Role of N-methyl-D-aspartate receptors in action-based predictive coding deficits in schizophrenia

Published in final edited form as:Biol Psychiatry. 2017 March 15; 81(6): 514–524. doi:10.1016/j.biopsych.2016.06.019.BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen’s d = 1.14) and schizophrenia (Cohen’s d = .85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.This work was supported by AstraZeneca for an investigator-initiated study (DHM) and the National Institute of Mental Health Grant Nos. R01 MH-58262 (to JMF) and T32 MH089920 (to NSK). JHK was supported by the Yale Center for Clinical Investigation Grant No. UL1RR024139 and the US National Institute on Alcohol Abuse and Alcoholism Grant No. P50AA012879. (AstraZeneca for an investigator-initiated study (DHM); R01 MH-58262 - National Institute of Mental Health; T32 MH089920 - National Institute of Mental Health; UL1RR024139 - Yale Center for Clinical Investigation; P50AA012879 - US National Institute on Alcohol Abuse and Alcoholism)Accepted manuscrip

Using flow gauges to determine stem and root conductance in hybrid poplars.

Non-Peer ReviewedA study was conducted using sap flow gauges to determine stem and root conductance in hybrid poplars at two sites near Swift Current, Saskatchewan. At the Rushlake site, sap flow rates were compared between CanAm and Walker poplars using Dynamax (Model SGA-10) stem flow gauges. The primary objective was to determine if the difference in susceptibility to midsummer terminal shoot dieback in Walker and CanAm poplar clones could be attributed to leaf-specific conductance. Walker poplars appear to be well-suited to mesic sites and, under good soil moisture conditions, perform better than CanAm . However, they are susceptible to mid-season terminal shoot dieback, while CanAm poplars do not seem to be as susceptible. We suspect that this is primarily attributable to a greater leaf-specific conductance (LSC) of CanAm poplars. As a tertiary cause, perhaps CanAm poplars achieve a more complete stomatal closure during periods of extended vapor pressure deficits. The gauges were mounted at the distal ends (where the shoot diameter is about 10 mm) of actively growing branches near the crown of each tree. For a period of 14 days, the sap flow rates of each tree were measured. Preliminary results indicate that CanAms did indeed have a greater LSC and showed higher stem flow rates than Walker poplars. Under the study conditions at the Rushlake site, air temperatures were not of sufficient magnitude to determine differences in leaf stomatal closure between the CanAm and Walker trees. The LSC characteristics, however, would have benefited the CanAm poplars in functioning under extended vapor pressure deficits. A secondary objective was to determine if differences in root conductances of poplars subjected to varying saline conditions were possible to measure using sap flow gauges. Although great care must be taken during gauge installation on tree roots, we found it is possible to measure root sap conductance on trees subjected to varying levels of salinity

Using flow gauges to determine leaf specific conductance in hybrid poplars under mesic and xeric conditions

Non-Peer ReviewedA study was conducted using sap flow gauges to determine leaf specific conductance (LSC) in hybrid poplars in an environmentally-controlled greenhouse at Swift Current, Saskatchewan. Sap flow rates were compared between CanAm and Walker poplar clones using stem flow gauges. The primary objectives were to verify differences in LSC observed between the clones under moist field conditions in a previous study and to compare the responses in sap flow and LSC within these trees as imposed soil conditions changed from moist to dry. Walker poplars appear to be well-suited to mesic sites, and, under ample soil moisture, perform better than CanAms. However, they are susceptible to mid-season terminal shoot dieback, while CanAm poplars do not seem to be as susceptible. We suspect that this is primarily attributable to a greater LSC of CanAm poplars and possibly achieving better stomatal responses during periods of extended vapor pressure deficits. The gauges were mounted near the base of each tree. Following gauge installation, the trees were watered to field capacity. No additional water was added during the course of the test. Sap flow, leaf water potentials and tree conditions were monitored for 17 days as the soil conditions evolved from moist to dry. Results indicate that the CanAms displayed a greater LSC under moist as well as dry conditions compared to the Walkers. Throughout the testing period, CanAm mid-day leaf water potentials were slightly more negative than for the Walker poplars. Although CanAm poplars appear to be less water efficient than Walkers, they are better able to function and survive during periods of extended vapour pressure deficits

Transposable elements maintain genome-wide heterozygosity in inbred populations.

Elevated levels of inbreeding increase the risk of inbreeding depression and extinction, yet many inbred species are widespread, suggesting that inbreeding has little impact on evolutionary potential. Here, we explore the potential for transposable elements (TEs) to maintain genetic variation in functional genomic regions under extreme inbreeding. Capitalizing on the mixed mating system of Arabidopsis lyrata, we assess genome-wide heterozygosity and signatures of selection at single nucleotide polymorphisms near transposable elements across an inbreeding gradient. Under intense inbreeding, we find systematically elevated heterozygosity downstream of several TE superfamilies, associated with signatures of balancing selection. In addition, we demonstrate increased heterozygosity in stress-responsive genes that consistently occur downstream of TEs. We finally reveal that TE superfamilies are associated with specific signatures of selection that are reproducible across independent evolutionary lineages of A. lyrata. Together, our study provides an important hypothesis for the success of self-fertilizing species

Acute antibody-mediated rejection in pancreas and kidney transplantation

In this thesis, acute rejection after kidney, simultaneous pancreas and kidney (SPKT), and islets of Langerhans transplantation was addressed. The focus is on acute antibody-mediated rejection (AMR) after transplantation and on a potential strategy using cellular immune modulation to prevent acute rejection. First, we retrospectively evaluated the relevance of diffuse C4d-positive peritubular capillary staining in a well-defined kidney transplantation cohort with proven early acute rejections (Chapter 2). Second, the negative impact of AMR on pancreas graft survival was investigated, which proved to be significant (Chapter 3). We subsequently analyzed all SPKT patients at the LUMC with early pancreas graft loss to examine the role of AMR due to presumed thrombosis and/or acute rejection (Chapter 4). In Chapter 5, a clinical update is presented on islets of Langerhans transplantation, focusing on the alternative _-cell replacement therapy that is currently employed in the LUMC (Chapter 5). Furthermore, we reviewed the role of both lymphatic- and blood-vessel vascularization and the role of neuronal reconnection after islet transplantation with data from our own rat islet transplantation models (Chapter 6). Finally, in a rodent allogeneic islet transplantation model, we attempted to induce tolerance by using donor-derived, dexamethasone-pretreated dendritic cells (Chapter 7).Astellas Pharma BV, Novartis Pharma BV, Roche Nederland BV, Novo Nordisk BV, Sakura Finetek Europe BV, de Nederlandse Transplantatie Vereniging, het Diabetes FondsUBL - phd migration 201

The Role of Diagenesis in Reservoir Development of the Big Clifty (Jackson) Sandstone in South-Central Kentucky

The Big Clifty is a Chesterian-age Mississippian sandstone member of the Golconda Formation that extends from south-central Kentucky into adjacent Illinois and Indiana. Asphaltic deposits and conventional petroleum plays are distributed along the Pennyrile Fault System and Plateau in the southeastern portion of the Illinois basin. In south-central Kentucky anomalous oil-saturation geometries are observed in cored sections of the Big Clifty from wells in Warren and Butler counties along the margin of the Pennyrile Plateau. Petrographic study of the cores has revealed several diagenetic processes that have contributed to, or are directly responsible for, the anomalous oil saturation geometries and resultant reservoir partitioning. This study utilizes standard transmitted and reflected light microscopy, UVepifluorescence, optical cold-cathode cathodoluminescence microscopy, scanning electron microscopy, and alizarin red S and potassium ferricyanide staining in petrographic examination. Raman microscopy, energy-dispersive X-ray spectroscopy, transmitted electron microscopy, and X-ray diffraction assisted in identification and compositional analysis of minerals. Quantification of framework grains and cement compositions, porosity, and grain-size distributions was also conducted. This study’s data classified the Big Clifty as a fine to very-fine grained, quartz arenite with predominantly silicious and phyllosilicate cements and a mean of porosity of 7%. Oil-saturation geometries concordant to rock fabric are due to compaction, weathering of labile grains, and precipitation of authigenic cements (mainly quartz, kaolinite, and pyrite). A paragenetic sequence, established from textural evidence, places quartz, kaolinite, and pyrite phases early in paragenesis with labile grain dissolution, compaction, and precipitation of ferroan carbonate cement, with development of vugular porosity occuring later during burial. These phases and processes enhanced preexisting porosity and permeability heterogeneities within the rock. Nodular pyrite, oil emplacement, and precipitation of poikilotopic calcite are the latest diagenetic events. Nodular pyrite and poikilotopic calcite are responsible for oil-saturation geometries distinctly discordant with rock fabric. Poikilotopic calcite forms interstratal seals, occluding porosity, replacing framework grains and cements, and overprinting primary rock fabric. This study’s preliminary research into the poikiloptopic calcite suggests its occurrence is possibly associated with the cored wells’ shallow depths less than 500 feet (150 meters), and proximity to near-vertical faults and waters from drainage systems of karstified carbonate aquifers updip

Evidence for trans-cis isomerization of the p-coumaric acid chromophore as the photochemical basis of the photocycle of photoactive yellow protein

AbstractAnalysis of the chromophore p-courmaix acid, extracted from the ground state and the long-lived blue-shifted photocycle intermediate of photoactive yellow protein, shows that the chromophore is reversibly converted from the trans to the cis configuration, while progressing through the photocycle. The detection of the trans and cis isomers was carried out by high performance capillary zone electrophoresis and further substained by 1H NMR spectroscopy. The data presented here establish the photo-isomerization of the vinyl double bond in the chromophore yellow protein, a eubacterial photosensory protein. A similar isomerization process occurs in the structurally very different sensory rhodopsins, offering an explanation for the strong spectroscopic similarities between photoactive yellow protein and the sensory rhodopsins. This is the first demonstration of light-induced isomerization of a chromophore double bond as the photochemical basis for photosensing in the domain of Bacteria

On the Connection of Anisotropic Conductivity to Tip Induced Space Charge Layers in Scanning Tunneling Spectroscopy of p-doped GaAs

The electronic properties of shallow acceptors in p-doped GaAs{110} are investigated with scanning tunneling microscopy at low temperature. Shallow acceptors are known to exhibit distinct triangular contrasts in STM images for certain bias voltages. Spatially resolved I(V)-spectroscopy is performed to identify their energetic origin and behavior. A crucial parameter - the STM tip's work function - is determined experimentally. The voltage dependent potential configuration and band bending situation is derived. Ways to validate the calculations with the experiment are discussed. Differential conductivity maps reveal that the triangular contrasts are only observed with a depletion layer present under the STM tip. The tunnel process leading to the anisotropic contrasts calls for electrons to tunnel through vacuum gap and a finite region in the semiconductor.Comment: 11 pages, 8 figure