RESTORATION OF MOTOR AND NON-MOTOR FUNCTIONS BY NEUROTROPHIC FACTORS IN NONHUMAN PRIMATES WITH DOPAMINE DEPLETION

Parkinson’s disease (PD) is a progressive debilitating neurodegenerative disorder characterized by resting tremor, rigidity, bradykinesia and postural instability. As the disease progresses there is a loss of dopamine (DA) neurons in the substantia nigra projecting to the various forebrain and sub-cortical regions. Current treatments for PD are unable to prevent or curtail the neurodegenerative process; so rescuing remaining dopamine in the mid-brain has been the recent focus of research examining the effectiveness of neurotrophic factors (NTFs) in the treatment of PD. In this dissertation, the ability of three novel, recently discovered NTFs to restore DA neurons and motor function in a nonhuman primate model of PD was examined. The NTFs were Cerebral Dopamine Neurotrophic Factor (CDNF) and two variants of Neurturin (NRTN), N2 and N4, that have mutations that prevent binding to heparin sulfate binding sites in the brain. These studies used the unilateral low dose (0.15 ± 0.001 mg/kg) monkey 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to cause loss of DA neurons. Six groups of monkeys were studied: vehicle-treated (negative control), Glial Cell-line Derived Neurotropic Factor (GDNF, positive control), two groups of CDNF-treated monkeys (450 μg and 150 μg), and N2 and N4-treated groups. After MPTP, monkeys developed moderate symptoms of PD (PD rating scale score=7.9±0.5 on a scale of 0-22, p<0.001), motor dysfunction and increased daytime sleepiness. After three months of infusions, all three NTFs (150 μg CDNF, N2 and N4) significantly increased the number of DA neurons in the substantia nigra, p=0.03, and improved parkinsonian symptoms measured by rating scale, p<0.001. Most motor functions were significantly correlated with the number of DA neurons in the substantia nigra. N4 significantly improved daytime sleep duration, bouts and wake-latency (p=0.02, p=0.06 and p=0.02, respectively). In summary, CDNF, N2 and N4 trophic factors are neurorestorative to DA neurons, motor function is tightly correlated with DA neuronal number, and N4 improved the non-motor symptom of increased daytime sleepiness in this monkey PD model. These factors hold promise for clinical therapy for PD patients

Optimal Reasoning of Opposing Non-functional Requirements based on Game Theory

Goal-Oriented Requirement Engineering is a modeling technique that represents software system requirements using goals as goal models. In a competitive environment, these requirements may have opposing objectives. Therefore, there is a requirement for a goal reasoning method, which offers an alternative design option that achieves the opposing objectives of inter-dependent actors. In this paper, a multi-objective zero-sum game theory-based approach is applied for choosing an optimum strategy for dependent actors in the i* goal model. By integrating Java with IBM CPLEX optimisation tool, a simulation model based on the proposed method was developed. A successful evaluation was performed on case studies from the existing literature. Results indicate that the developed simulation model helps users to choose an optimal design option feasible in real-time competitive environments

AHP based Optimal Reasoning of Non-functional Requirements in the i∗ Goal Model

Goal-Oriented Requirements Engineering (GORE) has been found to be a valuable tool in the early stages of requirements engineering. GORE plays a vital role in requirements analysis like alternative design/ goal selection during decision-making. The decision-making process of alternative design/ goal selection is performed to assess the practicability and value of alternative approaches towards quality goals. Majority of the GORE models manage alternative selection based on qualitative approach, which is extremely coarse-grained, making it impossible for separating two alternatives. A few works are based on quantitative alternative selection, yet this does not provide a consistent judgement on decision-making. In this paper, Analytic Hierarchy Process (AHP) is modified to deal with the evaluation of selecting the alternative strategies of inter-dependent actors of i∗ goal model. The proposed approach calculates the contribution degrees of alternatives to the fulfilment of top softgoals. It is then integrated with the normalized relative priority values of top softgoals. The result of integration helps to evaluate the alternative options based on the requirements problem against each other. To clarify the proposed approach, a simple telemedicine system is considered in this paper

Characterization of an olfactory receptor mediating aversive behaviour to a death-associated odour

Olfaction or the sense of smell is a strong driver of behavior in many animals and is important for their survival. Odors are perceived through a complex molecular recognition process which involves detection of odorants by odorant receptors in olfactory sensory neurons located in the nasal olfactory epithelium. The odorant receptors belong to the G protein–coupled receptors (GPCRs) class of proteins, which includes the trace amine–associated receptors (TAARs), a class of GPCRs associated with the detection of social cues. The present study focused on molecular characterization of a TAAR receptor, TAAR13c, in zebrafish. Cadaverine, a diamine produced by bacterial decarboxylation of lysine, and thus associated with odor emanating from decaying flesh was reported to be the primary ligand for TAAR13c. Aversion to cadaverine was observed in adult Zebrafish by behavior experiments. Here, the cell type expressing TAAR13c receptors was identified as ciliated OSNs. Double-labeling of TAAR13c-expressing neurons with cFos as neuronal activity marker after stimulation with cadaverine showed widespread expression of cFos in many cells, a few of which were also TAAR13c-positive. Another activity marker tested, Egr1, was also found to be nonselective. However, pERK, an activity marker, which does not rely on gene expression, but on phosphorylation and is therefore much faster, showed sparse cells activated after stimulation with cadaverine and a series of other diamines with different chain length. Double-labeling with pERK antibody and TAAR13c antibody showed cellular co-localization of pERK and TAAR13c signals upon cadaverine stimulus. Ontogenetic onset of avoidance behavior was studied using a two channel choice apparatus in Zebrafish larvae. A trend towards avoidance of cadaverine was observed from the larval behavior experiments. 6 Knockout of TAAR13c was attempted using TALEN and Crispr-Cas9 mediated mutagenesis. Unfortunately it was not possible to design completely specific screening strategies due to high sequence identity within the five members of the TAAR13 subfamily and the AT-rich coding region of TAAR13c. Two putative knockout mutations were obtained with optimized screening methods. Finally, the design of new constructs for a TAAR13 subfamily knockout may provide a useful tool in the future for creating a functional Taar13 knockout in zebrafish

Correlation between peak expiratory flow rate and pectoralis muscle length

Background: Peak expiratory flow rate (PEFR) is a measure of the maximum speed of exhalation after a deep inspiration. The peak expiratory flow is measured by a device named peak flow meter. This study concentrates on the correlation of the PEFR with the pectoral muscle length.Methods: It is a cross sectional study of 30 convenient samples based on gender distribution where the PEFR and pectoralis muscle length were measured in the subjects.Results: Statistical analysis shows that there is a significant correlation between right pectoralis major general muscle length and PEFR (p=0.030), left pectoralis major general muscle length and PEFR (p=0.014), right pectoralis major clavicular end muscle length with PEFR (p=0.010).Conclusions: There is a significant correlation between peak expiratory flow and pectoralis muscle length.

FLAT: An Optimized Dataflow for Mitigating Attention Performance Bottlenecks

Attention mechanisms form the backbone of state-of-the-art machine learning models for a variety of tasks. Deploying them on deep neural network (DNN) accelerators, however, is prohibitively challenging especially under long sequences, as this work identifies. This is due to operators in attention layers exhibiting limited reuse opportunities and quadratic growth in memory footprint, leading to severe memory-boundedness. To address this, we introduce a new attention-tailored dataflow, termed FLAT, which identifies fusion opportunities within the attention layer, and implements an on-chip memory-aware interleaved execution and tiling mechanism. FLAT increases the effective memory bandwidth by efficiently utilizing the high-bandwidth, low-capacity on-chip buffer and thus achieves better run time and compute resource utilization. In our evaluation, FLAT achieves 1.94x and 1.76x speedup and 49% and 42% of energy reduction comparing to baseline execution over state-of-the-art edge and cloud accelerators

Effect of insulin on small intestinal transit in normal mice is independent of blood glucose level

BACKGROUND: Insulin is the drug of choice in the management of diabetes mellitus (DM). About 76 % of diabetic patients suffer from gastrointestinal (GI) disorders. Therapy of DM with insulin primarily involves lowering of elevated blood glucose levels. Hence, on any organ in addition to insulin's effect, hypoglycaemic effect also prevails. A systematic study exploring the effect of insulin on small intestinal transit in normal laboratory animals is lacking. Hence, in the present study, the possible effect of insulin with or without associated hypoglycaemia on small intestinal transit in normal mice was examined. RESULTS: Insulin in all the doses tested (2 μ, 2 m and 2 U/kg) elicited a significant acceleration of SIT. The lower doses of insulin (2 μ and 2 m U/kg) produced significant acceleration of SIT and were associated with normal blood glucose levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with significant fall in blood glucose levels. Further, the 2 m and 2 U doses of insulin significantly elevated serum insulin and C-peptide levels. CONCLUSION: Insulin at the lowest dose produced an acceleratory effect on SIT that was independent of blood glucose and serum insulin levels in normal mice

Ataxia Telangiectasia Mutated Kinase Plays a Protective Role in β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling

β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis and plays an important role in myocardial remodeling. Here we investigated expression of various apoptosis-related genes affected by β-AR stimulation, and examined first time the role of ataxia telangiectasia mutated kinase (ATM) in cardiac myocyte apoptosis and myocardial remodeling following β-AR stimulation. cDNA array analysis of 96 apoptosis-related genes indicated that β-AR stimulation increases expression of ATM in the heart. In vitro, RT-PCR confirmed increased ATM expression in adult cardiac myocytes in response to β-AR stimulation. Analysis of left ventricular structural and functional remodeling of the heart in wild-type (WT) and ATM heterozygous knockout mice (hKO) 28 days after ISO-infusion showed increased heart weight to body weight ratio in both groups. M-mode echocardiography showed increased percent fractional shortening (%FS) and ejection fraction (EF%) in both groups 28 days post ISO-infusion. Interestingly, the increase in %FS and EF% was significantly lower in the hKO-ISO group. Cardiac fibrosis and myocyte apoptosis were higher in hKO mice at baseline and ISO-infusion increased fibrosis and apoptosis to a greater extent in hKO-ISO hearts. ISO-infusion increased phosphorylation of p53 (Serine-15) and expression of p53 and Bax to a similar extent in both groups. hKO-Sham and hKO-ISO hearts exhibited reduced intact β1 integrin levels. MMP-2 protein levels were significantly higher, while TIMP-2 protein levels were lower in hKO-ISO hearts. MMP-9 protein levels were increased in WT-ISO, not in hKO hearts. In conclusion, ATM plays a protective role in cardiac remodeling in response to β-AR stimulation