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By mediating estrogen synthesis and follicular growth in response to FSH, the ovarian FSH receptor (FSHR) is essential for female fertility. Indeed, ovarian stimulation via administration of FSH to women with infertility is part of the primary therapeutic intervention used in assisted reproductive technology. In physiological and therapeutic contexts, current dogma dictates that once ovulation has occurred, FSH/FSHR signaling is no longer required for successful pregnancy outcomes. However, a continued role for FSH during pregnancy is suggested by recent studies demonstrating extraovarian FSHR in the female reproductive tract. Furthermore, functional roles for FSHR in placenta and in uterine myometrium have now been demonstrated. In placenta, vascular endothelial FSHR of fetal vessels within the chorionic villi (human) or labyrinth (mouse) mediate angiogenesis, and it has further been shown that deletion of placental Fshr in mice has deleterious effects on pregnancy. In uterine myometrium, changes in the densities of FSHR in muscle fiber and stroma in the nonpregnant state, early pregnancy, and term pregnancy differentially regulate contractile activity, suggesting that signaling through myometrial FSHR may contribute to the quieting of contractile activity required for successful implantation and that the temporal upregulation of the FSHR at term pregnancy may be required for the appropriate timing of parturition. In addition, extraovarian expression of mRNAs encoding the glycoprotein hormone α subunit and the FSH β subunit has been demonstrated, suggesting that these novel aspects of extraovarian FSH/FSHR signaling during pregnancy may be mediated by locally synthesized FSH.

Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1.

Ischemic stroke is a devastating brain injury resulting in high mortality and substantial loss of function. Understanding the pathophysiology of ischemic stroke risk, mortality, and functional loss is critical to the development of new therapies. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest nonmodifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality and morbidity and poorer functional recovery than their young counterparts. Importantly, patient age modifies the influence of patient sex in ischemic stroke. Early in life, the burden of ischemic stroke is higher in men, but stroke becomes more common and debilitating for women in elderly populations. The profound effects of sex and age on clinical ischemic stroke are mirrored in the results of experimental in vivo and in vitro studies. Here, we review current knowledge on the influence of age and sex in the incidence, mortality, and functional outcome of ischemic stroke in clinical populations. We also discuss the experimental evidence for sex and age differences in stroke pathophysiology and how a better understanding of these biological variables can improve clinical care and enhance development of novel therapies.

It is well established that obesity increases the incidence and worsens the prognosis of women’s cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin’s role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women’s cancer.

Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss-independent manner. In support of this classification, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation of type 2 diabetes mellitus (T2DM) medication can occur before substantial postoperative weight loss. The mechanisms that underlie this effect are unknown. However, one of the common findings after VSG and RYGB in both animal models and humans is the sharp postprandial rise in several gut peptides, including the incretin and satiety peptide glucagonlike peptide-1 (GLP-1). The increase in endogenous GLP-1 signaling has been considered a primary pathway leading to postsurgical weight loss and improvements in glucose metabolism. However, the degree to which GLP-1 and other gut peptides are responsible for the metabolic successes after bariatric surgery is continually debated. In this review we discuss the mechanisms underlying the increase in GLP-1 and its potential role in the metabolic improvements after bariatric surgery, including remission of T2DM. Understanding the role of changes in gut peptides, or lack thereof, will be crucial in understanding the critical factors necessary for the metabolic success of bariatric surgery.

The capacity of embryonic stem (ES) cells to differentiate into cell lineages comprising the three germ layers makes them powerful tools for studying mammalian early embryonic development in vitro. The human body consists of approximately 210 different somatic cell types, the majority of which have limited proliferative capacity. However, both stem cells and cancer cells bypass this replicative barrier and undergo symmetric division indefinitely when cultured under defined conditions. Several signal transduction pathways play important roles in regulating stem cell development, and aberrant expression of components of these pathways is linked to cancer. Among signaling systems, the critical role of leukemia inhibitory factor (LIF) coupled to the Jak/STAT3 (signal transduction and activation of transcription-3) pathway in maintaining stem cell self-renewal has been extensively reviewed. This pathway additionally plays multiple roles in tumorigenesis. Likewise, the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway has been determined to play an important role in both stem cell maintenance and tumor development. This pathway is often induced in cancer with frequent mutational activation of the catalytic subunit of PI3K or loss of a primary PI3K antagonist, phosphatase and tensin homolog deleted on chromosome ten (PTEN). This review focusses on roles of the PI3K signal transduction pathway components, with emphasis on functions in stem cell maintenance and cancer. Since the PI3K pathway impinges on and collaborates with other signaling pathways in regulating stem cell development and/or cancer, aspects of the canonical Wnt, Ras/mitogen-activated protein kinase (MAPK), and TGF-β signaling pathways are also discussed. J. Cell. Physiol. 229: 1312–1322, 2014.

Systemic treatment of advanced prostate cancer is initiated with androgen deprivation therapy by gonadal testosterone depletion. Response durations are variable and tumors nearly always become resistant as castration-resistant prostate cancer (CRPC), which is driven, at least in part, by a continued dependence on the androgen receptor (AR). The proposed mechanisms that underlie AR function in this clinical setting are quite varied. These include intratumoral synthesis of androgens from inactive precursors, increased AR expression, AR activation through tyrosine kinase-dependent signaling, alterations in steroid receptor coactivators, and expression of a truncated AR with constitutive activity. Various pharmacologic interventions have clinically validated some of these mechanisms, such as those that require the AR ligand-binding domain. Clinical studies have failed to validate other mechanisms, and additional mechanisms have yet to be tested in patients with CRPC. Here, we review the mechanisms that elicit AR activity in CRPC, with a particular focus on recent developments.

Evidence on biological plausibility from mechanistic studies and highly consistent data from observational studies raise the possibility that optimizing vitamin D status may reduce the risk of type 2 diabetes. However, the observational nature of cohort studies precludes a definitive assessment of cause and effect because residual confounding or reverse causation cannot be excluded. Confounding is especially problematic with studies of vitamin D because blood 25-hydoxyvitamin D concentration is not only an excellent biomarker of vitamin D status, reflecting intake or biosynthesis, but also an excellent marker of good overall health. Results from underpowered trials and post hoc analyses of trials designed for nondiabetic outcomes do not support a role of vitamin D supplementation for prevention of type 2 diabetes among people with normal glucose tolerance. Whether vitamin D supplementation may have a role in the prevention of diabetes in high-risk populations remains to be seen. Adequately powered, randomized trials in well-defined populations (e.g., prediabetes) are ongoing and expected to establish whether vitamin D supplementation lowers risk of diabetes.

In the last few years, the survival of patients with castration-resistant prostate cancer (CRPC) has significantly improved as a result of the development of second-generation androgen deprivation therapies such as abiraterone and second-generation antagonists such as enzalutamide. However, CRPC patients rapidly develop resistance to these drugs, in many cases because of reactivation of the therapeutic target, the androgen receptor (AR) transcription factor. Several mechanisms responsible for AR transcriptional reactivation have been demonstrated, including mutation, amplification, and rearrangement of the AR gene, transcriptional compensation by alternative steroid receptors, and mutation or copy number alteration of genes encoding AR coregulators. In addition, CRPC tumors display elevated expression of truncated AR variants (AR-Vs) that can arise from alternative splicing or underlying AR gene rearrangements. In this review, we discuss general mechanisms of resistance to androgen/AR-targeted therapies, with a focus on the role of AR-Vs in conferring resistance to abiraterone or enzalutamide in CRPC patients.

Amyloid-β (Aβ) peptides, as well as a variety of other protein fragments, are derived from proteolytical cleavage of the amyloid precursor protein (APP) and have been demonstrated to play a key role in the pathological changes underlying Alzheimer disease (AD). In AD mouse models, altered neurogenesis has been repeatedly reported to be associated with further AD-typical pathological hallmarks such as extracellular plaque deposition, behavioral deficits or neuroinflammation. While a toxic role of Aβ in neurodegeneration and impaired neuronal progenitor proliferation is likely and well-accepted, recent findings also suggest an important influence of APP-derived proteolitical fragments like the APP intracellular domain (AICD), as well as of APP itself.

International audience; Current literature makes a distinction between two pathways for thyroid hormone signaling: genomic and nongenomic. However, this classification is a source of confusion. We propose a clarification in the nomenclature that may help to avoid unproductive controversies and favor progress in this field of research. Four types of thyroid hormone signaling are defined, and the experimental criteria for classification are discussed.

The seven members of the tumor necrosis factor receptor (TNF‐R)‐associated factor (TRAF) family of intracellular proteins were originally discovered and characterized as signaling adaptor molecules coupled to the cytoplasmic regions of receptors of the TNF‐R superfamily. Functionally, TRAFs act both as a scaffold and/or enzymatic proteins to regulate activation of mitogen‐activated protein kinases (MAPKs) and transcription factors of nuclear factor‐κB family (NF‐κB). Given the wide variety of stimuli intracellularly conveyed by TRAF proteins, they are physiologically involved in multiple biological processes, including embryonic development, tissue homeostasis, and regulation of innate and adaptive immune responses. In the last few years, it has become increasingly evident the involvement of TRAF7, the last member of the TRAF family to be discovered, in the genesis and progression of several human cancers, placing TRAF7 in the spotlight as a novel tumor suppressor protein. In this paper, we review and discuss the literature recently produced on this subject. J. Cell. Physiol. 232: 1233–1238, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Androgen excess (hyperandrogenism) is a common endocrine disorder affecting women of reproductive age. The potential causes of androgen excess in women include polycystic ovary syndrome, congenital adrenal hyperplasia (CAH), adrenal tumors, and racial disparity among many others. During pregnancy, luteoma, placental aromatase deficiency, and fetal CAH are additional causes of gestational hyperandrogenism. The present report reviews the various phenotypes of hyperandrogenism during pregnancy and its origin, pathophysiology, and the effect of hyperandrogenism on the fetal developmental trajectory and offspring consequences.

Polycystic kidney diseases (PKD) are a group of inherited nephropathies marked with the formation of fluid-filled cysts along the nephron. This renal disorder affects millions of people worldwide, but current treatment strategies are unfortunately limited to supportive therapy, dietary restrictions, and, eventually, renal transplantation. Recent advances in PKD management are aimed at targeting exaggerated cell proliferation and dedifferentiation to interfere with cyst growth. However, not nearly enough is known about the ion transport properties of the cystic cells, or specific signaling pathways modulating channels and transporters in this condition. There is growing evidence that abnormally elevated concentrations of adenosine triphosphate (ATP) in PKD may contribute to cyst enlargement; change in the profile of purinergic receptors may also result in promotion of cystogenesis. The current mini-review is focused on the role of ATP and associated signaling affecting ion transport properties of the renal cystic epithelia.

Sex differences in brain development and aging are important to identify, as they may help to understand risk factors and outcomes in brain disorders that are more prevalent in one sex compared with the other. Brain imaging techniques have advanced rapidly in recent years, yielding detailed structural and functional maps of the living brain. Even so, studies are often limited in sample size, and inconsistent findings emerge, one example being varying findings regarding sex differences in the size of the corpus callosum. More recently, large‐scale neuroimaging consortia such as the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium have formed, pooling together expertise, data, and resources from hundreds of institutions around the world to ensure adequate power and reproducibility. These initiatives are helping us to better understand how brain structure is affected by development, disease, and potential modulators of these effects, including sex. This review highlights some established and disputed sex differences in brain structure across the life span, as well as pitfalls related to interpreting sex differences in health and disease. We also describe sex‐related findings from the ENIGMA consortium, and ongoing efforts to better understand sex differences in brain circuitry. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

The mechanical properties of the ECM strongly influence the behavior of all cell types within a given tissue. Increased matrix tension promotes epithelial cell proliferation by engaging mitogenic mechanotransduction signaling including the Salvador/Warts/Hippo, PI 3-kinase, Rho, Wnt and MAP kinase pathways. The Rho signaling pathways in particular are capable of increasing intra-cellular tension by elevating the production and contractility of the actomyosin cytoskeleton, which counteracts tension changes within the matrix in a process termed mechano-reciprocity. We have discovered that Rho-ROCK signaling increases the production of ECM through paracrine signaling between the epithelium and fibroblasts and also the remodeling of the ECM by regulating focal adhesion dynamics in fibroblasts. These two phenomena together cause increased ECM tension. Enhanced mechano-reciprocity results in ever-increasing intra- and extra-cellular tension in a vicious cycle that promotes cell proliferation and tumor progression. These insights reveal that inhibiting mechano-reciprocity, reducing ECM tension and targeting cancer-associated fibroblasts in a coordinated fashion has potential as cancer therapy. Refereed/Peer-reviewed

A controlled balance between cell proliferation and differentiation is essential to maintain normal intestinal tissue renewal and physiology. Such regulation is powered by several intracellular pathways that are translated into the establishment of specific transcription programs, which influence intestinal cell fate along the crypt-villus axis. One important check-point in this process occurs in the transit amplifying zone of the intestinal crypts where different signaling pathways and transcription factors cooperate to manage cellular proliferation and differentiation, before secretory or absorptive cell lineage terminal differentiation. However, the importance of epigenetic modifications such as histone methylation and acetylation in the regulation of these processes is still incompletely understood. There have been recent advances in identifying the impact of histone modifications and chromatin remodelers on the proliferation and differentiation of normal intestinal crypt cells. In this review we discuss recent discoveries on the role of the cellular epigenome in intestinal cell fate, development, and tissue renewal. J. Cell. Physiol. 231: 2361-2367, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

The mutations in the LRRK2 gene cause clinically typical, late-onset Parkinson disease, strengthening the idea that the familial forms of the disease represent an important tool for the study of the idiopathic forms. Despite the great effort to describe and functionally characterize the LRRK2 gene product, its physiological role remains elusive. In this article, we will discuss along with other references, our recent findings that assigned a critical role of LRRK2 protein on cytosleketal dynamics and how this direction could provide a valuable platform to further appreciate the mechanism underlying LRRK2-mediated pathophysiology of the disease.

Exosomes are endosome-derived vesicles (40-100 nm) formed during the formation of multi-vesicular bodies (MVBs). Occasionally, the MVBs fuse with the plasma membrane releasing their intra-luminal vesicles into the extracellular media, which are then known as exosomes. Different cell types such as B-cells, dendritic cells, platelets, reticulocytes and macrophages can release exosomes and current research in this area is more focused towards exosomes released by antigen-presenting cells. Exosomes have recently been shown to be immunomodulatory and the mechanism of immune response initiation by them is beginning to emerge. Besides molecules present inside the lumen of exosomes, it has been suggested that certain exosomal membrane molecules can interact with their surface receptors on the target cells thereby inducing an immunomodulatory response. In this review, Hsp70 and galectin-5, two immunogenic molecules present on exosomal membrane, are discussed in detail for initiating this response.

STriatal-Enriched Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that plays a role in synaptic plasticity and has recently been implicated in neurodegenerative disease. STEP opposes the development of synaptic strengthening by dephosphorylating and inactivating key signaling proteins that include the MAP kinases ERK1/2 and p38, as well as the tyrosine kinase Fyn. STEP also dephosphorylates the GluR2 subunit of the AMPAR and the NR2B subunit of the NMDAR, which leads to internalization of the NR1/NR2B and GluR1/GluR2 receptors. STEP levels and activity are regulated through phosphorylation, local translation, ubiquitination and degradation and proteolytic cleavage. Here we review recent progress in understanding the normal regulation of STEP and how this regulation is disrupted in Alzheimer's disease, in which abnormally increased STEP levels and activity contribute to the cognitive deficits.

Cripto-1 is critical for early embryonic development and, together with its ligand Nodal, has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes, Cripto-1 performs important roles in the formation and progression of several types of human tumors, stimulating cell proliferation, migration, epithelial to mesenchymal transition, and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways, suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells, which may re-express embryonic genes, Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore, the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer, leading to the elimination of undifferentiated stem-like tumor initiating cells.

Allergic diseases and asthma are caused by dysregulated Th2-type immune responses, which drive disease development in susceptible individuals. Immune tolerance to allergens prevents inflammatory symptoms in the respiratory mucosa and provides protection against inflammation in the airways. Increasing evidence indicates that Foxp3+ regulatory T cells (Tregs) play a critical role in immune tolerance and control Th2-biased responses. Tregs develop in the thymus from CD4(+) T cells (natural Tregs) and also in the periphery by the conversion of naïve CD4(+) T cells (induced Tregs). Increased susceptibility to allergy and airway inflammation is hypothesized to result from impaired development and function of Tregs. Thus, strategies to induce allergen-specific Tregs hold great promise for treatment and prevention of asthma.

Plant cells are encased within a complex polysaccharide wall that strengthens the cell and has key roles in all aspects of plant cell growth, differentiation, and interaction with the environment. This dynamic structure is under continual modification during plant development, and its synthesis and modification require the activity of a myriad of enzymes. The mucilage secretory cells (MSCs) of the Arabidopsis thaliana seed coat provide a model for the discovery of novel genes involved in the synthesis, secretion and modification of cell wall components, particularly pectin. These cells synthesize copious amounts of pectinaceous mucilage during development and, upon hydration of the desiccated seed, the mucilage rapidly swells, bursts from the MSCs and surrounds the seed in a gelatinous capsule. Several genes affecting MSC differentiation, pectin synthesis, and mucilage release have been identified and additional genes involved in these and related processes including pectin secretion and the mechanical alteration of cell walls await to be discovered.

4 pages, 1 figure, 35 references., Potassium (K+) is a major osmoticum of plant cells, and the vacuolar accumulation of this element is an especially crucial feature for plants under high-salt conditions. Emerging evidence indicates that cation/proton transporters of the NHX family are instrumental in the H+-linked K+ transport that mediate active K+ uptake at the tonoplast for the unequal partitioning of K+ between vacuole and cytosol. However, and in spite of tenuous supporting evidence, NHX proteins are widely regarded as key players in the sequestration of sodium (Na+) into vacuoles to avert ion toxicity in the cytosol of plants under salinity stress. Here, we propose an updated model positing that NHX proteins fulfill a protective function to minimize salt-related stress mainly through the vacuolar compartmentalization of K+ and, in some cases, of Na+ as well thereby preventing toxic Na+-K+ ratios in the cytosol while accruing solutes for osmotic balance., This work was supported by the Spanish Ministry of Science and Technology grants BIO2009-08641 and CSD2007-00057 to J.M.P. X.J. was supported by a JAE-Doc grant from C.S.I.C.

Heterokairy refers to plasticity in the timing of onset of developmental events at the level of an individual. When two developmental stages do not share the same ecological niche, referred to as ‘ontogenetic niches’, the control of the niche shift through a change in developmental timing can be advantageous for the individual (e.g., when mortality risk is different in the two niches). Heterokairy can arise either from plasticity in developmental rate (ontogenetic shift) or by a purely behavioral decision (behavioral shift). Parasitic species living inside of their hosts often inherit the predators of their hosts. To cope with the predation risk on their hosts, parasites and parasitoids show either host-manipulation abilities or either host-leaving strategies. Nevertheless, leaving the host should be associated with developmental costs, since the parasitic individuals are usually unable to parasitize another host. This process is thus related to the classical tradeoff between size and developmental time. Recent studies provided examples of behavioral heterokairy in invertebrates. The goal of this publication is to review and discuss recent results on developmental plasticity in parasitic species in an evolutionary perspective.

In this work, I asked whether and how honeybees (Apis mellifera) adjust their behaviour in relation to their past experience with reward variations. First, I performed a series of experiments with free-flying bees under conditions closely mimicking a natural foraging situation (Chapters 1 and 2). Next, I performed a series of laboratory experiments focused on a honeybee's proboscis extension response (PER) (Chapters 3 and 4). In all these experiments, I used the same general approach: First, I offered bees with increasing, decreasing or constant reward levels, and then recorded their subsequent behaviour in the absence of reward. I found that foraging bees learn both the sign and magnitude of reward variations. This form of learning is manifested through several measures of the bees’ 'eagerness' to search for food. For example, bees that experience increasing rewards across foraging excursions subsequently search for food during longer periods, when compared to bees that experience either decreasing or constant rewards. This type of behavioural adjustments can not be accounted for by classical and/or operant associations between the reward and its related predicting signals or by the bees' energy balance during foraging. In the laboratory, I also found that harnessed bees learn that the level of reward increases or decreases over time. This form of learning is manifested through measures of a bee’s PER. Such response allows bees gathering sugar solution, and is reflexively elicited when gustatory receptors of the antennae, proboscis and tarsi are stimulated with sugar solution. Bees that experience increasing rewards across feeding events subsequently extend their proboscis earlier and during longer periods in response to sucrose and/or mechanical stimulation of the antennae, in comparison to bees that experience either decreasing or constant rewards. Furthermore, this form of learning can be side-specific, in that bees show short- and long-term side differences in the reaction-time of their PER depending on past side-specific variations in the reward level. These side- specific behavioural adjustments involve an interplay between gustatory and mechanosensory input, and correlate well with the activity of muscles responsible for controlling the movements of the proboscis. I discuss these results in the context of the formation of reward memories and expectations of reward, individual and collective foraging strategies, and further approaches to the study of the neural substrates underlying memories on specific properties of reward., In der vorliegenden Arbeit untersuchte ich, ob und wie Honigbienen (Apis mellifera) ihr Futtersammelverhalten in Bezug auf ihre Erfahrungen mit variierenden Belohnungen anpassen. Zuerst führte ich eine Reihe von Experimenten mit frei fliegenden Bienen unter ähnlichen Konditionen wie bei der natürlichen Futtersuche (Kapitel 1 und 2) und danach Laborexperimente zum Rüsselstreckreflexe (PER, Proboscis Extension Response) der Honigbienen durch (Kapitel 3 und 4). Allen diesen Experimenten liegt die gleiche Herangehensweise zu Grunde: Zunächst bot ich den Bienen Belohnungen in Form von steigenden, sinkenden oder konstanten Futtermengen an und nahm dann ihr Verhalten in Abwesenheit einer Belohnung auf. Ich fand heraus, dass Sammelbienen sowohl das Vorzeichen (d.h. die Zu- oder Abnahme) als auch die Stärke der Variation von Belohnungen lernen. Diese Form des Lernens zeigt sich durch verschiedene Messungen des „Eifers“ der Bienen bei der Futtersuche. So suchen zum Beispiel Bienen, die während der Futtersuche zunehmende Belohnungsmengen erhalten, anschließend länger nach Futter als Bienen, die während der Futtersuche Erfahrungen mit entweder abnehmenden oder konstanten Belohnungen sammeln. Diese Art der Verhaltensanpassung kann weder durch die klassische und/oder operante Assoziation zwischen der Belohnung und dem Signal, das mit der Belohnung verbunden ist und ihr vorausgeht, noch durch die Energiebilanz während der Futtersuche erklärt werden. Meine Untersuchungen im Labor zeigten, dass auch in Röhrchen eingespannte Bienen lernen, ob das Belohnungsniveau im Verlauf der Zeit zu- oder abnimmt. Diese Art des Lernens offenbart sich durch Messungen des Rüsselstreckreflexes der Bienen. Das Ausstrecken des Rüssels ermöglicht den Bienen, Zuckerlösung zu sammeln und wird als Verhaltensantwort reflexiv ausgelöst, wenn Geschmacksrezeptoren der Antennen, des Saugrüssels und der Tarsi durch Zuckerlösung stimuliert werden. Bienen, die während der Fütterungen mit steigenden Belohnungen Erfahrungen sammeln, strecken nachfolgend als Verhaltensantwort auf die Stimulation mit Saccharose und/oder eine mechanische Stimulation der Antennen ihren Rüssel früher und länger aus als Bienen, die während der Fütterungen Belohnungen sinkender oder konstanter Quantität erhalten. Des Weiteren kann diese Form des Lernens insofern seitenspezifisch sein, dass Bienen kurz- und langfristige Unterschiede in der PER-Reaktionszeit bis zum Ausstrecken des Rüssels als Verhaltensantwort auf einen Reiz, in Abhängigkeit von vorherigen seitenspezifischen Variationen in der Belohnungsphase, zeigen. Diese seitenspezifischen Verhaltensanpassungen umfassen ein Zusammenspiel zwischen gustatorischen und mechanosensorischen Eingängen und korrelieren positiv mit der Aktivität der für das Ausstrecken des Rüssels verantwortlichen Muskeln. Ich diskutiere diese Ergebnisse im Zusammenhang mit der Bildung von Erinnerungen an und Erwartungen von Belohnungen, individuellen und kollektiven Strategien bei der Futtersuche und weiteren Ansätzen zur Erforschung der neuronalen Grundlagen, die für das Erinnern an bestimmte Eigenschaften von Belohnungen eine wichtige Rolle spielen.

Certolizumab pegol (Cimzia(®)) is currently the only PEGylated anti-TNFα biologic approved for the treatment of rheumatoid arthritis and Crohn disease. The product, developed by UCB, is a humanized antigen-binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol. Certolizumab pegol was approved as a treatment for rheumatoid arthritis in the EU, US and Canada in 2009, and as a treatment for Crohn disease in Switzerland in 2007 and the US in 2008. Certolizumab pegol is entering into an increasingly competitive marketplace, especially in rheumatoid arthritis, but clinical data demonstrate benefits across a range of clinical, radiographic and patient reported outcomes.

The cytosolic protein alpha-synuclein is enriched at the pre-synaptic terminals of almost all types of neurons in the central nervous system. alpha-Synuclein overexpression and the expression of three different mutants have been shown to sustain the pathogenesis of selected forms of Parkinson's disease. The localization of the protein and the defects found in knocked out or transgenic animals suggest a role of alpha-synuclein in the regulation of synaptic efficiency. However, the precise function of the protein and the molecular mechanisms of its action are still unclear. At synapses the synaptic vesicle release cycle is a finely tuned process composed of sequential steps that require the interconnected participation of several proteins and cytoskeletal elements. Actin microfilaments are required for the regulation of synaptic vesicle mobilization between different functional pools, for their organization at the active zone and influence the exocytotic process. We recently identified actin as a possible target of alpha-synuclein function. Through its binding to actin and the regulation of actin dynamics, alpha-synuclein could participate in the tuning of the vesicle release process, thereby modulating synaptic function and plasticity.

Catumaxomab, a monoclonal bispecific trifunctional antibody, was approved in the European Union in April 2009 for the intraperitoneal treatment of patients with malignant ascites. The marketing authorization holder Fresenius Biotech GmbH developed catumaxomab (Removab(®)) together with its partner TRION Pharma GmbH, Germany. It is the first substance worldwide with a regulatory label for the treatment of malignant ascites due to epithelial carcinomas. Since the peritoneum is of mesothelial origin and therefore lacks EpCAM expression, the intraperitoneal administration of catumaxomab is an attractive targeted immunotherapeutic approach. Catumaxomab is able to destroy EpCAM positive tumor cells in the peritoneal cavity known as the main cause of malignant ascites. In addition, catumaxomab is a potential therapeutic option for several primary tumors since the EpCAM molecule is expressed on the majority of epithelial carcinomas. This review focuses on the clinical development of catumaxomab and indicates future directions.

The bacterial pathogen Agrobacterium tumefaciens produces the quorum-sensing (QS) signal 3-oxo-octanoylhomoserine lactone (OC8HSL) for controlling horizontal transfer of its tumor inducing (Ti) plasmid that carries both the T-DNA and the virulence genes. Over-accumulation of OC8HSL also increases severity of plant symptoms (number of emerging tumors at infection site) by an unknown mechanism. A. tumefaciens strain C58 expresses two lactonases, AttM (BlcC) and AiiB, that cleave OC8HSL and are potential modulators of QS. Recent data highlight the direct contribution of lactonases AttM and AiiB in the control of OC8HSL level and QS-regulated functions such as conjugation of Ti plasmid and seriousness of plant symptoms. Expression of the two lactonases is regulated by different plant signals. A working model of QS in the course of the A. tumefaciens-plant host interaction is proposed and discussed.

The long-standing association between hosts and microbes has generated some of most intricate relationships. The studies on molecular mechanisms of host-microbe interaction have been revealing many fascinating stories. Here we zoom in on a specific topic on the interplay between bacterial effectors and plant innate immune signaling. In particular, we will summarize our recent discovery that bacterial effector proteins, AvrPto and AvrPtoB, target plant immune signaling receptor complexes to interfere with host immune responses and development.

Ecological networks are a useful tool to study the complexity of biotic interactions at a community level. We introduce a framework for network analysis to be harnessed to advance biodiversity conservation by using plant–pollinator networks and islands as model systems. Conservation practitioners require indicators to assess management effectiveness and validate overall conservation goals. We propose the use of several network metrics that indicate human-induced changes to plant-pollinator communities, and illustrate an implementation pathway to successfully embed a network approach in biodiversity conservation. We list potential obstacles to the framework, highlight the shortfall in experimental network data, and discuss solutions., Ecological networks are a useful tool to study the complexity of biotic interactions at a community level. Advances in the understanding of network patterns encourage the application of a network approach in other disciplines than theoretical ecology, such as biodiversity conservation. So far, however, practical applications have been meagre. Here we present a framework for network analysis to be harnessed to advance conservation management by using plant–pollinator networks and islands as model systems. Conservation practitioners require indicators to monitor and assess management effectiveness and validate overall conservation goals. By distinguishing between two network attributes, the ‘diversity’ and ‘distribution’ of interactions, on three hierarchical levels (species, guild/group and network) we identify seven quantitative metrics to describe changes in network patterns that have implications for conservation. Diversity metrics are partner diversity, vulnerability/generality, interaction diversity and interaction evenness, and distribution metrics are the specialization indices d′ and H2′, and modularity. Distribution metrics account for sampling bias and may therefore be suitable indicators to detect human-induced changes to plant–pollinator communities, thus indirectly assessing the structural and functional robustness and integrity of ecosystems. We propose an implementation pathway that outlines the stages that are required to successfully embed a network approach in biodiversity conservation. Most importantly, only if conservation action and study design are aligned by practitioners and ecologists through joint experiments, are the findings of a conservation network approach equally beneficial for advancing adaptive management and ecological network theory. We list potential obstacles to the framework, highlight the shortfall in empirical, mostly experimental, network data and discuss possible solutions.

The targeting of mRNAs to neuronal dendrites is an important protein sorting mechanism. Recent studies have revealed that mRNAs are transported by molecular motors. The kinesin superfamily protein KIF5 transports mRNAs such as calcium/calmodulin-dependent kinase IIα (CaMKIIα) and Arc mRNAs along microtubules in large granules containing proteins involved in RNA transport, protein synthesis, RNA helicases, heterogeneous nuclear ribonucleoproteins (hnRNPs), and RNA-associated proteins. This transport is fundamental to local protein synthesis and to the regulation of neuronal function.

Local or dendritic protein synthesis is required for long-term functional synaptic change, such as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD both rely on similar signal transduction cascades, which regulate translation initiation. Current research indicates that the specificity by which new proteins participate in either LTP or LTD may be determined in part by specific RNA-binding proteins as well as activity-dependent capture.

As its name implies, calcium/calmodulin-dependent protein kinase II (CaMKII) is calcium dependent. In its basal state, the activity of CaMKII is extremely low. Regulation of intracellular calcium levels allows the neuron to link activity with phosphorylation by CaMKII. This review will briefly

It has been nearly 30 years since the introduction of x-ray computed tomography (CT) set in motion a revolution in medical imaging that changed forever the practice of medicine. The introduction of CT also proved to be an immediate and powerful catalyst for the development of other imaging

What we perceive depends critically on where we direct our attention. For example, attention to a location dramatically improves the accuracy and speed of detecting a target at that location. Attention has been shown not only to increase perceptual sensitivity for target discrimination but also to

The current advances in fluorescence microscopy, coupled with the development of new fluorescent probes, make fluorescence resonance energy transfer (FRET) a powerful technique for studying molecular interactions inside living cells with improved spatial (angstrom) and temporal (nanosecond) resolution, distance range, and sensitivity and a broader range of biological applications.

Many nuclear factors are concentrated within nonmembrane-bound subnuclear bodies. The Cajal body is an example of a conserved nuclear compartment that has been linked to molecular disease. Recent studies have shown Cajal bodies to be surprisingly mobile and offer clues about their function in the cell.

Studies of the cell invasion mechanism of the parasite Trypanosoma cruzi led to a series of novel findings, which revealed a previously unsuspected ability of conventional lysosomes to fuse with the plasma membrane. This regulated exocytic process, previously regarded mostly as a specialization of certain cell types, was recently shown to play an important role in the mechanism by which cells reseal their plasma membrane after injury.

The transfer of glutamine between cells contributes to signaling as well as to metabolism. The recent identification and characterization of the system N and A family of transporters has begun to suggest mechanisms for the directional transfer of glutamine, and should provide ways to test its physiological significance in diverse processes from nitrogen to neurotransmitter release.

Listeria monocytogenes has emerged as a remarkably tractable pathogen to dissect basic aspects of cell biology, intracellular pathogenesis, and innate and acquired immunity. In order to maintain its intracellular lifestyle, L. monocytogenes has evolved a number of mechanisms to exploit host processes to grow and spread cell to cell without damaging the host cell. The pore-forming protein listeriolysin O mediates escape from host vacuoles and utilizes multiple fail-safe mechanisms to avoid causing toxicity to infected cells. Once in the cytosol, the L. monocytogenes ActA protein recruits host cell Arp2/3 complexes and enabled/vasodilator-stimulated phosphoprotein family members to mediate efficient actin-based motility, thereby propelling the bacteria into neighboring cells. Alteration in any of these processes dramatically reduces the ability of the bacteria to establish a productive infection in vivo.

Phagosomes containing the bacterial pathogen Legionella pneumophila are transported to the ER after macrophage internalization. To modulate phagosome transport, Legionella use a specialized secretion system that injects bacterial proteins into eukaryotic cells. This review will focus on recent studies that have identified bacterial proteins and host processes that play a concerted role in transporting Legionella to the ER.

Pathogenic Mycobacterium reside inside vacuoles in their host macrophages. These vacuoles fail to fuse with lysosomes yet interact with early endosomes. Glycoconjugates released by the intracellular bacilli traffic through the host cell and are released through exocytosis. These molecules represent both antigens for immune recognition and modulators of immune function. The molecules play key roles in the induction and maintenance of the granuloma, a tissue response that limits bacterial spread yet ensures persistence of the infection.

The contributions of key molecules predicted to align chromosomes at the center of the mitotic spindle have been recently examined. New results dictate that models for how chromosomes align during the early stages of mitosis must be revised to integrate properties of microtubule-based motor proteins as well as microtubule dynamics.

Thirty years of literature have shown that changes in mRNA abundance provide insight into cellular functioning. Indeed, mRNA abundance measurements have been used to determine how effective particular drugs are in eliciting cellular responses, in monitoring behavioral responses, and in several other

Proteomic tools offer a new platform for studies of complex biological functions involving large numbers and networks of proteins. Intracellular networks of proteins perform key functions in neurons and glia. The unicellular eukaryote Saccharomyces cerevisiae has been the prototype for eukaryotic proteomic studies, and when combined with genomics, microarrays, genetics, and pharmacology, new insights into the integrated function of the cell emerge. The anatomical complexity of the nervous system both in cell types and in the vast number of synapses introduces novel technical and biological issues regarding the subcellular organization of protein networks. Here we will discuss the technology of proteomics and its applications to the nervous system.

In vivo microscopy has recently revealed the dynamic nature of many cellular organelles. The dynamic properties of several cellular structures are consistent with a role for self-organization in their formation, maintenance, and function; therefore, self-organization might be a general principle in cellular organization.

Adenomatous polyposis coli (APC) protein has been thought to function as a tumor suppressor through its involvement in the Wnt/β-catenin signaling pathway. However, its connections to the cytoskeleton and microtubules in particular are becoming apparent, and the discovery of these new functions for APC is leading to a reevaluation of its role not only in tumorigenesis, but also in normal physiology.

Recently, two new ligands of the Arp2/3 complex have been described that may shed light on the way cells organize complex networks of actin in response to signals. Abp1p, a yeast protein involved in endocytosis, and cortactin, a mammalian src substrate, both enhance the ability of the Arp2/3 complex to assemble branched actin filament networks.