Mapping pathways to neuronal atrophy in healthy, mid-aged adults: From chronic stress to systemic inflammation to neurodegeneration?

Growing evidence implicates systemic inflammation in the loss of structural brain integrity in natural ageing and disorder development. Chronic stress and glucocorticoid exposure can potentiate inflammatory processes and may also be linked to neuronal atrophy, particularly in the hippocampus and the human neocortex. To improve understanding of emerging maladaptive interactions between stress and inflammation, this study examined evidence for glucocorticoid- and inflammation-mediated neurodegeneration in healthy mid-aged adults. N = 169 healthy adults (mean age = 39.4, 64.5% female) were sampled from the general population in the context of the ReSource Project. Stress, inflammation and neuronal atrophy were quantified using physiological indices of chronic stress (hair cortisol (HCC) and cortisone (HEC) concentration), systemic inflammation (interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP)), the systemic inflammation index (SII), hippocampal volume (HCV) and cortical thickness (CT) in regions of interest. Structural equation models were used to examine evidence for pathways from stress and inflammation to neuronal atrophy. Model fit indices indicated good representation of stress, inflammation, and neurological data through the constructed models (CT model: robust RMSEA = 0.041, robust χ2 = 910.90; HCV model: robust RMSEA <0.001, robust χ2 = 40.95). Among inflammatory indices, only the SII was positively associated with hair cortisol as one indicator of chronic stress (ß = 0.18, p < 0.05). Direct and indirect pathways from chronic stress and systemic inflammation to cortical thickness or hippocampal volume were non-significant. In exploratory analysis, the SII was inversely related to mean cortical thickness. Our results emphasize the importance of considering the multidimensionality of systemic inflammation and chronic stress, with various indicators that may represent different aspects of the systemic reaction. We conclude that inflammation and glucocorticoid-mediated neurodegeneration indicated by IL-6 and hs-CRP and HCC and HEC may only emerge during advanced ageing and disorder processes, still the SII could be a promising candidate for detecting associations between inflammation and neurodegeneration in younger and healthy samples. Future work should examine these pathways in prospective longitudinal designs, for which the present investigation serves as a baseline.

Electrophysiological signatures of veridical head direction in humans.

Information about heading direction is critical for navigation as it provides the means to orient ourselves in space. However, given that veridical head-direction signals require physical rotation of the head and most human neuroimaging experiments depend upon fixing the head in position, little is known about how the human brain is tuned to such heading signals. Here we adress this by asking 52 healthy participants undergoing simultaneous electroencephalography and motion tracking recordings (split into two experiments) and 10 patients undergoing simultaneous intracranial electroencephalography and motion tracking recordings to complete a series of orientation tasks in which they made physical head rotations to target positions. We then used a series of forward encoding models and linear mixed-effects models to isolate electrophysiological activity that was specifically tuned to heading direction. We identified a robust posterior central signature that predicts changes in veridical head orientation after regressing out confounds including sensory input and muscular activity. Both source localization and intracranial analysis implicated the medial temporal lobe as the origin of this effect. Subsequent analyses disentangled head-direction signatures from signals relating to head rotation and those reflecting location-specific effects. Lastly, when directly comparing head direction and eye-gaze-related tuning, we found that the brain maintains both codes while actively navigating, with stronger tuning to head direction in the medial temporal lobe. Together, these results reveal a taxonomy of population-level head-direction signals within the human brain that is reminiscent of those reported in the single units of rodents.

Workers' Sensation Seeking Matters: Development and Validation of the Need for Sensations at Work Scale (NSWS).

Although sensation seeking (SS) may be a highly relevant trait in the occupational context, it is still understudied in the field of work and organizational psychology. Probably, one reason is the lack of an appropriate SS instrument for the work context. We therefore developed a scale that measures work-related SS. Results based on a sample of 304 workers provided evidence for the convergent and discriminant validity of the instrument. In an independent sample of 271 workers, confirmatory factor analyses supported a bifactor structure with a global SS factor and three specific domain factors (tension seeking, adrenaline seeking, and heartbeat increase seeking). Based on bifactor indices, essential unidimensionality of the instrument could be assumed. Work-related SS was positively associated with increasing challenging job demands, and a moderating effect of task variety on the relationship between work-related SS and job satisfaction was found. SS was not associated with the number of past job terminations. Overall, the findings indicate that SS may be relevant with regard to workers' proactive work behaviors and job attitudes. The Need for Sensations at Work Scale (NSWS) now provides a promising measurement instrument to further investigate SS in the work context.

Mobile Virtual Reality Versus Mobile 360° Video to Promote Enrollment in the Diabetes Prevention Program Among Hispanic Adults: Pilot Study.

BACKGROUND: Hispanic adults are at increased risk of developing type 2 diabetes. The Diabetes Prevention Program (DPP) reduces the risk of developing type 2 diabetes; however, the rate of enrollment is very low. OBJECTIVE: The goal of this pilot project was to determine whether presenting brief motivational mobile videos in virtual reality vs 360° video has differential effects on risk perceptions and enrollment in the DPP. METHODS: Adults with prediabetes were recruited at a clinic serving a low-income Hispanic community. After consenting, the participants completed a baseline survey that collected information about demographics and risk perceptions. All participants then viewed 2 videos. Per random assignment, the videos were presented either using the participant's smartphone alone (360° video) or were viewed with their smartphone in a virtual reality (VR) cardboard headset. Two weeks later, a follow-up survey collected measures of enrollment in the DPP, risk perceptions, health literacy, the importance of contextual factors related to the decision of whether to enroll in the DPP (eg, distance to the class), and qualitative feedback on the interventions. We used logistic regression to determine whether enrollment in the DPP differed by intervention mode, while accounting for health literacy and contextual factors related to the DPP. We used unpaired t tests to examine differences in change in risk perceptions between groups. Paired t tests were used to examine within-subject changes in risk perceptions. RESULTS: A total of 116 participants provided complete data. Most participants were middle-aged (mean age 44.6 years; SD 11.9) Hispanic (114/116), female (79/116), with low health literacy (mean score 12.3/20; SD 3.4). Enrollment in the DPP was 44/116 (37.9%) overall but did not differ by group (odds ratio for enrolling in VR group 1.78, 95% CI 0.75-4.3; P=.19). Individuals who rated the distance needed to travel to attend the DPP as more important were less likely to enroll in the DPP (odds ratio 0.56, 95% CI 0.33-0.92; P=.03). Risk perceptions did not differ by group (mean change in 360° video group -0.07, mean change in VR group 0.03, t=0.6, P=.54) and did not change within subjects (mean 0.02, t=0.21, P=.83). Participant feedback suggested that the videos are emotionally engaging and educational. CONCLUSIONS: The videos presented in 360° video and mobile VR had equal efficacy in promoting enrollment in the DPP. Future work to rigorously evaluate this intervention, its mechanism of action, and potential moderators of the efficacy are discussed.

Parent Interventions Improve Behavior After Pediatric Traumatic Brain Injury: A Systematic Review and Meta-analysis.

OBJECTIVE: To examine child behavior change scores from randomized controlled trials (RCTs) of parent interventions for pediatric traumatic brain injury (TBI). METHODS: MEDLINE, EMBASE, PsycINFO, and CINAHL were searched to identify studies that examined parent interventions for pediatric TBI. Inclusion criteria included (i) a parent intervention for children with TBI; (ii) an RCT study design; (iii) statistical data for child behavior outcome(s); and (iv) studies that were published in English. RESULTS: Seven studies met inclusion criteria. All interventions reported improved child behavior after pediatric TBI; however, child and parent factors contributed to behavior change scores in some interventions. Factors found to contribute to the level of benefit included age of child, baseline behavior levels, sociodemographics (eg, parent income, parent education), and parent mental health. CONCLUSION: Improved child behavior outcomes resulting from parent interventions for pediatric TBI are well supported by the evidence in the peer-reviewed literature. Clinicians are encouraged to consider child and parent factors as they relate to child behavior outcomes.

The use of machine learning in rare diseases: a scoping review.

BACKGROUND: Emerging machine learning technologies are beginning to transform medicine and healthcare and could also improve the diagnosis and treatment of rare diseases. Currently, there are no systematic reviews that investigate, from a general perspective, how machine learning is used in a rare disease context. This scoping review aims to address this gap and explores the use of machine learning in rare diseases, investigating, for example, in which rare diseases machine learning is applied, which types of algorithms and input data are used or which medical applications (e.g., diagnosis, prognosis or treatment) are studied. METHODS: Using a complex search string including generic search terms and 381 individual disease names, studies from the past 10 years (2010-2019) that applied machine learning in a rare disease context were identified on PubMed. To systematically map the research activity, eligible studies were categorized along different dimensions (e.g., rare disease group, type of algorithm, input data), and the number of studies within these categories was analyzed. RESULTS: Two hundred eleven studies from 32 countries investigating 74 different rare diseases were identified. Diseases with a higher prevalence appeared more often in the studies than diseases with a lower prevalence. Moreover, some rare disease groups were investigated more frequently than to be expected (e.g., rare neurologic diseases and rare systemic or rheumatologic diseases), others less frequently (e.g., rare inborn errors of metabolism and rare skin diseases). Ensemble methods (36.0%), support vector machines (32.2%) and artificial neural networks (31.8%) were the algorithms most commonly applied in the studies. Only a small proportion of studies evaluated their algorithms on an external data set (11.8%) or against a human expert (2.4%). As input data, images (32.2%), demographic data (27.0%) and "omics" data (26.5%) were used most frequently. Most studies used machine learning for diagnosis (40.8%) or prognosis (38.4%) whereas studies aiming to improve treatment were relatively scarce (4.7%). Patient numbers in the studies were small, typically ranging from 20 to 99 (35.5%). CONCLUSION: Our review provides an overview of the use of machine learning in rare diseases. Mapping the current research activity, it can guide future work and help to facilitate the successful application of machine learning in rare diseases.

Taming the Cationic Beast: Novel Developments in the Synthesis and Application of Weakly Coordinating Anions.

This Review gives a comprehensive overview of the most topical weakly coordinating anions (WCAs) and contains information on WCA design, stability, and applications. As an update to the 2004 review, developments in common classes of WCA are included. Methods for the incorporation of WCAs into a given system are discussed and advice given on how to best choose a method for the introduction of a particular WCA. A series of starting materials for a large number of WCA precursors and references are tabulated as a useful resource when looking for procedures to prepare WCAs. Furthermore, a collection of scales that allow the performance of a WCA, or its underlying Lewis acid, to be judged is collated with some advice on how to use them. The examples chosen to illustrate WCA developments are taken from a broad selection of topics where WCAs play a role. In addition a section focusing on transition metal and catalysis applications as well as supporting electrolytes is also included.

Gold(I) mediated rearrangement of [7]-helicene to give a benzo[cd]pyrenium cation embedded in a chiral framework.

The facile gold-mediated skeletal rearrangement of [7]-helicene into a cationic polyaromatic hydrocarbon is described. We report in-depth studies on the structure and aromaticity of this novel stable cation and propose a mechanism for its formation.

A systematic investigation of coinage metal carbonyl complexes stabilized by fluorinated alkoxy aluminates.

The reaction of Cu(I), Ag(I), and Au(I) salts with carbon monoxide in the presence of weakly coordinating anions led to known and structurally unknown non-classical coinage metal carbonyl complexes [M(CO)n][A] (A = fluorinated alkoxy aluminates). The coinage metal carbonyl complexes [Cu(CO)n(CH2Cl2)m](+)[A](-) (n = 1, 3; m = 4-n), [Au2(CO)2Cl](+)[A](-), [(OC)nM(A)] (M = Cu: n = 2; Ag: n = 1, 2) as well as [(OC)3Cu⋅⋅⋅ClAl(OR(F))3] and [(OC)Au⋅⋅⋅ClAl(OR(F))3] were analyzed with X-ray diffraction and partially IR and Raman spectroscopy. In addition to these structures, crystallographic and spectroscopic evidence for the existence of the tetracarbonyl complex [Cu(CO)4](+)[Al(OR(F))4](-) (R(F) = C(CF3)3) is presented; its formation was analyzed with the help of theoretical investigations and Born-Fajans-Haber cycles. We discuss the limits of structure determinations by routine X-ray diffraction methods with respect to the C-O bond lengths and apply the experimental CO stretching frequencies for the prediction of bond lengths within the carbonyl ligand based on a correlation with calculated data. Moreover, we provide a simple explanation for the reported, partly confusing and scattered CO stretching frequencies of [Cu(I)(CO)n] units.

[7]-Helicene: a chiral molecular tweezer for silver(I) salts.

We have unambiguously demonstrated the binding of the silver(I) ion in the central cavity of [7]-helicene, given that the counterion is weakly coordinating. In such a binding mode, the helicene is functioning as a chiral molecular tweezer.

Magnetic resonance perfusion of the myocardium: semiquantitative and quantitative evaluation in comparison with coronary angiography and fractional flow reserve.

PURPOSE: The aim of this study was to investigate if a quantitative evaluation of a magnetic resonance (MR) perfusion examination of the myocardium can achieve a comparable diagnostic accuracy as a semiquantitative evaluation. METHODS: A total of 31 patients with suspected coronary artery disease underwent MR imaging and conventional coronary angiography. Stenoses with a diameter reduction between 50% and 75% were evaluated by an intracoronary pressure wire examination (fractional flow reserve) for assessment of their hemodynamic relevance. A 0.05 mmol/kg contrast material bolus (gadopentetate dimeglumine) was applied during adenosine-induced stress (140 µg/kg/min) and at rest with a flow rate of 5 mL/s. Signal intensity time curves of the first-pass MR perfusion images, acquired at rest and under adenosine stress with a Saturation Recovery-turbo Fast Low Angle Shot Magnetic Resonance Imaging sequence, were analyzed by Argus Dynamic Signal Analysis (Siemens Healthcare, Erlangen, Germany). For the semiquantitative evaluation, the upslope value of a linear fit from the foot point to the signal maximum was calculated for 18 segments (signal intensity units per second). For the quantitative evaluation, a model-independent deconvolution was used to calculate coronary blood flow (MBF in mL/100 g/min). For each segment for the stress and rest examination, upslope value and MBF were determined. In addition, the ratio of the stress and rest value for each segment was determined (myocardial perfusion reserve index [MPRI]). The mean value of the 2 segments with the lowest value was calculated for each patient. Coronary artery stenosis greater than 75% or greater than 50% with positive fractional flow reserve less than 0.75 was considered as hemodynamically relevant. Receiver-operator-curves were calculated. RESULTS: The values of the area under the ROC curves were 0.74, 0.66, and 0.92 for the US(Stress), US(Rest), and US(MPRI) evaluations (semiquantitative evaluation). The values for the MBF(Stress), MBF(Rest), and MBF(MPRI) evaluations (quantitative evaluation) were 0.92, 0.68, and 0.84, respectively. Comparing US(MPRI) and MBF(Stress), identical values and no significant difference were found for the area under the ROC curves. CONCLUSION: A quantitative evaluation using a model-free deconvolution provides identical diagnostic performance when only a stress examination is used, much similar to a semiquantitative evaluation, if both stress and rest examinations are used.

Buffer-dependent regulation of aquaporin-1 expression and function in human peritoneal mesothelial cells.

BACKGROUND: Biocompatible peritoneal dialysis fluids (PDF) are buffered with lactate and/or bicarbonate. We hypothesized that the reduced toxicity of the biocompatible solutions might unmask specific effects of the buffer type on mesothelial cell functions. METHODS: Human peritoneal mesothelial cells (HPMC) were incubated with bicarbonate (B-)PDF or lactate-buffered (L-)PDF followed by messenger RNA (mRNA) and protein analysis. Gene silencing was achieved using small interfering RNA (siRNA), functional studies using Transwell culture systems, and monolayer wound-healing assays. RESULTS: Incubation with B-PDF increased HPMC migration in the Transwell and monolayer wound-healing assay to 245 ± 99 and 137 ± 11% compared with L-PDF. Gene silencing showed this effect to be entirely dependent on the expression of aquaporin-1 (AQP-1) and independent of AQP-3. Exposure of HPMC to B-PDF increased AQP-1 mRNA and protein abundance to 209 ± 80 and 197 ± 60% of medium control; the effect was pH dependent. L-PDF reduced AQP-1 mRNA. Addition of bicarbonate to L-PDF increased AQP-1 abundance by threefold; mRNA half-life remained unchanged. Immunocytochemistry confirmed opposite changes of AQP-1 cell-membrane abundance with B-PDF and L-PDF. CONCLUSIONS: Peritoneal mesothelial AQP-1 abundance and migration capacity is regulated by pH and buffer agents used in PD solutions. In vivo studies are required to delineate the impact with respect to long-term peritoneal membrane integrity and function.

Adapting the γ-H2AX assay for automated processing in human lymphocytes. 1. Technological aspects.

The immunofluorescence-based detection of γ-H2AX is a reliable and sensitive method for quantitatively measuring DNA double-strand breaks (DSBs) in irradiated samples. Since H2AX phosphorylation is highly linear with radiation dose, this well-established biomarker is in current use in radiation biodosimetry. At the Center for High-Throughput Minimally Invasive Radiation Biodosimetry, we have developed a fully automated high-throughput system, the RABIT (Rapid Automated Biodosimetry Tool), that can be used to measure γ-H2AX yields from fingerstick-derived samples of blood. The RABIT workstation has been designed to fully automate the γ-H2AX immunocytochemical protocol, from the isolation of human blood lymphocytes in heparin-coated PVC capillaries to the immunolabeling of γ-H2AX protein and image acquisition to determine fluorescence yield. High throughput is achieved through the use of purpose-built robotics, lymphocyte handling in 96-well filter-bottomed plates, and high-speed imaging. The goal of the present study was to optimize and validate the performance of the RABIT system for the reproducible and quantitative detection of γ-H2AX total fluorescence in lymphocytes in a multiwell format. Validation of our biodosimetry platform was achieved by the linear detection of a dose-dependent increase in γ-H2AX fluorescence in peripheral blood samples irradiated ex vivo with γ rays over the range 0 to 8 Gy. This study demonstrates for the first time the optimization and use of our robotically based biodosimetry workstation to successfully quantify γ-H2AX total fluorescence in irradiated peripheral lymphocytes.

Cu[Al(OR(F))4] starting materials and their application in the preparation of [Cu(S(n))]+ (n=12, 8) complexes.

An effective route to stable, almost-"naked" Cu(I) salts of weakly coordinating anions (WCAs) of the type [Al(OR(F))4]- has been developed. Born-Fajans-Haber cycles and theoretical calculations suggest that this methodology is useful for the generation of Cu(I) salts regardless of the larger WCA used. The first homoleptic Cu(I)-arene complex [Cu(1,2-F2C6H4)2](+)[Al{OC(CF3)3}4]- (1), the first Cu(I)-methylenechloride complex [Cu(CH2Cl2)Al{OC(CH3)(CF3)2}4] (2), and the donor-free dimer [CuAl{OCH(CF3)2}4]2 (3) were synthesized in quantitative yields by sonicating Li[Al(OR(F))4] (R(F)=C(CF3)3, C(CH3)(CF3)2, or CH(CF3)2), AgF, and a three-fold excess of CuI in 1,2-F2C6H4 (1) or CH2Cl2 (2, 3). Substances 1-3 are good starting materials for further Cu(I) chemistry, and the reaction of 1-3 with the weak Lewis base cyclooctasulfur gave the first Cu(I)-sulfur complexes of type [Cu(S12)(S8)](+)[Al{OC(CF3)3}4]- (4), [Cu(CH2Cl2)(S12)](+)[Al{OC(CF3)3}4]- (5), [A1Cu(1,5-eta1,eta1-S8)CuA1] (6; A1=[Al{OC(CH3)(CF3)2}4]-), and a Cu(I)-S8 1D coordination polymer with [Cu2(S8)2A(2)(2)] (7; A2=[Al{OCH(CF3)2}4]-), as a monomeric repeat unit. Complexes 4 and 5 are the first example of any metal coordinated to cyclo-S12 and 4 is the first example of a complex having an element in two allotropic modifications as a ligand.

C5a-blockade improves burn-induced cardiac dysfunction.

We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

Chloride and bicarbonate have similar affinities to the intestinal anion exchanger DRA (down regulated in adenoma).

DRA (down regulated in adenoma, SLC26A3) is an anion exchanger that mediates electroneutral NaCl absorption in the ileum and proximal colon together with NHE3 (Na/H exchanger isoform 3), and that is involved in duodenal and possibly pancreatic bicarbonate secretion. Thus, its chloride and bicarbonate affinities are important for both processes. [Cl]i and pHi transients were measured using MQAE and BCECF. HEK293 cells stably expressing DRA were exposed to 0 mM Cl at various [HCO3] (9 to 51 mM, at 5% CO2 or 15 to 57 mM, at pH 7.5) to determine the HCO3 affinity. After intracellular Cl depletion, 10, 30, and 90 mM Cl were readded at various [HCO3]s to determine the relative Cl and HCO3 affinities. The k0.5 for extracellular HCO3 is between 18.5 and 32.8 mM. Cl and HCO3 compete with similar affinities for transport by DRA. DRA activity is independent of pHo between 7.0 and 7.75. DRA is activated by alkaline pHi. Competition of Cl and HCO3 does not significantly impair NaCl absorption, because in the ileum and colon, luminal Cl is comparably high. Activation at alkaline pHi supports functional coupling of DRA and NHE3 by the subapical pHi. In the distal pancreatic ductal system, luminal HCO3 is high compared to luminal Cl. Under these conditions, competition of Cl and HCO3 is difficult to reconcile with a role of DRA in Cl reabsorption in exchange for HCO3. Our data, thus, provide indirect evidence against a role of DRA in pancreatic HCO3 secretion.

Molecular examination of the transmembrane requirements of the platelet-derived growth factor beta receptor for a productive interaction with the bovine papillomavirus E5 oncoprotein.

The small transmembrane E5 protein of bovine papillomavirus (BPV) transforms cells by forming a stable complex with and activating the platelet-derived growth factor beta receptor (PDGFbetaR). The E5/PDGFbetaR interaction is thought to involve specific physical contacts between the transmembrane domains of the two proteins. Lys(499) at the extracellular juxtamembrane position and Thr(513) within the transmembrane domain of the PDGFbetaR are required for the interaction and are predicted to contact analogously positioned residues in the E5 protein. Here, mutagenic analysis of the transmembrane region of the PDGFbetaR was performed to further characterize the nature of the E5/PDGFbetaR interaction. We show that the receptor transmembrane domain, with minimal extracellular and intracellular sequence, is sufficient for the interaction. In addition, we provide evidence that the polar nature of Thr(513) as well as its positioning along the transmembrane alpha-helix is important for the interaction. We also identify the receptor transmembrane amino acids Ile(506) and Leu(520) as additional requirements for the interaction. Because Lys(499), Thr(513), Ile(506), and Leu(520) all align along the same face of the predicted PDGFbetaR transmembrane alpha-helix, our data support the model that the PDGFbetaR contacts the E5 protein via multiple amino acids along a single alpha-helical interface.