Bio-Inspired Solutions and Its Impact on Real-World Problems: A Network on Chip (NoC) Perspective

Bio-inspired solutions are used to solve the real-world problems as they are able to resolve the complex issues. Already existing bio-inspired solutions are reviewed in this chapter which solved the complex engineering problems. Moreover, this chapter also discusses the implementation of biological brain mechanism in Network on Chip to address the fault-tolerant issues. Network on Chip (NoC) is a communication framework for System on Chip (SoC). Due to routers and interconnect failure, NoC suffers from faults. Therefore, bio-inspired solutions help us to recover from these faults. The techniques from the biological brain were implemented in NoC as the brain is fault tolerant and highly adaptive. Results showed that bio-inspired techniques are performing well compared to the traditional fault-tolerant algorithms

Hyperoxia evokes pericyte-mediated capillary constriction

Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF. Here, we used bright-field imaging of cerebral capillaries and modeling of CBF to show that hyperoxia (95% superfused O2) led to an increase in intracellular calcium level in pericytes and a significant capillary constriction, sufficient to cause an estimated 25% decrease in CBF. Although hyperoxia is reported to cause vascular smooth muscle cell contraction via generation of reactive oxygen species (ROS), endothelin-1 and 20-HETE, we found that increased cytosolic and mitochondrial ROS levels and endothelin release were not involved in the pericyte-mediated capillary constriction. However, a 20-HETE synthesis blocker greatly reduced the hyperoxia-evoked capillary constriction. Our findings establish pericytes as regulators of CBF in hyperoxia and 20-HETE synthesis as an oxygen sensor in CBF regulation. The results also provide a mechanism by which clinically administered oxygen can lead to a worse neurological outcome

Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via α2 adrenergic receptors

Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles. In acute brain slices, NA contracted pericytes but did not raise the pericyte cytoplasmic Ca2+ concentration, while the α1 agonist phenylephrine did not evoke contraction. Blocking α2 adrenergic receptors (α2Rs, which induce contraction by inhibiting cAMP production), greatly reduced the NA-evoked pericyte contraction, whereas stimulating α2Rs using xylazine (a sedative) or clonidine (an anti-hypertensive drug) evoked pericyte contraction. Noradrenaline-evoked pericyte contraction and capillary constriction are thus mediated via α2Rs. Consequently, α2Rs may not only modulate CBF in health and pathological conditions, but also contribute to CBF changes evoked by α2R ligands administered in research, veterinary and clinical settings

Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington's Disease.

In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology and both the mutant gene and the protein are found in cells and tissues throughout the body. Despite the adipose tissue gene expression alterations described in HD mouse models, adipose tissue and its gene expression signature have not been previously explored in human HD

The Ca²⁺-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activates chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplifies the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction and pericyte death, reduces neutrophil stalling and improves cerebrovascular reperfusion. Genetic analysis implicates altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function, and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia

SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane, and was mimicked by blocking ACE2. The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in Covid-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney

Abnormal molecular signatures of inflammation, energy metabolism, and vesicle biology in human Huntington disease peripheral tissues

BACKGROUND: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. RESULTS: We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients—those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. CONCLUSIONS: Our ‘omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02752-5

Targeting Protein Homeostasis in Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein VCP mice, which develop an inclusion body myopathy (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial

Efficacy of Endoscopic Submucosal Dissection for Superficial Gastric Neoplasia in a Large Cohort in North America

Background & Aims Endoscopic submucosal dissection (ESD) is a widely accepted treatment option for superficial gastric neoplasia in Asia, but there are few data on outcomes of gastric ESD from North America. We aimed to evaluate the safety and efficacy of gastric ESD in North America. Methods We analyzed data from 347 patients who underwent gastric ESD at 25 centers, from 2010 through 2019. We collected data on patient demographics, lesion characteristics, procedure details and related adverse events, treatment outcomes, local recurrence, and vital status at the last follow up. For the 277 patients with available follow-up data, the median interval between initial ESD and last clinical or endoscopic evaluation was 364 days. The primary endpoint was the rate of en bloc and R0 resection. Secondary outcomes included curative resection, rates of adverse events and recurrence, and gastric cancer-related death. Results Ninety patients (26%) had low-grade adenomas or dysplasia, 82 patients (24%) had high-grade dysplasia, 139 patients (40%) had early gastric cancer, and 36 patients (10%) had neuroendocrine tumors. Proportions of en bloc and R0 resection for all lesions were 92%/82%, for early gastric cancers were 94%/75%, for adenomas and low-grade dysplasia were 93%/ 92%, for high-grade dysplasia were 89%/ 87%, and for neuroendocrine tumors were 92%/75%. Intraprocedural perforation occurred in 6.6% of patients; 82% of these were treated successfully with endoscopic therapy. Delayed bleeding occurred in 2.6% of patients. No delayed perforation or procedure-related deaths were observed. There were local recurrences in 3.9% of cases; all occurred after non-curative ESD resection. Metachronous lesions were identified in 14 patients (6.9%). One of 277 patients with clinical follow up died of metachronous gastric cancer that occurred 2.5 years after the initial ESD. Conclusions ESD is a highly effective treatment for superficial gastric neoplasia and should be considered as a viable option for patients in North America. The risk of local recurrence is low and occurs exclusively after non-curative resection. Careful endoscopic surveillance is necessary to identify and treat metachronous lesions

Safety and efficacy of brain biopsy: Results from a single institution retrospective cohort study

Introduction: Brain biopsy provides important histopathological diagnostic information for patients with new intracranial lesions. Although a minimally invasive technique, previous studies report an associated morbidity and mortality between 0.6% and 6.8%. We sought to characterise the risk linked to this procedure, and to establish the feasibility of instigating a day-case brain biopsy pathway at our institution. Materials and methods: This single-centre retrospective case series study included neuronavigation guided mini craniotomy and frameless stereotactic brain biopsies carried out between April 2019 and December 2021. Exclusion criteria were interventions performed for non-neoplastic lesions. Demographic data, clinical and radiological presentation, type of biopsy, histology and complications in the post-operative period were recorded. Results: Data from 196 patients with a mean age of 58.7 years (SD+/-14.4 years) was analysed. 79% (n=155) were frameless stereotactic biopsies and 21% (n=41) neuronavigation guided mini craniotomy biopsies. Complications resulting in acute intracerebral haemorrhage and death, or new persistent neurological deficits were observed in 2% of patients (n=4; 2 frameless stereotactic; 2 open). Less severe complications or transient symptoms were noted in 2.5% of cases (n=5). 8 patients had minor haemorrhages in the biopsy tract with no clinical ramifications. Biopsy was non-diagnostic in 2.5% (n=5) of cases. Two cases were subsequently identified as lymphoma. Other reasons included insufficient sampling, necrotic tissue, and target error. Discussion and conclusion: This study demonstrates that brain biopsy is a procedure with an acceptably low rate of severe complications and mortality, in line with previously published literature. This supports the development of day-case pathway allowing improved patient flow, reducing the risk of iatrogenic complications associated with hospital stay, such as infection and thrombosis