The connection matrix of the human brain (the human “connectome”) represents an indispensable foundation for basic and applied neurobiological research. However, the network of anatomical connections linking the neuronal elements of the human brain is still largely unknown. While some databases or collations of large-scale anatomical connection patterns exist for other mammalian species, there is currently no connection matrix of the human brain, nor is there a coordinated research effort to collect, archive, and disseminate this important information. We propose a research strategy to achieve this goal, and discuss its potential impact.

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The Human Connectome: A Structural Description of the Human Brain

Multicellular animals detect pathogens via a set of receptors that recognize pathogen-associated molecular patterns (PAMPs). However, pathogens are not the only causative agents of tissue and cell damage: trauma is another one. Evidence is accumulating that trauma and its associated tissue damage are recognized at the cell level via receptor-mediated detection of intracellular proteins released by the dead cells. The term "alarmin" is proposed to categorize such endogenous molecules that signal tissue and cell damage. Intriguingly, effector cells of innate and adaptive immunity can secrete alarmins via nonclassical pathways and often do so when they are activated by PAMPs or other alarmins. Endogenous alarmins and exogenous PAMPs therefore convey a similar message and elicit similar responses; they can be considered subgroups of a larger set, the damage-associated molecular patterns (DAMPs).

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0306164

DAMPs, PAMPs and alarmins: all we need to know about danger

Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Stem Cells,Cancer and Cancer Stem Cells

Annexins are Ca2+ and phospholipid binding proteins forming an evolutionary conserved multigene family with members of the family being expressed throughout animal and plant kingdoms. Structurally,...

/pdf/annexins-from-structure-to-function-4sosiwfhgs.pdf

Annexins: from structure to function.

Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death (ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD.

Immunogenic cell death and DAMPs in cancer therapy.

Annexin-immunoreactive proteins in the nervous system and eye of the gastropods, Aplysia and Helix

In a recent report, Schulte et al. (2012) have measured elevated serum levels of S100B protein in athletes in the absence of traumatic brain injury (TBI) of which high serum S100B is one accepted biomarker. The authors have hypothesized that such an increase may be consequent to tissue hypoperfusion reflected by blood lactate concentrations and/or increased serotonin activity reflected by prolactin levels. However, sodium lactate infusion into human subjects resulted in no changes in serum S100B, and enhanced prolactin levels were also excluded as a cause of increased serum S100B after physical activity (Schulte et al. 2012). Thus, the authors concluded that neither increased blood lactate nor serum prolactin plays an exclusive role in the regulation of S100B. Also, the cause of elevated serum S100B in athletes has remained unidentified. It is known that serum levels of S100B increase remarkably following an intense physical exercise, and that intense physical exercise is associated with reversible skeletal muscle tissue damage and release of intracellular proteins. There is evidence that upon acute muscle injury S100B, that is expressed in mature muscle myofibers, is rapidly and massively released from injured muscle tissue (Riuzzi et al. 2012 and references therein), in advance of other factors such as bFGF and HMGB1 (amphoterin) shown to regulate myogenesis. The local concentration of released S100B may thus be as high (although in the subnanomolar-nanomolar range) as to regulate myoblast proliferation and differentiation (Riuzzi et al. 2012), which raises the possibility that the protein may participate in the process of skeletal muscle regeneration (Fig. 1a). In accordance with this possibility, current work indicates that blockade of S100B released from skeletal myofibers upon acute injury results in significantly delayed muscle regeneration (F. Riuzzi, G. Sorci, S. Beccafico and R. Donato, manuscript in preparation). Clearly, S100B released from damaged myofibers can diffuse into the bloodstream (Fig. 1a), also as suggested by the kinetics of its local decline after day 1 post-injury (Riuzzi et al. 2012), thus explaining its enhanced serum levels after intense physical exercise. Another potential cause of increased serum S100B is catecholamine-dependent activation of adipocytes that occurs during intense physical exercise. It is known that S100B is released by catecholamine-treated adipocytes along with free fatty acids that can diffuse into the bloodstream (Fig. 1b). In conclusion, the rise in serum S100B in coincidence with an intense physical activity (in the absence of TBI) may well depend on reversible skeletal muscle tissue damage and enhanced release from adipocytes. In this respect, it should be kept in mind that S100B is expressed in great abundance by astrocytes, oligodendrocytes and ependymocytes in the central nervous system, by Schwann cells and ganglion glial cells in the peripheral nervous system as well as by several non-nervous cells including adipocytes. Considering the high abundance of skeletal muscle and adipose tissue, it is conceivable that rises in Communicated by Håkan Westerblad.

Causes of elevated serum levels of S100B protein in athletes.

Neurotrophins are expressed in muscle cells both during development and postnatally. Furthermore, during development muscle cells express high levels of the common p75 neurotrophin receptor, which binds all neurotrophins. Only fragmentary and controversial data are available regarding the responsiveness of muscle cells to neurotrophins and the importance of low-affinity p75 receptor in muscle development. The present study investigates in vitro the immunocytochemical expression of p75 in a rat myogenic cell line (L6) at various time points and in response to different coating substrates as a first step in elucidating the regulation of p75 in muscle. We found that in L6 myoblasts, p75 is expressed only at very early stages of maturation and its levels of expression are regulated by the nature of the coating substrates. p75 expression decreases in cells growing on substrates more suitable for myoblast fusion into myotubes. Time course analysis indicates a reverse correlation between myoblast fusion into myotubes and the levels of p75 expression. Myotubes were always p75 negative. Substrates not suitable for the fusion process induced a prolonged presence of p75 in myoblasts with an increase of their apoptosis. We conclude that expression of p75, at least in this in vitro condition, is regulated by the stages of myoblast differentiation and the nature of the coating substrates. According to the observed time- and substrate-related evidences, future studies should investigate in vivo both the regulation of p75 in the myoblast fusion and the effects and the importance of neurotrophins binding during myoblast differentiation.

Regulation of the p75 neurotrophin receptor in a rat myogenic cell line (L6).

The cytochemical localization of particulate guanylate cyclase and adenylate cyclase activities in rabbit platelets were studied after stimulation with various agents, at the electron microscope level. In the presence of platelet aggregating agents such as thrombin and ADP, the particulate reaction product of guanylate cyclase activity was detectable on plasma membrane and on membranes of the open canalicular system. In contrast, samples incubated with platelet-activating factor showed no activation of the cyclase activity. Atrial natriuretic factor stimulated the particulate guanylate cyclase. The ultracytochemical localization of this activated cyclase was the same as that of thrombin-or ADP-stimulated guanylate cyclase. Adenylate cyclase activity was studied in platelets incubated with prostaglandin E1 plus or minus insulin. The enzyme reaction product was found at the same sites where guanylate cyclase was detected. Therefore guanylate and adenylate cyclase activities do not seem to be preferentially localised in platelet membranes.

Rosario Donato

Papers

Annexin-immunoreactive proteins in the nervous system and eye of the gastropods, Aplysia and Helix

Causes of elevated serum levels of S100B protein in athletes.

Regulation of the p75 neurotrophin receptor in a rat myogenic cell line (L6).

Particulate guanylate cyclase and adenylate cyclase activities after activation with various agents in rabbit platelets. An ultracytochemical study

S-100b protein regulates aggregation and fusion of cardiolipin vesicles.