A self-generated Toddler gradient guides mesodermal cell migration

The sculpting of germ layers during gastrulation relies on coordinated migration of progenitor cells, yet the cues controlling these long-range directed movements remain largely unknown. While directional migration often relies on a chemokine gradient generated from a localized source, we find that zebrafish ventrolateral mesoderm is guided by the uniformly expressed and secreted protein Toddler/ELABELA/Apela, acting as a self-generated gradient. We show that the Apelin receptor, which is specifically expressed in mesodermal cells, has a dual role during gastrulation, acting as a scavenger receptor to generate a Toddler gradient, and as a chemokine receptor to sense this guidance cue. Thus, we uncover a single receptor-based self-generated gradient as the enigmatic guidance cue that can robustly steer the directional migration of mesoderm through the complex and continuously changing environment of the gastrulating embryo.

Risk factors and spatio-temporal patterns of livestock anthrax in Khuvsgul Province, Mongolia

Anthrax is a worldwide zoonotic disease. Anthrax has long been a public health and socio-economic issue in Mongolia. Presently, there is no spatial information on carcass burial sites as a potential hazard of future anthrax outbreaks and possible risk factors associated with anthrax occurrences in Mongolia. Here, we analyze retrospective data (1986–2015) on the disposal sites of livestock carcasses to describe historical spatio-temporal patterns of livestock anthrax in Khuvsgul Province, which showed the highest anthrax incidence rate in Mongolia. From the results of spatial mean and standard deviational ellipse analyses, we found that the anthrax spatial distribution in livestock did not change over the study period, indicating a localized source of exposure. The multi-distance spatial cluster analysis showed that carcass sites distributed in the study area are clustered. Using kernel density estimation analysis on carcass sites, we identified two anthrax hotspots in low-lying areas around the south and north regions. Notably, this study disclosed a new hotspot in the northern part that emerged in the last decade of the 30-year study period. The highest proportion of cases was recorded in cattle, whose prevalence per area was highest in six districts (i.e., Murun, Chandmani-Undur, Khatgal, Ikh-Uul, Tosontsengel, and Tsagaan-Uul), suggesting that vaccination should prioritize cattle in these districts. Furthermore, size of outbreaks was influenced by the annual summer mean air temperature of Khuvsgul Province, probably by affecting the permafrost freeze-thawing activity.

The pattern of Nodal morphogen signaling is shaped by co-receptor expression

Embryos must communicate instructions to their constituent cells over long distances. These instructions are often encoded in the concentration of signals called morphogens. In the textbook view, morphogen molecules diffuse from a localized source to form a concentration gradient, and target cells adopt fates by measuring the local morphogen concentration. However, natural patterning systems often incorporate numerous co-factors and extensive signaling feedback, suggesting that embryos require additional mechanisms to generate signaling patterns. Here, we examine the mechanisms of signaling pattern formation for the mesendoderm inducer Nodal during zebrafish embryogenesis. We find that Nodal signaling activity spans a normal range in the absence of signaling feedback and relay, suggesting that diffusion is sufficient for Nodal gradient formation. We further show that the range of endogenous Nodal ligands is set by the EGF-CFC co-receptor Oep: in the absence of Oep, Nodal activity spreads to form a nearly uniform distribution throughout the embryo. In turn, increasing Oep levels sensitizes cells to Nodal ligands. We recapitulate these experimental results with a computational model in which Oep regulates the diffusive spread of Nodal ligands by setting the rate of capture by target cells. This model predicts, and we confirm in vivo, the surprising observation that a failure to replenish Oep transforms the Nodal signaling gradient into a travelling wave. These results reveal that patterns of Nodal morphogen signaling are shaped by co-receptor-mediated restriction of ligand spread and sensitization of responding cells.

The Kerr-Schild double copy in Lifshitz spacetime

The Kerr-Schild double copy is a map between exact solutions of general relativity and Maxwell’s theory, where the nonlinear nature of general relativity is circumvented by considering solutions in the Kerr-Schild form. In this paper, we give a general formulation, where no simplifying assumption about the background metric is made, and show that the gauge theory source is affected by a curvature term that characterizes the deviation of the background spacetime from a constant curvature spacetime. We demonstrate this effect explicitly by studying gravitational solutions with non-zero cosmological constant. We show that, when the background is flat, the constant charge density filling all space in the gauge theory that has been observed in previous works is a consequence of this curvature term. As an example of a solution with a curved background, we study the Lifshitz black hole with two different matter couplings. The curvature of the background, i.e., the Lifshitz spacetime, again yields a constant charge density; however, unlike the previous examples, it is canceled by the contribution from the matter fields. For one of the matter couplings, there remains no additional non-localized source term, providing an example for a non-vacuum gravity solution corresponding to a vacuum gauge theory solution in arbitrary dimensions.

Wave Patterns of Gravity–Capillary Waves from Moving Localized Sources

We study wave patterns of gravity–capillary waves from moving localized sources within the classic setup of the problem of ship wakes. The focus is on the co-existence of two wave systems with opposite signatures of group velocity relative to the localized source. It leads to the problem of choice of signs for phase functions of the gravity (“slow”) and capillary (“fast”) branches of the dispersion relation: the question generally ignored when constructing phase patterns of the solutions. We detail characteristic angles of the wake patterns: (i) angle of demarcation of gravity and capillary waves—“the phase Mach” cone, (ii) angle of the minimal group velocity of gravity–capillary waves—“the group Mach” cone, (iii, iv) angles of cusps of isophases that appear after a threshold current speed. The outer cusp cone is naturally associated with the classic cone of Kelvin for pure gravity waves. The inner one results from the effect of capillarity and tends to the “group Mach” pattern at high speeds of current. Amplitudes of the wave patterns are estimated within the recently proposed approach of reference functions for the problem of propagation of packets of linear dispersive waves. The effect of shape is discussed for elliptic reference sources.

Wave Patterns of Gravity-Capillary Waves from Moving Localized Sources

We study wave patterns of gravity-capillary waves from moving localized sources within the classic setup of the problem of ship wakes. The focus is made on the co-existence of two wave systems with opposite signatures of group velocity relative to the localized source. It leads to the problem of choice of signs for phase functions of the gravity (“slow”) and capillary (“fast”) branches of the dispersion relation: the question generally ignored when constructing phase patterns of the solutions. We detail characteristic angles of the wake patterns: (i) angle of demarcation of gravity and capillary waves – “the phase Mach” cone, (ii) angle of the minimal group velocity of gravity-capillary waves – “the group Mach” cone, (iii, iv) angles of cusps of isophases that appear after a threshold current speed. The outer cusp cone is naturally associated with the classic cone of Kelvin for pure gravity waves. The inner one results from the effect of capillarity and tends to the “group Mach” pattern at high speeds of current. Amplitudes of the wave patterns are estimated within the recently proposed approach of reference functions for the problem of propagation of packets of linear dispersive waves. The effect of shape is discussed for elliptic reference sources.

Ruptured Abdominal Aortic Aneurysm Presenting as Septic Shock

A patient presented to the emergency department with undifferentiated shock 4 days after discharge from a hospitalization for a lower gastrointestinal bleed. The patient fulfilled 4/4 of the Systemic Inflammatory Response Syndrome criteria and 3/3 of the quick Sequential Organ Failure Assessment criteria on presentation to the emergency department, notably, without a localized source of infection and no localizing symptoms. After admission, the patient’s hemoglobin was found to have dropped more than expected after intravenous (IV) fluid administration, suggesting a potential alternative or concurrent etiology of the patient’s shock state. A digital rectal and focused assessment with sonography in trauma exam were performed and negative. The patient was then diagnosed with a ruptured infrarenal abdominal aortic aneurysm contained in the retroperitoneum by repeat point-of-care ultrasound. The patient was hemodynamically stabilized and taken for emergent grafting without confirmatory imaging. The patient was later found to also have 4/4 blood cultures positive with methicillin-sensitive Staphylococcus aureus associated with an aortic valvular vegetation and a mycotic aneurysm which contributed to the abdominal aortic aneurysm rupture. This case supports the use of comprehensive point-of-care ultrasound imaging to more rapidly and more definitively differentiate types of shock and etiologies of a shock state which can lead to more timely changes in management and improvement in outcomes.

Engineering synthetic morphogen systems that can program multicellular patterning

In metazoan tissues, cells decide their fates by sensing positional information provided by specialized morphogen proteins. To explore what features are sufficient for positional encoding, we asked whether arbitrary molecules (e.g., green fluorescent protein or mCherry) could be converted into synthetic morphogens. Synthetic morphogens expressed from a localized source formed a gradient when trapped by surface-anchoring proteins, and they could be sensed by synthetic receptors. Despite their simplicity, these morphogen systems yielded patterns reminiscent of those observed in vivo. Gradients could be reshaped by altering anchor density or by providing a source of competing inhibitor. Gradient interpretation could be altered by adding feedback loops or morphogen cascades to receiver cell response circuits. Orthogonal cell-cell communication systems provide insight into morphogen evolution and a platform for engineering tissues.