Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases

A Novel Technique of Uterine Manipulation in Laparoscopic Pelvic Oncosurgical Procedures: “The Uterine Hitch Technique”

Aim. To describe a new technique of uterine manipulation in laparoscopic management of pelvic cancers. Material and Methods. We used a novel uterine hitch technique in 23 patients from May 2008 to October 2008. These patients underwent pelvic oncologic surgery including laparoscopic radical hysterectomy (n = 7), laparoscopic anterior resection (n = 4), laparoscopic abdominoperineal resection (n = 3), laparoscopic posterior exenteration (n = 4), or laparoscopic anterior exenteration (n = 5). The uterus was hitched to the anterior abdominal.wall by either a single suture in the fundus or by sutures through the round ligaments. Results. The uterine hitch technique was successfully accomplished in all procedures. It was performed in less than 5 minutes in all cases. It obviated the need for vaginal manipulation. An extra port for retraction could be avoided. There were no intraoperative complications. Conclusion. A practical, cheap and reproducible method for uterine manipulation, during pelvic oncologic surgery is described. It improves the stability of the uterus and also obviates the need for keeping an additional assistant for vaginal manipulation in any of the procedures

The fatty oil from the seeds of Mallotus philippinensis, Muel

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Pyrethrin content of Indian pyrethrum

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Serum Amyloid P Component (SAP)-Like Protein From Botryllid Ascidians Provides a Clue to Amyloid Function

The HA-1 lectin isolated from Botrylloides leachii has an amino acid composition similar to that of mammalian serum amyloid protein (SAP). SAP is a universal component of mammalian amyloid deposits. Like SAP, HA-1 has a disc ultrastructure, and antibody to HA-1 binds both (a) to amyloidlike fibers deposited between rejected Botrylloides colonies and (b) to cerebral amyloid deposits in Alzheimer's disease brains. Deposition of protochordate amyloid within rejection sites and surrounding fouling organisms implies that these fibers function as barriers to allogeneic and infectious challenge. Similarly, mammalian amyloid may also function to contain inflammatory lesions and to limit the spread of certain infections. Pathological amyloidotic conditions in humans, such as Alzheimer's disease, may result from unregulated expression of this primitive encapsulation response

Cellular players that shape evolving pathology and neurodegeneration following traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and has emerged as a critical risk factor for multiple neurodegenerative diseases, particularly Alzheimer’s disease (AD). How the inflammatory cascade resulting from mechanical stress, axonal shearing and the loss of neurons and glia following initial impact in TBI, contributes to the development of AD-like disease is unclear. Neuroinflammation, characterized by blood-brain barrier (BBB) dysfunction and activation of brain-resident microglia and astrocytes, resulting in secretion of inflammatory mediators and subsequent recruitment of peripheral immune cells has been the focus of extensive research in attempts to identify drug-targets towards improving functional outcomes post TBI. While knowledge of intricate cellular interactions that shape lesion pathophysiology is incomplete, a major limitation in the field is the lack of understanding of how distinct cell types differentially alter TBI pathology. The aim of this review is to highlight functional differences between populations of bone marrow derived, infiltrating monocytes/macrophages and brain-resident microglia based on differential expression of the chemokine receptors CCR2 and CX3CR1. This review will focus on how unique subsets of mononuclear phagocytes shape TBI pathophysiology, neurotoxicity and BBB function, in a disease-stage dependent manner. Additionally, this review summarizes the role of multiple microglia and macrophage receptors, namely CCR2, CX3CR1 and Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) in pathological neuroinflammation and neurodegeneration vs. recovery following TBI. TREM2 has been implicated in mediating AD-related pathology, and variants in TREM2 are particularly important due to their correlation with exacerbated neurodegeneration. Finally, this review highlights behavioral outcomes associated with microglial vs. macrophage variances, the need for novel treatment strategies that target unique subpopulations of peripheral macrophages, and the importance of development of therapeutics to modulate inflammatory functions of brain-resident microglia at specific stages of TBI

Experience with the Fabrication and Testing of the Sextupole Superconducting Corrector Magnets for the LHC

The LHC main dipoles will be equipped with sextupole corrector magnets with a field strength of 1700 x2 (T,m) and a magnetic length of 110 mm to correct sextupole field errors. Within the LHC magnet programme CERN has developed in collaboration with CAT a cosine-q type of design where much emphasis has been put on the cost reduction. The magnet features a two-layer racetrack coil, without end spacers, wound from a rectangular NbTi-wire. The two layers are wound simultaneously turning in opposite directions. The yoke is made of a scissor-type of lamination, which allows bringing the iron close to the coil for field enhancement. In this paper we review the manufacturing experiences with the first 12 prototypes built at CERN and CAT. The results of the training at 4.2 K and 1.9 K are presented along with the magnetic field quality measured at room temperature and at 1.9 K

Further Development of the Sextupole and Decapole Spool Corrector Magnets for the LHC

In the Large Hadron Collider (LHC) the main dipoles will be equipped with sextupole (MCS) and decapole (MCD) spool correctors to meet the very high demands of field quality required for the satisfactory operation of the machine. Each decapole corrector will in addition have an octupole insert (MCO) and the assembly of the two is designated MCDO. These correctors are needed in relatively large quantities, i.e. 2464 MCS Sextupoles and 1232 MCDO Decapole-Octupole assemblies. Half the number of the required spool correctors will be made in India through a collaboration between CERN and CAT (Centre for Advanced Technology, Indore, India), the other half will be built by European industry. The paper describes final choices concerning design, materials, production techniques, and testing so as to assure economic magnet manufacture but while maintaining a homogenous magnetic quality that results in a robust product

Designing citizen science tools for learning: lessons learnt from the iterative development of nQuire

This paper reports on a 4-year research and development case study about the design of citizen science tools for inquiry learning. It details the process of iterative pedagogy-led design and evaluation of the nQuire toolkit, a set of web-based and mobile tools scaffolding the creation of online citizen science investigations. The design involved an expert review of inquiry learning and citizen science, combined with user experience studies involving more than 200 users. These have informed a concept that we have termed ‘citizen inquiry’, which engages members of the public alongside scientists in setting up, running, managing or contributing to citizen science projects with a main aim of learning about the scientific method through doing science by interaction with others. A design-based research (DBR) methodology was adopted for the iterative design and evaluation of citizen science tools. DBR was focused on the refinement of a central concept, ‘citizen inquiry’, by exploring how it can be instantiated in educational technologies and interventions. The empirical evaluation and iteration of technologies involved three design experiments with end users, user interviews, and insights from pedagogy and user experience experts. Evidence from the iterative development of nQuire led to the production of a set of interaction design principles that aim to guide the development of online, learning-centred, citizen science projects. Eight design guidelines are proposed: users as producers of knowledge, topics before tools, mobile affordances, scaffolds to the process of scientific inquiry, learning by doing as key message, being part of a community as key message, every visit brings a reward, and value users and their time