The effects of 3 months of spaceflight (SF), hindlimb suspension, or exposure to 2G on the characteristics of neck muscle in mice were studied. Three 8-week-old male C57BL/10J wild-type mice were exposed to microgravity on the International Space Station in mouse drawer system (MDS) project, although only one mouse returned to the Earth alive. Housing of mice in a small MDS cage (11.6 × 9.8-cm and 8.4-cm height) and/or in a regular vivarium cage was also performed as the ground controls. Furthermore, ground-based hindlimb suspension and 2G exposure by using animal centrifuge (n = 5 each group) were performed. SF-related shift of fiber phenotype from type I to II and atrophy of type I fibers were noted. Shift of fiber phenotype was related to downregulation of mitochondrial proteins and upregulation of glycolytic proteins, suggesting a shift from oxidative to glycolytic metabolism. The responses of proteins related to calcium handling, myofibrillar structure, and heat stress were also closely related to the shift of muscular properties toward fast-twitch type. Surprisingly, responses of proteins to 2G exposure and hindlimb suspension were similar to SF, although the shift of fiber types and atrophy were not statistically significant. These phenomena may be related to the behavior of mice that the relaxed posture without lifting their head up was maintained after about 2 weeks. It was suggested that inhibition of normal muscular activities associated with gravitational unloading causes significant changes in the protein expression related to metabolic and/or morphological properties in mouse neck muscle.
5AMP-activated protein kinase (AMPK) plays an important role as a negative regulator of skeletal muscle mass. However, the precise mechanism of AMPK-mediated regulation of muscle mass is not fully clarified. Heat shock proteins (HSPs), stress-induced molecular chaperones, are related with skeletal muscle adaptation, but the association between AMPK and HSPs in skeletal muscle hypertrophy is unknown. Thus, it was investigated whether AMPK regulates hypertrophy by mediating HSPs in C2C12 cells. The treatment with 5-aminoimidazole-4-carboxamide-1-?-D-ribonucleoside (AICAR), a potent stimulator of AMPK, decreased 72 kDa HSP (HSP72) expression. Whereas there were no changes in the expressions of 25 kDa HSP, 70 kDa heat shock cognate, and heat shock transcription factor 1 in myotubes. Protein content and diameter were less in the AICAR-treated myotubes compared to those without treatment. AICAR-induced suppression of myotube hypertrophy and HSP72 expression were attenuated in the siRNA-mediated AMPK?-knockdown myotubes. AICAR increased microRNA (miR)-1, a modulator of HSP72. And the increase of miR-1 was not induced in AMPK?-knockdown condition. Furthermore, siRNA-mediated HSP72-knockdown blocked AICAR-induced inhibition of myotube hypertrophy. AICAR up-regulated the gene expression of muscle Ring-finger 1 and this alteration was suppressed in either AMPK?- or HSP72-knockdown myotubes. The phosphorylation of p70 S6 kinase Thr(389) was down-regulated by AICAR, while this was attenuated in AMPK?-, but not HSP72-, knockdown myotubes. These results suggest that AMPK inhibits hypertrophy through, in part, a HSP72-associated mechanism via miR-1 and protein degradation pathways in skeletal muscle cells.
The purpose of this study was to investigate a role of heat shock transcription factor 1 (HSF1)-mediated stress response during regeneration of injured soleus muscle by using HSF1-null mice. Cardiotoxin (CTX) was injected into the left muscle of male HSF1-null and wild-type mice under anesthesia with intraperitoneal injection of pentobarbital sodium. Injection of physiological saline was also performed into the right muscle. Soleus muscles were dissected bilaterally 2 and 4 weeks after the injection. The relative weight and fiber cross-sectional area in CTX-injected muscles of HSF1-null, not of wild-type, mice were less than controls with injection of physiological saline 4 weeks after the injury, indicating a slower regeneration. Injury-related increase of Pax7-positive muscle satellite cells in HSF1-null mice was inhibited versus wild-type mice. HSF1-deficiency generally caused decreases in the basal expression levels of heat shock proteins (HSPs). But the mRNA expression levels of HSP25 and HSP90? in HSF1-null mice were enhanced in response to CTX-injection, compared with wild-type mice. Significant up-regulations of proinflammatory cytokines, such as interleukin (IL) -6, IL-1?, and tumor necrosis factor mRNAs, with greater magnitude than in wild-type mice were observed in HSF1-deficient mouse muscle. HSF1 and/or HSF1-mediated stress response may play a key role in the regenerating process of injured skeletal muscle. HSF1 deficiency may depress the regenerating process of injured skeletal muscle via the partial depression of increase in Pax7-positive satellite cells. HSF1-deficiency-associated partial depression of skeletal muscle regeneration might also be attributed to up-regulation of proinflammatory cytokines.
The purpose of this study was to investigate the expression level of adiponectin and its related molecules in hypertrophied and atrophied skeletal muscle in mice. The expression was also evaluated in C2C12 myoblasts and myotubes. Both mRNA and protein expression of adiponectin, mRNA expression of adiponectin receptor (AdipoR) 1 and AdipoR2, and protein expression of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif 1 (APPL1) were observed in C2C12 myoblasts. The expression levels of these molecules in myotubes were higher than those in myoblasts. The expression of adiponectin-related molecules in soleus muscle was observed at mRNA (adiponectin, AdipoR1, AdipoR2) and protein (adiponectin, APPL1) levels. The protein expression levels of adiponectin and APPL1 were up-regulated by 3 weeks of functional overloading. Down-regulation of AdipoR1 mRNA, but not AdipoR2 mRNA, was observed in atrophied soleus muscle. The expression of adiponectin protein, AdipoR1 mRNA, and APPL1 protein was up-regulated during regrowth of unloading-associated atrophied soleus muscle. Mechanical loading, which could increase skeletal muscle mass, might be a useful stimulus for the up-regulations of adiponectin and its related molecules in skeletal muscle.
Hypertrophic stimuli, such as mechanical stress and overloading, induce stress response, which is mediated by heat shock transcription factor 1 (HSF1), and up-regulate heat shock proteins (HSPs) in mammalian skeletal muscles. Therefore, HSF1-associated stress response may play a key role in loading-associated skeletal muscle hypertrophy. The purpose of this study was to investigate the effects of HSF1-deficiency on skeletal muscle hypertrophy caused by overloading. Functional overloading on the left soleus was performed by cutting the distal tendons of gastrocnemius and plantaris muscles for 4 weeks. The right muscle served as the control. Soleus muscles from both hindlimbs were dissected 2 and 4 weeks after the operation. Hypertrophy of soleus muscle in HSF1-null mice was partially inhibited, compared with that in wild-type (C57BL/6J) mice. Absence of HSF1 partially attenuated the increase of muscle wet weight and fiber cross-sectional area of overloaded soleus muscle. Population of Pax7-positive muscle satellite cells in HSF1-null mice was significantly less than that in wild-type mice following 2 weeks of overloading (p<0.05). Significant up-regulations of interleukin (IL)-1? and tumor necrosis factor mRNAs were observed in HSF1-null, but not in wild-type, mice following 2 weeks of overloading. Overloading-related increases of IL-6 and AFT3 mRNA expressions seen after 2 weeks of overloading tended to decrease after 4 weeks in both types of mice. In HSF1-null mice, however, the significant overloading-related increase in the expression of IL-6, not ATF3, mRNA was noted even at 4th week. Inhibition of muscle hypertrophy might be attributed to the greater and prolonged enhancement of IL-6 expression. HSF1 and/or HSF1-mediated stress response may, in part, play a key role in loading-induced skeletal muscle hypertrophy.
Microcurrent electrical nerve stimulation (MENS) has been used to facilitate recovery from skeletal muscle injury. However, the effects of MENS on unloading-associated atrophied skeletal muscle remain unclear. Effects of MENS on the regrowing process of unloading-associated atrophied skeletal muscle were investigated. Male C57BL/6J mice (10-week old) were randomly assigned to untreated normal recovery (C) and MENS-treated (M) groups. Mice of both groups are subjected to continuous hindlimb suspension (HS) for 2 weeks followed by 7 days of ambulation recovery. Mice in M group were treated with MENS for 60 min 1, 3, and 5 days following HS, respectively, under anesthesia. The intensity, the frequency, and the pulse width of MENS were set at 10 ?A, 0.3 Hz, and 250 msec, respectively. Soleus muscles were dissected before and immediately after, 1, 3 and 7 days after HS. Soleus muscle wet weight and protein content were decreased by HS. The regrowth of atrophied soleus muscle in M group was faster than that in C group. Decrease in the reloading-induced necrosis of atrophied soleus was facilitated by MENS. Significant increases in phosphorylated levels of p70 S6 kinase and protein kinase B (Akt) in M group were observed, compared with C group. These observations are consistent with that MENS facilitated regrowth of atrophied soleus muscle. MENS may be a potential extracellular stimulus to activate the intracellular signals involved in protein synthesis.
Effects of heat shock transcription factor 1 (HSF1) gene on the regrowth of atrophied mouse soleus muscles were studied. Both HSF1-null and wild-type mice were subjected to continuous hindlimb suspension for 2 wk followed by 4 wk of ambulation recovery. There was no difference in the magnitude of suspension-related decrease of muscle weight, protein content, and the cross-sectional area of muscle fibers between both types of mice. However, the regrowth of atrophied soleus muscle in HSF1-null mice was slower compared with that in wild-type mice. Lower baseline expression level of HSP25, HSC70, and HSP72 were noted in soleus muscle of HSF1-null mice. Unloading-associated downregulation and reloading-associated upregulation of HSP25 and HSP72 mRNA were observed not only in wild-type mice but also in HSF1-null mice. Reloading-associated upregulation of HSP72 and HSP25 during the regrowth of atrophied muscle was observed in wild-type mice. Minor and delayed upregulation of HSP72 at mRNA and protein levels was also seen in HSF1-null mice. Significant upregulations of HSF2 and HSF4 were observed immediately after the suspension in HSF1-null mice, but not in wild-type mice. Therefore, HSP72 expression in soleus muscle might be regulated by the posttranscriptional level, but not by the stress response. Evidence from this study suggested that the upregulation of HSPs induced by HSF1-associated stress response might play, in part, important roles in the mechanical loading (stress)-associated regrowth of skeletal muscle.
Skeletal muscle metabolism is a major determinant of resting energy expenditure (REE). Although the severe muscle loss that characterizes Duchenne muscular dystrophy (DMD) may alter REE, this has not been extensively investigated.
Heat stress is one of the hypertrophic stimuli on mammalian skeletal muscle. Nuclear factor-?B (NF-?B) signaling plays an important role in the regulation of skeletal muscle mass. However, the effects of heat stress on NF-?B signaling in skeletal muscle cells remain unclear. Effects of heat stress and/or administration of BAY11-7082, an inhibitor of NF-?B, on NF-?B signals and protein content of skeletal muscle were studied by using cell culture system. Differentiated mouse myoblasts (C2C12) were subjected to either (1) control (cultured at 37°C without BAY11-7082), (2) heat stress at 41°C for 60 min, (3) BAY11-7082 administration (1.25 ?M) or (4) heat stress combined with BAY11-7082 administration. Heat shock protein 72 (HSP72) was upregulated by heat stress with or without administration of BAY11-7082. The increase in inhibitor of ?B? (I?B?), which regulates the phosphorylation of NF-?B, and the decrease in phosphorylated NF-?B were also induced by administration of BAY11-7082 and/or heat stress. Protein content in C2C12 cells was increased by the administration of BAY11-7082 with a semi-logarithm fashion. Significant increases in the protein content of C2C12 cells were observed 48 h following heating with or without administration of BAY11-7082. These observations suggest that heat stress might increase muscle protein through the downregulation of NF-?B signaling. Inhibition of NF-?B induced by application of heat stress might be one of the hypertrophic stimuli on skeletal muscle cells.
Effects of heat stress on phosphorylated nuclear factor-kappaB (phospho-NF-kappaB) and tumor necrosis factor alpha (TNFalpha) contents in skeletal muscles were studied. Male Wistar rats (7-week-old) were randomly assigned to control and heat-stressed groups. Rats in heat-stressed group were exposed to heat stress (42 degrees C for 60 min) in an incubator without anesthesia. Soleus muscles were dissected and weighted 1, 3, and 7 days after the heat exposure. Significant increases in the wet weight and protein content of soleus were observed 7 days following the exposure (p < 0.05). Heat stress also induced the up-regulation of heat shock protein 72 (HSP72), IkappaBalpha (inhibitor of NF-kappaB) and the increase in the relative population of Pax7-positive satellite cells to total muscle nuclei before the increase in muscle mass. The content levels of phospho-NF-kappaB and TNFalpha were significantly decreased 1 and 3 days after heat stress, respectively (p < 0.05). A negative correlation between HSP72 and phospho-NF-kappaB contents was observed 1 day after the heat exposure. These observations suggest that the decrease in NF-kappaB signaling may play a part of a role in heat stress-associated muscle hypertrophy.
The present study was performed to investigate the effects of long-term heat stress on mass, strength and gene expression profile of human skeletal muscles without exercise training. Eight healthy men were subjected to 10-week application of heat stress, which was performed for the quadriceps muscles for 8 h/day and 4 days/week by using a heat- and steam-generating sheet. Maximum isometric force during knee extension of the heated leg significantly increased after heat stress (~5.8%, P < 0.05). Mean cross-sectional areas (CSAs) of vastus lateralis (VL, ~2.7%) and rectus femoris (~6.1%) muscles, as well as fiber CSA (8.3%) in VL, in the heated leg were also significantly increased (P < 0.05). Statistical analysis of microarrays (SAM) revealed that 10 weeks of heat stress increased the transcript level of 925 genes and decreased that of 1,300 genes, and gene function clustering analysis (Database for Annotation, Visualization and Integrated Discovery: DAVID) showed that these regulated transcripts stemmed from diverse functional categories. Transcript level of ubiquinol-cytochrome c reductase binding protein (UQCRB) was significantly increased by 10 weeks of heat stress (~3.0 folds). UQCRB is classified as one of the oxidative phosphorylation-associated genes, suggesting that heat stress can stimulate ATP synthesis. These results suggested that long-term application of heat stress could be effective in increasing the muscle strength associated with hypertrophy without exercise training.
A 50-year-old woman, who had consanguineous parents, developed gait disturbance at age 3, and revealed nystagmus, cerebellar ataxia, peripheral neuropathy, and spastic tetraparesis. She admitted to our hospital at age 14, and the symptoms progressed very slowly. MRI of this case at age 45 showed a remarkable, diffuse hypomyelination of the cerebrum. Her older sister who already deceased at age 16 showed neurological symptoms similar to this case. The patient was found to have no proteolipid protein-1 gene duplications and deletions and base substitution. Her symptoms were considered to be different from those of typical HLD2, 3, 4 and 5. She carried no GJA12 mutations. These facts suggested that this disease is a novel, autosomal recessive hypomyelinating leukodystrophy.
Effects of gravitational loading or unloading on the gain of the characteristics in soleus muscle fibers were studied in rats. The tail suspension was performed in newborn rats from postnatal day 4 to month 3, and the reloading was allowed for 3 mo in some rats. Single expression of type I myosin heavy chain (MHC) was observed in approximately 82% of fibers in 3-mo-old controls, but the fibers expressing multiple MHC isoforms were noted in the unloaded rats. Although 97% of fibers in 3-mo-old controls had a single neuromuscular junction at the central region of fiber, fibers with multiple nerve endplates were seen in the unloaded group. Faster contraction speed and lower maximal tension development, even after normalization with fiber size, were observed in the unloaded pure type I MHC fibers. These parameters generally returned to the age-matched control levels after reloading. It was suggested that antigravity-related tonic activity plays an important role in the gain of single neural innervation and of slow contractile properties and phenotype in soleus muscle fibers.
Effects of administration of granulocyte colony-stimulating factor (G-CSF) on the regeneration of injured mammalian skeletal muscles were studied in male C57BL/6J mice. Muscle injury was induced by injection of cardiotoxin (CTX) into tibialis anterior muscles bilaterally. G-CSF was administrated for 8 consecutive days from 3 days before and 5 days after the injection. Significant decreases of wet weight and protein content were noted in the necrotic muscle with CTX injection. A large number of the regenerating fibers having central nucleus were observed 7 days after the injection. The regeneration of injured muscle was further facilitated by the G-CSF treatment. Population of Pax7-positive nuclei was increased by the G-CSF treatment at day 7. Phospho-Akt and phospho-glycogen synthase kinase 3alphabeta (GSK3alphabeta) signals were also activated by G-CSF-administrated group during the regenerative process. It was suggested that G-CSF treatment may facilitate the regeneration of injured skeletal muscles via the activation of Akt/GSK3alphabeta signals.
This study investigated the effects of voluntary wheel running on satellite cells in the rat plantaris muscle. Seventeen 5-week-old male Wistar rats were assigned to a control (n = 5) or training (n = 12) group. Each rat in the training group ran voluntarily in a running-wheel cage for 8 weeks. After the training period, the animals were anesthetized, and the plantaris muscles were removed, weighed, and analyzed immunohistochemically and biochemically. Although there were no significant differences in muscle weight or fiber area between the groups, the numbers of satellite cells and myonuclei per muscle fiber, percentage of satellite cells, and citrate synthase activity were significantly higher in the training group compared with the control group (p < 0.05). The percentage of satellite cells was also positively correlated with distance run in the training group (r = 0.61, p < 0.05). Voluntary running can induce an increase in the number of satellite cells without changing the mean fiber area in the rat plantaris muscle; this increase in satellite cell content is a function of distance run. Key pointsThere is no study about the effect of voluntary running on satellite cells in the rat plantaris muscle.Voluntary running training causes an increase of citrate synthase activity in the rat plantaris muscle but does not affect muscle weight and mean fiber area in the rat plantaris muscle.Voluntary running can induce an increase in the number of satellite cells without hypertrophy of the rat plantaris muscle.
Effects of 3-month exposure to microgravity environment on the expression of genes and proteins in mouse brain were studied. Moreover, responses of neurobiological parameters, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), were also evaluated in the cerebellum, hippocampus, cortex, and adrenal glands. Spaceflight-related changes in gene and protein expression were observed. Biological processes of the up-regulated genes were related to the immune response, metabolic process, and/or inflammatory response. Changes of cellular components involving in microsome and vesicular fraction were also noted. Molecular function categories were related to various enzyme activities. The biological processes in the down-regulated genes were related to various metabolic and catabolic processes. Cellular components were related to cytoplasm and mitochondrion. The down-regulated molecular functions were related to catalytic and oxidoreductase activities. Up-regulation of 28 proteins was seen following spaceflight vs. those in ground control. These proteins were related to mitochondrial metabolism, synthesis and hydrolysis of ATP, calcium/calmodulin metabolism, nervous system, and transport of proteins and/or amino acids. Down-regulated proteins were related to mitochondrial metabolism. Expression of NGF in hippocampus, cortex, and adrenal gland of wild type animal tended to decrease following spaceflight. As for pleiotrophin transgenic mice, spaceflight-related reduction of NGF occurred only in adrenal gland. Consistent trends between various portions of brain and adrenal gland were not observed in the responses of BDNF to spaceflight. Although exposure to real microgravity influenced the expression of a number of genes and proteins in the brain that have been shown to be involved in a wide spectrum of biological function, it is still unclear how the functional properties of brain were influenced by 3-month exposure to microgravity.
Effects of heat stress on skeletal muscle mass in young and aged mice were investigated. Young (7-week) and aged (106-week) male C57BL/6J mice were randomly assigned to control and heat-stressed groups in each age. Mice in heat-stressed group were exposed to heat stress (41 °C for 60 min) in an incubator without anesthesia. Seven days after the exposure, soleus muscles were dissected from both hindlimbs. Protein content and the relative composition of Type II fibers in aged soleus were lower than those in young muscle. In aged soleus, higher baseline expression levels of HSP25, HSP72, and cathepsin L were observed compared with those in young muscle (p < 0.05). However, there were no significant differences in the expression levels of phosphorylated p70 S6 kinase (p-p70S6K), calpain 1, and calpain 2 of soleus between two age groups. A significant increase in muscle mass of both age groups was induced by heat stress (p < 0.05). Heat stress also upregulated the expressions of HSP25, HSP72, and p-p70S6K in both ages (p < 0.05). On the other hand, a significant decrease in cathepsin L expression by heating was observed in aged soleus, but not in young (p < 0.05). Both the percentage of Type I fibers and the expression of calpains in both age groups were unchanged following heat stress. Heat stress-associated downregulation of cathepsin L may be attributed to the upregulation of HSP72, which stabilizes lysosomal membranes (p < 0.05). Upregulations of HSP25, HSP72, and p-p70S6K and/or the downregulation of cathepsin L may play a role in heat stress-associated muscle hypertrophy in aged soleus muscle.
A 79-year-old female had a spinal lesion that was definitely diagnosed as intravascular large B-cell lymphoma on the basis of skin biopsy findings, and she was treated by rituximab-containing chemotherapy. The spinal lesion showed high and low signal intensities on T? weighted magnetic resonance imaging (MRI) scans, those low signal intensity lesions were suspected to be hemorrhages. The hemorrhages were thought to have been caused by interaction between atypical lymphoma cells and the endothelial cells of spinal blood vessels, by hemorrhagic infarction or by rupture of the capillary endothelium due to interaction between rituximab and lymphoma cells. Intravascular large B-cell lymphoma cases rarely show low signal intensity on spinal T? weighted MRI scans.
Hormonal changes in humans during spaceflight have been demonstrated but the underlying mechanisms are still unknown. To clarify this point thyroid and testis/epididymis, both regulated by anterior pituitary gland, have been analyzed on long-term space-exposed male C57BL/10 mice, either wild type or pleiotrophin transgenic, overexpressing osteoblast stimulating factor-1. Glands were submitted to morphological and functional analysis.In thyroids, volumetric ratios between thyrocytes and colloid were measured. cAMP production in 10(-7)M and 10(-8)M thyrotropin-treated samples was studied. Thyrotropin receptor and caveolin-1 were quantitized by immunoblotting and localized by immunofluorescence. In space-exposed animals, both basal and thyrotropin-stimulated cAMP production were always higher. Also, the structure of thyroid follicles appeared more organized, while thyrotropin receptor and caveolin-1 were overexpressed. Unlike the control samples, in the space samples thyrotropin receptor and caveolin-1 were both observed at the intracellular junctions, suggesting their interaction in specific cell membrane microdomains.In testes, immunofluorescent reaction for 3?- steroid dehydrogenase was performed and the relative expressions of hormone receptors and interleukin-1? were quantified by RT-PCR. Epididymal sperm number was counted. In space-exposed animals, the presence of 3? and 17? steroid dehydrogenase was reduced. Also, the expression of androgen and follicle stimulating hormone receptors increased while lutenizing hormone receptor levels were not affected. The interleukin 1 ? expression was upregulated. The tubular architecture was altered and the sperm cell number was significantly reduced in spaceflight mouse epididymis (approx. -90% vs. laboratory and ground controls), indicating that the space environment may lead to degenerative changes in seminiferous tubules.Space-induced changes of structure and function of thyroid and testis/epididymis could be responsible for variations of hormone levels in human during space missions. More research, hopefully a reflight of MDS, would be needed to establish whether the space environment acts directly on the peripheral glands or induces changes in the hypotalamus-pituitary-glandular axis.
The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5-20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca(2+)-activated K(+) channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures.
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