Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Ability of Primary HIV-1 Nef Isolates To Downregulate HIV-1 Entry Receptors

ABSTRACT HIV-1 Nef downregulates the viral entry receptor CD4 as well as the coreceptors CCR5 and CXCR4 from the surface of HIV-infected cells, and this leads to promotion of viral replication through superinfection resistance and other mechanisms. Nef sequence motifs that modulate these functions have been identified via in vitro mutagenesis with laboratory HIV-1 strains. However, it remains unclear whether the same motifs contribute to Nef activity in patient-derived sequences and whether these motifs may differ in Nef sequences isolated at different infection stages and/or from patients with different disease phenotypes. Here, nef clones from 45 elite controllers (EC), 46 chronic progressors (CP), and 43 acute progressors (AP) were examined for their CD4, CCR5, and CXCR4 downregulation functions. Nef clones from EC exhibited statistically significantly impaired CD4 and CCR5 downregulation ability and modestly impaired CXCR4 downregulation activity compared to those from CP and AP. Nef's ability to downregulate CD4 and CCR5 correlated positively in all cohorts, suggesting that they are functionally linked in vivo. Moreover, impairments in Nef's receptor downregulation functions increased the susceptibility of Nef-expressing cells to HIV-1 infection. Mutagenesis studies on three functionally impaired EC Nef clones revealed that multiple residues, including those at novel sites, were involved in the alteration of Nef functions and steady-state protein levels. Specifically, polymorphisms at highly conserved tryptophan residues (e.g., Trp-57 and Trp-183) and immune escape-associated sites were responsible for reduced Nef functions in these clones. Our results suggest that the functional modulation of primary Nef sequences is mediated by complex polymorphism networks. IMPORTANCE HIV-1 Nef, a key factor for viral pathogenesis, downregulates functionally important molecules from the surface of infected cells, including the viral entry receptor CD4 and coreceptors CCR5 and CXCR4. This activity enhances viral replication by protecting infected cells from cytotoxicity associated with superinfection and may also serve as an immune evasion strategy. However, how these activities are maintained under selective pressure in vivo remains elusive. We addressed this question by analyzing functions of primary Nef clones isolated from patients at various infection stages and with different disease phenotypes, including elite controllers, who spontaneously control HIV-1 viremia to undetectable levels. The results indicated that downregulation of HIV-1 entry receptors, particularly CCR5, is impaired in Nef clones from elite controllers. These functional impairments were driven by rare Nef polymorphisms and adaptations associated with cellular immune responses, underscoring the complex molecular pathways responsible for maintaining and attenuating viral protein function in vivo.
Direct and Indirect Effectiveness of the 10-Valent Pneumococcal Conjugate Vaccine Against Carriage in a Cluster Randomized Trial

Finnish invasive pneumococcal disease (FinIP) vaccine trial was designed to evaluate effectiveness of 10-valent pneumococcal conjugate vaccine (PHiD-CV10; GSK; Rixensart, Belgium). We conducted 2 satellite studies to evaluate ten-valent Pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) effectiveness against pneumococcal carriage in FinIP-vaccinated children (long-term direct and indirect effectiveness combined) and in their unvaccinated siblings (indirect effectiveness within the family). FinIP was a cluster randomized trial, where >47,000 children <19 months of age were recruited in 2009–2010. Children received PHiD-CV10 in 2/3, and control vaccine in 1/3 of clusters according to age-specific infant and catch-up schedules. We obtained nasopharyngeal samples from subgroups of FinIP-vaccinated children at 3–5 years of age in 2013 and their unvaccinated older siblings in 2011 and 2013, and compared carriage in PHiD-CV10 clusters to control clusters in parallel. National Vaccination Programme with PHiD-CV10 for all 3-month-old children started in 2010 resulting in 92% vaccination coverage. To investigate indirect effects, over 2200 nasopharyngeal swabs were obtained during each round from unvaccinated older siblings. In 2011, we observed a 29% (95% confidence interval: 6–47) reduction in vaccine-type carriage in siblings of PHiD-CV10 participants vaccinated according to infant schedules. Vaccine-type carriage prevalences were low with no differences observed in 2013, 3 years after PHiD-CV10 introduction. For estimation of combined direct and indirect effectiveness, 1550 swabs from FinIP-vaccinated children were obtained in 2013. We observed a reduction of 54% (95% confidence interval: 34–68) in vaccine-type carriage in PHiD-CV10–vaccinated children. This study was the first randomized trial to show the indirect effect of extended valency pneumococcal conjugate vaccination on carriage. Also, long-term effectiveness against vaccine-type carriage was demonstrated in vaccinated children.
Murphy-Topel Adjustment of the Variance-Covariance Matrix of a Two-Step Panel Data Model: Evidence from Competition-Fragility Nexus in Banking

We develop the Murphy-Topel adjustment of the variance-covariance matrix for two-step panel data models. We apply it on the competition-fragility nexus in banking with different samples for two equations. Indeed, this issue is often observed in this field of research. A competition measure of banks is constructed for each country (first equation), whereas a risk measure is regressed on the entire sample of countries (second equation). Any statistical adjustment will only provide approximate results for the second equation, because of possible correlations between the results of both models. The Murphy-Topel method eventually seems to be more appropriate.
Evidence of subthalamic PGO-like waves during REM sleep in humans: a deep brain polysomnographic study.

STUDY OBJECTIVES The aim of this study was to examine whether the subthalamic nucleus (STN) plays a role in the transmission of PGO-like waves during REM sleep in humans. DESIGN Simultaneous recordings from deep brain electrodes to record local field potentials (LFPs), and standard polysomnography to ascertain sleep/wake states. SETTING Main Hospital, department of clinical neurophysiology sleep laboratory. PARTICIPANTS 12 individuals with Parkinson's disease, with electrodes implanted in the STN; and, as a control for localization purposes, 4 cluster headache patients with electrodes implanted in the posterior hypothalamus. INTERVENTIONS All subjects underwent functional neurosurgery for implantation of deep brain stimulation electrodes. RESULTS Sharp, polarity-reversed LFPs were recorded within the STN during REM sleep in humans. These subthalamic PGO-like waves (2-3 Hz, 80-200 pV, and 300-500 msec) appeared during REM epochs as singlets or in clusters of 3-13 waves. During the pre-REM period, subthalamic PGO-like waves were temporally related to drops in the submental electromyogram and/or onset of muscular atonia. Clusters of PGO-like waves occurred typically before and during the bursts of rapid eye movements and were associated with an enhancement in fast (15-35 Hz) subthalamic oscillatory activity. CONCLUSION Subthalamic PGO-like waves can be recorded during pre-REM and REM sleep in humans. Our data suggest that the STN may play an active role in an ascending activating network implicated in the transmission of PGO waves during REM sleep in humans.
Role of Toll-like receptor 4 on pancreatic and pulmonary injury in a mice model of acute pancreatitis associated with endotoxemia

Objective:Infection of pancreatic necrosis is a severe complication of acute pancreatitis. Because Toll-like receptor 4 (TLR4) has been identified as a receptor necessary to transduct the signal of bacteria-derived lipopolysaccharide into cells, we investigated the role of TLR4 on pancreatic and pulmonary injury in acute pancreatitis and acute pancreatitis associated with endotoxemia in wild-type and TLR4-deficient mice. Design:Laboratory investigation. Setting:University laboratory. Subjects:Heterozygous TLR4 mice. Interventions:Mice were injected intraperitoneally with a supramaximal dose of cerulein each hour for 10 hrs. To mimic infection, additional groups of mice were injected with lipopolysaccharide in the presence or absence of cerulein injections. Measurements and Main Results:The severity of acute pancreatitis was assessed by serum amylase activity, pancreatic edema, acinar cell necrosis, and pancreas myeloperoxidase activity. Lung injury was quantitated by lung microvascular permeability and lung myeloperoxidase activity. Injections of cerulein induced an edematous pancreatitis that was of similar severity in wild-type and TLR4-deficient mice. Lipopolysaccharide alone had no toxic effect on pancreas and lungs and did not worsen the pancreatic injury induced by cerulein in wild-type and TRL4-deficient mice. In contrast, lipopolysaccharide worsened pancreatitis-associated lung injury, and the deficiency in TLR4 fully prevented this aggravation. Conclusions:TLR4 may not play a role in the pancreatitis-associated lung injury but participates in the pulmonary injury mediated by endotoxemia.
Long-term self-reported exposure to occupational noise is associated with BMI-defined obesity in the US general population.

BACKGROUND Evidence is emerging about the risk of obesity associated with traffic noise. The present study aimed to explore the association between self-reported occupational noise exposure and body mass index (BMI)-defined obesity in the US general population. METHODS This study is based on the 2014 National Health Interview Survey. Information regarding self-reported occupational lifetime noise exposure was linked to self-reported BMI, adjusting for other covariates. RESULTS The multivariate models yielded OR = 1.46 (95% CI: 1.27, 1.68) for obesity, and 0.97 kg/m2 (95% CI: 0.57, 1.36) higher BMI among participants exposed to high level of noise for ≥15 years, in comparison to never exposed participants. Moderation analysis revealed that among those less than 55 years of age noise had significantly stronger adverse effect. Those without cancer and diabetes also experienced stronger adverse effect. CONCLUSIONS Self-reported exposure to occupational noise was associated with increased odds of obesity and continuously measured BMI. Am. J. Ind. Med. 59:1009-1019, 2016. © 2016 Wiley Periodicals, Inc.
Sleep Practices, Attitudes, and Beliefs in Inner City Middle School Children: A Mixed-Methods Study

The objective of this study was to utilize both semi-quantitative and qualitative data to examine the sociodemographic, social environmental, and behavioral context of sleep practices in a group of 64 middle school students enrolled in a summer camp program. Participants completed the Sleep Habits Survey; semi-structured interviews were used to collect data regarding sleep knowledge, perceived barriers to healthy sleep, consequences of inadequate sleep, sources of sleep information, and suggestions for improved sleep. Environmental and social factors figured prominently as perceived barriers to healthy sleep. Many of the respondents mentioned adult guidance regarding sleep habits as potentially helpful. Identification of predictive factors for insufficient sleep may be helpful in developing interventions to change sleep health risk behaviors in middle school populations.
Molecular and cellular basis of radiation fibrosis.

PURPOSE Recent data from the literature and the experimental work of the authors clearly indicate that TGF-beta1 is a key modulator of cellular events, for example, induction of terminal differentiation, resulting in radiation-induced fibrosis. Therefore, the present study analysed which cellular processes induced by exogenously added TGF-beta could be responsible for the induction, development and manifestation of the fibrotic phenotype in culture. MATERIALS AND METHODS Rat lung fibroblast cultures (passage 1) were used. As a function of treatment with TGF-beta and/or anti-TGF-beta-antibody, the clonogenic activity and differentiation pattern were analysed by colony-formation assays. RESULTS It could be demonstrated that treatment of rat lung progenitor fibroblasts with TGF-beta1 resulted in a pronounced shift in the differentiation pattern, i.e. induction of post-mitotic fibrocytes. This TGF-beta1-dependent terminal differentiation could be abolished by simultaneous treatment with a neutralizing antibody directed against TGF-beta1. CONCLUSIONS The data presented indicate that TGF-beta1 is one major candidate mediating the accelerated terminal differentiation of progenitor fibroblasts to post-mitotic functional fibrocytes, which results in the fibrotic phenotype of this cell system.
The role of upstream U3 sequences in the pathogenesis of simian immunodeficiency virus-induced AIDS in rhesus monkeys

The nef reading frame overlaps about 70% of the U3 region of the 3' long terminal repeat (LTR) in primate lentiviruses. We investigated the functional role of these overlapping U3 sequences by analyzing the properties of three mutant forms of the pathogenic SIVmac239 clone. In mutant UScon, 90 of 275 bp in the upstream sequences (US) of U3 were changed in a conservative fashion without changing the predicted nef coding sequence. In mutant USnon, 101 of 275 bp in this region were changed in a nonconservative fashion, again without changing the predicted nef coding sequence. In mutant delta US, 275 bp in this region were deleted. Full-size, immunoreactive nef protein was synthesized in cells infected with the UScon and USnon mutants. The USnon and delta US mutants replicated with similar kinetics and to similar extents as wild-type, parental SIVmac239 in primary rhesus monkey peripheral blood mononuclear cell (PBMC) cultures. The UScon mutant replicated with slightly delayed kinetics in rhesus monkey PBMC cultures. In the CEMx174 cell line, the delta US mutant replicated similarly to the wild type, but the UScon and USnon mutants replicated with significantly delayed kinetics. Analysis of LTR-driven chloramphenicol acetyltransferase (CAT) activity and the effects of 5-azacytidine on virus replication suggested that the growth defect of the point mutants in CEMx174 cells was due in whole or in part to the introduction of multiple CG methylation sites in proviral DNA. Rhesus monkeys were experimentally infected with the UScon and USnon mutants, and the characteristics of the infection were compared with those of the parental SIVmac239. Analysis of the levels of plasma antigenemia, virus load, and CD4+ cells in PBMC revealed no decreased virulence of the mutant viruses. Analysis of lymph node biopsies taken from animals that received mutant viruses revealed histologic changes and levels of virus expression indistinguishable from those of the wild type. Furthermore, the wild-type behavior of the mutant viruses in rhesus monkeys occurred without any specific reversional events through at least 20 weeks of infection. These results, and the recent results of Kirchhoff et al. (F. Kirchoff, H. W. Kestler III, and R. C. Desrosiers, J. Virol. 68:2031-2037, 1994), suggest that these upstream sequences in U3 are primarily or exclusively nef coding sequence.
Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7

Significance MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression. The aberrant expression of miRNAs is commonly associated with cancer. miRNAs can be packaged in exosomes/microvesicles secreted by the cells and involved in cell-to-cell signaling and communication; tumor-secreted miRNAs promote tumor spread and growth in the surrounding microenvironment. Apoptosis is reported to take place in wasting muscle in cancer cachexia, a debilitating syndrome associated with multiple types of cancer, although the mechanism remains elusive. This study shows that tumor-secreted microvesicles contain an elevated expression of miR-21 and induce myoblast apoptosis in cancer cachexia via a Toll-like receptor 7-c-Jun N-terminal kinase-dependent pathway. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression and, in cancers, are often packaged within secreted microvesicles. The cachexia syndrome is a debilitating state of cancer that predominantly results from the loss of skeletal muscle mass, which is in part associated with apoptosis. How tumors promote apoptosis in distally located skeletal muscles has not been explored. Using both tumor cell lines and patient samples, we show that tumor-derived microvesicles induce apoptosis of skeletal muscle cells. This proapoptotic activity is mediated by a microRNA cargo, miR-21, which signals through the Toll-like 7 receptor (TLR7) on murine myoblasts to promote cell death. Furthermore, tumor microvesicles and miR-21 require c-Jun N-terminal kinase activity to regulate this apoptotic response. Together, these results describe a unique pathway by which tumor cells promote muscle loss, which might provide a great insight into elucidating the causes and treatment options of cancer cachexia.
Childhood psychiatric disorders and young adult crime: a prospective, population-based study.

OBJECTIVE While psychopathology is common in criminal populations, knowing more about what kinds of psychiatric disorders precede criminal behavior could be helpful in delineating at-risk children. The authors determined rates of juvenile psychiatric disorders in a sample of young adult offenders and then tested which childhood disorders best predicted young adult criminal status. METHOD A representative sample of 1,420 children ages 9, 11, and 13 at intake were followed annually through age 16 for psychiatric disorders. Criminal offense status in young adulthood (ages 16 to 21) was ascertained through court records. RESULTS Thirty-one percent of the sample had one or more adult criminal charges. Overall, 51.4% of male young adult offenders and 43.6% of female offenders had a child psychiatric history. The population-attributable risk of criminality from childhood disorders was 20.6% for young adult female participants and 15.3% for male participants. Childhood psychiatric profiles predicted all levels of criminality. Severe/violent offenses were predicted by comorbid diagnostic groups that included both emotional and behavioral disorders. CONCLUSIONS The authors found that children with specific patterns of psychopathology with and without conduct disorder were at risk of later criminality. Effective identification and treatment of children with such patterns may reduce later crime.
Two-Year and Four-Year Tertiary Education: Measuring Human Capital Effects on Economic Growth in Developing and Developed Countries with the Uzawa-Lucas Model

Two-Year and Four-Year Tertiary Education: Measuring Human Capital Effect on Economic Growth in Developed and Developing Countries with the Uzawa-Lucas Model Darryl M. Tyndorf Jr. Old Dominion University, 2015 Director: Dr. Christopher Glass Tertiary education is believed to be a driver of economic development through the relationship between human capital development and economic output. Global massification efforts of tertiary education have led to increased global demand. Countries with limited tertiary education systems, like developing countries, have employed policies to increase domestic tertiary education opportunities instead of sending students abroad. Many tertiary education policies have focused on importing tertiary education from countries with established tertiary education systems. Import efforts first emphasized university models, but limited success prompted the import of more flexible short-cycle education modeled after the United States’ community college system. Limited empirical research has studied the relationship between tertiary education and economic growth. Currently, there has been no research on the effect of importing U.S. four-year and two-year tertiary education models in other countries and the effect on economic growth. The purpose of this study was to examine differences between twoand four-year U.S. university models implemented in developing countries by examining changes in economic growth. Utilizing country level economic and tertiary education data spanning 1970 to 2013 from The World Bank and the United National Education, Scientific, and Cultural Organization Institute for Statistics in the Uzawa-Lucas model with a General Method of Moments (GMM) estimation of an autoregressive distribution lag model to take into account the lagged effect of tertiary education on economic indicators.
Construction and characterization of ack knock‐out mutants of Propionibacterium acidipropionici for enhanced propionic acid fermentation

Propionibacterium acidipropionici produces propionic acid from glucose with acetic acid, succinic acid, and CO2 as byproducts. In this work, inactivation of ack gene, encoding acetate kinase (AK), by gene disruption and integrational mutagenesis was studied as a method to reduce acetate formation in propionic acid fermentation. The partial ack gene of ∼750 bp in P. acidipropionici was cloned using a PCR‐based method with degenerate primers and sequenced. The deduced amino acid sequence had 88% similarity and 76% identity with the amino acid sequence of AK from Bacillus subtilis. The partial ack gene was used to construct a linear DNA fragment with an inserted tetracycline resistance cassette and a nonreplicative integrational plasmid containing a tetracycline resistance gene cassette. These DNA constructs were then introduced into P. acidipropionici by electroporation, resulting in two mutants, ACK‐Tet and TAT‐ACK‐Tet, respectively. Southern hybridization confirmed that the ack gene in the mutant ACK‐Tet was disrupted by the inserted tetracycline resistance gene. As compared to the wild‐type, the activities of AK were reduced by 26% and 43% in ACK‐Tet and TAT‐ACK‐Tet mutants, respectively. The specific growth rate of these mutants was reduced by ∼25% to 0.10/h (0.13/h for the wild‐type), probably because of reduced acetate and ATP production. Both mutants produced ∼14% less acetate from glucose. Although ack disruption alone did not completely eliminate acetate production, the propionate yield was increased by ∼13%. © 2006 Wiley Periodicals, Inc.
In vivo activation of N‐methyl‐d‐aspartate receptors in the rat hippocampus increases prostaglandin E2 extracellular levels and triggers lipid peroxidation through cyclooxygenase‐mediated mechanisms

Cyclooxygenases (COX) are a family of enzymes involved in the biosynthesis of prostaglandin (PG) and thromboxanes. The inducible enzyme cyclooxygenase‐2 (COX‐2) is the major isoform found in normal brain, where it is constitutively expressed in neurons and is further up‐regulated during several pathological events, including seizures and ischaemia. Emerging evidence suggests that COX‐2 is implicated in excitotoxic neurodegenerative phenomena. It remains unclear whether PGs or other products associated to COX activity take part in these processes. Indeed, it has been suggested that reactive oxygen species, produced by COX, could mediate neuronal damage. In order to obtain direct evidence of free radical production during COX activity, we undertook an in vivo microdialysis study to monitor the levels of PGE2 and 8‐epi‐PGF2α following infusion of N‐methyl‐d‐aspartate (NMDA). A 20‐min application of 1 mm NMDA caused an immediate, MK‐801‐sensitive increase of both PGE2 and 8‐epi‐PGF2α basal levels. These effects were largely prevented by the specific cytosolic phospholipase A2 (cPLA2) inhibitor arachidonyl trifluoromethyl ketone (ATK), by non‐ selective COX inhibitors indomethacin and flurbiprofen or by the COX‐2 selective inhibitor NS‐398, suggesting that the NMDA‐evoked prostaglandin synthesis and free radical‐mediated lipid peroxidation are largely dependent on COX‐2 activity. As several lines of evidence suggest that prostaglandins may be potentially neuroprotective, our findings support the hypothesis that free radicals, rather than prostaglandins, mediate the toxicity associated to COX‐2 activity.