Early detection of Alzheimer’s disease in experimental and natural animal models using novel biologics

According to the World Alzheimer report published in 2020, 50 million people are currently living with dementia and this number is predicted to rise to 150 million in 2050. Alzheimer’s disease (AD) is the most common form of dementia (60% - 70% of cases). Early and accurate diagnosis of AD is a major goal in order to reduce the impact of dementia and also represents an urgent unmet medical need globally. Canine Cognitive Dysfunction (CCD) in aged dogs is a progressive neurodegenerative disorder exhibiting gradual decline of cognitive function and memory loss similar to human AD. In parallel with progressive amyloid beta (Aβ) neuropathology, aged dogs display progressive decline in measures of learning and memory. Of importance, for both AD in human and CCD in dogs, the abnormal accumulation of amyloid beta plaques (Aβp) in the brain is one of the major pathological lesions associated with this devastating disorder. Aβ is subdivided into three major assemblies, including monomers, oligomers, and fibrils of which Aβ soluble oligomers (Aβo) are the most neurotoxic to neurons. Aβo is believed to trigger the pathophysiology of AD and is normally detected two decades before clinical onset of the disease. Similarly, aged dogs affected with CCD display cognitive decline which occurs prior to accumulation of Aβp in the canine brain, suggesting that earlier assembly states of Aβ (e.g., oligomers) may be the neurotoxic species in dogs, as described for human AD. This thesis particularly focused on the early detection of Aβo with the aim of developing a cost-effective diagnostic test for AD before neuropathological and clinical deficits have ensued. Also, to provide an insight to develop the dog as a natural translational model of AD. Accumulating evidence described in my thesis suggested that retinal changes and pathophysiological processes could provide valuable insights into early diagnosis of AD. This thesis provides a strong basis to further validate dogs as a natural AD model where all the AD neuropathological hallmarks have been observed in the brain and retina. Finally, such a model will certainly facilitate the development and clinical applications of an easily accessible, inexpensive, and non-invasive retinal imaging of preclinical AD diagnostic platform to predict and diagnose early stages of AD and monitor disease therapies

Molecular characterization using RAPD marker of Blackgram

Abstract: RAPD assay was conducted for molecular genetic analysis. Out of 13 random primers tested, finally three (S1027, S1239 and OPP13) were used. The primers yielded a total of 24 countable band of which 9 (37.5%) were considered as polymorphic. The highest number of bands (10) was generated by the primer S1239 whereas the lowest number of bands was (6) generated by the primer S1027

Design of SIW Bandpass filter using DGS-DMS technique for 5G applications

A novel SIW bandpass filter based on the combination of DGS (Defected Ground Structure) and DMS (Defected Microstrip structure) is proposed. Their excellent defected characteristics are verified through the simulated results. The proposed filter is designed by etching a dumbbell shaped DGS in the ground plane of the SIW cavity in order to improve the stopband performance. Defected Microstrip structure (DMS) is made by etching a single or double slots to create a finite passband, rejection band and slow wave characteristics. The filter is fed using microstrip to SIW transition technique over a material with dielectric constant of 3.5 and thickness of 0.5mm. Additionally to a sharp cutoff, the filter exhibits simple design, low insertion loss of 0.5dB and it achieves rejection bandwidth with overall 28dB attenuation from 26GHz to 28GHz. Utilizing this concept, SIW BPF of 27.4GHz center frequency with 7.2%fractional bandwidth at -3dB has been implemented for the application of 5G spectrum bands. The structure has been simulated using Advanced Design Software (ADS)

Utilization of Electromagnetic Band Gap Cells for performance improvement of Co-Planar Waveguide Ultra Wide Band Filters

This paper presents the characteristic design of compact coplanar waveguide (CPW) band pass filter cascaded with electromagnetic band gap (EBG) resonator. The electromagnetic band gap resonator used in this design reduces the size and suppresses the harmonic response of the filter. An accurate bandwidth is achieved by alteration incidences of the announcement zeros at the pass ensemble edge. The designed filter exhibits a good upper stop band with rejection greater than 25dB below 20GHz.  Electromagnetic Band-Gap cells in combination with CPW structures are presented with good performance metrics

Design and analysis of compact SIW Bandpass filter using DGS-DMS technique for satellite applications

This letter proposes a new compact substrate integrated waveguide based bandpass filter for satellite application. First SIW BPF is designed by tapered via transition to provide a smooth transition from microstip line to SIW cavity with minimal reflection and better S11 performance. The stop band performance of the proposed filter is improved by introducing a two square head DGS connected by U-slot on the bottom ground palne which introduces transmission zeros in upper stopband. DMS is made by etching two horizontal slots on the top of the SIW cavity in order to provide finite passband and to suppress undesired harmonic response. The filter with center frequency of 7GHz and fractional bandwidth of 2.8% is developed on the Rogers substrate with dielectric constant of 3.5 and substrate thickness of 0.5mm. By combining the concept of DGS-DMS, the proposed filter exhibits very low insertion loss of 0.02dB, return loss >20dB and compact size. The structure is simulated and analyzed by using Advanced Design software

Analysis and Design of Substrate Integrated Waveguide Bandpass Filter with DGS for Ku-Band Applications

The technology of Substrate Integrated Waveguide (SIW) and Defected Ground Structure (DGS) are combined and a novel compact bandpass filter is proposed in this paper. The SIW cavity connected in between two tapered microstrip lines used to provide passband characteristic and it has the advantage of high quality factor, low insertion loss. The proposed filter is designed by square slots connected with narrow slot at the edge is etched on the bottom ground plane in order to provide stopband performance of the filter. Moreover a flexible bandwidth and center frequency can be achieved by proper adjusting the dimensions of the SIW and DGS of the filter. The simulated results used to verify the defected characteristic of the filter. The simulated insertion loss and return loss of the filter operated at center frequency of 13.85GHz are 0.002dB and better than 26dB respectively, which makes it suitable for Ku-band applications. The proposed filter structure has been simulated using Advanced Design Software (ADS)

Case report : synucleinopathy associated with phalaris neurotoxicity in sheep

Chronic intoxication with tryptamine-alkaloid-rich Phalaris species (spp.) pasture plants is known colloquially as Phalaris staggers syndrome, a widely occurring neurological disorder of sheep, cattle, horses, and kangaroos. Of comparative interest, structurally analogous tryptamine-alkaloids cause experimental parkinsonism in primates. This study aimed to investigate the neuropathological changes associated with spontaneous cases of Phalaris staggers in sheep with respect to those encountered in human synucleinopathy. In sheep affected with Phalaris staggers, histological, immunohistochemical, and immunofluorescence analysis revealed significant accumulation of neuromelanin and aggregated α-synuclein in the perikaryon of neurons in the cerebral cortex, thalamus, brainstem, and spinal cord. Neuronal intracytoplasmic Lewy bodies inclusions were not observed in these cases of ovine Phalaris staggers. These important findings established a clear link between synucleinopathy and the neurologic form of Phalaris plant poisoning in sheep, demonstrated in six of six affected sheep. Synucleinopathy is a feature of a number of progressive and fatal neurodegenerative disorders of man and may be a common endpoint of such disorders, which in a variety of ways perturb neuronal function. However, whether primary to the degenerative process or a consequence of it awaits clarification in an appropriate model system

A cross-sectional study of traditional practices affecting maternal and newborn health in rural Nigeria

Introduction: certain traditional practices which have negative effects on maternal and child health continue to be practiced in sub-Saharan African countries. A survey was carried out in a rural village in Nigeria to understand the scale and range of these practices. Methods: this was a cross-sectional study in which trained interviewers administered pre-tested questionnaires on child-bearing women using questionnaires embedded on android devices. Results: the median age of marriage and pregnancy were 15 and 16 years respectively. Home births were high (90.4%) while non-skilled birth attendant was 87.4%. The community had a son preference index ratio of 1:1.4. Up to 81.5% of mothers responded that one form of unhygienic traditional procedure or the other was performed on their children. Time to initiation of breast feeding was in hours in the majority (76.3%) of mothers, with a high rate of use of prelacteal feeds (85.2%). Being an adolescent mother (AOR 0.403, 95%CI 0.203, 0,797) and utilizing a skilled provider at birth (AOR 0.245, 95%CI 0.088, 0.683) were associated with less likelihood of having an unhygienic procedure performed on children. Conclusion: the findings of our study suggest that traditional practices which could have negative effects on maternal and child health are still ongoing in the study community. Child protection laws and safeguarding principles could help to reduce these practices and would need to be developed and implemented in these settings where these practices are still prevalent

Detection of retinal and blood Aβ oligomers with nanobodies

Introduction: Abnormal retinal changes are increasingly recognized as an early pathological change in Alzheimer’s disease (AD). Although amyloid beta oligomers (Aβo) have been shown to accumulate in the blood and retina of AD patients and animals, it is not known whether the early Aβo deposition precedes their accumulation in brain. Methods and results: Using nanobodies targeting Aβ1-40 and Aβ1-42 oligomers we were able to detect Aβ oligomers in the retina and blood but not in the brain of 3-month-old APP/PS1 mice. Furthermore, Aβ plaques were detected in the brain but not the retina of 3-month-old APP/PS1 mice. Conclusion: These results suggest that retinal accumulation of Aβo originates from peripheral blood and precedes cognitive decline and Aβo deposition in the brain. This provides a very strong basis to develop and implement an “eye test” for early detection of AD using nanobodies targeting retinal Aβ

Cross-linking cellular prion protein induces neuronal type 2-like hypersensitivity

Background: Previous reports identified proteins associated with ‘apoptosis’ following cross-linking PrPC with motif-specific anti-PrP antibodies in vivo and in vitro. The molecular mechanisms underlying this IgG-mediated neurotoxicity and the role of the activated proteins in the apoptotic pathways leading to neuronal death has not been properly defined. Previous reports implicated a number of proteins, including apolipoprotein E, cytoplasmic phospholipase A2, prostaglandin and calpain with antiPrP antibody-mediated ‘apoptosis’, however, these proteins are also known to play an important role in allergy. In this study, we investigated whether cross-linking PrPC with anti-PrP antibodies stimulates a neuronal allergenic response. Methods: Initially, we predicted the allergenicity of the epitope sequences associated with ‘neurotoxic’ anti-PrP antibodies using allergenicity prediction servers. We then investigated whether anti-PrP antibody treatment of mouse primary neurons (MPN), neuroblastoma cells (N2a) and microglia (N11) cell lines lead to a neuronal allergenic response. Results: In-Silico studies showed that both tail- and globular-epitopes were allergenic. Specifically, binding regions that contain epitopes for previously reported ‘neurotoxic’ antibodies such as ICSM18 (146-159), ICSM35 (91-110), POM 1 (138-147) and POM 3 (95-100) lead to activation of allergenic related proteins. Following direct application of antiPrPC antibodies on N2a cells, we identified 4 neuronal allergenic-related proteins when compared with untreated cells. Furthermore, we identified 8 neuronal allergenic-related proteins following treatment of N11 cells with anti-PrPC antibodies prior to co-culture with N2a cells when compared with untreated cells. Antibody treatment of MPN or MPN co-cultured with antibody-treated N11 led to identifying 10 and 7 allergenic-related proteins when compared with untreated cells. However, comparison with 3F4 antibody treatment revealed 5 and 4 allergenic-related proteins respectively. Of importance, we showed that the allergenic effects triggered by the anti-PrP antibodies were more potent when antibody-treated microglia were co-cultured with the neuroblastoma cell line. Finally, co-culture of N2a or MPN with N11-treated with anti-PrP antibodies resulted in significant accumulation of NO and IL6 but not TNF-a in the cell culture media supernatant. Conclusions: This study showed for the first time that anti-PrP antibody binding to PrPC triggers a neuronal hypersensitivity response and highlights the important role of microglia in triggering an IgG-mediated neuronal hypersensitivity response. Moreover, this study provides an important impetus for including allergenic assessment of therapeutic antibodies for neurodegenerative disorders to derive safe and targeted biotherapeutics