Characterisation of monoclonal antibodies specific for hamster leukocyte differentiation molecules

Flow cytometry was used to identify mAbs that recognize conserved epitopes on hamster leukocyte differentiation molecules (hLDM) and also to characterize mAbs developed against hLDM. Initial screening of mAbs developed against LDMs in other species yielded mAbs specific for the major histocompatibility (MHC) II molecule, CD4 and CD18. Screening of sets of mAbs developed against hLDM yielded 22 new mAbs, including additional mAbs to MHC II molecules and mAbs that recognize LDMs expressed on all leukocytes, granulocytes, all lymphocytes, all T cells, a subset of T cells, or on all B cells. Based on comparison of the pattern of expression of LDMs expressed on all hamster leukocytes with the patterns of expression of known LDMs in other species, as detected by flow cytometry (FC), four mAbs are predicted to recognize CD11a, CD44, and CD45. Cross comparison of mAbs specific for a subset of hamster T cells with a cross reactive mAb known to recognize CD4 in mice and one recognising CD8 revealed they recognize CD4. The characterization of these mAbs expands opportunities to use hamsters as an additional model species to investigate the mechanisms of immunopathogenesis of infectious diseases

Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro

Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB) / octafluoropropane (OFP) PCCAs for 1 hour, imaged via confocal microscopy, exposed to ultrasound (9 MHz, MI = 1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p < 0.001) in MDA-MB-231 cells (93.0% internalization at MI = 1.0, 79.5% at MI = 1.5) than MCF-7 cells (42.4% internalization at MI = 1.0, 35.7% at MI = 1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500 nm to 6 microns (IQR = 800 nm – 1.5 microns) with a mean diameter of 1.15 ± 0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound

Combined effects of tidal and rotational distortions on the equilibrium configuration of low-mass, pre-main sequence stars

In close binary systems, rotation and tidal forces of the component stars deform each other and destroy their spherical symmetry. We present new models for low-mass, pre-main sequence stars that include the combined distortion effects of tidal and rotational forces on the equilibrium configuration of stars. We investigate the effects of interaction between tides and rotation on the stellar structure and evolution. The Kippenhahn & Thomas (1970) approximation, along with the Clairaut-Legendre expansion for the gravitational potential of a self-gravitating body, is used to take the distortion effects into account. We obtained values of internal structure constants for low-mass, pre-main sequence stars from stellar evolutionary models that consider the combined effects of rotation and tidal forces due to a companion star. We also derived a new expression for the rotational inertia of a tidally and rotationally distorted star. Our distorted models were successfully used to analyze the eclipsing binary system EK Cep, reproducing the stellar radii, effective temperature ratio, lithium depletion, rotational velocities, and the apsidal motion rate in the age interval of 15.5-16.7 Myr. In the low-mass range, the assumption that harmonics greater than j=2 can be neglected seems not to be fully justified, although it is widely used when analyzing the apsidal motion of binary systems. The non-standard evolutionary tracks are cooler than the standard ones, mainly for low-mass stars. Distorted models predict more mass-concentrated stars at the zero-age main-sequence than standard models

Towards Large-Scale Learned Solvers for Parametric PDEs with Model-Parallel Fourier Neural Operators

Fourier neural operators (FNOs) are a recently introduced neural network architecture for learning solution operators of partial differential equations (PDEs), which have been shown to perform significantly better than comparable approaches based on convolutional networks. Once trained, FNOs can achieve speed-ups of multiple orders of magnitude over conventional numerical PDE solvers. However, due to the high dimensionality of their input data and network weights, FNOs have so far only been applied to two-dimensional or small three-dimensional problems. To remove this limited problem-size barrier, we propose a model-parallel version of FNOs based on domain-decomposition of both the input data and network weights. We demonstrate that our model-parallel FNO is able to predict time-varying PDE solutions of over 3.2 billions variables on Summit using up to 768 GPUs and show an example of training a distributed FNO on the Azure cloud for simulating multiphase CO$_2$ dynamics in the Earth's subsurface

Ground reaction forces of overground galloping in ridden Thoroughbred racehorses

The horse has evolved to gallop economically at high speed. Limb force increases with speed but direct measures of limb ground reaction forces (GRFs) at gallop are sparse. This study reports GRFs for multiple limbs, using force plates, across seven Thoroughbred racehorses during ridden galloping. The results show peak vertical GRF values of 13.6 N kg−1 (non-lead hindlimb), 12.3 N kg−1 (lead hindlimb), 14.0 N kg−1 (non-lead forelimb) and 13.6 N kg−1 (lead forelimb) at 11.4 m s−1 and recorded values are consistent with those predicted from duty factor. The distribution of body weight between the forelimbs and hindlimbs is approximated to 50:50, and is variable with speed, unlike the 60:40 commonly stated for cursorial quadrupeds in the literature. An even distribution of load on all limbs may help minimise accumulation of fatigue and assist in injury avoidance. Cranio-caudal force data concur with the observation that horses apply a net accelerative impulse with the hindlimbs and a net decelerative impulse with the forelimbs. Capturing GRFs enhances our knowledge on the mechanics of galloping in fast-moving species and provides insight into injury risk and factors limiting athletic performance

The scaling of postcranial muscles in cats (Felidae) I: forelimb, cervical, and thoracic muscles

The body masses of cats (Mammalia, Carnivora, Felidae) span a ~300‐fold range from the smallest to largest species. Despite this range, felid musculoskeletal anatomy remains remarkably conservative, including the maintenance of a crouched limb posture at unusually large sizes. The forelimbs in felids are important for body support and other aspects of locomotion, as well as climbing and prey capture, with the assistance of the vertebral (and hindlimb) muscles. Here, we examine the scaling of the anterior postcranial musculature across felids to assess scaling patterns between different species spanning the range of felid body sizes. The muscle architecture (lengths and masses of the muscle‐tendon unit components) for the forelimb, cervical and thoracic muscles was quantified to analyse how the muscles scale with body mass. Our results demonstrate that physiological cross‐sectional areas of the forelimb muscles scale positively with increasing body mass (i.e. becoming relatively larger). Many significantly allometric variables pertain to shoulder support, whereas the rest of the limb muscles become relatively weaker in larger felid species. However, when phylogenetic relationships were corrected for, most of these significant relationships disappeared, leaving no significantly allometric muscle metrics. The majority of cervical and thoracic muscle metrics are not significantly allometric, despite there being many allometric skeletal elements in these regions. When forelimb muscle data were considered in isolation or in combination with those of the vertebral muscles in principal components analyses and MANOVAs, there was no significant discrimination among species by either size or locomotory mode. Our results support the inference that larger felid species have relatively weaker anterior postcranial musculature compared with smaller species, due to an absence of significant positive allometry of forelimb or vertebral muscle architecture. This difference in strength is consistent with behavioural changes in larger felids, such as a reduction of maximal speed and other aspects of locomotor abilities

Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G &gt; A; CRP + 1444T &gt; C; CRP + 4899T &gt; G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP