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Background Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p(Sidak) = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p(Sidak) = 4.01E-04), RHBDF2 (- 3.45% UC, p(Sidak) = 4.85E-06), and C3 (- 1.20% UC, p(Sidak) = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p(Sidak) = 7.14E-04). Conclusions The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

Background Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p(Sidak) = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p(Sidak) = 4.01E-04), RHBDF2 (- 3.45% UC, p(Sidak) = 4.85E-06), and C3 (- 1.20% UC, p(Sidak) = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p(Sidak) = 7.14E-04). Conclusions The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

IntroductionWe have comprehensively described the expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I-V) in the hippocampus from young controls, age matched, mild cognitively impaired (MCI), and Alzheimer's disease (AD) subjects.MethodsHippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 AD cases were analyzed on Affymetrix Hg-U133 plus 2.0 arrays.ResultsThe microarray data revealed significant down regulation in OXPHOS genes in AD, particularly those encoded in the nucleus. In contrast, there was up regulation of the same gene(s) in MCI subjects compared to AD and ND cases. No significant differences were observed in mtDNA genes identified in the array between AD, ND, and MCI subjects except one mt-ND6.DiscussionOur findings suggest that restoration of the expression of nuclear-encoded OXPHOS genes in aging could be a viable strategy for blunting AD progression.

BackgroundThis study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD).MethodsIn a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus.ResultsSeveral novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II.C

Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biochemistry and Biophysics, 2009., Mitochondrial ultra structure appears abnormal in human neurons in end stage Alzheimer’s disease (AD). Alterations in cristae structure and fragmented mitochondria have been reported. We observe a similar loss of mitochondrial cristae structure in a blood cell model induced by diazoxide (Dz), a known K-ATP channel activator. In the blood cell model, Dz altered mitochondrial structure and also protected the cells from a potent inducer of apoptosis. The apoptotic protection of Dz extended to a neuronal cell model in their un-differentiated state with no Dz protection afforded after the neuronal cells differentiated. Whether or not Dz altered mitochondrial structure in the neuronal model was not determined. The dual effects of Dz, on mitochondrial structure and on apoptotic protection, appear to occur on different time-scales and it was not clear if the Dz effect on mitochondrial structure was related to Dz apoptotic protection. Primary blood cells were examined to investigate both effects of Dz. Monocytes could be protected from apoptosis with Dz pre-treatment and monocyte mitochondrial structure was altered in a dose dependent manner within the Dz one-hour pre-treatment period. The Dz dose required to confer apoptotic protection produced slight alterations in mitochondrial structure but a higher dose produced mitochondrial structure like mitochondrial structure previously reported in neurons of AD patients. Since mitochondrial structure in primary blood cells could be induced to appear identical to mitochondria in AD neurons and blood cells are affected in AD, our goal became to determine if morphological variation would be evident in AD blood cells and/or their mitochondria. The hypothesis that structural anomalies exist in tissue outside the brain in AD was tested by close examination of blood cells, specifically monocytes, from human donors. Whole blood was donated and peripheral blood mononuclear cells (PBMCs) were isolated. An aliquot of PBMCs was fixed immediat

BackgroundThis study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD).MethodsIn a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus.ResultsSeveral novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II.C

This report describes research on proof of principle that a AlGaAs-GaAs heterostructure can display a negative differential resistance suitable for constructing an oscillator operating in the 100 GHz range. The conjecture is that if the electrons in the GaAs layer are heated by the application of an electric field parallel to the layer interface, they can be made to return to their parent donors in the Si doped AlGaAs layer where their mobilities are much smaller than in the GaAs. (Author)

This report summarizes studies on optically pumped far infrared molecular gas lasers. The research has been concerned with the general subjects of far infrared integrated optics and technology, the discovery of new optically pumped molecular laser systems, and the study and analysis of nonlinear processes (Raman and hyper-Raman) that can occur in optically pumped systems. The theoretical density matrix analysis of the gain spectra of nonlinear systems and the first detailed experimental measurements of these systems are presented. It is demonstrated that third and fifth order nonlinear processes can exceed first order laser processes. An experimental study of the generation of a 22.653 GHz signal (the largest wavelength yet reported) in optically pumped NH3 is described. The frequency tunability and single shot spectral characteristics of the signal were measured with precision. A single laser pump in a four-level system can yield two laser signals, which in the linear case are not coupled together. However, with stronger pumping, nonlinear effects can couple the two laser signals with the result that the behavior of one laser signal is determined by the other and vice versa. The self-consistent analysis of this problem is described.

Experiments and theory regarding the emission processes in optically pumped far infrared laser sources are reported. Super-radiance from CH3F at 496 micrometers in the homogeneously broadened regime has been identified for the first time. Stimulated Raman emission on pure rotational transitions in D2O at 50 and 66 micrometers has also been identified for the first time. Generally good agreement between experiments and a Maxwell-Bloch approach was obtained for the superradiance study, and good qualitative agreement between experiments and a Maxwell-density matrix approach using three waves interacting in a four-level system was noted for the Raman study; both implying that the processes are now reasonably well characterized and understood. (Author)

This annual report describes research on two-photon pumping of molecular lasers operating on hot band transitions of the molecules and the associated nonlinear effects (Raman and hyper-Raman) that contribute to the gain spectrum of the molecular system. Accessing the hot bands of a molecule results in more lasing transitions that would otherwise be observed, and modifies the characteristics of the gain spectrum, i.e., the saturation, AC Stark shifts and width. Specific experiments described are: infrared-microwave pumping of NH3, infrared-infrared pumping on NH3, and hot band lasing in NH3. Ammonia has been chosen for study since it has both a rich known, so that absorption and laser assignments can readily be made. (Author)

This report describes research on (1) optically pumped NH3 and PH3 with particular attention given to the 12.08 and 11.46 micrometer lines, (2) four-wave four-level nonlinear molecular systems, and (3) laser line assignments in the important far IR CH3OH laser. (Author)

This annual report summarizes research done on (a) the study of guided waves in dielectric waveguides in the far IR along with prism and grating couplers, (b) the exploratory study of tunable laser signals in the far IR via collisionally broadened gain curves, (c) the development of inexpensive (approximately 1K$) IR lasers for optical pumping of molecules and (d) the study of tunable IR signals via coherent scattering from polariton modes in semiconductor crystals., See also report dated Mar 74, AD-783 179.

This report summarizes research done on (a) far infrared integrated optics, (b) a step-tunable coherent far infrared source, and (c) a continuously tunable near infrared and far infrared source. The far infrared optics work has required developing a stable far IR optically pumped laser which is described in detail. One of the principle problems in this effort is that of the output laser mirror. The step-tunable coherent far IR source uses frequency mixing in a dielectric waveguide to achieve phase matching. The continuously tunable source is based on a nonlinear action in a material (GaAs) which has both a Raman and an IR active mode. A problem with this work is that of developing a laboratory CO2 pump source and the damage problem of the crystal material., See also Annual rept. dated 1 Mar 74, AD-783 179.

This final report describes research on the demonstration of a new solid state oscillator source principle in a GaAs/AlGaAs heterostructure. The negative differential resistance is based upon a real space transfer of hot electrons from a high mobility GaAs layer to a low mobility AlGaAs layer in the heterostructure. Tunable radiation in the 2-25 MHz range was achieved at a power level of 30 milliwatts in a first device. The potential exists to extend this oscillator into the 100-1000 GHz range since the transit time is associated with time of travel between the 100 A layers in the heterostructure.

The report describes research done on far IR integrated optics and frequency tunable coherent sources. The integrated optics studies are being performed in crystalline quartz dielectric waveguides using a CW optically pumped CH3F molecular laser operating at 496 micrometers. Particular problems being studied at this time are waveguide couplers and the characteristics of single mode operation. Discrete frequency tuning in the 70-5,000 micrometer range is being obtained by mixing selected CO2 laser lines in a GaAs dielectric waveguide. A second frequency tunable source using a simultaneous Raman and infrared active mode in GaAs is being studied to generate multi-kilowatt tunable power in the 11-12 micrometer range and 1-10 watt power in the 10-400 micrometer region. (Modified author abstract)

An experimental and theoretical investigation of electrically excited glow discharge CO2 lasers has resulted in new data on the electron excitation efficiency and the intrinsic V-V relaxation rates for the 10.6 and 9.6 micrometers laser transitions. Preliminary experimental results on the E-beam controlled CO2 laser are desirable. Experiments using both high power and low power CO2 lasers as excitation sources for the generation of far IR laser IR laser action are described. Subsequent research includes the discovery of over 100 new lasing transitions and the generation of over 5 kW pulse power at 496 micrometers in CH3F. (Author), See also report dated 16 Aug 72, AD-756 015.

The report is a summary report of investigations on molecular lasers in the far infrared (25-1000 microns). Lasers studied were H2O, SO2, and H2S. Problems investigated are the assignment of levels for the laser transitions and extricating the details of the excitation mechanisms and relaxation. This understanding is needed to optimize the power output and efficiency of the molecular lasers. A new excitation method investigated was that of Franck-Condon pumping. (Author)

Experimental work on SO2, H2S, and the boron trihalide, molecular lasers operating in the far infrared is reported along with chemical excitation of molecules by atomic nitrogen. Attempts at laser line assignments in SO2 are discussed. Cascade-competition and precision wavelength measurements in H2S were studied. A model for gain saturation under pulsed laser conditions is presented. Also given are the publications and personnel associated with this research. (Author)

The report summarizes nine months of the second year activity of research on molecular lasers in the 100 to 1000 micron range. Progress on identifying the lasing specie and making energy level assignments for a water vapor laser are described. Also included is a summary of optimum output coupling of lasers by means of apertures and semi-transparent mirrors. This study was carried out at 337 microns wavelength. (Author), See also AD-632 306.

The report summarizes the first year's activities of research on gas lasers in the 100 to 1000 micron range. A general description and experimental results of a water vapor laser covering the 48 to 118 micron range is described. Research problems to be explored during the second year of the grant are discussed along with a brief comparison with classical electronic methods of generation. (Author)

This paper describes an experiment in which approximately one watt of power was produced at 105 Gc by a traveling wave multiple photon interaction in HCN gas., of a paper presented at the Annual Review of Electronics (2nd), Univ. of Illinois, Urbana, 17-18 Nov 64.

Experimental work on H2O, H2S, SO2, NH3, OCS, and HCN molecular lasers operating in the 16 to 700 micron wavelength range of the spectrum is reported. These studies include: search for new molecules, new lasing lines, excitation and relaxation processes, and identification of lasing levels in the molecule. The 24 lasing lines in H2S are the first to be reported anywhere while 12 new lines in NH3 have been found in the range 21 to 32 microns. Possible matches of most of the 24 H2S lines have been made. Preliminary work on a chemical laser using the reaction N + C2H4 is discussed. (Author)