Biomarkers of geroprotection and cardiovascular health: An overview of omics studies and established clinical biomarkers in the context of diet.

The slowdown, inhibition, or reversal of age-related decline (as a composite of disease, dysfunction, and, ultimately, death) by diet or natural compounds can be defined as dietary geroprotection. While there is no single reliable biomarker to judge the effects of dietary geroprotection, biomarker signatures based on omics (epigenetics, gene expression, microbiome composition) are promising candidates. Recently, omic biomarkers started to supplement established clinical ones such as lipid profiles and inflammatory cytokines. In this review, we focus on human data. We first summarize the current take on genetic biomarkers based on epidemiological studies. However, most of the remaining biomarkers that we describe, whether omics-based or clinical, are related to intervention studies. Then, because of their promising potential in the context of dietary geroprotection, we focus on the effects of berry-based interventions, which up to now have been mostly described employing clinical markers. We provide an aggregation and tabulation of all the recent systematic reviews and meta-analyses that we could find related to this topic. Finally, we present evidence for the importance of the "nutribiography," that is, the influence that an individual's history of diet and natural compound consumption can have on the effects of dietary geroprotection.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1975638.

Variational kinetic clustering of complex networks.

Efficiently identifying the most important communities and key transition nodes in weighted and unweighted networks is a prevalent problem in a wide range of disciplines. Here, we focus on the optimal clustering using variational kinetic parameters, linked to Markov processes defined on the underlying networks, namely, the slowest relaxation time and the Kemeny constant. We derive novel relations in terms of mean first passage times for optimizing clustering via the Kemeny constant and show that the optimal clustering boundaries have equal round-trip times to the clusters they separate. We also propose an efficient method that first projects the network nodes onto a 1D reaction coordinate and subsequently performs a variational boundary search using a parallel tempering algorithm, where the variational kinetic parameters act as an energy function to be extremized. We find that maximization of the Kemeny constant is effective in detecting communities, while the slowest relaxation time allows for detection of transition nodes. We demonstrate the validity of our method on several test systems, including synthetic networks generated from the stochastic block model and real world networks (Santa Fe Institute collaboration network, a network of co-purchased political books, and a street network of multiple cities in Luxembourg). Our approach is compared with existing clustering algorithms based on modularity and the robust Perron cluster analysis, and the identified transition nodes are compared with different notions of node centrality.

miR-96 is required for normal development of the auditory hindbrain.

The peripheral deafness gene Mir96 is expressed in both the cochlea and central auditory circuits. To investigate whether it plays a role in the auditory system beyond the cochlea, we characterized homozygous Dmdo/Dmdo mice with a point mutation in miR-96. Anatomical analysis demonstrated a significant decrease in volume of auditory nuclei in Dmdo/Dmdo mice. This decrease resulted from decreased cell size. Non-auditory structures in the brainstem of Dmdo/Dmdo mice or auditory nuclei of the congenital deaf Cldn14-/- mice revealed no such differences. Electrophysiological analysis in the medial nucleus of the trapezoid body (MNTB) showed that principal neurons fired preferentially multiple action potentials upon depolarization, in contrast to the single firing pattern prevalent in controls and Cldn14-/- mice. Immunohistochemistry identified significantly reduced expression of two predicted targets of the mutated miR-96, Kv1.6 and BK channel proteins, possibly contributing to the electrophysiological phenotype. Microscopic analysis of the Dmdo/Dmdo calyx of Held revealed a largely absent compartmentalized morphology, as judged by SV2-labeling. Furthermore, MNTB neurons from Dmdo/Dmdo mice displayed larger synaptic short-term depression, slower AMPA-receptor decay kinetics and a larger NMDA-receptor component, reflecting a less matured stage. Again, these synaptic differences were not present between controls and Cldn14-/- mice. Thus, deafness genes differentially affect the auditory brainstem. Furthermore, our study identifies miR-96 as an essential gene regulatory network element of the auditory system which is required for functional maturation in the peripheral and central auditory system alike.

Bedside Sonographic Duplex Technique as a Monitoring Tool in Patients after Decompressive Craniectomy: A Single Centre Experience.

BACKGROUND AND OBJECTIVES: Bedside sonographic duplex technique (SDT) may be used as an adjunct to cranial computed tomography (CCT) to monitor brain-injured patients after decompressive craniectomy (DC). The present study aimed to assess the value of SDT in repeated measurements of ventricle dimensions in patients after DC by comparing both techniques. MATERIALS AND METHODS: Retrospective assessment of 20 consecutive patients after DC for refractory intracranial pressure (ICP) increase following subarachnoid hemorrhage (SAH), bleeding and trauma which were examined by SDT and CCT in the context of routine clinical practice. Whenever a repeated CCT was clinically indicated SDT examinations were performed within 24 hours and correlated via measurement of the dimensions of all four cerebral ventricles. Basal cerebral arteries including pathologies such as vasospasms were also evaluated in comparison to selected digital subtraction angiography (DSA). RESULTS: Repeated measurements of all four ventricle diameters showed high correlation between CCT and SDT (right lateral r = 0.997, p < 0.001; left lateral r = 0.997, p < 0.001; third r = 0.991, p < 0.001, fourth ventricle r = 0.977, p < 0.001). SDT performed well in visualizing basal cerebral arteries including pathologies (e.g., vasospasms) as compared to DSA. CONCLUSIONS: Repeated SDT measurements of the dimensions of all four ventricles in patients after DC for refractory ICP increase delivered reproducible results comparable to CCT. SDT may be considered as a valuable bedside monitoring tool in patients after DC.

Large-deviations of the basin stability of power grids.

Energy grids play an important role in modern society. In recent years, there was a shift from using few central power sources to using many small power sources, due to efforts to increase the percentage of renewable energies. Therefore, the properties of extremely stable and unstable networks are of interest. In this paper, distributions of the basin stability, a nonlinear measure to quantify the ability of a power grid to recover from perturbations, and its correlations with other measurable quantities, namely, diameter, flow backup capacity, power-sign ratio, universal order parameter, biconnected component, clustering coefficient, two core, and leafs, are studied. The energy grids are modeled by an Erdos-Rényi random graph ensemble and a small-world graph ensemble, where the latter is defined in such a way that it does not exhibit dead ends. Using large-deviation techniques, we reach very improbable power grids that are extremely stable as well as ones that are extremely unstable. The 1/t-algorithm, a variation of Wang-Landau, which does not suffer from error saturation, and additional entropic sampling are used to achieve good precision even for very small probabilities ranging over eight decades.

From Spin Glasses to Negative-Weight Percolation.

Spin glasses are prototypical random systems modelling magnetic alloys. One important way to investigate spin glass models is to study domain walls. For two dimensions, this can be algorithmically understood as the calculation of a shortest path, which allows for negative distances or weights. This led to the creation of the negative weight percolation (NWP) model, which is presented here along with all necessary basics from spin glasses, graph theory and corresponding algorithms. The algorithmic approach involves a mapping to the classical matching problem for graphs. In addition, a summary of results is given, which were obtained during the past decade. This includes the study of percolation transitions in dimension from d = 2 up to and beyond the upper critical dimension d u = 6 , also for random graphs. It is shown that NWP is in a different universality class than standard percolation. Furthermore, the question of whether NWP exhibits properties of Stochastic-Loewner Evolution is addressed and recent results for directed NWP are presented.

Papilloedema from Dural Venous Sinus Compression by Meningiomas.

Intracranial mass lesions may cause intracranial hypertension secondary to venous hypertension when they compress the dural venous sinuses (DVS) and may present with isolated papilloedema, mimicking idiopathic intracranial hypertension. We report a series of 16 patients with isolated papilloedema related to meningiomas compressing the DVS seen from 2012 to 2016 at three institutions. Correct diagnosis was delayed in 10/16 patients and treatment required a multidisciplinary approach, often with multiple sequential interventions, including combinations of acetazolamide, cerebrospinal fluid-shunt, optic nerve sheath fenestration, surgical resection of the meningioma, radiation therapy, and endovascular venous stenting. Two patients also received anticoagulation for venous thrombosis secondary to venous sinus compression.

Cerebral Ventricular Dimensions After Decompressive Craniectomy: A Comparison Between Bedside Sonographic Duplex Technique and Cranial Computed Tomography.

BACKGROUND: The objective of this study was to assess and compare ventricle diameters in patients after decompressive craniectomy by using cranial computed tomography (CCT) versus sonographic duplex technique (SDT). METHODS: A total of 102 consecutive patients after decompressive craniectomy following brain infarct, bleeding and trauma were examined by CCT and SDT. SDT was performed within 24 h after repeated postinterventional control CCT and the correlation between both methods was assessed via measurement of dimensions of all four ventricles. In addition, midline shifts and overall cerebral anatomy was evaluated. RESULTS: A high correlation was found between CCT and SDT in measuring the diameters of all four ventricles (right lateral r = 0.978, p < 0.001; left lateral r = 0.975, p < 0.001; third r = 0.987, p < 0.001 and fourth ventricle r = 0.954, p < 0.001). Deviations of midline structure was observed in SDT as well as in CCT (r = 0.992, p < 0.001). CONCLUSION: SDT in patients after decompressive craniectomy may represent an additional bedside tool to assess the dimensions of the ventricular system, anatomical structures, e.g., subdural hygromas, hematomas, midline shifts, gyri and sulci. The measurement of the dimensions of all four ventricles by using SDT delivers accurate values and may be considered as an alternative to CCT or a trigger for CCT prior to further treatment.

Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity.

Alzheimer's disease is a common neurodegenerative, progressive, and fatal disorder. Generation and deposition of amyloid beta (Aß) peptides associate with its pathogenesis and small soluble Aß oligomers show the most pronounced neurotoxic effects and correlate with disease initiation and progression. Recent findings showed that Aß oligomers bind to the cellular prion protein (PrP(C) ) eliciting neurotoxic effects. The role of exosomes, small extracellular vesicles of endosomal origin, in Alzheimer's disease is only poorly understood. Besides serving as disease biomarkers they may promote Aß plaque formation, decrease Aß-mediated synaptotoxicity, and enhance Aß clearance. Here, we explore how exosomal PrP(C) connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrP(C) knockout cell line using transcription activator-like effector nucleases. Using these, as well as SH-SY5Y human neuroblastoma cells, we show that PrP(C) is highly enriched on exosomes and that exosomes bind amyloid beta via PrP(C) . Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric Aß species. Thioflavin T assays revealed that exosomal PrP(C) accelerates fibrillization of amyloid beta, thereby reducing neurotoxic effects imparted by oligomeric Aß. Our study provides further evidence for a protective role of exosomes in Aß-mediated neurodegeneration and highlights the importance of exosomal PrP(C) in molecular mechanisms of Alzheimer's disease. We show that the prion protein (PrP(C) ) on exosomes captures neurotoxic species of amyloid beta (Aß) promoting its fibrillization. Our study provides evidence for a protective role of exosomes in Alzheimer`s disease and suggests that, depending on its membrane topology, PrP(C) holds a dual function: when expressed at the neuronal surface it acts as receptor for Aß leading to neurotoxic signaling, whereas it detoxifies Aß when present on exosomes. This provides further support for key roles of PrP(C) in Alzheimer's disease.

COMADRE: a global data base of animal demography.

UNLABELLED: The open-data scientific philosophy is being widely adopted and proving to promote considerable progress in ecology and evolution. Open-data global data bases now exist on animal migration, species distribution, conservation status, etc. However, a gap exists for data on population dynamics spanning the rich diversity of the animal kingdom world-wide. This information is fundamental to our understanding of the conditions that have shaped variation in animal life histories and their relationships with the environment, as well as the determinants of invasion and extinction. Matrix population models (MPMs) are among the most widely used demographic tools by animal ecologists. MPMs project population dynamics based on the reproduction, survival and development of individuals in a population over their life cycle. The outputs from MPMs have direct biological interpretations, facilitating comparisons among animal species as different as Caenorhabditis elegans, Loxodonta africana and Homo sapiens. Thousands of animal demographic records exist in the form of MPMs, but they are dispersed throughout the literature, rendering comparative analyses difficult. Here, we introduce the COMADRE Animal Matrix Database, an open-data online repository, which in its version 1.0.0 contains data on 345 species world-wide, from 402 studies with a total of 1625 population projection matrices. COMADRE also contains ancillary information (e.g. ecoregion, taxonomy, biogeography, etc.) that facilitates interpretation of the numerous demographic metrics that can be derived from its MPMs. We provide R code to some of these examples. SYNTHESIS: We introduce the COMADRE Animal Matrix Database, a resource for animal demography. Its open-data nature, together with its ancillary information, will facilitate comparative analysis, as will the growing availability of databases focusing on other aspects of the rich animal diversity, and tools to query and combine them. Through future frequent updates of COMADRE, and its integration with other online resources, we encourage animal ecologists to tackle global ecological and evolutionary questions with unprecedented sample size.

Add-on Effects of Repetitive Transcranial Magnetic Stimulation on Subacute Aphasia Therapy: Enhanced Improvement of Functional Communication and Basic Linguistic Skills. A Randomized Controlled Study.

OBJECTIVE: To determine to what extent repetitive transcranial magnetic stimulation (rTMS) combined with speech and language therapy improves functional communication and basic linguistic skills of individuals with subacute aphasia. DESIGN: Randomized, blinded, and sham-controlled study. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Participants (N=30) with subacute aphasia after stroke. INTERVENTIONS: During a 2-week treatment period, half of the participants received 10 sessions of 20-minute inhibitory 1-Hz rTMS over the right inferior frontal gyrus (Brodmann area 45), and the other half received sham stimulation. Directly thereafter, all the participants underwent 45 minutes of speech and language therapy. MAIN OUTCOME MEASURES: Aachen Aphasia Test, Amsterdam-Nijmegen Everyday Language Test (ANELT), a naming screening, and subscales of the FIM, all assessed the day before and the day after treatment period. RESULTS: The participants who received real rTMS significantly improved with respect to all 10 measures of basic linguistic skills and functional communication, whereas sham-treated participants significantly improved in only 6 of 10 measures (paired t tests, P<.05). There was a significant difference in the gains made by the 2 groups on 5 of 10 measures including functional communication (ANELT) (repeated-measures analysis of variance, P≤.05). CONCLUSIONS: For the first time, this study has demonstrated that basic linguistic skills as well as functional communication are bolstered by combining rTMS and behavioral language therapy in patients with subacute aphasia.

Non-invasive repeated therapeutic stimulation for aphasia recovery: a multilingual, multicenter aphasia trial.

Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30 days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45 minutes speech and language therapy session for 10 days. Efficacy is evaluated at 1 and 30 days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add an effective new strategy for early stage poststroke aphasia rehabilitation.

Time-dependent gene expression analysis of the developing superior olivary complex.

The superior olivary complex (SOC) is an essential auditory brainstem relay involved in sound localization. To identify the genetic program underlying its maturation, we profiled the rat SOC transcriptome at postnatal days 0, 4, 16, and 25 (P0, P4, P16, and P25, respectively), using genome-wide microarrays (41,012 oligonucleotides (oligos)). Differences in gene expression between two consecutive stages were highest between P4 and P16 (3.6%) and dropped to 0.06% between P16 and P25. To identify SOC-related genetic programs, we also profiled the entire brain at P4 and P25. The number of differentially expressed oligonucleotides between SOC and brain almost doubled from P4 to P25 (4.4% versus 7.6%). These data demonstrate considerable molecular specification around hearing onset, which is rapidly finalized. Prior to hearing onset, several transcription factors associated with the peripheral auditory system were up-regulated, probably coordinating the development of the auditory system. Additionally, crystallin-γ subunits and serotonin-related genes were highly expressed. The molecular repertoire of mature neurons was sculpted by SOC-related up- and down-regulation of voltage-gated channels and G-proteins. Comparison with the brain revealed a significant enrichment of hearing impairment-related oligos in the SOC (26 in the SOC, only 11 in the brain). Furthermore, 29 of 453 SOC-related oligos mapped within 19 genetic intervals associated with hearing impairment. Together, we identified sequential genetic programs in the SOC, thereby pinpointing candidates that may guide its development and ensure proper function. The enrichment of hearing impairment-related genes in the SOC may have implications for restoring hearing because central auditory structures might be more severely affected than previously appreciated.

Miniaturized sensor for particles in air using Fresnel ring lenses and an enhanced intensity ratio technique.

We present a miniaturized particle sensor collecting scattered light in two solid angle intervals by Fresnel ring lenses. The particle size is determined from the ratio of both scattering amplitudes (intensity ratio) in addition to a linear diversity combining technique, generating a 3D particle size matrix that reduces the ambiguity by the index of refraction on the particle size identification. A signal-to-noise ratio of 30.3 was achieved for 147 nm sized polystyrene latex particles. Measurements of polydisperse particle size distribution show good agreement with the results by a scanning mobility particle sizer.

First-passage area distribution and optimal fluctuations of fractional Brownian motion.

We study the probability distribution P(A) of the area A=∫_{0}^{T}x(t)dt swept under fractional Brownian motion (fBm) x(t) until its first passage time T to the origin. The process starts at t=0 from a specified point x=L. We show that P(A) obeys exact scaling relation P(A)=D^{1/2H}/L^{1+1/H}Φ_{H}(D^{1/2H}A/L^{1+1/H}), where 0

Optimized finite-time work protocols for the Higgs RNA model with external force.

The Higgs RNA model with an added term for a coupling to an external force is studied in regard to finite-time force-driving protocols with a minimal-work requirement. In this paper, RNA sequences which at low temperature exhibit hairpins are considered, which are often cited as typical template systems in stochastic thermodynamics. The optimized work protocols for this glassy many-particle system are determined numerically using the parallel tempering method. The protocols show distinct jumps at the beginning and end, which have been observed for single-particle systems and are proven to be optimal in the fast protocol limit generally. Optimality seems to be achieved by staying close to the equilibrium unfolding transition point, in agreement with experimental and theoretical observations. The change of work distributions, compared to those resulting from a naive linear driving protocol, are discussed generally and in terms of free energy estimation as well as the effect of optimized protocols on rare work process starting conditions.

Probing the large deviations for the beta random walk in random medium.

We consider a discrete-time random walk on a one-dimensional lattice with space- and time-dependent random jump probabilities, known as the beta random walk. We are interested in the probability that, for a given realization of the jump probabilities (a sample), a walker starting at the origin at time t=0 is at position beyond ξsqrt[T/2] at time T. This probability fluctuates from sample to sample and we study the large-deviation rate function, which characterizes the tails of its distribution at large time T≫1. It is argued that, up to a simple rescaling, this rate function is identical to the one recently obtained exactly by two of the authors for the continuum version of the model. That continuum model also appears in the macroscopic fluctuation theory of a class of lattice gases, e.g., in the so-called KMP model of heat transfer. An extensive numerical simulation of the beta random walk, based on an importance sampling algorithm, is found in good agreement with the detailed analytical predictions. A first-order transition in the tilted measure, predicted to occur in the continuum model, is also observed in the numerics.

Viscosity Modeling for Blood and Blood Analog Fluids in Narrow Gap and High Reynolds Numbers Flows.

For the optimization of ventricular assist devices (VADs), flow simulations are crucial. Typically, these simulations assume single-phase flow to represent blood flow. However, blood consists of plasma and blood cells, making it a multiphase flow. Cell migration in such flows leads to a heterogeneous cell distribution, significantly impacting flow dynamics, especially in narrow gaps of less than 300 µm found in VADs. In these areas, cells migrate away from the walls, forming a cell-free layer, a phenomenon not usually considered in current VAD simulations. This paper addresses this gap by introducing a viscosity model that accounts for cell migration in microchannels under VAD-relevant conditions. The model is based on local particle distributions measured in a microchannels with a blood analog fluid. We developed a local viscosity distribution for flows with particles/cells and a cell-free layer, applicable to both blood and analog fluids, with particle volume fractions of up to 5%, gap heights of 150 µm, and Reynolds numbers around 100. The model was validated by comparing simulation results with experimental data of blood and blood analog fluid flow on wall shear stresses and pressure losses, showing strong agreement. This model improves the accuracy of simulations by considering local viscosity changes rather than assuming a single-phase fluid. Future developments will extend the model to physiological volume fractions up to 40%.

Management of Neurogenic Respiratory Alkalosis and Concomitant Lactatemia After Resection of a Posterior Fossa Meningioma: A Case Report.

Central neurogenic hyperventilation (CNH) is a rare disease, caused by chemical or mechanical disturbance of respiratory centers. It is characterized by the absence of extracerebral respiratory stimuli. A woman developed severe respiratory alkalosis and lactatemia after resection of a posterior fossa meningioma despite lack of cardio-respiratory or metabolic alterations. Cerebral computed tomography (cCT) revealed edema of the pontomedullary area. Treatment with mannitol and dexamethasone reestablished normal breathing patterns. Lactatemia was likely due to reduced splanchnic lactate utilization. Intracranial pathologies should be suspected in case of hyperventilation without overt reasons. cCT to confirm edema or ischemia and prompt treatment is suggested.

Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia.

BACKGROUND AND PURPOSE: Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. METHODS: Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15-water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. RESULTS: The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group (t test, P=0.003). Increases were largest for subtest naming (P=0.002) and tended to be higher for comprehension, token test, and writing (P<0.1). Patients in the rTMS group activated proportionally more voxels in the left hemisphere after treatment than before (difference in activation volume index) compared with sham-treated patients (t test, P=0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change (r2=0.25; P=0.015). CONCLUSIONS: Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks.