Miracle-dz/UniFAR-FTUs huggingface dataset:
Protein Kinase A Phosphorylation of the Proteasome: A Contribution to the α‐Secretase Pathway in Human Cells

Abstract: The β‐amyloid precursor protein undergoes a physiological cleavage by α‐secretase that leads to the release of a secreted C‐terminally truncated fragment called APPα and likely concomitantly reduces the formation of the amyloidogenic Aβ peptide. Here we demonstrate that APPα secretion is increased by the protein kinase A (PKA) effectors 8‐bromo cyclic AMP and forskolin in human embryonic kidney cells (HK293), and that this can be prevented by a proteasome inhibitor. Furthermore, we establish that PKA effectors but not protein kinase C agonists increase the chymotrypsin‐like activity and phosphorylation state of the proteasome in vitro and in vivo in HK293 cells. Altogether, this report demonstrates that the α‐secretase pathway is under the control of PKA in human cells and that the proteasome likely contributes, either directly or through yet unknown intermediates, to the PKA‐stimulated APPα secretion in human cells.
Photobody Localization of Phytochrome B Is Tightly Correlated with Prolonged and Light-Dependent Inhibition of Hypocotyl Elongation in the Dark1[W][OPEN]

Photobody localization of Arabidopsis phytochrome B is tightly correlated with the degradation of a phytochrome-interacting factor and the inhibition of hypocotyl growth in the dark. Photobody localization of Arabidopsis (Arabidopsis thaliana) phytochrome B (phyB) fused to green fluorescent protein (PBG) correlates closely with the photoinhibition of hypocotyl elongation. However, the amino-terminal half of phyB fused to green fluorescent protein (NGB) is hypersensitive to light despite its inability to localize to photobodies. Therefore, the significance of photobodies in regulating hypocotyl growth remains debatable. Accumulating evidence indicates that under diurnal conditions, photoactivated phyB persists into darkness to inhibit hypocotyl elongation. Here, we examine whether photobodies are involved in inhibiting hypocotyl growth in darkness by comparing the PBG and NGB lines after the red light-to-dark transition. Surprisingly, after the transition from 10 μmol m−2 s−1 red light to darkness, PBG inhibits hypocotyl elongation three times longer than NGB. The disassembly of photobodies in PBG hypocotyl nuclei correlates tightly with the accumulation of the growth-promoting transcription factor PHYTOCHROME-INTERACTING FACTOR3 (PIF3). Destabilizing photobodies by either decreasing the light intensity or adding monochromatic far-red light treatment before the light-to-dark transition leads to faster PIF3 accumulation and a dramatic reduction in the capacity for hypocotyl growth inhibition in PBG. In contrast, NGB is defective in PIF3 degradation, and its hypocotyl growth in the dark is nearly unresponsive to changes in light conditions. Together, our results support the model that photobodies are required for the prolonged, light-dependent inhibition of hypocotyl elongation in the dark by repressing PIF3 accumulation and by stabilizing the far-red light-absorbing form of phyB. Our study suggests that photobody localization patterns of phyB could serve as instructive cues that control light-dependent photomorphogenetic responses in the dark.
Standard and quasi-standard stochastic power control algorithms

In an energy-efficient wireless communication system, transmit powers are minimized subject to predetermined signal-to-interference ratio (SIR) requirements. In this paper, a general framework for distributed stochastic power control (PC) algorithms is proposed, where the transmit powers are updated based on stochastic approximations. The proposed algorithms are distributed in the sense that no global information is needed in the power updates. Interference to each user is estimated locally via noisy observations. Two types of stochastic PC algorithms are studied: standard stochastic PC algorithms where the interference estimator is unbiased, and quasi-standard stochastic PC algorithms where the interference estimator is biased. The conditions under which the stochastic PC algorithms converge to the unique optimal solution are identified. Corresponding to two classes of iteration step-size sequences, two types of convergence, the probability one convergence and convergence in probability, are shown for both algorithms based on recent results in the stochastic approximation literature. Based on the theoretical results, some well-known stochastic PC algorithms, such as stochastic PC with matched filter receivers, and joint stochastic PC with blind minimum mean-squared error (MMSE) interference suppression, are revisited; several new stochastic PC algorithms, such as stochastic PC with minimum-power base-station assignment, and stochastic PC with limited diversity, are proposed. It is shown that these algorithms fall into either the standard or the quasi-standard stochastic PC framework. Simulation results are given to illustrate the performance of the proposed algorithms in practical systems.
Melatonin Promotes Osteoblast Differentiation and Bone Formation*

Prior studies have demonstrated that the pineal hormone, melatonin, can stimulate chloramphenicol acetyltransferase activity in Drosophila SL-3 cells transfected with a chloramphenicol acetyltransferase reporter construct containing the response element of rat bone sialoprotein (BSP). Based on these findings, studies were performed to determine whether melatonin could similarly modulate the expression of BSP in two cell lines, the MC3T3-E1(MC3T3) pre-osteoblast and rat osteoblast-like osteosarcoma 17/2.8 cell. Initial studies demonstrated that MC3T3 cells grown in the presence of 50 nm melatonin underwent cell differentiation and mineralization by day 12 instead of the 21-day period normally required for cells grown in untreated media. Melatonin increased gene expression of BSP and the other bone marker proteins, including alkaline phosphatase (ALP); osteopontin; secreted protein, acidic and rich in cysteine; and osteocalcin in MC3T3 cells in a concentration-dependent manner. Levels of melatonin as low as 10 nm were capable of stimulating transcription of these genes when cells were grown in the presence of β-glycerophosphate and ascorbic acid. Under these conditions, melatonin induced gene expression of the bone marker proteins; however, this does not occur until the 5th day after seeding the culture dishes. Thereafter, MC3T3 cells responded to melatonin within 2 h of treatment. The fully differentiated rat osteoblast-like osteosarcoma 17/2.8 cells responded rapidly to melatonin and displayed an increase in the expression of BSP, ALP, and osteocalcin genes within 1 h of exposure to the hormone. To determine whether melatonin-induced osteoblast differentiation and bone formation are mediated via the transmembrane receptor, MC3T3 cells were treated in the presence and absence of melatonin with either luzindole, a competitive inhibitor of the binding of melatonin to the transmembrane receptors, or pertussis toxin, an uncoupler of Gi from adenylate cyclase. Both luzindole and pertussis toxin were shown to reduce melatonin-induced expression of BSP and ALP. These results demonstrate, for the first time, that the pineal hormone, melatonin, is capable of promoting osteoblast differentiation and mineralization of matrix in culture and suggest that this hormone may play an essential role in regulating bone growth.
Aspects of Graphical Models Connected with Causality

ASPECTS OF GRAPHICAL MODELS CONNECTED WITH CAUSALITY J udea Pearl Cognitive Systems Laboratory Computer Science Department University of California, Los Angeles, CA 90024 judea@c5.ucla. edu Abstract This paper demonstrates the use of graphs as a mathematical tool for ex- pressing independenices, and as a formal language for communicating and pro- cessing causal information in statistical analysis. We show how complex infor- mation about external interventions can be organized and represented graphi- cally and, conversely, how the graphical representation can be used to facilitate quantitative predictions of the effects of interventions. We first review the Markovian account of causation and show that directed acyclic graphs (DAGS) offer an economical scheme for representing conditional independence assumptions and for deducing and displaying all the logical con- sequences of such assumptions. We then introduce the manipulative account of causation and show that any DAG deﬁnes a simple transformation which tells us how the probability distribution will change as a result of external in- terventions in the system. Using this transformation it is possible to quantify, from non—experimental data, the effects of external interventions and to specify conditions under which randomized experiments are not necessary. Finally, the paper offers a graphical interpretation for Rubin’s model of causal effects, and demonstrates its equivalence to the manipulative account of causation. We exemplify the tradeoffs between the two approaches by deriv- ing nonparametric bounds on treatment effects under conditions of imperfect compliance.
Bright light therapy of subsyndromal seasonal affective disorder in the workplace: morning vs. afternoon exposure

Objective: Bright light therapy in seasonal affective disorder (SAD) has been studied extensively. However, little attention has been given to subsyndromal seasonal affective disorder (SSAD) or the use of bright light in the workplace. Many patients using bright light boxes complain of the inconvenience of use. Much of this inconvenience involves the often‐recommended early timing of the bright light therapy. Patients, who already have difficulty awakening, often have difficulty using the bright light therapy soon after awakening before going to work. If bright light could be used effectively in the workplace, the treatment would be more convenient; the improved convenience would probably improve compliance. In this study, we studied the effectiveness of bright light therapy in subjects with SSAD in the workplace, comparing morning bright light with afternoon bright light.
Molecular Determinants of Mutant Phenotypes, Inferred from Saturation Mutagenesis Data

Understanding how mutations affect protein activity and organismal fitness is a major challenge. We used saturation mutagenesis combined with deep sequencing to determine mutational sensitivity scores for 1,664 single-site mutants of the 101 residue Escherichia coli cytotoxin, CcdB at seven different expression levels. Active-site residues could be distinguished from buried ones, based on their differential tolerance to aliphatic and charged amino acid substitutions. At nonactive-site positions, the average mutational tolerance correlated better with depth from the protein surface than with accessibility. Remarkably, similar results were observed for two other small proteins, PDZ domain (PSD95pdz3) and IgG-binding domain of protein G (GB1). Mutational sensitivity data obtained with CcdB were used to derive a procedure for predicting functional effects of mutations. Results compared favorably with those of two widely used computational predictors. In vitro characterization of 80 single, nonactive-site mutants of CcdB showed that activity in vivo correlates moderately with thermal stability and solubility. The inability to refold reversibly, as well as a decreased folding rate in vitro, is associated with decreased activity in vivo. Upon probing the effect of modulating expression of various proteases and chaperones on mutant phenotypes, most deleterious mutants showed an increased in vivo activity and solubility only upon over-expression of either Trigger factor or SecB ATP-independent chaperones. Collectively, these data suggest that folding kinetics rather than protein stability is the primary determinant of activity in vivo. This study enhances our understanding of how mutations affect phenotype, as well as the ability to predict fitness effects of point mutations.
Clustering and intra-processor scheduling for explicitly-parallel programs on distributed-memory systems

When mapping a parallel program onto a parallel architecture, the number of available processors is usually less than the number of tasks in the program. This gives rise to clustering and intra-processor scheduling problems. We address these two problems for distributed-memory systems where programs are explicitly-parallel in nature. We show that existing models of program representation are insufficient to capture temporal behavior of such programs. We use a new temporal communication graph model that allows identification of overlap of communication with computation and inter-task parallelism. Clustering and intra-processor scheduling heuristics, attempting to minimize program completion time, are proposed using this model. Simulation results on random task graphs show 10-25% improvement in completion time over existing heuristics. <<ETX>>
Role of Innate and Acquired Immune Mechanisms in Clinical Intestinal Transplant Rejection

Background Long-term outcomes of intestinal transplantation are limited by infection and rejection. To understand the underlying immune mechanisms, graft infiltrating and peripheral blood cells were analyzed using multiple ex vivo assays in intestinal transplantation recipients. Methods Infiltrating cells from rejected (graft enterectomy for rejection) and accepted or quiescent (stoma closure in stable transplant recipients) grafts were isolated and phenotypically characterized as to subsets and Toll-like receptor expressions as well as functionally tested for antimicrobial and antidonor immune responses. Multiparameter antidonor immunity was also assessed serially in the peripheral blood. Results The graft infiltrating lymphocytes were mostly of recipient origin in all patients tested. In rejecting grafts, the predominant populations were TcR&agr;&bgr;+CD3+CD8+ T cells, and CD14+ monocytes that coexpressed Toll-like receptor-2, receptor-3, receptor-4, receptor-5, and receptor-9, suggesting innate immune activation. In quiescent allografts the major cell subsets were CD13+CD14− monocytes and CD4+CD25+ T cells with possible regulatory functions. Infiltrating cells from rejected but not quiescent grafts proliferated in response to enteric bacterial and donor antigens as well as killed donor targets. Serial follow-up of peripheral blood indicated donor-specific posttransplant unresponsiveness in micro-cell–mediated lympholysis (m-CML) and mixed lymphocyte reaction (MLR) in recipients with quiescent grafts, but not in recipients with multiple rejection episodes. Enzyme-Linked ImmunoSpot assays yielded parallel results: granzyme-B with micro-cell–mediated lympholysis and interferon-&ggr; with MLR tests. Conclusion These results were consistent with the notion that rejection was associated with innate and acquired antimicrobial and antidonor immune reactivity and that patients with stable grafts were free from these deleterious effects.
SR ARQ for adaptive modulation systems combined with selection transmit diversity

Adaptive automatic repeat request (ARQ) schemes are quite effective for throughput enhancement in time-varying mobile channel environments. In this paper, both throughput and packet error rate are analyzed for a selective-repeat ARQ scheme based on a constant-power variable-rate adaptive M-QAM system combined with selection transmit diversity over multiple-input multiple-output Markovian-Nakagami channels. In this analysis, the impact of using outdated and/or imperfect channel state information on the performance of the system is considered.
Identification of Hammerstein Systems with Quantized Observations

This work is concerned with identification of Hammerstein systems whose outputs are measured by quantized sensors. The system consists of a memoryless nonlinearity that is polynomial and possibly noninvertible, followed by a linear subsystem. The parameters of linear and nonlinear parts are unknown but have known orders. Input design, identification algorithms, and their essential properties are presented under the assumptions that the distribution function of the noise is known and the quantization thresholds are known. The concept of strongly scaled full rank signals is introduced to capture the essential conditions under which the Hammerstein system can be identified with set-valued observations. Under strongly scaled full rank conditions, a strongly convergent algorithm is constructed. Asymptotic consistency and efficiency of the algorithm are investigated.
Star-formation in the central kpc of the starburst/LINER galaxy NGC 1614

Aims. The aim is to investigate the star-formation and LINER (low ionization nuclear emission line region) activity within the central kiloparsec of the galaxy NGC 1614. In this paper the radio continuum morphology, which provides a tracer of both nuclear and star-formation activity, and the distribution and dynamics of the cold molecular and atomic gas feeding this activity, are studied. In particular, the nature of an R approximate to 300 pc nuclear ring of star-formation and its relationship to the LINER activity in NGC 1614 is addressed. Methods. A high angular resolution, multi-wavelength study of the LINER galaxy NGC 1614 has been performed. Deep observations of the CO 1-0 spectral line were performed using the Owens Valley Radio Observatory (OVRO). These data have been complemented by extensive multi-frequency radio continuum and Hi absorption observations using the Very Large Array (VLA) and Multi-Element Radio Linked Interferometer Network (MERLIN). Results. Toward the center of NGC 1614, we have detected a ring of radio continuum emission with a radius of 300 pc. This ring is coincident with previous radio and Pa alpha observations. The dynamical mass of the ring based on Hi absorption is 3.1 x 10(9) M-circle dot. The peak of the integrated CO 1-0 emission is shifted by 1 '' to the north-west of the ring center. An upper limit to the molecular gas mass in the ring region is similar to 1.7 x 10(9) M-circle dot. Inside the ring, there is a north to south elongated 1.4 GHz radio continuum feature, with a nuclear peak. This peak is also seen in the 5 GHz radio continuum and in the CO. Conclusions. We suggest that the R = 300 pc star forming ring represents the radius of a dynamical resonance - as an alternative to the scenario that the starburst is propagating outwards from the center into a molecular ring. The ring-like appearance is probably part of a spiral structure. Substantial amounts of molecular gas have passed the radius of the ring and reached the nuclear region. The nuclear peak seen in 5 GHz radio continuum and CO is likely related to previous star formation, where all molecular gas was not consumed. The LINER-like optical spectrum observed in NGC 1614 may be due to nuclear starburst activity, and not to an active galactic nucleus (AGN). Although the presence of an AGN cannot be excluded.
Aiming accuracy in preferred and non-preferred limbs: implications for programing models of motor control

Most models of motor programing contend that one can perform learned actions with different muscle groups or limbs demonstrating the concept of motor equivalence. The goal of this review is to determine the generality of this concept within the context of aiming movements performed by both preferred and non-preferred limbs. Theoretical approaches to motor programing are described, followed by a comparison of a variety of kinematic measures taken from preferred and non-preferred limbs from simple and more complex aiming tasks. In general, the support for motor equivalency is strong for one- and two-dimensional aiming tasks and for simultaneous bimanual movements, but mixed for unconstrained throwing tasks and tasks that require feedback-based corrections.
Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing

The spread of multidrug-resistant Staphylococcus aureus (MRSA) strains in the clinical environment has begun to pose serious limits to treatment options. Yet virtually nothing is known about how resistance traits are acquired in vivo. Here, we apply the power of whole-genome sequencing to identify steps in the evolution of multidrug resistance in isogenic S. aureus isolates recovered periodically from the bloodstream of a patient undergoing chemotherapy with vancomycin and other antibiotics. After extensive therapy, the bacterium developed resistance, and treatment failed. Sequencing the first vancomycin susceptible isolate and the last vancomycin nonsusceptible isolate identified genome wide only 35 point mutations in 31 loci. These mutations appeared in a sequential order in isolates that were recovered at intermittent times during chemotherapy in parallel with increasing levels of resistance. The vancomycin nonsusceptible isolates also showed a 100-fold decrease in susceptibility to daptomycin, although this antibiotic was not used in the therapy. One of the mutated loci associated with decreasing vancomycin susceptibility (the vraR operon) was found to also carry mutations in six additional vancomycin nonsusceptible S. aureus isolates belonging to different genetic backgrounds and recovered from different geographic sites. As costs drop, whole-genome sequencing will become a useful tool in elucidating complex pathways of in vivo evolution in bacterial pathogens.
Benefits and pitfalls of scientific research during undergraduate medical education

Objective: The integration of scientific research into medical education is a widely discussed topic. Most research training programs are offered on a voluntary basis. In Germany, it is mandatory to complete a doctoral thesis to obtain the academic title “doctor”. The reasons why students start a dissertation project and the influence of this project on their undergraduate studies and later career choices are not well known. Method: This study was conducted at five German universities in 2003, with a total of 437 fifth-year students participating in it. A standardised questionnaire was used to ask participants about their current or finished dissertation (group A), a dissertation they had discontinued (group B) or why they had never started a dissertation project (group C). Results: The two most important reasons for students from group A to start a dissertation were “interest in the topic” and “advantage for job applications”. Compared with group B, they mentioned “improved ability to critically appraise scientific studies” and “doing scientific work independently” significantly more often as a result of working on their dissertation. Starting a dissertation project early during undergraduate studies was correlated with a less successful outcome. Moreover, working on a dissertation significantly reduced time spent on undergraduate studies. Students from group C named the "workload of undergraduate studies" and “no time” most frequently as reasons for not having started a dissertation. Conclusion: Students who have been working successfully on a dissertation rate items regarding the acquisition of scientific research skills significantly more positively, and participation in undergraduate studies seems to be negatively affected by working on a dissertation project. Therefore, basic training in scientific research methodology should become an integrated part of the medical undergraduate curriculum, while special programs should be offered for students with a particular interest in scientific research programs or an academic career.