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Idealized models are analyzed to quantify how large‐scale river plumes interact with coastal corners with and without wind‐driven currents. The configuration has a corner formed by two perpendicular shelves (with constant slope) that are joined with a coastal radius of curvature (rc). The buoyant plume originates from an upstream point source. The rc and wind forcing are varied among runs. Steep‐ and gentle‐slope runs are compared for some situations. Without winds, plumes separate from corners with rc smaller than two inertial radii (ri); this threshold is twice the rc < ri theoretical separation criterion. After separation, no‐wind plumes form an anticyclonic bulge, and reattach farther downstream. Offshore excursion increases as rc decreases. A downwelling‐favorable wind component along the upstream coast (τsx) favors separation by increasing total plume speed. An upwelling‐favorable wind component along the downstream coast (τsy) also increases offshore excursion. Winds blowing obliquely offshore with both these wind components advect the plume farther offshore. Wind‐driven currents that steer plumes in this situation include a downshelf jet originating on the upstream shelf and continuing around the coastal corner and beyond, offshore and upshelf surface transport downstream of the corner, and surface Ekman transport on the outer shelf. Multiple linear regressions quantify plume position sensitivity to rc, τsx, and τsy; results are discussed in a dynamical context. Globally, many river plumes interact with coastal corners under various wind conditions. Plain Language Summary: Freshwater from rivers can form long plumes that flow along the coast far from river mouths. When these plumes reach a sharp coastal corner, like the tip of a peninsula, the flow can detach from the coast and carry freshwater far offshore. This study applies a computer model to study river plume behavior at perpendicular coastal corners with and without wind influences. Without winds, plumes separate from the most tightly turning corners, form a bulge, and reattach to the coast farther downstream. Flows forced by winds are important in steering river plumes. Plume waters move farthest offshore when winds blow obliquely away from the coastal corner. Globally, many river plumes interact with coastal corners and wind influence can enhance offshore transport of freshwater in these areas. Key Points: Without winds, plumes separate from corners turning more tightly than two inertial radii, form a bulge, and reattach farther downstreamOffshore plume excursion is maximized when winds blow obliquely away from the coastal cornerWind‐driven flow favoring offshore plume transport includes a downshelf jet and offshore and upshelf transport downstream of the corner [ABSTRACT FROM AUTHOR]

The Connecticut River plume is influenced by energetic ambient tides in the Long Island Sound receiving waters. The objectives of this modeling study are (a) characterizing the spatial heterogeneity of turbulent buoyancy fluxes, (b) partitioning turbulent buoyancy fluxes into bottom‐generated and interfacial shear contributions, and (c) quantifying contributions to plume‐integrated mixing within the tidal plume. The plume formed during ambient flood tides under low river discharge, spring tides, and no winds is analyzed. Turbulent buoyancy fluxes (B) and depth‐integrated B through the plume (Bd) are characterized by pronounced spatial heterogeneity. Strong mixing (Bd ∼ 10−5‐10−4 m3/s3) occurs near the mouth, in the nearfield plume turning region, over shoals, and nearshore shallow areas. Low to moderate mixing (Bd ∼ 10−8‐10−6 m3/s3) occupies half the plume. Buoyancy fluxes are first partitioned based on the depth of the shear stress minimum between plume‐generated and bottom‐generated shear maxima. Four other tested partitioning methods are based on open channel flow and stratified shear flow parameterizations. Interfacial and bottom‐generated shear contribute to different areas of intense and moderate mixing. All methods indicate a significant plume mixing role for bottom‐generated mixing, but interfacial mixing is a bigger contributor. Plume‐integrated total and interfacial mixing peak at max ambient flood and the timing of peak bottom‐generated mixing varies among partitioning methods. Two‐thirds of the mixing occurs in concentrated intense mixing areas. A parameter space with the ambient tidal Froude number and plume thickness to depth ratio as axes indicates many tidally modulated plumes are moderately to dominantly influenced by bottom‐generated tidal mixing. Plain Language Summary: A plume of freshwater flows from the Connecticut River into Long Island Sound. Strong tidal currents influence the plume. How freshwater river plumes mix is an important area of research. This study explores where mixing occurs in the plume and which processes contribute to the mixing. A realistic computer simulation of the Connecticut River plume is analyzed. The strongest mixing areas are near the river mouth, in an area beyond the mouth where the plume turns, and over shallow waters. Mixing created by faster plume speeds relative to the surrounding waters is the most important contributor. Mixing driven by tidal currents interacting with the stationary bottom is a significant secondary contributor. The importance of this tidal contribution increases for faster tidal flow and plumes reaching closer to the bottom. Key Points: Turbulent buoyancy fluxes span several orders of magnitude over the river plumePlume‐generated interfacial shear is the most important mixing contributor overallBottom‐generated mixing importance increases with tidal currents and plume thickness [ABSTRACT FROM AUTHOR]

Microstructure profiling was utilized to estimate vertical mixing (via vertical turbulent buoyancy flux) during a tidal pulse in the interior Merrimack River plume in calm winds. Multiple stratified shear mixing regimes appear and evolve with time. Initially the plume acts as a nearfield jet, with mixing in the plume (plume layer mixing) and over the plume‐ambient interface (nearfield interfacial mixing). As the plume grows, interfacial mixing is suppressed offshore of the nearfield as currents slow, diminishing turbulent exchange between plume and shelf. At the end of ebb, ambient tidal currents reverse direction below plume, initiating another mode of internal, interfacial mixing (coined here as tidal interfacial mixing), allowing exchange between plume and ambient waters offshore. This work highlights previously unreported tidally modulated mixing within the near and midfield of a river plume. Plain Language Summary: Turbulence measurements are taken throughout a tidal river plume over an ebb tide. Three mixing regimes related to stratified‐shear processes (vertical differences in density and velocity) are identified: nearfield interfacial, plume layer, and tidal interfacial mixing. Each regime acts over different spatiotemporal scales and vary in importance. Collectively this work highlights previously unknown variability in tidal plume shear mixing processes which control how river‐borne tracers enter the coastal ocean. Key Points: Observations taken in a tidal river plume identify three shear mixing regimes: plume layer, nearfield interfacial, and tidal interfacialThe intensity of each regime is quantified via the vertical turbulent buoyancy flux and spatiotemporal evolution is discussed [ABSTRACT FROM AUTHOR]

River plumes transport and mix land‐based tracers into the ocean. In tidally pulsed river plumes, wind effects have long been considered negligible in modulating interfacial mixing in the energetic nearfield region. This research tests the influence of variable, realistic winds on mixing in the interior plume. A numerical model of the Merrimack River plume‐shelf system is utilized, with an application of the salinity variance approach employed to identify spatial and temporal variation in advection, straining, and dissipation (mixing) of vertical salinity variance (stratification). Results indicate that moderate wind stresses (∼0.5 Pa) with a northward component countering the downcoast rotation of the plume are most effective at decreasing stratification in the domain relative to other wind conditions. Northward winds advect plume and ambient shelf stratification offshore, allowing shelf water salinity to increase in the nearshore, which strengthens the density gradient at the plume base. Straining in the plume increases with winds enhancing offshore‐directed surface velocities, leading to increased shear at the plume base. Increased straining and larger density gradients at the plume base enhance variance dissipation in the near‐ and midfield plume, and dissipation remains enhanced if the shelf is clear of residual stratification. The smaller spatial and temporal scales of the Merrimack plume allow the mechanisms to occur at tidal time scales in direct response to instantaneous winds. This is the first study to show tidal time scale wind‐induced straining and advection as controlling factors on near‐ and midfield mixing rates in river plumes under realistic winds. Plain Language Summary: Rivers transport pollutants, nutrients, and sediments into the ocean. Often, fresh water from rivers spread out over the denser, salty ocean water, creating a river plume. How these plumes mix and move under different environmental conditions is important to understand for accurate tracing of river‐borne materials into the ocean. In river plumes which form anew on each ebbing, seaward‐directed tide (called tidally pulsed), winds have often been considered unimportant to mixing relative to tidal mixing. In this work, a numerical model of the tidally pulsed Merrimack River plume is used to test that assumption. Mixing in the energetic plume interior can, in fact, be enhanced during specific wind conditions, when the plume and coastal ocean surface waters are pushed offshore, the plume moves faster than normal, and the salinity difference from surface to bottom increases. Essentially, wind can control differences in density under the plume and how quickly the plume moves, both of which influence vertical mixing. The results presented are particularly applicable for smaller plumes over shallower water which are not influenced by larger scale ocean dynamics. Key Points: Wind opposing the direction of Kelvin wave propagation can enhance near‐ and midfield mixing in small‐ to midsized tidal plumesAdvection of plume and ambient stratification offshore and enhanced wind straining contribute to larger mixing ratesThe largest mixing events are linked to shelf stratification, while straining and advection are linked to instantaneous wind direction [ABSTRACT FROM AUTHOR]

This study builds on Huntley and Ryan (2018, https://doi.org/10.1002/2017JC012748) and related prior works on channels and estuaries by considering solutions for the same subtidal dynamics but with alternative integral flow constraints. Prior solutions do not have a truly two‐dimensional (2‐D) flow field, as axial changes in the axial flow are implied. Three constraint types are considered: the Constant case with spatially constant density gradients constrained with section‐integrated flow (as in prior works), Semi‐Variable case with a constant axial density gradient and laterally variable lateral density gradient constrained with depth‐integrated lateral flow, and Variable case with spatially variable density gradients in both directions constrained with depth‐integrated axial and lateral flows. The Semi‐Variable and Variable cases can produce solutions with truly 2‐D flow if the depth‐integrated lateral flow is set to zero everywhere. Differences among solutions are illustrated with idealized and realistic applications from Huntley and Ryan (2018, https://doi.org/10.1002/2017JC012748). For the idealized application, the Constant case and the Semi‐Variable case with 2‐D flow have clear differences in axial velocity and stark contrasts in lateral flow (and density gradients). For the Nares Strait application, the Variable case with observed depth‐averaged axial and lateral velocities is best able to represent the fastest observed down‐channel velocities, the weak reversed flow on one side of the channel, and the observed lateral flow structure. Overall, selecting different integral constraints on flow conspicuously changes the subtidal flow, opens up new possibilities for truly 2‐D flow solutions, and provides additional flexibility for representing observed conditions in realistic situations. Plain Language Summary: For straits and estuaries, flow (averaged over tidal cycles) often is represented with simplified channel models that include the responses to sea‐surface slopes, density differences, and winds. There is a rich variety of flow solutions that depends not only on the forcings and governing equations selected but also on the choice of flow constraints necessary to obtain solutions. This study builds on Huntley and Ryan (2018, https://doi.org/10.1002/2017JC012748) and earlier studies by exploring how flow solutions change when different types of constraints are applied. Constraints can be selected that only prescribe total transports, stringently ensure no along‐channel flow variations, or match flow observations. For idealized applications, solutions with different constraints have conspicuous differences in the along‐channel and across‐channel flow. For the realistic application of Nares Strait, the observation‐based constraint yields the solution that best represents the observed fastest down‐channel velocities, weak reversed flow on one side of the channel, and across‐channel flows. Key Points: Subtidal channel flow is represented with the dynamics in Huntley and Ryan (2018, https://doi.org/10.1002/2017JC012748), but with alternative integral constraints on flowSetting depth‐integrated (instead of section‐integrated) lateral flow to zero leads to 2‐D flow and starkly different flow structureConstraining with observed depth‐averaged velocities produces solutions that best represent observed flow in Nares Strait [ABSTRACT FROM AUTHOR]

Recent studies have explored the sensitivity of global ocean model simulations to the treatment of riverine freshwater and the representation of estuarine processes via an estuary box model applied within Community Earth System Model (CESM). This study builds on these efforts by assessing the model skill score relative to a new salinity climatology. The new climatology averages the original observational data of the World Ocean Database directly onto the CESM ocean component tracer grid cells without spatial interpolation, smoothing, or other gap-filling techniques to mitigate coastal ocean salinity bias present in the World Ocean Atlas. The mean square error for coastal upper ocean salinity relative to climatology is reduced by up to 14%, and the mean square error of near-surface salinity stratification is reduced by up to 28% near major river mouths in the simulations with improved treatments of river runoff. The improvement in upper ocean bulk salinity is attributed primarily to focusing runoff as point sources thereby avoiding the artificial horizontal spreading of the control run and to applying a locally varying instead of a global constant reference salinity for riverine virtual salt fluxes. The improvements in near-surface salinity stratification are primarily attributed to adding parameterized estuarine mixing with the estuary box model. Salinity and salinity stratification skill improvements are achieved not just near large rivers but also along the global coast and skill improvements extend far offshore. Despite these improvements, many other sources of model-climatology mismatch in coastal salinity and stratification remain and merit further attention. [ABSTRACT FROM AUTHOR]

Long Island Sound is a large macrotidal estuary. Connecticut River as the primary freshwater source enters near the sound's mouth. The summertime pathways of river water under low discharge and mild wind conditions are studied through both numerical simulations with a passive dye pulse and field surface drifter observations. Within the 19‐day modeling analysis period a third of the river dye pulse remains in the eastern sound; another third of the pulse moves up‐estuary with the near‐bottom dense inflow into the central and western sound with a spring‐neap tidal modulation; and another third leaves the sound with the near‐surface outflow toward the continental shelf through Block Island Sound. The latter pathway is confirmed by field surface drifter tracks. Three scenarios of wind forcing are tested: a WRF‐ROMS Coupled case, a NARR data forcing case, and a No‐Wind case. The results show though that the sound is tidal mixing dominated, mild winds still alter the position and strength of the estuarine exchange flow, and either enhances by the cross‐estuary winds or lateral straining. On the shelf, winds play a more important role on the fresher estuarine water distribution. The sensitivities of circulation, salinity, and numerical drifter tracks to different atmospheric forcings also are studied. The results suggest that the coupled model has better performance to simulate surface drifter tracks. Plain Language Summary: Connecticut River is the primary freshwater source to Long Island Sound. It enters near the sound mouth, where dense continental shelf water intrudes in. The aims are to find out where the summer river waters go and what drives it. In particular, the mild wind impacts on the river water distributions are studied. Simulations with a river water dye pulse show two main pathways simultaneously: in 19 days, a third of the river water moves toward the sound head with a near‐bottom dense inflow; another third of the river water leaves through the sound mouth at the surface and later on enters onto the shelf. The latter pathway is confirmed by field surface drifter tracks. Three scenarios of wind forcing are tested: a spatial varied wind case, a relatively spatial uniform wind case, and a no‐wind case. The results show that winds speedup the up‐estuary transport of the river water in central sound. On the continental shelf, winds play a more important role on the estuarine outflow distribution. Results suggest that the spatial varied wind model has better performance on modeling surface drifter tracks. This study gives a clear picture on the summertime Connecticut River water pathways and the related dynamics. Key Points: Summer Connecticut River water has two main pathways: up estuary entrained with dense water near bottom; down estuary near the surfaceDrifter observations confirm the surface outflow pathway in Long Island SoundMild winds alter position and strength of the bottom inflow and highly impact the estuarine water distribution on the continental shelf [ABSTRACT FROM AUTHOR]

Objective Functional imaging of synovitis could improve both early detection of rheumatoid arthritis (RA) and long-term outcomes. Given the intersection of inflammation with coagulation protease activation, this study was undertaken to examine coagulation protease activities in arthritic mice with a dual-fluorescence ratiometric activatable cell-penetrating peptide (RACPP) that has a linker, norleucine (Nle)-TPRSFL, with a cleavage site for thrombin. Methods K/BxN-transgenic mice with chronic arthritis and mice with day 1 passive serum-transfer arthritis were imaged in vivo for Cy5:Cy7 emission ratiometric fluorescence from proteolytic cleavage and activation of RACPPNleTPRSFL. Joint thickness in mice with serum-transfer arthritis was measured from days 0 to 10. The cleavage-evoked release of Cy5-tagged tissue-adhesive fragments enabled microscopic correlation with immunohistochemistry for inflammatory markers. Thrombin dependence of ratiometric fluorescence was tested by ex vivo application of RACPPNleTPRSFL and argatroban to cryosections obtained from mouse hind paws on day 1 of serum-transfer arthritis. Results In chronic arthritis, RACPPNleTPRSFL fluorescence ratios of Cy5:Cy7 emission were significantly higher in diseased swollen ankles of K/BxN-transgenic mice than in normal mouse ankles. A high ratio of RACPPNleTPRSFL fluorescence in mouse ankles and toes on day 1 of serum-transfer arthritis correlated with subsequent joint swelling. Foci of high ratiometric fluorescence localized to inflammation, as demarcated by immune reactivity for citrullinated histones, macrophages, mast cells, and neutrophils, in soft tissue on day 1 of serum-transfer arthritis. Ex vivo application of RACPPNleTPRSFL to cryosections obtained from mice on day 1 of serum-transfer arthritis produced ratiometric fluorescence that was inhibited by argatroban. Conclusion RACPPNleTPRSFL activation detects established experimental arthritis, and the detection of inflammation by RACPPNleTPRSFL on day 1 of serum-transfer arthritis correlates with disease progression. [ABSTRACT FROM AUTHOR]

A multi-year observational time series was evaluated across the 150 km central axis of the U.S. east coast's Long Island Sound (LIS) estuary, in three distinct regions. Fluxes were calculated at the boundaries of the regions using observations coupled to a hydrodynamic model and applied to a mass balance to assess organic carbon (OC) export from LIS. For all years, during stratified summer periods, LIS was a net exporter of OC to the continental shelf. LIS annual net carbon export however, varied with river flow. The heterotrophic or autotrophic nature of LIS also shifted inter-annually. During the mass balance analysis period (2009-2012), LIS ranged between net OC import from the continental shelf and heterotrophy in the lowest river flow year (2012) and net export of OC and autotrophy in the highest flow year (2011). Analysis suggests that LIS switches from net OC import to export when the annual river inputs exceed 19 km3 yr−1. Applying these thresholds to the annual river flow record suggests that net import occurred in 15% of the last 20 years and that LIS usually is a net exporter of OC (85%). Annually averaged LIS carbon export values based on river flow conditions over the last 20 yr are estimated at 56 ± 64 × 106 kg yr−1. Analysis also suggests that LIS shifts from net heterotrophic to net autotrophic when annual river flow exceeds 26 km3 yr−1 (35% of the last 20 yr). Net heterotrophic conditions are most common, representing 65% of the last 20 yr. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Additional intraoperative guidance could reduce the risk of iatrogenic injury during parotid gland cancer surgery. We evaluated the intraoperative use of fluorescently labeled nerve binding peptide NP41 to aid facial nerve identification and preservation during parotidectomy in an orthotopic model of murine parotid gland cancer. We also quantified the accuracy of intraoperative nerve detection for surface and buried nerves in the head and neck with NP41 versus white light (WL) alone.Study Design: Twenty-eight mice underwent parotid gland cancer surgeries with additional fluorescence (FL) guidance versus WL reflectance (WLR) alone. Eight mice were used for additional nerve-imaging experiments.Methods: Twenty-eight parotid tumor-bearing mice underwent parotidectomy. Eight mice underwent imaging of both sides of the face after skin removal. Postoperative assessment of facial nerve function measured by automated whisker tracking were compared between FL guidance (n = 13) versus WL alone (n=15). In eight mice, nerve to surrounding tissue contrast was measured under FL versus WLR for all nerve branches detectable in the field of view.Results: Postoperative facial nerve function after parotid gland cancer surgery tended to be better with additional FL guidance. Fluorescent labeling significantly improved nerve to surrounding tissue contrast for both large and smaller buried nerve branches compared to WLR visualization and improved detection sensitivity and specificity.Conclusions: NP41 FL imaging significantly aids the intraoperative identification of nerve braches otherwise nearly invisible to the naked eye. Its application in a murine model of parotid gland cancer surgery tended to improve functional preservation of the facial nerve.Level Of Evidence: NA Laryngoscope, 126:2711-2717, 2016. [ABSTRACT FROM AUTHOR]

Background: To date, there are limited therapeutic options for the treatment or symptomatic relief of degenerative dementia [1]. There has been growing interest in the class of medications known as tyrosine kinase inhibitors, such as bosutinib, as a therapeutic intervention for dementia [2]. Ongoing clinical and preclinical trials also suggest focused ultrasound may yield therapeutic potential for patients with neurodegenerative conditions such as Alzheimer's disease [3‐5]. Focused ultrasound may be used as an independent therapeutic intervention or adjunctively to facilitate delivery of medicine. The present study compares the efficacy of focused ultrasound as an independent intervention to the efficacy of focused ultrasound combined with bosutinib, using several outcome measures to demonstrate accuracy. Methods: Structural and functional imaging were used to navigate cerebral and subcortical ultrasound targets for 13 patients (9 female; Mage = 72.08 years, SDage = 9.30 years), 7 of which received therapeutic ultrasound as an independent intervention, and the remaining 6 received both therapeutic ultrasound in conjunction with bosutinib. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Montreal Cognitive Assessment [MoCA]. Results: The combination of therapeutic ultrasound with bosutinib was associated with 66% of patients maintaining or improving their Clinical Dementia Rating scale during the eight‐week protocol, whereas therapeutic ultrasound as a stand alone intervention showed 43% of patients maintaining or improving their Clinical Dementia Rating scale. Similarly, 67% of patients who underwent the combination intervention maintained or improved their MoCA scores, and of the patients who only received therapeutic ultrasound, 57% maintained or improved their MoCA scores. Conclusions: The results of these comparisons suggest a combination of medication and therapeutic ultrasound may have a more positive outcome than therapeutic ultrasound alone. Clinical studies have shown that this ultrasound technology has been successfully applied for small molecules [6]. This technique of tailored targeting for each patient's brain in conjunction with medication may represent a significant advancement to the field. Future studies should explore this combination. [ABSTRACT FROM AUTHOR]

Objective: (1) Obtain matrix-metalloproteinase (MMP) expression profiles for head and neck squamous cell carcinoma (HNSCC) specimens from the Cancer Genomic Atlas (TCGA). (2) Demonstrate HNSCC imaging using MMP-cleavable, fluorescently labeled ratiometric activatable cell-penetrating peptide (RACPP).Study Design: Retrospective human cohort study; prospective animal study.Setting: Translational research laboratory.Subjects and Methods: Patient clinical data and mRNA expression levels of MMP genes were downloaded from TCGA data portal. RACPP provides complementary ratiometric fluorescent contrast (increased Cy5 and decreased Cy7 intensities) when cleaved by MMP2/9. HNSCC-tumor bearing mice were imaged in vivo after RACPP injection. Histology was evaluated by a pathologist blinded to experimental conditions. Zymography confirmed MMP-2/9 activity in xenografts. RACPP was applied to homogenized human HNSCC specimens, and ratiometric fluorescent signal was measured on a microplate reader for ex vivo analysis.Results: Expression of multiple MMPs including MMP2/9 is greater in patient HNSCC tumors than matched control tissue. In patients with human papilloma virus positive (HPV+) tumors, higher MMP2 and MMP14 expression correlates with worse 5-year survival. Orthotopic tongue HNSCC xenografts showed excellent ratiometric fluorescent labeling with MMP2/9-cleavable RACPP (sensitivity = 95.4%, specificity = 95.0%). Fluorescence ratios were greater in areas of higher tumor burden (P < .03), which is useful for intraoperative margin assessment. Ex vivo, human HNSCC specimens showed greater cleavage of RACPP when compared to control tissue (P = .009).Conclusions: Human HNSCC tumors show increased mRNA expression of multiple MMPs including MMP2/9. We used RACPP, a ratiometric fluorescence assay of MMP2/9 activity, to show improved occult tumor identification and margin clearance. Ex vivo assays using RACPP in biopsy specimens may identify patients who will benefit from intraoperative RACPP use. [ABSTRACT FROM AUTHOR]

Although multiple sclerosis (MS) has been associated with the coagulation system, the temporal and spatial regulation of coagulation activity in neuroinflammatory lesions is unknown. Using a novel molecular probe, we characterized the activity pattern of thrombin, the central protease of the coagulation cascade, in experimental autoimmune encephalomyelitis. Thrombin activity preceded onset of neurological signs, increased at disease peak, and correlated with fibrin deposition, microglial activation, demyelination, axonal damage, and clinical severity. Mice with a genetic deficit in prothrombin confirmed the specificity of the thrombin probe. Thrombin activity might be exploited for developing sensitive probes for preclinical detection and monitoring of neuroinflammation and MS progression. Ann Neurol 2014;75:303-308 [ABSTRACT FROM AUTHOR]

In Echtzeit und ratiometrisch kann die Thrombin ‐ Aktivierung in vivo mithilfe aktivierbarer zellgängiger Peptide (RACPPs) verfolgt werden. RACPPs verbinden die 1) Ermittlung des Verhältnisses zweier Emissionen, 2) In ‐ vivo ‐ Bildgebung in Säugern im fernen Rot ‐ bis Infrarotbereich und 3) spaltungsabhängige räumliche Lokalisierung. Das beste RACPP nutzt Norleucin(Nle) ‐ TPRSFL als Linker, was die Empfindlichkeit für Thrombin um das 90 ‐ Fache erhöht (siehe Bild). [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: By phage display, we have developed a novel peptide (NP41) that binds selectively to nerves following systemic administration. We evaluated the pattern of facial nerve labeling with fluorescently-labeled NP41 (F-NP41). We also tested whether F-NP41 highlights facial nerves well enough to identify nerve stumps accurately several weeks after nerve transection. Study Design: Forty-seven wild-type mice were studied prospectively. One surgeon performed the nerve transection, reanastomoses, and monitoring of functional recovery. Methods: Fluorescent labeling: F-NP41 was administered intravenously (20 mice). Nerve labeling was studied with fluorescence microscopy. Transection and reanastomosis: the right facial nerve was transected (25 mice). Three weeks after transection, F-NP41 was administered intravenously and fluorescence microscopy was used to identify the nerve stumps and reanastomosis in one group. Nerve identification and renastomosis was performed with white light in another group without F-NP41. The control group underwent sham surgery. Time to nerve identification was recorded. Functional recovery was monitored for at least 8 weeks. Results: We found excellent labeling of intact and transected facial nerves following F-NP41 administration. Several weeks following nerve transection, F-NP41 provided accurate identification of the proximal and distal nerve stumps. Following reanastomosis, time to recovery and level of functional recovery was similar in the absence and presence of F-NP41. Conclusions: We show improved visualization of facial nerves with a novel systemically applied fluorescently labeled probe. Use of F-NP41 resulted in accurate identification of facial nerve stumps several weeks following transection. Functional recovery was similar with and without the use of F-NP41. [ABSTRACT FROM AUTHOR]

Background: A 2020 publication from Mahdavi and colleagues reported on clinical status changes observed among a sample of 31 older adults with neurodegenerative conditions who completed 12 months of bosutinib therapy. This abstract provides updated results for an additional 21 patients who have completed the 12‐month regimen since the time of the initial publication. This study pursues and updates data on an effective therapeutic intervention for dementia using TKI's such as bosutinib. Method: 52 patients with probable Alzheimer's dementia (AD) or Parkinson's spectrum disorder with dementia (PDD) completed 12 months of bosutinib therapy. The Clinical Dementia Rating scale (CDR) as estimated by the Quick Dementia Rating System (QDRS) was the primary cognitive status outcome measure. Results: For the updated sample size of 52 individuals who have completed the protocol, bosutinib was associated with improved CDR scores for 40% of participants (36% AD, and 46% PDD); bosutinib was also associated with clinically stable CDR scores for 38% of patients (36% AD, and 46% PDD). After completion of the protocol intervention, 29% of the AD population yielded decreased CDR scores while only 8% of PDD patients had decreased CDR scores. Conclusion: These results update findings from the previously reported study (Mahdavi et al., 2020) and continue to warrant further investigation of bosutinib as a potential therapeutic agent for dementia. The data continue to suggest an overall positive or stable outcome among participants after a year of bosutinib, with a clinical improvement rate of approximately 40% and a 38% rate of clinical stabilization. This observation remains consistent regardless of severity of cognitive impairment at baseline. We expect to report on an update for an additional 30 participants in the next year. [ABSTRACT FROM AUTHOR]

Objective Previous research has suggested that both lithium and buspirone could lessen alcoholics' desire to drink as well as reduce the actual amounts of alcohol consumed. The purpose of this study was to compare lithium and buspirone monotherapy with placebo on outcomes of abstinence, alcohol quantity consumed, treatment retention and compliance, and medication side effects. Methods: We conducted a randomized, double-blind, placebo-controlled, three-arm parallel group, clinical trial that compared lithium and buspirone with placebo in 156 alcohol-dependent men. Results: Study retention rates for the three treatment groups at 3 and 6 months, respectively, were 61% and 46% for lithium, 44% and 27% for buspirone, and 52% and 38% for placebo ( p= NS, for 3 and 6 months). Overall abstinence rates were 28% and 19% at 3 and 6 months, respectively. However, mean daily quantities of alcohol consumed and percentage of drinking days decreased significantly ( p < 0.0001) over time in all treatment groups. Differential improvement was seen only for the decrement in quantity consumed in the buspirone group, compared with the placebo group, but only at a trend level ( p= 0.07). According to pill counts, compliance did not differ significantly among the treatment groups. Conclusions: These results do not support the hypothesis that either lithium or buspirone, compared with placebo, produces differential reductions in alcohol consumption. The results suggest the need to enhance treatment retention to maximize outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Nerve degeneration after transection decreases intraoperative visibility under white light (WL), complicating repair and increasing the risk of additional injury to surrounding tissue. We previously described F‐NP41, a fluorescently‐labeled peptide which highlights peripheral nerves following systemic injection. In this study, we analyzed whether F‐NP41 highlights degenerated nerves and evaluated the use of additional fluorescence guidance in delayed facial nerve repair procedures. Methods: Degenerated distal facial nerve branches were imaged under WL and with fluorescence after systemic F‐NP41 application 1, 2, 3, 6, and 9 months (n = 4 per time point) after main branch transection. Nerve to non‐nerve tissue contrast was compared. Facial nerve repair surgeries with a cable graft were performed 6 weeks after transection, using WL alone (n = 9) or additional fluorescence guidance (n = 10). Time to nerve identification and total operating time were measured; postoperative functional recovery was assessed weekly by quantitative measurement of whisker movement for 6 weeks. Results: Nerve to non‐nerve tissue contrast was increased >2‐fold using fluorescence imaging versus WL at all time points (P <. 001). Fluorescence guidance decreased time to intraoperative nerve stump identification by 39% (P <. 0001). Postoperative functional recovery was similar for both groups after 6 weeks, although the rate of recovery tended to be increased after surgery with fluorescence guidance. Conclusions: F‐NP41 significantly improves intraoperative visualization of degenerated nerves in mice up to nine months following injury compared with WL alone. The use of F‐NP41 decreases intraoperative time to nerve identification by nearly 40%, thus reducing operating time and potentially improving functional recovery. [ABSTRACT FROM AUTHOR]

The article presents a study that investigates the biochemical approach in improving the visualization of papillary thyroid cancer (PTC) transgenic murine model. Researchers used the novel strategy in enhancing molecules in tumor cells and peripheral nerves. Researchers suggest the increase of uptake of activatable cell-penetrating peptides conjugated to dendrimers (ACPPD).

Three cross-shelf transects were conducted off northern Oregon in February, 2003, coincident with flooding of Coast Range rivers, to assess the riverine impact on coastal ocean biogeochemistry. During downwelling conditions, low salinity river-influenced water was located in a narrow band near the coast and contained elevated macronutrient, iron, and organic carbon concentrations. Wind relaxation allowed the river-influenced water to spread out at the surface across the shelf. Nutrients supplied by the rivers could result in winter carbon fixation equating to ~20% of the summer upwelling carbon fixation if conditions are suitable for phytoplankton growth, which is likely on the basis of recent studies. This implies that wintertime production may be significant and requires further study. Iron supplied by the rivers is sufficient to support the entire summer upwelling production and because downwelling conditions prevail during the winter and minimize cross-shelf transport, this iron may be retained on the shelf to support the summer phytoplankton blooms. Of the major eastern boundary current systems, the northern California Current (including Oregon) and Portugal Current (i.e., Iberian Peninsula) have the highest riverine discharge rates normalized to coastline length. In contrast, riverine inputs to the central California, Canary (i.e., northwest Africa), Benguela and Peruvian Current systems averaged only 3-35% of that in Oregon. This patchy riverine input (and narrower shelves) might explain why iron limitation is more widespread off California and Peru than Oregon. These results show that small coastal rivers, characteristic of the U.S. Pacific Northwest, can significantly alter coastal biogeochemical cycles and influence ecosystem structure. [ABSTRACT FROM AUTHOR]