Biomolecular characterization of 3500-year-old ancient Egyptian mummification balms from the Valley of the Kings

Ancient Egyptian mummification was practiced for nearly 4000 years as a key feature of some of the most complex mortuary practices documented in the archaeological record. Embalming, the preservation of the body and organs of the deceased for the afterlife, was a central component of the Egyptian mummification process. Here, we combine GC-MS, HT-GC-MS, and LC-MS/MS analyses to examine mummification balms excavated more than a century ago by Howard Carter from Tomb KV42 in the Valley of the Kings. Balm residues were scraped from now empty canopic jars that once contained the mummified organs of the noble lady Senetnay, dating to the 18th dynasty, ca. 1450 BCE. Our analysis revealed balms consisting of beeswax, plant oil, fats, bitumen, Pinaceae resins, a balsamic substance, and dammar or Pistacia tree resin. These are the richest, most complex balms yet identified for this early time period and they shed light on balm ingredients for which there is limited information in Egyptian textual sources. They highlight both the exceptional status of Senetnay and the myriad trade connections of the Egyptians in the 2nd millennium BCE. They further illustrate the excellent preservation possible even for organic remains long removed from their original archaeological context

Vasopressors and Inotropes in the Treatment of Human Septic Shock: Effect on Innate Immunity?

Catecholamines have been suggested to modulate innate immune responses in experimental settings. The significance hereof in the treatment of human septic shock is unknown. We therefore sought if and how vasopressor/inotropic doses relate to pro-inflammatory mediators during treatment of septic shock. We prospectively studied 20 consecutive septic shock patients. For 3 days after admission, hemodynamic variables, lactate and plasma levels of interleukins (IL)-6 and 8, tumor necrosis factor (TNF)-α, and elastase-α1-antitrypsin were measured six hourly. Doses of vasoactive drugs were recorded. Of the 20 patients, nine died in the intensive care unit. Dobutamine doses were positively associated and related to TNF-α plasma levels, independently of disease severity, hemodynamics, and outcome, in multivariable models. Dopamine doses were positively associated with IL-6, and norepinephrine was inversely associated with IL-8 and TNF-α levels. Our observations suggest that catecholamines used in the treatment of human septic shock differ in their potential modulation of the innate immune response to sepsis in vivo. Dobutamine treatment may contribute to circulating TNF-α and dopamine to IL-6, independently of activated neutrophils. Conversely, norepinephrine may lack pro-inflammatory actions

Pivotal Role of the α2A-Adrenoceptor in Producing Inflammation and Organ Injury in a Rat Model of Sepsis

Background: Norepinephrine (NE) modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs). Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP)-induced sepsis in rats, which then stimulates TNF-a production in Kupffer cells (KCs) through the activation of the a2-AR. It is important to know which of the three a2-AR subtypes (i.e., a2A, a2B or a2C) is responsible for the upregulation of TNF-a production. The aim of this study was to determine the contribution of a2A-AR in this process. Methodology/Principal Findings: Adult male rats underwent CLP and KCs were isolated 2 h later. Gene expression of a2A-AR was determined. In additional experiments, cultured KCs were incubated with NE with or without BRL-44408 maleate, a specific a2A-AR antagonist, and intraportal infusion of NE for 2 h with or without BRL-44408 maleate was carried out in normal animals. Finally, the impact of a2A-AR activation by NE was investigated under inflammatory conditions (i.e., endotoxemia and CLP). Gene expression of the a2A-AR subtype was significantly upregulated after CLP. NE increased the release of TNF-a in cultured KCs, which was specifically inhibited by the a2A-AR antagonist BRL-44408. Equally, intraportal NE infusion increased TNF-a gene expression in KCs and plasma TNF-a which was also abrogated by co-administration of BRL-44408. NE also potentiated LPS-induced TNF-a release via the a2A-AR in vitro and in vivo. This potentiation of TNF-a release by NE was mediated through the a2A-AR coupled Gai protein and the activation of the p38 MAP kinase. Treatment of septic animals with BRL-44408 suppressed TNF-a, prevented multiple organ injury and significantly improved survival from 45% to 75%. Conclusions/Significance: Our novel finding is that hyperresponsiveness to a2-AR stimulation observed in sepsis is primarily due to an increase in a2A-AR expression in KCs. This appears to be in part responsible for the increased proinflammatory response and ensuing organ injury in sepsis. These findings provide important feasibility information for further developing the a2A-AR antagonist as a new therapy for sepsis

A Src-Tks5 Pathway Is Required for Neural Crest Cell Migration during Embryonic Development

In the adult organism, cell migration is required for physiological processes such as angiogenesis and immune surveillance, as well as pathological events such as tumor metastasis. The adaptor protein and Src substrate Tks5 is necessary for cancer cell migration through extracellular matrix in vitro and tumorigenicity in vivo. However, a role for Tks5 during embryonic development, where cell migration is essential, has not been examined. We used morpholinos to reduce Tks5 expression in zebrafish embryos, and observed developmental defects, most prominently in neural crest-derived tissues such as craniofacial structures and pigmentation. The Tks5 morphant phenotype was rescued by expression of mammalian Tks5, but not by a variant of Tks5 in which the Src phosphorylation sites have been mutated. We further evaluated the role of Tks5 in neural crest cells and neural crest-derived tissues and found that loss of Tks5 impaired their ventral migration. Inhibition of Src family kinases also led to abnormal ventral patterning of neural crest cells and their derivatives. We confirmed that these effects were likely to be cell autonomous by shRNA-mediated knockdown of Tks5 in a murine neural crest stem cell line. Tks5 was required for neural crest cell migration in vitro, and both Src and Tks5 were required for the formation of actin-rich structures with similarity to podosomes. Additionally, we observed that neural crest cells formed Src-Tks5-dependent cell protrusions in 3-D culture conditions and in vivo. These results reveal an important and novel role for the Src-Tks5 pathway in neural crest cell migration during embryonic development. Furthermore, our data suggests that this pathway regulates neural crest cell migration through the generation of actin-rich pro-migratory structures, implying that similar mechanisms are used to control cell migration during embryogenesis and cancer metastasis

Pre-agricultural plant management in the uplands of the central Zagros: the archaeobotanical evidence from Sheikh-e Abad

Prior to the emergence of agriculture in southwest Asia, sedentarising human communities were experimenting with a diverse range of wild plant species over a prolonged period. In some cases, this involved the cultivation of species that would go on to be domesticated and form the foundation of future agricultural economies. However, many forms of plant use did not follow this trajectory, and in multiple places farming was only taken up later as an established ‘package’. In this paper, we present new archaeobotanical evidence from the Early Neolithic site of Sheikh-e Abad in the central Zagros of western Iran. Sheikh-e Abad is unique in being the only settlement known to date within southwest Asia that lies at an altitude above 1000m and which has occupation spanning the agricultural transition. Thus, it provides a rare opportunity to examine pre-agricultural plant management strategies in an upland zone. Our analyses of the plant remains from Sheikh-e Abad suggest that from its earliest occupation inhabitants were unconsciously ‘auditioning’ a suite of locally available wild grasses which ultimately were never domesticated. We discuss the possible reasons for this from a socio-ecological perspective, considering both the biology and ecology of the plant species in question, as well as the ways in which they were potentially managed

Man and the Last Great Wilderness: Human Impact on the Deep Sea

The deep sea, the largest ecosystem on Earth and one of the least studied, harbours high biodiversity and provides a wealth of resources. Although humans have used the oceans for millennia, technological developments now allow exploitation of fisheries resources, hydrocarbons and minerals below 2000 m depth. The remoteness of the deep seafloor has promoted the disposal of residues and litter. Ocean acidification and climate change now bring a new dimension of global effects. Thus the challenges facing the deep sea are large and accelerating, providing a new imperative for the science community, industry and national and international organizations to work together to develop successful exploitation management and conservation of the deep-sea ecosystem. This paper provides scientific expert judgement and a semi-quantitative analysis of past, present and future impacts of human-related activities on global deep-sea habitats within three categories: disposal, exploitation and climate change. The analysis is the result of a Census of Marine Life – SYNDEEP workshop (September 2008). A detailed review of known impacts and their effects is provided. The analysis shows how, in recent decades, the most significant anthropogenic activities that affect the deep sea have evolved from mainly disposal (past) to exploitation (present). We predict that from now and into the future, increases in atmospheric CO2 and facets and consequences of climate change will have the most impact on deep-sea habitats and their fauna. Synergies between different anthropogenic pressures and associated effects are discussed, indicating that most synergies are related to increased atmospheric CO2 and climate change effects. We identify deep-sea ecosystems we believe are at higher risk from human impacts in the near future: benthic communities on sedimentary upper slopes, cold-water corals, canyon benthic communities and seamount pelagic and benthic communities. We finalise this review with a short discussion on protection and management methods