Biomedical subjects

M L Yarmush

Publications and source records attributed to M L Yarmush.

At least 19 recordsLinked to original sources

PubMed2002

Critical issues in bioartificial liver development.

End-stage liver disease accounts for over 30,000 deaths annually in the United States. Orthotopic liver transplantation is the only clinically proven treatment for patients with end-stage liver failure. A limitation of this therapy is a shortage of donor organs available. This donor organ shortage is exacerbated by the fact that the number of patients listed for transplantation has continued to increase. As a result, there has been a continuing increase in the number of patients who die waiting for a donor liver. Extracorporeal bioartificial liver devices consisting of viable hepatocytes have the potential to provide temporary support for patients with fulminant hepatic failure, thereby serving as a "bridge" to transplantation. In some patients, this temporary support would allow the native liver to regenerate function, eliminating the need for transplantation and the resulting life-long immunosuppressive therapy, all of which translates into a cost savings to the health care system. Although the bioartificial liver device is a promising technology for the treatment of liver failure, significant technical challenges remain in order to develop systems with sufficient processing capacity and of manageable size. An overview of the critical issues in the development of bioartificial liver devices is discussed.

Animals↗

PubMed2001

Complexation of retrovirus with cationic and anionic polymers increases the efficiency of gene transfer.

Previously, we have demonstrated that chondroitin sulfate proteoglycans and glycosaminoglycans inhibit retrovirus transduction. While studying the mechanism of inhibition, we found that the combined addition of equal-weight concentrations (80 microg/ml) of Polybrene and chondroitin sulfate C to retrovirus stocks resulted in the formation of a high-molecular-weight retrovirus-polymer complex that could be pelleted by low-speed centrifugation. The pelleted complex contained more than 80% of the virus particles, but less than 0.3% of the proteins that were originally present in the virus stock. Surprisingly, the virus in the complex remained active and could be used to transduce cells. The titer of the pelleted virus, when resuspended in cell culture medium to the starting volume, was three-fold greater than the original virus stock. The selectivity (CFU/mg protein) of the process with respect to virus activity was more than 1000-fold. When the pelleted virus-polymer complex was resuspended in one-eighth of the original volume and used to transduce NIH 3T3 murine fibroblasts and primary human fibroblasts, gene transfer was increased 10- to 20-fold over the original unconcentrated retrovirus stock. The implications of our findings for the production, processing, and use of retrovirus stocks for human gene therapy protocols are discussed.

3T3 Cells↗

PubMed2001

Rational selection and quantitative evaluation of antisense oligonucleotides.

Antisense oligonucleotides are an attractive therapeutic option to modulate specific gene expression. However, not all antisense oligonucleotides are effective in inhibiting gene expression, and currently very few methods exist for selecting the few effective ones from all candidate oligonucleotides. The lack of quantitative methods to rapidly assess the efficacy of antisense oligonucleotides also contributes to the difficulty of discovering potent and specific antisense oligonucleotides. We have previously reported the development of a prediction algorithm for identifying high affinity antisense oligonucleotides based on mRNA-oligonucleotide hybridization. In this study, we report the antisense activity of these rationally selected oligonucleotides against three model target mRNAs (human lactate dehydrogenase A and B and rat gp130) in cell culture. The effectiveness of oligonucleotides was evaluated by a kinetic PCR technique, which allows quantitative evaluation of mRNA levels and thus provides a measure of antisense-mediated decreases in target mRNA, as occurs through RNase H recruitment. Antisense oligonucleotides that were predicted to have high affinity for their target proved effective in almost all cases, including tests against three different targets in two cell types with phosphodiester and phosphorothioate oligonucleotide chemistries. This approach may aid the development of antisense oligonucleotides for a variety of applications.

Animals↗

PubMed2001

Effects of oxygenation and flow on the viability and function of rat hepatocytes cocultured in a microchannel flat-plate bioreactor.

The goal of this study was to investigate the viability and synthetic function of rat hepatocytes cocultured with 3T3-J2 fibroblasts in a small-scale microchannel flat-plate bioreactor with and without an internal membrane oxygenator under flow. Bioreactor channel heights ranged between 85 and 500 microm and medium flow rates ranged between 0.06 and 4.18 mL/min. The results showed that the bioreactor without the oxygenator resulted in significantly decreased viability and function of hepatocytes, whereas hepatocytes in the bioreactor with internal membrane oxygenator were able to maintain their viability and function. The shear stress calculations showed that, at lower wall shear stresses (0.01 to 0.33 dyn/cm(2)), hepatocyte functions, measured as albumin and urea synthesis rates, were as much as 2.6- and 1.9-fold greater, respectively, than those at higher wall shear stresses (5 to 21 dyn/cm(2)). Stable albumin and urea synthesis rates for 10 days of perfusion were also demonstrated in the bioreactor with internal membrane oxygenator. These results are relevant in the design of hepatocyte bioreactors and the eventual scaling-up to clinical devices.

3T3 Cells↗

PubMed2001

Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate.

There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine. Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge but that the cells must prioritize their response under extreme cytokine challenges.

Acids↗

PubMed2001

Poloxamer-188 improves capillary blood flow and tissue viability in a cutaneous burn wound.

After cutaneous burn injury, an area of tissue 1-2 mm thick surrounding the wound is the site of a pronounced inflammatory response where blood flow is reduced. This "zone of stasis" undergoes progressive necrosis within 24-48 h, resulting in an expansion of the burn wound. Poloxamer-188 (P-188) is a surfactant that has been shown to prevent cell death due to electrical injury in vivo and heat shock in vitro. In this study, we investigated the effect of P-188 on blood flow within and around a burn wound and on the expansion of the wound area within 24 h after administration of a full-thickness burn injury. Results show that immediately (0-2 h) after the burn, red blood cell speed decreased to zero in a zone extending up to 1 mm from the center of the burn in both P-188 (200 mg/kg)- and saline (0.9%)-treated animals. Between 1 and 3 mm from the center of the burn, red blood cell speed decreased to 50% of preburn levels in saline controls (n = 5), while no decrease occurred in P-188-treated animals (n = 5). Beyond 3 mm from the center of the burn, red blood speed was equal to the preburn levels in saline controls, while it increased by about 10% in P-188 animals. Twenty-four hours after administration of burn, the "zero red blood cell speed zone," termed as the zone of coagulation, became smaller in P-188-treated animals, with an area of 2.4 +/- 0.5 mm(2) (n = 5) compared to 3.5 +/- 0.5 mm(2) (n = 4) in saline controls (P < 0.01). These results suggest that P-188 prevented the formation of a zone of stasis within 2 h after the burn injury and reduced the area of coagulation observed 24 h after cutaneous burn injury.

Animals↗

PubMed2001

A fulminant hepatic failure model in the rat: involvement of interleukin-1beta and tumor necrosis factor-alpha.

The development of a fulminant hepatic failure (FHF) model is necessary for evaluating the efficacy of extracorporeal liver support systems. Recognizing the multifaceted functions of the liver, including synthesis and degradation, we investigated blood chemistry, histological findings, and survival rate in D-galactosamine (GalN)-intoxicated rats. The pathophysiologic response of inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), was also measured. Sprague-Dawley rats (200-300 g) were divided into two groups: GalN and saline injection. Rats were killed at 1, 3, 6, 12, 24, 36, 48, 72, and 168 hr after intraperitoneal injection of GalN (1.4 g/kg) or saline. In both groups, liver-specific markers, liver histology, and IL-1beta and TNF-alpha levels in blood and liver tissue were analyzed. In a second series of experiments, the survival rates were examined after two administrations of GalN at 1.0, 1.4 or 2.0 g/kg, at a 12-hr interval. In the GalN injection group, the liver-specific markers reached peak levels between 36 and 48 hr after injection. Histologically, hepatocellular necrosis was seen at 6-48 hr, followed by a regenerative phase occurring between 72 and 168 hr. IL-1beta and TNF-alpha levels in liver tissue peaked at 12 hr and 1 hr, respectively. The levels of these cytokines in blood, however, did not change significantly. The survival rates at day 7 for 1.0, 1.4 or 2.0 g/kg GalN injected twice were 77.8%, 16.7%, and 0%, respectively. These results suggest that single and double injection of GalN enable the development of reversible and irreversible FHF models. The results also indicate that IL-1beta and TNF-alpha are useful markers of liver injury.

Animals↗

PubMed2001

In vitro and in vivo evaluation of albumin synthesis rate of porcine hepatocytes in a flat-plate bioreactor.

Several configurations of extracorporeal bioartificial liver devices have been developed for the potential treatment of fulminant hepatic failure or as a bridge to liver transplantation. Recently, we developed a microchannel flat-plate bioreactor with an internal membrane oxygenator in which porcine hepatocytes are cultured as a monolayer on the bottom glass surface. In the present study, we investigated synthetic function of porcine hepatocytes in the bioreactor in both in vitro and in vivo flow circuit models. In vitro, albumin synthesis was stable in the bioreactor for up to 4 days of perfusion. In vivo, with the extracorporeal connection of the bioreactor to rat vasculature, porcine albumin was detectable for 24 h in the rat plasma. We also developed a simple mathematical model to predict the in vivo porcine albumin concentration in rat plasma. These results indicate that this configuration of a microchannel flat-plate bioreactor has potential as a liver support device and warrants further investigation.

Albumins↗

PubMed2001

Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model.

A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/vol bovine serum albumin and oxygenated with 95% O(2)/5% CO(2). Control rats were fasted for 36 hours with no other treatment before perfusion. FHF rat livers exhibited reduced amino acid uptake, a switch from gluconeogenesis to glycolysis, and a decrease in urea synthesis, but no change in ammonia consumption compared with normal fasted rat livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to alpha-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function.

Amino Acids↗

PubMed2001

Long-term maintenance of cytochrome P450 activities by rat hepatocyte/3T3 cell co-cultures in heparinized human plasma.

Little information on the effect of plasma on hepatocyte cytochrome P450 (CYP) activities is currently available. We characterized the effect of plasma on CYPs of hepatocyte-mesenchymal cell co-cultures, which exhibit stable liver specific functions and may be potentially useful for bioartificial liver design. Rat hepatocyte-mouse 3T3-J2 cell co-cultures were maintained for 6 days in medium, and then switched to heparinized human plasma containing 3-methylcholanthrene (3MC; 2 microM), phenobarbital (PB; 1 mM), or no inducer for up to 7 days. CYP activities were measured in situ based on the o-dealkylation of ethoxy- (EROD), methoxy- (MROD), pentoxy- (PROD), or benzyloxy- (BROD) resorufin. Plasma alone increased PROD/BROD but not EROD/MROD. The endogenous inducer was in the high molecular weight fraction (>5 kD) of plasma and inhibited by >5 nM okadaic acid and >10 microM dibutyryl cyclic AMP, two inhibitors of PB-inducible CYPs. Furthermore, plasma increased CYP1A1 and CYP2B1/2 mRNA levels. In plasma, 3MC induced EROD/MROD to about 60% of the level induced in culture medium while PB induced PROD/BROD that were three- to 10-fold above levels induced in medium. CYP activities decreased between days 2 and 7 of plasma exposure, but were enhanced by plasma supplementation with amino acids, insulin, glucagon, and hydrocortisone.

3T3 Cells↗

PubMed2001

Keratinocyte growth factor induces hyperproliferation and delays differentiation in a skin equivalent model system.

Keratinocyte growth factor (KGF) is a paracrine mediator of epithelial cell growth. To examine the direct effects of KGF on the morphogenesis of the epidermis, we generated skin equivalents in vitro by seeding human keratinocytes on the papillary surface of acellular dermis and raising them up to the air-liquid interface. KGF was either added exogenously or expressed by keratinocytes via a recombinant retrovirus encoding KGF. KGF induced dramatic changes to the 3-dimensional organization of the epidermis including pronounced hyperthickening, crowding, and elongation of the basal cells, flattening of the rete ridges, and a ripple-like pattern in the junction of stratum corneum and granular layers. Quantitative immunostaining for the proliferation antigen, Ki67, revealed that in addition to increasing basal proliferation, KGF extended the proliferative compartment by inducing suprabasal cell proliferation. KGF also induced expression of the integrin alpha 5 beta 1 and delayed expression of keratin 10 and transglutaminase. However, barrier formation of the epidermis was not disrupted. These results demonstrate for the first time that a single growth factor can alter the 3-dimensional organization and proliferative function of an in vitro epidermis. In addition to new strategies for tissue engineering, such a well-defined system will be useful for analyzing growth factor effects on the complex links between cell proliferation, cell movement and differentiation within a stratified tissue.

Cell Differentiation↗

PubMed2001

Peripheral blood mononuclear cells exhibit hypercatabolic activity in response to thermal injury correlating with diminished MHC I expression.

BACKGROUND: Muscle wasting is one of the major consequences of severe injury or infection. Although the mechanisms underlying this hypercatabolic state are not completely characterized, it was hypothesized that other cells in the body would be similarly affected. In particular, we sought to determine whether lymphoid cell populations experienced increased protein turnover after burn injury in a fashion analogous to that seen in skeletal muscle. METHODS: BALB/c mice received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 after treatment, skeletal muscle, peripheral blood, spleen, and lymph nodes were harvested from both groups. Protein synthesis and degradation rates were measured using 14C-phenylalanine incorporation and tyrosine release. Lymphocyte subpopulations (CD4 and CD8 T cells, macrophages, and B cells) and expression of major histocompatibility complex I (MHC I) molecules were assessed by flow cytometry. RESULTS: The burn model used in this study resulted in increased skeletal muscle protein turnover in the first 2 days after injury. Protein synthetic and degradation rates of peripheral blood mononuclear cells (PBMNCs) in burned mice also demonstrated comparable changes, but persisted through day 7. Splenocytes showed similar hypercatabolic effects, whereas lymph node cells showed no change. Cell viability analysis confirmed that the observed alterations were not caused by cell death. MHC I expression was depressed in tandem with the increased catabolic rate in PBMNCs. CONCLUSION: This study demonstrates that various lymphoid populations undergo protein catabolic changes similar to those characteristically observed in skeletal muscle, and these correlated with diminished MHC I expression. Moreover, PBMNCs exhibited prolonged sensitivity to burn injury, of a duration exceeding that observed in skeletal muscles or other lymphoid tissues.

Animals↗

PubMed2001

Analysis of oxygen transport to hepatocytes in a flat-plate microchannel bioreactor.

Oxygen transfer to cultured hepatocytes in microchannel parallel-plate bioreactors with and without an internal membrane oxygenator was investigated with a mathematical model and the results were corroborated with fluorescence imaging experiments. The consumption of oxygen by hepatocytes was assumed to follow Michaelis-Menten kinetics. Our simulations indicate that under conditions of low Péclet (Pe) number (<80) and fixed Damlkohler number (= 0.14, corresponding to rat hepatocytes) the cells are hypoxic in the bioreactor without an internal membrane oxygenator. Under the same conditions, the bioreactor with an internal membrane oxygenator can avoid cell hypoxia by appropriate selection of membrane Sherwood number and/or the gas phase oxygen partial pressure, thus providing greater control of cell oxygenation. At high Pe, both bioreactors are well oxygenated. Experimentally determined oxygen concentrations within the bioreactors were in good qualitative agreement with model predictions. At low Pe, cell surface oxygen depletion was predicted from analytically derived criteria. Hepatocytes with oxygen dependent functional heterogeneity may exhibit optimal function in the bioreactor with the internal membrane oxygenator.

Animals↗

PubMed2001

Effect of flow on the detoxification function of rat hepatocytes in a bioartificial liver reactor.

Ethoxyresorufin-o-deethylation (EROD) can be used as a sensitive measure of hepatic detoxification function. In this study, we employed a fluorescence assay based on EROD to study the effect of varying Peclet number (or flow) on hepatic function in a microchannel flat-plate bioartificial liver (BAL) reactor containing a coculture of hepatocytes and fibroblasts. Static culture and reactor flow experiments established that: 1) a pseudo-steady-state detoxification rate could be attained at each Peclet number, 2) the steady-state detoxification rate increased nonlinearly with Peclet number (ranging from 167 to 2500), 3) the uptake rate of substrate was a linear function of cell surface substrate concentration (<1 microM), and 4) a shear stress of 10 dyne/cm2 did not adversely affect hepatic function for at least 12 h. A convection-diffusion-reaction model supports the conclusion that increased convective mass transfer of substrate to the cell surface is the primary cause of the observed increase in EROD rate with Peclet number. Our results suggest that detoxification rates can be enhanced by an order of magnitude by choosing an appropriate Peclet number. For our bioreactor configuration, this optimum corresponds to a Peclet number range of 1000-2000 at a Damkohler number of 0.55. The usefulness of the mathematical model is discussed in the context of scale-up to a clinical BAL reactor for human application.

Animals↗

PubMed2000

Aromatic residues mediate the pressure-induced association of digoxigenin and antibody 26-10.

We have previously found that the complex between fluorescently labeled digoxigenin and the monoclonal antibody 26-10 forms with a decrease in volume of approximately 30 ml/mol, leading to increased association of these species under applied hydrostatic pressure. In the present study, we have utilized a panel of mutant antibodies and Fab fragments, previously characterized for their importance in the binding affinity of digoxin:26-10, to probe the molecular basis of pressure sensitivity in this complex, as measured by fluorescence polarization spectroscopy. Several mutations that result in marked decreases in affinity exerted little or no significant effect on the association volume. Mutation at any of several key aromatic residues of the 26-10 Fab heavy chain led to a decrease in the pressure-induced association, and two mutants with Trp-->Arg mutations at heavy chain residue 100 exhibited pressure-induced dissociation. The effect of charged groups was found to depend on their proximity to contacting aromatic groups. The ability to understand and control the pressure sensitivity of antigen-antibody complexes has numerous potential applications in immunoseparations and immunosensors.

Amino Acids↗

PubMed2000

Dynamics of tissue neutrophil sequestration after cutaneous burns in rats.

BACKGROUND: Neutrophil recruitment in organs after burns may cause local vascular damage, which can be reduced by agents blocking neutrophil adhesion to the vascular wall. Because these agents may increase susceptibility to infection, it is important to characterize the dynamics of neutrophil sequestration in order to optimize an eventual anti-adhesion therapy. MATERIALS AND METHODS: Rats were scald burned over 20 or 40% of their total body surface area (TBSA) and saline resuscitated. Sham controls were used. Myeloperoxidase (MPO) activity was measured in lungs, liver, kidney, gut, and burned skin up to 1 week postburn. Extravascular accumulation of (125)I-labeled bovine serum albumin ((125)I-BSA) was measured at 12 h postburn. RESULTS: MPO activity in lungs, liver, and kidney was increased within 3 h postburn and returned to normal within 24-48 h. Peak MPO levels occurred at 6-12 h postburn and were similar for both burn sizes. No MPO increase was observed in gut. MPO levels in burned skin did not increase before 6 h, peaked at 24 h, decreased at 48 h, but remained elevated for up to 7 days. Neutrophil recruitment in lungs and liver was confirmed histochemically. No neutrophils were found in kidneys. Extravascular (125)I-BSA was increased in lungs, liver, kidneys, and gut, in the 40% TBSA group only. CONCLUSIONS: Neutrophil sequestration in remote organs is a transient phenomenon while neutrophil homing into the wound site is sustained. Neutrophil accumulation dynamics are independent of burn size, although a minimum size is required to trigger vascular damage. Temporary early anti-adhesion therapy to reduce lung and liver neutrophil sequestration with little impact on neutrophil homing into the burn wound may be possible.

Animals↗

PubMed2000

Optimization of rat hepatocyte culture in citrated human plasma.

BACKGROUND: Maintenance of liver-specific functions in hepatocyte cultures during plasma exposure is critical for the clinical application of bioartificial liver assist systems. Sodium citrate is a common anticoagulant but has been shown to be cytotoxic to hepatocytes. We have tested the effect of various supplements on the viability and function of adult primary rat hepatocytes exposed to citrated plasma. MATERIALS AND METHODS: Freshly isolated rat hepatocytes were cultured in the collagen gel sandwich configuration in culture medium for 6 days followed by exposure to citrated human plasma with various supplements for 1 week. Controls were left in culture medium throughout. Viability and synthetic functions were evaluated. RESULTS: Hepatocytes exposed to unsupplemented citrated plasma lost significant viability and function within the first 2 days. Cells cultured in plasma supplemented with a fivefold concentrate of standard hepatocyte culture medium maintained urea (1. 2-2.1 micromol/day/10(6) cells) and albumin (51-62 microg/day/10(6) cells) synthesis rates equal to or higher than those of controls. Among the various components of the concentrated medium supplement, calcium chloride (1.8 mM), magnesium sulfate (0.8 mM), amino acids (fourfold Basal Medium Eagle amino acids including 4 mM glutamine), and glucagon (14 ng/ml) were found to be essential in maintaining urea synthesis. Maintenance of a high albumin synthesis rate also required the addition of hydrocortisone (7.5 microg/ml) and insulin (0.5 U/ml). CONCLUSIONS: Appropriate metabolic and hormonal supplementation of citrated human plasma prevents its cytotoxic effects and may be used in conjunction with in vivo use of bioartificial liver assist systems.

Albumins↗

PubMed2000

Dynamics of gene expression in rat hepatocytes under stress.

The response of cells to physical or biochemical stress involves concerted changes in the expression of a large number of genes encoding various functions. We have used a quantitative kinetic RT-PCR technique to follow the dynamics of changes in transcription factor and acute-phase mRNA levels in cultured rat hepatocytes subjected to either elevated temperature (40 degrees C) or exposure to the inflammatory cytokine interleukin-6. The profiles of transcription factor gene expression displayed rapid and coordinate regulation, attainment of new steady-states, transitions in some instances from up-regulation to down-regulation (or vice versa), and, for elevated temperature, multiple spikes of up-regulation. Transcripts of acute-phase genes generally displayed relatively small changes during the first few hours followed by more significant changes over the course of tens of hours (elevated temperature) to days (IL-6 exposure). These observations are all consistent with the notion of genetic reprogramming due to a network of interacting transcription factor proteins and transcripts. We utilized a simple transcription/translation model incorporating autoregulation to describe the dynamics of transcription factor gene expression. This model successfully described key features of the transcription factor dynamics, most notably the multiple spikes observed after exposure to elevated temperature. The dynamics of gene expression are rich in information that, with considerably more study, may eventually be exploited to provide insights into the interplay of genetic networks in regulating a variety of cellular responses.

Acute-Phase Reaction↗