Fibrous Osteodystrophy,Chronic Renal Disease,and Uterine Adenocarcinoma in Aged Gray Mouse Lemurs (Microcebus murinus)

The gray mouse lemur (Microcebus murinus, GML) is a nocturnal, arboreal, prosimian primate that is native to Madagascar. Captive breeding colonies of GMLs have been established primarily for noninvasive studies on questions related to circadian rhythms and metabolism. GMLs are increasingly considered to be a strong translational model for neurocognitive aging due to overlapping histopathologic features shared with aged humans. However, little information is available describing the clinical presentations, naturally occurring diseases, and histopathology of aged GMLs. In our colony, a 9 y-old, male, GML was euthanized after sudden onset of weakness, lethargy, and tibial fracture. Evaluation of this animal revealed widespread fibrous osteodystrophy (FOD) of the mandible, maxilla, cranium, appendicular, and vertebral bones. FOD and systemic metastatic mineralization were attributed to underlying chronic renal disease. Findings in this GML prompted periodic colony-wide serum biochemical screenings for azotemia and electrolyte abnormalities. Subsequently, 3 additional GMLs (2 females and 1 male) were euthanized due to varying clinical and serum biochemical presentations. Common to all 4 animals were FOD, chronic renal disease, uterine adenocarcinoma (females only), cataracts, and osteoarthritis. This case study highlights the concurrent clinical and histopathologic abnormalities that are relevant to use of GMLs in the expanding field of aging research.

Within the past 5 y, recognition of the translational utility of the gray mouse lemur (Microcebus murinus, GML) has greatly expanded, in part due to the sequencing of its genome.²⁷ GMLs have been proposed as an animal model in the context of aging research,^14,35 most notably within the fields of Alzheimer disease and dementia^33,39 and circadian rhythms.^15,20 GMLs are nocturnal, arboreal, prosimian primates (family Cheirogaleidae) that are endemic to Madagascar. They are among the smallest primates, with a body weight of 49 to 80 g in the wild³⁷ (60 to 110 g in captivity) and have a life expectancy of approximately 8 to 10 y in captivity.¹⁴ A small number of captive breeding colonies have been established throughout Europe and the United States, many of which have arisen from a closed captive breeding colony at the Muséum National d''Histoire Naturelle (MNHN) in Brunoy, France.Despite an ever-growing interest in the GML as a model organism, clinical and pathologic case reports focusing on naturally occurring disease are rare for this species.^{1,4,10,16,17,20,28,31,34,38} Reports of spontaneous disease often focus on neoplasia^28,31,34 or on ocular abnormalities, which are accessible without invasive interventions.^1,4,12 Apart from age-related neurodegenerative disease and cognitive impairment,^{5,23,25,26,32,36} little is known about the natural disease predilection and histologic aging phenotypes of GMLs.In June 2017, a 9 y-old male GML was euthanized after the sudden onset of weakness, lethargy, and tibial fracture. Necropsy and histopathology revealed chronic renal disease, widespread fibrous osteodystrophy (FOD), and systemic metastatic mineralization. These findings prompted colony-wide serum biochemical screenings for potential underlying renal disease and subsequent metabolic bone disease within the population.Herein, we report the clinical, gross, and histologic multisystemic pathology of 4 aged GMLs. This is the first documentation of FOD secondary to chronic renal disease in GMLs in a captive research colony. In addition, we corroborate previous reports^31,34 of uterine adenocarcinoma in aged female GMLs. Together, these findings aid in providing appropriate clinical care to GMLs as their use in the field of aging research continues to expand.     

Evaluating the forced oscillation technique in the detection of early smoking-induced respiratory changes

Background  

Early detection of the effects of smoking is of the utmost importance in the prevention of chronic obstructive pulmonary disease (COPD). The forced oscillation technique (FOT) is easy to perform since it requires only tidal breathing and offers a detailed approach to investigate the mechanical properties of the respiratory system. The FOT was recently suggested as an attractive alternative for diagnosing initial obstruction in COPD, which may be helpful in detecting COPD in its initial phases. Thus, the purpose of this study was twofold: (1) to evaluate the ability of FOT to detect early smoking-induced respiratory alterations; and (2) to compare the sensitivity of FOT with spirometry in a sample of low tobacco-dose subjects.     

Investigating life‐history traits of Steller sea lions with multistate hidden Markov mark–recapture models: Age at weaning and body size effects

The duration of offspring care is critical to female fitness and population resilience by allowing flexibility in life‐history strategies in a variable environment. Yet, for many mammals capable of extended periods of maternal care, estimates of the duration of offspring dependency are not available and the relative importance of flexibility of this trait on fitness and population viability has rarely been examined. We used data from 4,447 Steller sea lions Eumetopias jubatus from the Gulf of Alaska and multistate hidden Markov mark–recapture models to estimate age‐specific weaning probabilities. Maternal care beyond age 1 was common: Weaning was later for animals from Southeast Alaska (SEAK) and Prince William Sound (PWS, weaning probabilities: 0.536–0.648/0.784–0.873 by age 1/2) compared with animals born to the west (0.714–0.855/0.798–0.938). SEAK/PWS animals were also smaller than those born farther west, suggesting a possible link. Females weaned slightly earlier (+0.080 at age 1 and 2) compared with males in SEAK only. Poor survival for weaned versus unweaned yearlings occurred in southern SEAK (female survival probabilities: 0.609 vs. 0.792) and the central Gulf (0.667 vs. 0.901), suggesting poor conditions for juveniles in these areas. First‐year survival increased with neonatal body mass (NBM) linearly in the Gulf and nonlinearly in SEAK. The probability of weaning at age 1 increased linearly with NBM for SEAK animals only. Rookeries where juveniles weaned at earlier ages had lower adult female survival, but age at weaning was unrelated to population trends. Our results suggest the time to weaning may be optimized for different habitats based on long‐term average conditions (e.g., prey dynamics), that may also shape body size, with limited short‐term plasticity. An apparent trade‐off of adult survival in favor of juvenile survival and large offspring size in the endangered Gulf of Alaska population requires further study.     

Noncontact dipole effects on channel permeation. III. Anomalous proton conductance effects in gramicidin

Proton transport on water wires, of interest for many problems in membrane biology, is analyzed in side-chain analogs of gramicidin A channels. In symmetrical 0.1 N HCl solutions, fluorination of channel Trp(11), Trp-(13), or Trp(15) side chains is found to inhibit proton transport, and replacement of one or more Trps with Phe enhances proton transport, the opposite of the effects on K(+) transport in lecithin bilayers. The current-voltage relations are superlinear, indicating that some membrane field-dependent process is rate limiting. The interfacial dipole effects are usually assumed to affect the rate of cation translocation across the channel. For proton conductance, however, water reorientation after proton translocation is anticipated to be rate limiting. We propose that the findings reported here are most readily interpreted as the result of dipole-dipole interactions between channel waters and polar side chains or lipid headgroups. In particular, if reorientation of the water column begins with the water nearest the channel exit, this hypothesis explains the negative impact of fluorination and the positive impact of headgroup dipole on proton conductance.     

GWAS‐based pathway analysis differentiates between fluid and crystallized intelligence

Cognitive abilities vary among people. About 40–50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) – the ability to reason in novel situations – and general crystallized intelligence (gC) – the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome‐wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene‐ and pathway‐based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long‐term depression (LTD) seemed to underlie gC. Thus, this study supports the gF–gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.     

Hybrid Monte Carlo simulations theory and initial comparison with molecular dynamics

A formal partially dynamical approach to ergodic sampling, hybrid Monte Carlo, has been adapted for the first time from its proven application in quantum chromodynamics to realistic molecular systems. A series of simulations of pancreatic trypsin inhibitor were run using temperature-rescaled molecular dynamics and hybrid Monte Carlo. It was found that simulations run using hybrid Monte Carlo equilibrated an order of magnitude faster than those run using temperature-rescaled molecular dynamics. Certain aspects of improved performance obtained using hybrid Monte Carlo are probably due to the increased efficiency with which this algorithm explores phase space. To discuss this we introduce the notion of “trajectory stiffness”. © 1993 John Wiley & Sons, Inc.     

A conceptual model for the identification, organization, and measure of influence of fertility policies and programs.

The fertility program of any government is the procedural action intended to effect the government fertility policy. There may also be unintended results of any fertility program. A conceptual model was designed to measure the effect of governmental action on fertility and to identify sociocultural factors that have the greatest influence on fertility. The model uses sociocultural variables as intervening variables between fertility programs and changes in actual fertility. The structural variables considered by the model are characteristics of the pattern of social order; the cultural variables consist of shared values and norms. Fertility trend analysis is effected by polynomial regression formulae. Puerto Rican data from 1946 to 1970 were used to test the proposed model. Analysis of the data indicated that emigration between 1940-1962 had little effect on national fertility. Governmental family planning programs, beginning in 1946, contributed to a sharp decline in fertility. It is recommended that the model be used with data from other countries to assess the effects of their family planning programs.