Rabies Anterograde Monosynaptic Tracing Allows Identification of Postsynaptic Circuits Receiving Distinct Somatosensory Input.

Somatosensory neurons detect vital information about the environment and internal status of the body, such as temperature, touch, itch, and proprioception. The circuit mechanisms controlling the coding of somatosensory information and the generation of appropriate behavioral responses are not clear yet. In order to address this issue, it is important to define the precise connectivity patterns between primary sensory afferents dedicated to the detection of different stimuli and recipient neurons in the central nervous system.

Regulating muscle spindle and Golgi tendon organ proprioceptor phenotypes.

Proprioception is an essential part of motor control. The main sensory subclasses that underlie this feedback control system - muscle spindle and Golgi tendon organ afferents - have been extensively characterized at a morphological and physiological level. More recent studies are beginning to reveal the molecular foundation for distinct proprioceptor subtypes, offering new insights into their developmental ontogeny and phenotypic diversity.

The Positional Logic of Sensory-Motor Reflex Circuit Assembly.

Throughout his scientific career, Tom Jessell pioneered the spinal cord as a model system to study the molecular programs of neural specification, axon guidance, and connection specificity. His contributions to these fields and more broadly to that of developmental neuroscience will continue to inspire and define many generations of researchers. It is challenging to capture all of Tom's findings in one essay, and therefore, here we wish to briefly highlight his contributions to the problem of connection specificity, with a focus on the spinal sensory-motor reflex circuit.

[Hypercalcemia].

Calcium is pivotal for neuromuscular function, coagulation, and signal transduction. An imbalance of enteral calcium uptake, deposition in and resorption from bones, and renal calcium elimination causes hypercalcemia. The dissociation between total serum calcium and ionized calcium has important implications in diagnosing hypercalcemia.

Organization of motor pools depends on the combined function of N-cadherin and type II cadherins.

Type I and type II classical cadherins constitute a family of cell adhesion molecules expressed in complex combinatorial profiles in the nervous system, suggesting that a cadherin code implements specific adhesive recognition events that control the development of neural circuits. In the spinal cord, classical cadherins define at a molecular level the positional organization of motor neuron subtypes into discrete nuclear structures termed motor pools. However, the roles and contributions of different members of the family in defining motor neuron spatial organization are not yet clear.

[Hyperkalemia - causes, diagnostic evaluation and treatment].

Potassium is pivotal for membrane potentials and controls the functioning of a variety of organs, including nerves and muscles. The vast majority of potassium resides within cells. Disorders that compromise potassium influx into cells and decrease renal elimination cause hyperkalemia.

Dendritic cells tip the balance towards induction of regulatory T cells upon priming in experimental autoimmune encephalomyelitis.

Counter-balancing regulatory mechanisms, such as the induction of regulatory T cells (Treg), limit the effects of autoimmune attack in neuroinflammation. However, the role of dendritic cells (DCs) as the most powerful antigen-presenting cells, which are intriguing therapeutic targets in this context, is not fully understood. Here, we demonstrate that conditional ablation of DCs during the priming phase of myelin-specific T cells in experimental autoimmune encephalomyelitis (EAE) selectively aborts inducible Treg (iTreg) induction, whereas generation of T helper (Th)1/17 cells is unaltered.

Reduction of apoptosis and preservation of mitochondrial integrity under ischemia/reperfusion injury is mediated by estrogen receptor β.

Background: Estrogen improves cardiac recovery after ischemia/reperfusion (I/R) by yet incompletely understood mechanisms. Mitochondria play a crucial role in I/R injury through cytochrome c-dependent apoptosis activation. We tested the hypothesis that 17β-estradiol (E2) as well as a specific ERβ agonist improve cardiac recovery through estrogen receptor (ER)β-mediated mechanisms by reducing mitochondria-induced apoptosis and preserving mitochondrial integrity.

Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.

Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells.

Metabolic Profiling as Well as Stable Isotope Assisted Metabolic and Proteomic Analysis of RAW 264.7 Macrophages Exposed to Ship Engine Aerosol Emissions: Different Effects of Heavy Fuel Oil and Refined Diesel Fuel.

Exposure to air pollution resulting from fossil fuel combustion has been linked to multiple short-term and long term health effects. In a previous study, exposure of lung epithelial cells to engine exhaust from heavy fuel oil (HFO) and diesel fuel (DF), two of the main fuels used in marine engines, led to an increased regulation of several pathways associated with adverse cellular effects, including pro-inflammatory pathways. In addition, DF exhaust exposure was shown to have a wider response on multiple cellular regulatory levels compared to HFO emissions, suggesting a potentially higher toxicity of DF emissions over HFO.

The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration.

Chemotherapy is one of the pillars of anti-cancer therapy. Although chemotherapeutics cause regression of the primary tumor, many chemotherapeutics are often shown to induce or accelerate metastasis formation. Moreover, metastatic tumors are largely resistant against chemotherapy.

Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner.

Myeloid-derived suppressor cells (MDSCs) are well known for their capacity to suppress antitumor T-cell responses, but their effects on B-cell function and antibody production remain unclear. Here, we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B cells. In the presence of MDSCs, the antibody reaction to a surrogate antigen was significantly enhanced in mice, especially the immunoglobulin (Ig)A subtype.

Gatekeeper role of brain antigen-presenting CD11c+ cells in neuroinflammation.

Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen-presenting cells, dendritic cells.

Role of Sortilin in Models of Autoimmune Neuroinflammation.

The proneurotrophin receptor sortilin is a protein with dual functions, being involved in intracellular protein transport, as well as cellular signal transduction. The relevance of the receptor for various neuronal disorders, such as dementia, seizures, and brain injury, is well established. In contrast, little is known about the role of sortilin in immune cells and inflammatory diseases.

Particulate matter from both heavy fuel oil and diesel fuel shipping emissions show strong biological effects on human lung cells at realistic and comparable in vitro exposure conditions.

Background: Ship engine emissions are important with regard to lung and cardiovascular diseases especially in coastal regions worldwide. Known cellular responses to combustion particles include oxidative stress and inflammatory signalling.

Objectives: To provide a molecular link between the chemical and physical characteristics of ship emission particles and the cellular responses they elicit and to identify potentially harmful fractions in shipping emission aerosols.

Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes.

Background: Habitual red meat consumption was consistently related to a higher risk of type 2 diabetes in observational studies. Potentially underlying mechanisms are unclear.

Objective: This study aimed to identify blood metabolites that possibly relate red meat consumption to the occurrence of type 2 diabetes.

Cross-recognition of a myelin peptide by CD8+ T cells in the CNS is not sufficient to promote neuronal damage.

Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8(+) T cells are frequently found in multiple sclerosis lesions, their distinct role remains controversial because direct signs of cytotoxicity have not been confirmed in vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8(+) T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40-54 (MOG40-54) both in vitro and in vivo.

Mathematical modelling suggests a differential impact of β-transducin repeat-containing protein paralogues on Wnt/β-catenin signalling dynamics.

The Wnt/β-catenin signalling pathway is involved in the regulation of a multitude of cellular processes by controlling the concentration of the transcriptional regulator β-catenin. Proteasomal degradation of β-catenin is mediated by two β-transducin repeat-containing protein paralogues, homologous to Slimb protein (HOS) and F-box/WD repeat-containing protein 1A (FWD1), which are functionally interchangeable and thereby considered to function redundantly in the pathway. HOS and FWD1 are both regulated by Wnt/β-catenin signalling, albeit in opposite directions, thus establishing interlocked negative and positive feedback loops.

Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2.

Cyclic nucleotide phosphodiesterase 3A (PDE3) regulates cAMP-mediated signaling in the heart, and PDE3 inhibitors augment contractility in patients with heart failure. Studies in mice showed that PDE3A, not PDE3B, is the subfamily responsible for these inotropic effects and that murine PDE3A1 associates with sarcoplasmic reticulum Ca(2+) ATPase 2 (SERCA2), phospholamban (PLB), and AKAP18 in a multiprotein signalosome in human sarcoplasmic reticulum (SR). Immunohistochemical staining demonstrated that PDE3A co-localizes in Z-bands of human cardiac myocytes with desmin, SERCA2, PLB, and AKAP18.

Src homology 2 domain containing protein 5 (SH2D5) binds the breakpoint cluster region protein, BCR, and regulates levels of Rac1-GTP.

SH2D5 is a mammalian-specific, uncharacterized adaptor-like protein that contains an N-terminal phosphotyrosine-binding domain and a C-terminal Src homology 2 (SH2) domain. We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 domain.

JAMM: a peak finder for joint analysis of NGS replicates.

Motivation: Although peak finding in next-generation sequencing (NGS) datasets has been addressed extensively, there is no consensus on how to analyze and process biological replicates. Furthermore, most peak finders do not focus on accurate determination of enrichment site widths and are not widely applicable to different types of datasets.

Results: We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks.

Evaluation of various biomarkers as potential mediators of the association between coffee consumption and incident type 2 diabetes in the EPIC-Potsdam Study.

Background: The inverse association between coffee consumption and the risk of type 2 diabetes (T2D) is well established; however, little is known about potential mediators of this association.

Objective: We aimed to investigate the association between coffee consumption and diabetes-related biomarkers and their potential role as mediators of the association between coffee consumption and T2D.

Design: We analyzed a case-cohort study (subcohort: n = 1610; verified incident T2D cases: n = 417) nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam study involving 27,548 middle-aged participants.

Modulation of dendritic cell immunobiology via inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase.

The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function.

SecA defects are accompanied by dysregulation of MukB, DNA gyrase, chromosome partitioning and DNA superhelicity in Escherichia coli.

Spatial regulation of nucleoids and chromosome-partitioning proteins is important for proper chromosome partitioning in Escherichia coli. However, the underlying molecular mechanisms are unknown. In the present work, we showed that mutation or chemical perturbation of secretory A (SecA), an ATPase component of the membrane protein translocation machinery, SecY, a component of the membrane protein translocation channel and acyl carrier protein P (AcpP), which binds to SecA and MukB, a functional homologue of structural maintenance of chromosomes protein (SMC), resulted in a defect in chromosome partitioning.

Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products.