Miracle-dz/UniFAR-FTUs huggingface dataset:
Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells

Significance We have developed a family of rhodium compounds that bind DNA mismatches and are cytotoxic to mismatch repair (MMR)-deficient cancer cells. This study describes the cellular mechanism of action of the compounds that enables this selective cytotoxicity. The compound binding mode, metalloinsertion, displaces the mismatched base pairs from the DNA helix and creates a DNA lesion that activates the DNA damage response. This lesion is unable to be repaired in MMR-deficient cells. This mechanism is distinct from other compounds that target DNA and provides a therapeutic strategy for treatment of cancers with MMR deficiency. The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)]2+ (Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cell-cycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMR-deficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells.
Probing the antigenicity of hepatitis C virus envelope glycoprotein complex by high-throughput mutagenesis

The hepatitis C virus (HCV) envelope glycoproteins E1 and E2 form a non-covalently linked heterodimer on the viral surface that mediates viral entry. E1, E2 and the heterodimer complex E1E2 are candidate vaccine antigens, but are technically challenging to study because of difficulties in producing natively folded proteins by standard protein expression and purification methods. To better comprehend the antigenicity of these proteins, a library of alanine scanning mutants comprising the entirety of E1E2 (555 residues) was created for evaluating the role of each residue in the glycoproteins. The mutant library was probed, by a high-throughput flow cytometry-based assay, for binding with the co-receptor CD81, and a panel of 13 human and mouse monoclonal antibodies (mAbs) that target continuous and discontinuous epitopes of E1, E2, and the E1E2 complex. Together with the recently determined crystal structure of E2 core domain (E2c), we found that several residues in the E2 back layer region indirectly impact binding of CD81 and mAbs that target the conserved neutralizing face of E2. These findings highlight an unexpected role for the E2 back layer in interacting with the E2 front layer for its biological function. We also identified regions of E1 and E2 that likely located at or near the interface of the E1E2 complex, and determined that the E2 back layer also plays an important role in E1E2 complex formation. The conformation-dependent reactivity of CD81 and the antibody panel to the E1E2 mutant library provides a global view of the influence of each amino acid (aa) on E1E2 expression and folding. This information is valuable for guiding protein engineering efforts to enhance the antigenic properties and stability of E1E2 for vaccine antigen development and structural studies.
Psychotherapy and the Lonely Patient

Contents Loneliness and the Fuller Vision: A Preface * Interrelationships Between Religiousness and Loneliness * Treating Loneliness in Children * Loneliness and the Single, the Widowed, and the Divorced * Cognitive Pastoral Psychotherapy With Religious Persons Experiencing Loneliness * Will You Be My Friend? Group Psychotherapy With Lonely People * Loneliness and the Aging Client: Psychotherapeutic Considerations * Replication of the Phenomenology of Loneliness in the Therapeutic Dyad * A Model for Working With Lonely Clients: Sadler Revisited
CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury.

CM101, an antiangiogenic polysaccharide derived from group B streptococcus, was administered by i.v. injection 1 hr post-spinal-cord crush injury in an effort to prevent inflammatory angiogenesis and gliosis (scarring) in a mouse model. We postulated that gliosis would sterically prevent the reestablishment of neuronal connectivity; thus, treatment with CM101 was repeated every other day for five more infusions for the purpose of facilitating regeneration of neuronal function. Twenty-five of 26 mice treated with CM101 survived 28 days after surgery, and 24 of 26 recovered walking ability within 2-12 days. Only 6 of 14 mice in the control groups survived 24 hr after spinal cord injury, and none recovered function in paralyzed limbs. MRI analysis of injured untreated and treated animals showed that CM101 reduced the area of damage at the site of spinal cord compression, which was corroborated by histological analysis of spinal cord sections from treated and control animals. Electrophysiologic measurements on isolated central nervous system and neurons in culture showed that CM101 protected axons from Wallerian degeneration; reversed gamma-aminobutyrate-mediated depolarization occurring in traumatized neurons; and improved recovery of neuronal conductivity of isolated central nervous system in culture.
A case study of evaluation technique for soft error tolerance on SRAM-based FPGAs

SRAM-based field programmable gate arrays (FPGAs) are vulnerable to a single event upset (SEU), which is induced by radiation effect. Therefore, the dependable design techniques become important, and the accurate dependability analysis method is required to demonstrate their robustness. Most of present analysis techniques are performed by using full reconfiguration to emulate the soft error. However, it takes long time to analyze the dependability because it requires many times of reconfiguration to complete the soft error injection. In the present paper, we construct the soft error estimation system to analyze the reliability and to reduce the estimation time. Moreover, we apply monte carlo simulation to our approach, and identify trade-off between accuracy of error rate and estimation time. As a result of our experimentation for 8-bit full-adder and multiplier, we can show the dependability of the implemented system. Also, the constructed system can reduce the estimation time. According to the result, when performing about 50% circuit monte carlo simulation, the error rate is within 20%.
Experiences of Everyday Life in Men with Alcohol Dependency—A Qualitative Study

The aim of the present study is to describe and understand the meaning of living with alcohol dependency (AD) as a man. Studies point out a high prevalence of AD in men and the reasons for, and consequences of, that are complex. However, today there is a lack of knowledge about men's lived experiences of having AD. In-depth interviews were conducted with 15 alcohol dependent men and analyzed using a phenomenological-hermeneutic approach. In the comprehensive understanding, findings from the naïve understanding and the structural analysis were interpreted with help from both gender and caring theoretical perspectives. “A Fallible Man” and “A Man with Powerfulness” were disclosed as two main gender formations influencing senses of well-being. A Fallible Man involved varying experiences of restrictions, being in control, and meaninglessness. Being in control promoted a sense of well-being. A Man with Powerfulness involved energetic activity, and the development and maintaining of interests as well as risk-taking. Being powerful diminished feelings of meaninglessness, cravings, and social alienation. The results show, among other things, that the men live an incompatible life and, because of that, need support and guidance to find a more meaningful life. This can be accomplished if caregivers allow men to be in focus and involved in planning their own care. To avoid limiting the men while they are in treatment, the health care professionals also need to focus on the men's everyday life. This focus involves acknowledging the men's individual experiences of what enriches and limits their everyday lives.
The Timed Abstract State Machine Language: Abstract State Machines for Real-Time System Engineering

In this paper, we present the Timed Abstract State Machine (TASM) lan- guage, which is a language for the specification of embedded real-time systems. In the engineering of embedded real-time systems, the correctness of the system is defined in terms of three aspects - function, time, and resource consumption. The goal of the TASM language and its associated toolset is to provide a basis for specification-based real-time system engineering where these three aspects can be specified and analyzed. The TASM language is built on top of Abstract State Machines (ASM) by including facilities for compact and legible specification of non-functional behavior, namely time and resource consumption. The TASM language provides a notation which is well-suited to the specification needs of embedded real-time systems. We begin the presentation of the language with a historical survey on the use of ASM in specifying real-time systems. The core difference between the TASM language and ASM is that steps are inherently durative instead of being instantaneous and steps consume resources. These concepts capture the reality of physical systems in a flexible abstract model. We present the syntax and semantics of the language and illustrate the concepts using an extended version of the production cell case study.
Program monitoring with LTL in EAGLE

Summary form only given. We briefly present a rule-based framework, called EAGLE, shown to be capable of defining and implementing finite trace monitoring logics, including future and past time temporal logic, extended regular expressions, real-time and metric temporal logics (MTL), interval logics, forms of quantified temporal logics, and so on. In this paper we focus on a linear temporal logic (LTL) specialisation of EAGLE. For an initial formula of size m, we establish upper bounds of O(m/sup 2/2/sup m/logm) and O(m/sup 4/2/sup 2m/log/sup 2/m) for the space and time complexity, respectively, of single step evaluation over an input trace. EAGLE has been successfully used, in both LTL and metric LTL forms, to test a real-time controller of an experimental NASA planetary rover.
Pavlovian conditioning and the status of traditional learning theory

Volume I: Contents: R.R. Mowrer, S.B. Klein, Traditional Learning Theory and the Transition to Contemporary Learning Theory. Part I:Theories of Pavlovian Conditioning. P.J. Durlach, Learning and Performance in Pavlovian Conditioning: Are Failures of Contiguity Failures of Learning or Performance? R.R. Miller, L.D. Matzel, Contingency and Relative Associative Strength. A.G. Baker, P. Mercier, Attention, Retrospective Processing and Cognitive Representations. G. Hall, R. Honey, Perceptual and Associative Learning. A.R. Wagner, S.E. Brandon, Evolution of a Structured Connectionist Model of Pavlovian Conditioning (AESOP). A. Tomie, W. Brooks, Sign-Tracking: The Search for Reward. Part II:Current Status of Traditional Learning Theory. D.J. Levis, The Case for a Return to a Two-Factor Theory of Avoidance: The Failure of Non-Fear Interpretations. A. Dickinson, The Expectancy Theory of Animal Conditioning. Volume II: Contents: R.R. Mowrer, S.B. Klein. Part I:Introduction: A Contrast Between Traditional and Contemporary Learning Theory. Part II:Theories of Instrumental Conditioning. J. Allison, The Nature of Reinforcement. R.M. Church, Theories of Timing Behavior. S.F. Maier, Learned Helplessness: Event Co-Variation and Cognitive Changes. F. Vaccarino, B.B. Schiff, S.E. Glickman, A Biological View of Reinforcement. Part III:Biological Constraints in Learning. V.M. LoLordo, A. Droungas, Selective Associations and Adaptive Specializations: Food Aversion and Phobias. J. Garcia, L. Brett, K. Rusiniak, Limits of Darwinian Conditioning. A.L. Riley, C.L. Wetherington, Schedule-Induced Polydipsia: Is the Rat a Small Furry Human? W. Timberlake, G.A. Lucas, Behavior Systems and Learning: From Misbehavior to General Principles.
Cytoplasmic and nuclear quality control and turnover of single-stranded RNA modulate post-transcriptional gene silencing in plants

Eukaryotic RNA quality control (RQC) uses both endonucleolytic and exonucleolytic degradation to eliminate dysfunctional RNAs. In addition, endogenous and exogenous RNAs are degraded through post-transcriptional gene silencing (PTGS), which is triggered by the production of double-stranded (ds)RNAs and proceeds through short-interfering (si)RNA-directed ARGONAUTE-mediated endonucleolytic cleavage. Compromising cytoplasmic or nuclear 5′–3′ exoribonuclease function enhances sense-transgene (S)-PTGS in Arabidopsis, suggesting that these pathways compete for similar RNA substrates. Here, we show that impairing nonsense-mediated decay, deadenylation or exosome activity enhanced S-PTGS, which requires host RNA-dependent RNA polymerase 6 (RDR6/SGS2/SDE1) and SUPPRESSOR OF GENE SILENCING 3 (SGS3) for the transformation of single-stranded RNA into dsRNA to trigger PTGS. However, these RQC mutations had no effect on inverted-repeat–PTGS, which directly produces hairpin dsRNA through transcription. Moreover, we show that these RQC factors are nuclear and cytoplasmic and are found in two RNA degradation foci in the cytoplasm: siRNA-bodies and processing-bodies. We propose a model of single-stranded RNA tug-of-war between RQC and S-PTGS that ensures the correct partitioning of RNA substrates among these RNA degradation pathways.
FPGA-Based Real-Time Pedestrian Detection on High-Resolution Images

This paper focuses on real-time pedestrian detection on Field Programmable Gate Arrays (FPGAs) using the Histograms of Oriented Gradients (HOG) descriptor in combination with a Support Vector Machine (SVM) for classification as a basic method. We propose to process image data at twice the pixel frequency and to normalize blocks with the L1-Sqrt-norm resulting in an efficient resource utilization. This implementation allows for parallel computation of different scales. Combined with a time-multiplex approach we increase multiscale capabilities beyond resource limitations. We are able to process 64 high resolution images (1920 × 1080 pixels) per second at 18 scales with a latency of less than 150 u s. 1.79 million HOG descriptors and their SVM classifications can be calculated per second and per scale, which outperforms current FPGA implementations by a factor of 4.
PDB‐scale analysis of known and putative ligand‐binding sites with structural sketches

Computational investigation of protein functions is one of the most urgent and demanding tasks in the field of structural bioinformatics. Exhaustive pairwise comparison of known and putative ligand‐binding sites, across protein families and folds, is essential in elucidating the biological functions and evolutionary relationships of proteins. Given the vast amounts of data available now, existing 3D structural comparison methods are not adequate due to their computation time complexity. In this article, we propose a new bit string representation of binding sites called structural sketches, which is obtained by random projections of triplet descriptors. It allows us to use ultra‐fast all‐pair similarity search methods for strings with strictly controlled error rates. Exhaustive comparison of 1.2 million known and putative binding sites finished in ∼30 h on a single core to yield 88 million similar binding site pairs. Careful investigation of 3.5 million pairs verified by TM‐align revealed several notable analogous sites across distinct protein families or folds. In particular, we succeeded in finding highly plausible functions of several pockets via strong structural analogies. These results indicate that our method is a promising tool for functional annotation of binding sites derived from structural genomics projects. Proteins 2011. © 2012 Wiley Periodicals, Inc.
Divergence‐free discontinuous Galerkin schemes for the Stokes equations and the MAC scheme

We show that recently studied discontinuous Galerkin discretizations in their lowest order version are very similar to the marker and cell (MAC) finite difference scheme. Indeed, applying a slight modification, the exact MAC scheme can be recovered. Therefore, the analysis applied to the DG methods applies to the MAC scheme as well and the DG methods provide a natural generalization of the MAC scheme to higher order and irregular meshes. Copyright © 2007 John Wiley & Sons, Ltd.
Phone recognition using Restricted Boltzmann Machines

For decades, Hidden Markov Models (HMMs) have been the state-of-the-art technique for acoustic modeling despite their unrealistic independence assumptions and the very limited representational capacity of their hidden states. Conditional Restricted Boltzmann Machines (CRBMs) have recently proved to be very effective for modeling motion capture sequences and this paper investigates the application of this more powerful type of generative model to acoustic modeling. On the standard TIMIT corpus, one type of CRBM outperforms HMMs and is comparable with the best other methods, achieving a phone error rate (PER) of 26.7% on the TIMIT core test set.
Managing parallelism and resources in scientific dataflow programs

Abstract : Exploiting parallelism to achieve high performance invariably increases the resource requirements of a program. This is particularly serious under dynamic dataflow execution, because all the potential parallelism in a program is exposed. The resource requirements can be excessive, often leading to deadlock. This phenomenon is documented using parallelism and resource profiles derived under an ideal dataflow execution model. This report examines how resource requirements can be managed effectively by controlling the ways in which parallelism is exposed. A mechanism for controlling parallelism in scientific programs, called k-bounded loops, is presented. This involves compiling loops into dataflow graphs in a manner that allows the maximum number of concurrent iterations to be set dynamically, when the loop is invoked. A policy for employing this mechanism is developed and tested on a variety of programs. Through static analysis of the program, parametric resource expressions are formulated and the potential parallelism is characterized. Based on this analysis, the program is augmented with resource management code that computes the k-bounds by simple formulae, involving program variables and an overall resource parameter that reflects the capacity of the machine. This approach is shown to be effective for containing the resource requirements of scientific dataflow programs, while exposing adequate parallelism.
C‐myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells

C‐myc is implicated in the initiation, progression and estrogen response of breast cancer. To further investigate the role of c‐myc in breast cancer, we have developed clonal MCF‐7 human breast cancer cell lines harboring a stably‐transfected human c‐myc gene, whose expression was stringently controlled by the bacterial reverse tetracycline transcription activator protein. The expression of the endogenous genomic c‐myc gene in MCF‐7 cells was abolished by the potent pure estrogen antagonist, ICI 182,780. Functional c‐Myc protein was identified by both Western immunoblotting and by its ability to transactivate a chimeric plasmid consisting of E‐box sequences upstream of the luciferase reporter gene. One MCF‐7 clone, 35im, was chosen for further characterization. C‐myc induction by doxycycline was rapid and dose dependent; c‐myc mRNA appeared as early as 30 min after doxycycline addition and stimulation of c‐myc expression required as little as 50 ng/ml doxycycline, with c‐myc mRNA levels reaching a plateau at 2.5 μg/ml doxycycline. ICI 182,780 or doxycycline (a tetracycline analog) treatment did not alter the mRNA levels of Max, the c‐myc binding partner. As in wildtype MCF‐7 cells, the growth of clone 35im was inhibited by 1 μM or less of ICI 182,780 and stimulated by 10 nM to 1 μM 17β‐estradiol. When maintained in a complete medium containing 5% normal fetal bovine serum (FBS) and ICI 182,780, doxycycline induced cell growth by 400% in an 8‐day assay. A similar level of growth was achieved with doxycycline treatment in cells that were arrested by the use of charcoal‐stripped FBS. Doxycycline had no effect on the growth of a control MCF‐7 clone (18c). Apoptosis, assessed by caspase‐dependent cleavage of poly(ADP‐ribose) polymerase, was unchanged in clone 35im cells after treatments with doxycycline or ICI 182,780. The present study demonstrates that c‐myc alone is sufficient to confer antiestrogen resistance in human breast cancer. Our novel c‐myc‐inducible MCF‐7 cell model offers a unique opportunity to study the diverse actions of the c‐myc proto‐oncogene in human breast cancer. © 2002 Wiley‐Liss, Inc.
Angiotensin AT(1)-receptors depolarize neonatal spinal motoneurons and other ventral horn neurons via two different conductances.

Angiotensin receptors are highly expressed in neonatal spinal cord. To identify their influence on neuronal excitability, we used patch-clamp recordings in spinal cord slices to assess responses of neonatal rat (5-12 days) ventral horn neurons to bath-applied angiotensin II (ANG II; 1 microM). In 14/34 identified motoneurons tested under current clamp, ANG II induced a slowly rising and prolonged membrane depolarization, blockable with Losartan (n = 5) and (Sar(1), Val(5), Ala(8))-ANG II (Saralasin, n = 4) but not PD123319 (1 microM each; n = 4). Under voltage clamp (V(H) -65 mV), 7/22 motoneurons displayed an ANG-II-induced tetrodotoxin-resistant inward current (-128 +/- 31 pA) with a similar time course, an associated reduction in membrane conductance and net current reversal at -98.8 +/- 3.9 mV. Losartan-sensitive ANG II responses were also evoked in 27/78 tested ventral horn "interneurons. " By contrast with motoneurons, their ANG-II-induced inward current was smaller (-39.9 +/- 5.2 pA) and analysis of their I-V plots revealed three patterns. In eight cells, membrane conductance decreased with net inward current reversing at -103.8 +/- 4.1 mV. In seven cells, membrane conductance increased with net current reversing at -37.9 +/- 3.6 mV. In 12 cells, I-V lines remained parallel with no reversal within the current range tested. Intracellular dialysis with GTP-gamma-S significantly prolonged the ANG II effect in seven responsive interneurons and GDP-beta-S significantly reduced the ANG II response in four other cells. Peak inward currents were significantly reduced in all 13 responding neurons recorded in slices incubated in pertussis toxin (5 microgram/ml) for 12-18 h or in 12 neurons perfused with N-ethylmaleimide. Of 29 interneurons sensitive to pertussis toxin or N-ethylmaleimide treatment, 9 cells displayed a decrease in membrane conductance that reversed at -101.3 +/- 3.8 mV. In eight cells, membrane conductance increased and reversed at -38.7 +/- 3.4 mV. In 12 cells, the I-V lines remained parallel with no reversal within the current range tested, suggesting that both conductances are modulated by pertussis toxin-sensitive G proteins. These observations reveal a direct, G-protein-mediated depolarizing action of ANG II on neonatal rat ventral horn neurons. They also imply involvement of two distinct conductances that are differentially distributed among different cell types.