Distinct characteristics of two types of alternative lengthening of telomeres in mouse embryonic stem cells.

Telomere length must be maintained in actively dividing cells to avoid cellular arrest or death. In the absence of telomerase activity, activation of alternative lengthening of telomeres (ALT) allows the maintenance of telomeric length and prolongs the cellular lifespan. Our previous studies have established two types of ALT survivors from mouse embryonic stem cells. The key differences between these ALT survivors are telomere-constituting sequences: non-telomeric sequences and canonical telomeric repeats, with each type of ALT survivors being referred to as type I and type II, respectively. We explored how the characteristics of the two types of ALT lines reflect their fates using multi-omics approaches. The most notable gene expression signatures of type I and type II ALT cell lines were chromatin remodelling and DNA repair, respectively. Compared with type II cells, type I ALT cells accumulated more mutations and demonstrated persistent telomere instability. These findings indicate that cells of the same origin have separate routes for survival, thus providing insights into the plasticity of crisis-suffering cells and cancers.

The Impact of Phytochemicals in Obesity-Related Metabolic Diseases: Focus on Ceramide Metabolism.

The prevalence of obesity and related metabolic diseases has increased dramatically worldwide. As obesity progresses, various lipid species accumulate in ectopic tissues. Amongst them, ceramides-a deleterious sphingolipid species-accumulate and cause lipotoxicity and metabolic disturbances. Dysregulated ceramide metabolism appears to be a key feature in the pathogenesis of obesity-related metabolic diseases. Notably, dietary modification might have an impact on modulating ceramide metabolism. Phytochemicals are plant-derived compounds with various physiological properties, which have been shown to protect against obesity-related metabolic diseases. In this review, we aim to examine the impact of a myriad of phytochemicals and their dietary sources in altering ceramide deposition and ceramide-related metabolism from in vitro, in vivo, and human clinical/epidemiological studies. This review discusses how numerous phytochemicals are able to alleviate ceramide-induced metabolic defects and reduce the risk of obesity-related metabolic diseases via diverse mechanisms.

GPS-Derived Daily Mobility and Daily Well-Being in Community-Dwelling Older Adults.

INTRODUCTION: Mobility as a multidimensional concept has rarely been examined as a day-to-day varying phenomenon in its within-person association with older adults' daily well-being. This study examined associations between daily mobility and daily well-being in community-dwelling older adults with a set of GPS-derived mobility indicators that were representative of older adults' daily mobility. METHODS: Participants wore a custom-built mobile GPS sensor ("uTrail") and completed smartphone-based experience sampling questionnaires on momentary affective states (7 times per day) and daily life satisfaction (in the evening). Analyses included data across 947 days from 109 Swiss older adults aged 65-89 years. RESULTS: Multilevel modeling showed that, within persons, a day with a larger life space area, more time spent in passive transport modes, and a higher number of different locations was associated with higher daily life satisfaction but not daily positive or negative affect. Follow-up analysis showed that the daily maximum distance from home was positively associated with daily life satisfaction, providing a first indication that exposure to non-habitual environments might be a possible underlying mechanism to explain the effects of mobility. CONCLUSIONS: Traveling a long distance away from home and visiting diverse locations may be a way to improve life satisfaction. Results are discussed in the context of research on healthy aging.

Timed up-and-go performance is associated with objectively measured life space in patients 3 months after ischemic stroke: a cross-sectional observational study.

BACKGROUND: Stroke is a common cause of mobility limitation, including a reduction in life space. Life space is defined as the spatial extent in which a person moves within a specified period of time. We aimed to analyze patients' objective and self-reported life space and clinical stroke characteristics. METHODS: MOBITEC-Stroke is a prospective observational cohort study addressing poststroke mobility. This cross-sectional analysis refers to 3-month data. Life space was assessed by a portable tracking device (7 consecutive days) and by self-report (Life-Space Assessment; LSA). We analysed the timed up-and-go (TUG) test, stroke severity (National Institutes of Health Stroke Scale; NIHSS), and the level of functional outcome (modified Rankin Scale; mRS) in relation to participants' objective (distance- and area-related life-space parameters) and self-reported (LSA) life space by multivariable linear regression analyses, adjusted for age, sex, and residential area. RESULTS: We included 41 patients, mean age 70.7 (SD11.0) years, 29.3% female, NIHSS score 1.76 (SD1.68). We found a positive relationship between TUG performance and maximum distance from home (p = 0.006), convex hull area (i.e. area enclosing all Global Navigation Satellite System [GNSS] fixes, represented as a polygon linking the outermost points; p = 0.009), perimeter of the convex hull area (i.e. total length of the boundary of the convex hull area; p = 0.008), as well as the standard ellipse area (i.e. the two-dimensional ellipse containing approximately 63% of GNSS points; p = 0.023), in multivariable regression analyses. CONCLUSION: The TUG, an easily applicable bedside test, seems to be a useful indicator for patients' life space 3 months poststroke and may be a clinically useful measure to document the motor rehabilitative process.

Psychometric properties of the MOBITEC-GP mobile application for real-life mobility assessment in older adults.

Aim of this study was to test the reliability and validity of the life-space measures and walking speed delivered by the MOBITEC-GP app. Participants underwent several supervised walking speed assessments as well as a 1-week life-space assessment during two assessment sessions 9 days apart. Fifty-seven older adults (47.4% male, mean age= 75.3 (±5.9) years) were included in the study. The MOBITEC-GP app showed moderate to excellent test-retest reliability (ICCs between 0.584 and 0.920) and validity (ICCs between 0.468 and 0.950) of walking speed measurements of 50 meters and above and of most 1-week life-space parameters, including life-space area, time spent out-of-home, and action range. The MOBITEC-GP app for Android is a reliable and valid tool for the assessment of real-life walking speed (at distances of 50 metres and above) and life-space parameters of older adults. Future studies should look into technical issues more systematically in order to avoid invalid measurements.

Temperament and Character of High Suicide Risk Group Among Psychiatric Patients.

OBJECTIVE: The purpose of this study was to classify patients with suicidal tendencies into suicide attempts (SA), suicidal ideation (SI), and non-suicidal self-injury (NSSI) and to identify differences in temperaments and characters of the groups. It also aimed to identify difference between the groups and non-suicidal tendencies. METHODS: Using psychiatric diagnostic data of 195 patients, temperaments and characters were measured with the Temperament and Character Inventory, and the level of depression was measured with the Beck Depression Inventory. The subjects were classified into SA, SI, NSSI, psychiatric patients without suicidal tendencies (PP), and non-patient (Normal) groups, and multivariate analysis of variance and multinomial logistic regression were conducted. RESULTS: The NSSI group had higher novelty seeking compared to the SI group, while having higher harm avoidance, lower persistence, and lower self-directedness compared to the SA group. Furthermore, low persistence was a better predictor for the SA group between SA and NSSI groups, and low novelty seeking was found to be a better predictor for the SI group between the SI and NSSI groups. CONCLUSION: As a result, the group differences in temperaments and characters were found, which would be useful to identify patients with suicidal tendencies and provide appropriate interventions tailored to the temperaments and characters of each group.

Points of Interest (POI): a commentary on the state of the art, challenges, and prospects for the future.

In this commentary, we describe the current state of the art of points of interest (POIs) as digital, spatial datasets, both in terms of their quality and affordings, and how they are used across research domains. We argue that good spatial coverage and high-quality POI features - especially POI category and temporality information - are key for creating reliable data. We list challenges in POI geolocation and spatial representation, data fidelity, and POI attributes, and address how these challenges may affect the results of geospatial analyses of the built environment for applications in public health, urban planning, sustainable development, mobility, community studies, and sociology. This commentary is intended to shed more light on the importance of POIs both as standalone spatial datasets and as input to geospatial analyses.

Long-read sequencing and de novo genome assemblies reveal complex chromosome end structures caused by telomere dysfunction at the single nucleotide level.

Karyotype change and subsequent evolution is triggered by chromosome fusion and rearrangement events, which often occur when telomeres become dysfunctional. Telomeres protect linear chromosome ends from DNA damage responses (DDRs), and telomere dysfunction may result in genome instability. However, the complex chromosome end structures and the other possible consequences of telomere dysfunction have rarely been resolved at the nucleotide level due to the lack of the high-throughput methods needed to analyse these highly repetitive regions. Here we applied long-read sequencing technology to Caenorhabditis elegans survivor lines that emerged after telomere dysfunction. The survivors have preserved traces of DDRs in their genomes and our data revealed that variants generated by telomere dysfunction are accumulated along all chromosomes. The reconstruction of the chromosome end structures through de novo genome assemblies revealed diverse types of telomere damage processing at the nucleotide level. When telomeric repeats were totally eroded by telomere dysfunction, DDRs were mostly terminated by chromosome fusion events. We also partially reconstructed the most complex end structure and its DDR signatures, which would have been accumulated via multiple cell divisions. These finely resolved chromosome end structures suggest possible mechanisms regarding the repair processes after telomere dysfunction, providing insights into chromosome evolution in nature.

Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells.

Telomeres are part of a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes to protect chromosomal ends; however, in some species or telomerase-defective situations, an alternative lengthening of telomeres (ALT) mechanism is used. ALT mainly utilises recombination-based replication mechanisms and the constituents of ALT-based telomeres vary depending on models. Here we show that mouse telomeres can exploit non-telomeric, unique sequences in addition to telomeric repeats. We establish that a specific subtelomeric element, the mouse template for ALT (mTALT), is used for repairing telomeric DNA damage as well as for composing portions of telomeres in ALT-dependent mouse embryonic stem cells. Epigenomic and proteomic analyses before and after ALT activation reveal a high level of non-coding mTALT transcripts despite the heterochromatic nature of mTALT-based telomeres. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributes to the maintenance of telomere stability by regulating telomeric transcription. These findings provide a molecular basis to study the evolution of new structures in telomeres.

Assessing Older Adults' Daily Mobility: A Comparison of GPS-Derived and Self-Reported Mobility Indicators.

Interest in global positioning system (GPS)-based mobility assessment for health and aging research is growing, and with it the demand for validated GPS-based mobility indicators. Time out of home (TOH) and number of activity locations (#ALs) are two indicators that are often derived from GPS data, despite lacking consensus regarding thresholds to be used to extract those as well as limited knowledge about their validity. Using 7 days of GPS and diary data of 35 older adults, we make the following three main contributions. First, we perform a sensitivity analysis to investigate how using spatial and temporal thresholds to compute TOH and #ALs affects the agreement between self-reported and GPS-based indicators. Second, we show how daily self-reported and GPS-derived mobility indicators are compared. Third, we explore whether the type and duration of self-reported activity events are related to the degree of correspondence between reported and GPS event. Highest indicator agreement was found for temporal interpolation (Tmax) of up to 5 h for both indicators, a radius (Dmax) to delineate home between 100 and 200 m for TOH, and for #ALs a spatial extent (Dmax) between 125 and 200 m, and temporal extent (Tmin) between 5 and 6 min to define an activity location. High agreement between self-reported and GPS-based indicators is obtained for TOH and moderate agreement for #ALs. While reported event type and duration impact on whether a reported event has a matching GPS event, indoor and outdoor events are detected at equal proportions. This work will help future studies to choose optimal threshold settings and will provide knowledge about the validity of mobility indicators.

Towards a comprehensive set of GPS-based indicators reflecting the multidimensional nature of daily mobility for applications in health and aging research.

BACKGROUND: GPS tracking is increasingly used in health and aging research to objectively and unobtrusively assess individuals' daily-life mobility. However, mobility is a complex concept and its thorough description based on GPS-derived mobility indicators remains challenging. METHODS: With the aim of reflecting the breadth of aspects incorporated in daily mobility, we propose a conceptual framework to classify GPS-derived mobility indicators based on their characteristic and analytical properties for application in health and aging research. In order to demonstrate how the classification framework can be applied, existing mobility indicators as used in existing studies are classified according to the proposed framework. Then, we propose and compute a set of selected mobility indicators based on real-life GPS data of 95 older adults that reflects diverse aspects of individuals' daily mobility. To explore latent dimensions that underlie the mobility indicators, we conduct a factor analysis. RESULTS: The proposed framework enables a conceptual classification of mobility indicators based on the characteristic and analytical aspects they reflect. Characteristic aspects inform about the content of the mobility indicator and comprise categories related to space, time, movement scope, and attribute. Analytical aspects inform how a mobility indicator is aggregated with respect to temporal scale and statistical property. The proposed categories complement existing studies that often underrepresent mobility indicators involving timing, temporal distributions, and stop-move segmentations of movements. The factor analysis uncovers the following six dimensions required to obtain a comprehensive view of an older adult's daily mobility: extent of life space, quantity of out-of-home activities, time spent in active transport modes, stability of life space, elongation of life space, and timing of mobility. CONCLUSION: This research advocates incorporating GPS-based mobility indicators that reflect the multi-dimensional nature of individuals' daily mobility in future health- and aging-related research. This will foster a better understanding of what aspects of mobility are key to healthy aging.

Kruppel-Like Factor 4 Positively Regulates Autoimmune Arthritis in Mouse Models and Rheumatoid Arthritis in Patients via Modulating Cell Survival and Inflammation Factors of Fibroblast-Like Synoviocyte.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes mild to severe joint inflammation. During RA pathogenesis, fibroblast-like synoviocytes (FLS) acquire a tumor-like phenotype and mediate cartilage destruction both directly and indirectly by producing proinflammatory cytokines and matrix metalloproteinases (MMPs). Kruppel-like factor (KLF) 4, a member of the KLF family, plays significant roles in cell survival, proliferation, and differentiation. A recent study reported increased expression of KLF4 in synovial tissue from RA patients. However, its precise role in RA in different models, including mouse autoimmune disease models, remains unclear. In this study, we examined the role of KLF4 during development of autoimmune arthritis in mouse models. To do this, we used KLF4 knockout mice rendered by ribonucleic acid (RNA)-guided endonuclease (RGEN) and performed collagen antibody-induced arthritis (CAIA). We found that deletion of KLF4 reduces inflammation induced by CAIA. In addition, we assessed collagen-induced arthritis (CIA) in control mice and KLF4-overexpressing mice generated by a minicircle vector treatment. Severity of CIA in mice overexpressing KLF4 was greater than that in mice injected with control vector. Finally, we verified the inflammatory roles of KLF4 in CIA by treating Kenpaullone which is used as KLF4 inhibitor. Next, we focused on human/mouse FLS to discover the cellular process involved in RA pathogenesis including proliferation, apoptosis, and inflammation including MMPs. In FLS, KLF4 upregulated expression of mRNA encoding proinflammatory cytokines interleukin (IL)-1ß and IL-6. KLF4 also regulated expression of matrix metallopeptidase 13 in the synovium. We found that blockade of KLF4 in FLS increased apoptosis and suppressed proliferation followed by downregulation of antiapoptotic factor BCL2. Our results indicate that KLF4 plays a crucial role in pathogenesis of inflammatory arthritis in vivo, by regulating apoptosis, MMP expression, and cytokine expression by FLS. Thus, KLF4 might be a novel transcription factor for generating RA by modulating cellular process of FLS.

Measuring burstiness for finite event sequences.

Characterizing inhomogeneous temporal patterns in natural and social phenomena is important to understand underlying mechanisms behind such complex systems and, hence, even to predict and control them. Temporal inhomogeneities in event sequences have been described in terms of bursts that are rapidly occurring events in short time periods alternating with long inactive periods. The bursts can be quantified by a simple measure, called the burstiness parameter, which was introduced by Goh and Barabási [Europhys. Lett. 81, 48002 (2008)EULEEJ0295-507510.1209/0295-5075/81/48002]. The burstiness parameter has been widely used due to its simplicity, which, however, turns out to be strongly affected by the finite number of events in the time series. As the finite-size effects on burstiness parameter have been largely ignored, we analytically investigate the finite-size effects of the burstiness parameter. Then we suggest an alternative definition of burstiness that is free from finite-size effects and yet simple. Using our alternative burstiness measure, one can distinguish the finite-size effects from the intrinsic bursty properties in the time series. We also demonstrate the advantages of our burstiness measure by analyzing empirical data sets.

Telomere maintenance through recruitment of internal genomic regions.

Cells surviving crisis are often tumorigenic and their telomeres are commonly maintained through the reactivation of telomerase. However, surviving cells occasionally activate a recombination-based mechanism called alternative lengthening of telomeres (ALT). Here we establish stably maintained survivors in telomerase-deleted Caenorhabditis elegans that escape from sterility by activating ALT. ALT survivors trans-duplicate an internal genomic region, which is already cis-duplicated to chromosome ends, across the telomeres of all chromosomes. These 'Template for ALT' (TALT) regions consist of a block of genomic DNA flanked by telomere-like sequences, and are different between two genetic background. We establish a model that an ancestral duplication of a donor TALT region to a proximal telomere region forms a genomic reservoir ready to be incorporated into telomeres on ALT activation.

Micro-nano hierarchical superhydrophobic electrospray-synthesized silica layers.

This paper reports the preparation of superhydrophobic SiO(2) layers with a micro-nano hierarchical surface structure. SiO(2) layers, which were rough on the microscale, were prepared using an electrospraying method combined with a sol-gel chemical route. To create a nanoscale structure, the surface of the SiO(2) layers was coated with Au nanoparticles using an ultraviolet-enhanced chemical reduction process, resulting in a micro-nano hierarchical surface structure. A subsequent fluorination treatment with a solution containing trichloro(1H,1H,2H,2H-perfluorooctyl)silane resulted in fluorination of the micro-nano hierarchical SiO(2) layers. The resulting SiO(2) layers showed outstanding repellency toward a range of liquid droplets, for example, a water-repellency of 170°. The surface fraction and work of adhesion of the fluorinated, micro-nano hierarchical SiO(2) layers were estimated using the Cassie-Baxter and Young-Dupre equations, respectively. The long-term durability and ultraviolet resistance of the superhydrophobic SiO(2) layers prepared in this study highlight their potential in a range of practical applications.

Superhydrophobicity of electrospray-synthesized fluorinated silica layers.

The preparation of superhydrophobic SiO(2) layers through a combination of a nanoscale surface roughness and a fluorination treatment is reported. Electrospraying SiO(2) precursor solutions that had been prepared by a sol-gel chemical route produced very rough SiO(2) layers. Subsequent fluorination treatment with a solution containing trichloro(1H,1H,2H,2H-perfluorooctyl)silane resulted in highly rough, fluorinated SiO(2) layers. The fluorinated rough SiO(2) layers exhibited excellent repellency toward various liquid droplets. In particular, water repellency of 168° was observed. On the bases of Cassie-Baxter and Young-Dupre equations, the surface fraction and the work of adhesion of the rough, fluorinated SiO(2) layers were respectively estimated. In light of the durability in water, ultraviolet resistance, and thermal stability, the superhydrophobic SiO(2) layers prepared in this work hold promise in a range of practical applications.

Change in microstructure and surface properties of electrospray-synthesized silica layers.

Silica layers with different microstructures were prepared by electrospraying. The microstructure of the layers was changed by controlling the viscosity of the precursor solutions in the electrospray deposition. Precursor solutions of low viscosity produced particulated silica layers, exhibiting superhydrophobicity. In contrast, fibrous silica layers exhibiting superhydrophilicity were attained with viscous precursor solutions. In particular, the particulated silica layers showed a good durability and resistance to ultraviolet illumination. The dramatic change in the wettability of silica layers without any chemical treatment is promising in speeding up their use in many fields.

Alterations in lipid profile of autistic boys: a case control study.

We hypothesize that autism is associated with alterations in the plasma lipid profile and that some lipid fractions in autistic boys may be significantly different than those of healthy boys. A matched case control study was conducted with 29 autistic boys (mean age, 10.1 +/- 1.3 years) recruited from a school for disabled children and 29 comparable healthy boys from a neighboring elementary school in South Korea. Fasting plasma total cholesterol (T-Chol), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), the LDL/HDL ratio, and 1-day food intakes were measured. Multiple regression analyses were performed to assess the association between autism and various lipid fractions. The mean TG level (102.4 +/- 52.4 vs 70.6 +/- 36.3; P = .01) was significantly higher, whereas the mean HDL-C level (48.8 +/- 11.9 vs 60.5 +/- 10.9 mg/dL; P = .003) was significantly lower in cases as compared to controls. There was no significant difference in T-Chol and LDL-C levels between cases and controls. The LDL/HDL ratio was significantly higher in cases as compared to controls. Multiple regression analyses indicated that autism was significantly associated with plasma TG (beta = 31.7 +/- 11.9; P = .01), HDL (beta = -11.6 +/- 2.1; P = .0003), and the LDL/HDL ratio (beta = 0.40 +/- 0.18; P = .04). There was a significant interaction between autism and TG level in relation to plasma HDL level (P = .02). Fifty-three percent of variation in the plasma HDL was explained by autism, plasma TG, LDL/HDL ratio, and the interaction between autism and plasma TG level. These results indicate the presence of dyslipidemia in boys with autism and suggest a possibility that dyslipidemia might be a marker of association between lipid metabolism and autism.

Collection of peripheral blood progenitor cells: analysis of factors predicting the yields.

We retrospectively analyzed data on 628 leukapheresis from 160 consecutive patients with hematologic or solid malignancies to identify predictive factors affecting the achievement of optimal peripheral blood progenitor cell (PBPC) collection, which was defined as > or = 5x10(6) CD34+ cells/kg. In univariate analysis, a diagnosis of multiple myeloma, no prior axial skeletal radiotherapy, absence of exposure to alkylating agents and cisplatin, fewer cycles of chemotherapy, and fewer number of previous chemotherapy regimens favored the achievement of target number of PBPC. In multivariate analysis, the absence of prior exposure to alkylating agents, especially cyclophosphamide, (P=0.003, RR=2.08) and cisplatin (P=0.015, RR=2.50) were independent predicting factors affecting the probability of achieving the target PBPC and the time to reach the target PBPC collection. In addition, the total dose of cyclophosphamide the patient received significantly alters the mobilization.