Targeting Neutrophil Adhesive Events to Address Vaso-Occlusive Crisis in Sickle Cell Patients

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.

A neural code for egocentric spatial maps in the human medial temporal lobe

SummarySpatial navigation relies on neural systems that encode information about places, distances, and directions in relation to the external world or relative to the navigating organism. Since the proposal of cognitive maps, the neuroscience of navigation has focused on allocentric (world-referenced) neural representations including place, grid, and head-direction cells. Here, using single-neuron recordings during virtual navigation, we identify “anchor cells” in the human brain as a neural code for egocentric (self-centered) spatial maps: Anchor cells represent egocentric directions towards “anchor points” located in the environmental center or periphery. Anchor cells were abundant in parahippocampal cortex, supported full vectorial representations of egocentric space, and were integrated into a neural memory network. Neurons encoding allocentric direction complemented anchor-cell activity, potentially assisting anchor cells in transforming percepts into allocentric representations. Anchor cells may facilitate egocentric navigation strategies, may support route planning from egocentric viewpoints, and may underlie the first-person perspective in episodic memories.

The structure and composition of the teeth and grasping spines of chaetognaths

The teeth and grasping spines of Sagitta are similar in structure, both having a central pulp cavity surrounded by two electron-dense chitinous layers. The cells of the pulp cavity contain microtubules arranged along the long axis. The two chitinous tubes are separated by a less-dense zone crossed by coarse fibrils linking the two. The teeth and spines insert into less electron-dense chitin (presumably flexible) and are moved by processes of anchor cells which pass into the basal chitinous zone. The inner region of the anchor cells is apposed to the connective tissue layer on to which the muscles of the teeth and spines insert. At the base of the pulp cavity, i.e. at the secretory zone where the teeth and spines are formed, the cells of the pulp cavity contain electron-dense granules in which zinc is found; zinc is also present in the inner and outer dense chitin layers at high concentration (0·5–1·0% of the dry wt).Both spines and teeth are tipped with fibrous cones containing silicon. It is suggested that the zinc associated with the chitin serves to toughen the teeth and spines and render them less liable to fracture, and that the silicon in the tips confers hardness to this vulnerable region.

A study of the oviducal glands and ovisacs of Balanus balanoides (L.) together with comparative observations on the ovisacs of Balanus hameri (Ascanius) and the reproductive biology of the two species

A mainly microscopical study has been carried out on the oviducal glands and ovisacs of two hermaphroditic sessile barnacles, Balanus balanoides and Balanus hameri . In both species each gland secretes an ovisac, once a year, for a very restricted period before copulation. The morphology of the glands of B. balanoides has been worked out from serial sections and a Plasticine model. Three regions have been established within the glands; two are ectodermal in origin, namely the main chamber and exit canal, while the third, the proximal chamber, is mesodermal. The exit canal is always lined with cuticle, but the main chamber for most of the year is not. However, in both species main chamber cells begin to secrete the ovisacs several weeks before copulation. Ovisacs are undoubtedly cuticular structures. The cytology of B. balanoides main chamber cells during the sequence of events leading to the formation of ovisacs has been followed by means of transmission electron microscopy. The cells each develop a long apical cytoplasmic extension; from these extensions and the apical cell surfaces secretions pass out to form the ovisac wall. This wall has two zones, an outer electron-dense zone 14 pm thick and an inner flocculent zone 6 pm thick. When fully formed the ovisac is released from the main chamber cells to lie in the oviducal gland lumen, although the neck of the ovisac continues to be firmly attached to specialized anchor cells. The cytoplasmic extensions of the main chamber cells break away with the ovisac as it is released and eventually form the pores in the ovisac wall. Scanning electron microscopy was used to examine such unstretched sacs. In B. balanoides the main chamber cells then partially retrogress, shedding secretions and portions of cytoplasm into the gland lumen. It is proposed that these ‘formed bodies’, by their osmotic activity, draw water and low molecular mass solutes into the gland lumen from the haemolymph. The ‘formed bodies ’ swell and burst, thereby accumulating fluid in the lumen of the gland, which becomes highly swollen. It is this fluid that has the activating factor(s), thought to be the ammonium ion, needed to activate inseminated sperm. In this condition B.balanoides becomes a receptive female. In B. hameri , although there is some retrogression of the main chamber cells with secretion of ‘formed bodies’, there is much less accumulation of fluid and so the oviducal glands do not become so highly swollen. The copulatory act of B. hameri was observed closely and comparison was made with that of B. balanoides . In B. hameri a single male is involved and a single insemination is sufficient for egg laying to commence, while in B. balanoides more than one male may be involved and multiple inseminations are needed before egg laying begins. Oocytes (eggs) pass from the ovaries down the oviducts and into the elastic ovisacs lying in the oviducal glands. As the ovisacs distend with eggs they first expel the oviducal gland fluid into the mantle cavity and then they themselves are forced out into the mantle cavity. As the stretching continues the ovisac wall becomes very thin and the pores enlarge. Although B. balanoides sperm, which are 0.5 pm in diameter, can easily pass into the 0.7 to 1.6 pm diameter pores of an unstretched ovisac, those of B. hameri , which are also 0.5 pm in diameter, need the ovisac to stretch and the pores to enlarge from their original diameter of 0.2 pm before sperm can pass through and fertilize the eggs. Inseminated sperm, in both species, are deposited as gelled masses. In B. balanoides the expelled oviducal gland fluid activates such sperm, but inseminated sperm of B. hameri become active in seawater. At any one time, only those sperm on the outer surface of the masses are active, and so a staggered release takes place. This is essential when egg laying takes more than 30 min and the sperm of B. balanoides and B. hameri are active for only 5-6 min and 12-13 min respectively. The fully formed egg masses are finally freed from the anchor cells within the glands and moved to the bottom of the mantle cavity, where egg development takes place.