Role of prohormone convertases in pro-neuropeptide Y processing: coexpression and in vitro kinetic investigations.

Proneuropeptide Y (ProNPY) undergoes cleavage at a single dibasic site Lys38-Arg39 resulting in the formation of 1-39 amino acid NPY which is further processed successively by carboxypeptidase-like and peptidylglycine alpha-amidating monooxygenase enzymes. To investigate whether prohormone convertases are involved in ProNPY processing, a vaccinia virus derived expression system was used to coexpress recombinant ProNPY with each of the prohormone convertases PC1/3, PC2, furin, and PACE4 in Neuro2A and NIH 3T3 cell lines as regulated neuroendocrine and constitutive prototype cell lines, respectively. The analysis of processed products shows that only PC1/3 generates NPY in NIH 3T3 cells while both PC1/3 and PC2 are able to generate NPY in Neuro2A cells. The convertases furin and PACE4 are unable to process ProNPY in either cell line. Moreover, comparative in vitro cleavage of recombinant NPY precursor by the enzymes PC1/3, PC2 and furin shows that only PC1/3 and PC2 are involved in specific cleavage of the dibasic site. Kinetic studies demonstrate that PC1/3 cleaves ProNPY more efficiently than PC2. The main difference between the cleavage efficiency is observed in the Vmax values whereas no major difference is observed in Km values. In addition the cleavage by PC1/3 and PC2 of two peptides reproducing the dibasic cleavage site with different amino acid sequence lengths namely (20-49)-ProNPY and (28-43)-ProNPY was studied. These shortened ProNPY substrates, when recognized by the enzymes, are more efficiently cleaved than ProNPY itself. The shortest peptide is not cleaved by PC2 while it is by PC1/3. On the basis of these observations it is proposed, first, that the constitutive secreted NPY does not result from the cleavage carried out by ubiquitously expressed enzymes furin and PACE4; second, that PC1/3 and PC2 are not equipotent in the cleavage of ProNPY; and third, substrate peptide length might discriminate PC1/3 and PC2 processing activity.

Estimating Design-Flood Discharges for Streams in Iowa Using Drainage-Basin and Channel-Geometry Characteristics, HR-322, 1993

Drainage-basin and channel-geometry multiple-regression equations are presented for estimating design-flood discharges having recurrence intervals of 2, 5, 10, 25, 50, and 100 years at stream sites on rural, unregulated streams in Iowa. Design-flood discharge estimates determined by Pearson Type-III analyses using data collected through the 1990 water year are reported for the 188 streamflow-gaging stations used in either the drainage-basin or channel-geometry regression analyses. Ordinary least-squares multiple-regression techniques were used to identify selected drainage-basin and channel-geometry regions. Weighted least-squares multiple-regression techniques, which account for differences in the variance of flows at different gaging stations and for variable lengths in station records, were used to estimate the regression parameters. Statewide drainage-basin equations were developed from analyses of 164 streamflow-gaging stations. Drainage-basin characteristics were quantified using a geographic-information-system (GIS) procedure to process topographic maps and digital cartographic data. The significant characteristics identified for the drainage-basin equations included contributing drainage area, relative relief, drainage frequency, and 2-year, 24-hour precipitation intensity. The average standard errors of prediction for the drainage-basin equations ranged from 38.6% to 50.2%. The GIS procedure expanded the capability to quantitatively relate drainage-basin characteristics to the magnitude and frequency of floods for stream sites in Iowa and provides a flood-estimation method that is independent of hydrologic regionalization. Statewide and regional channel-geometry regression equations were developed from analyses of 157 streamflow-gaging stations. Channel-geometry characteristics were measured on site and on topographic maps. Statewide and regional channel-geometry regression equations that are dependent on whether a stream has been channelized were developed on the basis of bankfull and active-channel characteristics. The significant channel-geometry characteristics identified for the statewide and regional regression equations included bankfull width and bankfull depth for natural channels unaffected by channelization, and active-channel width for stabilized channels affected by channelization. The average standard errors of prediction ranged from 41.0% to 68.4% for the statewide channel-geometry equations and from 30.3% to 70.0% for the regional channel-geometry equations. Procedures provided for applying the drainage-basin and channel-geometry regression equations depend on whether the design-flood discharge estimate is for a site on an ungaged stream, an ungaged site on a gaged stream, or a gaged site. When both a drainage-basin and a channel-geometry regression-equation estimate are available for a stream site, a procedure is presented for determining a weighted average of the two flood estimates.

Alternative Flexible Overlays, HR-229, 1988

The objective of this project was to determine if any of several cutback and emulsified asphalt plant mixed and road mixed overlays had the ability to resist thermal cracking at low temperatures without inducing shoving and/or ruttinq at high temperatures. A 2.6 mile section of Osceola County road A-34 and a 7.0 mile section of A-46 were divided into 14 test sections of various lengths. After six years, results show an MC-3000 asphalt cutback cold mix can reduce the amount of reflective cracking when compared to an AC-5 hot mix. This can be done without inducing high temperature related problems. Cold road mixing can be effective in reducing cracking on low volume roads. However, more experience is required if the full benefits of road mixing are to be realized.

Composite Precast Prestressed Concrete Bridge Slabs, HR-310, 1991

Precast prestressed concrete panels have been used as subdecks in bridge construction in Iowa and other states. To investigate the performance of these types of composite slabs at locations adjacent to abutment and pier diaphragms in skewed bridges, a research prcject which involved surveys of design agencies and precast producers, field inspections of existing bridges, analytical studies, and experimental testing was conducted. The survey results from the design agencies and panel producers showed that standardization of precast panel construction would be desirable, that additional inspections at the precast plant and at the bridge site would be beneficial, and that some form of economical study should be undertaken to determine actual cost savings associated with composite slab construction. Three bridges in Hardin County, Iowa were inspected to observe general geometric relationships, construction details, and to note the visual condition of the bridges. Hairline cracks beneath several of the prestressing strands in many of the precast panels were observed, and a slight discoloration of the concrete was seen beneath most of the strands. Also, some rust staining was visible at isolated locations on several panels. Based on the findings of these inspections, future inspections are recommended to monitor the condition of these and other bridges constructed with precast panel subdecks. Five full-scale composite slab specimens were constructed in the Structural Engineering Laboratory at Iowa State University. One specimen modeled bridge deck conditions which are not adjacent to abutment or pier diaphragms, and the other four specimens represented the geometric conditions which occur for skewed diaphragms of 0, 15, 30, and 40 degrees. The specimens were subjected to wheel loads of service and factored level magnitudes at many locations on the slab surface and to concentrated loads which produced failure of the composite slab. The measured slab deflections and bending strains at both service and factored load levels compared reasonably well with the results predicted by simplified Finite element analyses of the specimens. To analytically evaluate the nominal strength for a composite slab specimen, yield-line and punching shear theories were applied. Yield-line limit loads were computed using the crack patterns generated during an ultimate strength test. In most cases, these analyses indicated that the failure mode was not flexural. Since the punching shear limit loads in most instances were close to the failure loads, and since the failure surfaces immediately adjacent to the wheel load footprint appeared to be a truncated prism shape, the probable failure mode for all of the specimens was punching shear. The development lengths for the prestressing strands in the rectangular and trapezoidal shaped panels was qualitatively investigated by monitoring strand slippage at the ends of selected prestressing strands. The initial strand transfer length was established experimentally by monitoring concrete strains during strand detensioning, and this length was verified analytically by a finite element analysis. Even though the computed strand embedment lengths in the panels were not sufficient to fully develop the ultimate strand stress, sufficient stab strength existed. Composite behavior for the slab specimens was evaluated by monitoring slippage between a panel and the topping slab and by computation of the difference in the flexural strains between the top of the precast panel and the underside of the topping slab at various locations. Prior to the failure of a composite slab specimen, a localized loss of composite behavior was detected. The static load strength performance of the composite slab specimens significantly exceeded the design load requirements. Even with skew angles of up to 40 degrees, the nominal strength of the slabs did not appear to be affected when the ultimate strength test load was positioned on the portion of each slab containing the trapezoidal-shaped panel. At service and factored level loads, the joint between precast panels did not appear to influence the load distribution along the length of the specimens. Based on the static load strength of the composite slab specimens, the continued use of precast panels as subdecks in bridge deck construction is recommended.

Geostatistical inversion of seismic and GPR reflection images: what can we actually resolve?

Estimation of the spatial statistics of subsurface velocity heterogeneity from surface-based geophysical reflection survey data is a problem of significant interest in seismic and ground-penetrating radar (GPR) research. A method to effectively address this problem has been recently presented, but our knowledge regarding the resolution of the estimated parameters is still inadequate. Here we examine this issue using an analytical approach that is based on the realistic assumption that the subsurface velocity structure can be characterized as a band-limited scale-invariant medium. Our work importantly confirms recent numerical findings that the inversion of seismic or GPR reflection data for the geostatistical properties of the probed subsurface region is sensitive to the aspect ratio of the velocity heterogeneity and to the decay of its power spectrum, but not to the individual values of the horizontal and vertical correlation lengths.

Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial.

BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820).

Evaluation of Experimental Data Obtained from Lightweight Aggregate Bridge Girders, HR-104, 1968

The use of lightweight aggregates in prestressed concrete is becoming more of a reality as our design criteria become more demanding. Bridge girders of greater lengths have been restricted from travel on many of our highways because the weight of the combined girders and transporting vehicle is excessive making hauls of any distance prohibitive. This, along with new safety recommendations, prompted the State of Iowa to investigate the use of lightweight aggregate bridge girders. A series of three projects was started to investigate the possibility of using lightweight aggregate in prestressed concrete. The object of this project is to study the effect which lightweight aggregate concrete has on the camber of bridge girders when used in a field situation.

Field Observation of Five Lightweight Aggregate Pretensioned Prestressed Bridge Beams, HR-104, 1969

The use of lightweight aggregates in pretensioned prestressed concrete beams is becoming more advantageous as our design criteria dictate longer span concrete bridges. Bridge beams of greater lengths have been restricted from travel on many of our highways because the weight of the combined beams and transporting vehicle was excessive, making hauls of any distance prohibitive. This, along with the fact that new safety requirements necessitate the use of longer spans in grade separation structures over major highways, prompted the State of Iowa to investigate the use of lightweight aggregate bridge beams. The objective of this project is the collection of field deflection measurements for five pretensioned prestressed lightweight aggregate concrete bridge beams fabricated by conventional plant processes; also the comparison of the actual cambers and deflections of the beams with that predicted from the design assumptions.

Do seismic waves sense fracture connectivity?

A defining characteristic of fractured rocks is their very high level of seismic attenuation, which so far has been assumed to be mainly due to wave-induced fluid flow (WIFF) between the fractures and the pore space of the embedding matrix. Using oscillatory compressibility simulations based on the quasi-static poroelastic equations, we show that another important, and as of yet undocumented, manifestation of WIFF is at play in the presence of fracture connectivity. This additional energy loss is predominantly due to fluid flow within the connected fractures and is sensitive to their lengths, permeabilities, and intersection angles. Correspondingly, it contains key information on the governing hydraulic properties of fractured rock masses and hence should be accounted for whenever realistic seismic models of such media are needed.

Nonlinear Finite Element Study of Piles in Integral Abutment Bridges, HR-227, Part 2, 1982

The highway departments of the states which use integral abutments in bridge design were contacted in order to study the extent of integral abutment use in skewed bridges and to survey the different guidelines used for analysis and design of integral abutments in skewed bridges. The variation in design assumptions and pile orientations among the various states in their approach to the use of integral abutments on skewed bridges is discussed. The problems associated with the treatment of the approach slab, backfill, and pile cap, and the reason for using different pile orientations are summarized in the report. An algorithm based on a state-of-the-art nonlinear finite element procedure previously developed by the authors was modified and used to study the influence of different factors on behavior of piles in integral abutment bridges. An idealized integral abutment was introduced by assuming that the pile is rigidly cast into the pile cap and that the approach slab offers no resistance to lateral thermal expansion. Passive soil and shear resistance of the cap are neglected in design. A 40-foot H pile (HP 10 X 42) in six typical Iowa soils was analyzed for fully restrained pile head and pinned pile head. According to numerical results, the maximum safe length for fully restrained pile head is one-half the maximum safe length for pinned pile head. If the pile head is partially restrained, the maximum safe length will lie between the two limits. The numerical results from an investigation of the effect of predrilled oversized holes indicate that if the length of the predrilled oversized hole is at least 4 feet below the ground, the vertical load-carrying capacity of the H pile is only reduced by 10 percent for 4 inches of lateral displacement in very stiff clay. With no predrilled oversized hole, the pile failed before the 4-inch lateral displacement was reached. Thus, the maximum safe lengths for integral abutment bridges may be increased by predrilling. Four different typical Iowa layered soils were selected and used in this investigation. In certain situations, compacted soil (> 50 blow count in standard penetration tests) is used as fill on top of natural soil. The numerical results showed that the critical conditions will depend on the length of the compacted soil. If the length of the compacted soil exceeds 4 feet, the failure mechanism for the pile is similar to one in a layer of very stiff clay. That is, the vertical load-carrying capacity of the H pile will be greatly reduced as the specified lateral displacement increases.

Kinetics of atrial repolarization alternans in a free-behaving ovine model.

Kinetics of Atrial Repolarization Alternans. INTRODUCTION: Repolarization alternans (Re-ALT), a beat-to-beat alternation in action potential repolarization, promotes dispersion of repolarization, wavebreaks, and reentry. Recently, Re-ALT has been shown to play an important role in the transition from rapid pacing to atrial fibrillation (AF) in humans. The detailed kinetics of atrial Re-ALT, however, has not been reported so far. We developed a chronic free-behaving ovine pacing model to study the kinetics of atrial Re-ALT as a function of pacing rate. METHODS: Thirteen sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms and delivery of rapid pacing protocols. Beat-to-beat differences in the atrial T-wave apex amplitude as a measure of Re-ALT and activation time were analyzed at incremental pacing rates until the effective refractory period (ERP) defined as stable 2:1 capture. RESULTS: Atrial Re-ALT appeared intermittently but without periodicity, and increased in amplitude as a function of pacing rate until ERP. Intermittent 2:1 atrial capture was observed at pacing cycle lengths 40 ms above ERP, and increased in duration as a function of pacing rate. Episodes of rapid pacing-induced AF were rare, and were preceded by Re-ALT or complex oscillations of atrial repolarization, but without intermittent capture. CONCLUSION: We show in vivo that atrial Re-ALT developed and increased in magnitude with rate until stable 2:1 capture. In rare instances where capture failure did not occur, Re-ALT and complex oscillations of repolarization surged and preceded AF initiation. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1003-1012, September 2012).

Objective results at 1 year of a new ultracongruent postero-stabilized total knee arthroplasty

Introduction: A new ultra congruent, postero-stabilized total knee arthroplasty (TKA) with a mobile bearing, the FIRST knee prosthesis (Free Insert in Rotation Stabilized in Translation, Symbios SA), was designed and expected to significantly reduce polyethylene wear, to improve the range of motion and the overall stability of the knee while ensuring a physiological ligament balance. Gait analysis has proven to give really objective outcome parameters after lower limb surgery. The goal of our study was to compare the subjective and really objective results of this new TKA with two other widespread models of TKA. Methods: A clinical prospective monocentric cohort study of 100 consecutive patients (47-88 yrs) undergoing a FIRST TKA for primary osteoarthritis is currently being done. Pre- and post-operative follow-ups (6 weeks, 4 months and 1 year) were done with well-recognized subjective evaluations (EQ-5D and WOMAC scores) and semi-objective questionnaires (KSS score and radiography evaluation) as well as with a really objective evaluation using gait parameters from 6 walking trials, performed at different speeds (slow, normal and fast) with an ambulatory gait analysis system (Physilog®, BioAGM CH). The outcomes of the first 32 new TKA after one year of follow-up were compared to the results after 1 year of a randomized controlled clinical trial comparing 29 NexGen® postero-stabilized TKA (Zimmer Inc) with a fixed bearing and 26 NexGen® TKA with a mobile bearing using the same methods. Results: Subjective and semi-objective results were similar for the three types of TKA. As for the really objective parameters, the gait cycle time of the FIRST TKA was statistically significantly shorter at normal speed of walk, as well as double-support periods, as compared to both standard models. The extension (in terms of range of motion when walking) of the operated knee was significantly improved for all three types of walk in favour of the FIRST TKAs compared to both NexGen TKAs. The normal walking speed was significantly higher with faster swing speed and stride lengths for the new TKA. Significantly better coordination scores were observed at normal walking speed for the FIRST TKA as compared to the fixed-bearing TKAs. Conclusion: The FIRST TKAs showed statistically significantly better objective outcomes in terms of gait after one year of follow-up with similar subjective and semi-objective results in comparison with widespread TKA designs. These encouraging short-terms results will have to be confirmed at a 5 years follow-up of the FIRST TKAs.

Standards for Single Span Prefabricated Bridges, Phase I - Concept Development, TR-663, 2014

In coordination with a Technical Advisory Committee (TAC) consisting of County Engineers and Iowa DOT representatives, the Iowa DOT has proposed to develop a set of standards for a single span prefabricated bridge system for use on the local road system. The purpose of the bridge system is to improve bridge construction, accelerate project delivery, improve worker safety, be cost effective, reduce impacts to the travelling public by reducing traffic disruptions and the duration of detours, and allow local forces to construct the bridges. HDR Inc. was selected by the Iowa DOT to perform the initial concept screening of the bridge system. This Final Report summarizes the initial conceptual effort to investigate potential systems, make recommendations for a preferred system and propose initial details to be tested in the laboratory in Phase 2 of the project. The prefabricated bridge components were to be based on the following preliminary criteria set forth by the TAC. The criteria were to be verified and/ or modified as part of the conceptual development. - 24’ and 30’ roadway widths - Skews of 0o, 15o, and 30o - Span lengths of 30’ – 70’ in 10’ increments using precast concrete beams - Voided box beams could be considered - Limit precast element weight to 45,000 pounds for movement and placement of beams - Beams could be joined transversely with threaded rods - Abutment concepts may included precast as well as an option for cast-in-place abutments with pile foundations In addition to the above criteria, there was an interest to use a single-width prefabricated bridge component to simplify fabrication as well as a desire to utilize non-prestressed concrete systems where possible to allow for precasting of the beam modules by local forces or local precast plants. The SL-1 modular steel bridge rail was identified for use with this single span prefabricated bridge system.

A pathogenic mechanism in Huntington"s disease involves small CAG-repeated RNAs with neurotoxic activity

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches

Modeling Merging Behavior at Lane Drops, InTrans Projects 13-466 and 06-277, 2015

In work-zone configurations where lane drops are present, merging of traffic at the taper presents an operational concern. In addition, as flow through the work zone is reduced, the relative traffic safety of the work zone is also reduced. Improving work-zone flow-through merge points depends on the behavior of individual drivers. By better understanding driver behavior, traffic control plans, work zone policies, and countermeasures can be better targeted to reinforce desirable lane closure merging behavior, leading to both improved safety and work-zone capacity. The researchers collected data for two work-zone scenarios that included lane drops with one scenario on the Interstate and the other on an urban arterial roadway. The researchers then modeled and calibrated these scenarios in VISSIM using real-world speeds, travel times, queue lengths, and merging behaviors (percentage of vehicles merging upstream and near the merge point). Once built and calibrated, the researchers modeled strategies for various countermeasures in the two work zones. The models were then used to test and evaluate how various merging strategies affect safety and operations at the merge areas in these two work zones.