Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in ...age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.
Background
Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of ...age‐related pathologies, where they promote “non‐microbial” inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age.
Methods
Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte‐enriched fractions were used to characterize the age‐related senescence‐associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS).
Results
Increased senescence‐associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin‐6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte‐enriched samples. Interestingly, SCM potentiated the LPS‐induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190.
Conclusions
Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell‐intrinsic response to DNA damage, and a host‐related mechanism associated with aging that could potentiate inflammation induced by bacterial components.
Cellular senescence is associated with inflammation and extracellular matrix tissue remodeling through the secretion of proteins termed the senescence-associated secretory phenotype (SASP). Although ...osteocyte senescence in older individuals in the skeleton is well recognized, whether young alveolar osteocytes can also become senescent is unknown. This is potentially important in the context of periodontal disease, which is an inflammatory condition caused by a gradual change from symbiotic to pathogenic oral microflora that can lead to tooth loss. Our aim was to identify whether senescent osteocytes accumulate in young alveolar bone and whether bacterial-derived lipopolysaccharide (LPS) can influence cellular senescence in alveolar bone. An osteocyte-enriched cell population isolated from alveolar bone expressed increased levels of the known senescence marker p16Ink4a, as well as select SASP markers known to be implicated alveolar bone resorption (Icam1, Il6, Il17, Mmp13 and Tnfα), compared to ramus control cells. Increased senescence of alveolar bone osteocytes was also observed in vivo using the senescence-associated distension of satellites (SADS) assay and increased γH2AX, a marker of DNA damage associated with senescent cells. To approximate a bacterial infection in vitro, alveolar osteocytes were treated with LPS. We found increased expression of various senescence and SASP markers, increased γH2AX staining, increased SA-β-Gal activity and the redistribution of F-actin leading to a larger and flattened cell morphology, all hallmarks of cellular senescence. In conclusion, our data suggests a model whereby bacterial-derived LPS stimulates premature alveolar osteocyte senescence, which in combination with the resultant SASP, could potentially contribute to the onset of alveolar bone loss.
•Premature osteocyte senescence is a host response to bacterial infection and a mechanism implicated in alveolar bone loss.•Increased numbers of dysfunctional senescent osteocytes in alveolar bone could jeopardize tissue homeostasis.•Alveolar osteocytes may be more susceptible to LPS-induced stress due to their proximity to periodontal bacterial infection.•Osteocytes secreted factors represent a “non-microbial” source of pro-inflammatory factors that exacerbate inflammation.•Premature osteocyte accumulation may be a novel mechanism implicated in the pathogenesis of early-onset periodontitis.
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•Simulation-guided development of a completely 3D printed hot wire anemometer packaged inside a flow channel for the first time.•Finite element analysis in transient ...state predicted relative change in resistivity of 0.036 per sccm at 10 C below glass transition temperature with a 10 s response time.•Experimentally obtained relative change in resistivity of 0.014−0.065 per sccm and a response time ranging from 10 to 40 s.
Here, we demonstrate a completely 3D printed flow sensor that operates on the principle of Joule heating and hot wire anemometry. Finite element modeling with experimentally determined properties of the fused deposition modeling filaments was used to confirm the feasibility of such a sensor. Steady-state simulations were used to calculate the operating voltage that produces the maximum sensitivity while keeping the wire temperature 10 °C below the glass transition temperature. At this operation voltage, the transient simulations indicated a response time of 10 s (>95 % of the change in resistance) and a flow sensitivity of −2.33 Ω/sccm, or a relative change in resistivity of 0.036 per sccm. The flow sensor was realized through fused deposition modeling of a combination of electrically conductive and non-conductive filaments. A proof of concept was demonstrated by simultaneously recording infrared images and measuring the change in resistance of the sensor. Experimentally, higher operation voltage (12−15 V) was required compared to the simulations. At 12 V, the flow sensitivity ranged from 0.014 to 0.032 per sccm, whereas at 15 V, it ranged from 0.039 to 0.065 per sccm. The completely 3D printed flow sensors hold potential to be used as an alternate to existing range of flow sensors, more prominently, manufacturing on-demand and integrating with product packaging.
This article examines the interruption of the phenomenological experience of reading caused by an encounter with a particularly striking sentence or passage. More specifically, the text interprets ...the passage of language from text to reader as a moment of quotation whereby language is inscribed within the register of biological life. Drawing on the work of Blanchot and Benjamin the article suggests that this capture of a textual fragment, its transfer into the reader’s memory, simultaneously challenges and reaffirms the violence of conceptuality Hegel identified at the heart of language.
Bacterial infections continue to pose serious public health challenges. Though anti-bacterial therapeutics are effective remedies for treating these infections, the emergence of antibiotic resistance ...has imposed new challenges to treatment. Often, there is a delay in prescribing antibiotics at initial symptom presentation as it can be challenging to clinically differentiate bacterial infections from other organisms (e.g., viruses) causing infection. Moreover, bacterial infections can arise from food, water, or other sources. These challenges have demonstrated the need for rapid identification of bacteria in liquids, food, clinical spaces, and other environments. Conventional methods of bacterial identification rely on culture-based approaches which require long processing times and higher pathogen concentration thresholds. In the past few years, microfluidic devices paired with various bacterial identification methods have garnered attention for addressing the limitations of conventional methods and demonstrating feasibility for rapid bacterial identification with lower biomass thresholds. However, such culture-free methods often require integration of multiple steps from sample preparation to measurement. Research interest in using microfluidic methods for bacterial identification is growing; therefore, this review article is a summary of current advancements in this field with a focus on comparing the efficacy of polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and emerging spectroscopic methods.
This study characterizes the microstructure and temperature dependence of resistance of two commercially available electrically conductive polylactic acid (PLA) composites for fused deposition ...modeling (FDM): PLA-carbon black and PLA-graphene. No microstructural changes were observed between the filament and the printed parts; however, the resistivity of the filament was found to drop by four to six times upon FDM. Also, compared to the resistivity of individual extruded wire, the resistivity of the printed parts was found to be up to 1500 times higher for PLA-graphene and up to 300 times higher for PLA-carbon black. The raw PLA-carbon black filament and printed wire showed a positive temperature coefficient of resistance (
α
) value between ~ 0.03 and 0.01 °C
−1
, which makes them more suitable for sensor development. The raw PLA-graphene filament and printed wire did not exhibit a significant
α
, which makes them more suitable for printing wires. However, the parts made with multilayer FDM exhibited a negative or a negligible
α
up to a certain temperature prior to exhibiting a positive
α
; further, these
α
values were significantly lower than those obtained for the filaments before or after extrusion. These findings enable proper selection of commercial conductive FDM filaments for enabling quicker prototyping of electronics and sensors.
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