Testing Foundations of Biological Scaling Theory Using Automated Measurements of Vascular Networks

Scientists have long sought to understand how vascular networks supply blood and oxygen to cells throughout the body. Recent work focuses on principles that constrain how vessel size changes through branching generations from the aorta to capillaries and uses scaling exponents to quantify these changes. Prominent scaling theories predict that combinations of these exponents explain how metabolic, growth, and other biological rates vary with body size. Nevertheless, direct measurements of individual vessel segments have been limited because existing techniques for measuring vasculature are invasive, time consuming, and technically difficult. We developed software that extracts the length, radius, and connectivity of in vivo vessels from contrast-enhanced 3D Magnetic Resonance Angiography. Using data from 20 human subjects, we calculated scaling exponents by four methods--two derived from local properties of branching junctions and two from whole-network properties. Although these methods are often used interchangeably in the literature, we do not find general agreement between these methods, particularly for vessel lengths. Measurements for length of vessels also diverge from theoretical values, but those for radius show stronger agreement. Our results demonstrate that vascular network models cannot ignore certain complexities of real vascular systems and indicate the need to discover new principles regarding vessel lengths

Vancomycin-induced gut microbial dysbiosis alters enteric neuron-macrophage interactions during a critical period of postnatal development

Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions. This suggests that early-life antibiotic exposure could disrupt these interactions in the neonatal gut. Notably, a subset of tissue-resident intestinal macrophages, muscularis macrophages, has been identified as important contributors to the development of postnatal ENS. We hypothesized that vancomycin-induced neonatal dysbiosis impacts postnatal ENS development through its effects on macrophages. Using a mouse model, we found that exposure to vancomycin in the first 10 days of life, but not in adult mice, resulted in an expansion of pro-inflammatory colonic macrophages by increasing the recruitment of bone-marrow-derived macrophages. Single-cell RNA sequencing of neonatal colonic macrophages revealed that early-life vancomycin exposure was associated with an increase in immature and inflammatory macrophages, consistent with an influx of circulating monocytes differentiating into macrophages. Lineage tracing confirmed that vancomycin significantly increased the non-yolk-sac-derived macrophage population. Consistent with these results, early-life vancomycin exposure did not expand the colonic macrophage population nor decrease enteric neuron density in CCR2-deficient mice. Collectively, these findings demonstrate that early-life vancomycin exposure alters macrophage number and phenotypes in distinct ways compared with vancomycin exposure in adult mice and results in altered ENS development

Environmental enrichment reduces signs of boredom in caged mink

Animals housed in impoverished cages are often labelled 'bored'. They have also been called 'apathetic' or 'depressed', particularly when profoundly inactive. However, these terms are rarely operationally defined and validated. As a negative state caused by under-stimulation, boredom should increase interest in stimuli of all kinds. Apathy (lack of interest), by contrast, should manifest as decreased interest in all stimuli, while anhedonia (loss of pleasure, a depressive symptom) should specifically decrease interest in normally rewarding stimuli. We tested the hypotheses that mink, a model carnivore, experience more boredom, depression-like apathy, or anhedonia in non-enriched (NE) cages than in complex, enriched (E) cages. We exposed 29 subjects (13 E, 16 NE) to ten stimuli categorized a priori as aversive (e.g. air puffs), rewarding (e.g. evoking chasing) or ambiguous/neutral (e.g. candles). Interest in stimuli was assessed via latencies to contact, contact durations, and durations oriented to stimuli. NE mink contacted all stimuli faster (P = 0.003) than E mink, and spent longer oriented to/in contact with them, albeit only significantly so for ambiguous ones (treatment*type P<0.013). With stimulus category removed from statistical models, interest in all stimuli was consistently higher among NE mink (P<0.0001 for all measures). NE mink also consumed more food rewards (P = 0.037). Finally, we investigated whether lying down while awake and stereotypic behaviour (both increased by NE housing) predicted these responses. Lying awake positively co-varied with certain measures of increased exploration. In contrast, stereotypic 'scrabbling' or locomotion (e.g. pacing) did not. Overall, NE mink showed no evidence of apathy or depression, but instead a heightened investigation of diverse stimuli consistent with boredom. This state was potentially indicated by spending much time lying still but awake (although this result requires replication). Boredom can thus be operationalized and assessed empirically in non-human animals. It can also be reduced by environmental enrichment

A Single Acidic Residue Can Guide Binding Site Selection but Does Not Govern QacR Cationic-Drug Affinity

Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and rhodamine 6G, and therefore may contribute to drug neutralization and binding affinity. Here, we report structural, biochemical and in vivo effects of substituting these glutamate residues. Unexpectedly, substitutions had little impact on ligand affinity or in vivo induction capabilities. Structures of QacR(E90Q) and QacR(E120Q) with ethidium or malachite green took similar global conformations that differed significantly from all previously described QacR-drug complexes but still prohibited binding to cognate DNA. Strikingly, the QacR(E90Q)-rhodamine 6G complex revealed two mutually exclusive rhodamine 6G binding sites. Despite multiple structural changes, all drug binding was essentially isoenergetic. Thus, these data strongly suggest that rather than contributing significantly to ligand binding affinity, the role of acidic residues lining the QacR multidrug-binding pocket is primarily to attract and guide cationic drugs to the “best available” positions within the pocket that elicit QacR induction

Transgenesis in Animal Agriculture: Addressing Animal Health and Welfare Concerns

The US Food and Drug Administration’s final Guidance for Industry on the regulation of transgenesis in animal agriculture has paved the way for the commercialization of genetically engineered (GE) farm animals. The production-related diseases associated with extant breeding technologies are reviewed, as well as the predictable welfare consequences of continued emphasis on prolificacy at the potential expense of physical fitness. Areas in which biotechnology could be used to improve the welfare of animals while maintaining profitability are explored along with regulatory schema to improve agency integration in GE animal oversight

Self-Similar Processes Follow a Power Law in Discrete Logarithmic Space.

Cities, wealth, and earthquakes follow continuous power-law probability distributions such as the Pareto distribution, which are canonically associated with scale-free behavior and self-similarity. However, many self-similar processes manifest as discrete steps that do not produce a continuous scale-free distribution. We construct a discrete power-law distribution that arises naturally from a simple model of hierarchical self-similar processes such as turbulence and vasculature, and we derive the maximum-likelihood estimate (MLE) for its exponent. Our distribution is self-similar, in contrast to previously studied discrete power laws such as the Zipf distribution. We show that the widely used MLE derived from the Pareto distribution leads to inaccurate estimates in systems that lack continuous scale invariance such as branching networks and data subject to logarithmic binning. We apply our MLE to data from bronchial tubes, blood vessels, and earthquakes to produce new estimates of scaling exponents and resolve contradictions among previous studies

Testing Foundations of Biological Scaling Theory Using Automated Measurements of Vascular Networks.

Scientists have long sought to understand how vascular networks supply blood and oxygen to cells throughout the body. Recent work focuses on principles that constrain how vessel size changes through branching generations from the aorta to capillaries and uses scaling exponents to quantify these changes. Prominent scaling theories predict that combinations of these exponents explain how metabolic, growth, and other biological rates vary with body size. Nevertheless, direct measurements of individual vessel segments have been limited because existing techniques for measuring vasculature are invasive, time consuming, and technically difficult. We developed software that extracts the length, radius, and connectivity of in vivo vessels from contrast-enhanced 3D Magnetic Resonance Angiography. Using data from 20 human subjects, we calculated scaling exponents by four methods-two derived from local properties of branching junctions and two from whole-network properties. Although these methods are often used interchangeably in the literature, we do not find general agreement between these methods, particularly for vessel lengths. Measurements for length of vessels also diverge from theoretical values, but those for radius show stronger agreement. Our results demonstrate that vascular network models cannot ignore certain complexities of real vascular systems and indicate the need to discover new principles regarding vessel lengths