BRENDA in 2015: exciting developments in its 25th year of existence.

The BRENDA enzyme information system (http://www.brenda-enzymes.org/) has developed into an elaborate system of enzyme and enzyme-ligand information obtained from different sources, combined with flexible query systems and evaluation tools.

The Influence of Energetic Factors on Biomarkers of Postmenopausal Breast Cancer Risk.

Strong and consistent evidence exists that physical activity reduces breast cancer risk by 10-25 %, and several proposed biologic mechanisms have now been investigated in randomized, controlled, exercise intervention trials. Leading hypothesized mechanisms relating to postmenopausal breast cancer include adiposity, endogenous sex hormones, insulin resistance, and chronic low-grade inflammation. In addition, other pathways are emerging as potentially important, including those involving oxidative stress and telomere length, global DNA hypomethylation, immune function, and vitamin D exposure.

Dexamethasone inhibits inflammation and cartilage damage in a new model of post-traumatic osteoarthritis.

Corticosteroids are used in musculoskeletal diseases, and offer patient relief. Injections of corticosteroids are recommended for management of osteoarthritis (OA). Current data have shown the role of corticosteroids in ameliorating pain.

The transcriptional co-repressor TLE3 regulates development of trophoblast giant cells lining maternal blood spaces in the mouse placenta.

TLE3 is a transcriptional co-repressor that interacts with several DNA-binding repressors, including downstream effectors of the Notch signaling pathway. We generated Tle3-deficient mice and found that they die in utero and their death is associated with abnormal development of the placenta with major defects in the maternal vasculature. In the normal placenta, maternal blood spaces are lined, not as usual in the mammalian circulation by endothelial cells, but rather by specialized embryo-derived cells of the trophoblast cell lineage named trophoblast giant cells (TGC).

A comparison of orthopaedic resident performance on surgical fixation of an ulnar fracture using virtual reality and synthetic models.

Background: Surgical trainees develop surgical skills using various techniques, with simulators providing a safe learning environment. Fracture fixation is the most common procedure in orthopaedic surgery, and residents may benefit from simulated fracture fixation. The performance of residents on a virtual simulator that allows them to practice the surgical fixation of fractures by providing a sense of touch (haptics) has not yet been compared with their performance using other methods of practicing fracture fixation, such as a Sawbones simulator model.

Surface expression and function of Cav3.2 T-type calcium channels are controlled by asparagine-linked glycosylation.

Low-voltage-activated T-type calcium channels play important roles in neuronal physiology where they control cellular excitability and synaptic transmission. Alteration in T-type channel expression has been linked to various pathophysiological conditions such as pain arising from diabetic neuropathy. In the present study, we looked at the role of asparagine (N)-linked glycosylation on human Cav3.

Ca2+ sensitization due to myosin light chain phosphatase inhibition and cytoskeletal reorganization in the myogenic response of skeletal muscle resistance arteries.

Abstract  The myogenic response of resistance arteries to intravascular pressure elevation is a fundamental physiological mechanism of crucial importance for blood pressure regulation and organ-specific control of blood flow. The importance of Ca(2+) entry via voltage-gated Ca(2+) channels leading to phosphorylation of the 20 kDa myosin regulatory light chains (LC20) in the myogenic response is well established. Recent studies, however, have suggested a role for Ca(2+) sensitization via activation of the RhoA/Rho-associated kinase (ROK) pathway in the myogenic response.

Glucose-responsive artificial promoter-mediated insulin gene transfer improves glucose control in diabetic mice.

Aim: To investigate the effect of insulin gene therapy using a glucose-responsive synthetic promoter in type 2 diabetic obese mice.

Methods: We employed a recently developed novel insulin gene therapy strategy using a synthetic promoter that regulates insulin gene expression in the liver in response to blood glucose level changes. We intravenously administered a recombinant adenovirus expressing furin-cleavable rat insulin under the control of the synthetic promoter (rAd-SP-rINSfur) into diabetic Lepr(db/db) mice.

How useful are delta checks in the 21 century? A stochastic-dynamic model of specimen mix-up and detection.

Introduction: Delta checks use two specimen test results taken in succession in order to detect test result changes greater than expected physiological variation. One of the most common and serious errors detected by delta checks is specimen mix-up errors. The positive and negative predictive values of delta checks for detecting specimen mix-up errors, however, are largely unknown.

Morphometric characteristics of basal cell carcinoma peritumoral stroma varies among basal cell carcinoma subtypes.

Background: The role that the peritumoral stroma plays in the growth of tumours is currently poorly understood. In this manuscript the morphometric characteristics of basal cell carcinoma subtypes and their associated peritumoral stromas are presented.

Methods: Ninety eight digitized basal cell carcinoma histology slides were categorized as infiltrative, nodular, or superficial subtypes, and were analysed using a combination of manual and computer-assisted approaches.

An open-source software program for performing Bonferroni and related corrections for multiple comparisons.

Increased type I error resulting from multiple statistical comparisons remains a common problem in the scientific literature. This may result in the reporting and promulgation of spurious findings. One approach to this problem is to correct groups of P-values for "family-wide significance" using a Bonferroni correction or the less conservative Bonferroni-Holm correction or to correct for the "false discovery rate" with a Benjamini-Hochberg correction.

Distinct roles for I(T) and I(H) in controlling the frequency and timing of rebound spike responses.

The ability for neurons to generate rebound bursts following inhibitory synaptic input relies on ion channels that respond in a unique fashion to hyperpolarization. Inward currents provided by T-type calcium channels (I(T)) and hyperpolarization-activated HCN channels (I(H)) increase in availability upon hyperpolarization, allowing for a rebound depolarization after a period of inhibition. Although rebound responses have long been recognized in deep cerebellar nuclear (DCN) neurons, the actual extent to which I(T) and I(H) contribute to rebound spike output following physiological levels of membrane hyperpolarization has not been clearly established.

Hand biomechanics during simulated stone tool use.

Human radial digits have derived features compared with apes, with long robust thumbs, relatively larger joint surfaces, and hypertrophic thenar muscles. Here we test the hypothesis that these features evolved in the context of making and using stone tools, specifically for producing large gripping forces and for countering large joint contact stresses. We used portable force plates simulating early stone tools to: 1) document and compare the magnitude of external/internal forces and joint stresses in the radial digits during hardhammer percussion and flake use, and 2) examine how variation in digit morphology affects muscle and joint mechanics during stone tool use.

Stromatoxin-sensitive, heteromultimeric Kv2.1/Kv9.3 channels contribute to myogenic control of cerebral arterial diameter.

Cerebral vascular smooth muscle contractility plays a crucial role in controlling arterial diameter and, thereby, blood flow regulation in the brain. A number of K(+) channels have been suggested to contribute to the regulation of diameter by controlling smooth muscle membrane potential (E(m)) and Ca(2+) influx. Previous studies indicate that stromatoxin (ScTx1)-sensitive, Kv2-containing channels contribute to the control of cerebral arterial diameter at 80 mmHg, but their precise role and molecular composition were not determined.

The tetrodotoxin receptor of voltage-gated sodium channels--perspectives from interactions with micro-conotoxins.

Neurotoxin receptor site 1, in the outer vestibule of the conducting pore of voltage-gated sodium channels (VGSCs), was first functionally defined by its ability to bind the guanidinium-containing agents, tetrodotoxin (TTX) and saxitoxin (STX). Subsequent studies showed that peptide micro-conotoxins competed for binding at site 1. All of these natural inhibitors block single sodium channels in an all-or-none manner on binding.

Sex-dependent effects of neonatal inflammation on adult inflammatory markers and behavior.

Inflammatory molecules, such as cyclooxygenase (COX), a prostaglandin synthetic enzyme, have been identified as a marker of depressive symptomology. Previously, we have observed elevated basal COX-2 expression in the hypothalamus of adult male rats treated neonatally with lipopolysaccharide (LPS), which might suggest a phenotype for disrupted hedonic behavior, a symptom of depression. However, COX-2 and its contribution to the expression of anhedonic behavior has not been investigated in these males or in female rats across the estrous cycle, which is the purpose of the current work.

Reversal of autoimmunity by boosting memory-like autoregulatory T cells.

Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals.

Pressure-dependent contribution of Rho kinase-mediated calcium sensitization in serotonin-evoked vasoconstriction of rat cerebral arteries.

Our understanding of the cellular signalling mechanisms contributing to agonist-induced constriction is almost exclusively based on the study of conduit arteries. Resistance arteries/arterioles have received less attention as standard biochemical approaches lack the necessary sensitivity to permit quantification of phosphoprotein levels in these small vessels. Here, we have employed a novel, highly sensitive Western blotting method to assess: (1) the contribution of Ca(2+) sensitization mediated by phosphorylation of myosin light chain phosphatase targeting subunit 1 (MYPT1) and the 17 kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17) to serotonin (5-HT)-induced constriction of rat middle cerebral arteries, and (2) whether there is any interplay between pressure-induced myogenic and agonist-induced mechanisms of vasoconstriction.

The lactoferrin receptor complex in Gram negative bacteria.

Bacteria that inhabit the respiratory and genitourinary tracts of mammals encounter an iron-deficient environment on the mucosal surface where iron is complexed by the host iron-binding proteins transferrin and lactoferrin. Lactoferrin is also present in high concentrations at sites of inflammation where the cationic anti-microbial peptide lactoferricin is produced by proteolysis of lactoferrin. Several members of the Neisseriaceae and Moraxellaceae families express surface receptors, capable of specifically binding host lactoferrin and extracting the iron from lactoferrin as a source of iron for growth.

Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor-dependent mechanism.

The G-protein-linked receptor, proteinase-activated receptor-4 (PAR(4)) is activated by proteinases released into the joint during inflammation. It is unclear whether PAR(4) has a pro- or anti-nociceptive effect and whether it directly affects nerve activity. In this study, we examined the expression of PAR(4) in joints and dorsal root ganglion (DRG) neurons and whether activation of PAR(4) has an effect on nociception in normal rat knee joints.

Taking advantage of the systemic immune system to cure brain diseases.

The systemic immune system has the ability to modulate multiple brain functions, including autonomic responses, glial reactivity following neural injuries, and neuronal excitability. Immune stimuli also influence microglia subpopulations originating from blood progenitors, and neuroprotective and reparative capacities of blood-derived microglia were recently described in mouse models of spinal cord injury and brain disorders. Furthermore, reparative roles for various immune subsets have been recognized, such as in inducing myelin repair.