Dorsolateral Striatal Task-initiation Bursts Represent Past Experiences More than Future Action Plans.

The dorsolateral striatum (DLS) is involved in learning and executing procedural actions. Cell ensembles in the DLS, but not the dorsomedial striatum (DMS), exhibit a burst of firing at the start of a well-learned action sequence ("task-bracketing"). However, it is currently unclear what information is contained in these bursts. Some theories suggest that these bursts should represent the procedural action sequence itself (that they should be about future action chains), whereas others suggest that they should contain representations of the current state of the world, taking into account primarily past information. In addition, the DLS local field potential shows transient bursts of power in the 50 Hz range (γ50) around the time a learned action sequence is initiated. However, it is currently unknown how bursts of activity in DLS cell ensembles and bursts of γ50 power in the DLS local field potential are related to each other. We found that DLS bursts at lap initiation in rats represented recently experienced reward locations more than future procedural actions, indicating that task-initiation DLS bursts contain primarily retrospective, rather than prospective, information to guide procedural actions. Furthermore, representations of past reward locations increased during periods of increased γ50 power in the DLS. There was no evidence of task-initiation bursts, increased γ50 power, or retrospective reward location information in the neighboring dorsomedial striatum. These data support a role for the DLS in model-free theories of procedural decision-making over planned action-chain theories, suggesting that procedural actions derive from representations of the current and recent past.SIGNIFICANCE STATEMENT While it is well-established that the dorsolateral striatum (DLS) plays a critical role in procedural decision-making, open questions remain about the kinds of representations contained in DLS ensemble activity that guide procedural actions. We found that DLS, but not DMS, cell ensembles contained nonlocal representations of past reward locations that appear moments before task-initiation DLS bursts. These retrospective representations were temporally linked to a rise in γ50 power that also preceded the characteristic DLS burst at task-initiation. These results support models of procedural decision-making based on associations between available actions and the current state of the world over models based on planning over action-chains.

Understanding Disorder, Vibronic Structure, and Delocalization in Electronically Coupled Dimers on DNA Duplexes.

Structural DNA nanotechnology is a promising approach to create chromophore networks with modular structures and Hamiltonians to control the material's functions. The functional behaviors of these systems depend on the interactions of the chromophores' vibronic states, as well as interactions with their environment. To optimize their functions, it is necessary to characterize the chromophore network's structural and energetic properties, including the electronic delocalization in some cases. In this study, parameters of interest are deduced in DNA-scaffolded Cyanine 3 and Cyanine 5 dimers. The methods include steady-state optical measurements, physical modeling, and a genetic algorithm approach. The parameters include the chromophore network's vibronic Hamiltonian, molecular positions, transition dipole orientations, and environmentally induced energy broadening. Additionally, the study uses temperature-dependent optical measurements to characterize the spectral broadening further. These combined results reveal the quantum mechanical delocalization, which is important for functions like coherent energy transport and quantum information applications.

Development of a Flexible Dielectric Sensor for Flow Monitoring of the Liquid Resin Infusion Process.

The analysis and design of a novel flexible dielectric sensor, which can be integrated into a composite materials manufacturing process to measure the resin frontal flow, is presented in this paper. The proposed sensor consists of two parallel line electrodes and a ground plane covered by a dielectric material. The analytical description and the electrostatic modelling were considered for the design of the sensor and to enhance the understanding of the response of the sensor to the resin impregnation of a carbon fabric during the infusion phase. The optimization of the sensor's response and the increase of its sensitivity with regards to the geometric characteristics and the materials used were the main objectives of this study. An experimental set-up for the vacuum infusion process which includes the proposed sensor was used to measure the capacitance and validate the derived resin flow against visual measurements. The results indicate that the sensor can provide information on the resin frontal flow within 2% accuracy against visual measurements, which make this technology promising for monitoring the liquid resin infusion processes.

Optical determination of the electronic coupling and intercalation geometry of thiazole orange homodimer in DNA.

Sequence-selective bis-intercalating dyes exhibit large increases in fluorescence in the presence of specific DNA sequences. This property makes this class of fluorophore of particular importance to biosensing and super-resolution imaging. Here we report ultrafast transient anisotropy measurements of resonance energy transfer (RET) between thiazole orange (TO) molecules in a complex formed between the homodimer TOTO and double-stranded (ds) DNA. Biexponential homo-RET dynamics suggest two subpopulations within the ensemble: 80% intercalated and 20% non-intercalated. Based on the application of the transition density cube method to describe the electronic coupling and Monte Carlo simulations of the TOTO/dsDNA geometry, the dihedral angle between intercalated TO molecules is estimated to be 81° ± 5°, corresponding to a coupling strength of 45 ± 22 cm-1. Dye intercalation with this geometry is found to occur independently of the underlying DNA sequence, despite the known preference of TOTO for the nucleobase sequence CTAG. The non-intercalated subpopulation is inferred to have a mean inter-dye separation distance of 19 Å, corresponding to coupling strengths between 0 and 25 cm-1. This information is important to enable the rational design of energy transfer systems that utilize TOTO as a relay dye. The approach used here is generally applicable to determining the electronic coupling strength and intercalation configuration of other dimeric bis-intercalators.

Task-specific reach-to-grasp training after stroke: development and description of a home-based intervention.

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is to transparently describe the process of developing a complex intervention for people after stroke as part of a feasibility randomised controlled trial. OBJECTIVE: To describe and justify the development of a home-based, task-specific upper limb training intervention to improve reach-to-grasp after stroke and pilot it for feasibility and acceptability prior to a randomized controlled trial. INTERVENTION DESCRIPTION: The intervention is based on intensive practice of whole reach-to-grasp tasks and part-practice of essential reach-to-grasp components. A 'pilot' manual of activities covering the domains of self-care, leisure and productivity was developed for the feasibility study. The intervention comprises 14 hours of therapist-delivered sessions over six weeks, with additional self-practice recommended for 42 hours (i.e. one hour every day). As part of a feasibility randomized controlled trial, 24 people with a wide range of upper limb impairment after stroke experienced the intervention to test adherence and acceptability. The median number of repetitions in one-hour therapist-delivered sessions was 157 (interquartile range IQR 96-211). The amount of self-practice was poorly documented. Where recorded, the median amount of practice was 30 minutes (interquartile range 22-45) per day. Findings demonstrated that the majority of participants found the intensity, content and level of difficulty of the intervention acceptable, and the programme to be beneficial. Comments on the content and presentation of the self-practice material were incorporated in a revised 'final' intervention manual. DISCUSSION: A comprehensive training intervention to improve reach-to-grasp for people living at home after stroke has been described in accordance with the Template for Intervention Description and Replication (TIDieR) reporting guidelines. The intervention has been piloted, and found to be acceptable and feasible in the home setting. TRIAL REGISTRATION: ISRCTN56716589.

Transforming Medical Education is the Key to Meeting North Carolina's Physician Workforce Needs.

To meet the needs of the population of North Carolina, an epic transformation is under way in health care. This transformation requires that we find new ways to educate and train physicians and other health care professionals. In this commentary, we propose that the success of the Brody School of Medicine in preparing a primary care physician workforce can serve as a model for meeting the state's future physician workforce needs. Other considerations include increasing graduate medical education positions through state funding and providing incentives for medical students who stay in North Carolina.

Meeting North Carolina's health care needs through interprofessional education and practice.

To meet the future health care needs of North Carolinians, health professions students must learn how to work together as part of an interdisciplinary team. This commentary describes how interprofessional education and team-based care can decrease the number of adverse events, improve health care delivery, and support consistent outcomes.

Hexagonal Boron Nitride Slab Waveguides for Enhanced Spectroscopy of Encapsulated 2D Materials.

The layered insulator hexagonal boron nitride (hBN) is a critical substrate that brings out the exceptional intrinsic properties of two-dimensional (2D) materials such as graphene and transition metal dichalcogenides (TMDs). In this work, the authors demonstrate how hBN slabs tuned to the correct thickness act as optical waveguides, enabling direct optical coupling of light emission from encapsulated layers into waveguide modes. Molybdenum selenide (MoSe2 ) and tungsten selenide (WSe2 ) are integrated within hBN-based waveguides and demonstrate direct coupling of photoluminescence emitted by in-plane and out-of-plane transition dipoles (bright and dark excitons) to slab waveguide modes. Fourier plane imaging of waveguided photoluminescence from MoSe2 demonstrates that dry etched hBN edges are an effective out-coupler of waveguided light without the need for oil-immersion optics. Gated photoluminescence of WSe2 demonstrates the ability of hBN waveguides to collect light emitted by out-of-plane dark excitons.Numerical simulations explore the parameters of dipole placement and slab thickness, elucidating the critical design parameters and serving as a guide for novel devices implementing hBN slab waveguides. The results provide a direct route for waveguide-based interrogation of layered materials, as well as a way to integrate layered materials into future photonic devices at arbitrary positions whilst maintaining their intrinsic properties.

Lymphatic absorption, metabolism, and excretion of a therapeutic peptide in dogs and rats.

The objective of the current study was to evaluate the mechanism of absorption and metabolism of a PEGylated peptide, MRL-1 (46 kDa), after s.c. dosing in dogs and rats. Thoracic lymph duct-cannulated (LDC) dog and rat models were developed that allowed continuous collection of lymph for up to 8 days. When [(3)H]MRL-1 was administered s.c. to LDC dogs, ∼73% of the administered radioactivity was recovered in pooled lymph over a period of 120 hours, suggesting that lymphatic uptake is the major pathway of s.c. absorption for this peptide. In agreement with these data, the systemic exposure of radioactivity related to [(3)H]MRL-1 in LDC dogs was decreased proportionately when compared with that in noncannulated control dogs. After i.v. dosing with [(3)H]MRL-1 in LDC dogs, 20% of the administered radioactivity was recovered in pooled lymph over 168 hours, suggesting some level of recirculation of radioactivity related to [(3)H]MRL-1 from the plasma compartment into the lymphatic system. Experiments conducted in the LDC rat model also resulted in similar conclusions. Analysis of injection site s.c. tissue showed significant metabolism of [(3)H]MRL-1, which provides an explanation for the <100% bioavailability of therapeutic proteins and peptides after s.c. dosing. After s.c. dosing, the major circulating components in plasma were the parent peptide and the PEG-linker [(3)H]MRL-2. The metabolism profiles in lymph were similar to those in plasma, suggesting that the loss of peptide was minimal during lymphatic transport. After i.v. dosing in rats, [(3)H]MRL-1 was metabolized and excreted primarily in the urine as metabolites.

Towards control of excitonic coupling in DNA-templated Cy5 aggregates: the principal role of chemical substituent hydrophobicity and steric interactions.

Understanding and controlling exciton coupling in dye aggregates has become a greater focus as potential applications such as coherent exciton devices, nanophotonics, and biosensing have been proposed. DNA nanostructure templates allow for a powerful modular approach. Using DNA Holliday junction (HJ) templates variations of dye combinations and precision dye positions can be rapidly assayed, as well as creating aggregates of dyes that could not be prepared (either due to excess or lack of solubility) through alternative means. Indodicarbocyanines (Cy5) have been studied in coupled systems due to their large transition dipole moment, which contributes to strong coupling. Cy5-R dyes were recently prepared by chemically modifying the 5,5'-substituents of indole rings, resulting in varying dye hydrophobicity/hydrophilicity, steric considerations, and electron-donating/withdrawing character. We utilized Cy5-R dyes to examine the formation and properties of 30 unique DNA templated homodimers. We find that in our system the sterics of Cy5-R dyes play the determining factor in orientation and coupling strength of dimers, with coupling strengths ranging from 50-138 meV. The hydrophobic properties of the Cy5-R modify the percentage of dimers formed, and have a secondary role in determining the packing characteristics of the dimers when sterics are equivalent. Similar to other reports, we find that positioning of the Cy5-R within the HJ template can favor particular dimer interactions, specifically oblique or H-type dimers.

Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs.

The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ∼70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2- to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

Photoexcitation dynamics in films of C60 and Zn phthalocyanine with a layered nanostructure.

We elucidate photoexcitation dynamics in C(60) and zinc phthalocyanine (ZnPc) from picoseconds to milliseconds by transient absorption and time-resolved terahertz spectroscopy. Autoionization of C(60) is a precursor to photocarrier generation. Decay of the terahertz signal is due to decreasing photocarrier mobility over the first 20 ps and thereafter reflects recombination dynamics. Singlet diffusion rates in C(60) are determined by modeling the rise of ground state bleaching of ZnPc absorption following C(60) excitation. Recombination dynamics transform from bimolecular to monomolecular as the layer thickness is reduced, revealing a metastable exciplex at the C(60)/ZnPc interface with a lifetime of 150 µs.

Transverse sinus thrombosis after internal jugular vein ligation.

BACKGROUND: Cerebral vein and dural sinus thrombosis is a rare condition with a wide range of causes and a highly variable presentation. It can lead to significant morbidity, but scant literature is available describing diagnosis and treatment when this occurs after ligation of the internal jugular vein. OBJECTIVES: To discuss potential risk factors for cerebral vein and dural sinus thrombosis after ligation of the internal jugular vein, and present current options for diagnosis and treatment. CASE REPORT: A 23-year-old male construction worker was brought to the Emergency Department by Emergency Medical Services after sustaining a severe neck laceration from a hand-held grinder. He was treated with ligation of the left internal jugular vein, but subsequently developed severe headaches and symptoms of increased intracranial pressure. A magnetic resonance venogram of the head revealed a left transverse sinus thrombosis requiring treatment with anticoagulation. The placement of a lumboperitoneal shunt was ultimately needed for relief of his symptoms. CONCLUSIONS: Early diagnosis and aggressive therapeutic interventions are critical to prevent further morbidity in patients who develop cerebral vein and dural sinus thrombosis after ligation of the internal jugular vein.

Enhanced multiple exciton generation in quasi-one-dimensional semiconductors.

The creation of a single electron-hole pair (i.e., exciton) per incident photon is a fundamental limitation for current optoelectronic devices including photodetectors and photovoltaic cells. The prospect of multiple exciton generation per incident photon is of great interest to fundamental science and the improvement of solar cell technology. Multiple exciton generation is known to occur in semiconductor nanostructures with increased efficiency and reduced threshold energy compared to their bulk counterparts. Here we report a significant enhancement of multiple exciton generation in PbSe quasi-one-dimensional semiconductors (nanorods) over zero-dimensional nanostructures (nanocrystals), characterized by a 2-fold increase in efficiency and reduction of the threshold energy to (2.23 ± 0.03)E(g), which approaches the theoretical limit of 2E(g). Photovoltaic cells based on PbSe nanorods are capable of improved power conversion efficiencies, in particular when operated in conjunction with solar concentrators.

The future of community-centred health services in Australia - an alternative view.

Community-centred healthcare works in conjunction with hospital-centred healthcare. Both have strengths and limitations. Community-centred healthcare has been demonstrated to be a more cost-efficient and cost-effective alternative to hospital-centred care at best in a limited fashion. If hospital-centred services dominate healthcare services in Australia, as argued previously in this journal, then this has not extended to maintenance of inpatient bed provision. The author, as a hospital-based emergency specialist, has observed case load and models of care in hospitals and emergency departments for 30 years and is sceptical of promises to substantially further decrease emergency department demand and acute bed requirements. The real benefits of community, primary and preventive care should not be over sold.

Vibrio cholerae high cell density quorum sensing activates the host intestinal innate immune response.

Quorum sensing fundamentally alters the interaction of Vibrio cholerae with aquatic environments, environmental hosts, and the human intestine. At high cell density, the quorum-sensing regulator HapR represses not only expression of cholera toxin and the toxin co-regulated pilus, virulence factors essential in human infection, but also synthesis of the Vibrio polysaccharide (VPS) exopolysaccharide-based matrix required for abiotic and biotic surface attachment. Here, we describe a feature of V. cholerae quorum sensing that shifts the host-pathogen interaction toward commensalism. By repressing pathogen consumptive anabolic metabolism and, in particular, tryptophan uptake, V. cholerae HapR stimulates host intestinal serotonin production. This, in turn, activates host intestinal innate immune signaling to promote host survival.

Sunk cost sensitivity during change-of-mind decisions is informed by both the spent and remaining costs.

Sunk cost sensitivity describes escalating decision commitment with increased spent resources. On neuroeconomic foraging tasks, mice, rats, and humans show similar escalations from sunk costs while quitting an ongoing countdown to reward. In a new analysis taken across computationally parallel foraging tasks across species and laboratories, we find that these behaviors primarily occur on choices that are economically inconsistent with the subject's other choices, and that they reflect not only the time spent, but also the time remaining, suggesting that these are change-of-mind re-evaluation processes. Using a recently proposed change-of-mind drift-diffusion model, we find that the sunk cost sensitivity in this model arises from decision-processes that directly take into account the time spent (costs sunk). Applying these new insights to experimental data, we find that sensitivity to sunk costs during re-evaluation decisions depends on the information provided to the subject about the time spent and the time remaining.

Emergent Moiré Phonons Due to Zone Folding in WSe2-WS2 Van der Waals Heterostructures.

Bilayers of 2D materials offer opportunities for creating devices with tunable electronic, optical, and mechanical properties. In van der Waals heterostructures (vdWHs) where the constituent monolayers have different lattice constants, a moiré superlattice forms with a length scale larger than the lattice constant of either constituent material regardless of twist angle. Here, we report the appearance of moiré Raman modes from nearly aligned WSe2-WS2 vdWHs in the range of 240-260 cm-1, which are absent in both monolayers and homobilayers of WSe2 and WS2 and in largely misaligned WSe2-WS2 vdWHs. Using first-principles calculations and geometric arguments, we show that these moiré Raman modes are a consequence of the large moiré length scale, which results in zone-folded phonon modes that are Raman active. These modes are sensitive to changes in twist angle, but notably, they occur at identical frequencies for a given small twist angle away from either the 0-degree or 60-degree aligned heterostructure. Our measurements also show a strong Raman intensity modulation in the frequency range of interest, with near 0 and near 60-degree vdWHs exhibiting a markedly different dependence on excitation energy. In near 0-degree aligned WSe2-WS2 vdWHs, a nearly complete suppression of both the moiré Raman modes and the WSe2 A1g Raman mode (∼250 cm-1) is observed when exciting with a 532 nm CW laser at room temperature. Temperature-dependent reflectance contrast measurements demonstrate the significant Raman intensity modulation arises from resonant Raman effects.

Tuning between Quenching and Energy Transfer in DNA-Templated Heterodimer Aggregates.

Molecular excitons, which propagate spatially via electronic energy transfer, are central to numerous applications including light harvesting, organic optoelectronics, and nanoscale computing; they may also benefit applications such as photothermal therapy and photoacoustic imaging through the local generation of heat via rapid excited-state quenching. Here we show how to tune between energy transfer and quenching for heterodimers of the same pair of cyanine dyes by altering their spatial configuration on a DNA template. We assemble "transverse" and "adjacent" heterodimers of Cy5 and Cy5.5 using DNA Holliday junctions. We find that the transverse heterodimers exhibit optical properties consistent with excitonically interacting dyes and fluorescence quenching, while the adjacent heterodimers exhibit optical properties consistent with nonexcitonically interacting dyes and disproportionately large Cy5.5 emission, suggestive of energy transfer between dyes. We use transient absorption spectroscopy to show that quenching in the transverse heterodimer occurs via rapid nonradiative decay to the ground state (∼31 ps) and that in the adjacent heterodimer rapid energy transfer from Cy5 to Cy5.5 (∼420 fs) is followed by Cy5.5 excited-state relaxation (∼700 ps). Accessing such drastically different photophysics, which may be tuned on demand for different target applications, highlights the utility of DNA as a template for dye aggregation.

Tunable Electronic Structure via DNA-Templated Heteroaggregates of Two Distinct Cyanine Dyes.

Molecular excitons are useful for applications in light harvesting, organic optoelectronics, and nanoscale computing. Electronic energy transfer (EET) is a process central to the function of devices based on molecular excitons. Achieving EET with a high quantum efficiency is a common obstacle to excitonic devices, often owing to the lack of donor and acceptor molecules that exhibit favorable spectral overlap. EET quantum efficiencies may be substantially improved through the use of heteroaggregates-aggregates of chemically distinct dyes-rather than individual dyes as energy relay units. However, controlling the assembly of heteroaggregates remains a significant challenge. Here, we use DNA Holliday junctions to assemble homo- and heterotetramer aggregates of the prototypical cyanine dyes Cy5 and Cy5.5. In addition to permitting control over the number of dyes within an aggregate, DNA-templated assembly confers control over aggregate composition, i.e., the ratio of constituent Cy5 and Cy5.5 dyes. By varying the ratio of Cy5 and Cy5.5, we show that the most intense absorption feature of the resulting tetramer can be shifted in energy over a range of almost 200 meV (1600 cm-1). All tetramers pack in the form of H-aggregates and exhibit quenched emission and drastically reduced excited-state lifetimes compared to the monomeric dyes. We apply a purely electronic exciton theory model to describe the observed progression of the absorption spectra. This model agrees with both the measured data and a more sophisticated vibronic model of the absorption and circular dichroism spectra, indicating that Cy5 and Cy5.5 heteroaggregates are largely described by molecular exciton theory. Finally, we extend the purely electronic exciton model to describe an idealized J-aggregate based on Förster resonance energy transfer (FRET) and discuss the potential advantages of such a device over traditional FRET relays.