Brobdingnagians and Goliaths: two forms of gigantism in fish.

Two forms of gigantism are differentiated in fish, Brobdingnagian and Goliathan gigantism, the former applying to populations whose individuals are all larger than is typical for the taxon, the latter to single individuals within a population. While Brobdingnagian gigantism is largely explained by various ecological and evolutionary rules, Goliathan gigantism is not. A mechanistic hypothesis is proposed which explains Goliathan gigantism in terms of the reduction of oxygen requirements of individual fish via moving to cooler temperatures and/or acquiring larger, more energy-dense prey, which enable them to get bigger, and, in the process, sometimes generate bimodal size distributions that may qualify as gradual forms between Goliathan and Brobdingnagian gigantism. This mechanism, which relies on the manner in which their gill surface area grows, is more likely to operate in fish that can get big in the first place than in fish that remain small.

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.

The ratio of length at first maturity to maximum length across marine and freshwater fishes.

The prevailing determinant of maturation in fishes is thought to be a redirection of energy from growth to reproduction. Instead, the Gill Oxygen Limitation Theory predicts that maturation, and thus reproduction, is induced when a fish reaches a critical ratio of oxygen supply to demand (Qm /Qmaint ). The consistency of this critical ratio has been previously documented in many fishes, but a broader test was lacking. In this study, the authors assess if this critical ratio is consistent across 132 unique fish species, as measured by the slope of the relationship between Lmax D and Lm D , where Lmax is the maximum length reached in a given population, Lm is the mean size at first maturity in that population and D is a gill-related exponent which renders the Lmax D /Lm D ratio equivalent to the Qm /Qmaint ratio. The authors found that across all species, the Lmax D /Lm D ratio was 1.40 (95% c.i. 1.38-1.42), which was not significantly different from that previously estimated across other species groups (1.35, 95% c.i. 1.22-1.53), especially when phylogenetic relationships were considered (1.25, 95% Bayesian credible interval 1.09-1.40). The consistency of the Lmax D /Lm D ratio across taxa, which expresses the difference in metabolic rate at maturity and maximum size, suggests that the scaling of gill surface area is the factor that underlies this ratio, and which triggers the maturation in fishes.

Behavior Problems During Early Childhood in Children With Prenatal Methamphetamine Exposure.

BACKGROUND AND OBJECTIVES: The effects of in utero methamphetamine exposure on behavioral problems in school-aged children are unclear. Our objective for this study was to evaluate behavior problems in children at aged 3, 5, and 7.5 years who were prenatally exposed to methamphetamine. METHODS: Subjects were enrolled in the Infant Development, Environment, and Lifestyle study, a longitudinal prospective study of prenatal methamphetamine exposure and child outcomes. Exposed and comparison groups were matched on birth weight, race, education, and health insurance.  At ages 3, 5, and 7.5 years, 339 children (171 exposed) were assessed for behavior problems by using the Child Behavior Checklist. Generalized estimating equations were used to determine the effects of prenatal methamphetamine exposure, age, and the interaction of exposure and age on behavior problems. Caregiver psychological symptoms were assessed by using the Brief Symptom Inventory. RESULTS: Analyses adjusted for covariates revealed that relative to age 3, children at 5 years had less externalizing and aggressive behavior and more internalizing behavior, somatic complaints, and withdrawn behavior.  By age 7.5, aggressive behavior continued to decrease, attention problems increased and withdrawn behavior decreased. There were no main effects for methamphetamine exposure and no interactions of exposure and age.  Caregiver psychological symptoms predicted all behavior problems and the quality of the home predicted externalizing problems and externalizing syndrome scores. CONCLUSIONS: Behavioral effects longitudinally from ages 3 to 7.5 years were not associated with prenatal methamphetamine exposure, whereas caregiver psychological symptoms and the quality of the home were predictors of behavior problems.

Three-hourly feeding intervals are associated with faster advancement in very preterm infants.

OBJECTIVE: To compare the effect of two-hourly (Q2H) vs. three-hourly (Q3H) feeding on time to achieve full enteral feeding, growth metrics and respiratory tolerance in very preterm infants with birth weight ≤ 1250 g. STUDY DESIGN: Retrospective study review of 18 months before and after a change in our feeding guideline from Q3H to Q2H feedings. RESULTS: 113 infants were included, 59 in Q3H and 54 in Q2H groups. Q2H infants required 10% more days to achieve full enteral feeding, however it was not statistically significant (P = 0.054). Q2H feeding was associated with 16% more central catheter days (P = 0.02) and 17% more parenteral nutrition days (P = 0.019). There were no differences in respiratory outcomes or growth metrics between the groups. CONCLUSION: Very preterm infants fed Q3H had less central catheter and parenteral nutrition days when compared to those fed Q2H, without significant differences in growth or respiratory outcomes.

Culicoides species community composition and infection status with parasites in an urban environment of east central Texas, USA.

BACKGROUND: Despite their importance as vectors of zoonotic parasites that can impact human and animal health, Culicoides species distribution across different habitat types is largely unknown. Here we document the community composition of Culicoides found in an urban environment including developed and natural sites in east central Texas, a region of high vector diversity due to subtropical climates, and report their infection status with haemoparasites. RESULTS: A total of 251 individual Culicoides were collected from May to June 2016 representing ten Culicoides species, dominated by C. neopulicaris followed by C. crepuscularis. We deposited 63 sequences to GenBank among which 25 were the first deposition representative for six Culicoides species: C. arboricola (n = 1); C. nanus (n = 4); C. debilipalpis (n = 2); C. haematopotus (n = 14); C. edeni (n = 3); and C. hinmani (n = 1). We also record for the first time the presence of C. edeni in Texas, a species previously known to occur in the Bahamas, Florida and South Carolina. The urban environments with natural area (sites 2 and 4) had higher species richness than sites more densely populated or in a parking lot (sites 1 and 3) although a rarefaction analysis suggested at least two of these sites were not sampled sufficiently to characterize species richness. We detected a single C. crepuscularis positive for Onchocercidae gen. sp. DNA and another individual of the same species positive for Haemoproteus sacharovi DNA, yielding a 2.08% prevalence (n = 251) for both parasites in this species. CONCLUSIONS: We extend the knowledge of the Culicoides spp. community in an urban environment of Texas, USA, and contribute to novel sequence data for these species. Additionally, the presence of parasite DNA (Onchocercidae gen. sp. and H. sacharovi) from C. crepuscularis suggests the potential for this species to be a vector of these parasites.

Role of the activation gate in determining the extracellular potassium dependency of block of HERG by trapped drugs.

Drug induced long QT syndrome (diLQTS) results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases long QT syndrome can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with serum potassium abnormalities due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, and aging. Extracellular potassium influences HERG channel inactivation and can alter block of HERG by some drugs. However, block of HERG by a number of drugs is not sensitive to extracellular potassium. In this study, we show that block of WT HERG by bepridil and terfenadine, two drugs previously shown to be trapped inside the HERG channel after the channel closes, is insensitive to extracellular potassium over the range of 0 mM to 20 mM. We also show that bepridil block of the HERG mutant D540K, a mutant channel that is unable to trap drugs, is dependent on extracellular potassium, correlates with the permeant ion, and is independent of HERG inactivation. These results suggest that the lack of extracellular potassium dependency of block of HERG by some drugs may in part be related to the ability of these drugs to be trapped inside the channel after the channel closes.