Miracle-dz/UniFAR-FTUs huggingface dataset:
The Dynamics of the MgATP-driven Closure of MalK, the Energy-transducing Subunit of the Maltose ABC Transporter*

The nucleotide binding domains (NBDs) are the energy supplying subunits of ATP-binding cassette (ABC) proteins. They power transport by binding and hydrolyzing ATP. Tracing the pathway between different conformational states of the NBDs during ATP binding, hydrolysis, and release has, however, proven difficult. We have used molecular dynamics simulations to study the ATP-driven association of the NBDs of the maltose ABC transporter, MalK, based on the crystal structures of its open and semiopen dimers. When MgATP was introduced into the binding pockets, the semiopen dimer transitioned to a closed conformation, whereas the open dimer evolved to a semiopen state. In the absence of docked MgATP, however, the twin NBDs of both the open and semiopen starting configurations drifted further apart. Both the presence of MgATP and direct cross-interface protein-protein hydrogen bonds, primarily involving the D-loop, quite likely play a key role in initiating closure. The simulations of the MgATP-docked semiopen form indicate that completion of closure is driven mainly by cross-interface contacts between the γ-phosphate of ATP and residues in the signature motif. Our simulations also give insight into possible interactions of MalK with the regulatory proteins MalT and enzyme IIAglc
Personal Distributed Exposimeter for Radio Frequency Electromagnetic Field Assessment

A personal distributed exposimeter (PDE) consisting of 3 radio frequency (RF) acquisition nodes is constructed using textile antennas and wearable electronics. Numerical simulations are used to design the PDE. Calibration measurements at 950 MHz, using a human subject, are performed in an anechoic chamber. Compared to conventional exposimeters, which only measure in 1 position on the body, an excellent 95% confidence interval of 7 dB on measured power (densities) and isotropy of 0.5 dB are measured.
Multi‐centre experience on the use of perhexiline in chronic heart failure and refractory angina: old drug, new hope

The objective of this study is to report on our 5‐year collective experience on the use of perhexiline in the UK, in patients with chronic heart failure (CHF) and/or refractory angina with respect to ‘real‐life’ drug side effects and toxicity, therapeutic drug level monitoring, 5 year mortality outcomes and predictors of response to perhexiline therapy.
Dispersal will limit ability of mammals to track climate change in the Western Hemisphere

As they have in response to past climatic changes, many species will shift their distributions in response to modern climate change. However, due to the unprecedented rapidity of projected climatic changes, some species may not be able to move their ranges fast enough to track shifts in suitable climates and associated habitats. Here, we investigate the ability of 493 mammals to keep pace with projected climatic changes in the Western Hemisphere. We modeled the velocities at which species will likely need to move to keep pace with projected changes in suitable climates. We compared these velocities with the velocities at which species are able to move as a function of dispersal distances and dispersal frequencies. Across the Western Hemisphere, on average, 9.2% of mammals at a given location will likely be unable to keep pace with climate change. In some places, up to 39% of mammals may be unable to track shifts in suitable climates. Eighty-seven percent of mammalian species are expected to experience reductions in range size and 20% of these range reductions will likely be due to limited dispersal abilities as opposed to reductions in the area of suitable climate. Because climate change will likely outpace the response capacity of many mammals, mammalian vulnerability to climate change may be more extensive than previously anticipated.
Alternative Splicing of Intron 3 of the Serine/Arginine-rich Protein 9G8 Gene

9G8 protein belongs to the conserved serine/arginine-rich (SR) protein family, whose members exhibit multiple functions in constitutive and alternative splicing. We have previously shown that 9G8 primary transcripts are subjected to alternative splicing by excision/retention of intron 3 and to a tissue specific modulation. Because both 5′- and 3′-splice sites of intron 3 appear to be suboptimal in vertebrates, we tested the 9G8 intron 3 as a novel model system of alternative splicing. By using an in vitro approach and a mutational analysis, we have identified two purine-rich exonic splicing enhancers (ESE) located in exon 4 and a (GAA)3 enhancer located in exon 3. These elements act in concert to promote efficient splicing activation both in vitro and in vivo. Titration experiments with an excess of exonic enhancers or SR-specific RNA targets strongly suggest that SR proteins are specifically involved in the activation process. Although ASF/SF2 was expected to interact the most efficiently with ESE according to the enhancer sequences, UV cross-linking coupled or not to immunopurification demonstrates that 9G8 is highly recruited by the three ESE, followed by SC35. In contrast, ASF/SF2 only binds significantly to the (GAA)3 motif. S100 complementation experiments with individual SR proteins demonstrate that only 9G8 is able to fully restore splicing of intron 3. These results, and the fact that the exon 3 and 4 ESE sequences are conserved in vertebrates, strongly suggest that the alternative splicing of intron 3 represents an important step in the regulation of the expression of 9G8.
Effects of Spatial Distribution of Stormwater Management Infrastructure on Pollutant Removal Efficiencies at the Watershed Scale: A Geographic Information Systems Approach

EFFECTS OF SPATIAL DISTRIBUTION OF STORMWATER MANAGEMENT INFRASTRUCTURE ON POLLUTANT REMOVAL EFFICIENCIES AT THE WATERSHED SCALE: A GEOGRAPHIC INFORMATION SYSTEMS APPROACH Stephanie Sparkman, M.S. George Mason University, 2015 Thesis Director: Dr. Paul Houser Although urban areas comprise only 7% of the Chesapeake Bay Watershed, stormwater runoff from these areas represents a serious impairment to local streams and downstream ecosystems. Urban stormwater best management practices (SWBMPs) may be designed to retain, detain, or infiltrate stormwater runoff, and are sometimes also designed to treat stormwater runoff by removing or reducing nutrients and sediment. Using SWBMPs to protect streams in the Chesapeake Bay Watershed is of both ecological and economic importance. Conventional management of urban stormwater aims to convey runoff away from a developed area as quickly as possible. More recently, SWBMPs have been used in a distributed or decentralized manner to treat stormwater close to its source. This is sometimes referred to as a low impact development approach to stormwater management. The objective of this research is to compare annual pollutant removal efficiencies of two watersheds in Clarksburg, MD with differing spatial patterns of SWBMP implementation (centralized and distributed), and determine if spatially distributed SWBMPs offer the best water quality benefit. Annual pollutant removal efficiency (APRE) is the measured reduction of pollutants, typically in percent, from the inflow to the outflow of a SWBMP. The Monte Carlo method is applied to the ranges of APRE for each SWBMP. By utilizing the GIS data generated for DAs to each SWBMP, the information given for APRE are integrated to calculate a water quality benefit for the two watersheds. Because each watershed is similar in land cover characteristics, this research emphasizes the effectiveness of the spatial configuration of the SWBMPs. This research shows that spatially distributed SWBMPs remove annually between 0.95-1.00 lbs. more nitrogen, 0.048-0.049 lbs. more phosphorus, and 0.87-0.89 lbs. more sediment on average per acre as compared to centralized SWBMPs. In conclusion, this research utilizes a geographic information system to aid local and state governments to achieve federally mandated water quality regulations. Combined with cost and land use/land cover data, these new APRE data could optimize infrastructure design protocol for new urban development.
A survey of vision-based vehicle detection and tracking techniques in ITS

There has been an ever-increasing interest in research on traffic detection and traffic scene understanding based on computer vision, driven by the increasing processor speed and the increasing deployment of cameras. This field is of increasing relevance for the intelligent transport system (ITS). Therefore, there seems to be a real need for an analytical review of recent developments in this domain. We present here is a comprehensive review of video processing techniques state of the art for vehicle detection and tracking and an outlook to future research directions.
Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms.

PURPOSE To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint. CONCLUSION UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
Rates of early intervention services in very preterm children with developmental disabilities at age 2 years

Aim: Preterm birth is increasing in prevalence and long‐term follow‐up studies have documented high rates of neurosensory, intellectual, academic and behavioural disabilities. The importance of early intervention (EI) is well recognised but significant barriers to receiving EI exist in the community. This study explores the association of levels of disability at age 2 years with EI services and social risk in a large cohort of very preterm children.
Orchestrated response: a symphony of transcription factors for gene control.

An enormous body of work generated over the past three decades has revealed that eukaryotic gene transcription is a remarkably intricate biochemical process that is tightly regulated at many levels. Biochemical and genetic analysis of various model organisms has identified an astounding number of protein factors responsible for transcriptional control. Although a large assortment of gene-specific DNA-binding regulators was somewhat anticipated, the sheer complexity of the general machinery relative to prokaryotes has been a surprise. Even more unexpected were the numerous and intricate layers of control imposed by the diversification of co-activators and co-repressors, some of which possess enzymatic activities. Many interactions between the identified factors and some of their rate-limiting steps have been discerned. Despite these advances, surprisingly little is known about the detailed mechanisms by which individual genes are turned on or off in a cell. Recent evidence suggests that there is an ordered progression of events leading to RNA synthesis in vivo and that a highly structured eukaryotic nucleus may be important in orchestrating transcription. In this review, we present our interpretation of recent findings and discuss various models that integrate these observations with the emerging elaborate molecular apparatus that has evolved to control gene expression. Eukaryotic cells carry a tremendous amount of genetic information just to encode the 6000 to 100,000 proteins necessary to perpetuate life from yeast to animals. In addition, genomes must also contain vast amounts of cis-regulatory DNA responsible for directing spatial and temporal patterns of gene expression in response to metabolic requirements, developmental programs, and a plethora of external stimuli. To maintain and control such a large genetic load, eukaryotes have organized colinear DNA into discrete chromosomes each packaged into chromatin, the minimal unit of which has been defined as the nucleosome (Kornberg 1974; Luger et al. 1997). Variable degrees of DNA sequence accessibility exist within chromatin throughout the cell cycle to accommodate essential biological processes such as DNA replication, gene expression, and cell division. However, classically held notions of chromatin as merely a passive DNA-packaging vehicle and global repressor of transcription have proven to be inadequate to explain its role in gene expression (Lorch et al. 1987; for review, see Grunstein 1992). Instead, it has become clear that chromatin is a dynamic and active participant in regulating transcription of the eukaryotic genome. Thus, the question of how gene expression is regulated in complex eukaryotic genomes has re-focused on the molecular machines that have evolved to navigate through chromatin and mediate transcriptional control.
Effects of phonology and meaning on processing Chinese Sign Language sentences

The investigation on sentence processing has been the focus of language psychologists. The factors that affect sentence processing continue to be explored. However, Chinese Sign Language (CSL), which is a natural language for the deaf community, has not been analyzed on whether similar processing mechanisms underlie the procession of sentences of the spoken language. We examined the electrophysiological correlates of online sentence processing to clarify the role of phonology and meaning in CSL sentences. Electroencephalogram was recorded while 18 native signers observed the CSL sentences for comprehension. The subjects were presented with sentences in which semantic expectancy and phonological form were systematically manipulated to create four types of violations. These four conditions of interest were contrasted to a baseline sentence with a preferred semantic ending. We observed evidence that the phonetic and semantic related signs shared similar time course and effect direction verified that the semantic and phonological properties access already existed in the CSL sentence comprehension and generated a similar online processing cost.
Molecular chaperones in mammary cancer growth and breast tumor therapy

Heat shock protein (HSP) levels are elevated in breast cancer and are molecular targets for novel therapies. HSPs were first observed as proteins induced in massive amounts in normal cells exposed to stresses that lead to protein denaturation. Their expanded expression in mammary carcinoma appears to be largely due to the proliferation of malfolded mutant proteins and overexpressed oncoproteins that trigger transcription of HSP genes. HSPs play major roles in malignant transformation and progression mediated through their intrinsic molecular chaperone properties. These permit the emergence of new malignant traits through the facilitated accumulation of altered oncoproteins. The elevation of HSP concentrations in mammary carcinoma is at least partially dependent on heat shock transcription factor 1 (HSF1), a protein that responds to unfolded proteins and leads to HSP transcription. HSF1 activation has additional downstream activities, crucial for emergence of the breast cancer phenotype and these include activated cell signaling, HSP‐mediated ability to evade apoptosis and senescence and an HSF1‐dependent bias in transcriptional activity towards a metastatic phenotype. The HSPs are currently being targeted in breast cancer therapy and effective drugs for Hsp90 have been synthesized and evaluated in clinical trial. Mammary carcinoma cells also contain abundant quantities of HSP–tumor antigen complexes and these complexes are being used to develop effective tumor vaccine approaches that provide personalized therapy for each individual's cancer. J. Cell. Biochem. 113: 1096–1103, 2012. © 2011 Wiley Periodicals, Inc.
QUANTITATIVE GENETICS OF SHAPE IN CRICKET WINGS: DEVELOPMENTAL INTEGRATION IN A FUNCTIONAL STRUCTURE

The role of developmental and genetic integration for evolution is contentious. One hypothesis states that integration acts as a constraint on evolution, whereas an alternative is that developmental and genetic systems evolve to match the functional modularity of organisms. This study examined a morphological structure, the cricket wing, where developmental and functional modules are discordant, making it possible to distinguish the two alternatives. Wing shape was characterized with geometric morphometrics, quantitative genetic information was extracted using a full‐sibling breeding design, and patterns of developmental integration were inferred from fluctuating asymmetry of wing shape. The patterns of genetic, phenotypic, and developmental integration were clearly similar, but not identical. Heritabilities for different shape variables varied widely, but no shape variables were devoid of genetic variation. Simulated selection for specific shape changes produced predicted responses with marked deflections due to the genetic covariance structure. Three hypotheses of modularity according to the wing structures involved in sound production were inconsistent with the genetic, phenotypic, or developmental covariance structure. Instead, there appears to be strong integration throughout the wing. The hypothesis that genetic and developmental integration evolve to match functional modularity can therefore be rejected for this example.
2. What is the role of phytoestrogens in treating menopausal symptoms?

Most randomised placebo-controlled trials show no benefit of phytoestrogens in managing menopausal vasomotor symptoms. Concentrated phytoestrogen supplements appear to have oestrogenic actions in the breast and may interfere with the therapeutic use of tamoxifen. Unlike concentrated supplements, foods rich in phytoestrogens, such as vegetables, grains and legumes, are also excellent sources of fibre, unsaturated protein, vitamins and minerals and their consumption should be encouraged.
Molecular characterization of regenerated cardiomyocytes derived from adult mesenchymal stem cells

ABSTRACT We recently isolated a cardiomyogenic (CMG) cell line from murine bone marrow stroma, and in this paper characterize regenerated cardiomyocytes derived from adult mesenchymal stem cells at the molecular level. Stromal cells were immortalized, exposed to 5‐azacytidine, and repeatedly screened for spontaneously beating cells. CMG cells began to beat spontaneously after 2 weeks, and beat synchronously after 3 weeks. They exhibited sinus‐node‐like or ventricular‐cell‐like action potentials. Analysis of the isoforms of contractile protein genes, such as of myosin and α‐actin, indicated that their phenotype was similar to that of fetal ventricular cardiomyocytes. The cells expressed Nkx2.5, GATA4, TEF‐1, and MEF2‐C mRNA before 5‐azacytidine exposure, and MEF2‐A and MEF2‐D after exposure. CMG cells expressed α1A, α1B, and α1D‐adrenergic receptor mRNA prior to differentiation, and β1, β2‐adrenergic and M1, M2‐muscarinic receptors after acquiring the cardiomyocyte phenotype. Phenylephrine induced phosphorylation of ERK1/ 2, and the phosphorylation was inhibited by prazosin. Isoproterenol increased the cAMP level 38‐fold and beating rate, cell motion, % shortening, and contractile velocity by 48%, 38%, 27%, and 51%, respectively, and the increases were blocked by CGP20712A (β1‐selective blocker). Car‐bachol increased IP3 32‐fold, and the increase was inhibited by AFDX116 (M2‐selective blocker). These findings demonstrated that the regenerated cardiomyocytes were capable of responding to adrenergic and muscarinic stimulation. This new cell line provides a model for the study of cardiomyocyte transplantation.
Mutation patterns in cancer genomes

Recent large-scale cancer sequencing studies have focused primarily on identifying cancer-associated genes, but as an important byproduct provide “passenger mutation” data that can potentially illuminate the mutational mechanisms at work in cancer cells. Here, we explore patterns of nucleotide substitution in several cancer types using published data. We first show that selection (negative or positive) has affected only a small fraction of mutations, allowing us to attribute observed trends to underlying mutational processes rather than selection. We then show that the increased CpG mutation frequency observed in some cancers primarily occurs outside of CpG islands and CpG island shores, thus rejecting the hypothesis that the increase is a byproduct of island or shore methylation followed by deamination. We observe an A→G vs. T→C mutational asymmetry in some cancers similar to one that has been observed in germline mutations in transcribed regions, suggesting that the mutation process may be influenced by gene expression. We also demonstrate that the relative frequency of mutations at dinucleotide “hotspots” can be used as a tool to detect likely technical artifacts in large-scale studies.
A Shock Tube Experimental System for Communication Performance Evaluation Under the Time-Varying Plasma Flow Channel

Plasma sheath can severely affect the electromagnetic waves and lead to the radio blackout problem. Existing simulation works on the influence of plasma on communications, either failed to illustrate the high dynamics of the plasma or suffered from high computational complexity. In this paper, we propose an experimental system based on a shock tube to evaluate the communication performance over the plasma channel. In order to compare the performance of different modulation modes simultaneously, we initiatively mixed frequency-shift keying (FSK), pulse-position modulation, and quadrature phase-shift keying (QPSK) together in the transmission signal. Since the duration of the plasma generated by the shock tube is short in each experiment instance, we employ the achievable rate to evaluate the communication performance. Specifically, according to our experimental results, the communication performance of FSK is the best and most stable, while the QPSK is the worst and most unstable, indicating that the plasma channel has the greatest impact on the phase domain compared with the frequency domain and the time domain. Finally, the nonstationary and high dynamic characteristics of the plasma channel are verified in our designed experiment.