The study aim was to assess rater agreement of the Resistance Training Skills Battery (RTSB) for adolescents. The RTSB provides an assessment of resistance training skill competency and includes six exercises. The RTSB can be used to assess performance and progress in adolescent resistance training programmes and to provide associated feedback to participants. Individual skill scores are based on the number of performance criteria successfully demonstrated and an overall resistance training skill quotient (RTSQ) is created by summing the six skill scores.
Rationale: Neurocognitive impairments are associated with reduced quality of life and may adversely impact medical compliance, but their prevalence following lung transplantation has not been extensively studied. Objectives: To examine the frequency of neurocognitive impairment following transplantation as well as perioperative factors affecting post-transplant neurocognitive function. Measurements and Main Results: We performed serial assessments of neurocognitive function in a consecutive series of 47 transplant recipients, transplanted between March, 2013 and November, 2013 (45% women; mean age = 53.5 + 17.2). Neurocognitive function was assessed using a composite measure including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score and Trail Making Test parts A and B obtained prior to transplant, at hospital discharge and 3 months following discharge. In addition, the presence of neurocognitive impairment was assessed using the Montreal Cognitive Assessment Battery (MoCA) and in-hospital delirium was assessed using the Confusion Assessment Method (CAM). Results demonstrated that neurocognitive performance initially worsened among non-CF patients and subsequently improved over follow-up (P = .002). Time effects were strongest on Trail making Part B (P < .001) and the RBANS (P = .054). Participants who exhibited delirium during their hospitalization showed poorer performance during follow-up assessments (P = .006). Examination of cognitive impairment rates demonstrated that 21 participants (45%) exhibited neurocognitive impairment (MoCA <26) prior to transplantation while 27 (57%) of participants exhibited impairment after transplantation and 19 (57%) continued to neurocognitive impairment during a 3-month follow-up. Conclusion: Neurocognitive impairments are prevalent among lung transplant candidates and appear to worsen in some patients following transplant. Delirium during hospitalization is associated with worse neurocognitive function following transplant among non-CF patients.
N,N'-Dihexyl-6,6'-dicyanoisoindigo, N,N'-didecyl-5,5',6,6'-tetracyanoisoindigo, N,N'-dihexyl-5,5',6,6'-tetracyanoisoindigo, and N,N'-dihexyl-5,5',6,6'-tetracyanothienoisoindigo have been synthesised in moderate yields by the reaction of corresponding di and tetrabromo species with CuCN, with microwave heating leading to higher yields and fewer side products for the tetrasubstituted species. Di- and tetracyano substitution anodically shifts the molecular reduction potential relative to the unsubstituted cores by ca. 0.4 and 0.8 V, respectively, with the resultant values for the tetracyano derivatives (-0.58 to -0.67 V vs. FeCp2(+/0)) suggesting the possibility of air-stable electron transport. All the synthesised cyano derivatives operate in n-channel OFETs, while the tetrabromothienoisoindigo derivative functions in a p-channel transistor. The tetracyanothienoisoindigo derivative exhibits the highest field-effect electron mobility values - up to 0.04 and 0.09 cm(2) V(-1) s(-1) in spin-coated and inkjet-printed devices respectively - and OFETs incorporating this compound have been shown to operate in air without significant degradation of their mobility values in the saturation regime.
We present a plasmon-active hybrid nanomaterial design with electrochemical tunability of the localized surface plasmon resonances. The plasmonic-active nanostructures are composed of silver nanocube aggregates embedded into an electrochromic polymer coating on an indium tin oxide electrode with the nanocube aggregation controlled by the surface pressure. Such polymer-nanocube hybrid nanomaterials demonstrated unique tunable plasmonic behavior under an applied electrochemical potential. A significant reversible experimental peak shift of 22 nm at an electrical potential of 200 mV has been achieved in these measurements. Finite-difference time-domain (FDTD) simulations show that, under full oxidation potential, a maximal spectral shift of ca. 80 nm can be potentially achieved, which corresponds to a high sensitivity of 178 nm per refractive index unit. Furthermore, FDTD modeling suggests that the electrochemically controlled tunability of plasmonic peaks is caused by reversible changes in the refractive index of the electrochromic polymer coating caused by oxidation or reduction reactions under external electrical potential. Consequently, we define the orthogonal plasmonic resonance shift as a shift that is orthogonal to the redox process responsible for the refractive index change. On the basis of these results, we suggest that the combination of anisotropic nanostructures and electrochromic matrix has the potential to reversibly electrically tune plasmonic resonances over the full visible spectrum.
Esophageal adenocarcinoma is the eighth most common malignancy worldwide. The overall prognosis is poor, with 5-year survival ranges of approximately 15-25%, and 30-50% for patients who can be treated with curative intent. There has been a marked increase in incidence of esophageal adenocarcinoma over the last 30 years, with chronic and severe reflux, diet and obesity identified as principal factors fuelling this rise in the West. Esophageal adenocarcinoma is an exemplar model of an inflammation-associated cancer. The key molecular pathways driving tumor development and influencing tumor biology are the subject of considerable research efforts, and is the principal focus of this review. In addition, the diverse range of changes occurring in the local immune response, tissue microenvironment, metabolic profile, intracellular signaling mechanisms and microRNA signatures are discussed, as well as novel targeted therapies.
Following a cerebral cortex injury such as stroke, excessive inhibition around the core of the injury is thought to reduce the potential for new motor learning. In part, this may be caused by an imbalance of interhemispheric inhibition (IHI); therefore, treatments that relieve the inhibitory drive from the healthy hemisphere to the peri-lesional area may enhance motor recovery. Theta burst stimulation delivered by transcranial magnetic stimulation has been tested as a means of normalizing IHI, but clinical results have been variable. Here we use a new rat model of synaptic IHI to demonstrate that electrical intracranial theta burst stimulation causes long-lasting changes in motor cortex excitability. Further, we show that contralateral intermittent theta burst stimulation (iTBS) blocks IHI via a mechanism involving cannabinoid receptors. Finally, we show that contralesional iTBS applied during recovery from cortical injury in rats improves the recovery of motor function. These findings suggest that theta burst stimulation delivered through implanted electrodes may be a promising avenue to explore for augmenting rehabilitation from brain injury.
We report on a sexithienyl and two donor-acceptor-donor oligothiophenes, employing benzothiadiazole and isoindigo as electron-acceptors, each functionalized with a phosphonic acid group for anchoring onto TiO2 substrates as light-harvesting molecules for dye sensitized solar cells (DSSCs). These dyes absorb light to wavelengths as long as 700 nm, as their optical HOMO/LUMO energy gaps are reduced from 2.40 to 1.77 eV with increasing acceptor strength. The oligomers were adsorbed onto mesoporous TiO2 films on fluorine doped tin oxide (FTO)/glass substrates and incorporated into DSSCs, which show AM1.5 power conversion efficiencies (PCEs) ranging between 2.6% and 6.4%. This work demonstrates that the donor-acceptor-donor (D-A-D) molecular structures coupled to phosphonic acid anchoring groups, which have not been used in DSSCs, can lead to high PCEs.
The VOC loss in several polymer-fullerene solar cells is determined. Based on these data, a major source of photovoltage loss is attributed to the low dielectric constants of the polymers. Such loss is close to zero if the dielectric constant of the polymer-fullerene blend is close to 5.
Although synthetic efforts have been fruitful in coarse color control, variations to an electrochromic polymer (ECP) backbone are less likely to allow for the fine control necessary to access the variations and shades of color needed in display applications. Through the use of thin films of cyan, magenta, and yellow ECPs, non-emissive subtractive color mixing allows the color of an electrochromic device (ECD) to be selected and tailored, increasing access to various subtle shades and allowing for a non-emissive display to exhibit a wide range of colors. Using a dual-active ECD, subtractive color mixing utilizing the cyan-magenta-yellow (CMY) primary system was examined. The bounds of the gamut, or the subset of accessible colors, using these three 3,4-propylenedioxythiophene (PProDOT)-derived materials in combination with the recently recognized 3,4-propylenedioxypyrrole-based minimally color changing polymer (MCCP) were mapped, highlighting the benefit of applying subtractive color mixing toward the development of full-color non-emissive displays. Here, we demonstrate that ECPs are suitable for the generation of a wide gamut of colors through secondary mixing when layered as two distinct films, exhibiting both vibrantly colored and highly transmissive states.
Esophageal resection is associated with a high incidence of postoperative pneumonia. Respiratory complications account for almost half of the readmissions to the critical care unit. Postoperative complications can result in prolonged hospital stay and consequently increase healthcare costs. In cardiac surgery a preoperative inspiratory muscle training program has shown to prevent postoperative pneumonia and reduce length of hospital stay. While in some surgical centers inspiratory muscle training is already used in the preoperative phase in patients undergoing esophageal resection, the added value of this intervention on the reduction of pulmonary complications has not yet been investigated in large surgical populations other than cardiac surgery in a randomized and controlled study design.
Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several in vivo models. However, the effect of SYK inhibition on autoantibody production remains unclear, and SYK inhibition has not been studied in an autoimmune model of renal disease. We, therefore, studied the effect of SYK inhibition in experimental autoimmune GN, a rodent model of antiglomerular basement membrane disease. We show glomerular SYK expression and activation by immunohistochemistry in both experimental and clinical disease, and we show that treatment with fostamatinib, a small molecule kinase inhibitor selective for SYK, completely prevents the induction of experimental autoimmune GN. In established experimental disease, introduction of fostamatinib treatment led to cessation of autoantibody production, reversal of renal injury, preservation of biochemical renal function, and complete protection from lung hemorrhage. B cell ELISpot and flow cytometric analysis suggest that short-term fostamatinib treatment inhibits the generation and activity of antigen-specific B cells without affecting overall B-cell survival. Additionally, fostamatinib inhibited proinflammatory cytokine production by nephritic glomeruli ex vivo and cultured bone marrow-derived macrophages in vitro, suggesting additional therapeutic effects independent of effects on autoantibody production that are likely related to inhibited Fc receptor signaling within macrophages in diseased glomeruli. Given these encouraging results in an in vivo model that is highly applicable to human disease, we believe clinical studies targeting SYK in GN are now warranted.
A solution-processed self-powered polymer electrochromic/photovoltaic (EC/PV) device is realized by vertically integrating two transparent PV cells with an ECD. The EC/PV cell is a net energy positive dual functional device, which can be reversibly switched between transparent and colored states by PV cells for regulating incoming sunlight through windows. The two PV cells can individually, or in pairs, generate electricity.
We report on quadrupolar (donor)2-acceptor sensitizers for dye-sensitized solar cells (DSSCs). The acceptor units are based on dithieno[2,3-a:3',2'-c]phenazine and dithieno[3,2-a:2',3'-c]phenazine coupled to thiophene donors. The optoelectronic and photophysical properties of two sets of isomers reveal a rigid structure for linear isomers and an efficient nonradiative decay for branched isomers. These sensitizers were integrated into DSSCs, and the quadrupolar structure is an operational design, as the IPCE reached up to 38% from 400 nm to 600 nm. The lengthening of the donor chain increases the efficiency, demonstrating the appeal of these oligomeric dyes for DSSCs.
Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine--a key neurotransmitter of the central nervous system--thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.
Eosinophilic disease of the gastrointestinal tract is rare and is characterized by the presence of gastrointestinal symptoms in association with eosinophilic infiltration of any part of the gastrointestinal tract. Clinical presentation of eosinophilic gastroenteritis (EGE) varies not only by the part of the gastrointestinal tract involved but also with the depth of eosinophilic infiltration of the gut wall. We describe the case of a 41-year-old woman with a history of atopy who presented with severe abdominal pain and diarrhoea. Investigations showed large-volume eosinophil-rich ascites and a markedly elevated peripheral blood eosinophil count and immunoglobulin E level. Bone marrow aspirate, trephine biopsy and T-cell studies showed no evidence of underlying haematological malignancy. Vasculitic disease and parasitic infection were systematically excluded. Colonic and upper gastrointestinal biopsies confirmed a diagnosis of EGE with eosinophilic ascites. The patient was treated with systemic corticosteroids and dietary allergen elimination with dramatic therapeutic response. The diagnostic and therapeutic challenges associated with EGE in its various forms are discussed.
Targeting specific molecules and their associated molecular pathways in cancers is becoming an attractive treatment modality with remarkable success in some forms of human cancer. We review a recent study by Maurer and colleagues which examined the level of expression of five different proteins in esophageal cancers and compared this to adjacent normal tissues and whether neoadjuvant chemotherapy has any effect on their level of expression. Among the five proteins investigated, TIMP-4 was suggested as the most promising target as it is not significantly expressed by adjacent normal tissues and its high expression levels persist after neoadjuvant chemotherapy.
The structural organization of three different families of semicrystalline ?-conjugated polymers is reported (poly(3-hexylthiophene) (P3HT), poly[2,6-(4,4-bis-alkyl-4H-cyclopenta-[2,1-b;3,4-b0]-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)](cyclopentadithiophene-benzothiadiazole) (CDT-BTZ) and poly(N,N"-bis-2-octyldodecylnaphtalene-1,4,5,8-bis-dicarboximide-2,6-diyl-alt-5,5-2,2-bithiophene (P(NDI2OD-T2))). These have triggered significant interest for their remarkable charge-transport properties. By performing molecular mechanics/dynamics simulations with carefully re-parameterized force fields, it is illustrated in particular how the supramolecular organization of these conjugated polymers is driven by an interplay between the length and nature of the conjugated monomer unit and the packing of their alkyl side chains, and to what extent it impacts the charge-carrier mobility, as monitored by quantum-chemical calculations of the intermolecular hopping transfer integrals. This Progress Report is concluded by providing generic guidelines for the design of materials with enhanced degrees of supramolecular organization.
In the mammalian neocortex, cells that express parvalbumin (PV neurons) comprise a dominant class of inhibitory neuron that substantially overlaps with the fast/narrow-spiking physiological phenotype. Attention has pronounced effects on narrow-spiking neurons in the extrastriate cortex of macaques, and more consistently so than on their broad-spiking neighbors. Cortical neuromodulation by acetylcholine (ACh) is a candidate mechanism for aspects of attention and in the primary visual cortex (V1) of the macaque, receptors for ACh (AChRs) are strongly expressed by inhibitory neurons. In particular, most PV neurons in macaque V1 express m1 muscarinic AChRs and exogenously applied ACh can cause the release of ?-aminobutyric acid. In contrast, few PV neurons in rat V1 express m1 AChRs. While this could be a species difference, it has also been argued that macaque V1 is anatomically unique when compared with other cortical areas in macaques.
The common marmoset (Callithrix jacchus), a small-bodied New World primate, offers several advantages to complement vision research in larger primates. Studies in the anesthetized marmoset have detailed the anatomy and physiology of their visual system (Rosa et al., 2009) while studies of auditory and vocal processing have established their utility for awake and behaving neurophysiological investigations (Lu et al., 2001a,b; Eliades and Wang, 2008a,b; Osmanski and Wang, 2011; Remington et al., 2012). However, a critical unknown is whether marmosets can perform visual tasks under head restraint. This has been essential for studies in macaques, enabling both accurate eye tracking and head stabilization for neurophysiology. In one set of experiments we compared the free viewing behavior of head-fixed marmosets to that of macaques, and found that their saccadic behavior is comparable across a number of saccade metrics and that saccades target similar regions of interest including faces. In a second set of experiments we applied behavioral conditioning techniques to determine whether the marmoset could control fixation for liquid reward. Two marmosets could fixate a central point and ignore peripheral flashing stimuli, as needed for receptive field mapping. Both marmosets also performed an orientation discrimination task, exhibiting a saturating psychometric function with reliable performance and shorter reaction times for easier discriminations. These data suggest that the marmoset is a viable model for studies of active vision and its underlying neural mechanisms.
Theta burst stimulation (TBS) is a pattern of repetitive transcranial magnetic stimulation that has been demonstrated to facilitate or suppress human corticospinal excitability when applied intermittently (iTBS) or continuously (cTBS), respectively. While the fundamental pattern of TBS, consisting of bursts of 50 Hz stimulation repeated at a 5 Hz theta frequency, induces synaptic plasticity in animals and in vitro preparations, the relationship between TBS and underlying cortical firing patterns in the human cortex has not been elucidated.
Cardiovascular disease (CVD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus. The etiopathogenesis of premature CVD is not fully understood, but recently interferon-alpha (IFN?) has been implicated as a contributing factor. Since IFN? has been associated with both disease activity and endothelial dysfunction in lupus patients, we aimed to determine whether IFN? has direct effects on human aortic endothelial cell (HAoEC) function in vitro. We studied the function of IFN?2b-treated HAoECs in terms of cell proliferation, capillary-like network formation, and nitric oxide (NO) generation. Changes in gene expression were also analyzed using an exon gene array. IFN?2b regulated the expression of 198 genes, including recognized interferon-stimulated genes (ISGs). Gene ontology analysis showed over-representation of genes involved in antigen presentation and host response to virus but no significant changes in clusters of genes recognized as important in endothelial cell activation or dysfunction. HAoEC proliferation, tubule formation, and NO bioavailability were unchanged, suggesting that IFN? in isolation does not have a direct impact on aortic endothelial cell function.
There is increasing recognition of the impact of being overweight and obese on the development of cancers at diverse sites including the gastrointestinal tract. Large epidemiological studies indicate that up to 14% of tumours may be related to obesity. Pathophysiological mechanisms underpinning this association are not well understood and so are discussed in this review.
Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC.
Cross-boundary nutrient inputs can enhance and sustain populations of organisms in nutrient-poor recipient ecosystems. For example, Pacific salmon (Oncorhynchus spp.) can deliver large amounts of marine-derived nutrients to freshwater ecosystems through their eggs, excretion, or carcasses. This has led to the question of whether nutrients from one generation of salmon can benefit juvenile salmon from subsequent generations. In a study of 12 streams on the central coast of British Columbia, we found that the abundance of juvenile coho salmon was most closely correlated with the abundance of adult pink salmon from previous years. There was a secondary role for adult chum salmon and watershed size, followed by other physical characteristics of streams. Most of the coho sampled emerged in the spring, and had little to no direct contact with spawning salmon nutrients at the time of sampling in the summer and fall. A combination of techniques suggest that subsidies from spawning salmon can have a strong, positive, time-delayed influence on the productivity of salmon-bearing streams through indirect effects from previous spawning events. This is the first study on the impacts of nutrients from naturally-occurring spawning salmon on juvenile population abundance of other salmon species.
Anatomical investigations have revealed connections between the intralaminar thalamic nuclei and areas such as the superior colliculus (SC) that receive short latency input from visual and auditory primary sensory areas. The intralaminar nuclei in turn project to the major input nucleus of the basal ganglia, the striatum, providing this nucleus with a source of subcortical excitatory input. Together with a converging input from the cerebral cortex, and a neuromodulatory dopaminergic input from the midbrain, the components previously found necessary for reinforcement learning in the basal ganglia are present. With this intralaminar sensory input, the basal ganglia are thought to play a primary role in determining what aspect of an organism's own behavior has caused salient environmental changes. Additionally, subcortical loops through thalamic and basal ganglia nuclei are proposed to play a critical role in action selection. In this mini review we will consider the anatomical and physiological evidence underlying the existence of these circuits. We will propose how the circuits interact to modulate basal ganglia output and solve common behavioral learning problems of agency determination and action selection.
We report on the optimization of the capacitive behavior of poly(3,4-ethylenedioxythiophene) (PEDOT) films as polymeric electrodes in flexible, Type I electrochemical supercapacitors (ESCs) utilizing ionic liquid (IL) and organic gel electrolytes. The device performance was assessed based on figures of merit that are critical to evaluating the practical utility of electroactive polymer ESCs. PEDOT/IL devices were found to be highly stable over hundreds of thousands of cycles and could be reversibly charged/discharged at scan rates between 500 mV/s and 2 V/s depending on the polymer loading. Furthermore, these devices exhibit leakage currents and self-discharge rates that are comparable to state of the art electrochemical double-layer ESCs. Using an IL as device electrolyte allowed an extension of the voltage window of Type I ESCs by 60%, resulting in a 2.5-fold increase in the energy density obtained. The efficacies of tjese PEDOT ESCs were assessed by using them as a power source for a high-contrast and fast-switching electrochromic device, demonstrating their applicability in small organic electronic-based devices.
Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) have a significantly increased risk of cardiovascular disease (CVD). The reason for this is unclear but may be due, at least in part, to the failure of endothelial repair mechanisms. Over the last 15years there has been much interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD. In the circulation there are two distinct populations of cells; myeloid angiogenic cells (MACs) which augment repair by the paracrine secretion of angiogenic factors, and outgrowth endothelial cells (OECs) which are true endothelial progenitor cells (EPCs) and promote vasculogenesis by differentiating into mature endothelium. There are marked abnormalities in the number and function of these cells in patients with RA and SLE. Inflammatory cytokines including interferon-alpha (IFN?) and tumour-necrosis factor alpha (TNF?) both impair MAC and OEC function ex vivo and may therefore contribute to the CVD risk in these patients. Whilst administration of mononuclear cells, MACs and other progenitors has improved cardiovascular outcomes in the acute setting, this is not a viable option in chronic disease. The pharmacological manipulation of MAC/OEC function in vivo however has the potential to significantly improve endothelial repair and thus reduce CVD in this high risk population.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.
The following paper on gastroesophageal reflux disease (GERD) and Barretts esophagus (BE) includes commentaries on defining esophageal landmarks; new techniques for evaluating upper esophageal sphincter (UES) tone; differential diagnosis of GERD, BE, and hiatal hernia (HH); the use of high-resolution manometry for evaluation of reflux; the role of fundic relaxation in reflux; the use of 24-h esophageal pH-impedance testing in differentiating acid from nonacid reflux and its potential inclusion in future Rome criteria; classification of endoscopic findings in GERD; the search for the cell origin that generates BE; and the relationship between BE, Barretts carcinoma, and obesity.
This paper presents commentaries on animal models used for Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) research; acid- and bile-induced chromosomal instability and clonal selection during the progression of BE to EAC; how the components of gastric refluxate, especially acid and bile salts, promote carcinogenesis in metaplastic BE; genome-wide changes in DNA methylation and transcription involved in BE carcinogenesis; the potential role of miRNA in the development of BE and EAC; the effect of inflammatory cytokines linked to obesity on the activation of cell-death pathways and cell survival in BE and esophageal cancer; and the role of autophagy in esophageal cancer development.
Aging poses one of the largest risk factors for the development of cardiovascular disease. The increased propensity toward vascular pathology with advancing age maybe explained, in part, by a reduction in the ability of circulating endothelial progenitor cells to contribute to vascular repair and regeneration. Although there is evidence to suggest that colony forming unit-Hill cells and circulating angiogenic cells are subject to age-associated changes that impair their function, the impact of aging on human outgrowth endothelial cell (OEC) function has been less studied. We demonstrate that OECs isolated from cord blood or peripheral blood samples from young and old individuals exhibit different characteristics in terms of their migratory capacity. In addition, age-related structural changes were discovered in OEC heparan sulfate (HS), a glycocalyx component that is essential in many signalling pathways. An age-associated decline in the migratory response of OECs toward a gradient of VEGF significantly correlated with a reduction in the relative percentage of the trisulfated disaccharide, 2-O-sulfated-uronic acid, N, 6-O-sulfated-glucosamine (UA[2S]-GlcNS[6S]), within OEC cell surface HS polysaccharide chains. Furthermore, disruption of cell surface HS reduced the migratory response of peripheral blood-derived OECs isolated from young subjects to levels similar to that observed for OECs from older individuals. Together these findings suggest that aging is associated with alterations in the fine structure of HS on the cell surface of OECs. Such changes may modulate the migration, homing, and engraftment capacity of these repair cells, thereby contributing to the progression of endothelial dysfunction and age-related vascular pathologies.
Obliterative bronchiolitis (OB) post-lung transplantation involves IL-17-regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB is unknown. The current study examines the role of complement activation in OB. Complement-regulatory protein (CRP) (CD55, CD46, complement receptor 1-related protein y/CD46) expression was downregulated in human and murine OB; and C3a, a marker of complement activation, was upregulated locally. IL-17 differentially suppressed complement receptor 1-related protein y expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen- or autoantigen (type V collagen)-reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17-mediated downregulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed-forward loop that may enhance CRP downregulation, suggesting that complement blockade could be a therapeutic strategy for OB.
Oncologists are now prescribing more oral chemotherapy than ever before, thus placing the onus for taking the right dose at the right time under the right circumstances directly on the patient. This study was undertaken to understand emerging adherence issues and to explore available adherence assessment tools. This two-part study (1) examined N0747, a randomized phase II trial that tested the oral agents, sunitinib and capecitabine, in patients with metastatic esophageal cancer from an adherence standpoint, and (2) conducted a systematic review to compile and assess adherence tools that can be used in future clinical trials. First, in N0747, patients were assigned to sunitinib and capecitabine versus capecitabine; 53 chemotherapy cycles were prescribed to this 12-patient cohort. Nearly all patients denoted that they "always or almost always" took their pills as prescribed, and two patients who reported lack of full adherence suffered from grade 3+ adverse events. Surprisingly, however, over 14 cycles, 9 patients reported grade 3+ toxicity but checked "always or almost always" to describe their adherence. No relationships were observed between adherence and cancer outcomes. Secondly, 21 articles identified the following adherence tools: (1) healthcare providers interviews, (2) patient-reported adherence with diaries/calendars, (3) patient-completed adherence scales, (4) medication event monitoring, (5) automated voice response, (6) drug/metabolite assays, and (7) prescription databases. Of note, only the automated voice response seems capable of real-time detection of over-adherence, as observed in N0747. Oral chemotherapy adherence should be further studied, particularly from the standpoint of over-adherence.
Humans can rapidly recognize a multitude of objects despite differences in their appearance. The neural mechanisms that endow high-level sensory neurons with both selectivity to complex stimulus features and "tolerance" or invariance to identity-preserving transformations, such as spatial translation, remain poorly understood. Previous studies have demonstrated that both tolerance and selectivity to conjunctions of features are increased at successive stages of the ventral visual stream that mediates visual recognition. Within a given area, such as visual area V4 or the inferotemporal cortex, tolerance has been found to be inversely related to the sparseness of neural responses, which in turn was positively correlated with conjunction selectivity. However, the direct relationship between tolerance and conjunction selectivity has been difficult to establish, with different studies reporting either an inverse or no significant relationship. To resolve this, we measured V4 responses to natural scenes, and using recently developed statistical techniques, we estimated both the relevant stimulus features and the range of translation invariance for each neuron. Focusing the analysis on tuning to curvature, a tractable example of conjunction selectivity, we found that neurons that were tuned to more curved contours had smaller ranges of position invariance and produced sparser responses to natural stimuli. These trade-offs provide empirical support for recent theories of how the visual system estimates 3D shapes from shading and texture flows, as well as the tiling hypothesis of the visual space for different curvature values.
Optogenetics combines optics and genetics to control neuronal activity with cell-type specificity and millisecond temporal precision. Its use in model organisms such as rodents, Drosophila, and Caenorhabditis elegans is now well-established. However, application of this technology in nonhuman primates (NHPs) has been slow to develop. One key challenge has been the delivery of viruses and light to the brain through the thick dura mater of NHPs, which can only be penetrated with large-diameter devices that damage the brain. The opacity of the NHP dura prevents visualization of the underlying cortex, limiting the spatial precision of virus injections, electrophysiological recordings, and photostimulation. Here, we describe a new optogenetics approach in which the native dura is replaced with an optically transparent artificial dura. This artificial dura can be penetrated with fine glass micropipettes, enabling precisely targeted injections of virus into brain tissue with minimal damage to cortex. The expression of optogenetic agents can be monitored visually over time. Most critically, this optical window permits targeted, noninvasive photostimulation and concomitant measurements of neuronal activity via intrinsic signal imaging and electrophysiological recordings. We present results from both anesthetized-paralyzed (optical imaging) and awake-behaving NHPs (electrophysiology). The improvements over current methods made possible by the artificial dura should enable the widespread use of optogenetic tools in NHP research, a key step toward the development of therapies for neuropsychiatric and neurological diseases in humans.
Advances in colloidal inorganic nanocrystal synthesis and processing have led to the demonstration of organic-inorganic hybrid photovoltaic (PV) cells using low-cost solution processes from blends of conjugated polymer and colloidal nanocrystals. However, the performance of such hybrid PV cells has been limited due to the lack of control at the complex interfaces between the organic and inorganic hybrid active materials. Here we show that the efficiency of hybrid PV devices can be significantly enhanced by engineering the polymer-nanocrystal interface with proper chemical treatment. Using two different conjugated polymers, poly(3-hexylthiophene) (P3HT) and poly[2,6-(4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b]-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (PCPDTBT), we show that treating the polymer:nanocrystal hybrid film in an ethanedithiol-containing acetonitrile solution can increase the efficiency of the hybrid PV devices by 30-90%, and a maximum power conversion efficiency of 5.2 ± 0.3% was obtained in the PCPDTBT:CdSe devices at 0.2 sun (AM 1.5G), which was slightly reduced to 4.7 ± 0.3% at 1 sun. The ethanedithiol treatment did not result in significant changes in the morphology and UV-vis optical absorption of the hybrid thin films; however, infrared absorption, NMR, and X-ray photoelectron spectroscopies revealed the effective removal of organic ligands, especially the charged phosphonic acid ligands, from the CdSe nanorod surface after the treatment, accompanied by the possible monolayer passivation of nanorod surfaces with Cd-thiolates. We attribute the hybrid PV cell efficiency increase upon the ethanedithiol treatment to the reduction in charge and exciton recombination sites on the nanocrystal surface and the simultaneous increase in electron transport through the hybrid film.
Neuroepithelial Transforming Gene 1 (NET1) is a well characterised oncoprotein and a proven marker of an aggressive phenotype in a number of cancers, including gastric adenocarcinoma. We aimed to investigate whether NET1 plays a functional role in oesophageal cancer (OAC) and its pre-malignant phenotype Barretts oesophagus.
Accurate pretreatment staging is essential to decision making for patients with esophageal and junctional cancers, particularly when choosing endoscopic therapy or a multimodal approach. As the efficacy of endoscopic ultrasonography (EUS) has been reported as variable, we assessed it prospectively in a large cohort from a high-volume center.
Previous studies have shown that neurons in area V4 are involved in the processing of shapes of intermediate complexity and are sensitive to curvature. These studies also suggest that curvature-tuned neurons are position invariant. We sought to examine the mechanisms that endow V4 neurons with these properties. Consistent with previous studies, we found that response rank order to the most- and least-preferred stimuli was preserved throughout the receptive field. However, a fine-grained analysis of shape tuning revealed a surprising result: V4 neurons tuned to highly curved shapes exhibit very limited translation invariance. At a fine spatial scale, these neurons exhibit local variation in orientation. In contrast, neurons that prefer straight contours exhibit spatially invariant orientation-tuning and homogenous fine-scale orientation maps. Both of these patterns are consistent with a simple orientation-pooling model, with tuning for straight or curved shapes resulting, respectively, from pooling of homogenous or heterogeneous orientation signals inherited from early visual areas.
Iatrogenic diaphragmatic hernias can occur after abdominal or thoracic surgery. Acute presentation of a diaphragmatic hernia varies depending on the extent and nature of the organ which has herniated. The initial diagnosis can be challenging due to the nonspecific nature of the presenting symptoms. Delay in diagnosis poses a significant risk to the patient, and a rapid deterioration can occur in the context of strangulation. We outline two cases of acute gastric herniation through a defect in the diaphragm after an open and a laparoscopic nephrectomy. Both had characteristic findings on imaging, required emergency, surgery and had a successful outcome. Both cases highlight the potential for late presentation with non-specific symptoms and the necessity for urgent surgical management where gastric perfusion is compromised.
Recent studies have demonstrated that some patients with chronic myeloid leukemia (CML) can maintain remission after discontinuation of imatinib. A prerequisite is stable, undetectable BCR-ABL1. It is not known how many patients achieve this response or the factors associated with its achievement. We examined 423 de novo imatinib-treated patients to determine the cumulative incidence of achieving the discontinuation criteria as defined in the CML8 study (?2 years of undetectable BCR-ABL1 [Stable MR(4.5)]), and predictive factors. After 8 years of imatinib, the cumulative incidence of Stable MR(4.5) was 36.5%. Therefore, 9% to 15% of first-line imatinib-treated patients would maintain remission after discontinuation. The BCR-ABL1 level at 3 months and factors at diagnosis were examined for association with Stable MR(4.5): Sokal risk, age, sex, and assigned imatinib dose. The only independent predictors were female sex (54.4% vs 27.2%; P = .018) and the 3-month BCR-ABL1 (P < .001). The highest cumulative incidence of Stable MR(4.5) after 8 years was 78.2% for patients with BCR-ABL1 ? 0.10%(IS) at 3 months (n = 38). Time to major molecular response (MMR) influenced the time to reach Stable MR(4.5) (P < .001), suggesting slower dynamics of response with a delayed MMR. The findings justify the focus on rapid reduction of BCR-ABL1 as a strategy to maximize potential suitability for imatinib discontinuation studies. The Iris trial was registered at http://www.clinicaltrials.gov as NCT00006343. The Tops trial was registered at http://www.clinicaltrials.gov as NCT00124748. The TIDEL I trial was registered at www.ANZCTR.org.au as ACTRN12607000614493. The TIDEL II trial was registered at www.ANZCTR.org.au as ACTRN12607000325404.
Life-history traits such as fecundity and offspring size are shaped by investment trade-offs faced by mothers and mediated by environmental conditions. We use a 21-year time series for three populations of wild sockeye salmon (Oncorhynchus nerka) to test predictions for such trade-offs and responses to conditions faced by females during migration, and offspring during incubation. In years when their 1100 km upstream migration was challenged by high water discharges, females that reached spawning streams had invested less in gonads by producing smaller but not fewer eggs. These smaller eggs produced lighter juveniles, and this effect was further amplified in years when the incubation water was warm. This latter result suggests that there should be selection for larger eggs to compensate in populations that consistently experience warm incubation temperatures. A comparison among 16 populations, with matching migration and rearing environments but different incubation environments (i.e., separate spawning streams), confirmed this prediction; smaller females produced larger eggs for their size in warmer creeks. Taken together, these results reveal how maternal phenotype and environmental conditions can shape patterns of reproductive investment and consequently juvenile fitness-related traits within and among populations.
4,4-Bis-(4-pentenyl)-dithieno[3,2-b:2,3-d]germole was synthesized as a functional building block for the efficient preparation of dithienogermole (DTG) derivatives with varying alkyl chain lengths and pendant functionalities in excellent yields. These derivatives were efficiently isolated via olefin cross-metathesis followed by hydrogenation.
Excess visceral adiposity is associated with increased gastrointestinal cancer risk. Evidence suggests that the systemic inflammation and dysmetabolism observed in visceral obesity underpins this association. Along with magnetic resonance imaging, computed tomography is a gold standard for abdominal fat quantification and is routinely available for gastrointestinal cancer research. However, no gender-specific cutoff values are currently available for classifying visceral obesity in white populations. Using the metabolic syndrome (MetSyn) as an indicator of obesity-associated dysmetabolism, this study aimed to establish pathologically relevant, gender-specific cut-off values for use in obesity-associated cancer research. Total, visceral and subcutaneous fat areas were calculated between the L3 and L4 invertebral space from computed tomography scans in a cohort of 170 males and 66 females undergoing gastrointestinal resection. Receiver operating characteristics analysis was used to determine cut-off values for total, visceral and subcutaneous fat areas associated with MetSyn. Linear regression was used to correlate these values with waist circumference. Visceral fat area (VFA) strongly correlated with the presence of MetSyn (P < .0001). The cut-off value for VFA associated with the presence of MetSyn was 163.8 cm(2) in males (83.6% sensitivity, 62.5% specificity) and 80.1 cm(2) for females (96% sensitivity, 73.2% specificity). The waist circumference corresponding to these VFA values was 96.1 cm in males and 83.2 cm in females. This study is the first to generate gender-specific and pathologically relevant cut-off values for VFA in patients with gastrointestinal cancer. In the field of obesity-associated research, this new anthropometric measure is of paramount importance for determining the accurate pathological obesity status of cancer patients.
Esophageal perforation in achalasia is rare. The risk would mainly follow pneumatic dilatation, and spontaneous perforation has not been described. We report a case of spontaneous rupture of the midesophagus in a 56-year-old woman with treated achalasia in whom the perforation occurred during a meal and was not preceded by emesis. A gastrografin swallow confirmed extravasation of contrast medium from the esophagus, and endoscopy revealed significant esophageal food stasis, consistent with achalasia, with a large tear in the midesophagus and gross mediastinal contamination. She subsequently underwent a three-stage esophagectomy with an uneventful recovery.
Attention improves the encoding of visual stimuli. One mechanism that is implicated in facilitating sensory encoding is the firing of action potentials in bursts. We tested the hypothesis that when spatial attention is directed to a stimulus, this causes an increase in burst firing to the attended stimulus. To the contrary, we found an attention-dependent reduction in burstiness among putative pyramidal neurons in macaque area V4. We accounted for this using a conductance-based Hodgkin-Huxley style model in which attentional modulation stems from scaling excitation and inhibition. The model exhibited attention-dependent increases in firing rate and made the surprising and correct prediction that when attention is directed into a neurons receptive field, this reduces action-potential height. The model thus provided a unified explanation for three distinct forms of attentional modulation, two of them previously undescribed, and implicates scaling of the responses of excitatory and inhibitory input populations in mediating attention.
Neurodegeneration accompanies the process of natural aging, reducing the ability to perform functional daily activities. Transcranial direct current stimulation (tDCS) alters neuronal excitability and motor performance; however its beneficial effect on the induction of primary motor cortex (M1) plasticity in older adults is unclear. Moreover, little is known as to whether the tDCS electrode arrangement differentially affects M1 plasticity and motor performance in this population. In a double-blinded, cross-over trial, we compared unilateral, bilateral and sham tDCS combined with visuomotor tracking, on M1 plasticity and motor performance of the non-dominant upper limb, immediately post and 30 min following stimulation. We found (a) unilateral and bilateral tDCS decreased tracking error by 12-22% at both time points; with sham decreasing tracking error by 10% at 30 min only, (b) at both time points, motor evoked potentials (MEPs) were facilitated (38-54%) and short-interval intracortical inhibition was released (21-36%) for unilateral and bilateral conditions relative to sham, (c) there were no differences between unilateral and bilateral conditions for any measure. These findings suggest that tDCS modulated elements of M1 plasticity, which improved motor performance irrespective of the electrode arrangement. The results provide preliminary evidence indicating that tDCS is a safe non-invasive tool to preserve or improve neurological function and motor control in older adults.
Scientific management of wildlife requires confronting the complexities of natural and social systems. Uncertainty poses a central problem. Whereas the importance of considering uncertainty has been widely discussed, studies of the effects of unaddressed uncertainty on real management systems have been rare. We examined the effects of outcome uncertainty and components of biological uncertainty on hunt management performance, illustrated with grizzly bears (Ursus arctos horribilis) in British Columbia, Canada. We found that both forms of uncertainty can have serious impacts on management performance. Outcome uncertainty alone - discrepancy between expected and realized mortality levels - led to excess mortality in 19% of cases (population-years) examined. Accounting for uncertainty around estimated biological parameters (i.e., biological uncertainty) revealed that excess mortality might have occurred in up to 70% of cases. We offer a general method for identifying targets for exploited species that incorporates uncertainty and maintains the probability of exceeding mortality limits below specified thresholds. Setting targets in our focal system using this method at thresholds of 25% and 5% probability of overmortality would require average target mortality reductions of 47% and 81%, respectively. Application of our transparent and generalizable framework to this or other systems could improve management performance in the presence of uncertainty.
A general rule in ecology is that the abundance of species or individuals in communities sharing a common energy source decreases with increasing body size. However, external energy inputs in the form of resource subsidies can modify this size spectrum relationship. Here, we provide the first test of how a marine resource subsidy can affect size spectra of terrestrial communities, based on energy derived from Pacific salmon carcasses affecting a forest soil community beside streams in western Canada. Using both species-based and individual approaches, we found size structuring in this forest soil community, and transient community-wide doubling of standing biomass in response to energy pulses from Pacific salmon carcasses. One group of species were clear outliers in the middle of the size spectrum relationship: larval calliphorid and dryomyzid flies, which specialize on salmon carcasses, and which showed a tenfold increase in biomass in their size class when salmon were available. Thus, salmon subsidize their escape from the size spectrum. These results suggest that using a size-based perspective of resource subsidies can provide new insights into the structure and functioning of food webs.
A combination of electrochromism and electroluminescence in functional materials could lead to single-layer dual electrochromic/electroluminescent (EC/EL) display devices, capable of simultaneous operation in emissive and reflective modes. Whereas such next generation displays could provide optimal visibility in any ambient lighting situation, materials available that exhibit such characteristics in the active layer are limited due to the required intrinsic multifunctionality (i.e., redox activity, electroluminescence, electrochromism, and ion conductivity) and to date can only be achieved via the rational design of ionic transition-metal complexes. Reported herein is the synthesis and characterization of a new family of acrylate-containing ruthenium (tris)bipyridine-based coordination complexes with multifunctional characteristics. Potential use of the presented compounds in EC/EL devices is established, as they are applied as cross-linked electrochromic films and electrochemiluminescent layers in light-emitting electrochemical cell devices. Electrochromic switching of the polymeric networks between yellow, orange, green, brown and transmissive states is demonstrated, and electrochemiluminescent devices based on the complexes synthesized show red-orange to deep red emission with ?(max) ranging from 680 to 722 nm and luminance up to 135 cd/m(2). Additionally, a dual EC/EL device prototype is presented where light emission and multicolor electrochromism occur from the same pixel comprised of a single active layer, demonstrating a true combination of these properties in ionic transition-metal complexes.
The insulin-like growth factor (IGF) pathway and visceral obesity have been independently linked with esophageal cancer. This study aimed to delineate the differential and interlinked role of visceral obesity and the IGF-1 system in esophageal adenocarcinoma and esophageal squamous-cell carcinoma (SCC).
This paper presents emerging evidence linking visceral adiposity and the metabolic syndrome (MetSyn) with carcinogenesis. The link between obesity and cancer has been clearly identified in a multitude of robust epidemiological studies. Research is now focusing on the role of visceral adipose tissue in carcinogenesis; as it is recognised as an important metabolic tissue that secretes factors that systemically alter the immunological, metabolic and endocrine milieu. Excess visceral adipose tissue gives rise to a state of chronic systemic inflammation with associated insulin resistance and dysmetabolism, collectively known as the MetSyn. Prospective cohort studies have shown associations between visceral adiposity, the MetSyn and increased risk of breast cancer, colorectal cancer and oesophageal adenocarcinoma. Furthermore, visceral adiposity and the MetSyn have been associated with increased tumour progression and reduced survival. The mechanisms by which visceral adiposity and the MetSyn are thought to promote tumorigenesis are manifold. These include alterations in adipokine secretion and cell signalling pathways. In addition, hyperinsulinaemia, subsequent insulin resistance and stimulation of the insulin-like growth factor-1 axis have all been linked with visceral adiposity and promote tumour progression. Furthermore, the abundance of inflammatory cells in visceral adipose tissue, including macrophages and T-cells, create systemic inflammation and a pro-tumorigenic environment. It is clear from current research that excess visceral adiposity and associated dysmetabolism play a central role in the pathogenesis of certain cancer types. Further research is required to elucidate the exact mechanisms at play and identify potential targets for intervention.
A general scheme for the synthesis of ?-conjugated molecules based on 3,4-dioxypyrroles is presented. The ?-conjugated molecules were synthesized via Pd-mediated decarboxylative cross-coupling using various 3,4-propylenedioxypyrrole carboxylic acids and aryl bromides, including the base-sensitive electron acceptor 4,7-dibromobenzo[c][1,2,5]thiadiazole (BTD). N-Methylpyrrolidone was used as solvent, Pd(acac)(2) was employed as the palladium source and P(o-tol)(3) as the ligand. The methodology was applied to 3,4-dioxypyrrole monoacids and 3,4-dioxypyrrole diacids to produce multi-ring ?-conjugated systems containing phenyl, thiophenyl, BTD, and pyridinyl units. In general, the method has yielded a practical approach for the synthesis of 3,4-dioxypyrrole-based ?-conjugated molecules in acceptable to high yields of 44-94%.
Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols.
Experimental autoimmune glomerulonephritis (EAG) can be induced in Wistar-Kyoto (WKY) rats by immunization with the recombinant NC1 domain of the alpha 3 chain of type IV collagen [?3(IV)NC1]. EAG is characterized by circulating and deposited anti-?3(IV)NC1 antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. Programmed death-1 (PD-1) receptor is preferentially expressed on activated T cells and binds two known ligands present on antigen presenting cells, PDL-1 and PDL-2. Engagement of PD-1 by its ligands results in a negative regulatory effect, with inhibition of downstream cellular signalling events and diminished cellular proliferation.
The nanoscale morphology and photoactivity of conjugated polyelectrolytes (CPEs) deposited from different solvents onto single crystal TiO(2) were investigated with atomic force microscopy (AFM) and photocurrent spectroscopy. CPE surface coverages on TiO(2) could be incremenentally increased by adsorbing the CPEs from static solutions. The solvents used for polymer adsorption influenced the surface morpohology of the CPEs on the TiO(2) surface. Photocurrent spectroscopy measurements in aqueous electrolytes, using iodide as a hole scavenger, revealed that the magnitude of the sensitized photocurrents was related to the surface coverages and the degree of aggregation of the CPEs as determined by AFM imaging. Absorbed photon-to-current efficiencies approaching 50% were measured for CPE layers as thick as 4 nm on TiO(2). These results suggest that precise control of CPE morphology at the TiO(2) interface can be achieved through optimization of the deposition conditions to improve the power conversion efficiencies of polymer-sensitized solar cells.
In this work, we develop an experimental testbed that couples biotic and abiotic metrics for studying, quantifying and predicting the effects of chronic electrode implantation on neural electrode performance. The rationale is based on the observation that long-term functionality is the outcome of the interactions between the dynamics of the neuronal environment and the properties of the electrode itself. By combining and analyzing the substantially richer information available in the spatiotemporal dynamics of neurons with biotic and abiotic metrics such as biochemical markers, histochemistry, SEM imaging, and electrochemistry, we seek to quantitatively improve our understanding of the functional modifications underlying the long-term responses of electrode implants. The goal is to ultimately enable the design of future reliable interfaces. In our preliminary analysis using this biotic-abiotic approach of an electrode 18 days post-implant, we observed both structural and histochemical responses related to chronic electrode implantation. These were coupled to daily functional changes in electrode performance. Interestingly, these changes were not correlated with markers of brain injury at the time of electrode explantation. Future work using this multidisciplinary approach is directed to providing a detailed perspective into long-term microelectrode performance.
While the normal inflammatory cascade is self-limiting and crucial for host protection against invading pathogens and in the repair of damaged tissue, a wealth of evidence suggests that chronic inflammation is the engine driving carcinogenesis. Over a period of almost 150 years the link between inflammation and cancer development has been well established. In this chapter we discuss the fundamental concepts and mechanisms behind normal inflammation as it pertains to wound healing. We further discuss the association of inflammation and its role in carcinogenesis, highlighting the different stages of cancer development, namely tumour initiation, promotion and progression. With both the innate and adaptive arms of the immune system being central to the inflammatory process, we examine the role of a number of immune effectors in contributing to the carcinogenic process. In addition, we highlight the influences of host genetics in altering cancer risk.
Tonically active neurons in the primate striatum, believed to be cholinergic interneurons (CINs), respond to sensory stimuli with a pronounced pause in firing. Although inhibitory and neuromodulatory mechanisms have been implicated, it is not known how sensory stimuli induce firing pauses in CINs in vivo. Here, we used intracellular recordings in anesthetized rats to investigate the effectiveness of a visual stimulus at modulating spike activity in CINs. Initially, no neuron was visually responsive. However, following pharmacological activation of tecto-thalamic pathways, the firing pattern of most CINs was significantly modulated by a light flashed into the contralateral eye. Typically, this induced an excitation followed by a pause in spike firing, via an underlying depolarization-hyperpolarization membrane sequence. Stimulation of thalamic afferents in vitro evoked similar responses that were independent of synaptic inhibition. Thus, visual stimulation likely induces an initial depolarization via a subcortical tecto-thalamo-striatal pathway, pausing CIN firing through an intrinsic afterhyperpolarization.
One of the most well established forms of attentional modulation is an increase in firing rate when attention is directed into the receptive field of a neuron. The degree of rate modulation, however, can vary considerably across individual neurons, especially among broad spiking neurons (putative pyramids). We asked whether this heterogeneity might be correlated with a neuronal response property that is used in intracellular recording studies to distinguish among distinct neuronal classes: the burstiness of the neuronal spike train. We first characterized the burst spiking behavior of visual area V4 neurons and found that this varies considerably across the population, but we did not find evidence for distinct classes of burst behavior. Burstiness did, however, vary more widely across the class of neurons that shows the greatest heterogeneity in attentional modulation, and within that class, burstiness helped account for differences in attentional modulation. Among these broad spiking neurons, rate modulation was primarily restricted to bursty neurons, which as a group showed a highly significant increase in firing rate with attention. Furthermore, every bursty broad spiking neuron whose firing rate was significantly modulated by attention exhibited an increase in firing rate. In contrast, non-bursty broad spiking neurons exhibited no net attentional modulation, and, although some individual neurons did show significant rate modulation, these were divided among neurons showing increases and decreases. These findings show that macaque area V4 shows a range of bursting behavior and that the heterogeneity of attentional modulation can be explained, in part, by variation in burstiness.
Fast-spiking interneurones (FSIs) constitute a prominent part of the inhibitory microcircuitry of the striatum; however, little is known about their recruitment by synaptic inputs in vivo. Here, we report that, in contrast to cholinergic interneurones (CINs), FSIs (n = 9) recorded in urethane-anaesthetized rats exhibit Down-to-Up state transitions very similar to spiny projection neurones (SPNs). Compared to SPNs, the FSI Up state membrane potential was noisier and power spectra exhibited significantly larger power at frequencies in the gamma range (55-95 Hz). The membrane potential exhibited short and steep trajectories preceding spontaneous spike discharge, suggesting that fast input components controlled spike output in FSIs. Spontaneous spike data contained a high proportion (43.6 ± 32.8%) of small inter-spike intervals (ISIs) of <30 ms, setting FSIs clearly apart from SPNs and CINs. Cortical-evoked inputs had slower dynamics in SPNs than FSIs, and repetitive stimulation entrained SPN spike output only if the stimulation was delivered at an intermediate frequency (20 Hz), but not at a high frequency (100 Hz). Pharmacological induction of an activated ECoG state, known to promote rapid FSI spiking, mildly increased the power (by 43 ± 55%, n = 13) at gamma frequencies in the membrane potential of SPNs, but resulted in few small ISIs (<30 ms; 4.3 ± 6.4%, n = 8). The gamma frequency content did not change in CINs (n = 8). These results indicate that FSIs are uniquely responsive to high-frequency input sequences. By controlling the spike output of SPNs, FSIs could serve gating of top-down signals and long-range synchronisation of gamma-oscillations during behaviour.
There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective.
We report the synthesis and bulk heterojunction photovoltaic performance of the first dithienogermole (DTG)-containing conjugated polymer. Stille polycondensation of a distannyl-DTG derivative with 1,3-dibromo-N-octyl-thienopyrrolodione (TPD) results in an alternating copolymer which displays light absorption extending to 735 nm, and a higher HOMO level than the analogous copolymer containing the commonly utilized dithienosilole (DTS) heterocycle. When polyDTG-TPD:PC(70)BM blends are utilized in inverted bulk heterojunction solar cells, the cells display average power conversion efficiencies of 7.3%, compared to 6.6% for the DTS-containing cells prepared in parallel under identical conditions. The performance enhancement is a result of a higher short-circuit current and fill factor in the DTG-containing cells, which comes at the cost of a slightly lower open circuit voltage than for the DTS-based cells.
There is rapidly increasing prevalence of obesity throughout Western societies and increasing numbers of patients undergoing surgery are obese. Obesity is a condition of chronic systemic inflammation and is associated with an increased burden of comorbidities. Despite traditional teaching, obesity may not be an independent risk factor for poor postoperative outcomes. The Obesity Paradox describes the observation that small amounts of excess body fat may be protective against postoperative complications.
Overweight and obesity is linked to increased incidence and mortality of many cancer types. Of all cancers, oesophageal adenocarcinoma (OAC) displays one of the strongest epidemiological links with obesity, accounting for up to 40% of cases, but molecular pathways driving this association remain largely unknown. This study aimed to elucidate mechanisms underpinning the association of obesity and cancer, and to determine if visceral obesity is associated with aggressive tumour biology in OAC. Following co-culture with visceral adipose tissue explants, expression of genes involved in tumour cell invasion and metastasis (matrix metalloproteinase (MMP)2 and MMP9) were upregulated between 10-fold (MMP2) and 5000-fold (MMP9), and expression of tumour suppressor p53 was downregulated 2-fold in OAC cell lines. Western blotting confirmed these results at the protein level, while zymographic analysis detected increased activity of MMPs in OAC cell lines following co-culture with adipose tissue explants. When OAC cell lines were cultured with adipose tissue conditioned media (ACM) from visceral adipose tissue, increased proliferative, migratory and invasive capacity of tumour cells was observed. In OAC patient tumour biopsies, elevated gene expression of MMP9 was associated with visceral obesity, measured by visceral fat area, while increased gene expression of MMP9 and decreased gene expression of tumour suppressor p53 was associated with poor tumour differentiation. These novel data highlight an important role for visceral obesity in upregulation of pro-tumour pathways contributing to aggressive tumour biology, and may ultimately lead to development of stratified treatment for viscerally obese OAC patients.
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