Monoclonal Antibody Identification of Subpopulations of Cerebral Cortical Neurons Affected in Alzheimer disease

Neuronal degeneration is one of the hallmarks of Alzheimer disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, we have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mAbs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAb 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1, to the best of our knowledge, do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands on immunoblots of homogenates of normal and Ad cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired-helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible

Developing professionalism in new IT graduates? Who needs it?

A new graduate may require a period of ‘acclimatisation’ through a process of ‘developing their professionalism’ to fit into their work environment. The e-Skills UK Technology Counts Insights 2010 report suggests that 110,500 new entrants a year are required to fill IT & Telecoms professional job roles, with 20,800 coming from education (predominantly graduate level and higher). However, 43% of recruiters were reporting a lack of suitable candidates for IT & Telecoms posts where growing importance will be placed on relationship management, business process analysis and design, project and programme management. IT & Telecoms professionals are increasingly expected to be multi-skilled, with sophisticated business and interpersonal skills as well as technical competence. As the report also says: ‘UK growth will continue to be primarily in high-value roles with an increasing need for customer and business-oriented skills as well as sophisticated technical competencies.’ The diverse needs and requirements of the IT sector, as specified by various employer groups and professional bodies including BCS, IET, eSkills, the CBI and the SFIA Foundation, are discussed. According to the CBI, ‘62% of entrants to the IT sector need to draw on managerial and professional business skills almost immediately.’ For organisations to succeed, their IT graduate recruits must supplement their IT skills with managerial and professional business skills. Well considered CPD will ensure that recent graduates can enhance their ‘academic’ skills with the necessary work-based skills for the benefit of both themselves and their new employer. The focus of the improvement will balance the student-centred needs for development and the engaging employer’s commercial needs

Convenient immorality: a substantive theory of competitive procurement in the New Zealand construction industry

Fragmented and adversarial are words used routinely to describe firstly the structure of the construction industry, and secondly the inherent culture that continues to exist within it. Both are characteristics that ultimately serve to not only routinely constrain the efficiency, performance and resultant productivity of the New Zealand building sector, but moreover they persist to play a part in increasing related costs whilst diminishing the quality of the built environment surrounding us. The ubiquity of the outsource model goes some way towards mitigating much of the risk and financial encumbrances that large construction companies have historically faced. But consequentially it is directly responsible for an industry now propagated mostly by small, specialist trade subcontracting organisations that for the most part are reliant upon securing work through construction companies. Contiguous to a degree is the propensity of an industry focussed upon procuring construction by means of competitive tendering, an approach whereby successful bids are traditionally weighted towards those incorporating the lowest initial cost. To garner an understanding of the role that contextual significance plays in construction procurement this study was facilitated by utilising a constructivist grounded theoretical approach. Data was generated by the way of fifty interviews with construction industry stakeholders, inclusive of Sub-Contractors, Main Contractors, Consultants, Architects and Clients. Subsequent analysis reveals that in response to power asymmetry and other environmental conditions, organisations have developed numerous proactive, reactive and opportunistic strategies and behaviours that become evident as the procurement process progresses. This study highlights and explains the relationships and factors from which an industry actor’s rationale is drawn. Furthermore, however, it argues that the proponents of construction industry procurement will when necessary, relax their ordinarily pre-conditioned moral constraints and consciously venture into business practices considered by their peers to be somewhat immoral

Moe the Monkey: A Fun Way to Educate Children

This paper presents the development and usability testing of Evoke, an interactive avatar that can see, hear and respond to children in pitch-altered voice in real-time. The system uses Moe, a stylised monkey, as an interaction point between the teacher and children. Children remained fully engaged, responded more openly, and friendlier to the avatar (Moe), which was controlled by their teacher in a separate room. The user testing showed that the children listened to the character and were eager to ask questions, they grabbed and retained information given by Moe

Programmed cell death recruits macrophages into the developing mouse cochlea

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker\u27s organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5-15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR

The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice is a Major Cause of CNS Pathology Resulting in Fatal Encephalitis

This study was undertaken to investigate possible immune mechanisms in fatal HSV-1 encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brainstem lesions of primarily F4/80+ macrophages and Gr-1+ neutrophils detectable by MRI as early as day 6 post infection (PI). Depletion of macrophages and neutrophils significantly enhanced survival of infected 129 mice. Immunodeficient B6 (IL-7R-/-Kitw41/w41) mice lacking adaptive cells (B6-E mice) transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control non-transplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 bone marrow or B6 bone marrow. Acyclovir treatment of 129 mice beginning day 4 PI (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brainstem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brainstem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells

Kinetics of Cytokine mRNA Expression in the Central Nervous System Following Lethal and Nonlethal Coronavirus-Induced Acute Encephalomyelitis

AbstractThe potential role(s) of cytokines in the reduction of infectious virus and persistent viral infection in the central nervous system was examined by determining the kinetics of cytokine mRNA expression following infection with the neurotropic JHM strain of mouse hepatitis virus. Mice were infected with an antibody escape variant which produces a nonlethal encephalomyelitis and compared to a clonal virus population which produces a fulminant fatal encephalomyelitis. Infection with both viruses induced the accumulation of mRNAs associated with Th1- and Th2-type cytokines, including IFN-γ, IL-4, and IL-10. Peak mRNA accumulations were coincident with the clearance of virus and there was no obvious differences between lethally and nonlethally infected mice. TNF-α mRNA was induced more rapidly in lethally infected mice compared to mice undergoing a nonfatal encephalomyelitis. Rapid transient increases in the mRNAs encoding IL-12, iNOS, IL-1α, IL-1β, and IL-6 occurred following infection. Nonlethal infections were associated with increased IL-12, IL-1β, and earlier expression of IL-6, while lethal infections were associated with increased iNOS and IL-1α mRNA. These data suggest a rapid but differential response within the central nervous system cells to infection by different JHMV variants. However, neither the accumulation nor kinetics of induction provide evidence to distinguish lethal infections from nonlethal infections leading to a persistent infection. Accumulation of both Th1 and Th2 cytokines in the central nervous system of JHMV-infected mice is consistent with the participation of both cytokines and cell immune effectors during resolution of acute viral-induced encephalomyelitis