PurposeThe National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) is a cohort of participants who participated in health screening programmes provided by the NHIS in the Republic of ...Korea. The NHIS constructed the NHIS-HEALS cohort database in 2015. The purpose of this cohort is to offer relevant and useful data for health researchers, especially in the field of non-communicable diseases and health risk factors, and policy-maker.ParticipantsTo construct the NHIS-HEALS database, a sample cohort was first selected from the 2002 and 2003 health screening participants, who were aged between 40 and 79 in 2002 and followed up through 2013. This cohort included 514 866 health screening participants who comprised a random selection of 10% of all health screening participants in 2002 and 2003.Findings to dateThe age-standardised prevalence of anaemia, diabetes mellitus, hypertension, obesity, hypercholesterolaemia and abnormal urine protein were 9.8%, 8.2%, 35.6%, 2.7%, 14.2% and 2.0%, respectively. The age-standardised mortality rate for the first 2 years (through 2004) was 442.0 per 100 000 person-years, while the rate for 10 years (through 2012) was 865.9 per 100 000 person-years. The most common cause of death was malignant neoplasm in both sexes (364.1 per 100 000 person-years for men, 128.3 per 100 000 person-years for women).Future plansThis database can be used to study the risk factors of non-communicable diseases and dental health problems, which are important health issues that have not yet been fully investigated. The cohort will be maintained and continuously updated by the NHIS.
Objective
To assess the safety and efficacy of 2 repeated intrathecal injections of autologous bone marrow–derived mesenchymal stem cells (BM‐MSCs) in amyotrophic lateral sclerosis (ALS).
Methods
In ...a phase 2 randomized controlled trial (NCT01363401), 64 participants with ALS were randomly assigned treatments (1:1) of riluzole alone (control group, n = 31) or combined with 2 BM‐MSC injections (MSC group, n = 33). Safety was assessed based on the occurrence of adverse events. The primary efficacy outcome was changes in Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R) score from baseline to 4 and 6 months postinjection. Post hoc analysis includes investigation of cerebrospinal fluid biomarkers and long‐term survival analysis.
Results
Safety rating showed no groupwise difference with absence of serious treatment‐related adverse events. Mean changes in ALSFRS‐R scores from baseline to 4 and 6 months postinjection were reduced in the MSC group compared with the control group (4 months: 2.98, 95% confidence interval CI = 1.48–4.47, p < 0.001; 6 months: 3.38, 95% CI = 1.23–5.54, p = 0.003). The MSC group showed decreased proinflammatory and increased anti‐inflammatory cytokines. In good responders, transforming growth factor β1 significantly showed inverse correlation with monocyte chemoattractant protein‐1. There was no significant difference in long‐term survival between groups.
Interpretation
Repeated intrathecal injections of BM‐MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety, in ALS patients. A plausible action mechanism is that BM‐MSCs mediate switching from pro‐ to anti‐inflammatory conditions. A future randomized, double‐blind, large‐scale phase 3 clinical trial with additional BM‐MSC treatments is required to evaluate long‐term efficacy and safety. Ann Neurol 2018;84:361–373
Objective
Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have ...suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation.
Methods
OA progression was examined in wild‐type and Irf1−/− mice using histologic assessments and microcomputed tomography analysis of whole‐joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase‐accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ‐H2AX foci and senescence‐associated beta‐galactosidase activity.
Results
Our genome‐wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon‐responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down‐regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post‐traumatic OA in mice.
Conclusion
IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.
Delay tolerant networks (DTNs) are characterized by high end-to-end latency, frequent disconnection, and opportunistic communication over unreliable wireless links. In this paper, we design and ...validate a dynamic trust management protocol for secure routing optimization in DTN environments in the presence of well-behaved, selfish and malicious nodes. We develop a novel model-based methodology for the analysis of our trust protocol and validate it via extensive simulation. Moreover, we address dynamic trust management, i.e., determining and applying the best operational settings at runtime in response to dynamically changing network conditions to minimize trust bias and to maximize the routing application performance. We perform a comparative analysis of our proposed routing protocol against Bayesian trust-based and non-trust based (PROPHET and epidemic) routing protocols. The results demonstrate that our protocol is able to deal with selfish behaviors and is resilient against trust-related attacks. Furthermore, our trust-based routing protocol can effectively trade off message overhead and message delay for a significant gain in delivery ratio. Our trust-based routing protocol operating under identified best settings outperforms Bayesian trust-based routing and PROPHET, and approaches the ideal performance of epidemic routing in delivery ratio and message delay without incurring high message or protocol maintenance overhead.
Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by three main behavioral symptoms including social deficits, impaired communication, and stereotyped and repetitive ...behaviors. ASD prevalence shows gender bias to male. Prenatal exposure to valproic acid (VPA), a drug used in epilepsy and bipolar disorder, induces autistic symptoms in both human and rodents. As we reported previously, prenatally VPA‐exposed animals at E12 showed impairment in social behavior without any overt reproductive toxicity. Social interactions were not significantly different between male and female rats in control condition. However, VPA‐exposed male offspring showed significantly impaired social interaction while female offspring showed only marginal deficits in social interaction. Similar male inclination was observed in hyperactivity behavior induced by VPA. In addition to the ASD‐like behavioral phenotype, prenatally VPA‐exposed rat offspring shows crooked tail phenotype, which was not different between male and female groups. Both male and female rat showed reduced GABAergic neuronal marker GAD and increased glutamatergic neuronal marker vGluT1 expression. Interestingly, despite of the similar increased expression of vGluT1, post‐synaptic marker proteins such as PSD‐95 and α‐CAMKII expression was significantly elevated only in male offspring. Electron microscopy showed increased number of post‐synapse in male but not in female at 4 weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged post‐synaptic maturation only in male offspring prenatally exposed to VPA. Consistent with the increased post‐synaptic compartment, VPA‐exposed male rats showed higher sensitivity to electric shock than VPA‐exposed female rats. These results suggest that prenatally VPA‐exposed rats show the male preponderance of ASD‐like behaviors including defective social interaction similar to human autistic patients, which might be caused by ectopic increase in glutamatergic synapses in male rats.
Prenatal VPA exposure induces male inclined autistic symptoms including impaired social interactions and seizure susceptibility in rat fetus. These gender‐specific impairments of VPA‐exposed rats, which are similar to human autistic patients, may provide experimental models to elucidate the gender‐dependent symptoms and molecular mechanisms in anti‐social disorders including ASD, especially focusing on the development of excitatory/inhibitory nervous systems and synapses.
Alginate microribbons with longitudinally grooved microstructures are continuously fabricated by means of a microfluidic system. The number and dimensions of the microgroovesare successfully ...controlled by regulation of the slit‐shaped channel (yellow in figure). This method opens up the possibility of mass production of scaffolds for tissue engineering purposes, as it is proved that the grooved flat fibers can be used to align other types of cells in culture.
In this study, we aimed to investigate the meat quality characteristics, bioactive compound content, and antioxidant activity during refrigerated storage of breast meat of Arbor Acres broilers ...(carcass weight: 1.1 kg, raised for 35 D) obtained from a conventional farm (BCF, n = 30) and an animal welfare farm (BAF, n = 30) in Korea. The BCF and BAF did not differ in their proximate composition, color, water-holding capacity, creatine, creatinine, and carnosine contents. However, the shear force value was significantly higher in BAF than in BCF (P < 0.05). The 2-thiobarbituric acid reactive substance (TBARS) levels in BCF on days 7 and 9 were significantly higher than those in BAF (P < 0.001). During storage, the total volatile basic nitrogen (VBN) content of BAF was significantly lower, except on day 1. The fatty acid composition of samples was not affected by the storage period, however, saturated fatty acid and unsaturated fatty acid contents did differ among the types of farm systems (P < 0.05). Although the creatine, creatinine, and carnosine contents in BAF and BCF did not differ significantly, the carnosine and creatinine contents decreased with the increase in storage period (P < 0.05). The anserine content of BAF was significantly higher than that of BCF throughout storage. Superoxide dismutase activity was not affected by the type of farm system but was affected by storage period. Overall, BAF showed lower pH, microorganism, TBARS, and VBN values, and higher anserine contents than BCF. These findings can serve as reference data for the evaluation of chicken meat quality of broilers raised in animal welfare farm and conventional farm.
PurposeThe purpose of the Korean Frailty and Aging Cohort Study (KFACS) is to initiate a nationwide, population-based prospective cohort study of older adults living in the community to assess their ...frailty status and explore transitions between frailty states over time in Korea.ParticipantsThe KFACS is a multicentre longitudinal study with the baseline survey conducted from May 2016 to November 2017. Each centre recruited participants using quota sampling stratified by age and sex. The number of participants recruited through 2 years of baseline study from 10 centres was 3014, with each site accounting for approximately 300 participants. The inclusion criteria were: having an age of 70–84 years, currently living in the community, having no plans to move out in the next 2 years, having no problems with communication and no prior dementia diagnosis.Findings to dateTo define physical frailty, the KFACS used a modified version of the Fried Frailty Phenotype (FFP) consisting of five components of frailty: unintended weight loss, weakness, self-reported exhaustion, slowness and low physical activity. In the baseline study of 2016–2017, 2907 of 3014 individuals fulfilled all five components of FFP. The results indicated that 7.8% of the participants (n=228) were frail, 47.0% (n=1366) were prefrail and 45.2% (n=1313) were robust. The prevalence of frailty increased with age in both sexes; in the group aged 70–74 years, 1.8% of men and 3.7% of women were frail, whereas in the 80–84 years age group, 14.9% of men and 16.7% of women were frail. Women tended to exhibit a higher prevalence of frailty than men in all age groups.Future plansThe KFACS plans to identify outcomes and risk factors associated with frailty by conducting a 10-year cohort study, with a follow-up every 2 years, using 3014 baseline participants.
Abstract
The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (
IDH
) wild-type glioblastoma (GBM) is currently limited due to high ...molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of
IDH
wild-type GBM tumors derived from a quantitative proteomic analysis of 39
IDH
wild-type GBMs as well as
IDH
mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (
FKBP9
). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (
PHGDH
). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.
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