Possible Contribution of Altered Cholinergic Activity in the Visual Cortex in Visual Hallucinations in Parkinson's Disease.

OBJECTIVE: Up to one-third of patients with Parkinson's disease (PD) experience visual hallucinations (VHs). Lewy bodies are sparse in the visual cortices and seem unlikely to explain the hallucinations. Some neuroimaging studies have found that perfusion is reduced in the occipital lobe in individuals with VHs. Recent work has suggested that decreased cholinergic input may directly lead to the decreased perfusion. The investigators hypothesized that individuals with PD and VHs would have biochemical evidence of reduced microvascular perfusion and reduced cholinergic activity in areas of the brain that process visual images. METHODS: Tissue from Brodmann's area (BA) 18 and BA 19 was obtained from a well-characterized cohort matched for age, gender, and postmortem interval in 69 individuals (PD without VHs, N=11; PD without dementia plus VHs N=10, N=10; PD with dementia plus VHs, N=16; and control subjects, N=32). Von Willebrand factor, vascular endothelial growth factor A, and myelin-associated glycoprotein:proteolipid protein-1 (MAG:PLP1) ratio-a measure of tissue oxygenation relative to metabolic demand, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), choline acetyltransferase, and α-synuclein-were quantified by enzyme-linked immunosorbent assay. The primary outcome was the MAG:PLP1 ratio. RESULTS: There was no biochemical evidence of chronic hypoperfusion in PD, although microvessel density was decreased in ventral BA 18 and BA 19. There was no between-group difference in BChE in either dorsal BA 18 or BA 19. AChE concentration was reduced in individuals with PD compared with control subjects in dorsal and ventral BA 18 and dorsal BA 19, and it was increased in ventral BA 19. These changes were most marked in the PD plus VHs group. CONCLUSIONS: These results suggest that changes in cholinergic activity rather than chronic hypoperfusion may underlie VHs in PD.

Low dark current III-V on silicon photodiodes by heteroepitaxy.

Top-illuminated PIN and modified uni-traveling carrier (MUTC) photodiodes based on InGaAs/InAlAs/InP were epitaxially grown on Si templates. Photodiodes with 30-µm diameter have dark currents as low as 10 nA at 3 V corresponding to a dark current density of only 0.8 mA/cm2. The responsivity, 3-dB bandwidth, output power and third-order output intercept point (OIP3) were 0.79 A/W, 9 GHz, 2.6 dBm and 15 dBm, respectively.

Reflection sensitivity of 1.3 µm quantum dot lasers epitaxially grown on silicon.

We present measurements of relative intensity noise versus various levels of optical feedback for 1.3 µm quantum dot lasers epitaxially grown on silicon for the first time. A systematic comparison is made with heterogeneously integrated 1.55 µm quantum well lasers on silicon. Our results indicate up to 20 dB reduced sensitivity of the quantum dot lasers on silicon compared to the quantum wells.

Electrically pumped continuous wave quantum dot lasers epitaxially grown on patterned, on-axis (001) Si.

High performance III-V lasers at datacom and telecom wavelengths on on-axis (001) Si are needed for scalable datacenter interconnect technologies. We demonstrate electrically injected quantum dot lasers grown on on-axis (001) Si patterned with {111} v-grooves lying in the [110] direction. No additional Ge buffers or substrate miscut was used. The active region consists of five InAs/InGaAs dot-in-a-well layers. We achieve continuous wave lasing with thresholds as low as 36 mA and operation up to 80°C.

Electrically pumped continuous-wave 1.3 µm quantum-dot lasers epitaxially grown on on-axis (001) GaP/Si.

We demonstrate the first electrically pumped continuous-wave (CW) III-V semiconductor lasers epitaxially grown on on-axis (001) silicon substrates without offcut or germanium layers, using InAs/GaAs quantum dots as the active region and an intermediate GaP buffer between the silicon and device layers. Broad-area lasers with uncoated facets achieve room-temperature lasing with threshold current densities around 860 A/cm2 and 110 mW of single-facet output power for the same device. Ridge lasers designed for low threshold operations show maximum lasing temperatures up to 90°C and thresholds down to 30 mA.

Auto-induction of Pichia pastoris AOX1 promoter for membrane protein expression.

Pichia pastoris is a highly successful recombinant protein expression system due to its ability to quickly generate large quantities of recombinant proteins in simple media. P. pastoris has been used to successfully generate milligram quantities of many important human membrane proteins, including G-protein coupled receptors, ion channels, and transporters, which are becoming increasingly important therapeutic targets. Despite these successes, protein expression in P. pastoris is still cumbersome due to a need to change growth media from glycerol media to methanol induction media, which minimizes inhibition of the AOX1 promoter by residual glycerol. Taking advantage of this behavior of the AOX1 promoter, we developed Buffered extra-YNB Glycerol Methanol (BYGM) auto-induction media (100 mM potassium phosphate pH 6.0, 2.68% w/v YNB, 0.4% v/v glycerol, 0.5% v/v methanol, and 8 × 10-5% w/v biotin) which not only simplified the protein expression process, but also optimized protein expression levels in P. pastoris. We successfully used this auto-induction method to overexpress the target in both MutS and Mut+ strains. Moreover, we show that this method can facilitate screening high-expressing clones, as well as enable parallel protein production in P. pastoris.

1.3-µm InAs quantum-dot micro-disk lasers on V-groove patterned and unpatterned (001) silicon.

We report comparison of lasing dynamics in InAs quantum dot (QD) micro-disk lasers (MDLs) monolithically grown on V-groove patterned and planar Si (001) substrates. TEM characterizations reveal abrupt interfaces and reduced threading dislocations in the QD active regions when using the GaAs-on-V-grooved-Si template. The improved crystalline quality translates into lower threshold power in the optically pumped continuous-wave MDLs. Concurrent evaluations were also made with devices fabricated simultaneously on lattice-matched GaAs substrates. Lasing behaviors from 10 K up to room temperature have been studied systematically. The analyses spotlight insights into the optimal epitaxial scheme to achieve low-threshold lasing in telecommunication wavelengths on exact Si (001) substrates.

Optically pumped 1.3 µm room-temperature InAs quantum-dot micro-disk lasers directly grown on (001) silicon.

Direct integration of high-performance laser diodes on silicon will dramatically transform the world of photonics, expediting the progress toward low-cost and compact photonic integrated circuits (PICs) on the mainstream silicon platform. Here, we report, to the best of our knowledge, the first 1.3 µm room-temperature continuous-wave InAs quantum-dot micro-disk lasers epitaxially grown on industrial-compatible Si (001) substrates without offcut. The lasing threshold is as low as hundreds of microwatts, similar to the thresholds of identical lasers grown on a GaAs substrate. The heteroepitaxial structure employed here does not require the use of an absorptive germanium buffer and/or dislocation filter layers, both of which impede the efficient coupling of light from the laser active regions to silicon waveguides. This allows for full compatibility with the extensive silicon-on-insulator (SOI) technology. The large-area virtual GaAs (on Si) substrates can be directly adopted in various mature in-plane laser configurations, both optically and electrically. Thus, this demonstration represents a major advancement toward the commercial success of fully integrated silicon photonics.

Photomultiplier tube calibration based on Na lidar observation and its effect on heat flux bias.

Na lidar can measure vertical wind and temperature at high temporal and vertical resolutions, enough to resolve gravity wave perturbations. Heat flux due to dissipating gravity waves is an important quantity that can be derived from such perturbations. When lidar signals are high, a photomultiplier tube (PMT) used to count incoming photons may suffer from the saturation effect, and its output count is not linearly related to incoming photon counts. Corrections to this effect can be measured in a laboratory setting but may have large errors at high count rates. We show that the errors in the PMT correction can cause significant bias in the heat flux calculation due to the inherent correlation between wind and temperature errors. Using the measurements made by Na lidar at the Andes Lidar Observatory with Hamamatsu PMTs, we developed a calibration procedure to remove such PMT correction errors from laboratory measurements. By applying the revised PMT correction curve we demonstrated that the heat flux bias can be removed through this procedure.

Crystal structure of the cGMP-dependent protein kinase II leucine zipper and Rab11b protein complex reveals molecular details of G-kinase-specific interactions.

cGMP-dependent protein kinase (PKG)-interacting proteins (GKIPs) mediate cellular targeting of PKG isoforms by interacting with their leucine zipper (LZ) domains. These interactions prevent aberrant signaling cross-talk between different PKG isotypes. To gain detailed insight into isotype-specific GKIP recognition by PKG, we analyzed the type II PKG leucine zipper domain and found that residues 40-83 dimerized and specifically interacted with Rab11b. Next, we determined a crystal structure of the PKG II LZ-Rab11b complex. The PKG II LZ domain presents a mostly nonpolar surface onto which Rab11b docks, through van der Waals interactions. Contact surfaces in Rab11b are found in switch I and II, interswitch, and the ß1/N-terminal regions. This binding surface dramatically differs from that seen in the Rab11 family of interacting protein complex structures. Structural comparison with PKG Iα and Iß LZs combined with mutagenic analysis reveals that GKIP recognition is mediated through surface charge interactions.

Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease.

It has been well established that neuronal loss within the cholinergic nucleus basalis of Meynert (nbM) correlates with cognitive decline in dementing disorders such as Alzheimer's disease (AD). Friedrich Lewy first observed his eponymous inclusion bodies in the nbM of postmortem brain tissue from patients with Parkinson's disease (PD) and cell loss in this area can be at least as extensive as that seen in AD. There has been confusion with regard to the terminology and exact localisation of the nbM within the human basal forebrain for decades due to the diffuse and broad structure of this "nucleus". Also, while topographical projections from the nbM have been mapped out in subhuman primates, no direct clinicopathological correlations between subregional nbM and cortical pathology and specific cognitive profile decline have been performed in human tissue. Here, we review the evolution of the term nbM and the importance of standardised nbM sampling for neuropathological studies. Extensive review of the literature suggests that there is a caudorostral pattern of neuronal loss within the nbM in AD brains. However, the findings in PD are less clear due to the limited number of studies performed. Given the differing neuropsychiatric and cognitive deficits in Lewy body-associated dementias (PD dementia and dementia with Lewy bodies) as compared to AD, we hypothesise that a different pattern of neuronal loss will be found in the nbM of Lewy body disease brains. Understanding the functional significance of the subregions of the nbM could prove important in elucidating the pathogenesis of dementia in PD.

Neuropathological Assessment as an Endpoint in Clinical Trial Design.

Different neurodegenerative conditions can have complex, overlapping clinical presentations that make accurate diagnosis during life very challenging. For this reason, confirmation of the clinical diagnosis still requires postmortem verification. This is particularly relevant for clinical trials of novel therapeutics where it is important to ascertain what disease- and/or pathology-modifying effects the therapeutics have had. Furthermore, it is important to confirm that patients in the trial had the correct clinical diagnosis as this will have a major bearing on the interpretation of trial results. Here we present a simple protocol for pathological assessment of neurodegenerative changes.

Physiologic Fidelity as a Domain in Assessing Mixed Reality Trauma Simulation.

INTRODUCTION: Mixed reality has been used in trauma and emergency medicine simulation for more than a decade. As mixed reality potential in trauma simulation continues to expand, so too does the need to validate it as a surrogate for real-life emergency scenarios. Validation of these simulations can occur by measuring fidelity, or the degree to which a computing system can reproduce real-world experiences. After performing a literature review, we determined that most fidelity assessments of trauma and emergency simulations focus on how the user subjectively experiences the simulation. Although subjective user assessment is an important component of determining fidelity, we pose an introductory three-part framework that may assess mixed reality trauma simulation more adequately. MATERIALS AND METHODS: A literature review was conducted using Google Scholar, PubMed, and the Uniformed Services University PowerER search database. Relevant articles were assessed to identify how studies measured fidelity in trauma simulation. We then designed the three-part framework to aid researchers in assessing the fidelity of mixed reality trauma simulations. RESULTS: The domains we determined to best assess mixed reality emergency simulation are as follows:1. Continue assessing fidelity via subjective user assessments. This allows the researcher to know how real the simulation looked and felt to the user based on their individual report.2. Determine whether the trauma simulation changes the medical decision-making capacity of the user. If the user's decision-making capacity changes with a stress-inducing trauma simulation versus a non-stress-inducing simulation, then the stress-inducing trauma environment would be approaching greater fidelity.3. Study the domain of our newly proposed concept: physiologic fidelity. We define physiologic fidelity as the degree to which the simulation elicits a measurable, autonomic response independent of observed emotion or perceived affect. Recreating objective autonomic arousal may be the best way to ensure a trauma simulation reaches fidelity. CONCLUSION: We propose a methodology to assess mixed reality trauma simulation fidelity. Once fidelity is more fully known to the researcher and the simulation user, adjustments can be made to approach reality more closely. Improved simulators may enrich the preparedness of both junior and senior learners for real-life emergencies. We believe assessing the three domains using the Wide Area Virtual Experience at the Val G. Hemming simulation center in Bethesda, MD, will validate mixed reality-trauma simulators as invaluable surrogates for real-life emergency scenarios and ultimately contribute to improved clinical outcomes for clinicians and their patients.

Strain-dependent elastography of cancer cells reveals heterogeneity and stiffening due to attachment.

Because cells vary in thickness and in biomechanical properties, the use of a constant force trigger during atomic force microscopy (AFM) stiffness mapping produces a varied nominal strain that can obfuscate the comparison of local material properties. In this study, we measured the biomechanical spatial heterogeneity of ovarian and breast cancer cells by using an indentation-dependent pointwise Hertzian method. Force curves and surface topography were used together to determine cell stiffness as a function of nominal strain. By recording stiffness at a particular strain, it may be possible to improve comparison of the material properties of cells and produce higher contrast representations of cell mechanical properties. Defining a linear region of elasticity that corresponds to a modest nominal strain, we were able to clearly distinguish the mechanics of the perinuclear region of cells. We observed that, relative to the lamelopodial stiffness, the perinuclear region was softer for metastatic cancer cells than their nonmetastatic counterparts. Moreover, contrast in the strain-dependent elastography in comparison to conventional force mapping with Hertzian model analysis revealed a significant stiffening phenomenon in the thin lamellipodial region in which the modulus scales inversely and exponentially with cell thickness. The observed exponential stiffening is not affected by relaxation of cytoskeletal tension, but finite element modeling indicates it is affected by substrate adhesion. The novel cell mapping technique explores cancer cell mechanical nonlinearity that results from regional heterogeneity, which could help explain how metastatic cancer cells can show soft phenotypes while simultaneously increasing force generation and invasiveness.

Acute urinary retention in a 27-year-old male secondary to benign prostatic hyperplasia treated with Holmium Enucleation of the Prostate (HOLEP).

INTRODUCTION: Benign prostatic hyperplasia (BPH) is common in the ageing male. Clinical manifestations like retention impact on a patient's quality of life. Alterations in androgen activity at the androgen receptor complex level in the prostate contribute to prostatic hyperplasia with the highest incidence occurring in males in their 70's. There remains a paucity of cases in young males who develop acute urinary retention secondary to BPH. We present a case of a 27-year-old male who developed acute urinary retention secondary to BPH who required a Holmium Laser Enucleation of his Prostate (HOLEP). CASE DESCRIPTION: A 27 year old man was admitted in acute urinary retention. BPH was diagnosed via way of radiological imaging and histological assessment. After pre-operative sperm banking and suprapubic catheterisation, the patient underwent a HOLEP. He had biochemically confirmed hypogonadotrophic hypogonadism which was at odds with his muscular, physical appearance. Total testosterone levels had fluctuated following admission suggesting an exogenous substance was interfering with the hypothalamic-pituitary-gonadal axis but he denied exogenous steroid use. RESULT: The patient successfully passed his voiding trial on the second post-operative day and remained catheter free. Post-operative uroflowmetry and sexual function remain unknown as patient disengaged with follow up. CONCLUSION: HOLEP prostatectomy is a safe and effective way of managing BPH in younger patients following sperm banking and assessment by endocrinology.

Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders.

Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties and topographical distribution of astrocytic aSyn have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology using an expanded antibody toolset covering the entire sequence and key post-translational modifications (PTMs) of aSyn in Lewy body disorders (LBDs) and in MSA. Astrocytic aSyn was detected in the limbic cortical regions of LBDs but were absent in main pathological regions of MSA. The astrocytic aSyn was revealed only with antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34-99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations represent a major part of aSyn pathology in LBDs and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. This is the first description that aSyn accumulations are made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn is a mixture of Y39 phosphorylated and nitrated species. These observations underscore the importance of systematic characterization of aSyn accumulations in different cell types to capture the aSyn pathological diversity in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LBDs can pave the way towards identifying novel disease mechanisms and therapeutic targets.

Pathologic mechanobiological interactions between red blood cells and endothelial cells directly induce vasculopathy in iron deficiency anemia.

The correlation between cardiovascular disease and iron deficiency anemia (IDA) is well documented but poorly understood. Using a multi-disciplinary approach, we explore the hypothesis that the biophysical alterations of red blood cells (RBCs) in IDA, such as variable degrees of microcytosis and decreased deformability may directly induce endothelial dysfunction via mechanobiological mechanisms. Using a combination of atomic force microscopy and microfluidics, we observed that subpopulations of IDA RBCs (idRBCs) are significantly stiffer and smaller than both healthy RBCs and the remaining idRBC population. Furthermore, computational simulations demonstrated that the smaller and stiffer idRBC subpopulations marginate toward the vessel wall causing aberrant shear stresses. This leads to increased vascular inflammation as confirmed with perfusion of idRBCs into our "endothelialized" microfluidic systems. Overall, our multifaceted approach demonstrates that the altered biophysical properties of idRBCs directly lead to vasculopathy, suggesting that the IDA and cardiovascular disease association extends beyond correlation and into causation.

Modeling Studies of Gravity Wave Dynamics in Highly Structured Environments: Reflection, Trapping, Instability, Momentum Transport, Secondary Gravity Waves, and Induced Flow Responses.

A compressible numerical model is applied for three-dimensional (3-D) gravity wave (GW) packets undergoing momentum deposition, self-acceleration (SA), breaking, and secondary GW (SGW) generation in the presence of highly-structured environments enabling thermal and/or Doppler ducts, such as a mesospheric inversion layer (MIL), tidal wind (TW), or combination of MIL and TW. Simulations reveal that ducts can strongly modulate GW dynamics. Responses modeled here include reflection, trapping, suppressed transmission, strong local instabilities, reduced SGW generations, higher altitude SGW responses, and induced large-scale flows. Instabilities that arise in ducts experience strong dissipation after they emerge, while trapped smaller-amplitude and smaller-scale GWs can survive in ducts to much later times. Additionally, GW breaking and its associated dynamics enhance the local wind along the GW propagation direction in the ducts, and yield layering in the wind field. However, these dynamics do not yield significant heat transport in the ducts. The failure of GW breaking to induce stratified layers in the temperature field suggests that such heat transport might not be as strong as previously assumed or inferred from observations and theoretical assessments. The present numerical simulations confirm previous finding that MIL generation may not be caused by the breaking of a transient high-frequency GW packet alone.

The detection and management of emotional distress in cancer patients: the views of health-care professionals.

OBJECTIVE: Emotional distress (ED) is an under-diagnosed problem in cancer patients and over the last decade a number of national guidelines have recommended an assessment and management model based on appropriate health professional response to a hierarchy of patient need. This study explores the views of cancer professionals regarding their current roles and responsibilities in the detection and management of ED, use of screening tools and access to expert psychological support. METHODS: Interviews with 23 professionals were conducted [6 clinical nurse specialists (CNS), 8 oncologists, 4 surgeons and 5 ward sisters] from hospitals in Yorkshire, UK. Data were evaluated using framework analysis. RESULTS: Detection of ED was seen to be the responsibility of the whole cancer team though nurses, particularly CNSs, are heavily depended upon to assess and manage distress. Experience of screening tools was limited and a number of reservations were expressed about routine implementation. A wide range of services are used to support distressed patients but a lack of referral guidance and access to specialist psychological care were reported to be a significant barrier to effective management. CONCLUSIONS: Cancer professionals describe working within the fundamental principles of the guidance frameworks; however, access to specialist support do not appear to meet recommendations, leaving the CNS with considerable responsibility for the detection and management of ED. Support for ED may be improved by the introduction of routine screening along with appropriate training and implementation of referral guidelines to assist professionals in accessing specialist psychology services.