Investment and Capitalization of Firms in the USA

In the USA today, the precipitous rise of new financial mechanisms for capitalisation of firms as well as the merger and acquisition of others, especially risk equity capital through venture capitalist and investment banking, has sparked growth and helped to bring the economy out of the 1990s recession into a robust continuous growth pattern well positioned for the next century. The scenario is not new. For the venture capitalists of ''Silicon Valley'' in California, the experience is not new. They have seen the new industries arise before, like a phoenix from ashes of ruin, despair and even failure. Venture capital poured into high tech start-up companies has been an enormous source of financial support for the entrepreneurs who head new and growing companies. The mid-1990s marked the most dramatic increase yet recorded. Indicators, such as the NASDAQ document, outlined the solid and continuous growth in high tech industries. The paper discusses investment in US corporations within the context of governance and management of the company. Discussion about the various forms of finance are related to the organisation and management of the US corporation. Critical to any firm today are its ability to find innovative, new products or services. A growing literature on resource-base framework for analysis will be discussed as part of the firm's development of research for commercialisation. The results of a recent survey further shed light on the relationship between corporate financial management and allocated resources for research and development as the ''engine'' for new product development and therefore corporate market share and growth. The conclusion is that more financial mechanisms will be created and changed within US corporate systems to adjust, grow, and expand companies in the global economic arena, as the inevitable economic pattern leads to mergers, consolidations, and increasing cooperation and alliances among firms.

Changes in muscle recruitment patterns during skill acquisition

The control of movement is predicated upon a system of constraints of musculoskeletal and neural origin. The focus of the present study was upon the manner in which such constraints are adapted or superseded during the acquisition of motor skill. Individuals participated in five experimental sessions, ill which they attempted to produce abduction-adduction movements of the index finger in time with an auditory metronome. During each trial, the metronome frequency was increased in eight steps from an individually determined base frequency. Electromyographic (EMC) activity was recorded from first dorsal interosseous (FDI), first volar interosseous (FVI), flexor digitorum superficialis (FDS), and extensor digitorum communis (EDC) muscles. The movements produced on the final day of acquisition more accurately matched the required profile, and exhibited greater spatial and temporal stability, than those generated during initial performance. Tn the early stages of skill acquisition, an alternating pattern of activation in FDI and FVI was maintained, even at the highest frequencies. Tn contrast, as the frequency of movement was increased, activity in FDS and EDC was either tonic or intermittent. As learning proceeded, alterations in recruitment patterns were expressed primarily in the extrinsic muscles (EDC and FDS). These changes took the form of increases in the postural role of these muscles, shifts to phasic patterns of activation, or selective disengagement of these muscles. These findings suggest that there is considerable flexibility in the composition of muscle synergies, which is exploited by individuals during the acquisition of coordination.

Personnel radiation dose considerations in the use of an integrated PET–CT scanner for radiotherapy treatment planning of an integrated PET-CT scanner for radiotherapy treatment planning

The acquisition of radiotherapy planning scans on positron emission tomography (PET)-CT scanners requires the involvement of radiotherapy radiographers. This study assessed the radiation dose received by these radiographers during this process. Radiotherapy planning F- fluorodeoxyglucose (F-FDG) PET-CT scans were acquired for 28 non-small cell lung cancer patients. In order to minimise the radiation dose received, a two-stage process was used in which the most time-consuming part of the set-up was performed before the patient received their F-FDG injection. Throughout this process, the radiographers wore electronic personal dosemeters and recorded the doses received at different stages of the process. The mean total radiation dose received by a radiotherapy radiographer was 5.1±2.6 mSv per patient. The use of the two-stage process reduced the time spent in close proximity to the patient by approximately a factor of four. The two-stage process was effective in keeping radiation dose to a minimum. The use of a pre-injection set-up session reduces the radiation dose to the radiotherapy radiographers because of their involvement in PET-CT radiotherapy treatment planning scans by approximately a factor of three.

Molecular cloning and deduced organization of the pHpG/CNP precursor from the venom of the African forest viper, Atheris squamigera

The discovery that the hypotensive sequela of envenomation by the South American viper, Bothrops jararaca, was mediated by peptides, represented a milestone in drug discovery research that led to the introduction of ACE inhibitors. These bradykinin-potentiating peptides (BPPs) have been found in the venoms of many species of viper and molecular cloning of biosynthetic precursors has revealed that each encodes several different BPPs in tandem with a single copy of a C-type natriuretic peptide (CNP) located at the C-terminus. Venoms of the African forest vipers (Atheris) have been poorly studied possibly because they do not represent a major danger to humans. However, initial studies have indicated that they contain some of the “classical” protein toxins of viper venoms and a novel class of peptide, the polyglycine/polyhistidine (pGpH) peptides. These peptides occur in several molecular forms with different numbers of repetitive glycine and histidine repeats. We have cloned the biosynthetic precursor of A. squamigera pGpH peptides from a venom-derived cDNA library and have confirmed that a single copy of CNP is located at the C-terminus and additionally that, like BPPs in other vipers, pGpH peptides are encoded in tandem within this single precursor. Solid phase peptide synthesis of pGpH peptides has proven to be extremely difficult but is progressing and acquisition of synthetic replicates of each peptide is a necessary prerequisite for systematic pharmacological characterisation as establishment of a biological function for these peptides remains elusive. pGpH peptides may prove to play a role as fundamental as that of the BPPs.

Twenty-eight divergent polysaccharide loci specifying within and amongst strain capsule diversity in three strains of Bacteroides fragilis

Comparison of the complete genome sequence of Bacteroides fragilis 638R, originally isolated in the USA, was made with two previously sequenced strains isolated in the UK (NCTC 9343) and Japan (YCH46). The presence of 10 loci containing genes associated with polysaccharide (PS) biosynthesis, each including a putative Wzx flippase and Wzy polymerase, was confirmed in all three strains, despite a lack of cross-reactivity between NCTC 9343 and 638R surface PS-specific antibodies by immunolabelling and microscopy. Genomic comparisons revealed an exceptional level of PS biosynthesis locus diversity. Of the 10 divergent PS-associated loci apparent in each strain, none is similar between NCTC 9343 and 638R. YCH46 shares one locus with NCTC 9343, confirmed by mAb labelling, and a second different locus with 638R, making a total of 28 divergent PS biosynthesis loci amongst the three strains. The lack of expression of the phase-variable large capsule (LC) in strain 638R, observed in NCTC 9343, is likely to be due to a point mutation that generates a stop codon within a putative initiating glycosyltransferase, necessary for the expression of the LC in NCTC 9343. Other major sequence differences were observed to arise from different numbers and variety of inserted extra-chromosomal elements, in particular prophages. Extensive horizontal gene transfer has occurred within these strains, despite the presence of a significant number of divergent DNA restriction and modification systems that act to prevent acquisition of foreign DNA. The level of amongst-strain diversity in PS biosynthesis loci is unprecedented.

N1, P2 and T-complex of the auditory brain event-related potentials to tones with varying rise times in adults with and without dyslexia

Dyslexia is a learning difficulty affecting the acquisition of fluent reading and spelling skills due to poor phonological processing. Underlying deficits in processing sound rise time have also been found in children and adults with dyslexia. However, the neural basis for these deficits is unknown. In the present study event-related potentials were used to index neural processing and examine the effect of rise time manipulation on the obligatory N1. T-complex and P2 responses in English speaking adults with and without dyslexia. The Tb wave of the T-complex showed differences between groups, with the amplitudes for Tb becoming less negative with increased rise time for the participants with dyslexia only. Frontocentral N1 and P2 did not show group effects. Enhanced Tb amplitude that is modulated by rise time could indicate altered neural networks at the lateral surface of the superior temporal gyrus in adults with dyslexia. (C) 2011 Elsevier B.V. All rights reserved.

Selective block in erythropoietin-induced differentiation of growth factor-independent retrovirally-infected TF-1 cells

The erythroleukaemic cell line TF-1, infected with either the pBabe neo retrovirus or the retrovirus bearing the human erythropoietin (hEpo) gene, developed three growth factor-independent clones. Erythropoietin (Epo), interleukin-3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) accelerated the proliferation of these clones. Autonomous growth of the clones was independent of Epo because it was not altered by Epo anti-sense oligonucleotides, nor was Epo detectable in culture supernatants. Cells from the mutant clones could not be induced by Epo to express glycophorin A and haemoglobin synthesis was markedly reduced. Haemin reversed the block in Epo-induced haemoglobin synthesis. Acquisition of growth factor-independence appears to be linked with the selective loss of differentiation capacity. These cells may provide a useful model for the study of the mechanisms involved in leukaemic transformation.

Bidirectional, iterative approach to the structural delineation of the functional "Chemoprint" in GPR40 for agonist recognition

GPR40, free fatty acid receptor 1 (FFAR1), is a member of the GPCR superfamily and a possible target for the treatment of type 2 diabetes. In this work, we conducted a bidirectional iterative investigation, including computational modeling and site-directed mutagenesis, aimed at delineating amino acid residues forming the functional "chemoprint" of GPR40 for agonist recognition. The computational and experimental studies revolved around the recognition of the potent synthetic agonist GW9508. Our experimentally supported model suggested that H137(4.56), R183(5.39), N244(6.55), and R258(7.35) are directly involved in interactions with the ligand. We have proposed a polarized NH-pi interaction between H137(4.56) and GW9508 as one of the contributing forces leading to the high potency of GW9508. The modeling approach presented in this work provides a general strategy for the exploration of receptor-ligand interactions in G-protein coupled receptors beginning prior to acquisition of experimental data.

The Adult Cystic Fibrosis Airway Microbiota Is Stable over Time and Infection Type, and Highly Resilient to Antibiotic Treatment of Exacerbations

Cystic fibrosis (CF) is characterized by defective mucociliary clearance and chronic airway infection by a complex microbiota. Infection, persistent inflammation and periodic episodes of acute pulmonary exacerbation contribute to an irreversible decline in CF lung function. While the factors leading to acute exacerbations are poorly understood, antibiotic treatment can temporarily resolve pulmonary symptoms and partially restore lung function. Previous studies indicated that exacerbations may be associated with changes in microbial densities and the acquisition of new microbial species. Given the complexity of the CF microbiota, we applied massively parallel pyrosequencing to identify changes in airway microbial community structure in 23 adult CF patients during acute pulmonary exacerbation, after antibiotic treatment and during periods of stable disease. Over 350,000 sequences were generated, representing nearly 170 distinct microbial taxa. Approximately 60% of sequences obtained were from the recognized CF pathogens Pseudomonas and Burkholderia, which were detected in largely non-overlapping patient subsets. In contrast, other taxa including Prevotella, Streptococcus, Rothia and Veillonella were abundant in nearly all patient samples. Although antibiotic treatment was associated with a small decrease in species richness, there was minimal change in overall microbial community structure. Furthermore, microbial community composition was highly similar in patients during an exacerbation and when clinically stable, suggesting that exacerbations may represent intrapulmonary spread of infection rather than a change in microbial community composition. Mouthwash samples, obtained from a subset of patients, showed a nearly identical distribution of taxa as expectorated sputum, indicating that aspiration may contribute to colonization of the lower airways. Finally, we observed a strong correlation between low species richness and poor lung function. Taken together, these results indicate that the adult CF lung microbiome is largely stable through periods of exacerbation and antibiotic treatment and that short-term compositional changes in the airway microbiota do not account for CF pulmonary exacerbations.

Clinico-epidemiological features of infections caused by CTX-M type extended spectrum beta lactamase-producing Escherichia coli in hospitalised patients

A review of medical records of 45 of 53 hospitalised patients with positive cultures for CTX-M type ESBL-producing Escherichia coli between 01 January and 31 May 2004 was conducted. The mean age of the population studied was 73.1 (+/-14.6) years and the majority (55.6%) had been under the care of the internal medicine or elderly care service. In the majority (77.8%) of instances the isolate was attributed to a clinical infection rather than colonisation and the commonest clinical specimen to yield the organism was urine, which was positive in 57.8% of patients. Acquisition of the organism was categorised as nosocomial in 68.9% of patients; in this subgroup, the median duration of inpatient stay prior to recovery of the organism was 24 (range 3-240) days. Haemodialysis-dependence was the most common of the comorbidities evaluated. The mean number of antibiotics prescribed per patient in the 30 days prior to first isolation of the organism was 1.7 (range 0-4). Furthermore, the mean number of antibiotic-days exposure per patient during this period was 13.9 (range 0-48). The most frequently received class of antibiotic was beta-lactam/beta-lactamase inhibitor combinations. Of 35 infections, 26 (74.2%) were successfully treated. Overall 12 patients with infection died (34.3%); attributable mortality was presumed in seven (20%).

The Emotional Paradoxes of Adverse Possession

Property lawyers are generally viewed as a serious lot, not prone to feverish bursts of excitement as we seek comfort and solace in established legal rules and precepts. In the same way, property law disputes tend to have a fairly low profile and fail to capture the public imagination in the same way as, for example, those involving criminal or human rights law. Such apparent indifference might seem a little strange, given the centrality of property in everyday human life and the significance which legal systems and individuals attach to property rights. However, there is one issue which always inflames passions amongst lawyers and non-lawyers alike: the acquisition of land through the doctrine of adverse possession, often described as ‘squatter’s rights’. No property-related topic is likely to light up a radio show phone-in switchboard quite like squatting

Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr ΔF508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery

Cystic fibrosis is the most common inherited lethal disease in Caucasians. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), of which the cftr ?F508 mutation is the most common. ?F508 macrophages are intrinsically defective in autophagy because of the sequestration of essential autophagy molecules within unprocessed CFTR aggregates. Defective autophagy allows Burkholderia cenocepacia (B. cepacia) to survive and replicate in ?F508 macrophages. Infection by B. cepacia poses a great risk to cystic fibrosis patients because it causes accelerated lung inflammation and, in some cases, a lethal necrotizing pneumonia. Autophagy is a cell survival mechanism whereby an autophagosome engulfs non-functional organelles and delivers them to the lysosome for degradation. The ubiquitin binding adaptor protein SQSTM1/p62 is required for the delivery of several ubiquitinated cargos to the autophagosome. In WT macrophages, p62 depletion and overexpression lead to increased and decreased bacterial intracellular survival, respectively. In contrast, depletion of p62 in ?F508 macrophages results in decreased bacterial survival, whereas overexpression of p62 leads to increased B. cepacia intracellular growth. Interestingly, the depletion of p62 from ?F508 macrophages results in the release of the autophagy molecule beclin1 (BECN1) from the mutant CFTR aggregates and allows its redistribution and recruitment to the B. cepacia vacuole, mediating the acquisition of the autophagy marker LC3 and bacterial clearance via autophagy. These data demonstrate that p62 differentially dictates the fate of B. cepacia infection in WT and ?F508 macrophages.

JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone

Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygous-mutant colonies were common in patients with JAK2V617F-positive PV and were surprisingly prevalent in JAK2V617F-positive ET and JAK2 exon 12-mutated PV. Using microsatellite PCR to map loss-of-heterozygosity breakpoints within individual colonies, we demonstrate that recurrent acquisition of JAK2V617F homozygosity occurs frequently in both PV and ET. PV was distinguished from ET by expansion of a dominant homozygous subclone, the selective advantage of which is likely to reflect additional genetic or epigenetic lesions. Our results suggest a model in which development of a dominant JAK2V617F-homzygous subclone drives erythrocytosis in many PV patients, with alternative mechanisms operating in those with small or undetectable homozygous-mutant clones.

AßPP over-expressing transgenic rat model of Alzheimer's disease utilizing the Tg2576 mouse protocol.

The current study examined behavioral and histological effects of amyloid-ß (Aß) protein precursor (AßPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg- offspring. Tg+ rats and Tg- littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure. There were no significant behavioral differences between Tg+ rats and Tg- littermates at 4 months old but there were significant differences at 8 and 12 months old, and in probe trials at 8 and 12 months old, the Tg+ rats spent significantly less time and covered less distance in the platform zone. Under acquisition of a fixed-consecutive number schedule at 3 months old, Tg- littermates demonstrated a longer latency to learning the response rule than Tg+ rats; while this might seem paradoxical, it is consistent with the role of overexpression of AßPP in learning. Histological analyses revealed activated astrocytes in brains of Tg+ rats but not Tg- littermates at 6 months old, and thioflavin-S positive staining in the hippocampus and cortex of 17-month old Tg+ rats but not Tg- littermates. Quantification of Aß load in the brain at 22 months indicated high levels of Aß38, Aß40, and Aß42 in the Tg+ rats. These data suggest this model might provide a valuable resource for AD research.

Metamaterials Nanosensor for Label-free Analysis of Conformation and Molecular Interaction of Biomolecules

Analysis of molecular interaction and conformational dynamics of biomolecules is of paramount importance in understanding of their vital functions in complex biological systems, disease detection, and new drug development. Plasmonic biosensors based upon surface plasmon resonance and localized surface plasmon resonance have become the predominant workhorse for detecting accumulated biomass caused by molecular binding events. However, unlike surface-enhanced Raman spectroscopy (SERS), the plasmonic biosensors indeed are not suitable tools to interrogate vibrational signatures of conformational transitions required for biomolecules to interact. Here, we show that plasmonic metamaterials can offer two transducing channels for parallel acquisition of optical transmission and sensitive SERS spectra at the biointerface, simultaneously probing the conformational states and binding affinity of biomolecules, e.g. G-quadruplexes, in different environments (Fig. 1). We further demonstrate the use of the metamaterials for fingerprinting and detection of arginine-glycine-glycine domain of nucleolin, a cancer biomarker which specifically binds to a G-quadruplex, with the picomolar sensitivity. The dual-mode nanosensor will significantly contribute to unraveling the complexes of the conformational dynamics of biomolecules as well as to improving specificity of biodetection assays.