Search

The physical and engineering sciences have much to offer in understanding, diagnosing, and even treating cancer. Microfluidics, imaging, materials, and diverse measurement devices are all helping to shift paradigms of tumorigenesis and dissemination. Using materials and micro-probes of elasticity, for example, epithelia have been shown to transform into mesenchymal cells when the elasticity of adjacent tissue increases. Approaches common in engineering science enable such discoveries, and further application of such tools and principles will likely improve existing cancer models in vivo and also create better models for high throughput analyses in vitro. As profiled in this special topic issue composed of more than a dozen manuscripts, opportunities abound for the creativity and analytics of engineering and the physical sciences to make advances in and against cancer.

Human-induced thermal variability can disrupt energy balance and performance in ectotherms; however, phenotypic plasticity may play a pivotal protective role. Ectotherm performance can be maintained in thermally heterogeneous habitats by reducing the thermal sensitivity of physiological processes and concomitant performance. We examined the capacity of juvenile green sturgeon (Acipenser medirostris) to respond to daily thermal variation. Juveniles (47 days post-hatch) were exposed to either stable (15 ± 0.5 °C) or variable (narrowly variable: 13-17 °C day-1 or widely variable 11-21 °C day-1) thermoperiod treatments, with equivalent mean temperatures (15 ± 0.5 °C), for 21 days. Growth (relative growth rate, % body mass gain), upper thermal tolerance (critical thermal maxima, CTMax) and the thermal sensitivity of swimming performance (critical swimming speed, Ucrit) were assessed in fish from all treatments. Accelerated growth was observed in fish maintained under widely variable temperatures compared to narrowly variable and stable temperatures. No significant variation in CTMax was observed among thermoperiod treatments, suggesting all treatment groups acclimated to the mean temperature rather than daily maximums. The widely variable treatment induced a plastic response in swimming performance, where Ucrit was insensitive to temperature and performance was maintained across a widened thermal breadth. Maximum Ucrit attained was similar among thermoperiod treatments, but performance was maximised at different test temperatures (stable: 4.62 ± 0.44 BL s-1 at 15 °C; narrowly variable: 4.52 ± 0.23 BL s-1 at 21 °C; widely variable: 3.90 ± 0.24 BL s-1 at 11 °C, mean ± s.e.m.). In combination, these findings suggest juvenile A. medirostris are resilient to daily fluctuations in temperature, within the temperature range tested here.

ObjectiveTo evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship.Study designWe assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis.ResultsOf 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively.ConclusionsAmong former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences.Trial registrationClinicalTrials.gov: NCT01022580.

Exploiting species-specific behavioural responses of fish to light is an increasingly promising technique to reduce the entrainment or impingement of fish that results from the diversion of water for human activities, such as hydropower or irrigation. Whilst there is some evidence that white light can be an effective deterrent for Chinook salmon smolts, the results have been mixed. There is a need to test the response of fish to different spectra and strobing frequencies to improve deterrent performance. We tested the movement and spatial response of groups of four fish to combinations of light-emitting diode (LED) spectra (red, green, blue and white light) during the day and night, and strobing frequencies (constant and 2Hz) during the day, using innovative LED technology intended as a behavioural guidance device for use in the field. Whilst strobing did not alter fish behaviour when compared to constant light, the red light had a repulsive effect during the day, with fish under this treatment spending significantly less time in the half of the arena closest to the behavioural guidance device compared to both the control and blue light. Importantly, this effect disappeared at night, where there were no differences in movement and space use found between spectra. There was some evidence of a potential attractive response of fish to the blue and green light during the day. Under these light treatments, fish spent the highest amount of time closest to the behavioural guidance device. Further tests manipulating the light intensity in the different spectra are needed to verify the mechanistic determinants of the observed behaviours. Results are discussed in reference to the known spectral sensitivities of the cone and rod photopigments in these fish, and further experiments are suggested to better relate the work to mitigating the effects on fish of infrastructure used for hydropower and irrigation.

BackgroundHypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection.ObjectivesThe aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia.MethodsThis article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria.Results and conclusionsEpo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

Abstract Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a ‘brain-eating’ disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to combat Balamuthia infections of the central nervous system are sparse; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Current treatments of encephalitis due to B. mandrillaris lack efficacy, leading to case fatality rates above 90%. Using our recently published methodology to discover potential drugs against pathogenic amoebas, we screened a collection of 85 compounds with known antiparasitic activity and identified 59 compounds that impacted the growth of Balamuthia trophozoites at concentrations below 220 µM. Since there is no fully annotated genome or proteome of B. mandrillaris, we sequenced and assembled its transcriptome from a high-throughput RNA-sequencing (RNA-Seq) experiment and located the coding sequences of the genes potentially targeted by the growth inhibitors from our compound screens. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing. These will be used in the future in combination with the identified hits in structure guided drug discovery campaigns to develop new approaches for the treatment of Balamuthia infections.

Babesiosis developed in a 62-year-old immunocompetent physician, who had an uneventful recovery after receiving atovaquone and azithromycin. Three years later, babesiosis developed again, and he was again successfully given treatment. Clinical and laboratory evidence were highly supportive of Babesia reinfection. Healthcare professionals should be aware that reinfection might occur in babesiosis.

Abstract Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.

Abstract In light of ongoing environmental change, understanding the complex impact of interacting stressors on species, communities, and ecosystems is an important challenge. Many studies to date examine the effects of potential stressors on a single species of concern. Yet these effects often resonate throughout a community and may produce changes in ecosystem dynamics that are equally critical to species resilience. The aim of this study was to develop a mechanistic understanding of how a rapidly changing stressor, water temperature, will alter trophic interactions among ectothermic fish species. In our region, California's Sacramento–San Joaquin River Delta system, it has been speculated that the decreased survivorship of juvenile Chinook salmon (Oncorhynchus tshawytscha) in warming waters may be caused partly by increased predation. Temperature influences metabolic rate functions and the amount of energy available for fitness‐relevant parameters (i.e., swim performance and escape response). Consequently, we hypothesized that these patterns of predation emerge due to a physiological advantage of predators over prey at warmer temperatures. To explore this, our first objective was to determine the fundamental thermal physiology of juvenile Chinook salmon and their potential predators in the Delta. Three physiological performance traits were measured for each species across a spectrum of temperatures: aerobic scope, burst speed, and the ability to burst repeatedly. For our second objective, we assessed whether the effect of temperature on these performance traits predicted the outcome of predation trials conducted across the same temperature spectrum. We found that temperature effects were species or population specific. Additionally, absolute burst swimming ability and the relative burst performance between predator and prey were stronger indicators of trophic dynamics than aerobic scope. Our analyses also confirmed that a major predator in the Delta, specifically largemouth bass (Micropterus salmoides), is more thermally adapted to higher temperatures and will likely consume salmon with an increasing frequency as waters warm. Thus, we show that an improved understanding of how fundamental thermal physiology impacts predation can provide ecosystem managers with better tools to predictively model predation upon juvenile salmon based on prevailing and future water temperatures.

Stem cells are particularly 'plastic' cell types that are induced by various cues to become specialized, tissue-functional lineages by switching on the expression of specific gene programs. Matrix stiffness is among the cues that multiple stem cell types can sense and respond to. This seminar-style review focuses on mechanosensing of matrix elasticity in the differentiation or early maturation of a few illustrative stem cell types, with an intended audience of biologists and physical scientists. Contractile forces applied by a cell's acto-myosin cytoskeleton are often resisted by the extracellular matrix and transduced through adhesions and the cytoskeleton ultimately into the nucleus to modulate gene expression. Complexity is added by matrix heterogeneity, and careful scrutiny of the evident stiffness heterogeneity in some model systems resolves some controversies concerning matrix mechanosensing. Importantly, local stiffness tends to dominate, and 'durotaxis' of stem cells toward stiff matrix reveals a dependence of persistent migration on myosin-II force generation and also rigid microtubules that confer directionality. Stem and progenitor cell migration in 3D can be further affected by matrix porosity as well as stiffness, with nuclear size and rigidity influencing niche retention and fate choices. Cell squeezing through rigid pores can even cause DNA damage and genomic changes that contribute to de-differentiation toward stem cell-like states. Contraction of acto-myosin is the essential function of striated muscle, which also exhibit mechanosensitive differentiation and maturation as illustrated in vivo by beating heart cells and by the regenerative mobilization of skeletal muscle stem cells.

Abstract Background For the treatment of radicular pain, nerve root infiltrations can be performed under MRI guidance in select, typically younger, patients where repeated CT exams are not desirable due to associated radiation risk, or potential allergic reactions to iodinated contrast medium. Methods Fifteen 3 T MRI-guided nerve root infiltrations were performed in 12 patients with a dedicated surface coil combined with the standard spine coil, using a breathhold PD sequence. The needle artifact on the MR images and the distance between the needle tip and the infiltrated nerve root were measured. Results The distance between the needle tip and the nerve root was 2.1 ± 1.4 mm. The visual artifact width, perpendicular to the needle long axis, was 2.1 ± 0.7 mm. No adverse events were reported. Conclusion This technical note describes the optimization of the procedure in a 3 T magnetic field, including reported procedure time and an assessment of targeting precision.