This paper presents an online augmented surveillance system that aims at real-time monitoring of activities along a pipeline. The system is deployed in a fully realistic scenario and exposed to real ...activities carried out in unknown places at unknown times within a given test time interval (the so-called blind field tests). We describe the system architecture that includes specific modules to deal with the fact that continuous online monitoring needs to be carried out, while addressing the need of limiting the false alarms at reasonable rates. To the best of our knowledge, this is the first published work in which a pipeline integrity threat detection system is deployed in a realistic scenario (using a fiber optic along an active gas pipeline) and is thoroughly and objectively evaluated under realistic blind conditions. The system integrates two operation modes: the machine+activity identification mode identifies the machine that carries out a certain activity along the pipeline, and the threat detection mode directly identifies if the activity along the pipeline is a threat or not. The blind field tests are carried out in two different pipeline sections: the first section corresponds to the case in which the sensor is close to the sensed area, while the second one places the sensed area about 35 km far from the sensor. Results of the machine+activity identification mode showed an average machine+activity classification rate of 46.6%. For the threat detection mode, eight out of ten threats were correctly detected, with only one false alarm appearing in a 55.5-h sensed period.
Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process ...through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.
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•Partial reprogramming erases cellular markers of aging in mouse and human cells•Induction of OSKM in progeria mice ameliorates signs of aging and extends lifespan•In vivo reprogramming improves regeneration in 12-month-old wild-type mice
Cellular reprogramming by transient expression of Yamanaka factors ameliorates age-associated symptoms, prolongs lifespan in progeroid mice, and improves tissue homeostasis in older mice.
This paper presents the first available report in the literature of a system aimed at the detection and classification of threats in the vicinity of a long gas pipeline. The system is based on ...phase-sensitive optical time-domain reflectometry technology for signal acquisition and pattern recognition strategies for threat identification. The system operates in two different modes: 1) machine+activity identification, which outputs the activity being carried out by a certain machine; and 2) threat detection, aimed at detecting threats no matter what the real activity being conducted is. Different strategies dealing with position selection and normalization methods are presented and evaluated using a rigorous experimental procedure on realistic field data. Experiments are conducted with eight machine+activity pairs, which are further labeled as threat or nonthreat for the second mode of the system. The results obtained are promising given the complexity of the task and open the path to future improvements toward fully functional pipeline threat detection systems operating in real conditions.
Partial reprogramming by expression of reprogramming factors (Oct4, Sox2, Klf4 and c-Myc) for short periods of time restores a youthful epigenetic signature to aging cells and extends the life span ...of a premature aging mouse model. However, the effects of longer-term partial reprogramming in physiologically aging wild-type mice are unknown. Here, we performed various long-term partial reprogramming regimens, including different onset timings, during physiological aging. Long-term partial reprogramming lead to rejuvenating effects in different tissues, such as the kidney and skin, and at the organismal level; duration of the treatment determined the extent of the beneficial effects. The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways. Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes. We further conclude that longer-term partial reprogramming regimens are more effective in delaying aging phenotypes than short-term reprogramming.
Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have ...deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guide RNAs. As proof-of-concept, we used this technology to treat mouse models of diabetes, muscular dystrophy, and acute kidney disease. Results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to measurable phenotypes and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases.
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•A CRISPR/Cas9 system transcriptionally activates endogenous target genes in vivo•Recruiting the transcriptional machinery induces trans-epigenetic remodeling•Inducing target gene expression leads to physiological phenotypes in postnatal mammals•The system ameliorates symptoms associated with several mouse models of human diseases
In vivo delivery of a Cas9-based epigenetic gene activation system ameliorates disease phenotypes in mouse models of type I diabetes, acute kidney injury, and muscular dystrophy
Transit-amplifying nephron progenitor cells (NPCs) generate all of the nephrons of the mammalian kidney during development. Their limited numbers, poor in vitro expansion, and difficult accessibility ...in humans have slowed basic and translational research into renal development and diseases. Here, we show that with appropriate 3D culture conditions, it is possible to support long-term expansion of primary mouse and human fetal NPCs as well as NPCs derived from human induced pluripotent stem cells (iPSCs). Expanded NPCs maintain genomic stability, molecular homogeneity, and nephrogenic potential in vitro, ex vivo, and in vivo. Cultured NPCs are amenable to gene targeting and can form nephron organoids that engraft in vivo, functionally couple to the host’s circulatory system, and produce urine-like metabolites via filtration. Together, these findings provide a technological platform for studying human nephrogenesis, modeling and diagnosing renal diseases, and drug discovery.
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•Derivation and long-term culture of mouse and human NPC lines•Rapid and efficient nephron organoid formation from mouse and human NPC lines•Long-term cultured NPC lines show nephrogenic potential in vivo•NPC lines enable gene editing and disease modeling
Li et al. report the derivation and long-term culture of mouse and human nephron progenitor cell lines under chemically defined conditions in 3D format. Expanded NPCs have nephrogenic potential in vitro and in vivo and allow the study of kidney organogenesis, gene editing, drug screening, and disease modeling.
DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been ...studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8
) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its microRNA-processing activity. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1γ. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8
hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and mouse osteoarthritis. Taken together, these analyses uncovered a novel, microRNA processing-independent role in maintaining heterochromatin organization and attenuating senescence by DGCR8, thus representing a new therapeutic target for alleviating human aging-related disorders.
The evidence about the effectiveness and safety of oral anticoagulation in patients on hemodialysis is conflicting and scarce. Percutaneous left atrial appendage occlusion (LAAO) has demonstrated to ...be a valid alternative therapeutic option for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study is to present the outcomes of percutaneous LAAO in patients with end‐stage renal disease (ESRD) on hemodialysis and NVAF in our center. We conducted a retrospective review of clinical records, demographics, LAAO procedure, complications, and outcomes of patients with NVAF and ESRD on hemodialysis who underwent a percutaneous LAAO in our center between January 2017 and January 2019. In the period of the study, eight patients with ESRD on hemodialysis underwent a percutaneous LAAO in our center. The overall mean age was 67.5 years (range 56‐81; SD ± 7.2). All patients had permanent NVAF. The total mean dialysis duration was 8.49 years (range 0.83‐14.8; SD ± 6.2). The mean CHA2DS2‐VASc and HAS‐BLED scores were high (4.75 SD ± 1.16 and 4.62 SD ± 0.91, respectively). All patients had history of a major hemorrhagic event (BARC Score ≥3). Most patients (n = 6) showed left ventricular hypertrophy, and the average LVEF was 54% (SD ± 6.5). All devices were implanted successfully. Postprocedural antithrombotic regimen prescribed was based on antiplatelet therapy. No deaths, cardioembolic events, or major bleeding (according to the BARC scale) were reported during a mean follow‐up of 14.24 months (SD ± 9.44). Percutaneous LAAO could be of particular interest in patients with NVAF and CKD in hemodialysis. Further studies will be necessary to confirm this hypothesis.
Background
Chronic total occlusion (CTO) is common in patients with diabetes mellitus. Data on the long‐term outcomes after treatment of CTOs in this high‐risk population are scarce.
Aim
To compare ...the long‐term clinical outcomes of CTO revascularization either by coronary artery bypass graft (CABG) or successful percutaneous coronary intervention (PCI) versus optimal medical treatment (MT) alone in patients with diabetes.
Methods and Results
A total of 538 consecutive patients with diabetes and at least one CTO were identified from 2010 to 2014 in our center. In the present analysis, patients were stratified according to the CTO treatment strategy that was selected. MT was selected in 61% of patients whereas revascularization in the remaining 39%. Patients undergoing revascularization were younger, had higher left ventricular ejection fraction (LVEF), lower ACEF score, and more positive myocardial ischemia detection results compared to the MT group (p < .001).Patients referred for CABG had higher rates of left main disease compared to the PCI and MT groups (32% vs. 3% and 11%, respectively; p < .001). Complete revascularization was more often achieved in the CABG group, compared to the PCI group (62% vs. 32% p < .001). Multivariable analysis showed that revascularization with CABG was associated with lower rates of all‐cause and cardiac mortality rates compared to MT, hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.25–0.70, p < .001 and HR 0.40, 95% CI 0.20–81, p = .011, respectively. Successful CTO‐PCI showed a trend towards benefit in all‐cause mortality (HR 0.58, 95% CI 0.33–1.04, p = .06).
Conclusion
In our registry, CTO revascularization in diabetic patients, especially with CABG, was associated with lower long‐term mortality rates as compared to MT alone.
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