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Results of medical investigations carried out on board the Salyut orbital stations.

The purpose of the medical investigations carried out in flights of the Soviet orbital station Salyut were: to further studies and clarification of the phenomenology and mechanisms of changes in the main functions of the human body during prolonged weightlessness; to accumulate additional data on human responses at an early stage of adaptation to weightlessness; to assess the effectiveness of countermeasures against adverse effects of weightlessness during and after flight. The orbital station was equipped with a set of countermeasuring devices: a trainer for physical exercises (a treadmill), gravity simulation suit for long wear, bicycle ergometer, anti-G suit to be worn immediately post-flight, drugs, etc. The system of medical control included daily recordings of electrocardiography and respiration and regular physical examinations using provocative tests (physical exercises of a known force, lower-body negative pressure). Specific biomedical investigations were performed before, during and after flight. As in previous flights, the atmosphere in the habitable modules was similar to that on the earth. Food supply met the requirements for basic nutrients and satisfied individual preferences of the crew members. In addition to the time required to fulfil the flight programme, the work-rest schedule allowed the cosmonauts 8 hours sleep, four meals, 2.5 hours physical training and personal time. The biomedical investigations carried out during and after flight furnished information towards a better understanding of human responses to the effects of space flight factors and the mechanisms underlying their development.

Adaptation, Physiological↗

Heart pathology associated with exposure to high sustained +Gz.

The pathology of +Gz acceleration was examined using unanesthetized adult miniature and immature "farm-type" swine, with and without anti-G suit inflation. Following single exposures of +8 or 9 Gz for 45 to 90 s--acceleration exposures that have been shown "tolerable" to man--swine were sacrificed and a detailed necropsy performed. Considering only the adult miniature swine, the endocardial area of the left ventricles showed evidence grossly of recent hemorrhage of varying severity involving both the wall and papillary muscles. The degree and location of the subendocardial hemorrhage were quantitated by grading the area of ventricle involved--1 (slight) to 4 (extensive). Of the 23 adult miniature pigs autopsied, the scores for papillary muscle hemorrhage, after one exposure to +9 Gz (45 to 90 s) ranged from a mean of 2.3 to 3.3 and the extent of ventricular wall involvement was 2.5 to 3.3. Histologically, heart hemorrhage was limited to the subendocardial area, primarily involving the space between heart muscle and the endocardium and was particularly evident surrounding Pukinje's fibers. Similar studies using immature farm-type swine (not miniature pigs) found these younger swine (4 to 5 months of age) to be less susceptible to such endocardial hemorrhage. Heart tissue recovery in these pigs following one exposure to +9 Gz for 45 s, required approximately 14 d. It appears that this lesion is similar, although less severe, than heart muscle lesions associated with loss blood volume (hemorrhagic shock) studies and may have similar physiologic bases. It was concluded that particular attention should be made of the endocardium of victims of high-performance aircraft accidents.

Age Factors↗

A Markov model for blind image separation by a mean-field EM algorithm.

This paper deals with blind separation of images from noisy linear mixtures with unknown coefficients, formulated as a Bayesian estimation problem. This is a flexible framework, where any kind of prior knowledge about the source images and the mixing matrix can be accounted for. In particular, we describe local correlation within the individual images through the use of Markov random field (MRF) image models. These are naturally suited to express the joint pdf of the sources in a factorized form, so that the statistical independence requirements of most independent component analysis approaches to blind source separation are retained. Our model also includes edge variables to preserve intensity discontinuities. MRF models have been proved to be very efficient in many visual reconstruction problems, such as blind image restoration, and allow separation and edge detection to be performed simultaneously. We propose an expectation-maximization algorithm with the mean field approximation to derive a procedure for estimating the mixing matrix, the sources, and their edge maps. We tested this procedure on both synthetic and real images, in the fully blind case (i.e., no prior information on mixing is exploited) and found that a source model accounting for local autocorrelation is able to increase robustness against noise, even space variant. Furthermore, when the model closely fits the source characteristics, independence is no longer a strict requirement, and cross-correlated sources can be separated, as well.

Algorithms↗

Decision support tools for clinical trial design.

Many published clinical trials are poorly designed, suggesting that the protocol was incomplete, disorganised, or contained errors. This fact motivated the development of a suite of decision support tools for the design of randomised controlled clinical trials. In this paper we describe these tools, discussing both underlying theoretical issues and usage of the tools. The core tool--Design-a-Trial (DaT)--critiques data entered so as to guide design of a scientifically and ethically sound trial. DaT outputs a text protocol describing the trial, and a corresponding symbolic representation. Linked to DaT is a tool for authoring plans that form part of the trial. A key feature of this tool is the provision of macros for describing commonly occurring plan constructs. We describe another linked tool which generates solutions to Prolog queries requesting advice on how a plan should be revised so as to comply with safety and efficacy requirements. The user is able to navigate a path through the solution search space by interacting with natural language representations of the Prolog sub-goals. This provides the flexibility to generate useful and informative partial solutions, symbolic and textual, for inclusion in the symbolic plan representation and protocol document, respectively.

Clinical Trials as Topic↗

Adaptive stimulus optimization for auditory cortical neurons.

Despite the extensive physiological work performed on auditory cortex, our understanding of the basic functional properties of auditory cortical neurons is incomplete. For example, it remains unclear what stimulus features are most important for these cells. Determining these features is challenging given the considerable size of the relevant stimulus parameter space as well as the unpredictable nature of many neurons' responses to complex stimuli due to nonlinear integration across frequency. Here we used an adaptive stimulus optimization technique to obtain the preferred spectral input for neurons in macaque primary auditory cortex (AI). This method uses a neuron's response to progressively modify the frequency composition of a stimulus to determine the preferred spectrum. This technique has the advantage of being able to incorporate nonlinear stimulus interactions into a "best estimate" of a neuron's preferred spectrum. The resulting spectra displayed a consistent, relatively simple circumscribed form that was similar across scale and frequency in which excitation and inhibition appeared about equally prominent. In most cases, this structure could be described using two simple models, the Gabor and difference of Gaussians functions. The findings indicate that AI neurons are well suited for extracting important scale-invariant features in sound spectra and suggest that they are designed to efficiently represent natural sounds.

Acoustic Stimulation↗

Contemplating the plasmalemmal control center model.

An abundant epidermal mechanosensory calcium-selective ion channel appears able not only to detect mechanical stimuli such as those that initiate gravitropism but also to detect thermal, electrical, and various chemical stimuli. Because it responds to multimodal input with a second messenger output, this channel system seems likely to be an integrator that can engage in feedbacks with many other systems of the cell--and feedback is the hallmark of regulation. In general, the mechanical tension required for channel activation is likely transmitted from the relatively rigid cell wall to the plasma membrane system via linkage or adhesion sites that display antigenicities recognized by antibodies to animal beta-1 integrin, vitronectin, and fibronectin and which have mechanical connections to the cytoskeleton. Thus, functionally, leverage exerted against any given adhesion site will tend to control channels within a surrounding domain. Reactions initiated by passage of calcium ions through the channels could presumably be more effectively regulated if channels within the domains were somewhat clustered and if appropriate receptors, kinases, porters, pumps, and some key cytoskeletal anchoring sites were in turn clustered about them. Accumulating evidence suggests not only that activity of clusters of channels may contribute to control of cytoskeletal architecture and of regulatory protein function within their domain, but also that both a variety of regulatory proteins and components of the cortical cytoskeleton may contribute to control of channel activity. The emerging capabilities of electronic optical microscopy are well suited for resolving the spatial distributions of many of these cytoskeletal and regulatory molecules in living cells, and for following some of their behaviors as channels are stimulated to open and cytosolic calcium builds in their vicinity. Such microscopy, coupled with biochemical and physiological probing, should help to establish the nature of the feedback loops putatively controlled by the linkage sites and their channel domains.

Calcium Channels↗

Structure and proteoglycan composition of specialized regions of the elastic tendon of the chicken wing.

The elastic tendon of the avian wing has been described by others as a unique structure with elastic properties due to the predominance of elastic fibers in the midsubstance. Further analyses of the tendon have shown it to possess five anatomically distinct regions. Besides the major elastic region, a distally located fibrocartilage and three tendinous regions are present. The tendinous regions connect: (1) the muscle to the elastic region, (2) the elastic region to the fibrocartilage and (3) the latter to the insertion site. The elastic region possesses thick and abundant elastic fibers and very thin, interconnecting collagen fibers. The collagen fibers in the sesamoid fibrocartilage are thick and interwoven, defining spaces occupied by fibrochondrocytes embedded in a non-fibrillar and highly metachromatic matrix. Biochemical analyses have shown that the fibrocartilage has about tenfold the amount of glycosaminoglycans (GAGs) found in the other regions. The main GAG in this region was chondroitin sulfate (CS) (plus keratan sulfate as detected immunocytochemically), while the other regions showed variable amounts of CS, dermatan sulfate (DS) and heparan sulfate. Further analyses have shown that a large CS-bearing proteoglycan is found in the fibrocartilage. The elastic region possesses two main proteoglycans, a large CS-bearing proteoglycan (which reacted with an antibody against keratan sulfate after chondroitinase ABC treatment) and a predominant DS-bearing proteoglycan, which showed immunoreactivity when assayed with an anti-biglycan antibody. The results demonstrate that the elastic tendon is a complex structure with complex regional structural and compositional adaptations, suited to different biomechanical roles.

Animals↗

Affinity enhancement bivalent morpholino for pretargeting: initial evidence by surface plasmon resonance.

Pretargeting with bivalent effectors capable of bridging antitumor antibodies has been reported to provide superior results by affinity enhancement. Morpholinos (MORFs) and other DNA analogues used for pretargeting are ideally suited as bivalent effectors since they are easily synthesized and the distance between binding regions, likely to be a determinant of binding, may be adjusted simply by lengthening the chain. The goal of this investigation was to synthesize a bivalent MORF and to determine by surface plasmon resonance (SPR) whether the bivalent MORF exhibited bimolecular binding and whether the MORFs showed improved in vitro hybridization affinity in its bivalent form compared to its monovalent form. An 18 mer amino-derivitized MORF was made bivalent by dimerizing with disuccinimidyl suberate (DSS) in 1-methyl-2-pyrrolidinone (NMP) with N,N-diisopropylethylamine (DIEA) followed by purification by ion exchange chromatography. The in vitro hybridization affinity of bivalent compared to monovalent MORF was then measured by SPR. For these measurements, the complementary biotinylated cDNA was immobilized at coating densities that provided an average spacing of 20-100 angstroms and used to investigate the influence of this spacing on binding of the bivalent MORF with its binding regions separated by 25 A. The yield of bivalent MORF was as high as 45%, and the structure was confirmed by MALDI-TOF mass spectroscopy. When the sensograms obtained by SPR were analyzed using different binding models, the evidence was consistent with bimolecular binding of the bivalent MORF. The dissociation rate constant of the bivalent compared to monovalent MORF was more than 10-fold lower at 2.14 compared to 0.27 x 10(-5) (1/s) (p < 0.05), and since the association rate constants were similar at 8.53 and 5.64 x 10(5) (1/M.s) (p = 0.08), the equilibrium constant for hybridization to the immobilized cDNA of the bivalent compared to the monovalent MORF was almost 20-fold higher at 3.99 compared to 0.21 x 10(10) (1/M) (p < 0.05). In addition, qualitative evidence for bivalent binding of the bivalent MORF was apparent in the lower concentrations necessary to saturate the cDNA. Finally, the stoichiometry interpretation of the binding data provided estimates of the fraction of bivalent MORF binding bimolecularly. Under one set of conditions, this value was 20%. In conclusion, a bivalent MORF was easily synthesized by dimerization of a monovalent MORF. A lower dissociation rate constant and higher equilibrium constant was measured by SPR for the bivalent compared to monovalent MORF in their binding to an immobilized cDNA. These results show that bimolecular binding was occurring in the case of the bivalent MORF and suggest that bivalency may be superior to monovalency in MORF pretargeting applications.

Amines↗

[Measuring lung volume in the infant--problems with the nitrogen washout method].

The open-circuit nitrogen washout technique, as developed by Gerhardt et al., seems to be ideally suited for assessing functional residual capacity (FRC) in infants. By performing this measurement in over 250 infants throughout the last three years, we gathered considerable practical experience of our own, but also encountered several methodological problems, which, so far, have received only little attention by the relevant literature, or have remained unresolved altogether. Our data illustrate the importance of reproducing the infant's own breathing rate and tidal volume when calibrating the system. The choice of the O2-background-flow should be based on the individual peak tidal inspiratory flow, as derived from the tidal flow-volume loop. The importance of maintaining this O2-background-flow unchanged between calibration and measurement is also demonstrated. The question, at which N2-concentration the measurement should be terminated, has remained unresolved. Diffusion of N2 from blood and tissue into the alveolar space is responsible for considerable noise. Our own measurements resulted in widely differing FRC-values for different N2-target-concentrations; these differences seem to increase with more severe bronchial obstruction. Finally, there remains the question, how long the minimal interval between two subsequent measurements should be. In conclusion, these unresolved questions have to be answered in relevant prospective studies, before recommending this technique for routine clinical application.

Airway Obstruction↗

Radiation: microbial evolution, ecology, and relevance to mars missions.

Ultraviolet (UV) radiation has been an important environmental parameter during the evolution of life on Earth, both in its role as a mutagen and as a selective agent. This was probably especially true during the time from 3.8 to 2.5 billion years ago, when atmospheric ozone levels were less than 1% of present levels. Early Mars may not have had an "ozone shield" either, and it never developed a significant one. Even though Mars is farther away from the Sun than the Earth, a substantial surficial UV flux is present on Mars today. But organisms respond to dose rate, and on Mars, like on Earth, organisms would be exposed to diurnal variations in UV flux. Here we present data on the effect of diurnal patterns of UV flux on microbial ecosystems in nature, with an emphasis on photosynthesis and DNA synthesis effects. These results indicate that diurnal patterns of metabolism occur in nature with a dip in photosynthesis and DNA synthesis in the afternoon, in part regulated by UV flux. Thus, diurnal patterns must be studied in order to understand the effect of UV radiation in nature. The results of this work are significant to the success of human missions to Mars for several reasons. For example, human missions must include photosynthetic organisms for food production and likely oxygen production. An evolutionary approach suggests which organisms might be best suited for high UV fluxes. The diurnal aspect of these studies is critical. Terraforming is a potential goal of Mars exploration, and it will require studies of the effect of Martian UV fluxes, including their diurnal changes, on terrestrial organisms. Such studies may suggest that diurnal changes in UV only require mitigation at some times of day or year.

Atmosphere↗

Canal-down mastoidectomy: experience in 81 cases.

OBJECTIVES: To identify the common presentation(s) and the clinical and operative finding(s) in patients with cholesteatomatous and long-term noncholesteatomatous chronic suppurative otitis media and to adapt a surgical management best suited to ensure long-term safety in these Papua New Guinean patients for whom postoperative follow-up is minimal. DESIGN: Retrospective case series. SETTING: Port Moresby General Hospital, the tertiary referral center for otolaryngologic services. PATIENTS: Eighty-one patients in all age groups who received a clinical diagnosis of chronic suppurative otitis media, with or without cholesteatoma, with or without its associated complications. INTERVENTION: Canal-down (modified radical) mastoidectomy with wide meatoplasty. MAIN OUTCOME MEASURE AND RESULTS: Adults were more commonly affected than adolescent or pediatric cases, and there was a male preponderance. The median age was 24 years (range, 13 months to 73 years). Otorrhea remained the most common presentation in all age groups. Postauricular abscesses and fistulae were seen frequently. Cholesteatoma and granulation with polypoidal mucosa were frequent operative findings; a high incidence involved both the attic space and the antrum. Five (6%) patients had preoperative facial paralysis; in addition, postoperative facial paralysis developed in three (4%) patients. The incidence of postoperative "wet ear" was high in all age groups. Meningitis was the most common intracranial complication, followed by lateral sinus thrombosis. There were seven (9%) deaths altogether, and all the deaths occurred as a direct result of otogenic intracranial complication. CONCLUSION: Lack of health consciousness, poor socioeconomic status, and lack of health care delivery system resulted in late presentations and poor postoperative follow-up. Hence, the canal-wall-down technique with wide meatoplasty is recommended to ensure a best possible one-time treatment in Papua New Guinean patients with cholesteatomatous or long-term "dangerous" chronic suppurative otitis media with or without complications.

Adolescent↗

Disparity-tuning characteristics of neuronal responses to dynamic random-dot stereograms in macaque visual area V4.

Stereo processing begins in the striate cortex and involves several extrastriate visual areas. We quantitatively analyzed the disparity-tuning characteristics of neurons in area V4 of awake, fixating monkeys. Approximately half of the analyzed V4 cells were tuned for horizontal binocular disparities embedded in dynamic random-dot stereograms (RDSs). Their response preferences were strongly biased for crossed disparities. To characterize the disparity-tuning profile, we fitted a Gabor function to the disparity-tuning data. The distribution of V4 cells showed a single dense cluster in a joint parameter space of the center and the phase parameters of the fitted Gabor function; most V4 neurons were maximally sensitive to fine stereoscopic depth increments near zero disparity. Comparing single-cell responses with background multiunit responses at the same sites showed that disparity-sensitive cells were clustered within V4 and that nearby cells possessed similar preferred disparities. Consistent with a recent report by Hegdé and Van Essen, the disparity tuning for an RDS drastically differed from that for a solid-figure stereogram (SFS). Disparity-tuning curves were generally broader for SFSs than for RDSs, and there was no correlation between the fitted Gabor functions' amplitudes, widths, or peaks for the two types of stereograms. The differences were partially attributable to shifts in the monocular images of an SFS. Our results suggest that the representation of stereoscopic depth in V4 is suited for detecting fine structural features protruding from a background. The representation is not generic and differs when the stimulus is broad-band noise or a solid figure.

Action Potentials↗

Enhanced sampling of peptide and protein conformations using replica exchange simulations with a peptide backbone biasing-potential.

During replica exchange molecular dynamics (RexMD) simulations, several replicas of a system are simulated at different temperatures in parallel allowing for exchange between replicas at frequent intervals. This technique allows significantly improved sampling of conformational space and is increasingly being used for structure prediction of peptides and proteins. A drawback of the standard temperature RexMD is the rapid increase of the replica number with increasing system size to cover a desired temperature range. In an effort to limit the number of replicas, a new Hamiltonian-RexMD method has been developed that is specifically designed to enhance the sampling of peptide and protein conformations by applying various levels of a backbone biasing potential for each replica run. The biasing potential lowers the barrier for backbone dihedral transitions and promotes enhanced peptide backbone transitions along the replica coordinate. The application on several peptide cases including in all cases explicit solvent indicates significantly improved conformational sampling when compared with standard MD simulations. This was achieved with a very modest number of 5-7 replicas for each simulation system making it ideally suited for peptide and protein folding simulations as well as refinement of protein model structures in the presence of explicit solvent.

Alanine↗

The nature of the hydrogen bond: a synthesis from the interacting quantum atoms picture.

The interacting quantum atoms approach [IQA, as presented by Blanco et al., J. Chem. Theory Comput. 1, 1096 (2005)] is applied to standard hydrogen bonded dimers. IQA is an interpretation tool based on a real space energy decomposition scheme fully consistent with the quantum theory of atoms in molecules. It provides a partition of every physical term present in the Hamiltonian into atomic and interatomic contributions. The procedure is orbital-free and self-contained, needing neither external references nor artificial intermediate states. Binding is the result of a competition between the destabilizing deformations suffered by the interacting fragments upon interaction and the stabilizing interaction energy itself. According to IQA, there is no incompatibility between the prevalent electrostatic image of hydrogen bonded systems and that favoring important covalent contributions. Depending on how we gather the different energetic terms, we may recover electrostatic or covalent pictures from the same underlying quantum mechanical description. Our results show that the nonclassical contributions to hydrogen bonding are spatially localized, involving only the H atom and its two nearest neighbors. IQA is well suited as a comparative tool. Its thin energetic decomposition allows us to recover exactly (or to a very good approximation) the quantities of the most widely used energy decomposition schemes. Such a comparison sheds light on the virtues and faults of the different methods and on the origin of the 50 years old debate regarding the covalent/electrostatic nature of the hydrogen bond.

Journal Article↗

Application of high-performance computing to numerical simulation of human movement.

We have examined the feasibility of using massively-parallel and vector-processing supercomputers to solve large-scale optimization problems for human movement. Specifically, we compared the computational expense of determining the optimal controls for the single support phase of gait using a conventional serial machine (SGI Iris 4D25), a MIMD parallel machine (Intel iPSC/860), and a parallel-vector-processing machine (Cray Y-MP 8/864). With the human body modeled as a 14 degree-of-freedom linkage actuated by 46 musculotendinous units, computation of the optimal controls for gait could take up to 3 months of CPU time on the Iris. Both the Cray and the Intel are able to reduce this time to practical levels. The optimal solution for gait can be found with about 77 hours of CPU on the Cray and with about 88 hours of CPU on the Intel. Although the overall speeds of the Cray and the Intel were found to be similar, the unique capabilities of each machine are better suited to different portions of the computational algorithm used. The Intel was best suited to computing the derivatives of the performance criterion and the constraints whereas the Cray was best suited to parameter optimization of the controls. These results suggest that the ideal computer architecture for solving very large-scale optimal control problems is a hybrid system in which a vector-processing machine is integrated into the communication network of a MIMD parallel machine.

Computer Systems↗

Apomixis: a developmental perspective.

The term apomixis encompasses a suite of processes whereby seeds form asexually in plants. In contrast to sexual reproduction, seedlings arising from apomixis retain the genotype of the maternal parent. The transfer of apomixis and its effective utilization in crop plants (where it is largely absent) has major advantages in agriculture. The hallmark components of apomixis include female gamete formation without meiosis (apomeiosis), fertilization-independent embryo development (parthenogenesis), and developmental adaptations to ensure functional endosperm formation. Understanding the molecular mechanisms underlying apomixis, a developmentally fascinating phenomenon in plants, is critical for the successful induction and utilization of apomixis in crop plants. This review draws together knowledge gained from analyzing ovule, embryo, and endosperm development in sexual and apomictic plants. It consolidates the view that apomixis and sexuality are closely interrelated developmental pathways where apomixis can be viewed as a deregulation of the sexual process in both time and space.

Fertilization↗

[Transcultural spatial dispositions and the early parent-child interactions: joint hospitalization facilities].

Joint hospitalizations of father/mother and baby now routinely practiced in the United Kingdom and United States is generally founded on analytical or systemic theories. In France, the thirty or so existing joint parent/child hospitalization facilities should adopt a qualitative approach suited to the cultural context. A few socio-architectural examples could inspire psychiatric teams specialized in joint parent/baby care to transpose specific cultural relationships: the crib of the main house in Provence, the "cow camp" of the peul people in Niger, the "haouche" in Little Kabylia, the "rain hut" in the Casamance area of Senegal. This rediscovery would obviously draw its effectiveness from intercultural traditions buried not too deeply in our ethnocentrism.

Africa↗

Permeability and electrokinetic characterization of poly(ethylene terephthalate) capillary pore membranes with grafted temperature-responsive polymers.

Poly(ethylene terephthalate) (PET) track-etched membranes with average pore diameters of 692 and 1629 nm were functionalized using the monomer N-isopropylacrylamide (NIPAAm) and a photoinitiated "grafting-from" approach in which a surface-selective reaction has been most efficiently achieved by combinations of the unmodified PET surface with benzophenone and, alternatively, of an aminated PET surface with benzophenone carboxylic acid. Consistent estimations of the pore diameters of the base PET membranes and of the effective grafted polyNIPAAm layer thicknesses on the PET pore walls were possible only on the basis of the permeabilities measured with aqueous solutions of higher ionic strength (e.g., 0.1 M NaCl). However, the permeabilities measured with ultrapure water indicated that the "electroviscous effect" was significant for both base membranes. The influences of membrane pore diameter, surface charge, and solution ionic strength could be interpreted in the framework of the space-charge model. Functionalized membranes with collapsed grafted polymer hydrogel layer thicknesses of a few nanometers exhibited almost zero values of the zeta potential estimated from the trans-membrane streaming potential measurements. This was caused by a "hydrodynamic screening" of surface charge by the neutral hydrogel. Very pronounced changes in permeability as a function of temperature were measured for PET membranes with grafted polyNIPAAm layers, and the effective layer thickness in the swollen state--here up to approximately 300 nm--correlated well with the degree of functionalization. The subtle additional effects of solution ionic strength on the hydrodynamic layer thickness at 25 degrees C were different from the effects for the base PET membranes and could be explained by a variation in the degree of swelling, resembling a "salting-out" effect. Overall, it had been demonstrated that the functionalized capillary pore membranes are well suited for a detailed and quantitative evaluation of the relationships between the synthesis, the structure, and the function of grafted stimuli-responsive polymer layers.

Journal Article↗