Significant Strain Variation Research Articles

Ligand Tail Controls the Conformation of Indium Sulfide Ultrathin Nanoribbons.

We report the conformational control of 2D ultrathin indium sulfide nanoribbons by tuning their amine ligands' alkyl chain. The initial orthorhombic InS nanoribbons bare n-octylamine ligands and display a highly curved geometry with a characteristic figure of eight shapes. Exchanging the native ligand by oleylamine induces their complete unfolding to yield flat board-shaped nanoribbons. Significant strain variations in the InS crystal structure accompany this shape-shifting. By tuning the linear alkyl chain length from 4 to 18 carbon atoms, we show using small-angle X-ray scattering in solution and transmission electron microscopy that the curvature of the nanoribbon subtly depends on the ligand-ligand interactions at the nanoribbon's surface. The curvature decreases gradually as the chain length increases, while carbon unsaturation has an unexpectedly significant effect at constant chain length. These experiments shed light on the critical role of the ligand monolayer on the curvature of ultrathin 2D crystalline nanosheets and demonstrate that weak supramolecular forces within the organic part of colloidal nanocrystals can dramatically impact their shape. This transduction mechanism, in which changes in the organic monolayer impact the shape of a nanocrystal, will help to devise new strategies to design stimuli-responsive systems that take advantage of both the flexibility of organic moieties and the physical properties of the inorganic core.

Incorporating genetic diversity to improve alignment of mouse models to human Alzheimer’s disease

Previous work by our labs, and others, reveal the benefits of incorporating diverse mouse strains to better model human Alzheimer's disease (AD). For instance, mouse models of AD on genetically distinct wild-derived mouse strains demonstrated robust differences in immune response to amyloid and neurodegeneration, better representing the phenotypic spectrum of AD than previous models. To further investigate the importance of genetic diversity, as part of MODEL-AD, we generated AD-relevant mouse models on Collaborative Cross (CC) lines background, a recombinant inbred mouse panel created from eight highly diverse founder strains.C57BL/6J (B6J) mice homozygous for humanized APOE4 allele and carrying mutant APP and PS1 alleles (APPswe , PS1de9 ) were crossed to five CC strains that were selected based on variation in AD-relevant genes. Cohorts of male and female B6JCCnF1.APOE4.APP/PS1 mice and controls were aged to 8 months (a mid-point for amyloid deposition in B6.APP/PS1 mice) and brain hemispheres processed for RNA-Seq and neuropathological assessment. Expectation Maximization for Allele Specific Expression (EMASE) tool was used to quantify transcriptome-wide expression at allelic level. Differential expression and KEGG pathway enrichment analysis were performed to determine altered molecular processes in CC strains. Strain specific transcriptional signatures were mapped to co-expression gene modules of human Late-Onset AD (LOAD) from the AMP-AD consortium. Neuropathological assessment included characterization of plaque deposition, Tau pathology, glial activation, neurodegeneration and cerebrovascular health.RNA-Seq analysis revealed up-regulation of neuroinflammation related pathways (lysosome, complement and coagulation cascades) in all CC strains as an effect of mutant APP and PS1 transgenes in presence of APOE4 allele. On the other hand, we observed significant CC strain and sex specific variation in immune (Fc gamma R-mediated phagocytosis) and metabolic (glycosphingolipid biosynthesis) response to amyloid pathogenesis. Alignment with human LOAD signatures revealed high strain and sex specific variation in correlation with synaptic signaling, cell cycle and DNA repair related gene modules. Overall, novel AD mouse models that incorporated CC lines demonstrated increased alignment to human AD-like transcriptomic signatures compared to B6J.This work builds on previous work highlighting the strengths of including multiple diverse mouse strains to better model complex neurodegenerative disorders such as AD and related dementias.

Method for the biomechanical analysis of aqueous veins and perilimbal sclera by three-dimensional photoacoustic imaging and strain field calculation

A method motivated by the eye’s aqueous veins is described for the imaging and strain calculation within soft biological tissues. A challenge to the investigation of the biomechanics of the aqueous vein—perilimbal sclera tissue complex is resolution of tissue deformations as a function of intraocular pressure and the subsequent calculation of strain (a normalized measure of deformation). The method involves perfusion of the eye with a contrast agent during conduction of non-invasive, optical resolution photoacoustic microscopy. This imaging technique permits three-dimensional displacement measurements of tracked points on the inner walls of the veins which are used in a finite element model to determine the corresponding strains. The methods are validated against two standard strain measurement methods. Representative porcine globe perfusion experiments are presented that demonstrate the power of the method to determine complex strain fields in the veins dependent on intraocular pressure as well as vein anatomy. In these cases, veins are observed to move radially outward during increases in intraocular pressure and to possess significant spatial strain variation, possibly influenced by their branching patterns. To the authors’ knowledge, these are the only such quantitative, data driven, calculations of the aqueous vein strains available in the open literature.

Micromechanical modeling of the interfacial zone in hot mix asphalt through use of a heterogeneous numerical method

This work focuses on the use of a heterogeneous generation method in order to develop a micromechanical model of Hot Mix Asphalt (HMA) that takes into account the effects of characteristics at the interfacial zone (IZ), where aggregate surfaces come into contact with the mortar matrix. Numerical calculations are conducted to investigate the effect of IZ mechanical characteristics on both the overall viscoelastic response of HMA and the local scale behavior. First of all, the HMA is treated as a biphasic material composed of mortar and granular inclusions. Next, a third phase is added between these two at each point of aggregate/mortar contact. Elastic and viscoelastic behaviors are assigned to the aggregates and mortar, respectively. The mechanical behavior of IZ varies between that of the inclusions and the matrix. At the global scale, these numerical results demonstrate that the use of triphasic micromechanical models improves the predictive accuracy of the dynamic modulus. At the local scale, a significant strain variation was found in each model. These results justify our triphasic modeling approach whenever local zone characteristics are the subject of interest.

Development of Lateral Prestress in High-Strength Concrete-Filled FRP Tubes

This paper reports on an experimental investigation into the axial and lateral strain development of fiber reinforced polymer (FRP) confined high-strength concrete (HSC) with prestressed FRP shells. A total of 24 aramid FRP (AFRP)-confined concrete specimens were manufactured as concrete-filled FRP tubes (CFFTs) with instrumentation to measure the strain variations during application of prestress, removal of end constraints and progressive prestress losses. Prestressed CFFT specimens were prepared with three different dose rates of expansive mineral admixture to create a range of lateral prestress applied to AFRP tubes manufactured with sheet thicknesses of 0.2 or 0.3 mm/ply and referred to as lightly- or well-confined, respectively. In addition to these three levels of prestress, non-prestressed companion specimens were manufactured and tested to determine baseline performance. The experimental results from this study indicate that lateral prestressing of CFFTs manufactured with HSC can be achieved by varying the expansive mineral admixture dose rate with a lateral prestress of up to 7.3 MPa recorded in this study. Significant strain variations were measured during removal of the end constraints with up to 700 microstrain recorded in the axial direction. Finally, the measurement of prestress losses for the month following prestress application revealed minimal progressive losses, with only 250 and 100 με recorded for the axial and hoop strains, respectively.

Comparison of Antibacterial Activity of Nigella sativa Oil Against Clinical Isolates Using a Controlled Disc Diffusion Method

Objective: To compare the antibacterial potency of cold press Nigella sativa oil against 49 clinical isolates. Method: A controlled disc diffusion method based on British Society of Antimicrobial Chemotherapy antibiotic susceptibility testing guidelines was used. Results: Reproducible results were obtained that allowed comparison of intra species sensitivity. Staphylococcus aureus isolates (18) from skin and soft tissue infections were highly susceptible (31 to 51mm zones of inhibition, ZOI), with significant differences (p<0.01) in sensitivity between many of the isolates, but no significant difference (p >0.05) between methicillin- sensitive and -resistant isolates. Streptococcus spp. isolates (6) from skin and soft tissue infections produced consistently lower mean ZOI (22 to 27mm). Haemophilus infuenzae isolates (4) from respiratory tract infections showed little variation in ZOI (22 to 23mm). Conversely, two respiratory tract Streptococcus pneumoniae isolates showed markedly different sensitivity (p<0.01) to the oil (24 and 40mm). For the first time, antibacterial activity of N. sativa oil against Neisseria gonorrhoeae is reported (29 to 38mm). All Gram-negative isolates (14) - Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Klebsiella pneumoniae and Pseudomonas aeruginosa - were uninhibited by the oil, while ZOI for Grampositive isolates exceeded those obtained for first line antibiotics used to treat the relevant infections. There was no evident link between isolate antibiotic resistance profile and extent of growth inhibition by the oil. Conclusion: N. sativa oil has a potential for combatting antibiotic resistant Gram-positive infections at various body sites, including sexually transmitted disease. Significant strain variation in sensitivity to the oil within some species is revealed. Keywords: Nigella sativa, antibacterial, disc diffusion, clinical isolates, Staphylococcus aureus, Neisseria gonorrhoeae, BSAC.

First Report of a Potyvirus Infecting Albuca rautanenii in the Namib Desert.

Chlorotic, streak-like symptoms were observed in April 2013 on a single specimen of Albuca rautanenii (Schinz) J.C.Manning & Goldblatt (Family: Hyacinthaceae) found among other plants near Homeb in the Namib Desert, Namibia. No potential insect vectors (e.g., aphids) were observed on or around the infected plant. An extract from symptomatic leaves was assessed by transmission electron microscopy (leaf dip method) to ascertain if the symptoms were viral in origin. Long, flexuous threadlike particles 687 to 825 nm in length and 12.5 nm in diameter were observed. The morphology and size of the particles were indicative of a putative member of the taxonomic family Potyviridae. To confirm this, RT-PCR using universal potyvirus primers which amplify part of the nuclear inclusion b gene (NIb) was conducted (1) on total RNA extracted from leaf tissue (Qiagen RNeasy Plant Mini Kit). The triplicated reaction yielded amplicons of the expected size (~350 bp), which were cloned into the pJET 1.2 vector (Thermo Scientific, Waltham, MA) according to manufacturer's instructions. The sequences of 10 clones were trimmed to remove vector and primer ends and were deposited in the EBI database under the accession numbers LK995422 to LK995431. Curated sequences were used to search the GenBank database using BLASTn and tBLASTx, as well as for phylogenetic analysis. Intra-clonal nucleotide sequence similarity ranged from 97.99 to 99.72%. BLASTn searches showed all clones were 72% identical to Papaya ringspot virus isolate 1 accession JQ314105.1 (87% coverage), followed by Bean yellow mosaic virus clone Brn167 accession JF707769.1 (72% identity with 86% sequence coverage). The translated peptide fragment was most similar to Sugarcane mosaic virus isolate Beijing (AY042184.1), with a query cover of 98% and a similarity of 81%. Phylogenetic analysis was performed with a set of 57 reference potyvirus genomes, with their NIb regions aligned with the cloned nucleotide sequences according to the parameters used previously (1). The clones formed a distinct cluster, at a node with Cocksfoot streak virus (CSV) (NC_003742.1). An identity matrix of the aligned NIb clones and CSV showed a nucleotide identity range of 68.79 to 70.23%. These results suggest that the virus isolate belongs to the family Potyviridae, genus Potyvirus, supported by the characteristic morphological features of the virion and its relatedness to CSV. Moreover, the clustering of all sequences at a single node suggests a homogeneous viral population, without significant strain variation. Genetic distance inferred by phylogenetic analysis further suggests that the isolate is a novel species within the genus, which we tentatively name Albuca mosaic virus, AlbMV. To our knowledge, this is the first report of any plant virus infection in the native Namib Desert ecosystem. This is particularly relevant due to the scarcity and uniqueness of plant life in this hyperarid desert environment, and additional monitoring of this virus infection and other desert plant species is encouraged. Reference: (1) L. Zheng et al. Plant Pathol. 59:211, 2010.

Porphyromonas gingivalis Strain Specific Interactions with Human Coronary Artery Endothelial Cells: A Comparative Study

Both epidemiologic and experimental findings suggest that infection with Porphyromonas gingivalis exacerbates progression of atherosclerosis. As P. gingivalis exhibits significant strain variation, it is reasonable that different strains possess different capabilities and/or mechanisms by which they promote atherosclerosis. Using P. gingivalis strains that have been previously evaluated in the ApoE null atherosclerosis model, we assessed the ability of W83, A7436, 381, and 33277 to adhere, invade, and persist in human coronary artery endothelial (HCAE) cells. W83 and 381 displayed an equivalent ability to adhere to HCAE cells, which was significantly greater than both A7436 and 33277 (P<0.01). W83, 381, and 33277 were more invasive than A7436 (P<0.0001). However, only W83 and A7436 were able to remain viable up to 48 hours in HCAE cell cultures, whereas 381 was cleared by 48 hours and 33277 was cleared by 24 hours. These differences in persistence were in part due to strain specific differences in intracellular trafficking. Both W83 and 381 trafficked through the autophagic pathway, but not A7436 or 33277. Internalized 381 was the only strain that was dependent upon the autophagic pathway for its survival. Finally, we assessed the efficacy of these strains to activate HCAE cells as defined by production of IL-6, IL-8, IL-12p40, MCP-1, RANTES, TNF-α, and soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin). Only moderate inflammation was observed in cells infected with either W83 or A7436, whereas cells infected with 381 exhibited the most profound inflammation, followed by cells infected with 33277. These results demonstrate that virulence mechanisms among different P. gingivalis strains are varied and that pathogenic mechanisms identified for one strain are not necessarily applicable to other strains.

Rotavirus Genetic Diversity, Disease Association, and Temporal Change in Hospitalized Rural Kenyan Children

The effectiveness of rotavirus vaccines will be dependent on the immunity conferred against prevalent and emergent variants causing severe diarrheal disease. Longitudinal surveillance of disease-causing strains is a prerequisite to intervention. Molecular characterization was conducted on rotavirus-positive stool samples from children admitted with diarrhea to a rural district hospital during 2002-2004. Extracted viral RNA was separated by polyacrylamide gel electrophoresis, and rotavirus VP4 (P types) and VP7 (G types) specificities were determined. Among 558 investigated cases, the predominant genotype was P[8]G1 (42%), followed by P[8]G9 (15%), P[4]G8 (7%), P[6]G8 (6%), and P[8]G8 (4%), with 10% mixed strains. Overall, there were 6 different P types and 7 G types. No association was identified between genotype and child age, sex, or severity of diarrhea. The P and G genotypes and polyacrylamide gel electropherotypes showed significant temporal variation in frequency: P[8]G1 decreased from 51% (95% confidence interval [CI], 43%-58%) in 2002 to 30% (95% CI, 24%-37%) in 2004, and P[4]G8 increased from 2% (95% CI, 0%-5%) in 2002 to 13% (95% CI, 9%-19%). Quarterly data revealed seasonally endemic and emergence and/or decay patterns. Our study of rotavirus strains causing severe diarrhea in rural Kenyan children showed a predominance of P[8]G1 and confirms the importance of G8 and G9 strains in sub-Saharan Africa. Considerable genetic diversity of rotavirus strains was observed, including substantial mixed and unusual types, coupled with significant temporal strain variation and emergence. These results warn of variable vaccine efficacy and the need for long-term surveillance of circulating rotavirus genotypes.

Healing behavior of preexisting hydrogen micropores in aluminum alloys during plastic deformation

Synchrotron X-ray microtomography was used to observe the shrinkage and annihilation behaviors of hydrogen micropores in three dimensions during hot and cold plastic deformation of an Al–Mg alloy. Whether complete healing of micropores is achieved after plastic deformation was examined by exposing the material to a high temperature after plastic deformation. Although micropores generally show a pattern of shrinking and closing, closer inspection of a single specimen revealed a variety of geometrically variable behaviors. It is noteworthy that some of the micropores are reinitiated in positions identical to those before their annihilation, even after an 8–22% macroscopic strain has been further applied after annihilation. We attribute local variations such as these to significant local strain variation, which we measured in a series of tomographic volumes by tracking the microstructural features.

Atomic Mechanisms Governing the Elastic Limit and the Incipient Plasticity of Bending Si Nanowires

Individual single-crystalline Si nanowires (NWs) were bent by forming loops or arcs with different radius. Positional-resolved atomic level strain distribution (PRALSD) along both of the radial and axial directions were calculated and mapped directly from the atomic-resolution strained high-resolution electron microscopy (HREM) images of the bent Si NWs. For the first time, the neutral-strain axis shifted from the compressive zone to the tensile region was directly demonstrated from the PRALSD along the radial direction. Bending-induced ripple-buckling of the bent Si NW was observed and a significant strain variation along the bending axial direction in the compressive region was revealed. The tensile surface atomic steps and the compressive buckling are the physical origin of the asymmetric tensile-compressive properties of postelastic instabilities and the incipient plasticity. Both of the tensile surface atomic-steps and the compressive buckling initiated versatile ductile plastic dislocation events.

Physiological genetics of dietary restriction: uncoupling the body temperature and body weight responses

Numerous physiological and molecular changes accompany dietary restriction (DR), which has been a major impediment to elucidating the causal basis underlying DR's many health benefits. Two major metabolic responses to DR that potentially underlie many of these changes are the body temperature (T(b)) and body weight (BW) responses. These responses also represent an especially difficult challenge to uncouple during DR. We demonstrate in this study, using two recombinant inbred (RI) panels of mice (the LXS and LSXSS) that naturally occurring genetic variation serves as a powerful tool for modulating T(b) and BW independently during DR. The correlation coefficient between the two responses was essentially zero, with R = -0.04 in the LXS and -0.03 in the LSXSS, the latter averaged across replicate cohorts. This study is also the first to report that there is highly significant (P = 10(-10)) strain variation in the T(b) response to DR in the LXS (51 strains tested), with strain means ranging from 2 to 4 degrees C below normal. The results suggest that the strain variation in the T(b) response to DR is largely due to differences in the rate of heat loss rather than heat production (i.e., metabolic rate). This variation can thus be used to assess the long-term effects of lower T(b) independent of BW or metabolic rate, as well as independent of food intake and motor activity as previously shown. These results also suggest that murine genetic variation may be useful for uncoupling many more responses to DR.

Relationships Among Egg Characteristics, Chick Measurements, and Early Growth Traits in Ten Broiler Breeder Strains

This study evaluated egg traits, yolk utilization, chick conformation, and early growth rate in 10 broiler breeder strains. The strains included pure-, specialized- and commercial-line products. The 210 eggs/strain were weighed and randomly designated to 1 of 3 experimental determinations: 8 eggs for measurement of eggshell conductance, 52 eggs for determination of egg characteristics, and 150 eggs for incubation and chick traits. Egg characteristics included egg weight, specific gravity, yolk weight, albumen weight, albumen height, eggshell weight, and eggshell thickness. Chick traits included navel condition, hock color, chick length, shank length, and abdomen score by manual palpation. At hatch, half the birds per strain were dissected to assess the weight of the yolk sac, heart, liver, and breast muscle. The remaining chicks were randomly distributed into 4 rearing pens for a 14-d assessment of growth rate. There was a 3-g range in egg weight among the strains. Eggs from a pure line had the greatest amount of yolk (22.6 g), with yolk weight ranging to a low of 20.9 g in 2 other strains. The male line strain and 2 female line strains had the highest hatching weights (46.3, 46.5, and 45.4 g, respectively), whereas a commercial strain had the lowest hatching weight (43.1 g). Egg size affected chick weight more than did yolk size. The residual yolk mass at hatch ranged from 5.50 g (in the male line) to 3.70 g in the commercial strains. Residual yolk mass accounted for approximately 10 to 14% of chick BW at hatch. The abdominal palpation score correlated with actual hatch residual yolk weight (r = 0.50; P < 0.0001). At hatch, differences in breast muscle and internal organ weight were present. Shank length at hatch correlated more strongly with 14-d BW (r = 0.39; P < 0.0001) than did hatch weight and 14-d BW (r = 0.35; P < 0.0001). The results of this trial demonstrated significant strain variation in internal organ weight, residual yolk sac mass, and chick carcass reserves, which, when added together, resulted in observable differences in chick weights across strains.

Listeria monocytogenes: comparative interpretation of mouse virulence assay

Being an opportunistic bacterial pathogen, Listeria monocytogenes demonstrates significant strain variations in virulence and pathogenicity. The availability of laboratory procedures to ascertain the pathogenic potential of L. monocytogenes bacteria would greatly enhance the control and prevention of listerial infections. As a method that measures all virulent determinants, mouse virulence assay has been frequently used for assessing L. monocytogenes virulence. The pathogenic potential of a given L. monocytogenes strain as determined by mouse virulence assay is often calculated from mouse mortality data in combination with colony forming units (CFUs) derived from plate counts, and expressed by medium lethal dose (LD 50). In this report, we describe an alternative method [i.e., relative virulence (%)] that does not involve CFU estimation, and is comparable to LD 50 for interpretation of mouse virulence assay for L. monocytogenes. The relative virulence (%) is obtained by dividing the number of dead mice with the total number of mice tested for a particular strain using a known virulent strain (e.g., L. monocytogenes EGD) as reference. Besides providing a more direct interpretation in comparison with LD 50 values for mouse virulence assay, this method requires fewer dosage groups per L. monocytogenes strain, and eliminates CFU estimation that is step subject to variations between runs and also between laboratories.

Heritable differences in respiratory drive and breathing pattern in mice during anaesthesia and emergence

Postanaesthetic hypoxia and ischaemia can lead to postoperative morbidity and mortality. We studied the effect of isoflurane anaesthesia in two inbred mouse strains known for phenotypic differences in breathing pattern and respiratory drive during carbon dioxide challenge and their first-generation offspring (F(1)). Using whole body plethysmography, we assessed respiratory rate (RR) and pressure amplitude (Amp) in male B6 (high responder to hypercapnia), C3 (low responder), and F(1) mice at rest, during anaesthesia with isoflurane, and during recovery from anaesthesia. At each time point, the magnitude and pattern of breathing were determined during hypercapnic challenge (FI(CO(2)) = 0.08). Data (mean (SD)) were analysed by generalized ANOVA with post hoc Bonferroni's correction (P<0.05). During isoflurane anaesthesia, strain differences between B6 and C3 mice in RR were obscured while differences in Amp persisted. In contrast to baseline RR responses to carbon dioxide were significantly reduced at 0.5 MAC (increase in RR: 175 (33) bpm, 147 (44) bpm, 127 (33) bpm, for B6, C3, and F(1) strains respectively) and completely blocked at 1.5 MAC (change in RR: -3 (10) bpm, -2 (1) bpm, -4 (5) bpm, for B6, C3, and F(1) strains, respectively). During recovery, B6 mice showed a significant increase in RR (77 (33) bpm; P<0.0001) as well as in Amp. This was not observed in either C3 (-22 (31) bpm) or F(1) mice (23 (51) bpm). Isoflurane anaesthesia abolished the strain differences in respiratory drive between B6, C3, and F(1) mice. However, during recovery from anaesthesia, significant strain variation in respiratory drive reappeared and was more pronounced compared with pre-anaesthetic levels. These results suggested, that genetic differences may have minimal contribution to decreased respiratory drive during anaesthesia, but may be a major risk factor for post-operative hypoventilation and the associated morbidity and mortality.

Tail-suspension induced hyperthermia: a new measure of stress reactivity

The tail suspension test (TST), an antidepressant screening paradigm, uses the uncontrollable, inescapable stressor of tail suspension to elicit immobility. As hyperthermia occurs following numerous stressors, hyperthermia might exist following the TST. We tested whether tail suspension induced hyperthermia (TSIH) was a distinct variable for TST. Hyperthermia was measured by two methods: a rectal probe and a subcutaneously implanted microchip (ELAMS ™). In outbred ICR male mice, TSIH was robustly demonstrated compared to control (No-TST) mice. TSIH peaked after TST and remained elevated at 120 min. Among five (129/SvEvTac, A/J, C57BL/6J, NMRI and ICR) strains examined for TSIH, significant strain variations were detected. NMRI showed the highest temperature rise (2.3 °C) and A/J mice showed the lowest (0.6 °C). Sex differences were found for the C57BL/6J and NMRI strains on TSIH. TSIH and duration of immobility were not significantly correlated ( r=0.22, P=0.17) in outbred mice. Both duration of TST immobility and TSIH were measured when ICR male mice were administered diazepam, imipramine (a TCA antidepressant), venlafaxine (a SNRI antidepressant), sertraline and paroxetine (SSRI antidepressants), propranolol and nadolol (β-adrenergic receptor blockers), CP-154,526 (a CRF 1 receptor antagonist), and indomethacin (a cyclo-oxygenase inhibitor). Diazepam dose-dependently increased immobility and decreased TSIH. Propranolol blocked TSIH, but nadolol had no effect. Antidepressants showed more complex patterns of effects with venlafaxine, sertraline, and paroxetine inhibiting TSIH. TSIH demonstrated inter-strain variability, sex differences and a distinct pharmacology, suggesting that TSIH provides an independent, robust physiologic parameter to supplement the TST paradigm. This TSIH method may prove useful for pharmacologic, transgenic, and mechanistic studies.

Strain variation in the response of body temperature to dietary restriction

Dietary restriction (DR, also referred to as calorie restriction, energy restriction, and food restriction) retards senescence and increases longevity in mammals. DR also lowers mean body temperature ( T b), and thus mean T b might be useful as a covariate of DR-induced life extension. Indeed, lower T b could itself underlie some of the beneficial life-extension effects that occur during DR. To assess the relationship between lower T b during DR and life extension, we asked whether significant strain variation exists in the T b response of mice being fed 60% ad libitum (AL). Individually-housed, female mice from 28 strains, representing a genealogically diverse sample of the classical inbred strains, were directly compared. The mean T bs in response to DR exhibited highly significant strain variation, ranging from 1.5 °C below normal to a phenomenal 5 °C below normal. This variation was not explained by differences in loss of thermoregulation, AL adiposity, sensitivity to a nonadaptive hypothermia, motor activity, thermal arousal, absolute food intake, or efficacy of nutrient extraction. The variation in strain mean T b was also present in the absence of torpor. This strain variation could be used to critically test whether lower T b is a covariate of life extension during DR.

Inbred mouse strain differences in the establishment of long-term fear memory

Studies describing variations in fear-related memory in inbred mouse strains typically focus upon 24 h retention. As a consequence, little is known about strain differences in the establishment of longer lasting memories of aversive events. In the present study, male mice from the strains A/Ibg, AKR/J, BALB/cByJ, CBA/J, C3H/HeIbg, C57BL/6J, DBA/2J, LP/J, SJL/J and 129/SvevTac were tested 24 h, 14, or 60 days after contextual and auditory-cued fear conditioning. Consistent with previous data, 24 h after conditioning these strains exhibited substantial variation in levels of memory for the context and the auditory cue as measured by freezing scores. Sixty days after training, most strains exhibited some forgetting of the context and auditory cue, and again there was significant strain variation. Strain rankings at 60-day retention were similar to that at 24 h with a significant genetic correlation between freezing values for the two time periods. Fourteen days following training, nearly all strains exhibited generalized freezing, a behavioral phenotype originally observed in C57BL/6 but not DBA/2 mice [15]. These data confirm that cognitive differences exist between several popular inbred mouse strains during 24 h contextual fear recall. In addition, they extend these differences into retention time frames longer than those typically used and reveal several unique learning profiles of mouse strains that may be useful in furthering our understanding of how memories are formed. Emotionally arousing situations are often recalled a great deal of time after an event. Therefore, a more complete picture of the biochemical and genetic underpinnings of learning and memory will benefit from studies using time points that assess time points beyond 24 h retention. The utility of the 14-day hyper responsiveness phenotype as a potential model for fear-related psychopathology is also discussed.

Strain differences in the liver microsomal metabolism of the experimental anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in mice

The experimental anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mainly metabolised by acyl glucuronidation and to a lesser degree by 6-methyl hydroxylation. Strain differences in the maximum tolerated dose (MTD) of DMXAA in mice have been observed. The aim of this study was to compare the kinetics of DMXAA acyl glucuronidation and 6-methylhydroxylation in five various mouse strains, and correlate the in vitro metabolism data with MTD observed. In all mouse strains studied, DMXAA acyl glucuronidation and 6-methylhydroxylation in the liver microsomes followed Michaelis–Menten kinetics. Significant strain variations in the kinetic parameters ( K m, V max and K m/ V max, i.e., CL int) for DMXAA acyl glucuronidation and 6-methylhydroxylation in mouse liver microsomes were observed. A 2–6-fold variation was spanned across strains for K m, V max and CL int, respectively, for DMXAA glucuronidation and 6-methylhydroxylation. The rank order for total CL int by glucuronidation and 6-methylhydroxylation was BDF1 (1.70 ml/min per g)>wild type of mice lacking IFN-γ receptor (0.80 ml/min per g)>nude mice (0.70 ml/min per g)>Swiss CD mice (0.56 ml/min per g)>C57Bl/6 mice (0.46 ml/min per g), with a 4-fold variation between the mouse strain of the highest and lowest CL int. There was no significant correlation between total CL int and MTD ( r 2=0.88, P>0.05), but the rank order for CL int was consistent with that for MTD. These results suggested that there were significant strain differences in DMXAA metabolism in mouse liver microsomes and the strain-related differences in the metabolism of DMXAA did not provide an explanation for the strain differences in the MTD.

Studies of strain and rheology of conglomerates

Conglomerates can show significant strain variations among their component rock types. Previous studies have exploited this feature as a method of quantifying the effective viscosity ratios among different rock types, using inclusion–matrix models that we review here. We further investigate the rheology of conglomerates via models of multiphase mixtures of spherical clasts with varying phase fractions. Using idealised models with two to four phases, we can quantify the influence of phase viscosities and volume fractions on the bulk viscosity, and reveal how this controls the strain partitioning among the different phases. We consider practical methods of analysing conglomerates, and choose R f- φ analysis for measuring clast strain, and Fry analysis for whole-rock strain. The methods are illustrated through case studies of two very different conglomerates, the Port Askaig Tillite, Scotland, and Cesson Conglomerate, Brittany. We define the important rock phases in each, and assess their strain variations. Although providing strain measurements of regional interest, our main purpose is to quantify the viscosity ratios among the component rocks. We find that among the most common rock types (semipelite, quartzite, psammite, volcanics, granite), the viscosity ratios span about one order of magnitude, agreeing with previous studies. These small numerical values for viscosity ratios among many rock types, in many conglomerates, lead us to conclude that these rocks each deformed at approximately constant viscosity: i.e. as linearly viscous, rather than according to a power law.