and 12th months, respectively. Systolic blood pressure was lower with intensive than conventional therapy (113.5 +/- 1.4 vs 122.7 +/- 1.2 mm Hg; P < 0.01). We found an inverse relationship between percentage of decrease in proteinuria and change in eGFR (P < 0.001). Patients on intensive therapy were more likely to develop adverse events, such as hyperkalemia (9 vs 3 patients in the conventional therapy group) and discontinue therapy (15 vs 8 patients in the conventional therapy group). LIMITATIONS Open-label design. CONCLUSIONS A more intensive therapy that includes a combination of ACE inhibitors and ARBs plus high-dose statins and spironolactone may retard CKD progression more effectively than conventional therapy based on ACE inhibitors plus low-dose statin, but may lead to more adverse effects and discontinuation of therapy.
Healthcare resource utilization of second-generation long-acting injectable antipsychotics in schizophrenia: risperidone versus paliperidone palmitate

Abstract Objective: This retrospective longitudinal cohort study aimed to compare treatment patterns, healthcare resource utilization (HRU), and costs in patients with schizophrenia treated with second-generation antipsychotic long-acting injectables (SGA-LAIs): biweekly risperidone LAI versus once-monthly paliperidone palmitate. Methods: Patients who initiated risperidone LAI or paliperidone palmitate between 1 July 2007 and 31 December 2012 (index date) were identified from the Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases. Outcomes were assessed 12 months after the index date. Propensity score matching (1:1) based on patients’ demographics and comorbidities was conducted. Outcome differences between the two cohorts were evaluated using t-tests for continuous variables, chi-square tests for categorical variables, and Wilcoxon rank-sum tests for count and cost variables. Regression models estimated the difference in medication use and adherence, likelihood of HRU, number of HRU events, and healthcare costs when comparing risperidone LAI versus paliperidone palmitate, while further adjusting for patient characteristics and pre-index HRU. Results: Patient characteristics were well balanced between the two cohorts (n = 499 each). Significantly lower discontinuation rates (36.5% vs. 53.3%; p < 0.001) and longer days of LAI coverage (233.6 vs. 131.7 days; p < 0.001) were observed in the paliperidone palmitate cohort versus the risperidone LAI cohort, respectively. Patients treated with paliperidone palmitate were 12.5 (95% confidence interval [CI]: 9.0–17.8) and 11.7 (95% CI: 8.0–17.4) times more likely to be adherent based on medication possession ratio and proportion of days covered, respectively (p < 0.001). Patients treated with paliperidone palmitate had reduced likelihood of hospitalization (adjusted odds ratio [95% CI]: 0.72 [0.55–0.95]), fewer emergency department (ED) visits (adjusted incidence rate ratio [aIRR]: 0.67 [0.61–0.73]) and reduced length of inpatient stay (aIRR: 0.86 [0.82–0.90]), which resulted in lower monthly inpatient hospitalization costs (-$77.58; p = 0.038) and ED visits (-$9.77; p = 0.021) relative to risperidone LAI. Limitations: Pharmacy costs were derived from health plan payment in the claims data and do not account for any discounts or rebates. This may have overestimated the branded drug costs in this analysis. Conclusions: These findings highlight the value of once-monthly paliperidone palmitate in the treatment of patients with schizophrenia.