Macroscopic differences in adult human femora are linked to body mass index.

Bone functional adaptation is routinely invoked to interpret skeletal morphology despite ongoing debate regarding the limits of the bone response to mechanical stimuli. The wide variation in human body mass presents an opportunity to explore the relationship between mechanical load and skeletal response in weight-bearing elements. Here, we examine variation in femoral macroscopic morphology as a function of body mass index (BMI), which is used as a metric of load history. A sample of 80 femora (40 female; 40 male) from recent modern humans was selected from the Texas State University Donated Skeletal Collection. Femora were imaged using x-ray computed tomography (voxel size ~0.5 mm), and segmented to produce surface models. Landmark-based geometric morphometric analyses based on the Coherent Point Drift algorithm were conducted to quantify shape. Principal components analyses were used to summarize shape variation, and component scores were regressed on BMI. Within the male sample, increased BMI was associated with a mediolaterally expanded femoral shaft, as well as increased neck-shaft angle and decreased femoral neck anteversion angle. No statistically significant relationships between shape and BMI were found in the female sample. While mechanical stimulus has traditionally been applied to changes in long bong diaphyseal shape it appears that bone functional adaptation may also result in fundamental changes in the shape of skeletal elements.

Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques.

Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2M-/-CIITA-/-CD47+). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected.

Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice.

Manufacturing autologous chimeric antigen receptor (CAR) T cell therapeutics is complex, and many patients experience treatment delays or cannot be treated at all. Although current allogeneic CAR products have the potential to overcome manufacturing bottlenecks, they are subject to immune rejection and failure to persist in the host, and thus do not provide the same level of efficacy as their autologous counterparts. Here, we aimed to develop universal allogeneic CAR T cells that evade the immune system and produce a durable response. We generated human hypoimmune (HIP) T cells with disrupted B2M, CIITA, and TRAC genes using CRISPR-Cas9 editing. In addition, CD47 and anti-CD19 CAR were expressed using lentiviral transduction. These allogeneic HIP CD19 CAR T cells were compared to allogeneic CD19 CAR T cells that only expressed the anti-CD19 CAR (allo CAR T). In vitro assays for cancer killing and exhaustion revealed no differences between allo CAR T and HIP CAR T cells, confirming that the HIP edits did not negatively affect T cell performance. Clearance of CD19+ tumors by HIP CAR T cells in immunodeficient NSG mice was comparable to that of allo CAR T cells. In fully immunocompetent humanized mice, HIP CAR T cells significantly outperformed allo CAR T cells, showed improved persistence and expansion, and provided lasting cancer clearance. Furthermore, CD47-targeting safety strategies reliably and specifically eliminated HIP CAR T cells. These findings suggest that universal allogeneic HIP CAR T cell-based therapeutics might overcome the limitations associated with poor persistence of allogeneic CAR T cells and exert durable anti-tumor responses.

Mixed cumulative probit: a multivariate generalization of transition analysis that accommodates variation in the shape, spread and structure of data.

Biological data are frequently nonlinear, heteroscedastic and conditionally dependent, and often researchers deal with missing data. To account for characteristics common in biological data in one algorithm, we developed the mixed cumulative probit (MCP), a novel latent trait model that is a formal generalization of the cumulative probit model usually used in transition analysis. Specifically, the MCP accommodates heteroscedasticity, mixtures of ordinal and continuous variables, missing values, conditional dependence and alternative specifications of the mean response and noise response. Cross-validation selects the best model parameters (mean response and the noise response for simple models, as well as conditional dependence for multivariate models), and the Kullback-Leibler divergence evaluates information gain during posterior inference to quantify mis-specified models (conditionally dependent versus conditionally independent). Two continuous and four ordinal skeletal and dental variables collected from 1296 individuals (aged birth to 22 years) from the Subadult Virtual Anthropology Database are used to introduce and demonstrate the algorithm. In addition to describing the features of the MCP, we provide material to help fit novel datasets using the MCP. The flexible, general formulation with model selection provides a process to robustly identify the modelling assumptions that are best suited for the data at hand.

Agreement and error rates associated with standardized data collection protocols for skeletal and dental data on 3D virtual subadult crania.

Observer error and agreement rates for craniometrics, odontometrics, and cranial and dental morphological traits have been inconsistently evaluated on three-dimensional cranial reconstructions and almost never assessed on subadult individuals. This study uses a computed tomography (CT) scan sample of 12 subadults aged between birth and 20 years from the Subadult Virtual Anthropology Database (SVAD) to evaluate intra- and inter-observer error and agreement rates associated to these four types of data on virtual crania. Forty-eight cranial landmarks, 33 standard inter-landmark distances (ILDs), 13 cranial macromorphoscopic traits, four permanent and four deciduous dental landmarks and measurements per tooth, and 21 permanent and 12 deciduous dental morphological traits were collected on each individual. Results matched or improved on published standards for dry bones, teeth, or dental casts. Technical Error of Measurement (TEM) associated with metric data ranged from 0.00 mm to 0.99 mm and relative TEM ranged from 0% to 5.76%. Cohen's kappa coefficient values for agreement on morphological traits scores were above K = 0.5 for 90% of the traits. Type III cranial landmarks showed higher error rates than Type I and II cranial landmarks. Agreement on dental morphology scores seemed influenced by observer experience and rater agreement improved when using di- or tri-chotomized grades. Skeletal maturity did not significantly affect error rates, meaning most craniofacial and dental metrics and morphological traits can be reliably obtained from virtual subadult crania.