Individualized performance prediction of sleep-deprived individuals with the two-process model.

We present a new method for developing individualized biomathematical models that predict performance impairment for individuals restricted to total sleep loss. The underlying formulation is based on the two-process model of sleep regulation, which has been extensively used to develop group-average models. However, in the proposed method, the parameters of the two-process model are systematically adjusted to account for an individual's uncertain initial state and unknown trait characteristics, resulting in individual-specific performance prediction models. The method establishes the initial estimates of the model parameters using a set of past performance observations, after which the parameters are adjusted as each new observation becomes available. Moreover, by transforming the nonlinear optimization problem of finding the best estimates of the two-process model parameters into a set of linear optimization problems, the proposed method yields unique parameter estimates. Two distinct data sets are used to evaluate the proposed method. Results of simulated data (with superimposed noise) show that the model parameters asymptotically converge to their true values and the model prediction accuracy improves as the number of performance observations increases and the amount of noise in the data decreases. Results of a laboratory study (82 h of total sleep loss), for three sleep-loss phenotypes, suggest that individualized models are consistently more accurate than group-average models, yielding as much as a threefold reduction in prediction errors. In addition, we show that the two-process model of sleep regulation is capable of representing performance data only when the proposed individualized model is used.     

Late Quaternary paleoenvironmental records from the western Lena Delta,Arctic Siberia

The three main Lena Delta terraces were formed during different stages of the late Quaternary. While only the first floodplain terrace is connected with active deltaic processes, the second and third terraces, which dominate the western part of the delta, are erosional remnants of arctic paleolandscapes affected by periglacial processes. The landscape dynamics of the second and the third terraces, and their relationship to each other, are of particular importance in any effort to elucidate the late Quaternary paleoenvironment of western Beringia.Multidisciplinary studies of permafrost deposits on the second terrace were carried out at several sites of the Arga Complex, named after the largest delta island, Arga–Muora–Sise. The frozen sediments predominantly consist of fluvial sands several tens of meters thick, radiocarbon-dated from > 52 to 16 kyr BP. These sands were deposited under changing fluvial conditions in a dynamic system of shifting river channels, and have been additionally modified by synsedimentary and postsedimentary cryogenesis. Later thermokarst processes affected this late Pleistocene fluvial landscape during the Lateglacial and the Holocene. In addition, eolian activity reworked the fluvial sands on exposed surfaces at least since the Lateglacial, resulting in dune formation in some areas. Contrary to the Arga Complex, the third terrace is mainly composed of polygenetic alluvial and proluvial ice-rich permafrost sequences (Ice Complex deposits) radiocarbon-dated from 50 to 17 kyr BP which cover older fluvial sand units luminescence-dated to about 100–50 kyr BP. Paleoecological records reflect tundra-steppe conditions that varied locally, depending on landscape dynamics, during the Marine Isotope Stage (MIS) 4 and 3 periods, and a persistent change to shrub and arctic tundra during Lateglacial and Holocene periods.The study results indicate a continuous fluvial sedimentation environment for the Laptev Sea shelf in the region of the second Lena Delta terrace during the late Pleistocene, and confirm the presence of a dynamic channel system of the paleo-Lena River that flowed at the same time as the nearby subaerial Ice Complex deposits were being formed.     

Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

Background

A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment.

Results

Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP.

Conclusions

We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.     

Anti-inflammatory properties of intestinal Bifidobacterium strains isolated from healthy infants

Certain Bifidobacterium strains have been shown to inhibit inflammatory responses in intestinal epithelial cells. However, the precise mechanisms of these effects, including the chemical nature of the active compounds, remain to be elucidated. Here partial characterization of the anti-inflammatory properties of Bifidobacterium strains isolated from feces of healthy infants is reported. It was found that conditioned media (CM) of all strains studied are capable of attenuating tumor necrosis factor-α (TNF-α) and lipopolysaccharide- (LPS) induced inflammatory responses in the HT-29 cell line. In contrast, neither killed bifidobacterial cells, nor cell-free extracts showed such activities. Further investigations resulted in attribution of this activity to heat-stable, non-lipophilic compound(s) resistant to protease and nuclease treatments and of molecular weight less than 3 kDa. The anti-inflammatory effects were dose- and time-dependent and associated with inhibition of IκB phosphorylation and nuclear factor-κ light chain enhancer of activated B cells (NF-κB)-dependent promoter activation. The combined treatments of cells with CMs and either LPS or TNF-α, but not with CMs alone, resulted in upregulation of transforming growth factor-β1, IκBζ, and p21(CIP) mRNAs. Our data suggest certain species-specificities of the anti-inflammatory properties of bifidobacteria. This observation should prompt additional validation studies using larger set of strains and employing the tools of comparative genomics.     

The head of Bartonella adhesin A is crucial for host cell interaction of Bartonella henselae

Human pathogenic Bartonella henselae cause cat scratch disease and vasculoproliferative disorders (e.g. bacillary angiomatosis). Expression of Bartonella adhesin A (BadA) is crucial for bacterial autoagglutination, adhesion to host cells, binding to extracellular matrix proteins and proangiogenic reprogramming via activation of hypoxia inducible factor (HIF)-1. Like the prototypic Yersinia adhesin A, BadA belongs to the class of trimeric autotransporter adhesins and is constructed modularly consisting of a head, a long and repetitive neck-stalk module and a membrane anchor. Until now, the exact biological role of these domains is not known. Here, we analysed the function of the BadA head by truncating the repetitive neck-stalk module of BadA (B. henselae badA(-)/pHN23). Like B. henselae Marseille wild type, B. henselae badA(-)/pHN23 showed autoagglutination, adhesion to collagen and endothelial cells and activation of HIF-1 in host cells. Remarkably, B. henselae badA(-)/pHN23 did not bind to fibronectin (Fn) suggesting a crucial role of the deleted stalk domain in Fn binding. Additionally, the recombinantly expressed BadA head adhered to human umbilical vein endothelial cells and to a lesser degree to epithelial (HeLa 229) cells. Our data suggest that the head represents the major functional domain of BadA responsible for host adhesion and angiogenic reprogramming.     

SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner

In principle, a decline in base excision repair (BER) efficiency with age should lead to genomic instability and ultimately contribute to the onset of the aging phenotype. Although multiple studies have indicated a negative link between aging and BER, the change of BER efficiency with age in humans has not been systematically analyzed. Here, with foreskin fibroblasts isolated from 19 donors between 20 and 64 y of age, we report a significant decline of BER efficiency with age using a newly developed GFP reactivation assay. We further observed a very strong negative correlation between age and the expression levels of SIRT6, a factor which is known to maintain genomic integrity by improving DNA double strand break (DSB) repair. Our mechanistic study suggests that, similar to the regulatory role that SIRT6 plays in DNA DSB repair, SIRT6 regulates BER in a PARP1-depdendent manner. Moreover, overexpression of SIRT6 rescues the decline of BER in aged fibroblasts. In summary, our results uncovered the regulatory mechanisms of BER by SIRT6, suggesting that SIRT6 reactivation in aging tissues may help delay the process of aging through improving BER.     

A novel real-time driving fatigue detection system based on wireless dry EEG

Development of techniques for detection of mental fatigue has varied applications in areas where sustaining attention is of critical importance like security and transportation. The objective of this study is to develop a novel real-time driving fatigue detection methodology based on dry Electroencephalographic (EEG) signals. The study has employed two methods in the online detection of mental fatigue: power spectrum density (PSD) and sample entropy (SE). The wavelet packets transform (WPT) method was utilized to obtain the \(\theta \) (4–7 Hz), \(\alpha \) (8–12 Hz) and \(\beta \) (13–30 Hz) bands frequency components for calculating corresponding PSD of the selected channels. In order to improve the fatigue detection performance, the system was individually calibrated for each subject in terms of fatigue-sensitive channels selection. Two fatigue-related indexes: (\(\theta +\alpha \))/\(\beta \) and \(\theta \)/\(\beta \) were computed and then fused into an integrated metric to predict the degree of driving fatigue. In the case of SE extraction, the mean of SE averaged across two EEG channels (‘O1h’ and ‘O2h’) was used for fatigue detection. Ten healthy subjects participated in our study and each of them performed two sessions of simulated driving. In each session, subjects were required to drive simulated car for 90 min without any break. The results demonstrate that our proposed methods are effective for fatigue detection. The prediction of fatigue is consistent with the observation of reaction time that was recorded during simulated driving, which is considered as an objective behavioral measure.     

Hydrogen exchange of monomeric alpha-synuclein shows unfolded structure persists at physiological temperature and is independent of molecular crowding in Escherichia coli

Amide proton NMR signals from the N-terminal domain of monomeric α-synuclein (αS) are lost when the sample temperature is raised from 10°C to 35°C at pH 7.4. Although the temperature-induced effects have been attributed to conformational exchange caused by an increase in α-helix structure, we show that the loss of signals is due to fast amide proton exchange. At low ionic strength, hydrogen exchange rates are faster for the N-terminal segment of αS than for the acidic C-terminal domain. When the salt concentration is raised to 300 mM, exchange rates increase throughout the protein and become similar for the N- and C-terminal domains. This indicates that the enhanced protection of amide protons from the C-terminal domain at low salt is electrostatic in nature. Cα chemical shift data point to <10% residual α-helix structure at 10°C and 35°C. Conformational exchange contributions to R2 are negligible at both temperatures. In contrast to the situation in vitro, the majority of amide protons are observed at 37°C in ¹H-¹⁵N HSQC spectra of αS encapsulated within living Escherichia coli cells. Our finding that temperature effects on αS NMR spectra can be explained by hydrogen exchange obviates the need to invoke special cellular factors. The retention of signals is likely due to slowed hydrogen exchange caused by the lowered intracellular pH of high-density E. coli cultures. Taken together, our results emphasize that αS remains predominantly unfolded at physiological temperature and pH—an important conclusion for mechanistic models of the association of αS with membranes and fibrils.     

Indomethacin and ibuprofen induce Hsc70 nuclear localization and activation of the heat shock response in HeLa cells

It has been established that non-steroidal anti-inflammatory drugs (NSAIDs), such as sodium salicylate, sulindac, ibuprofen, and indomethacin, induce anti-inflammatory and anti-proliferative effects independent of cyclooxygenase. These cyclooxygenase-independent pharmacodynamic effects appear to regulate several signaling pathways involving proliferation, apoptosis, and heat shock response. However, the mechanisms of these actions remain an area of ongoing investigation. Hsc70 is a cytoplasmic chaperone protein involved in folding and trafficking of client proteins to different subcellular compartments, plays roles in signal transduction and apoptosis processes, and translocates to the nucleus following exposure to heat shock. Since NSAIDs induce some aspects of the heat shock response, we hypothesized that they may also induce Hsc70 nuclear translocation. Western immunoblotting and indirect cellular immunofluorescence showed that indomethacin and ibuprofen induce Hsc70 nuclear translocation at concentrations previously shown to induce HSF DNA-binding activity. Chemical inhibition of both p38(MAPK) and Erk42/44 had no effect on localization patterns. In addition, while indomethacin has been shown to behave as an oxidative stressor, the radical scavenging agent, N-acetyl cysteine, did not inhibit nuclear translocation. These results indicate that induction of the heat shock response by NSAIDs occurs at concentrations fivefold greater than those required to inhibit cyclooxygenase activity, suggesting a cyclooxygenase-independent mechanism, and in the presence or absence of kinase inhibitors and a free radical scavenger, suggesting independence of Erk42/44 or p38(MAPK) activities and intracellular oxidoreductive state.