Investigations into mechanisms of complement regulation and bacterial evasion of the innate immune response

The complement system is a major mechanism of the innate immune system, providing a first line of defence against infection. Many pathogens have evolved mechanisms of evading the complement response by recruitment of complement components onto their surface. Presented here is characterisation of the interface between a complement regulator, factor H, and a protein from Neisseria meningitidis, factor H binding protein (fHbp), which increases complement evasion by the meningococcus. The affinity of the interaction has been measured and experiments have been performed showing that fHbp mimics the glycosaminoglycans found on the surface of host cells. The atomic resolution structure of a mutant form of fHbp that ablates factor H binding is also presented which is a potential vaccine candidate. Borrelia burgdorferi evades complement by recruitment of factor H mediated by the complement regulator acquiring surface protein (CRASP) family of proteins. Investigations into a member of this family, CspA, has revealed that a dimeric form of the protein binds the complement regulator in a high-affinity interaction that utilises a binding site that has been mapped to domains five to seven of factor H. The atomic resolution structure of another member of the CRASP family, ErpC, has been determined that displays a different architecture to fHbp and CspA, yet experiments show that it is capable of binding factor H domains five through seven with an identical affinity. It is hypothesised that the multiple members of the CRASP family enable complement evasion across the range of reservoir hosts and throughout the different stages of the life-cycle of the zoonotic bacterium. Complement requires tight regulation on order to prevent damage to host cells. The structure of the oligomerisation domains from a complement regulator, C4bp, and a homologue from Gallus gallus, are presented providing the first examples of homoheptameric coiled-coil formation found in nature. Rationalisation of the different C4bp isoforms has also been achieved suggesting that only 7α0β and 7α1β species exist. A new model for incorporation of the beta chain is presented. The function of the complement factor H related (CFHR) family of proteins has never been reliably elucidated. Presented here is the structure of the N-terminus of CFHR-1 and data showing that CFHR-1, CFHR-2 and CFHR-5 form homo and heterodimeric species which behave as competitive antagonists towards factor H. This results in deregulation of complement, increasing the levels of activation and helping to maintain the homeostatic balance of complement regulation on the surface of host-cells. Rationalisation of the links between complement related diseases and polymorphisms within the CFHR family of proteins is also provided

The Camac Street Project : Operation Yellow Brick Road

This report chronicles the author's experiences as he completed his studies at the School of Community Economic Development. (Library-derived description)Caesar, J. A. (1992). The Camac Street Project: Operation Yellow Brick Road. Retrieved from http://academicarchive.snhu.eduMaster of Science (M.S.)School of Community Economic Developmen

Sweetheart Time

Contains advertisements and/or short musical examples of pieces being sold by publisher.https://digitalcommons.library.umaine.edu/mmb-vp/7153/thumbnail.jp

The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

Diwata-2: Earth Observation Microsatellite with a Compact Bus System, ElectronicallyTunable Multi-spectral Imager, and Amateur Radio Communications Capability

The microsatellite Diwata-2 was launched into the 600-km Sun-Synchronous Orbit (SSO) last October 29, 2018. It has a low-power, low-complexity, compact bus structure, capable of Earth observation and remote sensing mission through a 5-meter resolution Near-Infrared (NIR) High Precision Telescope (HPT) and a 125-meter resolution Space-borne Multispectral Imager (SMI) with two Liquid Crystal Tunable Filters (LCTF). The LCTF operates as an electronic-based band reconfiguration filter allowing for more than 600-channels of wavelength variation. As a secondary mission, Diwata-2 has full-duplex FM voice communications capability via a non-board module utilizing the amateur radio band at a 5W power requirement from mobile ground users. The structure has a 500-mm cubic external dimension, with JAXA’s Payload Attached Fairing (PAF) rocket interface and deployment mechanism. Deployable solar array panels (DSAP) were also introduced to increase the power generation capabilities of the microsatellite. The importance of detailed structural-mechanical models for finite-element analysis allowed for accurate structural simulation results. The observed accuracy is within 5-Hz for the first two modes compared to the actual vibration test results. Lastly, strict management of in-flight procedures allowed for consistent satellite performance, while modification of satellite maneuver based on imaging observation results improved target pointing accuracy to within 5-km

Different modes of variation for each BG lineage suggest different functions.

Mammalian butyrophilins have various important functions, one for lipid binding but others as ligands for co-inhibition of αβ T cells or for stimulation of γδ T cells in the immune system. The chicken BG homologues are dimers, with extracellular immunoglobulin variable (V) domains joined by cysteines in the loop equivalent to complementarity-determining region 1 (CDR1). BG genes are found in three genomic locations: BG0 on chromosome 2, BG1 in the classical MHC (the BF-BL region) and many BG genes in the BG region just outside the MHC. Here, we show that BG0 is virtually monomorphic, suggesting housekeeping function(s) consonant with the ubiquitous tissue distribution. BG1 has allelic polymorphism but minimal sequence diversity, with the few polymorphic residues at the interface of the two V domains, suggesting that BG1 is recognized by receptors in a conserved fashion. Any phenotypic variation should be due to the intracellular region, with differential exon usage between alleles. BG genes in the BG region can generate diversity by exchange of sequence cassettes located in loops equivalent to CDR1 and CDR2, consonant with recognition of many ligands or antigens for immune defence. Unlike the mammalian butyrophilins, there are at least three modes by which BG genes evolve.Wellcome Trust (Grant IDs: RG49834 (Studentship), 089305 and a Senior Investigator Award), Biotechnology and Biological Sciences Research Council (Studentship)This is the final version of the article. It first appeared from The Royal Society via http://dx.doi.org/10.1098/rsob.16018

Cervical Cancer at Mbarara Regional Referral Hospital: Magnitude, Trends, Stages at Presentation, Impact of Acetic Acid Screening and the Need for Radiotherapy Services

Background: Globally, cervical cancer the fourth most common cause of cancer death accountable for approximately 266,000 deaths of women, with sub-Saharan Africa and East Africa having the highest burden. In Uganda about 2,275 new cervical cancer deaths occur annually. The main objective of the study was to describe the magnitude, trends, clinical stage on presentation and show the importance of cervical cancer prevention and radiotherapy services at Mbarara Regional Referral Hospital. Methods: This was a descriptive cross-sectional study. In the first phase of the study, leading cancers at Mbarara Regional Referral Hospital were determined.  In the second phase of the study, the burden of cervical cancer on the gynecological ward was determined. In the third part of the study the trends of cervical cancer over a ten year period was determined. In the fourth phase of the study the effects of acetic acid screening on the trends of cervical cancer was determined. Results: With a proportion of 25.2%, cervical cancer is the single leading cancer in the hospital. Cervical cancer contributes 10.1% of all diseases on the gynecological ward and 73.9% of all gynecological cancers.  The frequency of cervical cancer more than doubled between 2006 and 2014) with 60.3% of presenting with late stage. The number of cases of early cervical cancer detected had shown a small but steady increase since 2009. There was a decline in clinic cervical cancer incidence rate from 3.2% in 2009, 0.9% in 2013. Conclusion: Cervical cancer is the leading cancer and also the leading gynecological cancer at Mbarara Regional Referral Hospital. Women with cervical cancer are diagnosed late. Screening increases the rate of early detection. Acetic acid screening is effective in reversing the trends of cervical cancer. Expanding cervical cancer preventive services is capable of reducing the burden of cervical. Recommendations: There is need for expansion of HPV vaccination. There is need for expansion of acetic acid cervical cancer screening in southwestern Uganda. There is need for making radiotherapy services more accessible in developing countries. Keywords: Cervical Cancer, Magnitude, Trends, Stages, Impact, Acetic Acid, Screening, Radiotherapy

Chronicling Country-Specific Response to Covid-19 Pandemic in Africa: From the Perspective of Ghana

Health is closely tied to human development and the overall development of a nation. Indeed, throughout history, improved public health has been a major determinant of development. Within this context, the consequences of infectious diseases including the novel Coronavirus are not in doubt. Particularly, the COVID-19 pandemic has destabilized the much-talked about world civilization with many nations still under various infection control measures. Globally, the pandemic has resulted in several losses in the areas of jobs, income, government revenues, foreign direct investments, among others. Beyond the incalculable economic losses, the pandemic constitutes a great threat to physical, social and mental health. Since the outbreak of the pandemic, several studies have been conducted on the experiences of different countries to help deepen global knowledge on the pandemic. This review paper chronicles the Ghanaian experience of COVID-19 and attempts to probe whether the country’s overall response to the disease is worthy of emulation by other nations. Part one introduces the paper by looking at the intersection of health and development, a brief history of COVID-19, challenges associated with the pandemic and measures some countries have employed to rebuild their economies. Part two describes the key issues underpinning the spread of the virus in Ghana whilst part three considers the efforts key stakeholders employed to contain and manage the spread of the virus. Part four focuses on the challenges Ghana has faced in the management of the pandemic whereas the concluding part presents the core issues which should engage the attention of stakeholders. Keywords: COVID-19 pandemic, misinformation, social risk amplification and attenuation theory, health services, development DOI: 10.7176/NMMC/97-03 Publication date:August 31st 202