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S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited β galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN + LLC. Some cortical NeuN + neurons, GFAP + glia limitans astrocytes, Iba-1 + microglia and S100β + ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes.

Multiciliated ependymal (E1) cells line the brain ventricles and are essential for brain homeostasis. We previously identified in the lateral ventricles a rare ependymal subpopulation (E2) with only two cilia and unique basal bodies. Here we show that E2 cells form a distinct biciliated epithelium extending along the ventral third into the fourth ventricle. In the third ventricle floor, apical profiles with only primary cilia define an additional uniciliated (E3) epithelium. E2 and E3 cells’ ultrastructure, marker expression and basal processes indicate that they correspond to subtypes of tanycytes. Using sonic hedgehog lineage tracing, we show that the third and fourth ventricle E2 and E3 epithelia originate from the anterior floor plate. E2 and E3 cells complete their differentiation 2–3 weeks after birth, suggesting a link to postnatal maturation. These data reveal discrete bands of E2 and E3 cells that may relay information from the CSF to underlying neural circuits along the ventral midline. Ependymal cells lining the adult brain ventricles are comprised of multiciliated cells and a rare subpopulation with two cilia (E2 cells) whose origin and function remain unknown. Here the authors find E2 cells in the 3rd ventricle of mice and humans, along with a third ependymal cell type with only a primary cilium, and provide details of their marker profile and developmental origins.

The unique ability of intrinsically disordered proteins (IDPs) to fold upon binding to partner molecules makes them functionally well-suited for cellular communication networks. For example, the folding-binding of different IDP sequences onto the same surface of an ordered protein provides a mechanism for signaling in a many-to-one manner. Here, we study the molecular details of this signaling mechanism by applying both Molecular Dynamics and Monte Carlo methods to S100B, a calcium-modulated homodimeric protein, and two of its IDP targets, p53 and TRTK-12. Despite adopting somewhat different conformations in complex with S100B and showing no apparent sequence similarity, the two IDP targets associate in virtually the same manner. As free chains, both target sequences remain flexible and sample their respective bound, natively [Formula: see text]-helical states to a small extent. Association occurs through an intermediate state in the periphery of the S100B binding pocket, stabilized by nonnative interactions which are either hydrophobic or electrostatic in nature. Our results highlight the importance of overall physical properties of IDP segments, such as net charge or presence of strongly hydrophobic amino acids, for molecular recognition via coupled folding-binding.

Mild traumatic brain injury (mTBI) has become a tough nut in forensic science because of its minor damages but serious consequences. Utilizing biomarkers to diagnose mTBI has become a promising approach due to various shortcomings of traditional diagnostic methods. In this work, we developed a peptide-modified ratiometric fluorescent nanoprobe based on carbon dots (CDs) and gold nanoclusters (AuNCs) for the measurements of a pivotal biomarker S100B protein in the early diagnosis of mTBI. It has been found that florescence intensity of AuNCs at 580 nm was decreased as report signal while the florescence intensity of CDs was unchanged as reference signal in this sensing system when the surface modified peptide bind tightly with calcium-activated S100B. Under the optimized conditions, S100B concentration ranging from 0.03 to 1 μg/mL was successfully determined within 30 min, and the detection limit of 0.01 μg/mL was acquired through the standard rule (S/N = 3). Moreover, the detection of S100B in spiked blood samples were conducted with satisfactory recoveries. The as-prepared ratiometric fluorescent nanoprobe was proved to be a time-saving, convenient, and sensitive strategy, and it showed great prospects in the early diagnosis of mTBI in forensic practice.

S100β-positive cells exist in the marginal cell layer (MCL) of the adenohypophysis and follicle structure in the parenchyma of anterior lobe (ALFS) in pituitary. They have multiple functions as phagocytes or cells that regulate hormone secretion. Majority of S100β-positive cells in the adenohypophysis express sex determining region Y-box 2 protein (SOX2), a stem cell marker; therefore, S100β/SOX2 double positive cells are also considered as one type of stem/progenitor cells. MCL and ALFS are consisting of morphologically two types of cells, i.e., multiciliated cells and non-ciliated cells. However, the relationship between the S100β-positive cells and multiciliated cells in the pituitary is largely unknown. In the present study, we first immunohistochemically verified the feature of multiciliated cells in MCL and ALFS. We then examined the expression patterns of FOXJ1, an essential expression factor for multiciliated cell-differentiation, and SOX2 in the S100β-positive multiciliated cells by in situ hybridization and immunohistochemistry. We identified anew the S100β/SOX2/FOXJ1 triple positive multiciliated cells, and revealed that they were dispersed throughout the MCL and ALFS. These results indicate that the MCL and ALFS are consisting of morphologically and functionally distinct two types of cells, i.e., S100β/SOX2 double positive non-ciliated cells and S100β/SOX2/FOXJ1 triple positive multiciliated cells.

The adult dentate gyrus produces new neurons that morphologically and functionally integrate into the hippocampal network. In the adult brain, most excitatory synapses are ensheathed by astrocytic perisynaptic processes that regulate synaptic structure and function. However, these processes are formed during embryonic or early postnatal development and it is unknown whether astrocytes can also ensheathe synapses of neurons born during adulthood and, if so, whether they play a role in their synaptic transmission. Here, we used a combination of serial-section immuno-electron microscopy, confocal microscopy, and electrophysiology to examine the formation of perisynaptic processes on adult-born neurons. We found that the afferent and efferent synapses of newborn neurons are ensheathed by astrocytic processes, irrespective of the age of the neurons or the size of their synapses. The quantification of gliogenesis and the distribution of astrocytic processes on synapses formed by adult-born neurons suggest that the majority of these processes are recruited from pre-existing astrocytes. Furthermore, the inhibition of astrocytic glutamate re-uptake significantly reduced postsynaptic currents and increased paired-pulse facilitation in adult-born neurons, suggesting that perisynaptic processes modulate synaptic transmission on these cells. Finally, some processes were found intercalated between newly formed dendritic spines and potential presynaptic partners, suggesting that they may also play a structural role in the connectivity of new spines. Together, these results indicate that pre-existing astrocytes remodel their processes to ensheathe synapses of adult-born neurons and participate to the functional and structural integration of these cells into the hippocampal network.

The molecular determinants and mechanisms involved in leukocyte trafficking across the blood–nerve barrier (BNB) in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) variant of Guillain–Barré syndrome are incompletely understood. Prior work using a flow-dependent in vitro human BNB model demonstrated a crucial role for α M -integrin (CD11b)-intercellular adhesion molecule-1 interactions in AIDP patient leukocyte trafficking. The aim of this study is to directly investigate the biological relevance of CD11b in AIDP pathogenesis. Immunohistochemistry was performed on three AIDP patient sural nerve biopsies to evaluate endoneurial leukocyte CD11b expression. A severe murine experimental autoimmune neuritis (sm-EAN) model was utilized to determine the functional role of CD11b in leukocyte trafficking in vivo and determine its effect on neurobehavioral measures of disease severity, electrophysiological assessments of axonal integrity and myelination and histopathological measures of peripheral nerve inflammatory demyelination. Time-lapse video microscopy and electron microscopy were employed to observe structural alterations at the BNB during AIDP patient leukocyte trafficking in vitro and in situ, respectively. Large clusters of endoneurial CD11b+ leukocytes associated with demyelinating axons were observed in AIDP patient sural nerves. Leukocyte CD11b expression was upregulated during sm-EAN. 5 mg/kg of a function-neutralizing monoclonal rat anti-mouse CD11b antibody administered after sm-EAN disease onset significantly ameliorated disease severity, as well as electrophysiological and histopathological parameters of inflammatory demyelination compared to vehicle- and isotype antibody-treated mice. Consistent with in vitro observations of leukocyte trafficking at the BNB, electron micrographs of AIDP patient sural nerves demonstrated intact electron-dense endoneurial microvascular intercellular junctions during paracellular mononuclear leukocyte transmigration. Our data support a crucial pathogenic role of CD11b in AIDP leukocyte trafficking, providing a potential therapeutic target for demyelinating variants of Guillain–Barré syndrome.

Previous research and clinical practice have indicated that damage to the vagal nerve may seriously affect gastrointestinal physiological movement behavior. The aim of the current study was to observe the change of gastric motility, as well as enteric glial cells (EGCs) in the stomach with different courses of vagal nerve transection in rats prior to and following synchronized dual pulse gastric electrical stimulation. The gastric emptying rates were measured to assess the gastric motility. The glial markers, containing calcium binding protein (S100B) and glial fibrillary acidic protein (GFAP), were detected by reverse transcription-quantitative polymerase chain reaction and double-labeling immunofluorescence analysis. Ultrastructural changes of EGCs were observed using transmission electron microscopy. Gastric emptying was delayed in the terminal vagotomy group, compared with the terminal control group. The effect of long-term synchronized dual pulse gastric electrical stimulation (SGES) was superior to short-term SGES in terminal groups. The expression levels of S100B/GFAP were markedly decreased in the terminal vagotomy group compared with the terminal control group. Following short-term or long-term SGES, S100B/GFAP gene and protein expression increased in terminal groups. However, long-term SGES was more effective than short-term SGES and the difference was statistically significant. Vagal nerve damage leads to gastric motility disorder and weakens the function of EGCs. Therefore, SGES may improve stomach movement behavior and restore the impaired EGCs. The underlying mechanism of the effect remains elusive, but maybe associated with activation of EGCs.

In the anterior and intermediate lobes of the rat pituitary gland, non-hormone-producing cells that express S-100 protein coexist with various types of hormone-producing cells and are believed to function as phagocytes, supporting and paracrine-controlling cells of hormone-producing cells and stem cells, among other functions; however, their cytological characteristics are not yet fully understood. Using a transgenic rat that expresses green fluorescent protein under the promoter of the S100β protein gene, we immunohistochemically detected expression of the luteinizing hormone, thyroid-stimulating hormone, prolactin, growth hormone and proopiomelanocortin by S-100 protein-positive cells located between clusters of hormone-producing cells in the intermediate lobe. These findings lend support to the hypothesis that S-100 protein-positive cells are capable of differentiating into hormone-producing cells in the adult rat pituitary gland.