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Using a large animal model and employing a comprehensive approach integrating hemodynamic, transcriptomic, proteomic, and immunohistochemical analyses, we examined the early (2 wk) effects of severe PH on the RV. We observed that RV remodeling during PH progression represents a continuum of transcriptionally driven processes whereby cardiac myocytes, fibroblasts, endothelial cells, and proremodeling macrophages act to coordinately maintain physiological homeostasis and protect myocyte survival during chronic, severe, and progressive pressure overload.

For centuries, scientists have recognized and worked to understand how Earth's mutable landscape and climate shape the distribution and evolution of species. Here, we describe the emerging field of geogenomics, which uses the reciprocal and deep integration of geologic, climatic, and population genomic data to define and test cause-effect relationships between Earth and life at intermediate spatial and temporal scales (i.e., the mesoscale). Technological advances now power the detailed reconstruction of landscape and evolutionary histories, but transdisciplinary collaborations and new quantitative tools are needed to better integrate Earth-life data. Geogenomics can help build a more unified theory and characterize the boundary conditions under which geologic and climatic processes generate new biodiversity, how species' responses differ, and why.

In recent decades, biologist have focused on the spatiotemporal regulation and function of genes to understand embryogenesis. It is clear that maternal diet impacts fetal development but how nutrients, like lipids and vitamins, modify developmental programs is not completely understood. Fish are useful research organisms for such investigations. Most species of fish produce eggs that develop outside the mother, dependent on a finite amount of yolk to form and grow. The developing embryo is a closed system that can be readily biochemically analyzed, easily visualized, and manipulated to understand the role of nutrients in tissue specification, organogenesis, and growth. Natural variation in yolk composition observed across fish species may be related to unique developmental strategies. In this review, we discuss the reasons that teleost fishes are powerful models to understand nutritional control of development and highlight three species that are particularly valuable for future investigations: the zebrafish, Danio rerio, the African Killifish, Nothobranchius furzeri, and the Mexican tetra, Astyanax mexicanus. This review is a part of a special issue on nutritional, hormonal, and metabolic drivers of development.

Background Despite a longstanding interest in understanding how animals adapt to environments with limited nutrients, we have incomplete knowledge of the genetic basis of metabolic evolution. The Mexican tetra, Astyanax mexicanus, is a species of fish that consists of two morphotypes; eyeless cavefish that have adapted to a low-nutrient cave environment, and ancestral river-dwelling surface fish with abundant access to nutrients. Cavefish have evolved altered blood sugar regulation, starvation tolerance, increased fat accumulation, and superior body condition. To investigate the genetic basis of cavefish metabolic evolution we carried out a quantitative trait loci (QTL) analysis in surface/cave F2 hybrids. We genetically mapped seven metabolism-associated traits in hybrids that were challenged with a nutrient restricted diet. Results We found that female F2 hybrids are bigger than males and have a longer hindgut, bigger liver, and heavier gonad, even after correcting for fish size. Although there is no difference between male and female blood sugar level, we found that high blood sugar is associated with weight gain in females and lower body weight and fat level in males. We identified a significant QTL associated with 24-h-fasting blood glucose level with the same effect in males and females. Differently, we identified sex-independent and sex-dependent QTL associated with fish length, body condition, liver size, hindgut length, and gonad weight. We found that some of the genes within the metabolism QTL display evidence of non-neutral evolution and are likely to be under selection. Furthermore, we report predicted nonsynonymous changes to the cavefish coding sequence of these genes. Conclusions Our study reveals previously unappreciated genomic regions associated with blood glucose regulation, body condition, gonad size, and internal organ morphology. In addition, we find an interaction between sex and metabolism-related traits in A. mexicanus. We reveal coding changes in genes that are likely under selection in the low-nutrient cave environment, leading to a better understanding of the genetic basis of metabolic evolution.

Samples of young type Ia supernovae have shown `early excess' emission in a few cases. Similar excesses are predicted by some explosion and progenitor scenarios and hence can provide important clues regarding the origin of thermonuclear supernovae. They are however, only predicted to last up to the first few days following explosion. It is therefore unclear whether such scenarios are intrinsically rare or if the relatively small sample size simply reflects the difficulty in obtaining sufficiently early detections. To that end, we perform toy simulations covering a range of survey depths and cadences, and investigate the efficiency with which young type Ia supernovae are recovered. As input for our simulations, we use models that broadly cover the range of predicted luminosities. Based on our simulations, we find that in a typical three day cadence survey, only $\sim$10% of type Ia supernovae would be detected early enough to rule out the presence of an excess. A two day cadence however, should see this increase to $\sim$15%. We find comparable results from more detailed simulations of the Zwicky Transient Facility surveys. Using the recovery efficiencies from these detailed simulations, we investigate the number of young type Ia supernovae expected to be discovered assuming some fraction of the population come from scenarios producing an excess at early times. Comparing the results of our simulations to observations, we find the intrinsic fraction of type Ia supernovae with early flux excesses is $\sim28^{+13}_{-11}%$%., 16 pages, 15 figures, 2 tables. Accepted for publication in MNRAS

Carotenoids are lipid-soluble yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and therefore limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed. Astyanax mexicanus is a species of fish with river-adapted (surface) and multiple cave-adapted populations (i.e. Tinaja, Pachón, Molino). Cavefish exhibit regressive features, such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here we show that unlike surface fish, Tinaja and Pachón cavefish accumulate carotenoids in the visceral adipose tissue (VAT). Carotenoid accumulation is not observed in Molino cavefish, indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci (QTL) mapping and RNA sequencing to investigate genetic changes associated with carotenoid accumulation. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into un-pigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishes A. mexicanus as a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.

The final explosive fate of massive stars, and the nature of the compact remnants they leave behind (black holes and neutron stars), are major open questions in astrophysics. Many massive stars are stripped of their outer hydrogen envelopes as they evolve. Such Wolf-Rayet (W-R) stars emit strong and rapidly expanding (v_wind>1000 km/s) winds indicating a high escape velocity from the stellar surface. A fraction of this population is also helium depleted, with spectra dominated by highly-ionized emission lines of carbon and oxygen (Types WC/WO). Evidence indicates that the most commonly-observed supernova (SN) explosions that lack hydrogen and helium (Types Ib/Ic) cannot result from massive WC/WO stars, leading some to suggest that most such stars collapse directly into black holes without a visible supernova explosions. Here, we present observations of supernova SN 2019hgp, discovered about a day after explosion. The short rise time and rapid decline place it among an emerging population of rapidly-evolving transients (RETs). Spectroscopy reveals a rich set of emission lines indicating that the explosion occurred within a nebula composed of carbon, oxygen, and neon. Narrow absorption features show that this material is expanding at relatively high velocities (>1500 km/s) requiring a compact progenitor. Our observations are consistent with an explosion of a massive WC/WO star, and suggest that massive W-R stars may be the progenitors of some rapidly evolving transients., Unedited author version, Nature in press

SN\,2020qlb (ZTF20abobpcb) is a hydrogen-poor superluminous supernova (SLSN-I) that is among the most luminous (maximum M$_{g} = -22.25$ mag) and that has one of the longest rise times (77 days from explosion to maximum). We estimate the total radiated energy to be $>2.1\times10^{51}$ erg. SN\,2020qlb has a well-sampled light curve that exhibits clear near and post peak undulations, a phenomenon seen in other SLSNe, whose physical origin is still unknown. We discuss the potential power source of this immense explosion as well as the mechanisms behind its observed light curve undulations. We analyze photospheric spectra and compare them to other SLSNe-I. We constructed the bolometric light curve using photometry from a large data set of observations from the Zwicky Transient Facility (ZTF), Liverpool Telescope (LT), and Neil Gehrels Swift Observatory and compare it with radioactive, circumstellar interaction and magnetar models. Model residuals and light curve polynomial fit residuals are analyzed to estimate the undulation timescale and amplitude. We also determine host galaxy properties based on imaging and spectroscopy data, including a detection of the [O III]$\lambda$4363, auroral line, allowing for a direct metallicity measurement. We rule out the Arnett $^{56}$Ni decay model for SN\,2020qlb's light curve due to unphysical parameter results. Our most favored power source is the magnetic dipole spin-down energy deposition of a magnetar. Two to three near peak oscillations, intriguingly similar to those of SN\,2015bn, were found in the magnetar model residuals with a timescale of $32\pm6$ days and an amplitude of 6$\%$ of peak luminosity. We rule out centrally located undulation sources due to timescale considerations; and we favor the result of ejecta interactions with circumstellar material (CSM) density fluctuations as the source of the undulations., Comment: 22 pages, 25 figures, submitted to A&A

The moss Physcomitrium patens diverged from green algae shortly after the colonization of land by ancient plants. This colonization posed new environmental challenges which drove evolutionary processes. The photosynthetic machinery of modern flowering plants is adapted to the high light conditions on land. Red shifted Lhca4 antennae are present in the photosystem I light harvesting complex of many green lineage plants but absent from P. patens. The Cryo-EM structure of the P. patens photosystem I light harvesting complex I supercomplex (PSI-LHCI) at 2.8 Å reveals that Lhca4 is replaced by a unique Lhca2 paralogue in moss. This PSI-LHCI supercomplex also retains the PsaM subunit, present in cyanobacteria and several algal species but lost in higher plants, and the PsaO subunit responsible for binding light harvesting complex II. The blue shifted Lhca2 paralogue and chlorophyll b enrichment relative to higher plants make the P. patens PSI-LHCI spectroscopically unique among other green lineage supercomplexes. Overall, the structure represents an evolutionary intermediate PSI with the crescent shaped LHCI common in higher plants and contains a unique Lhca2 paralogue which facilitates the mosses adaptation to low light niches.

Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by complement-dependent, fibroblast-induced perivascular accumulation and proinflammatory activation of macrophages. We hypothesized that, in PH, nanoscale-sized small extracellular vesicles (sEVs), released by perivascular/adventitial fibroblasts, are critical mediators of complement-dependent proinflammatory activation of macrophages. Pulmonary adventitial fibroblasts were isolated from calves with severe PH (PH-Fibs) and age-matched controls (CO-Fibs). PH-Fibs exhibited increased secretion of sEVs, compared with CO-Fibs, and sEV biological activity was tested on mouse and bovine bone marrow-derived macrophages (BMDMs) and showed similar responses. Compared with sEVs derived from CO-Fibs, sEVs derived from PH-Fibs (PH-Fib-sEVs) induced augmented expression of proinflammatory cytokines/chemokines and metabolic genes in BMDMs. Pharmacological blockade of exosome release from PH-Fibs resulted in significant attenuation of proinflammatory activation of BMDMs. "Bottom-up" proteomic analyses revealed significant enrichment of complement and coagulation cascades in PH-Fib-sEVs, including augmented expression of the complement component C3. We therefore examined whether the PH-Fib-sEV-mediated proinflammatory activation of BMDMs was complement C3 dependent. Treatment of PH-Fibs with siC3-RNA significantly attenuated the capacity of PH-Fib-sEVs for proinflammatory activation of BMDMs. PH-Fib-sEVs mediated proglycolytic alterations and complement-dependent activation of macrophages toward a proinflammatory phenotype, as confirmed by metabolomic studies. Thus, fibroblast-released sEVs served as critical mediators of complement-induced perivascular/microenvironmental inflammation in PH.

We report on the discovery of AT2018lqh (ZTF18abfzgpl) -- a rapidly-evolving extra-galactic transient in a star-forming host at 242 Mpc. The transient g-band light curve's duration above half-maximum light is about 2.1 days, where 0.4/1.7 days are spent on the rise/decay, respectively. The estimated bolometric light curve of this object peaked at about 7x10^42 erg/s -- roughly seven times brighter than AT2017gfo. We show that this event can be explained by an explosion with a fast (v~0.08 c) low-mass (~0.07 Msun) ejecta, composed mostly of radioactive elements. For example, ejecta dominated by Ni-56 with a time scale of t_0=1.6 days for the ejecta to become optically thin for gamma-rays fits the data well. Such a scenario requires burning at densities that are typically found in the envelopes of neutron stars or the cores of white dwarfs. A combination of circumstellar material (CSM) interaction power at early times and shock cooling at late times is consistent with the photometric observations, but the observed spectrum of the event may pose some challenges for this scenario. The observations are not consistent with a shock breakout from a stellar envelope, while a model involving a low-mass ejecta ramming into low-mass CSM cannot explain both the early- and late-time observations., 10 pages, ApJ in press

Metabolic syndrome affects 35% of individuals in the USA and has been correlated with increased complications following certain surgical procedures. There has been an increase of 11% in breast reduction procedures from 2016 to 2017 making it the seventh most common reconstructive procedure in the USA. Previous studies have identified an increase in demand for breast reduction among obese patients with BMI ≥ 30 but have not defined the role of metabolic syndrome in surgical outcomes. The authors aim to investigate the impact of metabolic syndrome on 30-day postoperative morbidity and mortality in patients who underwent reduction mammoplasty.

The current study explored preservice and inservice teachers’ perspectives on data literacy for teaching. Semi-structured interviews were employed with 12 teacher candidates in elementary and speci...

Although the importance of mentor teachers in clinical teacher preparation is well established, few researchers explore the social identity development of these individuals. Through our study we co...

Mammals have played a foundational role in the explosive growth of phylogeography over the past 30 years that it has been a recognized discipline. Novel discoveries of geographic patterns and processes using phylogeographic approaches have integrated disciplines including biogeography, evolutionary biology, ecology, and conservation biology. Here, we use several approaches to survey the scope and influence of phylogeography, beginning with use of a well-studied family of North American rodents to contrast information content derived from DNA-based phylogeography versus a popular older method, allozyme electrophoresis, of assaying genetic variation within and among species across geography. We conclude that phylogeography has elevated the quality of insights attainable regarding, for example, the causal role of Earth history events in processes including lineage divergence, speciation, and adaptive evolution. Next, we use searches of the Web of Science with an array of terms that return information on molecular markers employed, numbers of individuals and localities examined, time frames investigated, historical processes and ways that species and biotas have responded to Earth history, design of phylogeographic studies (e.g., single-taxon versus comparative), and current gaps in taxonomic and geographic sampling. Highlighted results from phylogeographic assays include: an average of 3.3 cryptic lineages per taxonomic species in rodents; a bias in number of studies toward less-diverse biogeographic regions; and a relatively low number of mammalian genera studied. We conclude with predicted and recommended directions for future growth in mammalian phylogeography, including prospects for an increasing role of next generation-based genomics.

The moss Physcomitrium patens diverged from green algae shortly after the colonization of land by ancient plants. This colonization posed new environmental challenges, which drove evolutionary processes. The photosynthetic machinery of modern flowering plants is adapted to the high light conditions on land. Red-shifted Lhca4 antennae are present in the photosystem I light-harvesting complex of many green-lineage plants but absent in P. patens. The cryo-EM structure of the P. patens photosystem I light-harvesting complex I supercomplex (PSI-LHCI) at 2.8 Å reveals that Lhca4 is replaced by a unique Lhca2 paralogue in moss. This PSI-LHCI supercomplex also retains the PsaM subunit, present in Cyanobacteria and several algal species but lost in vascular plants, and the PsaO subunit responsible for binding light-harvesting complex II. The blue-shifted Lhca2 paralogue and chlorophyll b enrichment relative to flowering plants make the P. patens PSI-LHCI spectroscopically unique among other green-lineage supercomplexes. Overall, the structure represents an evolutionary intermediate PSI with the crescent-shaped LHCI common in vascular plants, and contains a unique Lhca2 paralogue that facilitates the moss's adaptation to low-light niches.

The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.

A case-based laboratory event integrating neuroanatomy, neuroscience, and psychiatry was implemented into a pre-clerkship psychiatry-based course for second-year medical students. Learners rotating through lab stations to work on different cases to make interdisciplinary connections among these fields is an innovative way for them to integrate foundational neurology, neuroanatomy, and psychiatry concepts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-020-01171-0.

Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. In nature, adaptation to severe environmental change, such as encountered following colonization of caves, has dramatically altered genomes of species over varied time spans. Genomic sequencing approaches have identified mutations associated with troglomorphic trait evolution, but the functional impacts of these mutations remain poorly understood. The Mexican Tetra,Astyanax mexicanus, is abundant in the surface waters of northeastern Mexico, and also inhabits at least 30 different caves in the region. Cave-dwellingA. mexicanusmorphs are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses for pigmentation and eye size and found new candidate genes for eye loss such asdusp26. We used CRISPR gene editing inA. mexicanusto confirm the essential role of a gene within an eye size QTL,rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability that includes an analysis of the impact on protein-coding genes across cavefish populations to gain insight into this potential source of cave adaptation. The new surface fish genome reference now provides a more complete resource for comparative, functional, developmental and genetic studies of drastic trait differences within a species.

Articles Discussed: Stahl, B. A. et al. Manipulation of Gene Function in Mexican Cavefish. Journal of Visualized Experiments. (146) (2019). Peus, R. et al. Gamete Collection and In Vitro Fertilization of Astyanax mexicanus. Journal of Visualized Experiments. (147) (2019). Worsham, M. et al. Behavioral Tracking and Neuromast Imaging of Mexican Cavefish.Journal of Visualized Experiments. (147) (2019). Jaggard, J.B., Lloyd, E., Lopatto, A., Duboue, E.R., Keene, A.C. Automated Measurements of Sleep and Locomotor Activity in Mexican Cavefish. Journal of Visualized Experiments. (145) (2019). Luc, H., Sears, C., Raczka, A., Gross, J.B. Wholemount In Situ Hybridization for Astyanax Embryos. Journal of Visualized Experiments. (145) (2019). Riddle, M., Martineau, B., Peavey, M., Tabin, C. Raising the Mexican Tetra Astyanax mexicanus for Analysis of Post-larval Phenotypes and Whole-mount Immunohistochemistry. Journal of Visualized Experiments. (142) (2018).

Currently time-domain astronomy can scan the entire sky on a daily basis, discovering thousands of interesting transients every night. Classifying the ever-increasing number of new transients is one of the main challenges for the astronomical community. One solution that addresses this issue is the robotically controlled Spectral Energy Distribution Machine (SEDM) which supports the Zwicky Transient Facility (ZTF). SEDM with its pipeline PYSEDM demonstrates that real-time robotic spectroscopic classification is feasible. In an effort to improve the quality of the current SEDM data, we present here two new modules, BYECR and CONTSEP. The first removes contamination from cosmic rays, and the second removes contamination from non-target light. These new modules are part of the automated PYSEDM pipeline and fully integrated with the whole process. Employing BYECR and CONTSEP modules together automatically extracts more spectra than the current PYSEDM pipeline. Using SNID classification results, the new modules show an improvement in the classification rate and accuracy of 2.8% and 1.7%, respectively, while the strength of the cross-correlation remains the same. Improvements to the SEDM astrometry would further boost the improvement of the CONTSEP module. This kind of robotic follow-up with a fully automated pipeline has the potential to provide the spectroscopic classifications for the transients discovered by ZTF and also by the Rubin Observatory's Legacy Survey of Space and Time., 9 pages, 6 figures, 2 tables, accepted for publication in PASP

Through the course of evolution, the gastrointestinal (GI) tract has been modified to maximize nutrient absorption, forming specialized segments that are morphologically and functionally distinct. Here we show that the GI tract of the Mexican tetra, Astyanax mexicanus, has distinct regions, exhibiting differences in morphology, motility, and absorption. We found that A. mexicanus populations adapted for life in subterranean caves exhibit differences in the GI segments compared to those adapted to surface rivers. Cave-adapted fish exhibit bi-directional churning motility in the stomach region that is largely absent in river-adapted fish. We investigated how this motility pattern influences intestinal transit of powdered food and live prey. We found that powdered food is more readily emptied from the cavefish GI tract. In contrast, the transit of live rotifers from the stomach region to the midgut occurs more slowly in cavefish compared to surface fish, consistent with the presence of churning motility. Differences in intestinal motility and transit likely reflect adaptation to unique food sources available to post-larval A. mexicanus in the cave and river environments. We found that cavefish grow more quickly than surface fish when fed ad libitum, suggesting that altered GI function may aid in nutrient consumption or absorption. We did not observe differences in enteric neuron density or smooth muscle organization between cavefish and surface fish. Altered intestinal motility in cavefish could instead be due to changes in the activity or patterning of the enteric nervous system. Exploring this avenue will lead to a better understanding of how the GI tract evolves to maximize energy assimilation from novel food sources.

Metabolic syndrome affects 35% of individuals in the USA and has been correlated with increased complications following certain surgical procedures. There has been an increase of 11% in breast reduction procedures from 2016 to 2017 making it the seventh most common reconstructive procedure in the USA. Previous studies have identified an increase in demand for breast reduction among obese patients with BMI ≥ 30 but have not defined the role of metabolic syndrome in surgical outcomes. The authors aim to investigate the impact of metabolic syndrome on 30-day postoperative morbidity and mortality in patients who underwent reduction mammoplasty.

Most published studies addressing the role of HIFs in hypoxia-induced PH development employ models that may not recapitulate the clinical setting, including the use of animals having pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Further, critical questions including how and when HIF-signalling contributes to hypoxia-induced PH remains unanswered.Normal adult rodents in which global HIF1 or 2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides-ASO and small molecule inhibitors) were exposed to short-term (4 days) or chronic (4–5 weeks) hypoxia. Hemodynamic studies were performed, the animals euthanized and lungs and heart obtained for pathologic and transcriptomic analysis. Cell-type specific HIF signals for PH initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type specific HIF deletion).Global HIF1α deletion in mice did not prevent hypoxia-induced PH at 5 weeks. Mice with global HIF2α deletion did not survive long-term hypoxia. Partial HIF2α gene deletion, or HIF2-ASO (but not HIF1-ASO) reduced vessel muscularization, rises in pulmonary artery pressures and right ventricular hypertrophy in mice exposed to 4–5 week hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4-day hypoxia as well as vessel musculization, tenascin C accumulation and PH development in rats exposed to 5 week hypoxia. In vitro, HIF2 induced a distinct set of genes in normal pulmonary vascular EC, mediating inflammation and proliferation of EC and SMC. EC HIF2α knockout prevented hypoxia-induced PH in mice.Inhibition of HIF2, not HIF1 can provide a therapeutic approach to prevent the development of hypoxia-induced PH. Future studies are needed to investigate the role of HIFs in PH progression and reversal.

Studies in various animal models suggest an important role for pulmonary macrophages in the pathogenesis of pulmonary hypertension (PH). Yet, the molecular mechanisms characterizing the functional macrophage phenotype relative to time and pulmonary localization and compartmentalization remain largely unknown. In this study, we used a hypoxic murine model of PH in combination with FACS to quantify and isolate lung macrophages from two compartments over time and characterize their programing via RNA sequencing approaches. In response to hypoxia, we found an early increase in macrophage number that was restricted to the interstitial/perivascular compartment, without recruitment of macrophages to the alveolar compartment or changes in the number of resident alveolar macrophages. Principal component analysis demonstrated significant differences in overall gene expression between alveolar and interstitial macrophages (IMs) at baseline and after 4 and 14 d hypoxic exposure. Alveolar macrophages at both day 4 and 14 and IMs at day 4 shared a conserved hypoxia program characterized by mitochondrial dysfunction, proinflammatory gene activation, and mTORC1 signaling, whereas IMs at day 14 demonstrated a unique anti-inflammatory/proreparative programming state. We conclude that the pathogenesis of vascular remodeling in hypoxic PH involves an early compartment-independent activation of lung macrophages toward a conserved hypoxia program, with the development of compartment-specific programs later in the course of the disease. Thus, harnessing time- and compartment-specific differences in lung macrophage polarization needs to be considered in the therapeutic targeting of macrophages in hypoxic PH and potentially other inflammatory lung diseases.

Topographically complex regions on land and in the oceans feature hotspots of biodiversity that reflect geological influences on ecological and evolutionary processes. Over geologic time, topographic diversity gradients wax and wane over millions of years, tracking tectonic or climatic history. Topographic diversity gradients from the present day and the past can result from the generation of species by vicariance or from the accumulation of species from dispersal into a region with strong environmental gradients. Biological and geological approaches must be integrated to test alternative models of diversification along topographic gradients. Reciprocal illumination among phylogenetic, phylogeographic, ecological, paleontological, tectonic, and climatic perspectives is an emerging frontier of biogeographic research.

The differentiated cell identities and structure of fully formed organs are generally stable after their development. In contrast, we report here that development of the C. elegans proximal somatic gonad (hermaphrodite uterus and spermathecae, and male vas deferens) can be redirected into intestine-like organs by brief expression of the ELT-7 GATA transcription factor. This process converts one developing organ into another and can hence be considered “transorganogenesis.” We show that, following pulsed ELT-7 expression, cells of the uterus activate and maintain intestine-specific gene expression and are transformed at the ultrastructural level to form an epithelial tube resembling the normal intestine formed during embryogenesis. Ubiquitous ELT-7 expression activates intestinal markers in many different cell types but only cells in the somatic gonad and pharynx appear to become fully reprogrammed. We found that ectopic expression of other endoderm-promoting transcription factors, but not muscle- or ectoderm- promoting transcription factors, redirects the fate of these organs, suggesting that pharyngeal and somatic gonad cells are specifically competent to adopt intestine identity. Although the intestine, pharynx, and somatic gonad are derived from distant cell lineages, they all express the PHA-4/FoxA transcription factor. While we found that post-embryonic PHA-4 is not necessary for pharynx or uterus reprogramming and PHA-4 is not sufficient in combination with ELT-7 to induce reprogramming in other cells types, knock down of PHA-4 during embryogenesis, which abolishes normal pharynx differentiation, prevents pharyngeal precursors from being reprogrammed into intestine. These results suggest that differentiated cell identity determines susceptibility to transdifferentiation and highlight the importance of cellular context in controlling competency for reprogramming.

The gastrointestinal tract has evolved in numerous ways to allow animals to optimally assimilate energy from different foods. The morphology and physiology of the gut is plastic and can be greatly altered by diet in some animals. In this study, we investigated the evolution and plasticity of gastrointestinal tract morphology by comparing laboratory-raised cave- and river-adapted forms of the Mexican tetra, Astyanax mexicanus, reared under different dietary conditions. In the wild, river-dwelling populations (surface fish) consume plants and insects throughout the year, while cave-dwelling populations (cavefish) live in a perpetually dark environment and depend on nutrient-poor food brought in by bats or seasonal floods. We found that multiple cave populations converged on a reduced number of digestive appendages called pyloric caeca and that some cave populations have a lengthened gut while others have a shortened gut. Moreover, we identified differences in how gut morphology and proliferation respond to diet between surface fish and cavefish. Using a combination of quantitative genetic mapping, population genetics, and RNA sequencing, we found that changes to the molecular and genetic pathways that influence cell proliferation, differentiation, and immune system function may underlie evolution of the cavefish gut.

Carotenoids are yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and therefore limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed.Astyanax mexicanusis a species of fish with river-adapted (surface) and multiple cave-adapted populations (i.e. Tinaja, Pachón, Molino). Cavefish exhibit regressive features such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here we show that unlike surface fish, Tinaja and Pachón cavefish accumulate carotenoids in the visceral adipose tissue (VAT). Carotenoid accumulation is not observed in Molino cavefish indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci mapping and RNA sequencing to investigate genetic changes associated with this trait. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into un-pigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishesA. mexicanusas a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.Research HighlightsCavefish accumulate carotenoids in the visceral adipose tissue (VAT)Genetic mapping reveals candidate genes associated with yellow VATCarotenoid accumulation is linked with decreased expression of carotenoid-processing genes