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Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients’ and carers’ quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy. [ABSTRACT FROM AUTHOR]

A small impoundment (SI) inventory was made by county for Alabama by using Landsat 5 TM satellite imagery from the winter of 2007 to enumerate and measure surface areas of water bodies. The result was identification of 278,787 SIs >0.18 ha (0.44 ac) and <2,000 ha (4,972 ac) in surface area with a combined water surface area of 261,880 ha (647,105 ac).The average surface area of SIs was 0.94 ha (2.32 ac)—84.8% were <1 ha (2.5 ac), and 92.7% were <2 ha (4.94 ac) in area. Ground-truthing in one county revealed that the procedure had an accuracy of 80% in identifying SIs. The density of SIs tended to increase slightly in counties of higher population density. Some physiographic provinces had greater density of SIs than others; however, the average surface area of individual ponds did not differ greatly among provinces.The total volume of SIs was estimated to be 6 km3 (4,900,000 ac ft)—roughly 8.1% of annual runoff for the state. After initial filling by direct precipitation and runoff, SIs are seldom drained, and they overflow after periods of considerable rainfall mininiizing retention of runoff. It was estimated that SIs in Alabama lessen annual runoff by about 0.35 cm y-1(0.14 in yr-1)-a reduction of about 0.6%-mainly because evaporation from their surfaces exceeds evapotranspiration loss for an equal land area. Nevertheless, SIs probably flatten peaks of downstream hydrographs. It should be possible to use water from Sis to supplement existing water supplies in certain localities, and SIs create open-water, shoreline, and wetland habitat as well as detain and improve the quality of surface runoff. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to survey holdings of ephemeral veterinary literature. Methods: WorldCat OCLC catalog, the Library of Congress online catalog, the US National Agricultural Library online catalog, and the Dictionary Catalog of the National Agricultural Library, 1862-1965, were used to determine current library holdings of materials published by veterinary schools that are no longer in existence and veterinary associations that are defunct, veterinary supply catalogs, veterinary house organs, patent medicine publications, and veterinary advertisements. Individual library catalogs were also consulted. In addition, the practice of removing advertisements from bound volumes was examined. Results: There are many gaps in the cataloged library holdings of primary source materials relating to the history of the education of veterinarians in the United States. Conclusions: A proactive action plan needs to be designed and activated to locate, catalog, and preserve this primary source material of veterinary medicine for posterity. [ABSTRACT FROM AUTHOR]

Objective: This paper presents the methods and results of a study designed to produce the third edition of the "Basic List of Veterinary Medical Serials," which was established by the Veterinary Medical Libraries Section in 1976 and last updated in 1986. Methods: A set of 238 titles were evaluated using a decision matrix in order to systematically assign points for both objective and subjective criteria and determine an overall score for each journal. Criteria included: coverage in four major indexes, scholarly impact rank as tracked in two sources, identification as a recommended journal in preparing for specialty board examinations, and a veterinary librarian survey rating. Results: Of the 238 titles considered, a minimum scoring threshold determined the 123 (52%) journals that constituted the final list. The 36 subject categories represented on the list include general and specialty disciplines in veterinary medicine. A ranked list of journals and a list by subject category were produced. Conclusion: Serials appearing on the third edition of the "Basic List of Veterinary Medical Serials" met expanded objective measures of quality and impact as well as subjective perceptions of value by both librarians and veterinary practitioners. [ABSTRACT FROM AUTHOR]

New clinical and employment information, together with over-looked previously published information, on a patient (H.C.) is reviewed. H.C., who died at the age of 76 in 1939, was found, by chance during anatomical dissection, to lack a cerebellum. This synthesis challenges an unusual and interesting account of cerebellar agenesis published in Brain in 1994 by Glickstein (see also Glickstein, 2006), in which the allegedly ‘bogus’ oral history of this individual's motor skills was held to have led to ‘medical myth making’. Part of the burden of the 1994 paper was to show that ‘cerebellar agenesis is always associated with profound motor deficits’. Glickstein therefore focussed on an apparent ‘exception’ to this conclusion, concerning the brain of a single case, H.C., who died 70 years ago, who ‘had given rise to an oral tradition alleging that normal movement is possible despite total cerebellar agenesis’. Glickstein (1994) concludes ‘despite an oral tradition to the contrary there is absolutely no evidence about the motor capacities of this man during his life’. Rather remarkably, an extensive history of this individual has become available, its significance becoming noted only this year; this complements and adds to a previous brief history published on H.C. (and not mentioned in the 1994 paper; see below). The new evidence includes the death certificate stating the man's occupation to have been ‘manual labourer’ with all the implications relevant to his supposed incapacity. The written historical record thus confronts the alleged ‘myth’. It is interesting to note how medical records on an undoubtedly very ordinary citizen were recorded in London in the 1930s (before the NHS was set up in 1949) and how they could be made accessible to clinical colleagues in east London in the middle of World War II blitz bombing of the capital. [ABSTRACT FROM PUBLISHER]

Schwannomatosis is a third major form of neurofibromatosis that has recently been linked to mutations in the SMARCB1 ( hSnf5/ INI1) tumor suppressor gene. We analyzed the coding region of SMARCB1 by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) in genomic DNA from 19 schwannomatosis kindreds. Microsatellite markers in the SMARCB1 region were developed to determine loss of heterozygosity (LOH) in associated tumors. We detected four alterations in conserved splice acceptor or donor sequences of exons 3, 4 and 6. Two alterations that likely affect splicing were seen in introns 4 and 5. An additional four alterations of unclear pathogenicity were found to segregate on the affected allele in eight families including two non-conservative missense alterations in three families. No constitutional deletions or duplications were detected by MLPA. Nine of 13 tumors examined showed partial LOH of the SMARCB1 region consistent with ‘second hits.’ Alterations were detected in tumors both with and without somatic NF2 gene changes. These findings support the hypothesis that SMARCB1 is a tumor suppressor for schwannomas in the context of familial disease. Further work is needed to determine its role in other multiple and single tumor syndromes. [ABSTRACT FROM AUTHOR]

The hallmark of epithelial cells is their functional polarization. It is those membrane proteins that are distributed differentially, either to the apical or to the basal surface, that determine epithelial physiology. Such proteins will include ‘pumps’, ‘channels’ and ‘carriers’, and it is the functional interplay between the actions of these molecules that allows the specific properties of the epithelium to emerge. Epithelial properties will additionally depend on: (a) the extent to which there may be a route between adjacent cells (the ‘paracellular’ route); and (b) the folding of the epithelium (as, for example, in the loop of Henle). As for other transporters, there is polarized distribution of amino-acid carriers; the molecular basis of these is of considerable current interest with regard to function, including ‘inborn errors’ (amino-acidurias); some of these transporters have additional functions, such as in the regulation of cell fusion, in modulating cell adherence and in activating intracellular signalling pathways. Collaboration of physiologists with fly geneticists has generated new insights into epithelial function. One example is the finding that certain amino-acid transporters may act as ‘transceptors’ and play a role as sensors of the extracellular environment that then regulate intracellular pathways controlling cell growth. [ABSTRACT FROM AUTHOR]

This article shows a practical application for Distributed Coordination framework for Project Schedule Changes (DCPSC) wherein a project can be rescheduled dynamically through negotiations by all of the concerned project participants. This article presents the design and implementation of a multi-agent system called Distributed Subcontractor Agent System (DSAS), which consists of multiple subcontractor agents, multiple Graphic User Interfaces (GUIs), and an Agent Message Router. In the DSAS, subcontractors interact with their software agents to evaluate the impact of changes, simulate decisions, and get the negotiation results that they need to reschedule the project. This also presents the design and results of DSAS charrette tests, which demonstrated that DSAS produces the lower-cost results faster than manual centralized processes. DSAS can be useful for other domains, such as Mechanical, Electrical, and Plumbing (MEP) coordination and workspace management, if the appropriate agents are designed. [ABSTRACT FROM AUTHOR]

Change is ubiquitous in construction project schedules and there are many interrelationships and interdependencies in project schedule changes. Therefore, a schedule change in the work of a subcontractor might affect schedules of other subcontractors, as well as the project deadline. The subcontractor should resolve schedule conflicts with other affected subcontractors. This implies that there is a need for a methodology for the distributed coordination of project schedule changes (DCPSC). This paper presents a novel agent-based compensatory negotiation methodology to facilitate the DCPSC wherein a project can be rescheduled dynamically through negotiations by all of the concerned subcontractors. The methodology consists of a compensatory negotiation strategy based on utility of timing, multilinked negotiation protocols, and message-handling mechanisms. A simple case example illustrates the methodology. The methodology makes new contributions in both theoretical and practical areas. In practice, this methodology will improve project network schedules, by lowering the sum of the cost of the subcontractors associated with their resource constraints. In theory, the methodology provides a distributed coordination methodology that can improve interaction and collaboration among agents and people. [ABSTRACT FROM AUTHOR]

Presents the Uniclass construction information classification system developed by the International Standards Organization. Analysis of practical adaptability of Uniclass compared to the Construction Index/Samarbetskommitten for Byggnadsfragor; Methods for improving adaptability to civil engineering works.

Presents information on a study which suggests a tentative construction information classification system (CICS) for civil engineering projects. Components of the CICS system; Identification of information classification systems which engineers can utilize; Benefits of quantity surveying; Examination of the notation system in CICS.

This article describes a unified system architecture for representation and reasoning in a concurrent, collaborative architectural/engineering/construction (AEC) environment. The architecture is built on a formal unified modeling methodology for products and processes based on parametrics techniques. The architecture forms the core of a domain-independent shell that could be used for incremental knowledge integration. The integrated knowledge base could be used at any point of inference to propagate changes in data values or knowledge items using parameter-dependency networks. The article concentrates on the representation standards of the core elements of the collaborative architecture. It starts by describing the needs set by the nature of project organization in the AEC industry as well as the research philosophy. The article briefly illustrates the generic parametric representation and inference foundation, including the role of exogenous variables in domain knowledge control. The article concentrates on the standards of object-oriented representation that form the core of domain modeling and knowledge integration. The representation covers various tasks such as context knowledge control for version management, knowledge integration with other systems, and efficient propagation control. The article shows that the careful use of domain knowledge in modeling the problem and controlling inference through exogenous variables provides guidelines toward creating sound standards for representation. [ABSTRACT FROM AUTHOR]

Examines an information classification system in construction management, which is related to specifications, bills of quantities, network analysis and cost estimating. What is provided by a construction information classification system (CICS); Adaptability of the information classification system.

Midcareer reflections based on work combining computers and construction leave an appreciation for the rapid progress that has taken place in both fields in recent decades. Computers have brought many benefits in helping the industry to meet increasingly complex challenges, but as automation becomes pervasive, greater attention must be focused on the social and economic impacts on construction people. Construction education and research have also become much more computer-oriented, but it may be time to take stock of evolving curriculums and more systematically consider what should be done to meet future industry needs. In general, construction has a strong cadre of young researchers who have become well-grounded in advanced computer technologies and are in a position to continue bringing its benefits to construction practice in the future, but they must stay attuned to the needs of industry. [ABSTRACT FROM AUTHOR]

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson‐plus and the UK National PSP Research Network (PROSPECT‐MR). Resting‐state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large‐scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between‐network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five‐fold cross‐validation. In PSP and CBS, between‐network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between‐network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics. [ABSTRACT FROM AUTHOR]

Multimorbidity, the simultaneous presence of multiple health conditions in an individual, is an increasingly common phenomenon globally. The systematic assessment of the quality of care delivered to people with multimorbidity will be key to informing the organization of services for meeting their complex needs. Yet, current assessments tend to focus on single conditions and do not capture the complex processes that are required for providing care for people with multimorbidity. We conducted a scoping review on quality of care and multimorbidity in selected databases in June 2018 and identified 87 documents as eligible for review, predominantly original research and reviews from North America, Europe and Australasia and mostly frequently related to primary care settings. We synthesized data qualitatively in terms of perceived challenges, evidence and proposed metrics. Findings reveal that the association between quality of care and multimorbidity is complex and depends on the conditions involved (quality appears to be higher for those with concordant conditions, and lower in the presence of discordant conditions) and the approach used for measuring quality (quality appears to be higher in people with multimorbidity when measured using condition/drug-specific process or intermediate outcome indicators, and worse when using patient-centred reports of experiences of care). People with discordant multimorbidity may be disadvantaged by current approaches to quality assessment, particularly when they are linked to financial incentives. A better understanding of models of care that best meet the needs of this group is needed for developing appropriate quality assessment frameworks. Capturing patient preferences and values and incorporate patients' voices in the form of patient-reported experiences and outcomes of care will be critical towards the achievement of high-performing health systems that are responsive to the needs of people with multimorbidity. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article which discusses the identity analysis of schwannomatosis, form of neurofibromatosis, with changes of SMARCBI tumor suppressor gene.

Objective:We studied the annual change in measures of motor, oculomotor and cognitive function in progressive supranuclear palsy. This had twin objectives, to assess the potential for clinical parameters to monitor disease progression in clinical trials and to illuminate the progression of pathophysiology. Methods:Twenty three patients with progressive supranuclear palsy (Richardson’s syndrome) were compared to 22 matched controls at baseline and 16 of these patients compared at baseline and one year using: the progressive supranuclear palsy rating scale; the unified Parkinson’s disease rating scale; the revised Addenbrooke’s cognitive examination; the frontal assessment battery; the cubes section of the visual object and space perception battery; the Hayling and Brixton executive tests; and saccadic latencies. Results:Patients were significantly impaired in all domains at baseline. However, cognitive performance was maintained over a year on the majority of tests. The unified Parkinson’s disease rating scale, saccadic latency and progressive supranuclear palsy rating scale deteriorated over a year, with the latter showing the largest change. Power estimates indicate that using the progressive supranuclear palsy rating scale as an outcome measure in a clinical trial would require 45 patients per arm, to identify a 50% reduction in rate of decline with 80% power. Conclusions:Motor, oculomotor and cognitive domains deteriorate at different rates in progressive supranuclear palsy. This may be due to differential degeneration of their respective cortical-subcortical circuits, and has major implications for the selection of outcome measures in clinical trials due to wide variation in sensitivity to annual rates of decline. [ABSTRACT FROM AUTHOR]

Under binaural listening conditions, the detection of target signals within background masking noise is substantially improved when the interaural phase of the target differs from that of the masker. Neural correlates of this binaural masking level difference (BMLD) have been observed in the inferior colliculus and temporal cortex, but it is not known whether degeneration of the inferior colliculus would result in a reduction of the BMLD in humans. We used magnetoencephalography to examine the BMLD in 13 healthy adults and 13 patients with progressive supranuclear palsy (PSP). PSP is associated with severe atrophy of the upper brain stem, including the inferior colliculus, confirmed by voxel-based morphometry of structural MRI. Stimuli comprised inphase sinusoidal tones presented to both ears at three levels (high, medium, and low) masked by in-phase noise, which rendered the low-level tone inaudible. Critically, the BMLD was measured using a low-level tone presented in opposite phase across ears, making it audible against the noise. The cortical waveforms from bilateral auditory sources revealed significantly larger N1m peaks for the out-of-phase low-level tone compared with the in-phase low-level tone, for both groups, indicating preservation of early cortical correlates of the BMLD in PSP. In PSP a significant delay was observed in the onset of the N1m deflection and the amplitude of the P2m was reduced, but these differences were not restricted to the BMLD condition. The results demonstrate that although PSP causes subtle auditory deficits, binaural processing can survive the presence of significant damage to the upper brain stem. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of an intervention comprising (1) a practice-based care coordination program, (2) augmented by pay for performance (P4P) for meeting quality targets, and (3) complemented by a third-party disease management on quality of care and resource use for older adults with diabetes.Data Sources/study Setting: Claims files of a managed care organization (MCO) for 20,943 adults aged 65 and older with diabetes receiving care in Alabama, Tennessee, or Texas, from January 2004 to March 2007.Study Design: A quasi-experimental, longitudinal study in which pre- and postdata from 1,587 patients in nine intervention primary care practices were evaluated against 19,356 patients in MCO comparison practices (>900). Five incentivized quality measures, two nonincentivized measures, and two resource-use measures were investigated. We examined trends and changes in trends from baseline to follow-up, contrasting intervention and comparison group member results.Principal Findings: Quality of care generally improved for both groups during the study period. Only slight differences were seen between the intervention and comparison group trends and changes in trends over time.Conclusions: This study did not generate evidence supporting a beneficial effect of an on-site care coordination intervention augmented by P4P and complemented by third-party disease management on diabetes quality or resource use. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effects of 60-min bouts of intermittent moderate and vigorous exercise on postprandial plasma triacylglycerol (TAG) metabolism in eight healthy adolescent boys (mean +/- SD age: 13 +/- 0.3 yr). Methods: Participants completed three conditions in a counterbalanced order. On day 1, they either rested for 110 min (CON), completed 6 x 10-min blocks of intermittent treadmill exercise at 53% peak V[spacing dot above]O2 (MOD), or 6 x 10-min blocks at 75% peak V[spacing dot above]O2 (VIG). On day 2 after a 12-h fast, a capillary blood sample was taken for [TAG] and [glucose] (mmol[middle dot]L-1) and then a high-fat milkshake was consumed (1.50 g[middle dot]kg-1 fat, 1.22 g[middle dot]kg-1 CHO, and 0.22 g[middle dot]kg-1 protein; 80 kJ[middle dot]kg-1). Further blood samples were taken every hour for a 6-h postprandial rest period for [TAG] and [glucose]. Results: Estimated energy expenditure was 45% higher in VIG than in MOD (95% confidence interval [CI] 23-72%). Fasting [TAG] and [glucose] did not differ between the conditions. Average [TAG] for the postprandial period was lower by 24% in MOD (95% CI -47% to 9%, P = 0.06) and by 21% in VIG (95% CI -42% to 8%, P = 0.08) than CON, with no meaningful difference (4%; 95% CI -27% to 48%, P = 0.50) between MOD and VIG. The total area under the [TAG] versus time curve (mmol[middle dot]L-1 6 h) was lower by 24% in MOD (95% CI -42% to 0%, P = 0.05) and by 20% in VIG (95% CI -37% to 0%, P = 0.07) than CON. MOD and VIG were not different from each other (4%; 95% CI -18% to 32%, P = 0.54). Conclusion: Both 60 min of moderate and vigorous intermittent exercises reduced postprandial [TAG]. However, the extra energy expended in the vigorous condition did not produce a dose-related reduction compared with the moderate-intensity condition. [ABSTRACT FROM AUTHOR]

Growth in normal and tumour cells is regulated by evolutionarily conserved extracellular inputs from the endocrine insulin receptor (InR) signalling pathway and by local nutrients. Both signals modulate activity of the intracellular TOR kinase, with nutrients at least partly acting through changes in intracellular amino acid levels mediated by amino acid transporters. We show that in Drosophila, two molecules related to mammalian proton-assisted SLC36 amino acid transporters (PATs), CG3424 and CG1139, are potent mediators of growth. These transporters genetically interact with TOR and other InR signalling components, indicating that they control growth by directly or indirectly modulating the effects of TOR signalling. A mutation in the CG3424 gene, which we have named pathetic (path), reduces growth in the fly. In a heterologous Xenopus oocyte system, PATH also activates the TOR target S6 kinase in an amino acid-dependent way. However, functional analysis reveals that PATH has an extremely low capacity and an exceptionally high affinity compared with characterised human PATs and the CG1139 transporter. PATH and potentially other PAT-related transporters must therefore control growth via a mechanism that does not require bulk transport of amino acids into the cell. As PATH is likely to be saturated in vivo, we propose that one specialised function of high-affinity PAT-related molecules is to maintain growth as local nutrient levels fluctuate during development. [ABSTRACT FROM AUTHOR]

Background: Most individuals with dementia or mild cognitive impairment (MCI) have multiple chronic conditions (MCC). The combination leads to multiple medications and complex medication regimens and is associated with increased risk for significant treatment burden, adverse drug events, cognitive changes, hospitalization, and mortality. Optimizing medications through deprescribing (the process of reducing or stopping the use of inappropriate medications or medications unlikely to be beneficial) may improve outcomes for MCC patients with dementia or MCI.Methods: With input from patients, family members, and clinicians, we developed and piloted a patient-centered, pragmatic intervention (OPTIMIZE) to educate and activate patients, family members, and primary care clinicians about deprescribing as part of optimal medication management for older adults with dementia or MCI and MCC. The clinic-based intervention targets patients on 5 or more medications, their family members, and their primary care clinicians using a pragmatic, cluster-randomized design at Kaiser Permanente Colorado. The intervention has two components: a patient/ family component focused on education and activation about the potential value of deprescribing, and a clinician component focused on increasing clinician awareness about options and processes for deprescribing. Primary outcomes are total number of chronic medications and total number of potentially inappropriate medications (PIMs). We estimate that approximately 2400 patients across 9 clinics will receive the intervention. A comparable number of patients from 9 other clinics will serve as wait-list controls. We have > 80% power to detect an average decrease of - 0.70 (< 1 medication). Secondary outcomes include the number of PIM starts, dose reductions for selected PIMs (benzodiazepines, opiates, and antipsychotics), rates of adverse drug events (falls, hemorrhagic events, and hypoglycemic events), ability to perform activities of daily living, and skilled nursing facility, hospital, and emergency department admissions.Discussion: The OPTIMIZE trial will examine whether a primary care-based, patient- and family-centered intervention educating patients, family members, and clinicians about deprescribing reduces numbers of chronic medications and PIMs for older adults with dementia or MCI and MCC.Trial Registration: NCT03984396. Registered on 13 June 2019. [ABSTRACT FROM AUTHOR]

The phosphoinositide3-kinase (PI3K)/Akt and downstream mammalian target of rapamycin complex 1 (mTORC1) signalling cascades promote normal growth and are frequently hyperactivated in tumour cells. mTORC1 is also regulated by local nutrients, particularly amino acids, but the mechanisms involved are poorly understood. Unexpectedly, members of the proton-assisted amino-acid transporter (PAT or SLC36) family emerged from in vivo genetic screens in Drosophila as transporters with uniquely potent effects on mTORC1-mediated growth. In this study, we show the two human PATs that are widely expressed in normal tissues and cancer cell lines, namely PAT1 and PAT4, behave similarly to fly PATs when expressed in Drosophila. Small interfering RNA knockdown shows that these molecules are required for the activation of mTORC1 targets and for proliferation in human MCF-7 breast cancer and HEK-293 embryonic kidney cell lines. Furthermore, activation of mTORC1 in starved HEK-293 cells stimulated by amino acids requires PAT1 and PAT4, and is elevated in PAT1-overexpressing cells. Importantly, in HEK-293 cells, PAT1 is highly concentrated in intracellular compartments, including endosomes, wherein mTOR shuttles upon amino-acid stimulation. Therefore our data are consistent with a model in which PATs modulate the activity of mTORC1 not by transporting amino acids into the cell but by modulating the intracellular response to amino acids. [ABSTRACT FROM AUTHOR]

The effect of 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) activation of the AMP-activated protein kinase (AMPK) on the transport of the model radiolabeled dipeptide [³H]-D-Phe-L-Gln was investigated in the human epithelial colon cancer cell line Caco-2. Uptake and transepithelial fluxes of [³H]-D-Phe-L-Gln were carried out in differentiated Caco-2 cell monolayers, and hPepT1 and glucose transporter 2 (GLUT2) protein levels were quantified by immunogold electron microscopy. AICAR treatment of Caco-2 cells significantly inhibited apical [³H]-D-Phe-L-Gln uptake, matched by a decrease in brush-border membrane hPepT1 protein but with a concomitant increase in the facilitated glucose transporter GLUT2. A restructuring of the apical brush-border membrane was seen by electron microscopy. The hPepT1-mediated transepithelial (A-to-B) peptide flux across the Caco-2 monolayers showed no significant alteration in AICAR-treated cells. The electrical resistance in the AICAR-treated monolayers was significantly higher compared with control cells. Inhibition of the sodium/hydrogen exchanger 3 (NHE3) had an additive effect to AICAR, suggesting that the AMPK effect is not via NHE3. Fluorescence measurement of intracellular pH showed no reduction in the proton gradient driving PepT1-mediated apical uptake. The reduction in apical hPepT1 protein and dipeptide uptake after AICAR treatment in Caco-2 cells demonstrates a regulatory effect of AMPK on hPepT1, along with an influence on both the microvilli and tight junction structures. The absence of an associated reduction in transepithelial peptide movement implies an additional stimulatory effect of AICAR on the basolateral peptide transport system in these cells. These results provide a link between the hPepT1 transporter and the metabolic state of this model enterocyte. [ABSTRACT FROM AUTHOR]

CD98 heavy chain (CD98hc), expressed at high levels in developing human trophoblasts, is an integral membrane protein with multiple N-linked glycosylation sites and known to be important for cell fusion, adhesion, and amino acid transport. Western blotting and flow cytometry were used to study the effect of brefeldin A, an inhibitor of protein translocation through the Golgi, on CD98hc in the human placental trophoblast cell line BeWo. Although brefeldin A treatment caused increased cell surface expression of CD98hc, a novel partially glycosylated form of the protein was found and, concomitantly, cell fusion was reduced. Western blotting showed that CD98 and galectin 3, a proposed ligand for the glycosylated extracellular domain of CD98hc, co-immunoprecipitated, and double-label immuno-electron microscopy confirmed that CD98hc associated with galectin 3. Furthermore, cell fusion was reduced (specifically) by the disaccharide lactose, a known ligand for the carbohydrate recognition domain of galectin 3, suggesting that the association was functional. Taken together, the data suggest that N-glycosylation of CD98 and subsequent interaction with galectin 3 is critical for aspects of placental cell biology, and provides a rationale for the observation that, in the mouse, truncation of the CD98hc extracellular domain leads to early embryonic lethality [Tsumura H, Suzuki N, Saito H, Kawano M, Otake S, Kozuka Y, Komada H, Tsurudome M & Ito Y (2003) Biochem Biophys Res Commun 308, 847–851]. [ABSTRACT FROM AUTHOR]

The technical advancement of earthmoving equipment during the 20th century includes many improvements in key parts of machines. This paper uses five systems that make up earthmoving equipment (implement, traction, structure, power train, and control and information) to analyze this technical advancement. The analysis of each system includes its purpose and operation, technical limitations and key technologies, and a chronology of major advancements. The findings are the benefits of using the five systems for analysis of technical change, the sequence and timing of key technical advances in each system, the fundamental technologies that fostered these advances, and the integration of systems into balanced equipment designs. This increased understanding from this analysis results in significant implications and relevance for civil designers working on integrated teams, contractors selecting methods and planning operations, equipment suppliers developing new machines, construction educators teaching the technical basics of equipment, and researchers developing advanced modeling and simulation tools. [ABSTRACT FROM AUTHOR]

Two-electrode voltage-clamp electrophysiology has been used to study the actions of two amyloid peptides (Aβ1–42, Aβ1–40) on α7, α4β2 and α3β4 recombinant human neuronal nicotinic acetylcholine receptors (nicotinic AChRs), heterologously expressed in Xenopus laevis oocytes.The application of Aβ1–42 or Aβ1–40 (1 pM–100 nM) for 5 s does not directly activate expressed human α7, α4β2 or α3β4 nicotinic AChRs.Aβ1–42 and Aβ1–40 are antagonists of α7 nicotinic AChRs. For example, 10 nM Aβ1–42 and Aβ1–40 both reduced the peak amplitude of currents recorded (3 mM ACh) to 48±5 and 45±10% (respectively) of control currents recorded in the absence of peptide. In both the cases the effect is sustained throughout a 30 min peptide application and is poorly reversible.Aβ1–42 and Aβ1–40 (10 nM) enhance currents recorded in response to ACh (3 mM) from oocytes expressing α4β2 nicotinic AChRs by 195±40 and 195±41% respectively. This effect is transient, reaching a peak after 3 min and returning to control values after a 24 min application of 10 nM Aβ1–42. We observe an enhancement of 157±22% of control ACh-evoked current amplitude in response to 100 nM Aβ1–42 recorded from oocytes expressing α4β2 nicotinic AChRs.Aβ1–42 and Aβ1–40 (10 nM) were without antagonist actions on the responses of α3β4 nicotinic AChRs to ACh (1 nM–3 mM).British Journal of Pharmacology (2005) 146, 964–971. doi:10.1038/sj.bjp.0706403; published online 26 September 2005 [ABSTRACT FROM AUTHOR]

The binding affinities of a number of amino-acid and peptide derivatives by the mammalian intestinal peptide transporter PepT1 were investigated, using the Xenopus laevis expression system. A series of blocked amino acids, namely N-acetyl-Phe (Ac-Phe), phe-amide (Phe-NH2), N-acetyl-Phe-amide (Ac-Phe-NH2) and the parent compound Phe, was compared for efficacy in inhibiting the uptake of the peptide [3H]-d-Phe-l-Gln. In an equivalent set of experiments, the blocked peptides Ac-Phe-Tyr, Phe-Tyr-NH2 and Ac-Phe-Tyr-NH2 were compared with the parent compound Phe-Tyr. Comparing amino acids and derivatives, only Ac-Phe was an effective inhibitor of peptide uptake (Ki = 1.81 ± 0.37 mm). Ac-Phe-NH2 had a very weak interaction with PepT1 (Ki = 16.8 ± 5.64 mm); neither Phe nor Phe-NH2 interacted with PepT1 with measurable affinity. With the dipeptide and derivatives, unsurprisingly the highest affinity interaction was with Phe-Tyr (Ki = 0.10 ± 0.04 mm). The blocked C-terminal peptide Phe-Tyr-NH2 also interacted with PepT1 with a relatively high affinity (Ki = 0.94 ± 0.38 mm). Both Ac-Phe-Tyr and Ac-Phe-Tyr-NH2 interacted weakly with PepT1 (Ki = 8.41 ± 0.11 and 9.97 ± 4.01 mm, respectively). The results suggest that the N-terminus is the primary binding site for both dipeptides and tripeptides. Additional experiments with four stereoisomers of Ala-Ala-Ala support this conclusion, and lead us to propose that a histidine residue is involved in binding the C-terminus of dipeptides. In addition, a substrate binding model for PepT1 is proposed. [ABSTRACT FROM AUTHOR]