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Objective: Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) is a common treatment for motor symptoms of Parkinson's disease but its influence on non-motor symptoms is less clear. Sleep spindles are known to be reduced in patients with Parkinson's disease, but the effect of STN DBS is unknown. The objective of our study was to address this knowledge gap., Method: Polysomnograms were recorded for three consecutive nights in 15 patients with advanced Parkinson's disease (11 male, 4 female; age: 53-75 years), including at least one night each of unilateral STN DBS stimulation ON and OFF. Stimulation ON was set to 70 % of clinical amplitude to mitigate sleep being altered via changing motor symptoms or due to patient awareness of stimulation. Sleep spindles were detected in electroencephalogram (EEG) data by two previously published, validated automated sleep spindle detection algorithms: Ferrarelli et al. (2007) and Martin et al. (2013)., Results: Sleep spindle density was higher during stimulation ON than OFF nights in 11 of 12 subjects using either sleep spindle detection algorithm (p<=0.01, Wilcoxon rank sum). Stimulation ON versus OFF had no statistically significant effect on sleep spindle duration or amplitude., Conclusion: Our analysis indicates that a single night of sub-optimal STN stimulation significantly increases sleep spindle density in Parkinson's disease patients., Significance: These results further our understanding of how DBS impacts non-motor symptoms of Parkinson's disease., Competing Interests: Potential conflicts of interest Potential conflicts of interest: SVG, JAT and AA receive funding from Medtronic for an investigator-initiated research project that is unrelated to the project reported herein. SVG has licensed technology to Natus Neurology that is unrelated to this project. CHH receives speaking honoraria and consulting fees from Boston Scientific and Insightec unrelated to the project reported herein. AA receives consulting fees from Medtronic unrelated to the project reported herein. No other authors have any potential conflict of interests., (Copyright © 2024 International Federation of Clinical Neurophysiology. All rights reserved.)

Study Objectives: A growing body of literature suggests that deep brain stimulation to treat motor symptoms of Parkinson's disease may also ameliorate certain sleep deficits. Many foundational studies have examined the impact of stimulation on sleep following several months of therapy, leaving an open question regarding the time course for improvement. It is unknown whether sleep improvement will immediately follow onset of therapy or accrete over a prolonged period of stimulation. The objective of our study was to address this knowledge gap by assessing the impact of deep brain stimulation on sleep macro-architecture during the first nights of stimulation., Methods: Polysomnograms were recorded for 3 consecutive nights in 14 patients with advanced Parkinson's disease (10 male, 4 female; age: 53-74 years), with intermittent, unilateral subthalamic nucleus deep brain stimulation on the final night or 2. Sleep scoring was determined manually by a consensus of 4 experts. Sleep macro-architecture was objectively quantified using the percentage, latency, and mean bout length of wake after sleep onset and on each stage of sleep (rapid eye movement and non-rapid eye movement stages 1, 2, 3)., Results: Sleep was found to be highly disrupted in all nights. Sleep architecture on nights without stimulation was consistent with prior results in treatment naive patients with Parkinson's disease. No statistically significant difference was observed due to stimulation., Conclusions: These objective measures suggest that 1 night of intermittent subthreshold stimulation appears insufficient to impact sleep macro-architecture., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04620551; Identifier: NCT04620551., Citation: Das R, Gliske SV, West LC, et al. Sleep macro-architecture in patients with Parkinson's disease does not change during the first night of neurostimulation in a pilot study. J Clin Sleep Med . 2024;20(9):1489-1496., (© 2024 American Academy of Sleep Medicine.)

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Sleep dysregulation in Parkinson's disease (PD) has been hypothesized to occur, in part, from dysfunction in the basal ganglia-cortical circuit. Assessment of this relationship requires accurate sleep stage determination, a known challenge in this clinical population. Our objective was to optimize the consensus on the sleep staging process and reduce interrater variability in a cohort of advanced PD subjects., Methods: Fifteen PD subjects were enrolled from three sites in a clinical trial that involved recordings from subthalamic nucleus (STN) deep brain stimulation (DBS) leads (NCT04620551). Video polysomnography (vPSG) data for a total of 45 nights were analyzed. Four experienced scorers independently scored data on initial review. Epochs with less than 75% consensus were flagged for secondary review. In secondary review of discordant epochs, two of the original scorers re-assessed epochs, from which the final consensus stage was derived., Results: Sleep stage classification agreement averaged 83.10% across all sleep stages on initial scoring (IS), and on secondary consensus scoring (CS) review, agreement reached 96.58%. Greatest disagreement was noted in determination of awake epochs (33.6% of discordant epochs) and non-rapid-eye-movement stage 2 (N2) epochs (31.8% of discordant epochs). Scoring discrepancy was resolved with direct measurement of cortical frequency and amplitudes, physiologic context of the epoch, and video review., Conclusion: Our method of multi-level initial and then secondary consensus review scoring resulted in consensus scoring agreement superior to conventional standards. This work features a custom-engineered vPSG software and review platform for integration of consensus sleep stage scoring in a multi-site clinical trial., Competing Interests: Declaration of competing interest ad hoc consulting for Medtronic for A. Abosch., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: CAK reports personal fees related to consultancies or participation in medical advisory boards from XW Pharma, Idorsia, Merck, Jazz Pharmaceuticals, Avadel Pharmaceuticals, Cerebra, and VIVOS; grants or contracts with the National Institutes of Health, Avadel Pharmaceuticals, AmCad BioMed Corporation, Jazz Pharmaceuticals, Merck Sharp & Dohme, Parexel International Corporation, Asate, Inspire Medical Systems, and Respironics; lecture honoraria from ResMed Asia and Itamar Medical; and stock or stock options from M3 Public Benefit Corporation, Restful Robotics, VIVOS, and Koko. LCW declares no competing interests.

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune cross-talk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces health span, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (NRF2), which increases oxidative stress, enhances proinflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related disorders and aging., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Mitochondria are central key players in cell metabolism, and mitochondrial DNA (mtDNA) instability has been linked to metabolic changes that contribute to tumorigenesis and to increased expression of pro-tumorigenic genes. Here, we use melanoma cell lines and metastatic melanoma tumors to evaluate the effect of mtDNA alterations and the expression of the mtDNA packaging factor, TFAM, on energetic metabolism and pro-tumorigenic nuclear gene expression changes. We report a positive correlation between mtDNA copy number, glucose consumption, and ATP production in melanoma cell lines. Gene expression analysis reveals a down-regulation of glycolytic enzymes in cell lines and an up-regulation of amino acid metabolism enzymes in melanoma tumors, suggesting that TFAM may shift melanoma fuel utilization from glycolysis towards amino acid metabolism, especially glutamine. Indeed, proliferation assays reveal that TFAM-down melanoma cell lines display a growth arrest in glutamine-free media, emphasizing that these cells rely more on glutamine metabolism than glycolysis. Finally, our data indicate that TFAM correlates to VEGF expression and may contribute to tumorigenesis by triggering a more invasive gene expression signature. Our findings contribute to the understanding of how TFAM affects melanoma cell metabolism, and they provide new insight into the mechanisms by which TFAM and mtDNA copy number influence melanoma tumorigenesis.

Gamma-interferon-inducible lysosomal thiol reductase (GILT), a thioredoxin-related oxidoreductase, functions in MHC class II-restricted antigen processing and MHC class I-restricted cross-presentation by reducing disulfide bonds of endocytosed proteins and facilitating their unfolding and optimal degradation. However, recent reports have greatly expanded our understanding of GILT's function. Several studies of GILT and antigen processing have shown that the influence of GILT on the peptide repertoire can alter the character of the immune response and affect central tolerance. Furthermore, a few unexpected roles for GILT have been uncovered: as a host factor for Listeria monocytogenes infection, in the maintenance of cellular glutathione (GSH) levels, and possibly outside the cell, as enzymatically active GILT is secreted by activated macrophages., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is known to reduce disulfide bonds present in proteins internalized by antigen presenting cells, facilitating optimal processing and presentation of peptides on Major Histocompatibility Complex class II molecules, as well as the subsequent activation of CD4-positive T lymphocytes. Here, we show that GILT is required for class II-restricted processing and presentation of immunodominant epitopes from the major house dust mite allergen Der p 1. In the absence of GILT, CD4-positive T cell responses to Der p 1 are significantly reduced, resulting in mitigated allergic airway inflammation in response to Der p 1 and house dust mite extracts in a murine model of asthma.

Complexation of the Brilliant Yellow tetraanion, 3(4-), by two new diazacoronand linked beta-cyclodextrin (beta CD) dimers 4,13-bis(2-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl- and 4,13-bis(8-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl)-4,13- diaza-1,7,10-trioxacyclopentadecane, 1 and 2, respectively, has been studied in aqueous solution. UV-visible spectrophotometric studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NEt4ClO4) yielded complexation constants for the complexes 1 x 3(4-) and 2 x 3(4-), K1 = (1.08 +/- 0.01) x 10(5) and (6.21 +/- 0.08) x 10(3) dm3 mol-1, respectively. Similar studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NaClO4) yielded K3 = (4.63 +/- 0.09) x 10(5) and (3.38 +/- 0.05) x 10(4) dm3 mol-1 for the complexation of 3(4-) by Na+ x 1 and Na+ x 2 to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-), respectively. Potentiometric studies of the complexation of Na+ by 1 and 2 by the diazacoronand component of the linkers to give Na+ x 1 and Na+ x 2 yielded K2 = (2.00 +/- 0.05) x 10(3) and (1.8 +/- 0.05) x 10(3) dm3 mol-1, respectively, at 298.2 K and I = 0.10 mol dm-3(NEt4ClO4). For complexation of Na+ by 1 x 3(4-) and 2 x 3(4-) to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-) K2K3/K1 = K4 = 8.6 x 10(2) and 9.8 x 10(3) dm3 mol-1, respectively. The pKaS of 1H4(4+) are 7.63 +/- 0.01, 6.84 +/- 0.02, 5.51 +/- 0.04 and 4.98 +/- 0.03, and those of 2H4(4+) are 8.67 +/- 0.02, 8.11 +/- 0.02, 6.06 +/- 0.02 and 5.14 +/- 0.05. The larger magnitude of K1 for 1 by comparison with K1 for 2 is attributed to the octamethylene linkers of 2 competing with 3(4-) for occupancy of the annuli of the beta CD entities while the competitive ability of the dimethylene linkers of 1 is less. A similar argument applies to the relative magnitudes of K3 for Na+ x 1 and Na+ x 2. Increased electrostatic attraction probably accounts for K3 > K1 for Na+ x 1 x 3(4-) and 1 x 3(4-) and for Na+ x 2 x 3(4-) and 2 x 3(4-). The lesser magnitudes of K2 and K4 for Na+ x 1 and Na+ x 1 x 3(4-) compared with those for Na+ x 2 and Na+ x 2 x 3(4-) are attributed to the octamethylene linkers of 2 producing a more hydrophobic environment for the diazacoronand than that produced by the dimethylene linkers of 1. 1H NMR spectroscopic studies and the syntheses of 1 and 2 are described.

Iron-sulfur clusters are ubiquitous in biological systems, facilitating functions such as electron transfer (rubredoxins, ferredoxins, rieske centres), isomerization (aconitase) and small molecule activation such as dinitrogen reduction (nitrogenases). Of global importance and recently particular interest, is the iron-sulfur-containing iron-molybdenum cofactor (FeMoco) cluster that achieves the biological reduction of dinitrogen under mild conditions. This biologically unique cluster has proved difficult to investigate due to its extreme air sensitivity and the instability of the cluster's structural integrity, outside the protective protein matrix. Here, we report a model iron-sulfur cluster (Roussins black salt (NH(4))[Fe(4)S(3)(NO)(7)]) that has been used to achieve the first example of a metal cluster (guest) embedded within a pseudo-protein, cyclodextrin (host). The product formed is supramolecular, that is, it contained no covalent bonds and was stabilized by predominantly entropy effects. Formation of a 1 : 1 complex between the host and the guest was established for the iron-sulfur cluster with either seven- or eight-membered cyclodextrins (beta- or gamma-cyclodextrin). A range of techniques was used to characterize the new complexes in both the solid and solution states. Electrospray mass spectra indicated the presence of parent ions of the host-guest complexes and electrochemistry was also used to define the redox behavior of the complexes. The iron-sulfur clusters were significantly more stable in the presence of the host cyclodextrin, as revealed by a negative shift for the reduction potential for the host-guest product. Using the beta-cyclodextrin as host, the reduction potential of the iron-sulfur cluster shifted more negative by 60 mV; the effect was even more dramatic for the larger gamma-cyclodextrin where the reduction potential for the cluster was shifted by 90 mV more negative than the 'unbound' [Fe(4)S(3)(NO)(7)]- cluster. This is the first example of a metal cluster, stabilized as a supramolecular complex in a 'host' environment outside of a covalently bonded protein matrix. Creating such stable environments for metal cofactors or clusters that otherwise spontaneously degrade or are catalytically inactive outside the protein matrix could have enormous practical value. Specific implications for the development of extrusion methods for FeMoco from nitrogenase are enormous, with previously difficult, high-energy molecular transformations, such as dinitrogen to ammonia, now more realistically accessible.

High-frequency gratings with rectangular-groove profiles are used to generate high-efficiency beam splitters and beam deflectors. The effects of the grating design parameters, i.e., period, groove depth, duty cycle, number of phase levels, and polarization state (TE and TM) of the incoming signal, are considered. The case of the binary beam splitter grating is analyzed by using rigorous electromagnetic grating analysis. Fabrication techniques are presented in which three different lithographic techniques are considered (optical contact, deep-UV stepper reduction, and electron-beam direct write). Experimental results of 97% efficiency for the beam splitter grating and up to 80% for the beam deflector grating are reported.

Foetal retina was removed from donor rats at 15 days of gestation and transplanted to the occipital cortex of neonatal host rats. The purpose of this procedure was to examine the development of retinal neurons and photoreceptors, and document synaptic patterns during maturation of the transplanted retina in an environment lacking a normal target for optic axons. Host animals were sacrificed at 5, 10, 15, 20 and 30 days and samples of cortex containing the transplant were subjected to a light and electron microscopic analysis. During early stages of development, (5 days) the retina assumes a radial orientation with the scleral (outer) surface located centrally and the vitreal (inner) surface occupying the periphery. Numerous mitotic figures are found at the centre of the transplant and columns of primitive neuroblasts appear to radiate out from this zone. By 10 to 15 days after transplantation the retinal tissue contains numerous small rosettes each of which displays a histotypic organization with recognizable layers of sensory cells and their centrally-projecting processes, an outer limiting membrane, made up of a network of zonulae adherentes, and a rudimentary outer and inner plexiform layer which delineate the cells of the inner nuclear layer. Ultrastructural analysis of such rosettes confirmed the presence of typical bipolar, amacrine, horizontal and ganglion cells, but revealed that while the plexiform layers were occupied by numerous processes from these neurons, few if any, of these exhibited synaptic vesicles. By 20 to 30 days following transplantation sensory cells have completely differentiated, giving rise to prominent inner and outer segments which display typical cilia, centrioles and basal bodies, together with numerous stacked lamellae of photoreceptors which were contorted, presumably due to growth in an abnormal site. It should be further emphasized that these structures developed in the absence of pigment cells. Synaptic development ensues during this period to form characteristic dyads within the outer and inner plexiform layers. Additionally, clusters of amacrine to amacrine contacts occurred in the inner plexiform layer and were found to be increased relative to other types of junctions. In general, synaptogenesis takes place in the outer and inner plexiform layers and all categories of retinal synapses are established, but the process was found to be significantly delayed in comparison to normal retina at the same stage of development. Quantitative analysis revealed a reduced number of presumptive ganglion cells in proportion to the other categories of neurons. Optic fibres remained small and failed to myelinate. It is suggested that lack of an appropriate target for optic axons induced this alteration and may be indirectly related to the delay in the onset of synaptic development.

In a prospective trial we enrolled 157 women at increased risk of preterm birth, randomly assigning women in a ratio of 1:2 to receive either frequent (greater than or equal to 5 days/wk) nursing contact, education in preterm labor symptoms, and self-palpation of uterine activity (group E, n = 50), or daily nursing contact, preterm labor education, and the Term Guard home uterine activity monitor (group EM, n = 107). Comparison of the rate of preterm birth, the incidence of preterm labor and successful tocolysis, and the mean birth weight and gestational age revealed no significant differences and suggested that beneficial effects previously attributed to monitored contraction data may in fact be the result of frequent (five or more times per week) nursing contact and careful attention to preterm labor symptoms and perceived contractions.

Developmental alterations in the amount of tritiated proline and fucose incorporated by retinal neurons and transported within axons of the optic nerve to the dorsal lateral geniculate nucleus and superior colliculus were measured at 1, 5, 10 and 15 days postnatal using quantitative autoradiography and liquid scintillation analysis. The amount of axon transport inhibition induced by introacular injections of colchicine (10-4 M-5 X 10-3M) and xylocaine (10-3 M-10-1 M) was also determined by this methodology. Grain counts of retinal autoradiograms obtained from animals of all ages employed in this study demonstrated that [3H] proline is rapidly incorporated by all retinal neurons but becomes increasingly concentrated within the inner nuclear, ganglion cell and optic fiber layers between 2h and 2 days after injection. [3H] fucose is preferentially taken up and concentrated within the plexiform and sensory element layers. Intraocular colchicine administered 24 h prior to isotope injection exhibited no significant effect on incorporation but depressed the amount of activity in the layer of optic fibers. Comparison of the effects of colchicine and xylocaine on axon transport of [3H] proline injected at 3 days of age revealed dose-dependent suppression of transport occurring up to six hr after isotope injection; however, with longer survival periods the effects of xylocaine were no longer significant whereas colchicine maintained suppression of axon transport to 20% of normal for periods of up to 10 days. Additionally, the rate and quantity of 3H] proline transported to the dorsal lateral geniculate nucleus and tectum of 1-15 day old animals was found to be inversely proportional to the age of the animal. Maximally-effective concentrations of colchicine, determined for each age level examined by the previous study to be highest compatible with the viability of the retino-fugal projection, 34 also reduced transport to from 20-40% of normal, being most effective in animals of 1-10 days of age. Autoradiographs of the optic disc demonstrated a colchicine-induced suppression of the amount of label in the exiting optic fibers and similar preparations of the tectum revealed an elimination of activity in the stratum griseum superficialis and stratum opticum which are normally heavily labeled following intraocular [3H] proline or fucose. Following [3H] fucose injection at 10 days of age, isotope appears in the contralateral visual cortex between 3 and 10 days later, indicating a substantial amount of transneuronal transfer of label which appeared to occur in concert with periods of maximal synaptogenesis. Injection of colchicine reduced the amount of label in the cortex to background levels. Concomitantly, autoradiographs of the dorsal lateral geniculate nucleus revealed cytoplasmic labeling of geniculate neurons in control animals but this was eliminated following colchicine injection...