The role of mammalian target of rapamycin (mTOR) in the regulation of pancreatic β-cell mass: implications in the development of type-2 diabetes

Type-2 diabetes mellitus (T2DM) is a disorder that is characterized by high blood glucose concentration in the context of insulin resistance and/or relative insulin deficiency. It causes metabolic changes that lead to the damage and functional impairment of organs and tissues resulting in increased morbidity and mortality. It is this form of diabetes whose prevalence is increasing at an alarming rate due to the 'obesity epidemic', as obesity is a key risk factor in the development of insulin resistance. However, the majority of individuals who have insulin resistance do not develop diabetes due to a compensatory increase in insulin secretion in response to an increase in insulin demand. This adaptive response is sustained by an increase in both β-cell function and mass. Importantly, there is increasing evidence that the Serine/Threonine kinase mammalian target of rapamycin (mTOR) plays a key role in the regulation of β-cell mass and therefore likely plays a critical role in β-cell adaptation. Therefore, the primary focus of this review is to summarize our current understanding of the role of mTOR in stimulating pancreatic β-cell mass and thus, in the prevention of type-2 diabetes.     

The role of ‘complex’ empiricism in the debates about satellite data and climate models

Climate scientists have been engaged in a decades-long debate over the standing of satellite measurements of the temperature trends of the atmosphere above the surface of the earth. This is especially significant because skeptics of global warming and the greenhouse effect have utilized this debate to spread doubt about global climate models used to predict future states of climate. I use this case from an understudied science to illustrate two distinct philosophical approaches to the relations among data, scientist, measurement, models, and theory. I argue that distinguishing between ‘direct’ empiricist and ‘complex’ empiricist approaches helps us understand and analyze this important scientific episode. I also introduce a complex empiricist account of testing and evaluation, and contrast it with the basic Hypothetico-Deductive approach to the climate models used by the direct empiricists. This more developed complex empiricist approach will serve philosophy of science well, as computational models become more widespread in the sciences.     

The role of inflammation in sporadic and familial Parkinson’s disease

The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions.     

Some relationships between the pancreatic β-cells and the metabolism of the epiphyseal cartilage

Riassunto È stato studiato il contenuto di ATP nella cartilagine epifisaria di giovani ratti diabetici per allossana. Il deficit insulinico da diabete allossanico provoca, oltre ad arresto dell'accrescimento scheletrico, una diminuzione della concentrazione di ATP nella cartilagine di coniugazione. Il significato biologico di questo risultato è messo in relazione col meccanismo d'azione dell'insulina e con l'importanza dell'ATP nel processo di ossificazione encondrale.     

Some relationships between the pancreatic β-cells and the metabolism of the epiphyseal cartilage

Riassunto Studiando il meccanismo biochimico con cui la insulina controlla il processo di osteogenesi, si è stabilito che in condizioni di deficit insulinico (diabete allossanico) esiste nel ratto accanto ad un arresto dell'accrescimento scheletrico, una notevole riduzione dell'attività cocarbossilasica nella cartilagine epifisaria. Si conclude che nella cartilagine di coniugazione ATP e cocarbossilasi sono strettamente interdipendenti per quanto riguarda la loro biosintesi; inoltre che il loro normale metabolismo è indispensabile al normale svolgersi del processo di osteogenesi.     

Role of the ubiquitin–proteasome system in the regulation of P2Y13 receptor expression: impact on hepatic HDL uptake

The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y₁₃ receptor (P2Y₁₃-R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y₁₃-R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y₁₃-R. When transiently expressed, P2Y₁₃-R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y₁₂ receptor (P2Y₁₂-R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y₁₃-R in the ER, suggesting a close link between ubiquitination of P2Y₁₃-R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y₁₃-R and P2Y₁₂-R strongly restored plasma membrane expression of P2Y₁₃-R, suggesting the involvement of the intra-cytoplasmic tail of P2Y₁₃-R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y₁₃-R in hepatocytes, and consequently stimulated P2Y₁₃-R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (>200 %) in wild-type but not in P2Y₁₃-R-deficient mice, thus reinforcing the role of P2Y₁₃-R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin–proteasome system might be a novel powerful HDL therapy to enhance P2Y₁₃-R expression and consequently promote the overall RCT.     

The effects of 9α-halohydrocortisones and of aldosterone on survival,growth and sodium-potassium excretion in adrenalectomized rats

Zusammenfassung Die Wirkungen von Aldosteron und 9-Halogenhydrocortison-azetaten auf das Überleben und Wachstum adrenalektomierter Ratten wurden studiert. Im Na/K-Ausscheidungstest zeigten sich 9-Chlor-hydrocortison-azetat bzw. 9-Fluor-hydrocortison-azetat 35-bzw. 10mal wirksamer als DCA und wiesen 1/3 bzw. 1/10 der Wirksamkeit von Aldosteron auf.     

Tumor necrosis factor α in the pathogenesis of cerebral malaria

Physiologically in the brain, cytokines such as tumor necrosis factor-alpha (TN) are released by the immune system and can modulate neurological responses. Conversely, the central nervous system (CNS) is also able to modulate cytokine production. In the case of CNS disorders, cytokine release may be modified. Cerebral malaria (CM) is a complication of Plasmodium falciparum infection in humans and is characterized by a reversible encephalopathy with seizures and loss of consciousness. Central clinical signs are partly due to sequestration of parasitized red blood cells in the brain microvasculature due to interactions between parasite proteins and adhesion molecules. TNF is produced and released by host cells following exposure to various malarial antigens. The increase of TNF release is responsible for the overexpression of adhesion molecules. This article reviews the involvement of TNF in cerebral malaria and the relation with all the processes involved in this pathology. It shows that (i) TNF levels are increased in plasma and brain but with no clear correlation between TNF levels and occurrence and severity of CM; (ii) TNF is responsible for intercellular adhesion molecule-1 upregulation in CM, the relation being less clear for other adhesion molecules; (iii) TNF receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv) in murine CM, low doses of TNF seem to protect from CM, whereas excess TNF induces CM and anti-TNF therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM. Moreover, the involvement of lymphotoxin a, which shares with TNF the same receptors with similar affinity, appears to be an interesting target for further investigation.Received 4 December 2002; received after revision 7 February 2003; accepted 14 February 2003     

Horticulture in Portugal 1850–1900: The role of science and public utility in shaping knowledge

In this paper, we address the emergence of horticultural practice, agents, spaces and institutions in the two urban settings of Lisbon and Porto, in Portugal, during the second half of the nineteenth century. We do so by following the networking activities of two players: the self-made horticulturist and entrepreneur José Marques Loureiro, who created, in Porto, a commercial horticultural establishment and founded the Journal of Practical Horticulture; and the agronomist Francisco Simões Margiochi, head of the gardens and green grounds department of the municipality, who created the first course on gardening and horticulture, and founded the Royal Horticultural Society, both in Lisbon. Their joint activities were aimed at establishing horticulture as an applied science and to cater simultaneously to an extended audience of citizens. They enable us to enrich the narratives on the emergence and development of horticulture in Europe by calling attention to the participation in circulatory extended networks of actors who are often absent from these accounts. Additionally, they allow a comparative assessment of the outcome of their actions at the national level, and to understand their results in terms consonant with recent historiographical trends on the co-construction of centres and peripheries.

Abbreviations: AML – Arquivo Municipal de Lisboa (Municipal Archive of Lisbon).; ANTT – Arquivo Nacional da Torre do Tombo (National Archives at Torre do Tombo).; AHCPL – Arquivo Histórico da Casa Pia de Lisboa (Historical Archive of the Casa Pia of Lisbon).; JHP – Jornal de Horticultura Practica (Journal of Practical Horticulture). Online at: http://www.fc.up.pt/fa/?p=nav&;f=html.fbib-Periodico-oa&;item=378; BSNHP - Boletim da Sociedade Nacional de Horticultura de Portugal (Bulletin of the National Society of Horticulture of Portugal).     

The tumor necrosis factor α of the bony fish seabream exhibits the in vivo proinflammatory and proliferative activities of its mammalian counterparts,yet it functions in a species-specific manner

Information on the bioactivities of non-mammalian cytokines is scant due to the lack of the recombinant molecules and specific antibodies. We produced the mature predicted peptide of tumor necrosis factor (TNF) from the bony fish gilthead seabream (Sparus aurata L.) (sbTNF), and its biological role was determined in vitro and in vivo. We first demonstrated by analytical size-exclusion chromatography that sbTNF is an oligomeric protein but the dimer appears to predominate over the trimeric form, in contrast to mammalian TNF. Intraperitoneal injection of native sbTNF resulted in (i) priming of the respiratory burst of the peritoneal exudate and head-kidney (HK) leukocytes, the latter being the bone marrow equivalent in fish; (ii) rapid recruitment of phagocytic granulocytes to the injection site, and (iii) induction of granulopoiesis in the HK. Interestingly, sbTNF was able to induce a strong proliferation of HK cells in vitro, whereas human TNF did not. Conversely, sbTNF was not cytotoxic for murine L929 fibroblasts.Received 12 February 2004; received after revision 15 March 2004; accepted 29 March 2004     

The growth plate’s response to load is partially mediated by mechano-sensing via the chondrocytic primary cilium

Mechanical load plays a significant role in bone and growth-plate development. Chondrocytes sense and respond to mechanical stimulation; however, the mechanisms by which those signals exert their effects are not fully understood. The primary cilium has been identified as a mechano-sensor in several cell types, including renal epithelial cells and endothelium, and accumulating evidence connects it to mechano-transduction in chondrocytes. In the growth plate, the primary cilium is involved in several regulatory pathways, such as the non-canonical Wnt and Indian Hedgehog. Moreover, it mediates cell shape, orientation, growth, and differentiation in the growth plate. In this work, we show that mechanical load enhances ciliogenesis in the growth plate. This leads to alterations in the expression and localization of key members of the Ihh-PTHrP loop resulting in decreased proliferation and an abnormal switch from proliferation to differentiation, together with abnormal chondrocyte morphology and organization. Moreover, we use the chondrogenic cell line ATDC5, a model for growth-plate chondrocytes, to understand the mechanisms mediating the participation of the primary cilium, and in particular KIF3A, in the cell’s response to mechanical stimulation. We show that this key component of the cilium mediates gene expression in response to mechanical stimulation.     

The effect of γ-irradiation on the amount of 5-hydroxytryptamine in the gut and spleen in the early phase after irradiation

Résumé 24 et 48 h après irradiation- (900 r) la quantité de 5-hydroxytryptamine dans l'intestin du rat n'a pas changé de manière significative. La quantité de 5-hydroxytryptamine dans la rate du rat, exprimée par g de tissu frais a augmenté. Le prétraitement avec de la cystéamine abaisse nettement la quantité de 5-hydroxytryptamine dans la rate, après l'irradiation.     

Characterization of the role of the antioxidant proteins metallothioneins 1 and 2 in an animal model of Alzheimer’s disease

Alzheimer’s disease (AD) is by far the most commonly diagnosed dementia, and despite multiple efforts, there are still no effective drugs available for its treatment. One strategy that deserves to be pursued is to alter the expression and/or physiological action of endogenous proteins instead of administering exogenous factors. In this study, we intend to characterize the roles of the antioxidant, anti-inflammatory, and heavy-metal binding proteins, metallothionein-1?+?2 (MT1?+?2), in a mouse model of Alzheimer’s disease, Tg2576 mice. Contrary to expectations, MT1?+?2-deficiency rescued partially the human amyloid precursor protein-induced changes in mortality and body weight in a gender-dependent manner. On the other hand, amyloid plaque burden was decreased in the cortex and hippocampus in both sexes, while the amyloid cascade, neuroinflammation, and behavior were affected in the absence of MT1?+?2 in a complex manner. These results highlight that the control of the endogenous production and/or action of MT1?+?2 could represent a powerful therapeutic target in AD.