Modeling the connectome of a simple spinal cord.

In this paper we develop a computational model of the anatomy of a spinal cord. We address a long-standing ambition of neuroscience to understand the structure-function problem by modeling the complete spinal cord connectome map in the 2-day old hatchling Xenopus tadpole. Our approach to modeling neuronal connectivity is based on developmental processes of axon growth. A simple mathematical model of axon growth allows us to reconstruct a biologically realistic connectome of the tadpole spinal cord based on neurobiological data. In our model we distribute neuron cell bodies and dendrites on both sides of the body based on experimental measurements. If growing axons cross the dendrite of another neuron, they make a synaptic contact with a defined probability. The total neuronal network contains ∼1,500 neurons of six cell-types with a total of ∼120,000 connections. The anatomical model contains random components so each repetition of the connectome reconstruction procedure generates a different neuronal network, though all share consistent features such as distributions of cell bodies, dendrites, and axon lengths. Our study reveals a complex structure for the connectome with many interesting specific features including contrasting distributions of connection length distributions. The connectome also shows some similarities to connectivity graphs for other animals such as the global neuronal network of C. elegans. In addition to the interesting intrinsic properties of the connectome, we expect the ability to grow and analyze a biologically realistic spinal cord connectome will provide valuable insights into the properties of the real neuronal networks underlying simple behavior

Intermediate hyperglycaemia, diabetes and blood pressure in rural Bangladesh: Five-year post-randomisation follow-up of the DMagic cluster-randomised controlled trial

Summary Background: The DMagic trial showed that participatory learning and action (PLA) community mobilisation delivered through facilitated community groups, and mHealth voice messaging interventions improved diabetes knowledge in Bangladesh and the PLA intervention reduced diabetes occurrence. We assess intervention effects three years after intervention activities stopped. Methods: Five years post-randomisation, we conducted a cross-sectional survey among a random sample of adults aged ≥30-years living in the 96 DMagic villages, and a cohort of individuals identified with intermediate hyperglycaemia at the start of the DMagic trial in 2016. Primary outcomes were: 1) the combined prevalence of intermediate hyperglycaemia and diabetes; 2) five-year cumulative incidence of diabetes among the 2016 cohort of individuals with intermediate hyperglycaemia. Secondary outcomes were: weight, BMI, waist and hip circumferences, blood pressure, knowledge and behaviours. Primary analysis compared outcomes at the cluster level between intervention arms relative to control. Findings: Data were gathered from 1623 (82%) of the randomly selected adults and 1817 (87%) of the intermediate hyperglycaemia cohort. 2018 improvements in diabetes knowledge in mHealth clusters were no longer observable in 2021. Knowledge remains significantly higher in PLA clusters relative to control but no difference in primary outcomes of intermediate hyperglycaemia and diabetes prevalence (OR (95%CI) 1.23 (0.89, 1.70)) or five-year incidence of diabetes were observed (1.04 (0.78, 1.40)). Hypertension (0.73 (0.54, 0.97)) and hypertension control (2.77 (1.34, 5.75)) were improved in PLA clusters relative to control. Interpretation: PLA intervention effect on intermediate hyperglycaemia and diabetes was not sustained at 3 years after intervention end, but benefits in terms of blood pressure reduction were observed

Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction

BACKGROUND: PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival. CONCLUSIONS: PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI

Can simple rules control development of a pioneer vertebrate neuronal network generating behavior?

How do the pioneer networks in the axial core of the vertebrate nervous system first develop? Fundamental to understanding any full-scale neuronal network is knowledge of the constituent neurons, their properties, synaptic interconnections, and normal activity. Our novel strategy uses basic developmental rules to generate model networks that retain individual neuron and synapse resolution and are capable of reproducing correct, whole animal responses. We apply our developmental strategy to young Xenopus tadpoles, whose brainstem and spinal cord share a core vertebrate plan, but at a tractable complexity. Following detailed anatomical and physiological measurements to complete a descriptive library of each type of spinal neuron, we build models of their axon growth controlled by simple chemical gradients and physical barriers. By adding dendrites and allowing probabilistic formation of synaptic connections, we reconstruct network connectivity among up to 2000 neurons. When the resulting "network" is populated by model neurons and synapses, with properties based on physiology, it can respond to sensory stimulation by mimicking tadpole swimming behavior. This functioning model represents the most complete reconstruction of a vertebrate neuronal network that can reproduce the complex, rhythmic behavior of a whole animal. The findings validate our novel developmental strategy for generating realistic networks with individual neuron- and synapse-level resolution. We use it to demonstrate how early functional neuronal connectivity and behavior may in life result from simple developmental "rules," which lay out a scaffold for the vertebrate CNS without specific neuron-to-neuron recognition

Helicobacter pylori antibiotic susceptibility patterns in Bangladesh: Emerging levofloxacin resistance

Introduction: The most recent study to report Helicobacter pylori antibiotic resistance rates in Bangladesh was published 15 years ago and did not include levofloxacin. We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin in Bangladesh. Methodology: This study included 133 consecutive patients who underwent endoscopy examination at Dhaka Medical College in November 2014. The serial two-fold agar dilution method was used to determine the minimum inhibitory concentrations of the five antibiotics. Results: Among 56 cultured strains, H. pylori showed high rates of resistance to clarithromycin and metronidazole (39.3 and 94.6, respectively). Moreover, levofloxacin showed an emerging antimicrobial resistance pattern (66.1), which was higher in patients with gastritis than that in those with peptic ulcers (p = 0.02). The resistance rate of levofloxacin was significantly higher in patients living in Dhaka city compared to those living in the village (p = 0.049). However, amoxicillin and tetracycline resistance rates were very low. Resistance to both metronidazole and levofloxacin was most commonly observed. Conclusions: The rates of resistance to clarithromycin, metronidazole, and levofloxacin were high in Bangladesh, which suggests that triple therapy based on these drugs may not be useful as first-line therapies in Bangladesh. Alternative strategies such as furazolidone-based triple therapy, bismuth-based quadruple therapies, or sequential therapy may be more effective for patients in in Bangladesh. © 2016 Aftab et al

Equity impact of participatory learning and action community mobilisation and mHealth interventions to prevent and control type 2 diabetes and intermediate hyperglycaemia in rural Bangladesh: analysis of a cluster randomised controlled trial

BACKGROUND: A cluster randomised trial of mHealth and participatory learning and action (PLA) community mobilisation interventions showed that PLA significantly reduced the prevalence of intermediate hyperglycaemia and type 2 diabetes mellitus (T2DM) and the incidence of T2DM among adults in rural Bangladesh; mHealth improved knowledge but showed no effect on glycaemic outcomes. We explore the equity of intervention reach and impact. METHODS: Intervention reach and primary outcomes of intermediate hyperglycaemia and T2DM were assessed through interview surveys and blood fasting glucose and 2-hour oral glucose tolerance tests among population-based samples of adults aged ≥30 years. Age-stratified, gender-stratified and wealth-stratified intervention effects were estimated using random effects logistic regression. RESULTS: PLA participants were similar to non-participants, though female participants were younger and more likely to be married than female non-participants. Differences including age, education, wealth and marital status were observed between individuals exposed and those not exposed to the mHealth intervention.PLA reduced the prevalence of T2DM and intermediate hyperglycaemia in all age, gender and wealth strata. Reductions in 2-year incidence of T2DM of at least 51% (0.49, 95% CI 0.26 to 0.92) were observed in all strata except among the oldest and least poor groups. mHealth impact on glycaemic outcomes was observed only among the youngest group, where a 47% reduction in the 2-year incidence of T2DM was observed (0.53, 95% CI 0.28 to 1.00). CONCLUSION: Large impacts of PLA across all strata indicate a highly effective and equitable intervention. mHealth may be more suitable for targeting higher risk, younger populations. TRIAL REGISTRATION NUMBER: ISRCTN41083256

Endothelial and cardiomyocyte PI3Kβ divergently regulate cardiac remodelling in response to ischaemic injury

AIMS: Cardiac remodeling in the ischemic heart determines prognosis in patients with ischemic heart disease (IHD), while enhancement of angiogenesis and cell survival has shown great potential for IHD despite translational challenges. Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays a critical role in promoting angiogenesis and cell survival. However, the effect of PI3Kβ in the ischemic heart is poorly understood. This study investigates the role of endothelial and cardiomyocyte PI3Kβ in post-infarct cardiac remodeling. METHODS AND RESEARCH: PI3Kβ catalytic subunit-p110β level was increased in infarcted murine and human hearts. Using cell type-specific loss-of-function approaches, we reported novel and distinct actions of p110β in endothelial cells versus cardiomyocytes in response to myocardial ischemic injury. Inactivation of endothelial p110β resulted in marked resistance to infarction and adverse cardiac remodeling with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured endothelial cells with p110β knockout or inhibition displayed preferential PI3Kα/Akt/eNOS signaling that consequently promoted protective signaling and angiogenesis. In contrast, mice with cardiomyocyte p110β-deficiency exhibited adverse post-infarct ventricular remodeling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of cardiomyocytes to ischemia-mediated cell death. Disruption of cardiomyocyte p110β signaling compromised nuclear p110β and phospho-Akt levels leading to perturbed gene expression and elevated pro-cell death protein levels, increasing the susceptibility to cardiomyocyte death. A similar divergent response of PI3Kβ endothelial and cardiomyocyte mutant mice was seen using a model of myocardial ischemia-reperfusion injury. CONCLUSIONS: These data demonstrate novel, differential, and cell-specific functions of PI3Kβ in the ischemic heart. While loss of endothelial PI3Kβ activity produces cardioprotective effects, cardiomyocyte PI3Kβ is protective against myocardial ischemic injury

Physical and hybrid modelling techniques for earth-air heat exchangers in reducing building energy consumption: Performance, applications, progress, and challenges

Noteworthy advancements are seen in developing the earth-air heat exchanger (EAHE) models in the past several decades to reduce building energy consumption. However, it is still an ongoing challenge in selecting and implementing the most suitable and appropriate EAHE modelling technique in buildings based on the climates, performance, and limitations of the techniques. Therefore, this paper aims to review the published research related to the physical, and hybrid EAHE modelling techniques used in buildings, and highlight the prospects, benefits, progress, and challenges of these techniques. This is the first study that comprehensively evidences the prospects and technical challenges caused by unmeasured disturbances, assumptions, or the uncertainties generated in experimental and numerical works of all EAHE modelling techniques. Nevertheless, this study found that hybrid modelling is more effective than physical models for accurate prediction. On the contrary, the hybrid models suffer from high complexity if EAHE operating conditions and all key parameters are considered during the model development. Regarding the generalization capability, the physical models offer improved performance followed by the hybrid models. A minimum number of training data is needed for developing physical models, whereas medium training data is required for the hybrid models. The outcome of this study also provides valuable information regarding the physical and hybrid EAHE modelling techniques to the scientists, researchers, and so on in adopting the most appropriate EAHE modelling technique for their climates