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.

/pdf/the-human-connectome-a-structural-description-of-the-human-31vln7dys2.pdf

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.

S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.

The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.

Functions of S100 Proteins

S100, a multigenic family of non-ubiquitous Ca(2+)-modulated proteins of the EF-hand type expressed in vertebrates exclusively, has been implicated in intracellular and extracellular regulatory activities. Members of this protein family have been shown to interact with several effector proteins within cells thereby regulating enzyme activities, the dynamics of cytoskeleton constituents, cell growth and differentiation, and Ca(2+) homeostasis. Structural information indicates that most of S100 proteins exist in the form of antiparallelly packed homodimers (in some cases heterodimers), capable of functionally crossbridging two homologous or heterologous target proteins in a Ca(2+)-dependent (and, in some instances, Ca(2+)-independent) manner. In addition, extracellular roles have been described for several S100 members, although secretion (via an unknown mechanism) has been documented for a few of them. Extracellular S100 proteins have been shown to exert regulatory effects on inflammatory cells, neurons, astrocytes, microglia, and endothelial and epithelial cells, and a cell surface receptor, RAGE, has been identified as a potential S100A12 and S100B receptor transducing the effects of these two proteins on inflammatory cells and neurons. Other cell surface molecules with ability to interact with S100 members have been identified, suggesting that RAGE might not be a universal S100 protein receptor and/or that a single S100 protein might interact with more than one receptor. Collectively, these data indicate that members of the S100 protein family are multifunctional proteins implicated in the regulation of a variety of cellular activities.

Intracellular and extracellular roles of S100 proteins.

Nrf2-Keap1 signaling in oxidative and reductive stress.

Diffusion tensor MRI (DT‐MRI) provides information about the structural organization and orientation of white matter fibres and, through the technique of ‘tractography’, reveals the trajectories of cerebral white matter tracts. We used tractography in the living human brain to address the disputed issue of the nature of occipital and temporal connections. Classical anatomical studies described direct fibre connections between occipital and anterior temporal cortex in a bundle labelled the inferior longitudinal fasciculus (ILF). However, their presence has been challenged by more recent evidence suggesting that connections between the two regions are entirely indirect, conveyed by the occipito‐temporal projection system—a chain of U‐shaped association fibres. DT‐MRI data were collected from 11 right‐handed healthy subjects (mean age 33.3 ± 4.7 years). Each data set was co‐registered with a standard MRI brain template, and a group‐averaged DT‐MRI data set was created. ‘Virtual’ in vivo dissection of occipito‐temporal connections was performed in the group‐averaged data. Further detailed virtual dissection was performed on the single brain data sets. Our results suggest that in addition to the indirect connections of the occipito‐temporal projection system: (i) a major associative connection between the occipital and anterior temporal lobe is provided by a fibre bundle whose origin, course and termination are consistent with classical descriptions of the ILF in man and with monkey visual anatomy; (ii) the tractography‐defined ILF is structurally distinct from fibres of the optic radiation and from U‐shaped fibres connecting adjacent gyri; (iii) it arises in extrastriate visual ‘association’ areas; and (iv) it projects to lateral and medial anterior temporal regions. While the function of the direct ILF pathway is unclear, it appears to mediate the fast transfer of visual signals to anterior temporal regions and neuromodulatory back‐projections from the amygdala to early visual areas. Future tractography studies of patients with occipito‐temporal disconnection syndromes may help define the functional roles of the direct and indirect occipito‐temporal pathways.

/pdf/occipito-temporal-connections-in-the-human-brain-v30nm4w0g6.pdf

Rosario Donato

Papers

S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.

Functions of S100 Proteins

Intracellular and extracellular roles of S100 proteins.

Nrf2-Keap1 signaling in oxidative and reductive stress.

Occipito-temporal connections in the human brain