Iron metabolism in trypanosomatids, and its crucial role in infection.

Iron is almost ubiquitous in living organisms due to the utility of its redox chemistry. It is also dangerous as it can catalyse the formation of reactive free radicals - a classical double-edged sword. In this review, we examine the uptake and usage of iron by trypanosomatids and discuss how modulation of host iron metabolism plays an important role in the protective response. Trypanosomatids require iron for crucial processes including DNA replication, antioxidant defence, mitochondrial respiration, synthesis of the modified base J and, in African trypanosomes, the alternative oxidase. The source of iron varies between species. Bloodstream-form African trypanosomes acquire iron from their host by uptake of transferrin, and Leishmania amazonensis expresses a ZIP family cation transporter in the plasma membrane. In other trypanosomatids, iron uptake has been poorly characterized. Iron-withholding responses by the host can be a major determinant of disease outcome. Their role in trypanosomatid infections is becoming apparent. For example, the cytosolic sequestration properties of NRAMP1, confer resistance against leishmaniasis. Conversely, cytoplasmic sequestration of iron may be favourable rather than detrimental to Trypanosoma cruzi. The central role of iron in both parasite metabolism and the host response is attracting interest as a possible point of therapeutic intervention

Interacting Turing-Hopf Instabilities Drive Symmetry-Breaking Transitions in a Mean-Field Model of the Cortex: A Mechanism for the Slow Oscillation

Electrical recordings of brain activity during the transition from wake to anesthetic coma show temporal and spectral alterations that are correlated with gross changes in the underlying brain state. Entry into anesthetic unconsciousness is signposted by the emergence of large, slow oscillations of electrical activity (≲1  Hz) similar to the slow waves observed in natural sleep. Here we present a two-dimensional mean-field model of the cortex in which slow spatiotemporal oscillations arise spontaneously through a Turing (spatial) symmetry-breaking bifurcation that is modulated by a Hopf (temporal) instability. In our model, populations of neurons are densely interlinked by chemical synapses, and by interneuronal gap junctions represented as an inhibitory diffusive coupling. To demonstrate cortical behavior over a wide range of distinct brain states, we explore model dynamics in the vicinity of a general-anesthetic-induced transition from “wake” to “coma.” In this region, the system is poised at a codimension-2 point where competing Turing and Hopf instabilities coexist. We model anesthesia as a moderate reduction in inhibitory diffusion, paired with an increase in inhibitory postsynaptic response, producing a coma state that is characterized by emergent low-frequency oscillations whose dynamics is chaotic in time and space. The effect of long-range axonal white-matter connectivity is probed with the inclusion of a single idealized point-to-point connection. We find that the additional excitation from the long-range connection can provoke seizurelike bursts of cortical activity when inhibitory diffusion is weak, but has little impact on an active cortex. Our proposed dynamic mechanism for the origin of anesthetic slow waves complements—and contrasts with—conventional explanations that require cyclic modulation of ion-channel conductances. We postulate that a similar bifurcation mechanism might underpin the slow waves of natural sleep and comment on the possible consequences of chaotic dynamics for memory processing and learning

Group 2 Innate Lymphoid Cells Are Redundant in Experimental Renal Ischemia-Reperfusion Injury.

Acute kidney injury (AKI) can be fatal and is a well-defined risk factor for the development of chronic kidney disease. Group 2 innate lymphoid cells (ILC2s) are innate producers of type-2 cytokines and are critical regulators of homeostasis in peripheral organs. However, our knowledge of their function in the kidney is relatively limited. Recent evidence suggests that increasing ILC2 numbers by systemic administration of recombinant interleukin (IL)-25 or IL-33 protects against renal injury. Whilst ILC2s can be induced to protect against ischemic- or chemical-induced AKI, the impact of ILC2 deficiency or depletion on the severity of renal injury is unknown. Firstly, the phenotype and location of ILC2s in the kidney was assessed under homeostatic conditions. Kidney ILC2s constitutively expressed high levels of IL-5 and were located in close proximity to the renal vasculature. To test the functional role of ILC2s in the kidney, an experimental model of renal ischemia-reperfusion injury (IRI) was used and the severity of injury was assessed in wild-type, ILC2-reduced, ILC2-deficient, and ILC2-depleted mice. Surprisingly, there were no differences in histopathology, collagen deposition or mRNA expression of injury-associated (Lcn2), inflammatory (Cxcl1, Cxcl2, and Tnf) or extracellular matrix (Col1a1, Fn1) factors following IRI in the absence of ILC2s. These data suggest the absence of ILC2s does not alter the severity of renal injury, suggesting possible redundancy. Therefore, other mechanisms of type 2-mediated immune cell activation likely compensate in the absence of ILC2s. Hence, a loss of ILC2s is unlikely to increase susceptibility to, or severity of AKI

Hepatic breast cancer dissemination after an iatrogenic hepatic laceration during talc pleurodesis: a case report

<p>Abstract</p> <p>Background</p> <p>Talc pleurodesis is an effective treatment for malignant pleural effusion. We present a case of an asymptomatic hepatic laceration that occurred during pleurodesis in a breast cancer patient and led to hepatic tumor dissemination.</p> <p>Discussion</p> <p>Pleurodesis is a relatively safe procedure, although previous studies have described malignant invasion of scar tissue.</p> <p>Conclusion</p> <p>To our knowledge, this is the first case report of tumor spread due to a liver puncture during talc pleurodesis in a breast cancer patient.</p

Micromirror Angle Dependence with Etchant Choice on <100> Silicon Via Wet Etching

In creating mirrored silicon structures for micro-optics, the smoothness of the surface and etch rate are crucial parameters. We demonstrate a method of creating both 45° and 90° etch-planes from monocrystalline silicon for use as retro-reflective sidewalls in a microfluidic device. The technique uses the same photolithographic pattern orientation, but with two different etchants. Etching on direction in Si(100) with potassium hydroxide (KOH) gives vertical surfaces (where e.g. the high surface tension influences etching of crystallographic silicon planes), whilst tetramethylammonium hydroxide (TMAH) gives 45° sidewalls. We illustrate the use of these fabricated structures by creating arrays of micromirrors that enable an optical beam to be reflected parallel back and forth from 45° and -45° tilted vertical structures. This device has potential uses in optofluidic spectroscopic applications, where there is a need to increase the effective pathlength of a beam through a sample whilst keeping the device as small as possible

Challenges in Chagas Disease Drug Development.

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease has two types, the cardiac form and the digestive form; some patients have symptoms of both. How the parasite causes digestive disease is poorly understood. It is known that damage to the gut’s nervous system is an important factor, but it has been unclear exactly where and when this damage occurs during the course of an infection and also why only a subset of infected people suffer from this outcome. We studied infections in mice and found certain combinations of strains of parasites and mice that exhibited symptoms similar to human digestive Chagas patients, including a problem with peristalsis that localised specifically to the colon. Using parasites that were genetically engineered to emit both bioluminescent and fluorescent light, we tracked infections over time and were able to analyse rare infected cells deep within the muscle tissue of the wall of the colon. We found evidence of damaged neurons in the same location as these infection foci over 6 months after initial infection. Our results show that digestive Chagas disease probably develops as a result of chronic infection and inflammation, which potentially changes approaches to treatment