Miracle-dz/UniFAR-FTUs huggingface dataset:
Experimental Preemptive Immunotherapy of Murine Cytomegalovirus Disease with CD8 T-Cell Lines Specific for ppM83 and pM84, the Two Homologs of Human Cytomegalovirus Tegument Protein ppUL83 (pp65)

ABSTRACT CD8 T cells are the principal antiviral effectors controlling cytomegalovirus (CMV) infection. For human CMV, the virion tegument protein ppUL83 (pp65) has been identified as a source of immunodominant peptides and is regarded as a candidate for cytoimmunotherapy and vaccination. Two sequence homologs of ppUL83 are known for murine CMV, namely the virion protein ppM83 (pp105) expressed late in the viral replication cycle and the nonstructural protein pM84 (p65) expressed in the early phase. Here we show that ppM83, unlike ppUL83, is not delivered into the antigen presentation pathway after virus penetration before or in absence of viral gene expression, while other virion proteins of murine CMV are processed along this route. In cytokine secretion-based assays, ppM83 and pM84 appeared to barely contribute to the acute immune response and to immunological memory. Specifically, the frequencies of M83 and M84 peptide-specific CD8 T cells were low and undetectable, respectively. Nonetheless, in a murine model of cytoimmunotherapy of lethal CMV disease, M83 and M84 peptide-specific cytolytic T-cell lines proved to be highly efficient in resolving productive infection in multiple organs of cell transfer recipients. These findings demonstrate that proteins which fail to prime a quantitatively dominant immune response can nevertheless represent relevant antigens in the effector phase. We conclude that quantitative and qualitative immunodominance are not necessarily correlated. As a consequence of these findings, there is no longer a rationale for considering T-cell abundance as the key criterion for choosing specificities to be included in immunotherapy and immunoprophylaxis of CMV disease and of viral infections in general.
Mechanosensitive ion channels in skeletal muscle from normal and dystrophic mice.

1. We examined the activity of single mechanosensitive ion channels in recordings from cell‐attached patches on myoblasts, differentiated myotubes and acutely isolated skeletal muscle fibres from wild‐type and mdx and dy mutant mice. The experiments were concerned with the role of these channels in the pathophysiology of muscular dystrophy. 2. The predominant form of channel activity recorded with physiological saline in the patch electrode arose from an approximately 25 pS mechanosensitive ion channel. Channel activity was similar in undifferentiated myoblasts isolated from all three strains of mice. By contrast, channel activity in mdx myotubes was approximately 3‐4 times greater than in either wild‐type or dy myotubes and arose from a novel mode of mechanosensitive gating. 3. Single mechanosensitive channels in acutely isolated flexor digitorum brevis fibres had properties indistinguishable from those of muscle cells grown in tissue culture. The channel open probability in mdx fibres was approximately 2 times greater than the activity recorded from wild‐type fibres. The overall level of activity in fibres, however, was roughly an order of magnitude smaller than in myoblasts or myotubes. 4. Histological examination of the flexor digitorum brevis fibres from mdx mice showed no evidence of myonecrosis or regenerating fibres, suggesting that the elevated channel activity in dystrophin‐deficient muscle precedes the onset of fibre degeneration. 5. An early step in the dystrophic process of the mdx mouse, which leads to pathophysiological Ca2+ entry, may be an alteration in the mechanisms that regulate mechanosensitive ion channel activity.
Trends in the access to and the use of antipsychotic medications and psychotropic co-treatments in Asian patients with schizophrenia

To date, antipsychotics remain the mainstay of treatment for schizophrenia and related disorders although other psychotropic medications and non-pharmaceutical interventions have been used adjunctively in some patients and settings. Regular surveys on access to and prescription patterns of psychotropic medications in clinical practice are an important and efficient way of examining the use and time trends of treatments in a given population and region. Unlike developed Western countries, Asian countries have not fully undergone deinstitutionalisation of the severely and chronically mentally ill, and community-based mental health services are still under-developed. As a result, a large number of psychiatric patients still receive treatments in psychiatric hospitals. Moreover, there have been very limited studies examining access to and prescription patterns of psychotropic medications for schizophrenia patients in Asian countries. In this paper, we focus on the only international project on the use of psychotropic medications in schizophrenia patients in selected East and Southeast Asian countries/territories summarising its major findings. Most of the first- and second-generation antipsychotics (FGAs and SGAs) are available in Asian countries, but the access to psychotropic medications is largely affected by socio-cultural and historical contexts, health insurance schemes, health care policy, medication cost and consumers’ preference across different countries/territories. Overall, the proportional use of FGAs, high dose antipsychotic treatment and antipsychotic polypharmacy have decreased, while the use of SGAs and antidepressants have increased and the utilisation of benzodiazepines and mood stabilisers has remained relatively stable over time. However, within these general trends, there is great inter-country variation regarding the psychotropic prescribing patterns and trends in Asian schizophrenia patients that also seems to differ from data in many Western countries.
A Systematic Review of Brachial Plexus Surgery for Birth-Related Brachial Plexus Injury

Objective: Brachial plexus injury complicates 0.6–2.6 per 1,000 live births. Surgery is sometimes advocated for patients who fail to improve with conservative management. We reviewed the available literature on birth-related brachial plexus palsy in order to provide recommendations for surgical management, using evidence-based criteria. Methods: Studies were identified by searc hing Medline (1966–2002) and the Cochrane Library using the terms brachial plexus, neonate or infant, surgery and natural history. The reference lists of relevant articles were also reviewed. The search was restricted to articles published in English. Each article was classified according to its methodology. Management recommendations were suggested based on the results of the studies identified and the degree of certainty of the available literature. Results: Twenty-three papers were selected for detailed analysis. There are no randomized controlled trials that have investigated the role of brachial plexus surgery in the management of birth-related brachial plexus palsy. Two prospective studies of relevance were found, one describing the natural history of birth-related brachial plexus injury and one evaluating surgery for these patients. The remainder consisted of retrospective case series. Outcomes from surgical series are generally favorable (level III and V evidence). Direct comparison with the natural history could not be inferred from the series reviewed given the lack of controls. Conclusion: There is no conclusive evidence showing a benefit of surgery over conservative management approaches in the treatment of patients with birth-related brachial plexus injuries. Surgery remains a valid practice option given the level III and V evidence suggesting a possible benefit of surgery.
Colorectal Cancer Mortality in Shiraz, Iran.

BACKGROUND Mortality among Iranian patients with colorectal cancer has not been fully examined and the factors associated with their survival are still controversial. This study aimed to determine the mortality rate and its related factors among the patients with colorectal cancer in southwestern regions in Iran. MATERIALS AND METHODS This prospective cohort study was conducted on 220 patients with colorectal cancer referred to Fahighi Hospital, Shiraz, Iran from 2009 to 2014. Data were collected from the patients' medical records and were analyzed using Cox regression analysis. RESULTS Over a median follow-up of 29.3 months, 56 out of the 220 patients (25.5%) died, 32 (14.5%) aged below 40 years, and 45.5% were female. Based on the results of multiple Cox regression analysis, family history of gastrointestinal cancer, stage III, former smoking, type of lesion (fungative and polypoid), and opium use were associated with a greater risk of colorectal cancer mortality (all <0.05). CONCLUSIONS This cohort study found that the mortality rate of colorectal cancer in Iran is lower than that in European countries. In addition, behavioral and clinical factors were significantly associated with the survival rate. Addressing the related factors would help healthcare providers and physicians provide the best care and improve the survival rate.
Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway*

β-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free β-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3β (GSK3β) or p53-inducible Siah-1. Dysregulation of β-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of β-catenin. In this proteasomal pathway, RXR agonists induce degradation of β-catenin and RXRα and repress β-catenin-mediated transcription. In vivo, β-catenin interacts with RXRα in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3β inhibitors or deletion of the GSK3β-targeted sequence from β-catenin. In APC- and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous β-catenin via RXRα. Interestingly, deletion of the RXRα A/B region abolished ligand-induced β-catenin degradation but not RXRα-mediated transactivation. RXRα-mediated inactivation of oncogenic β-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of β-catenin turnover and related biological events.
BE, DO, and modal auxiliaries of 3-year-old African American English speakers.

PURPOSE This study examined African American English-speaking children's use of BE, DO, and modal auxiliaries. METHOD The data were based on language samples obtained from 48 three-year-olds. Analyses examined rates of marking by auxiliary type, auxiliary surface form, succeeding element, and syntactic construction and by a number of child variables. RESULTS The children produced 3 different types of marking (mainstream overt, nonmainstream overt, zero) for auxiliaries, and the distribution of these markings varied by auxiliary type. The children's nonmainstream dialect densities were related to their marking of BE and DO but not modals. Marking of BE was influenced by its surface form and the succeeding verbal element, and marking of BE and DO was influenced by syntactic construction. CONCLUSIONS Results extend previous studies by showing dialect-specific effects for children's use of auxiliaries and by showing these effects to vary by auxiliary type and children's nonmainstream dialect densities. Some aspects of the children's auxiliary systems (i.e., pattern of marking across auxiliaries and effects of syntactic construction) were also consistent with what has been documented for children who speak other dialects of English. These findings show dialect-specific and dialect-universal aspects of African American English to be present early in children's acquisition of auxiliaries.
Residual and Dynamic Range of Retinal Nerve Fiber Layer Thickness in Glaucoma: Comparison of Three OCT Platforms.

PURPOSE To estimate visual field (VF) sensitivity at which retinal nerve fiber layer (RNFL) thinning reaches the measurement floor and at which RNFL stops thinning (change points), the dynamic range of RNFL thickness, and the number of steps from normal to RNFL floor among three optical coherence tomography (OCT) devices. METHODS Glaucomatous patients (n = 58) and healthy subjects (n = 55-60) prospectively underwent VF testing and RNFL thickness measurement with Cirrus, Spectralis, and RTVue. Change points and corresponding RNFL thicknesses were estimated with simple linear regression (SLR) and Bayesian change point (BCP) analyses. The dynamic range and number of steps to RNFL floor were determined. RESULTS The average VF change points and corresponding residual thickness at the time RNFL stopped thinning were -22.2 dB and 57.0 μm (Cirrus), -25.3 dB and 49.2 μm (Spectralis), and -24.6 dB and 64.7 μm (RTVue). The RNFL dynamic ranges derived from SLR values were wider on Spectralis (52.6 μm) than on Cirrus (35.4 μm) and RTVue (35.5 μm); the corresponding number of steps to reach the RNFL floor were 9.0 on Cirrus, 10.6 on Spectralis, and 8.3 on RTVue. CONCLUSIONS The relative VF sensitivity at which average RNFL thickness reaches the measurement floor, the residual layer thickness, and RNFL dynamic measurement range differ among the three devices. However, the number of steps from normal to the RNFL thickness floor is comparable.
Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study.

OBJECTIVE To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to > or = 1 disease-modifying antirheumatic drug. METHODS This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (i.v.) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. RESULTS AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. CONCLUSION Our findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.
Visual Priming and Visual Hallucinations in Parkinson’s Disease. Evidence for Normal Top-Down Processes

Background: Visual hallucinations (VH) are common in Parkinson’s disease (PD) and are associated with increased morbidity and mortality. Current explanations for VH in PD suggest combined impairments in top-down attentional and bottom-up perceptual processes, which allow the passive “release” of stored images. Alternative models in other disorders have suggested that top-down factors may actively encourage hallucinations. In order to explore the interaction between top-down and bottom-up visual processing in PDVH, we developed novel experimental priming tasks in which top-down verbal cues were used to prime the bottom-up recognition of partial or ambiguous pictures. Method: Two groups of PD participants with (PD + VH, n = 16), and without VH (PD - VH, n = 20) were compared to a group of healthy older adults (NC, n = 20) on 3 novel measures of visual priming. Results: All tasks showed significant priming effects. The PD + VH group was more impaired at accurately identifying silhouette and fragmented images compared to the PD - VH group. There were no differences in priming between the 2 PD groups. Conclusions: The study showed that VH in PD are not associated with relatively greater top-down activation, and that the interaction between top-down and bottom-up processes is intact.
Impact of Training Modality on Strength and Physical Function in Older Adults

Background: The importance of maintaining strength in older adults is well documented and various training modalities have been recommended; however, the effectiveness of various interventions with high translation to public health practice has not been completely characterized. Additionally, the interrelations among mode, strength, and lower extremity physical function (LEPF) changes in older adults warrant further investigation. Purpose: The primary aims were to examine the effectiveness of cardiovascular endurance training (CVE) compared with balance and flexibility training (FLEX) and to explore the relationship of muscle strength to LEPF. Methods: Fifty-five adults (69.1 ± 5.6 years, 35 female) were randomly assigned to 10 months of CVE or FLEX. Knee extension and flexion at 60 and 120°·s–1 were measured using an isokinetic dynamometer. LEPF was measured using a battery of tasks. The CVE group exercised using treadmills, cycles, and elliptical trainers. The FLEX group participated in a group exercise class that incorporated flexibility and balance activities. Results: The CVE training group significantly improved peak oxygen consumption by 6% (p = 0.03), while the FLEX training group showed no change (p = 0.47). Participants significantly improved peak torque at both speeds and muscle actions by 21–65% (p ≤ 0.05), with no group effect (p > 0.05). Both groups also significantly improved performance on all LEPF tasks included in this study (4–7%, p ≤ 0.05). Significant correlations (all p = 0.00) were found between improvements in strength and improvements in LEPF including timed walk and peak torque extension and flexion at 60°·s–1 (r = 0.40 and 0.27, respectively), obstacle walk and peak torque extension and flexion at 60 and 120°·s–1 (r range 0.27–0.40), and stair ascent and peak torque extension at 120°·s–1 (r = 0.37). Conclusions: Sedentary older adults achieve similar improvements in strength and LEPF with either CVE or FLEX training with the latter being related to improvements in leg strength.
The public–private sector wage gap in Latvia

ABSTRACT This study investigates the public–private sector wage gap in Latvia using microdata from the labour force survey. The severity of public sector wage cuts employed as a response to the economic crisis and subsequent recovery provides a test bed to analyse whether and how the public–private sector wage gap has adjusted after consolidation-driven wage cuts. Findings reveal that the observed wage gap is slightly in favour of the public sector; however, once differences in individual characteristics and selection effects are considered, results point to a private sector wage premium. Findings also suggest that the private sector wage premium has increased since the pre-crisis period. A significant private sector wage premium raises doubts on whether a system that is reliant on discretionary fiscal measures is efficient enough in eliminating unwarranted differences in wage. In particular, whether a re-adjustment process of public sector wages works after consolidation-driven wage cuts.
Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site.

OBJECTIVE Reactive oxygen species have been implicated as signaling molecules modulating the activity of redox-sensitive transcription factors such as nuclear factor kappa B (NF-kappaB). Recently, the transcription factor hypoxia-inducible factor-1 (HIF-1), known to mediate gene expression by hypoxia, has been found to be also activated by nonhypoxic factors in a redox-sensitive manner. We therefore aimed to elucidate the link between these 2 important redox-sensitive transcription factors. METHODS AND RESULTS In pulmonary artery smooth muscle cells, reactive oxygen species generated either by exogenous H2O2 or by a NOX4-containing NADPH oxidase stimulated by thrombin activated or induced NF-kappaB and HIF-1alpha. The reactive oxygen species-mediated HIF-1alpha induction occurred on the transcriptional level and was dependent on NF-kappaB. Transfection experiments with wild-type or mutant HIF-1alpha promoter constructs revealed the presence of a yet unidentified NF-kappaB binding element. Gel shift analyses and chromatin immunoprecipitation verified binding of NF-kappaB to this site. Furthermore, reactive oxygen species enhanced expression of plasminogen activator inhibitor-1, which was prevented by dominant-negative IkappaB or mutation of the HIF-1 binding site within the plasminogen activator inhibitor-1 promoter. CONCLUSION These findings show for the first time to our knowledge that reactive oxygen species directly link HIF-1alpha and NF-kappaB, implicating an important pathophysiological role of this novel pathway in disorders associated with elevated levels of reactive oxygen species.
Irrational Exuberance Ed. 2

In this timely and prescient update of his celebrated 2000 bestseller Irrational Exuberance, Robert J. Shiller returns to the topic that gained him international fame: market volatility. Shiller breaks new ground in this second edition by laying out in even clearer and starker terms the market excesses that continue to destabilize the economy and disrupt our lives. Having predicted the stock market collapse that began just one month after the first edition was published, he now expands the book to cover other markets that have become volatile, particularly the recently red-hot housing market. He includes a full chapter on domestic and international housing prices in historical perspective. Shiller amasses impressive evidence to support his argument that the recent housing market boom bears many similarities to the stock market bubble of the late 1990s, and may eventually be followed by declining home prices for years to come. After stocks plummeted when the bubble burst in 2000, investors moved their money into housing. This precipitated the inflated real estate prices not only in America, but around the world, Shiller maintains. Hence, irrational exuberance did not disappear-it merely reappeared in other settings. Building on the original edition, Shiller draws out the psychological origins of volatility in financial markets, this time folding real estate into his analysis. He broadens the evidence that investing in capital markets of all kinds in the modern free-market economy is inherently unstable-subject to the profoundly human influences captured in Alan Greenspan's now-famous phrase, "irrational exuberance. " The ultimate solution to this troubling condition, he maintains, would involve better-designed public institutions such as a revamped social security system, new forms of insurance to protect people's incomes and homes, and a broader array of investment options. As was true of its predecessor, the second edition of Irrational Exuberance is destined to be widely read, discussed, and debated.