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991.
The development of design systems which ensure economic feasibility has been the focus of recent research in the manufacturing area. Traditional design and justification approaches have been cited as having shortcomings; thus, there have been a variety of modifications and enhancements developed. An approach that is conceptually different from the traditional approaches seeks the integration of the economic analysis within the design process. We denote this approach as thedesign justification method. This paper reviews literature related to the explicit and implicit integration of economic factors in the manufacturing system design process, followed by supporting issues for the implementation of the design justification concept. 相似文献
992.
Darcy S. O. Mora Madeline Cox Forgivemore Magunda Ashley B. Williams Lyndsey Linke 《Engineering in Life Science》2023,23(3):e2200037
There is an unmet need for delivery platforms that realize the full potential of next-generation nucleic acid therapeutics. The in vivo usefulness of current delivery systems is limited by numerous weaknesses, including poor targeting specificity, inefficient access to target cell cytoplasm, immune activation, off-target effects, small therapeutic windows, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we characterize the safety and efficacy of a delivery platform comprising engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli SVC1) for intracellular cargo delivery. SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to allow escape of their cargo from the phagosome, and to have minimal immunogenicity. We describe SVC1's ability to deliver short hairpin RNA (shRNA), localized SVC1 administration to various tissues, and its minimal immunogenicity. To validate the therapeutic potential of SVC1, we used it to deliver influenza-targeting antiviral shRNAs to respiratory tissues in vivo. These data are the first to establish the safety and efficacy of this bacteria-based delivery platform for use in multiple tissue types and as an antiviral in the mammalian respiratory tract. We expect that this optimized delivery platform will enable a variety of advanced therapeutic approaches. 相似文献
993.
Roger S. McIntyre Mohammad Alsuwaidan Bernhard T. Baune Michael Berk Koen Demyttenaere Joseph F. Goldberg Philip Gorwood Roger Ho Siegfried Kasper Sidney H. Kennedy Josefina Ly-Uson Rodrigo B. Mansur R. Hamish McAllister-Williams James W. Murrough Charles B. Nemeroff Andrew A. Nierenberg Joshua D. Rosenblat Gerard Sanacora Alan F. Schatzberg Richard Shelton Stephen M. Stahl Madhukar H. Trivedi Eduard Vieta Maj Vinberg Nolan Williams Allan H. Young Mario Maj 《World psychiatry》2023,22(3):394-412
Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population. 相似文献
994.
A new method of polarized light analysis is described in which a highly sensitive electronic detector specific for birefringence is used to identify the crystalline axes of an object and then measure its phase retardation due to birefringence. The microscopic system employed in the method consists of an electronic birefringence detection system (BDS), a microscope with strain-free lenses, and a driven stage for passing the specimen at appropriate velocities across the image of an aperture placed at the field stop and imaged in the specimen plane by the condenser. The detector registers retardations directly as voltage at a constant deflection sensitivity of ca. 1.1 v per angstrom unit over a range of 120 angstrom units. The basal rms noise level is 0.002 A for a spot 36 µ in diameter formed by a 95 x, N. A. 1.25 objective pair, and increases in proportion to the reciprocal of the diameter of the scanning spot. The increase in noise with high resolution scanning can be offset by increasing the instrumental time constant, which is adjustable in decades between 0.004 and 0.4 seconds. A number of difficult problems in high extinction polarization microscopy are avoided by the use of modulated light and a rapid electronic detector. For example: (a) The measured distribution of birefringence is unaffected by the usual diffraction anomaly; therefore polarization rectifiers are not required. (b) The detector is selective for birefringence, so that there is no problem in separating contrast due to different optical properties (e.g. dichroism, light scattering). (c) The speed and sensitivity are both increased by between one and two orders of magnitude over that attainable by visual or photographic methods, thereby rendering a vast number of weakly birefringent, light-scattering, and motile objects readily analyzable for the first time with polarized light. 相似文献
995.
Alkaline Phosphatase Content and the Effects of Prednisolone on Mammalian Cells in Culture 总被引:12,自引:1,他引:12 下载免费PDF全文
The alkaline phosphatase content of different tissue culture cell lines has been shown to vary from no detectable activity to high enzyme concentration. Within the epithelial lines studied alkaline phosphatase is either constitutive or inducible. Two epithelial cell strains in which alkaline phosphatase was "absent" could be induced to develop significant amounts of the enzyme when grown in the presence of Δ1-hydrocortisone. Phosphate did not repress enzyme induction by prednisolone. Under conditions of deadaptation the induced enzyme was diluted by cell multiplication. The mouse fibroblastic L line and several human fibroblastic lines did not contain alkaline phosphatase when grown under the conditions described nor could they be induced to produce the enzyme when cultivated in medium with prednisolone. Δ1-Hydrocortisone has other characteristic effects on established mammalian cell cultures which vary among cell lines. Human epithelial lines show reduction in cell multiplication with increase in mitotic index. The cytoplasm is increased and cell volume is nearly doubled. Mouse fibroblasts show a similar reduction in cell multiplication with a decrease in mitotic index. There is no increase in cell cytoplasm. Human fibroblast strains show no inhibition of multiplication or alteration in total cell protein when grown in medium containing prednisolone. Antisera prepared against "negative" prednisolone-inducible human cell lines and against a positive human line inhibited alkaline phosphatase activity to an equal degree. 相似文献
996.
Single units which discharged with regular spontaneous rhythms without intentional stimulation were observed in the ventral nerve cord by intracellular recording close to the sixth abdominal ganglion. These units were divided into two groups: group A units in which interspike intervals varied less than 10 msec.; group B units in which interspike intervals varied within a range of 10 to 30 msec. Group A units maintained "constant" interspike intervals and could not be discharged by sensory inputs, while the majority of group B units could be discharged by appropriate sensory nerve stimulation. Both group A and B units discharged to direct stimulation when the stimulating and recording electrodes were placed in the same ganglionic intersegment, and directly evoked single spikes reset the spontaneous rhythm. In group B units, presynaptic volleys reset the spontaneous rhythm of some units; but in others, synaptically evoked spikes were interpolated within the spontaneous rhythm without resetting. The phenomenon of enhancement could also be demonstrated in spontaneously active units as a result of repetitive stimulation. It is concluded that endogenous pacemaker activity is responsible for much of the regular spontaneous firing observed in crayfish central neurons, and that interaction of evoked responses with such pacemaker sites can produce a variety of effects dependent upon the anatomical relationships between pacemaker and synaptic regions. 相似文献
997.
998.
Cells of Chroomonas salina were exposed to [14C]acetate, [l4C]16:0,[14C]18:0, [14C]18:1(n-9), [14C]18:2(n6) or [14C]18:3(n3)for 1 h and then incubated for 24 h in non-radioactive medium.At the end of the pulse period, non-glycolipid polar lipidscontained the highest proportions of radioactivity incorporatedfrom [14C]acetate and [14C]18:3(n3) whereas with [14C]16:0,[14C]18:1 and [14C]18:2(n6), triacylglycerols were mosthighly labelled. 14C-18:0 was recovered mainly as non-esterifiedfatty acid. Monogalactosyldiacylglycerol initially contained17% of label incorporated from [14C]acetate but less than 3%of that from [14C]fatty acids. With all substrates, excluding[14C]18:0, a gradual transfer of label from polar lipids totriacylglycerols was observed during the chase period. Saturatesand monoenes synthesised from [14C]acetate were mostly transferedfrom phospholipids and glycolipids to neutral lipid withoutfurther desaturation. Most of the incorporated 14C-fatty acidsremained unchanged and only with [14C]18:3(n3) was substantialamounts of label recovered in penta- and hexaenoic fatty acids.The results indicate that, under the conditions of the study,lipid synthesis in the algae was heavily dominated by triacylglycerolformation and that the mechanisms of fatty acid desaturationin this species may differ from those in higher plants. (Received December 10, 1991; Accepted March 6, 1992) 相似文献
999.
James A. Bunce 《Physiologia plantarum》1992,86(1):173-179
The short-term stimulation of the net rate of carbon dioxide exchange of leaves by elevated concentrations of CO2 usually observed in C3 plants sometimes does not persist. Experiments were conducted to test whether the patterns of response to the environment during growth were consistent with the hypotheses that photosynthetic adjustment to elevated CO2 concentration is due to (1) feedback inhibition or (2) nutrient stress. Soybean [Glycine max (L.) Merr. cv. Williams] and sugar beet (Best vulgaris L. cv. Mono Hye-4) were grown from seed at 350 and 700 μl? CO2, at 20 and 25°C, at a photon flux density of 0.5 and 1.0 mmol m?2 S?1 and with three nutrient regimes until the third trifoliolate leaf of soybean or the sixth leaf of sugar beet had finished expanding. Net rates of CO2 exchange of the most recently expanded leaves were then measured at both 350 and 700 μl 1?1 CO2. Plants grown at the elevated CO2 concentration had net rates of leaf CO2 exchange which were reduced by 33% in sugar beet and 23% in soybean when measured at 350 μl 1?1 CO2 and when averaged over all treatments. Negative photosynthetic adjustment to elevated CO2 concentration was not greater at 20 than at 25°C, was not greater at a photon flux density of 1.0 than at 0.5 mmol m?2 S?1 and was not greater with limiting nutrients. Furthermore, in soybean, negative photosynthetic adjustment could be induced by a single night at elevated CO2 concentration, with net rates of CO2 exchange the next day equal to those of leaves of plants grown from seed at the elevated concentration of CO2. These patterns do not support either the feedback-inhibition or the nutrient-stress hypothesis of photosynthetic adjustment to elevated concentrations of CO2. 相似文献
1000.