Miracle-dz/UniFAR-FTUs huggingface dataset:
New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion

The kinase NUAK1, which is linked to tumor invasion, promotes cell detachment by activating cytoskeletal motor proteins. An LKB1 Pathway for Cell Adhesion The tumor suppressor LKB1 is a serine-threonine kinase that phosphorylates and activates a family of structurally related kinases, the best studied of which is AMPK (adenosine monophosphate–activated protein kinase). A role for LKB1 and AMPK in the control of metabolism has been firmly established, and several downstream targets in the LKB1-AMPK pathway have been characterized. In contrast, the functions and targets of other AMPK-related kinases are not as well defined. For example, the AMPK-related kinase NUAK1 has been linked to tumor invasion, but the underlying mechanisms are unknown. Zagórska et al. performed a proteomic screen that revealed associations between NUAK1 and protein phosphatase 1β (PP1β) and three of its regulatory subunits, including MYPT1. The PP1β-MYPT1 complex regulates the phosphorylation of various proteins involved in cytoskeletal organization, such as myosin light chain-2, a regulatory subunit of the motor protein myosin. Phosphorylation of multiple residues in MYPT1 by NUAK1 recruited 14-3-3 proteins to MYPT1, an interaction that decreased the phosphatase activity of PP1β. Cell detachment was associated with a NUAK1-mediated reduction in the activity of the PP1β-MYPT1 complex and increased phosphorylation of myosin light chain-2, and loss of NUAK1 activity blocked cell detachment. Together, these results define a new function for LKB1 in decreasing cell adhesion through inhibition of myosin phosphatase activity and indicate that NUAK1 may contribute to tumor invasion by activating cytoskeletal motor proteins and thereby promoting cell detachment. The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)–protein phosphatase-1β (PP1β) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1β. Phosphorylation of Ser445, Ser472, and Ser910 of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases but also by controlling phosphatase complexes.
Conservation and variation of nucleotide sequences within related bacterial genomes: enterobacteria

We have assessed the degree of relatedness of several portions of the Escherichia coli genome to the corresponding portions of the genomes of representative enteric bacteria, using the Southern transfer and hybridization technique (E. Southern, J. Mol. Biol. 98:503-517, 1975). The degree of relatedness varied among the regions examined. Judging both by the relative amounts of deoxyribonucleic acid in the various enteric genomes that are highly homologous and by the conservation of positions of restriction enzyme cleavage sites in these regions, the enteric genomes have diverged to greater extents in some parts of the genomes than in others. Portions of the genomes (including the tnaA and thyA genes, the trp operon, and one other unassigned segment) appear to have evolved in concert with the genome as a whole. By contrast, the lacZ gene and portions of the genome that are homologous to phage lambda vary more widely, perhaps reflecting a separate evolutionary origin for these segments of deoxyribonucleic acid.
Can potential mismeasurement of the digital economy explain the post-crisis slowdown in GDP and productivity growth?

The digital economy has created some new measurement challenges for macroeconomic statistics and may have exacerbated some older ones, raising some concerns about the scope and estimation of GDP. Against a backdrop of slowing rates of measured productivity growth, this has raised questions about the conceptual basis of GDP and output, and whether current compilation methods are adequate to capture them (known as the mismeasurement hypothesis). In response to these concerns the international statistics community has reinforced efforts to investigate these concerns, chiefly under the vehicle of OECD-IMF collaboration and a newly formed Advisory Expert Group working under the auspices of the OECD’s Committee for Statistics and Statistical Policy. This paper is intended to provide momentum to these on-going efforts and to address immediate concerns about the potential scale of GDP mismeasurement in key areas where mismeasurement is often suspected. Notwithstanding the need for further work in some areas, notably with regards to cross-border transactions as well as potential mismeasurement in other macro-economic statistics, such as the consumer prices index, this paper concludes that even if mismeasurement is occurring, its scale is not sufficient to explain the widespread slowdown in measured GDP growth or multi-factor productivity growth. Nevertheless it’s important to note that this is a backward looking exercise. Even though the distortionary impact of any potential mismeasurement is currently thought to be small the growing size of digitised transactions could point to larger impacts in the future.
Systematic Review and Meta-Analysis of the Efficacy of Sphingosine-1-Phosphate (S1P) Receptor Agonist FTY720 (Fingolimod) in Animal Models of Stroke

ABSTRACT Background and Purpose: FTY720 (fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist, which has been used in clinical trials for treating multiple sclerosis, renal transplantation, and decreasing reperfusion injury in heart, liver, and kidney. Most of these clinical trials have showed a positive effect. Especially, the trials of MS showed a reduction of relapse rate in FTY720-treated patients. Now, some animal experiments indicated that FTY720 could be a new compound available treatment for stroke patients by exerting neuroprotection via S1P1 mediated antiapoptotic mechanisms. Whether it could be effective in animals is unclear, so we conducted a systematic review to make it clear. Methods: We conducted a systematic review and meta-analysis of the efficacy of FTY720 in animal models of focal cerebral ischemia by electronic and manual searches of the literature. Data on study quality, FTY720 dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were analyzed by means of a standardized mean difference meta-analysis. Results: Of the 19 identified studies, 9 were included. Among all the included studies, 178 animals were calculated for infarct size and 194 animals were assessed of neurological deficits. The methodological quality of the studies ranged from 2 to 10 according to a published 11-item quality scale. Of the nine studies selected, only one reported a negative result of FTY720. The result indicated that FTY720 reduced the infarct volume (SMD = −1.31, 95% CI −1.99 to −0.63) and improve the functional outcome (SMD = −1.61,95% CI −2.17 to −1.05). Conclusions: The data we included supporting FTY720 was a candidate drug for stroke, but it should be considered with caution. More good quality experimental studies should be performed to evaluate the safety of FTY720 in the future. Whether FTY720 is effective in aged animals that mimicked human with comorbidities like diabetes and hypertension should also be deliberated.
Characterization of High Power Microwave Radiation by an Axially Extracted Vircator

Characterization results of high-power microwave radiation, from an axial vircator driven by pulsed electron beam accelerator AMBICA-600 are reported in this paper. We present a study on variation in pulsed microwave power output and dominant frequency by discretely varying anode-cathode (A-C) gap. While keeping the cathode diameter fixed at 40 mm, for the A-C gap distance in the range 5-9 mm, dominant frequencies have been measured to be lying in the range 4.7-9.8 GHz. The trend of a subsequent increase in the dominant frequency at lower A-C gap distances (and vice versa) revealed that center frequency is mainly governed by the longitudinal size of the potential well. The highest microwave power of ~ 14 MW for ~ 75-ns pulse duration was obtained at A-C gap of 7 mm having the dominant frequency in C-band at ~ 6.9 GHz. The beam-to-microwave power conversion efficiency of ~ 1.2% has been demonstrated in our experiments. On the basis of power distribution pattern obtained by the gas breakdown technique, the dominant mode of emission is believed to be transverse magnetic mode. Relative analysis of frequency spectrums obtained for various A-C gap distances evidenced experimental recognition of optimum A-C spacing as a generation of narrowband distinct frequency peak of large magnitude with minimal mode hopping.
Permanent His-bundle pacing maintains long-term ventricular synchrony and left ventricular performance, unlike conventional right ventricular apical pacing.

AIMS Right ventricular apical pacing (RVAP) may be deleterious, determining abnormal left ventricular (LV) electrical activation and progressive LV dysfunction. Permanent His-bundle pacing (HBP) has been proposed to prevent this detrimental effect. The aim of our study was to compare the long-term effects of HBP on LV synchrony and systolic performance with those of RVAP in the same group of patients. METHODS Our analysis included 26 patients who received both an HBP lead and an RVAP lead, as backup, in our electrophysiology laboratory between 2004 and 2007. After implantation, all devices were programmed to obtain HBP. An intra-patient comparison of the effects of HBP and RVAP on LV dyssynchrony and function was performed at the last available follow-up examination. RESULTS After a mean of 34.6 ± 11 months, the pacing modality was temporarily switched to RVAP. During RVAP, LV ejection fraction significantly decreased (50.1 ± 8.8% vs. 57.3 ± 8.5%, P < 0.001), mitral regurgitation significantly increased (22.5 ± 10.9% vs.16.3 ± 12.4%; P = 0.018), and inter-ventricular delay significantly worsened (33.4 ± 19.5 ms vs. 7.1 ± 4.7 ms, P = 0.003) in comparison with HBP. However, the myocardial performance index was not statistically different between the two pacing modalities (P = 0.779). No asynchrony was revealed by tissue Doppler imaging during HBP, while during RVAP the asynchrony index was significantly higher in both the four-chamber (125.8 ± 63.9 ms; P = 0.035 vs. HBP) and two-chamber (126 ± 86.5 ms; P = 0.037 vs. HBP) apical views. CONCLUSION His-bundle pacing has long-term positive effects on inter- and intra-ventricular synchrony and ventricular contractile performance in comparison with RVAP. It prevents asynchronous pacing-induced LV ejection fraction depression and mitral regurgitation.
The Effect of Piracy and Digital Rights Management on Vertically Related Content Industries

The purpose of this paper is to investigate how digitalization affects vertically related content industries with the threat of piracy. We construct a model of vertical relationship where an upstream [a downstream] firm is considered as a content provider [a retailer]. Three business models are proposed depending on who has the right to implement digital rights management (DRM): a vertically-integrated entity, an upstream, and a downstream. First, we analyze how different modes of control on DRM affect the optimal prices and the level of copy protection. The results are dependent upon the different control modes of DRM and the degree of opportunistic behavior responding to increasing piracy costs. Second, we analyze the effect of two types of piracy depending on distribution channels (non-digital versus digital). Strengthening intellectual property rights (IPR) protection results in a price hike for both cases, while we have opposite changes in quantities depending on the types of piracy.
Modeling the Intracellular Dynamics of Influenza Virus Replication To Understand the Control of Viral RNA Synthesis

ABSTRACT Influenza viruses transcribe and replicate their negative-sense RNA genome inside the nucleus of host cells via three viral RNA species. In the course of an infection, these RNAs show distinct dynamics, suggesting that differential regulation takes place. To investigate this regulation in a systematic way, we developed a mathematical model of influenza virus infection at the level of a single mammalian cell. It accounts for key steps of the viral life cycle, from virus entry to progeny virion release, while focusing in particular on the molecular mechanisms that control viral transcription and replication. We therefore explicitly consider the nuclear export of viral genome copies (vRNPs) and a recent hypothesis proposing that replicative intermediates (cRNA) are stabilized by the viral polymerase complex and the nucleoprotein (NP). Together, both mechanisms allow the model to capture a variety of published data sets at an unprecedented level of detail. Our findings provide theoretical support for an early regulation of replication by cRNA stabilization. However, they also suggest that the matrix protein 1 (M1) controls viral RNA levels in the late phase of infection as part of its role during the nuclear export of viral genome copies. Moreover, simulations show an accumulation of viral proteins and RNA toward the end of infection, indicating that transport processes or budding limits virion release. Thus, our mathematical model provides an ideal platform for a systematic and quantitative evaluation of influenza virus replication and its complex regulation.
Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti‐Aβ antibody into the third ventricle of TgCRND8 mice

We have previously shown that anti β‐amyloid (Aβ) antibody injected into the third ventricle of mice is distributed throughout the brain within 24 hr and is completely washed out of brain within 36 hr after injection and that, in Tg2576 animals, a single injection of antibody reduces cerebral Aβ and restores presynaptic deficits 1 month after injection without producing hemorrhage or inflammation at an early plaque stage. Here we report the effects of a single ICV injection of anti‐Aβ antibody on cerebral levels of immunoreactive Aβ and of microglial activation measured by immunoreactive interleukin‐1β (IL‐1β) at 1, 4, and 8 weeks after injections in TgCRND8 mice at two ages, 2 months (sparse plaques) and 8 months (abundant plaques). The data show that parenchymal amyloid accumulates before cerebral microvascular amyloid and that a single ICV injection reduces only parenchymal amyloid by about 70%, without affecting vascular amyloid, and reduces microglial activation by 46–60% at 1 week after injection. The reappearance of plaques after antibody injection takes 4–8 weeks, whereas plaque‐associated focal microglial activation begins increasing between 1 and 4 weeks, suggesting that accumulation of nonfibrillar oligomeric Aβ may account for the earlier onset of microglial activation. No perivascular hemorrhage or inflammation was observed. These results suggest that periodic intraventricular administration of anti‐Aβ is a potentially useful method for rapid reduction of both preexisting amyloid load and associated inflammation, providing a window of 4 weeks' duration for possible pharmacological cotreatment(s) to prevent de novo Aβ formation. This ICV method of passive immunization may be safer than active immunization, which has been known to produce encephalitis, or systemic passive immunization, which exposes amyloid‐laden cerebral microvasculature to high levels of antibody in the blood and the potential of perivascular hemorrhages. © 2004 Wiley‐Liss, Inc.
Head-Elevated Patient Positioning Decreases Complications of Emergent Tracheal Intubation in the Ward and Intensive Care Unit

BACKGROUND:Based on the data from elective surgical patients, positioning patients in a back-up head-elevated position for preoxygenation and tracheal intubation can improve patient safety. However, data specific to the emergent setting are lacking. We hypothesized that back-up head-elevated positioning would be associated with a decrease in complications related to tracheal intubation in the emergency room environment. METHODS:This retrospective study was approved by the University of Washington Human Subjects Division (Seattle, WA). Eligible patients included all adults undergoing emergent tracheal intubation outside of the operating room by the anesthesiology-based airway service at 2 university-affiliated teaching hospitals. All intubations were through direct laryngoscopy for an indication other than full cardiopulmonary arrest. Patient characteristics and details of the intubation procedure were derived from the medical record. The primary study endpoint was the occurrence of a composite of any intubation-related complication: difficult intubation, hypoxemia, esophageal intubation, or pulmonary aspiration. Multivariable logistic regression was used to estimate the odds of the primary endpoint in the supine versus back-up head-elevated positions with adjustment for a priori-defined potential confounders (body mass index and a difficult intubation prediction score [Mallampati, obstructive sleep Apnea, Cervical mobility, mouth Opening, Coma, severe Hypoxemia, and intubation by a non-Anesthesiologist score]). RESULTS:Five hundred twenty-eight patients were analyzed. Overall, at least 1 intubation-related complication occurred in 76 of 336 (22.6%) patients managed in the supine position compared with 18 of 192 (9.3%) patients managed in the back-up head-elevated position. After adjusting for body mass index and the Mallampati, obstructive sleep Apnea, Cervical mobility, mouth Opening, Coma, severe Hypoxemia, and intubation by a non-Anesthesiologist score, the odds of encountering the primary endpoint during an emergency tracheal intubation in a back-up head-elevated position was 0.47 (95% confidence interval, 0.26–0.83; P = 0.01). CONCLUSIONS:Placing patients in a back-up head-elevated position, compared with supine position, during emergency tracheal intubation was associated with a reduced odds of airway-related complications.
Outcomes following plyometric rehabilitation for the young throwing athlete: A case report

The current literature offers limited evidence supporting sport-specific plyometric rehabilitation for young throwing athletes. The purposes of this case report were to 1) describe the focused differential diagnosis of a young throwing athlete with shoulder pain and 2) use previously validated, region-specific, health-related quality of life measures to describe clinical outcomes for a rehabilitation program that included sport-specific, plyometric training. The 13-year-old male patient presented in this case report experienced a sudden onset of right shoulder pain while pitching in a baseball game. On physical examination, this patient demonstrated shoulder pain, pain with palpation of the infraspinatus and teres minor muscles, decreased strength of the infraspinatus and teres minor with resultant impaired rotator cuff performance, and signs consistent with anterior shoulder instability. Early rehabilitation consisted of modalities for pain relief and therapeutic exercises to improve strength. In the return to sport phase of rehabilitation, the patient performed sport-specific plyometric exercises that were progressed in difficulty based on the patient's report of pain and muscle soreness. Health-related quality of life was assessed by using the Shoulder Pain and Disability Index (SPADI) and the sports module of the Disability of Arm, Shoulder and Hand (DASH) questionnaires. A standard error of measurement (SEM)-based criterion was used to determine if the patient demonstrated meaningful changes in outcome measures. The patient did not demonstrate meaningful improvement in pain or general disability with the SPADI. The patient did demonstrate a meaningful improvement in sport-specific function with the DASH. It is possible that sport-specific plyometric rehabilitation may have provided additional benefit for this athlete's ability to return to sport, but definite conclusions regarding treatment effectiveness are limited by the case report design. Properly designed studies investigating the benefits of sport-specific plyometric rehabilitation are warranted before the effectiveness of these techniques can be determined.
Polarized light microscopic analyses of collagen fibers in the rat incisor periodontal ligament in relation to areas, regions, and ages

We prepared decalcified sagittal sections (20 μm thick) from the incisal, middle, and basal regions of the mandibular incisor of male Wistar rats aged 2, 6, 12, and 24 months, and examined the sections using polarized light microscopy. Most of the birefringent fibers appeared to run obliquely across the periodontal ligament. Birefringent fibers running parallel to the long axis of the incisor were also found in the intermediate area of the ligament. Similar fiber architecture was observed in all four age groups. Quantitative analysis showed that the retardation values of collagen were higher in the bone‐ and tooth‐related areas and lower in the intermediate area of the ligament. The values for the bone‐ and tooth‐related areas increased from the basal toward the incisal regions in all four age groups. Age‐related changes in the retardation values were found only in the incisal region of the incisor. In the incisal region, the values for the bone‐ and tooth‐related areas increased markedly from 2–24 months of age, whereas those for the intermediate area increased slightly but significantly with age. Our findings indicate that the degrees of molecular organization and alignment of collagen fibers in the bone‐ and tooth‐related areas of the ligament are higher than those in the intermediate area and increase near the incisal region and with age. It is also suggested that the collagen fibers in the intermediate area remain immature along the long axis of the incisor throughout the life span of the animal. Anat Rec 268:381–387, 2002. © 2002 Wiley‐Liss, Inc.
Increased peripheral blood expression of electron transport chain genes in bipolar depression.

OBJECTIVE To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD). METHODS Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences. RESULTS A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p < 0.05, covaried for age and sex). Of these, 559 genes were up-regulated in BPD subjects and 621 were down-regulated. Surprisingly, there was no difference between medicated (n = 11) and unmedicated (n = 9) subjects with BPD for any of these genes. Pathway analysis using GeneGo MetaCore software showed that the most significantly affected pathway was the mitochondrial electron transport chain (ETC). Of the 85 objects (genes or proteins) in this pathway, 22 were up-regulated and 2 down-regulated in subjects with BPD. qRT-PCR confirmed up-regulation of nuclear encoded ETC genes in complexes I, III, IV, and V and, in addition, demonstrated up-regulation of mitochondrially encoded genes in each of these complexes. CONCLUSION These results suggest that increased expression of multiple components of the mitochondrial ETC may be a primary deficit in bipolar depression, rather than an effect of medication.