Hypocalcemia-Induced Seizure: Demystifying the Calcium Paradox

Calcium is essential for both neurotransmitter release and muscle contraction. Given these important physiological processes, it seems reasonable to assume that hypocalcemia may lead to reduced neuromuscular excitability. Counterintuitively, however, clinical observation has frequently documented hypocalcemia’s role in induction of seizures and general excitability processes such as tetany, Chvostek’s sign, and bronchospasm. The mechanism of this calcium paradox remains elusive, and very few pathophysiological studies have addressed this conundrum. Nevertheless, several studies primarily addressing other biophysical issues have provided some clues. In this review, we analyze the data of these studies and propose an integrative model to explain this hypocalcemic paradox.     

Global sequencing of proteolytic cleavage sites in apoptosis by specific labeling of protein N termini

The nearly 600 proteases in the human genome regulate a diversity of biological processes, including programmed cell death. Comprehensive characterization of protease signaling in complex biological samples is limited by available proteomic methods. We have developed a general approach for global identification of proteolytic cleavage sites using an engineered enzyme to selectively biotinylate free protein N termini for positive enrichment of corresponding N-terminal peptides. Using this method to study apoptosis, we have sequenced 333 caspase-like cleavage sites distributed among 292 protein substrates. These sites are generally not predicted by in vitro caspase substrate specificity but can be used to predict other physiological caspase cleavage sites. Structural bioinformatic studies show that caspase cleavage sites often appear in surface-accessible loops and even occasionally in helical regions. Strikingly, we also find that a disproportionate number of caspase substrates physically interact, suggesting that these dimeric proteases target protein complexes and networks to elicit apoptosis.     

Modular growth and functional heterophylly of the phreatophyte Ziziphus lotus: A trait-based study

The variation of plant functional traits, from the cell to the whole-plant level, is a central question in trait-based ecology with regard to understanding ecological strategies and adaptations that result from environmental drivers. Here, we analyzed whole-plant and leaf traits of the phreatophyte Ziziphus lotus (L.) Lam., a long-lived shrub that dominates one of the few terrestrial groundwater-dependent ecosystems (GDEs) in Mediterranean Basin drylands. We (a) assessed architectural traits and growth patterns, (b) analyzed leaf morpho-functional traits (specific leaf area [SLA] and stomata pore index [SPI]) and physiological traits (gas exchange rates), as well as their variations within individuals, and (c) evaluated temporal variations in modular growth (i.e., sequential iteration of structural units) between growing seasons and in leaf traits within seasons. Z. lotus' growth pattern was based on the repetition of modules composed of shoots (short and long) and branches (flowering and plagiotropic) that promoted a functional differentiation between vegetative and reproductive structures, respectively. We identified morpho-functionally distinct leaves (i.e., heterophylly) borne on different types of branches. Leaves on flowering branches had higher SLA and water use efficiency (WUEi), but lower SPI and transpiration rates than leaves on vegetative ones. We also observed trade-offs in the elongation of vegetative and flowering structures between growing seasons: the shorter the long shoots, the larger the flowering branches. The modular differentiation and heterophylly of Z. lotus might contribute to prioritizing the investment of resources of this phreatophyte, either for growth or reproduction, and could improve the efficiency in uptake and conservation of resources in drylands.     

Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions

Lactate has long been considered a “waste” by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4⁺ and CD8⁺ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4⁺ and CD8⁺ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4⁺ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8⁺ T cell motility to be independent of glycolysis control. In CD4⁺ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8⁺ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.