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Highlights • The Proposed multi-microjet impact model suitable for high hydrostatic pressures. • Cavitation erosion experiments can be conducted in an ultrasonic cavitation system composed of a spherical cavity focused transducer with high acoustic energy in a sub-wavelength focal region. • Quantitative analysis of cavitation pit morphology can be achieved through the proposed microjet impact model. • A microjet velocity inversion model was proposed to quantitative evaluate the cavitation erosion intensity., Cavitation erosion at the high hydrostatic pressure causes the equipment to operate abnormally for the huge economic losses. Few methods can quantitatively evaluate the cavitation erosion intensity. In order to solve this problem, the cavitation erosion on a copper plate was carried out in a spherical cavity focused transducer system at the hydrostatic pressure of 3, 6, and 10 MPa. Meanwhile, the corresponding cavitation threshold, the initial bubble radius, and the microjet velocity in the ultrasonic field are theoretically analyzed to determine the dimension and velocity of microjet based on the following hypotheses: (1) the influence of the coalescence on the bubble collapse is ignored; (2) the dimension of the microjet is equal to the largest bubble size without the influence of gravity and buoyancy. Using the Westervelt equation for the nonlinear wave propagation and the Johnson-Cook material constitutive model for the high strain rate, a microjet impact model of the multi-bubble cavitation was constructed. In addition, through the analogy with the indentation test, an inversion model was proposed to calculate the microjet velocity and the cavitation erosion intensity. The microjet geometric model was constructed from the dimension and velocity of the microjet. The continuous microjet impact was proposed according to the equivalent impact momentum and solved by the finite element method. The relative errors of the pit depth are 4.02%, 3.34%, and 1.84% at the hydrostatic pressure of 3, 6, and 10 MPa, respectively, and the relative error in the evolution of pit morphology is 7.33% at 10 MPa, which verified the reliability of the proposed models. Experimental and simulation results show that the higher the hydrostatic pressure, the greater the pit depth, pit diameter, the pit-to-microjet diameter ratio, and the cavitation erosion intensity, but the smaller the pit diameter-to-depth ratio. The cavitation erosion intensity becomes significant with the ongoing ultrasonic exposure. In addition, a comparison of the cavitation pit morphology in the microjet pulsed and continuous impact modes shows that the continuous impact mode is effective without the elastic deformation caused by the residual stress. Using the cavitation pit morphology at the different hydrostatic pressures, the microjet velocity can be estimated successfully and accurately in a certain range, whose corresponding errors at the lower and upper limit are 5.98% and 0.11% at 3 MPa, 6.62% and 9.14% at 6 MPa, 6.54% and 5.42% at 10 MPa, respectively. Our proposed models are valid only when the cavitation pit diameter-to-depth ratio is close to 1. Altogether, the cavitation erosion induced by multi-bubble collapses in the focal region of a focused transducer could be evaluated both experimentally and numerically. Using the cavitation pit morphology and the inversion model, the microjet velocity in a certain range could be estimated successfully with satisfactory accuracy.

It is well-known that acoustic cavitation associated with the high intensity focused ultrasound (HIFU) treatment often would change the morphology and size of lesions in its treatment. In most studies reported in literature, high ambient hydrostatic pressure was used to suppress the cavitation completely. Investigation of the effects by varying the ambient hydrostatic pressure (Pstat) is still lacking. In this paper, the effects of HIFU on lesions in ex vivo bovine liver specimens under various Pstat are systematically investigated. A 1MHz HIFU transducer, with an aperture diameter of 70mm and a focal length of 55mm, was used to generate two groups US exposure of different acoustic intensities and exposure time (6095W/cm2×8s and 9752W/cm2×5s), while keeping the same acoustic energies per unit area (48760J/cm2). The peak acoustic negative pressures (p-) of the two groups were p1-=9.58MPa and p2-=10.82MPa, respectively, with the difference pd-=p2--p1-=1.24MPa. A passive cavitation detection (PCD) was used to monitor the ultrasonic cavitation signal during exposure of the two groups. The US exposures were done under the following ambient hydrostatic pressures, Pstat: atmospheric pressure, 0.5MPa, 1.0MPa, 1.5MPa, 2.0MPa, 2.5MPa and3.0MPa, respectively. The result of PCD showed that there was a statistically significant increase above background noise level in broadband emissions at dose of 9752W/cm2×5s, but not at dose of 6095W/cm2×8s under atmospheric pressure; i.e., the acoustic cavitation took place for p2- but not for p1- when under atmospheric pressure. The results also showed that there was no statistically difference of the morphology and size of lesions for 6095W/cm2×8s exposure under the aforementioned different ambient hydrostatic pressures. But the lesions generated at 9752W/cm2×5s exposure under Pstat=atmospheric pressure, 0.5MPa, 1.0MPa (all of them are less than pd-), were larger than those under 1.5MPa, 2.0MPa, 2.5MPa and 3.0MPa (all of them are over than pd-) which were consistence with 6095W/cm2×8s group. It was concluded that when Pstat>pd-, the acoustic cavitation was suppressed and prompted that there was no need to elevate Pstat higher than p- to suppress the acoustic cavitation in tissue, just need Pstat higher than pd-.

The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases. In Caenorhabditis elegans, knockdown of a pnc1 homolog was shown recently to shorten the worm life span, whereas its overexpression increased survival under conditions of oxidative stress. The function and regulation of nicotinamidases in higher organisms has not been determined. Here, we report the identification and biochemical characterization of the Drosophila nicotinamidase, D-NAAM, and demonstrate that its overexpression significantly increases median and maximal fly life span. The life span extension was reversed in Sir2 mutant flies, suggesting Sir2 dependence. Testing for physiological effectors of D-NAAM in Drosophila S2 cells, we identified oxidative stress as a primary regulator, both at the transcription level and protein activity. In contrast to the yeast model, stress factors such as high osmolarity and heat shock, calorie restriction, or inhibitors of TOR and phosphatidylinositol 3-kinase pathways do not appear to regulate D-NAAM in S2 cells. Interestingly, the expression of D-NAAM in human neuronal cells conferred protection from oxidative stress-induced cell death in a sirtuin-dependent manner. Together, our findings establish a life span extending the ability of nicotinamidase in flies and offer a role for nicotinamide-modulating genes in oxidative stress regulated pathways influencing longevity and neuronal cell survival.

Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer’s disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

No longer considered to be exclusive to cellular developmental pathways, the Wnt family of secreted cysteine-rich glycosylated proteins has emerged as versatile targets for a variety of conditions that involve cardiovascular disease, aging, cancer, diabetes, neurodegeneration, and inflammation. In particular, modulation of Wnt signaling may fill a critical void for the treatment of disorders that impact upon both cellular survival and cellular longevity. Yet, in some scenarios, Wnt signaling can become the catalyst for disease development or promote cell senescence that can compromise clinical utility. This double edge sword in regards to the role of Wnt and its signaling pathways highlights the critical need to further elucidate the cellular mechanisms governed by Wnt in conjunction with the development of robust pharmacological ligands that may open new avenues for disease treatment. Here we discuss the influence of the Wnt pathway during cell survival, metabolism, and aging in order for one to gain a greater insight for the novel role of Wnt signaling as well as exemplify its unique cellular pathways that influence both normal physiology and disease.

Despite our present knowledge of some of the cellular pathways that modulate central nervous system injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. The cellular mechanisms that precipitate these diseases are more involved than initially believed. As a result, identification of novel therapeutic targets for the treatment of cellular injury would be extremely beneficial to reduce or eliminate disability from nervous system disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we discuss novel pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Current work has identified exciting pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and their downstream substrates that include Forkhead transcription factors, glycogen synthase kinase-3beta, mitochondrial dysfunction, Bad, and Bcl-x(L). Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation. New therapeutic avenues that are just open to exploration, such as with brain temperature regulation, nicotinamide adenine dinucleotide modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat a variety of disorders that include stroke, Alzheimer's disease, and traumatic brain injury.

Erythropoietin (EPO) has emerged as a versatile growth factor that has transcended its traditional role as a mediator of erythroid maturation to one that modulates stem cell development, cellular protection and angiogenesis in the brain. As a possible candidate for nervous system disorders, it becomes crucial to understand the cellular mechanisms that foster cytoprotection rather than cytotoxicity for EPO. EPO offers novel neuronal and vascular protection not only through the maintenance of cellular integrity, but also through the prevention of cellular inflammation. The protective and anti-inflammatory capacities of EPO originate with the Janus tyrosine kinase 2 protein and protein kinase B (Akt). Downstream cellular pathways include FOXO3a, GSK-3beta, Bad, Bcl-xL, NF-kappaB, mitochondrial membrane permeability, APAF-1 and caspases. Further understanding of the cellular pathways that are susceptible to modulation by EPO will be crucial to foster the development of this agent as a robust and efficacious therapy for the brain.

The aim of this study was to explore a law of energy deposition of high-intensity focused ultrasound (HIFU) in various tissues and the expression of such a law. A focused ultrasound (US) tumor therapeutic system was used to apply a focused US beam to tissues both in vivo and in vitro . The formation of individual ellipsoid-shaped regions of coagulative necrosis has been observed. Results showed that the volume of the ellipsoid-shaped coagulative necrosis region was different from that of the acoustic focal region (AFR), both in vitro and in vivo . Acoustic intensities ranging from 7 × 10 3 W/cm 2 to 27.7 × 10 3 W/cm 2 and exposure times from 1 to 20 s gave volumes of ellipsoid-shaped coagulative necrosis of 0.2 to 2000 mm 3 . Although the HIFU doses applied were identical, the volumes of individual ellipsoid-shaped coagulative necrotic regions varied with the structures of tissues, their functional status and the irradiation depths. Individual ellipsoid-shaped regions of coagulative necrosis induced by HIFU can be added to produce coagulative necrosis of an entire tumor. We define the individual ellipsoid-shaped coagulative necrosis produced by the US energy deposition of a single exposure as the “biological focal region” (BFR) of HIFU. This serves as the basic unit for HIFU ablation of tumors, and is plotted as a function of AFR, acoustic intensity, exposure time, irradiation depth, the tissue structure and its functional status. (E-mail: wangzhibiao@netease.com)