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At least 235 records · Page 13

Amyloidogenesis: What Do We Know So Far?

The study of protein aggregation, and amyloidosis in particular, has gained considerable interest in recent times. Several neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) show a characteristic buildup of proteinaceous aggregates in several organs, especially the brain. Despite the enormous upsurge in research articles in this arena, it would not be incorrect to say that we still lack a crystal-clear idea surrounding these notorious aggregates. In this review, we attempt to present a holistic picture on protein aggregation and amyloids in particular. Using a chronological order of discoveries, we present the case of amyloids right from the onset of their discovery, various biophysical techniques, including analysis of the structure, the mechanisms and kinetics of the formation of amyloids. We have discussed important questions on whether aggregation and amyloidosis are restricted to a subset of specific proteins or more broadly influenced by the biophysiochemical and cellular environment. The therapeutic strategies and the significant failure rate of drugs in clinical trials pertaining to these neurodegenerative diseases have been also discussed at length. At a time when the COVID-19 pandemic has hit the globe hard, the review also discusses the plausibility of the far-reaching consequences posed by the virus, such as triggering early onset of amyloidosis. Finally, the application(s) of amyloids as useful biomaterials has also been discussed briefly in this review.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Heparan sulfate promotes TRAIL-induced tumor cell apoptosis

TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report, we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (K D = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL, and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.

60 APPLIED LIFE SCIENCES↗

Targeted protein degradation systems to enhance Wnt signaling

Molecules that facilitate targeted protein degradation (TPD) offer great promise as novel therapeutics. The human hepatic lectin asialoglycoprotein receptor (ASGR) is selectively expressed on hepatocytes. We have previously engineered an anti-ASGR1 antibody-mutant RSPO2 (RSPO2RA) fusion protein (called SWEETS) to drive tissue-specific degradation of ZNRF3/RNF43 E3 ubiquitin ligases, which achieved hepatocyte-specific enhanced Wnt signaling, proliferation, and restored liver function in mouse models, and an antibody–RSPO2RA fusion molecule is currently in human clinical trials. In the current study, we identified two new ASGR1- and ASGR1/2-specific antibodies, 8M24 and 8G8. High-resolution crystal structures of ASGR1:8M24 and ASGR2:8G8 complexes revealed that these antibodies bind to distinct epitopes on opposing sides of ASGR, away from the substrate-binding site. Both antibodies enhanced Wnt activity when assembled as SWEETS molecules with RSPO2RA through specific effects sequestering E3 ligases. In addition, 8M24-RSPO2RA and 8G8-RSPO2RA efficiently downregulate ASGR1 through TPD mechanisms. These results demonstrate the possibility of combining different therapeutic effects and degradation mechanisms in a single molecule.

59 BASIC BIOLOGICAL SCIENCES↗

Trends in liability affecting technical writers

Liability of technical writers for defective products is explored. Documents generated during a product's life cycle (including design memos, design tests, clinical trials, trial use reports, letters, and proposals) become relevant because they are likely to become the only available means of showing that the product was not defectively designed. These documents become the evidence that the product underwent balanced and well considered planning, development, testing, quality control, and field testing. The predicted increased involvement of technical writers in the prevention and defense of product liability claims is cited in view of a greater number of cases turning on "failure to warn".

Driskill, L. P.↗

Computer assessment of atherosclerosis from angiographic images

A computer method for detection and quantification of atherosclerosis from angiograms has been developed and used to measure lesion change in human clinical trials. The technique involves tracking the vessel edges and measuring individual lesions as well as the overall irregularity of the arterial image. Application of the technique to conventional arterial-injection femoral and coronary angiograms is outlined and an experimental study to extend the technique to analysis of intravenous angiograms of the carotid and cornary arteries is described.

Selzer, R. H.↗

Mechanical response tissue analyzer for estimating bone strength

One of the major concerns for extended space flight is weakness of the long bones of the legs, composed primarily of cortical bone, that functions to provide mechanical support. The strength of cortical bone is due to its complex structure, described simplistically as cylinders of parallel osteons composed of layers of mineralized collagen. The reduced mechanical stresses during space flight or immobilization of bone on Earth reduces the mineral content, and changes the components of its matrix and structure so that its strength is reduced. Currently, the established clinical measures of bone strength are indirect. The measures are based on determinations of mineral density by means of radiography, photon absorptiometry, and quantitative computer tomography. While the mineral content of bone is essential to its strength, there is growing awareness of the limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially osteoporosis. Other experimental methods in clinical trials that more directly evaluate the physical properties of bone, and do not require exposure to radiation, include ultrasound, acoustic emission, and low-frequency mechanical vibration. The last method can be considered a direct measure of the functional capacity of a long bone since it quantifies the mechanical response to a stimulus delivered directly to the bone. A low frequency vibration induces a response (impedance) curve with a minimum at the resonant frequency, that a few investigators use for the evaluation of the bone. An alternative approach, the method under consideration, is to use the response curve as the basis for determination of the bone bending stiffness EI (E is the intrinsic material property and I is the cross-sectional moment of inertia) and mass, fundamental mechanical properties of bone.

Arnaud, Sara B.↗

Applying Space Technology to Enhance Control of an Artificial Arm for Children and Adults With Amputations

The first single function myoelectric prosthetic hand was introduced in the 1960's. This hand was controlled by the electric fields generated by muscle contractions in the residual limb of the amputee user. Electrodes and amplifiers, embedded in the prosthetic socket, measured these electric fields across the skin, which increase in amplitude as the individual contracts their muscle. When the myoelectric signal reached a certain threshold amplitude, the control unit activated a motor which opened or closed a hand-like prosthetic terminal device with a pincher grip. Late in the 1990's, little has changed. Most current myoelectric prostheses still operate in this same, single-function way. To better understand the limitations of the current single-function myoelectric hand and the needs of those who use them, The Institute for Rehabilitation and Research (TIRR), sponsored by the National Institutes of Health (NUH), surveyed approximately 2,500 individuals with upper limb loss [1]. When asked to identify specific features of their current myoelectric prostheses that needed improvement, the survey respondents overwhelmingly identified the lack of wrist and finger movement, as well as poor control capability. However, simply building a mechanism with individual finger and wrist motion is not enough. In the 1960's and 1970's, engineers built a number of more dexterous prosthetic hands. Unfortunately, these were rejected during clinical trials due to a difficult and distracting control interface. The goal of this project, "Applying Space Technology to Enhance Control of an Artificial Arm for Children and Adults with Amputations," was to lay the foundation for a multi-function, intuitive myoelectric control system which requires no conscious thought to move the hand. We built an extensive myoelectric signal database for six motions from ten amputee volunteers, We also tested a control system based on new artificial intelligence techniques on the data from two of these subjects. This data is available to anyone doing myoelectric control research. Its availability is an important contribution to the prosthetics research community, as many researchers do not have access to amputee subjects. Since we collected myoelectric data from subjects' sound arms as well as their residual arms, this database will also prove useful to virtual reality and robotics researchers who want to explore myoelectric-based interfaces between any user and a machine. Currently, one small company (Intelligenta, Inc.) and one university (University of New Brunswick, Canada) are using this myoelectric database under other funding to develop multifunction control systems for prostheses. A prosthetics manufacturer (Liberty Technology, Inc.) is making plans to incorporate the results of their work into an artificial hand capable of several different movements to provide functionality only dreamed of by current myoelectric users. Methods Six adults and four children, all with unilateral, below-elbow amputations served as subjects. Five of the adults (3 male, 2 female, average age 34 years) had amputations due to traumatic injury, while one adult (female, age 32 years) and the four children (3 male, 1 female, average age 13 years) had congenital (i.e. from birth) limb deficiencies.

Atkins, Diane J.↗

Expression of Novel Gene Products Upregulated by Disuse is Normalized by an Osteogenic Mechanical Stimulus: Evidence for the Molecular Basis of a Low Level Biomechanical Countermeasure for Osteoporosis?

The National Research Council's report entitled: A Strategy for Space Biology and Medical Science, highlighted several areas of fundamental scientific investigation which must be addressed to make long-term space exploration not only feasible, but safe. This "Goldberg Strategy," as well as several subsequent reports published by the NRC's Space Studies Board (e.g., Assessment of Programs in Space Biology and Medicine, Smith et. al., 1991), suggests that the principal hurdle to man's extended presence in space is the osteopenia which parallels reduced gravity. Ironically, the most significant risk to the skeleton may only be realized on return to normal gravitational fields, and full recovery of bone mass may never occur. Effective counter-measures to this microgravity induced bone loss are thus essential. Considering the similarities of space and aging induced osteopenia, an indisputable benefit of such a prophylaxis would be its potential as a treatment for the bone loss which plagues over 25 million people in the U.S. The osteogenic potential of mechanical strain is strongly frequency dependent, with sensitivity increasing up through at least 60 Hz (cycles per second). One hundred seconds per day of a 1 Hz cyclic loading will inhibit disuse osteopenia only if sufficient in magnitude to engender 1000 microstrain (mu(epsilon)) in the tissue. When loading is applied at 30 Hz, however, mechanical strains on the order of 5O mu(epsilon) (approx. 1% of the peak strains which occur in bone during vigorous functional activity), can stimulate bone formation in a duration dependent manner. In longer term animal studies, strains of less than 10 mu(epsilon), induced non-invasively via a whole body vibration, will stimulate bone formation on the surfaces of trabeculae, increase bone density, and improve strength. Finally, preliminary results from a double blind prospective clinical trial shows promise in inhibiting the bone loss which parallels the menopause. Based on these observations, we propose that these high frequency, low magnitude, mechanical strains effectively serve as a "surrogate" for musculoskeletal ground reaction forces, and thus represent an ideal countermeasure to the osteopenia which parallels microgravity conditions. The specific goal of this NASA funded work is to identify genes in bone upregulated by disuse, and to determine the efficacy of an osteogenic mechanical stimulus to downregulate their expression.

Rubin, C.↗

Assessment of Countermeasure Efficacy for Long-Term Space Missions

One of the main functions of the upcoming International Space Station (ISS) will be to provide a venue for testing proposed countermeasures for their ability to protect humans from the debilitating effects of longterm space flight. However, several limiting factors preclude an evaluation process similar to that used in clinical trials which traditionally are implemented with large sample sizes of subjects, including control groups, and with blind or double-blind application of treatments according to factorial or other balanced experimental designs. In particular, only very limited numbers of human subjects will be available for actual field testing in the ISS With no more than 125 subjects planned to fly on all ISS missions over 10 years, it is not possible to test extensive combinations of some 15-20 proposed countermeasures. Furthermore because of safety concerns and operational considerations, it is unlikely that anything other than the current best guess at the most effective countermeasure package will ever be used on ISS. In particular, control or placebos will not be allowed. In view of these limitations, historical data and groundbased or animal studies will have to be used to compensate for small sample sizes and lack of controls in the field. As a result, statistical analysis methodology will have to be developed which allows for the integration of these disparate data types into a meaningful evaluation process. The process must be sequential, providing objective rules for deciding through time whether to reject or modify an ineffective countermeasure, or whether to certify one as effective. Additional output should include performance characteristics for all relevant physiological systems, including uncertainty analyses and estimates of accept/reject decision error rates.

Feiveson, Alan H.↗

Laser Angioplasty

The principal method of dealing with coronary artery blockage is bypass surgery. A non-surgical alternative available to some patients is balloon angioplasty. For several years, medical researchers have been exploring another alternative that would help a wider circle of patients than the balloon treatment and entail less risk than bypass surgery. A research group is on the verge of an exciting development: laser angioplasty with a 'cool' type of laser, called an excimer laser, that does not damage blood vessel walls and offers non-surgical cleansing of clogged arteries with extraordinary precision. The system is the Dymer 200+ Excimer Laser Angioplasty System, developed by Advanced Intraventional Systems. Used in human clinical tests since 1987, the system is the first fully integrated 'cool' laser capable of generating the requisite laser energy and delivering the energy to target arteries. Thirteen research hospitals in the U.S. have purchased Dymer 200+ systems and used them in clinical trials in 121 peripheral and 555 coronary artery cases. The success rate in opening blocked coronary arteries is 85 percent, with fewer complications than in balloon angioplasty. Food and Drug Administration approval for the system is hoped for in the latter part of 1990. * Advanced Intraventional Systems became Spectranetics in 1994 and discontinued the product.

Source record↗

NASA Smart Surgical Probe Project

Information Technologies being developed by NASA to assist astronaut-physician in responding to medical emergencies during long space flights are being employed for the improvement of women's health in the form of "smart surgical probe". This technology, initially developed for neurosurgery applications, not only has enormous potential for the diagnosis and treatment of breast cancer, but broad applicability to a wide range of medical challenges. For the breast cancer application, the smart surgical probe is being designed to "see" a suspicious lump, determine by its features if it is cancerous, and ultimately predict how the disease may progress. A revolutionary early breast cancer detection tool based on this technology has been developed by a commercial company and is being tested in human clinical trials at the University of California at Davis, School of Medicine. The smart surgical probe technology makes use of adaptive intelligent software (hybrid neural networks/fuzzy logic algorithms) with the most advanced physiologic sensors to provide real-time in vivo tissue characterization for the detection, diagnosis and treatment of tumors, including determination of tumor microenvironment and evaluation of tumor margins. The software solutions and tools from these medical applications will lead to the development of better real-time minimally-invasive smart surgical probes for emergency medical care and treatment of astronauts on long space flights.

Mah, Robert W.↗

Sensorimotor aspects of high-speed artificial gravity: I. Sensory conflict in vestibular adaptation

Short-radius centrifugation offers a promising and affordable countermeasure to the adverse effects of prolonged weightlessness. However, head movements made in a fast rotating environment elicit Coriolis effects, which seriously compromise sensory and motor processes. We found that participants can adapt to these Coriolis effects when exposed intermittently to high rotation rates and, at the same time, can maintain their perceptual-motor coordination in stationary environments. In this paper, we explore the role of inter-sensory conflict in this adaptation process. Different measures (vertical nystagmus, illusory body tilt, motion sickness) react differently to visual-vestibular conflict and adapt differently. In particular, proprioceptive-vestibular conflict sufficed to adapt subjective parameters and the time constant of nystagmus decay, while retinal slip was required for VOR gain adaptation. A simple correlation between the strength of intersensory conflict and the efficacy of adaptation fails to explain the data. Implications of these findings, which differ from existing data for low rotation rates, are discussed.

Non-NASA Center↗

Bimanual cross-talk during reaching movements is primarily related to response selection, not the specification of motor parameters

Simultaneous reaching movements made with the two hands can show a considerable increase in reaction time (RT) when they differ in terms of direction or extent, compared to when the movements involve the same direction and extent. This cost has been attributed to cross-talk in the specification of the motor parameters for the two hands. However, a recent study [Diedrichsen, Hazeltine, Kennerley, & Ivry, (2001). Psychological Science, 12, 493-498] indicates that when reaching movements are cued by the onset of the target endpoint, no compatibility effects are observed. To determine why directly cued movements are immune from interference, we varied the stimulus onset asynchrony for the two movements and used different combinations of directly cued and symbolically cued movements. In two experiments, compatibility effects were only observed when both movements were symbolically cued. No difference was found between compatible and incompatible movements when both movements were directly cued or when one was directly cued and the other was symbolically cued. These results indicate that interference is not related to the specification of movement parameters but instead emerges from processes associated with response selection. Moreover, the data suggest that cross-talk, when present, primarily shortens the RT of the second movement on compatible trials rather than lengthening this RT on incompatible trials.

Randomized Controlled Trial↗

Individual thermal profiles as a basis for comfort improvement in space and other environments

BACKGROUND: The development of individualized countermeasures to address problems in thermoregulation is of considerable importance for humans in space and other extreme environments. A methodology is presented for evaluating minimal/maximal heat flux from the total human body and specific body zones, and for assessing individual differences in the efficiency of heat exchange from these body areas. The goal is to apply this information to the design of individualized protective equipment. METHODS: A multi-compartment conductive plastic tubing liquid cooling/warming garment (LCWG) was developed. Inlet water temperatures of 8-45 degrees C were imposed sequentially to specific body areas while the remainder of the garment was maintained at 33 degrees C. RESULTS: There were significant differences in heat exchange level among body zones in both the 8 degrees and 45 degrees C temperature conditions (p < 0.001). The greatest amount of heat was absorbed/released by the following areas: thighs (8 degrees C: -2.12 +/- 0.14 kcal min(-1); 45 degrees C: +1.58 +/- 0.23); torso (8 degrees C: -2.12 +/- 0.13 kcal min(-1); 45 degrees C: +1.31 +/- 0.27); calves (8 degrees C: -1.59 +/- 0.26 kcal min(-1); 45 degrees C: +1.53 +/- 0.24); and forearms (8 degrees C: -1.67 +/- 0.29 kcal x min(-1); 45 degrees C: +1.45 +/- 0.20). These are primarily zones with relatively large muscle mass and adipose tissue. Calculation of absorption/release heat rates standardized per unit tube length and flow rate instead of zonal surface area covered showed that there was significantly greater heat transfer in the head, hands, and feet (p < 0.001). The areas in which there was considerable between-subject variability in rates of heat transfer and thus most informative for individual profile design were the torso, thighs, shoulders, and calves or forearms. CONCLUSIONS: The methodology developed is sensitive to individual differences in the process of heat exchange and variations in different body areas, depending on their size and tissue mass content. The design of individual thermal profiles is feasible for better comfort of astronauts on long-duration missions and personnel in other extreme environments.

NASA Discipline Life Sciences Technologies↗

Controlled breaks as a fatigue countermeasure on the flight deck

BACKGROUND: A major challenge for flight crews is the need to maintain vigilance during long, highly automated nighttime flights. No system currently exists to assist in managing alertness, and countermeasure options are limited. Surveys reveal many pilots use breaks as an in-flight countermeasure, but there have been no controlled studies of their effectiveness. HYPOTHESIS: We hypothesized that brief, regular breaks could improve alertness and performance during an overnight flight. METHOD: A 6-h, uneventful, nighttime flight in a Boeing 747-400 flight simulator was flown by fourteen two-man crews. The 14 subjects in the treatment group received 5 short breaks spaced hourly during cruise; the 14 subjects in the control group received 1 break in the middle of cruise. Continuous EEG/EOG, subjective sleepiness, and psychomotor vigilance performance data were collected. RESULTS: During the latter part of the night, the treatment group showed significant reductions for 15 min post-break in slow eye movements, theta-band activity, and unintended sleep episodes compared with the control group. The treatment group reported significantly greater subjective alertness for up to 25 min post-break, with strongest effects near the time of the circadian trough. There was no evidence of objective vigilance performance improvement at 15-25 min post-break, with expected performance deterioration occurring due to elevated sleep drive and circadian time. CONCLUSIONS: The physiological and subjective data indicate the breaks reduced nighttime sleepiness for at least 15 min post-break and may have masked sleepiness for up to 25 min, suggesting the potential usefulness of short-duration breaks as an in-flight fatigue countermeasure.

Non-NASA Center↗

Resistance exercise countermeasures for space flight: implications of training specificity

While resistance exercise should be a logical choice for prevention of strength loss during unloading, the principle of training specificity cannot be overlooked. Our purpose was to explore training specificity in describing the effect of our constant load exercise countermeasure on isokinetic strength performance. Twelve healthy men (mean +/- SD: 28.0 +/- 5.2 years, 179.4 +/- 3.9 cm, 77.5 +/- 13.6 kg) were randomly assigned to no exercise or resistance exercise (REX) during 14 days of bed rest. REX performed five sets of leg press exercise to volitional fatigue (6-10 repetitions) every other day. Unilateral isokinetic concentric-eccentric knee extension testing performed before and on day 15 prior to reambulation included torque-velocity and power-velocity relationships at four velocities (0.52, 1.75, 2.97, and 4.19 rad s-1), torque-position relationship, and contractile work capacity (10 repetitions at 1.05 rad s-1). Two (group) x 2 (time) ANOVA revealed no group x time interactions; thus, groups were combined. Across velocities, angle-specific torque fell 18% and average power fell 20% (p < 0.05). No velocity x time or mode (concentric/eccentric) x time interactions were noted. Torque x position decreased on average 24% (p < 0.05). Total contractile work dropped 27% (p < 0.05). Results indicate bed rest induces rapid and marked reductions in strength and our constant load resistance training protocol did not prevent isokinetic strength losses. Differences between closed-chain training and open-chain testing may explain the lack of protection.

Randomized Controlled Trial↗

Protein crystal growth and the International Space Station

Protein structural information plays a key role in understanding biological structure-function relationships and in the development of new pharmaceuticals for both chronic and infectious diseases. The Center for Macromolecular Crystallography (CMC) has devoted considerable effort studying the fundamental processes involved in macromolecular crystal growth both in a 1-g and microgravity environment. Results from experiments performed on more than 35 U.S. space shuttle flights have clearly indicated that microgravity can provide a beneficial environment for macromolecular crystal growth. This research has led to the development of a new generation of pharmaceuticals that are currently in preclinical or clinical trials for diseases such as cutaneous T-cell lymphoma, psoriasis, rheumatoid arthritis, AIDS, influenza, stroke and other cardiovascular complications. The International Space Station (ISS) provides an opportunity to have complete crystallographic capability on orbit, which was previously not possible with the space shuttle orbiter. As envisioned, the x-ray Crystallography Facility (XCF) will be a complete facility for growing protein crystals; selecting, harvesting, and mounting sample crystals for x-ray diffraction; cryo-freezing mounted crystals if necessary; performing x-ray diffraction studies; and downlinking the data for use by crystallographers on the ground. Other advantages of such a facility include crystal characterization so that iterations in the crystal growth conditions can be made, thereby optimizing the final crystals produced in a three month interval on the ISS.

STS Shuttle Project↗

Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.

Review Literature↗