The creatine kinase system and pleiotropic effects of creatine

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Influence of Hadean crust evident in basalts and cherts from the Pilbara Craton

Application of the 147Sm–143Nd and 146Sm–142Nd chronometers has suggested that the initial differentiation of Earth’s mantle into enriched and depleted reservoirs may have begun within the first 100–200 million years of Earth’s history1. However, little is known about the differentiation of the early crust; although evidence has suggested the presence of enriched crustal material2, 3, 4, 5, data regarding the nature and composition of this crust are limited. Here we present 147Sm–143Nd data from the weakly metamorphosed basalt and layered chert–barite successions from the Dresser Formation of the Pilbara Craton, Western Australia. The Sm–Nd isochron indicates an age of 3.49±0.10 billion years, in agreement with previous estimates from Pb–Pb (ref. 6) and U–Pb (ref. 7) dating, which indicates that the Sm–Nd system has not been reset. Our measured εNd value of −3.3±1.0 for the rocks at this site is consistent with formation from an older protolith. On the basis of our modelling of trace element and isotopic compositions from these rocks, we suggest that the older component was crustal in nature, and differentiated from the convective mantle more than 4.3 billion years ago

A template for an improved rock-based subdivision of the pre-Cryogenian timescale

The geological timescale before 720 Ma uses rounded absolute ages rather than specific events recorded in rocks to subdivide time. This has led increasingly to mismatches between subdivisions and the features for which they were named. Here we review the formal processes that led to the current timescale, outline rock-based concepts that could be used to subdivide pre-Cryogenian time and propose revisions. An appraisal of the Precambrian rock record confirms that purely chronostratigraphic subdivision would require only modest deviation from current chronometric boundaries, removal of which could be expedited by establishing event-based concepts and provisional, approximate ages for eon-, era- and period-level subdivisions. Our review leads to the following conclusions: (1) the current informal four-fold Archean subdivision should be simplified to a tripartite scheme, pending more detailed analysis, and (2) an improved rock-based Proterozoic Eon might comprise a Paleoproterozoic Era with three periods (early Paleoproterozoic or Skourian, Rhyacian, Orosirian), Mesoproterozoic Era with four periods (Statherian, Calymmian, Ectasian, Stenian) and a Neoproterozoic Era with four periods (pre-Tonian or Kleisian, Tonian, Cryogenian and Ediacaran). These proposals stem from a wide community and could be used to guide future development of the pre-Cryogenian timescale by international bodies