Caloric Restriction Suppresses Microglial Activation and Prevents Neuroapoptosis Following Cortical Injury in Rats

Traumatic brain injury (TBI) is a widespread cause of death and a major source of adult disability. Subsequent pathological events occurring in the brain after TBI, referred to as secondary injury, continue to damage surrounding tissue resulting in substantial neuronal loss. One of the hallmarks of the secondary injury process is microglial activation resulting in increased cytokine production. Notwithstanding that recent studies demonstrated that caloric restriction (CR) lasting several months prior to an acute TBI exhibits neuroprotective properties, understanding how exactly CR influences secondary injury is still unclear. The goal of the present study was to examine whether CR (50% of daily food intake for 3 months) alleviates the effects of secondary injury on neuronal loss following cortical stab injury (CSI). To this end, we examined the effects of CR on the microglial activation, tumor necrosis factor-α (TNF-α) and caspase-3 expression in the ipsilateral (injured) cortex of the adult rats during the recovery period (from 2 to 28 days) after injury. Our results demonstrate that CR prior to CSI suppresses microglial activation, induction of TNF-α and caspase-3, as well as neurodegeneration following injury. These results indicate that CR strongly attenuates the effects of secondary injury, thus suggesting that CR may increase the successful outcome following TBI

Irradiation-Induced Up-Regulation of HLA-E on Macrovascular Endothelial Cells Confers Protection against Killing by Activated Natural Killer Cells

BACKGROUND: Apart from the platelet/endothelial cell adhesion molecule 1 (PECAM-1, CD31), endoglin (CD105) and a positive factor VIII-related antigen staining, human primary and immortalized macro- and microvascular endothelial cells (ECs) differ in their cell surface expression of activating and inhibitory ligands for natural killer (NK) cells. Here we comparatively study the effects of irradiation on the phenotype of ECs and their interaction with resting and activated NK cells. METHODOLOGY/PRINCIPAL FINDINGS: Primary macrovascular human umbilical vein endothelial cells (HUVECs) only express UL16 binding protein 2 (ULBP2) and the major histocompatibility complex (MHC) class I chain-related protein MIC-A (MIC-A) as activating signals for NK cells, whereas the corresponding immortalized EA.hy926 EC cell line additionally present ULBP3, membrane heat shock protein 70 (Hsp70), intercellular adhesion molecule ICAM-1 (CD54) and HLA-E. Apart from MIC-B, the immortalized human microvascular endothelial cell line HMEC, resembles the phenotype of EA.hy926. Surprisingly, primary HUVECs are more sensitive to Hsp70 peptide (TKD) plus IL-2 (TKD/IL-2)-activated NK cells than their immortalized EC counterpatrs. This finding is most likely due to the absence of the inhibitory ligand HLA-E, since the activating ligands are shared among the ECs. The co-culture of HUVECs with activated NK cells induces ICAM-1 (CD54) and HLA-E expression on the former which drops to the initial low levels (below 5%) when NK cells are removed. Sublethal irradiation of HUVECs induces similar but less pronounced effects on HUVECs. Along with these findings, irradiation also induces HLA-E expression on macrovascular ECs and this correlates with an increased resistance to killing by activated NK cells. Irradiation had no effect on HLA-E expression on microvascular ECs and the sensitivity of these cells to NK cells remained unaffected. CONCLUSION/SIGNIFICANCE: These data emphasize that an irradiation-induced, transient up-regulation of HLA-E on macrovascular ECs might confer protection against NK cell-mediated vascular injury

The skull of Epidolops ameghinoi from the early Eocene Itaboraí fauna, southeastern Brazil, and the affinities of the extinct marsupialiform order Polydolopimorphia

The skull of the polydolopimorphian marsupialiform Epidolops ameghinoi is described in detail for the first time, based on a single well-preserved cranium and associated left and right dentaries plus additional craniodental fragments, all from the early Eocene (53-50 million year old) Itaboraí fauna in southeastern Brazil. Notable craniodental features of E. ameghinoi include absence of a masseteric process, very small maxillopalatine fenestrae, a prominent pterygoid fossa enclosed laterally by a prominent ectopterygoid crest, an absent or tiny transverse canal foramen, a simple, planar glenoid fossa, and a postglenoid foramen that is immediately posterior to the postglenoid process. Most strikingly, the floor of the hypotympanic sinus was apparently unossified, a feature found in several stem marsupials but absent in all known crown marsupials. "Type II" marsupialiform petrosals previously described from Itaboraí plausibly belong to E. ameghinoi; in published phylogenetic analyses, these petrosals fell outside (crown-clade) Marsupialia. "IMG VII" tarsals previously referred to E. ameghinoi do not share obvious synapomorphies with any crown marsupial clade, nor do they resemble those of the only other putative polydolopimorphians represented by tarsal remains, namely the argyrolagids. Most studies have placed Polydolopimorphia within Marsupialia, related to either Paucituberculata, or to Microbiotheria and Diprotodontia. However, diprotodonty almost certainly evolved independently in polydolopimorphians, paucituberculatans and diprotodontians, and Epidolops does not share obvious synapomorphies with any marsupial order. Epidolops is dentally specialized, but several morphological features appear to be more plesiomorphic than any crown marsupial. It seems likely Epidolops that falls outside Marsupialia, as do morphologically similar forms such as Bonapartherium and polydolopids. Argyrolagids differ markedly in their known morphology from Epidolops but share some potential apomorphies with paucituberculatans. It is proposed that Polydolopimorphia as currently recognised is polyphyletic, and that argyrolagids (and possibly other taxa currently included in Argyrolagoidea, such as groeberiids and patagoniids) are members of Paucituberculata. This hypothesis is supported by Bayesian non-clock phylogenetic analyses of a total evidence matrix comprising DNA sequence data from five nuclear protein-coding genes, indels, retroposon insertions and morphological characters: Epidolops falls outside Marsupialia, whereas argyrolagids form a clade with the paucituberculatans Caenolestes and Palaeothentes, regardless of whether the Type II petrosals and IMG VII tarsals are used to score characters for Epidolops or not. There is no clear evidence for the presence of crown marsupials at Itaboraí, and it is possible that the origin and early evolution of Marsupialia was restricted to the "Austral Kingdom" (southern South America, Antarctica, and Australia)

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

Multispectral analysis of Northern Hemisphere temperature records over the last five millennia

Aiming to describe spatio-temporal climate variability on decadal-to-centennial time scales and longer, we analyzed a data set of 26 proxy records extending back 1,000–5,000 years; all records chosen were calibrated to yield temperatures. The seven irregularly sampled series in the data set were interpolated to a regular grid by optimized methods and then two advanced spectral methods—namely singular-spectrum analysis (SSA) and the continuous wavelet transform—were applied to individual series to separate significant oscillations from the high noise background. This univariate analysis identified several common periods across many of the 26 proxy records: a millennial trend, as well as oscillations of about 100 and 200 years, and a broad peak in the 40–70-year band. To study common NH oscillations, we then applied Multichannel SSA. Temperature variations on time scales longer than 600 years appear in our analysis as a dominant trend component, which shows climate features consistent with the Medieval Warm Period and the Little Ice Age. Statistically significant NH-wide peaks appear at 330, 250 and 110 years, as well as in a broad 50–80-year band. Strong variability centers in several bands are located around the North Atlantic basin and are in phase opposition between Greenland and Western Europe