Self-repairing symmetry in jellyfish through mechanically driven reorganization

What happens when an animal is injured and loses important structures? Some animals simply heal the wound, whereas others are able to regenerate lost parts. In this study, we report a previously unidentified strategy of self-repair, where moon jellyfish respond to injuries by reorganizing existing parts, and rebuilding essential body symmetry, without regenerating what is lost. Specifically, in response to arm amputation, the young jellyfish of Aurelia aurita rearrange their remaining arms, recenter their manubria, and rebuild their muscular networks, all completed within 12 hours to 4 days. We call this process symmetrization. We find that symmetrization is not driven by external cues, cell proliferation, cell death, and proceeded even when foreign arms were grafted on. Instead, we find that forces generated by the muscular network are essential. Inhibiting pulsation using muscle relaxants completely, and reversibly, blocked symmetrization. Furthermore, we observed that decreasing pulse frequency using muscle relaxants slowed symmetrization, whereas increasing pulse frequency by lowering the magnesium concentration in seawater accelerated symmetrization. A mathematical model that describes the compressive forces from the muscle contraction, within the context of the elastic response from the mesoglea and the ephyra geometry, can recapitulate the recovery of global symmetry. Thus, self-repair in Aurelia proceeds through the reorganization of existing parts, and is driven by forces generated by its own propulsion machinery. We find evidence for symmetrization across species of jellyfish (Chrysaora pacifica, Mastigias sp., and Cotylorhiza tuberculata).The moon jelly, Aurelia aurita, is one of the most plentiful jellyfish in oceans across the world (Fig. 1A). This translucent, saucer-shaped jelly is easily recognizable by the four crescent-shaped gonads on its umbrella. The moon jelly varies greatly in size, from a few inches to a foot (1–3). Ranging from tropical seas to subarctic regions, from the open ocean to brackish estuaries, the moon jelly occupies diverse habitats (4–6). It can even thrive in dirty, polluted, acidified, warm, and oxygen-poor waters (7–10). Presently, jelly blooms have been increasing in size and frequency worldwide, which has been interpreted as a troubling sign of a disturbed ocean ecosystem (11, 12).Open in a separate windowFig. 1.Life cycle and anatomy of Aurelia aurita. (A) Adult Aurelia. The blue color is due to lighting. Image courtesy of Wikimedia Commons/Hans Hillewaert. Image © Hans Hillewaert. (B) Aurelia life cycle. Fertilized eggs develop into larval planulae, which settle and develop into polyps. Seasonally, or in the right conditions, the polyps metamorphose into strobilae and release free-swimming, juvenile jellyfish (a process called strobilation). The young jellyfish, called ephyrae, grow into medusae in 3–4 wk. Reprinted with permission from ref. 13. (C) A juvenile green sea turtle preying on Aurelia at Playa Tamarindo, Puerto Rico. Image courtesy of R. P. van Dam. (D) An Aurelia ephyra has eight radially symmetrical arms, surrounding the manubrium at the center. At the end of each arm is a light- and gravity-sensing organ, called rhopalium. (E) The epithelium of ephyra is composed of two cell layers, the ectoderm-derived epidermis that faces the outer side and the endoderm-derived gastrodermis that lines the gastric cavity. Between the two layers is the gelatinous, viscoelastic mesoglea. Embedded in the subumbrellar side (mouth side) is the coronal muscle (green).Aurelia belongs to the class Scyphozoa, of the ancient phylum Cnidaria, which includes corals, hydras, siphonophores, and box jellyfish (13, 14). Cnidarians are unified by common characteristics, such as radial symmetry, dipoblasticity, diffuse nerve nets, mesoglea, and the stinging cells, or cnidocytes, which give the group its name. Aurelia, and many other Scyphozoan jellyfish, have a dimorphic life cycle with two adult forms: the sexually reproducing, free-swimming medusa, and the asexually reproducing, sessile polyp (Fig. 1B). Fertilized eggs develop into ciliated planulae that settle and mature into polyps. The polyps reproduce asexually through budding, or metamorphose and strobilate to produce juvenile jellyfish, called ephyrae. The ephyrae mature into medusae as bell tissues grow between the arms and reproductive structures develop. Transition into medusa may proceed over 1 mo in the laboratory (with abundant feeding), or longer in the wild. The ephyra stage is hardy and can withstand months of starvation (15).Injury is common in marine invertebrates. Examining 105 studies, Lindsay (16) showed that, at any given time, about 33–47% of the benthic fauna is injured. Some cited studies recorded entire starfish populations with at least one injured arm. Injury may be due to numerous factors, including partial predation, autotomy, cannibalism, competitive interaction, and human activities. Jellyfish have many known predators. A well-studied group of predators are the sea turtles (e.g., the leatherback and the loggerhead; Fig. 1C). Juvenile sea turtles have been observed biting into foot-wide jellyfish, and adults gorge on an average of 261 jellyfish per day (12). In addition, over 124 species of fish, 11 species of birds, several species of shrimps, sea anemones, corals, and crabs are reported to assail Aurelia (17–20). Barnacles have been reported to catch and digest newly strobilated ephyrae (21).Here, we ask how Aurelia responds to injuries. Marine invertebrates are known for their regenerative ability. Reported cases of regenerating marine organisms include jellyfish, sponges, corals, ctenophores, sea anemones, clams, polychaetes, starfish, and brittlestars (14, 16, 22–26). Isolated striated muscle from hydromedusae can transdifferentiate to regenerate various cell types (27). The polyps of Aurelia, and a number of other species, can regenerate tentacles, stolonts, and hydrants (28–31), and an entire polyp can regrow from a single polyp tentacle (32). In this study, we investigated the repair capacity in the free-swimming forms of Aurelia and discovered that Aurelia have evolved a fast strategy of self-repair, one that does not involve regenerating lost body parts.     

牙龈软组织自我修复与拔牙创软组织愈合在前牙美学区软组织愈合中的比较

目的：观察残根保留情况下牙龈软组织的自我修复与拔牙后软组织愈合在犬前牙区软组织愈合中的不同。方法在A、B、C3只犬的上颌前牙区(右上颌侧切牙,左上颌中切牙)制造残根模型,将牙冠磨至龈缘下,勿损伤牙龈(将此设为残根组);拔除3只犬的左下颌侧切牙(将此设为拔牙组);术后第1、3、4、5周观察两种不同牙龈愈合生长的情况,并在术后第3、4、5周按照A、B、C顺序取左上颌中切牙牙龈增生组织、左下颌侧切牙拔牙创增生软组织进行组织学观察。结果术后第4周时肉眼观察到残根周围新生软组织基本长满断面,第5周时新生软组织的质地及颜色与正常牙龈基本一致;拔牙术后第3周时软组织已基本长满创面,但肉眼观察其颜色较浅,质地较硬;组织学观察残根周围新增生的软组织以增生的鳞状上皮为主,炎细胞浸润不明显;而拔牙创周围软组织则表现为明显的炎细胞浸润,鳞状上皮轻度增生。结论采用保留残根后新增生的牙龈软组织较拔牙后软组织愈合慢,但是更接近于正常牙龈组织。     

Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo

Tissue-engineered skeletal muscle can serve as a physiological model of natural muscle and a potential therapeutic vehicle for rapid repair of severe muscle loss and injury. Here, we describe a platform for engineering and testing highly functional biomimetic muscle tissues with a resident satellite cell niche and capacity for robust myogenesis and self-regeneration in vitro. Using a mouse dorsal window implantation model and transduction with fluorescent intracellular calcium indicator, GCaMP3, we nondestructively monitored, in real time, vascular integration and the functional state of engineered muscle in vivo. During a 2-wk period, implanted engineered muscle exhibited a steady ingrowth of blood-perfused microvasculature along with an increase in amplitude of calcium transients and force of contraction. We also demonstrated superior structural organization, vascularization, and contractile function of fully differentiated vs. undifferentiated engineered muscle implants. The described in vitro and in vivo models of biomimetic engineered muscle represent enabling technology for novel studies of skeletal muscle function and regeneration.Natural skeletal muscle consists of terminally differentiated, highly aligned, and contractile myofibers and a population of resident muscle stem cells, known as satellite cells (SCs), that are indispensable for muscle growth (1) and regeneration (2). The ability to create engineered muscle tissues that mimic the structural, functional, and regenerative properties of native muscle would enable design of accurate in vitro models for studies of muscle physiology and development (3, 4) and promote cell-based therapies for muscle injury and disease (5, 6). Pioneering studies of Vandenburgh and coworkers (7) and Dennis and Kosnik (8) were the first to demonstrate in vitro engineering of functional mammalian muscle constructs, followed by other studies reporting that differentiated engineered muscle can survive and vascularize upon implantation in vivo (9–13). Simultaneously, various studies have shown that, compared with differentiated or committed cells, undifferentiated SCs are a more potent myogenic cell source, with the ability to engraft and replenish the host satellite cell pool and support future rounds of muscle regeneration (14–16). Thus, it is likely that, for optimal therapy, engineered muscle tissues should fully recreate the cellular heterogeneity of native muscle and consist of both force-generating, differentiated myofibers and a functioning SC pool to allow further maturation and regeneration in vivo. Additionally, for long-term survival and efficient repair, implanted engineered muscle constructs must rapidly integrate into host vascular system and significantly increase their functional output compared with preimplantation levels.In this study, we used primary rat myogenic cells to engineer skeletal muscle tissues with highly organized architecture and force-generating capacity comparable with those of native muscle. We characterized the temporal dynamics of myogenic processes within engineered muscle and documented the in vitro formation of a homeostatic tissue state with the coexistence of highly contractile muscle fibers and functional satellite cells. To continuously monitor engineered tissue survival, function, and vascularization after implantation, we transduced myogenic cells with GCaMP3, a genetic indicator of intracellular Ca²⁺ concentration used previously in neurobiological (17) and cardiac (18) research, and implanted the muscle constructs in a dorsal skinfold chamber in nude mice. The use of this minimally invasive, in vivo platform allowed us to simultaneously, in real time, quantify and compare changes in Ca²⁺ transient amplitude and vascular density between highly differentiated and undifferentiated engineered muscle implants and to further assess the maintenance of satellite cell pool and enhancement of contractile function relative to those preimplantation. Overall, our studies describe important advances in the field of skeletal muscle tissue engineering and lay the foundation for novel studies of cellular function and signaling in a physiological environment in real time.     

Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells

Adult neural stem cell proliferation is dynamic and has the potential for massive self-renewal yet undergoes limited cell division in vivo. Here, we report an epigenetic mechanism regulating proliferation and self-renewal. The recruitment of the PI3K-related kinase signaling pathway and histone H2AX phosphorylation following GABA(A) receptor activation limits subventricular zone proliferation. As a result, NSC self-renewal and niche size is dynamic and can be directly modulated in both directions pharmacologically or by genetically targeting H2AX activation. Surprisingly, changes in proliferation have long-lasting consequences on stem cell numbers, niche size, and neuronal output. These results establish a mechanism that continuously limits proliferation and demonstrates its impact on adult neurogenesis. Such homeostatic suppression of NSC proliferation may contribute to the limited self-repair capacity of the damaged brain.     

Cellular interactions as a response to injury in the organ of corti in culture

We discovered and described ultrastructurally the intricate relationships between the sensory cells and their supporting cells in cultures of the organ of Corti following laser beam irradiation. Injury was performed using a 440 nm nitrogen-dye pulse laser aimed at the cuticular plates of inner hair cells. Laser injury is compared with mechanical injury inflicted on the hair cell region by a pulled-glass pipette. Regardless of the type of injury, but depending on its severity, the surviving hair cells may: (1) lose their stereocilia but subsist at the surface of the organ; (2) retain contact with the reticular lamina but be overgrown by the processes of the supporting cells; or (3) become sequestered from the reticular lamina and internalized among the supporting cells, where they either remain dedifferentiated or regrow an apical process which regains contact with the surface of the organ. All supporting cells, including pillar and Deiters' cells, take part in wrapping their respective inner or outer hair cells. The supporting cells not only cover the injured sensory cells, but also invert their villi toward the maimed cuticular plates and release an extracellular matrix around them. We suggest that the supporting cells play a protective and trophic role in the recovery of injured hair cells.     

Characteristics of health IT outage and suggested risk management strategies: An analysis of historical incident reports in China

BackgroundThe healthcare industry has become increasingly dependent on using information technology (IT) to manage its daily operations. Unexpected downtime of health IT systems could therefore wreak havoc and result in catastrophic consequences. Little is known, however, regarding the nature of failures of health IT.ObjectiveTo analyze historical health IT outage incidents as a means to better understand health IT vulnerabilities and inform more effective prevention and emergency response strategies.MethodsWe studied news articles and incident reports publicly available on the internet describing health IT outage events that occurred in China. The data were qualitatively analyzed using a deductive grounded theory approach based on a synthesized IT risk model developed in the domain of information systems.ResultsA total of 116 distinct health IT incidents were identified. A majority of them (69.8%) occurred in the morning; over 50% caused disruptions to the patient registration and payment collection functions of the affected healthcare facilities. The outpatient practices in tertiary hospitals seem to be particularly vulnerable to IT failures. Software defects and overcapacity issues, followed by malfunctioning hardware, were among the principal causes.ConclusionsUnexpected health IT downtime occurs more and more often with the widespread adoption of electronic systems in healthcare. Risk identification and risk assessments are essential steps to developing preventive measures. Equally important is institutionalization of contingency plans as our data show that not all failures of health IT can be predicted and thus effectively prevented. The results of this study also suggest significant future work is needed to systematize the reporting of health IT outage incidents in order to promote transparency and accountability.