Showing papers by "Churchill Hospital published in 2022"

Empirical analysis of impact of multi-class commercial vehicles on multi-lane highway traffic characteristics under mixed traffic conditions

Abstract: The presence and movement of multi-class commercial vehicles (CVs) under different traffic conditions in a shared roadway influences the highway traffic characteristics. The purpose of this study is to quantify the impact of the varying proportion of multi-class commercial vehicles (CVs) on the speed, dynamic passenger car unit (DPCU), capacity, and level of service (LoS) of the highways through empirical analysis. The speed-flow data were collected at highway sections in India, utilizing an Infra-Red (IR) sensor device. Individual vehicle speeds are predicted using the simultaneous equations approach, which are used to determine the respective DPCU factors of the vehicles and highway capacity at different proportions of multi-class CVs. The LoS threshold values are established based on the volume to capacity (v/C) ratio for the various percentages of multi-class CVs. The study results reveal that the multi-class CVs have had a unique effect on DPCU factors of the different vehicle categories under the influence of varying proportions of multi-class CVs. The highway speed reduced by 27.76% at 30% multi-class CVs compared to 5% multi-class CVs. Eventually, the highway capacity reduced by 24.25% at 30% multi-class CVs compared to 5% multi-class CVs. The LoS varied for each highway section accordingly from free-flow condition to the congested condition due to the incremental variation in the percentage of the multi-class CVs. The study indicates that the presence of a higher proportion of multi-class CVs significantly affects the speed, DPCU, capacity, and LoS of the highways.

Nanopore ReCappable sequencing maps SARS-CoV-2 5′ capping sites and provides new insights into the structure of sgRNAs

Abstract: The SARS-CoV-2 virus has a complex transcriptome characterised by multiple, nested subgenomic RNAsused to express structural and accessory proteins. Long-read sequencing technologies such as nanopore direct RNA sequencing can recover full-length transcripts, greatly simplifying the assembly of structurally complex RNAs. However, these techniques do not detect the 5' cap, thus preventing reliable identification and quantification of full-length, coding transcript models. Here we used Nanopore ReCappable Sequencing (NRCeq), a new technique that can identify capped full-length RNAs, to assemble a complete annotation of SARS-CoV-2 sgRNAs and annotate the location of capping sites across the viral genome. We obtained robust estimates of sgRNA expression across cell lines and viral isolates and identified novel canonical and non-canonical sgRNAs, including one that uses a previously un-annotated leader-to-body junction site. The data generated in this work constitute a useful resource for the scientific community and provide important insights into the mechanisms that regulate the transcription of SARS-CoV-2 sgRNAs.

Therapeutic Antiaging Strategies

Abstract: Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.

Direct RNA sequencing of respiratory syncytial virus infected human cells generates a detailed overview of RSV polycistronic mRNA and transcript abundance

Abstract: To characterize species of viral mRNA transcripts generated during respiratory syncytial virus (RSV) infection, human fibroblast-like MRC-5 lung cells were infected with subgroup A RSV for 6, 16 and 24 hours. In addition, we characterised the viral transcriptome in infected Calu-3 lung epithelial cells at 48 hours post infection. Total RNA was harvested and polyadenylated mRNA was enriched and sequenced by direct RNA sequencing using an Oxford nanopore device. This platform yielded over 450,000 direct mRNA transcript reads which were mapped to the viral genome and analysed to determine the relative mRNA levels of viral genes using our in-house ORF-centric pipeline. We examined the frequency of polycistronic readthrough mRNAs were generated and assessed the length of the polyadenylated tails for each group of transcripts. We show a general but non-linear decline in gene transcript abundance across the viral genome, as predicted by the model of RSV gene transcription. However, the decline in transcript abundance is not uniform. The polyadenylate tails generated by the viral polymerase are similar in length to those generated by the host polyadenylation machinery and broadly declined in length for most transcripts as the infection progressed. Finally, we observed that the steady state abundance of transcripts with very short polyadenylate tails less than 20 nucleotides is less for N, SH and G transcripts in both cell lines compared to NS1, NS2, P, M, F and M2 which may reflect differences in mRNA stability and/or translation rates within and between the cell lines.

First Report With Medium-term Follow-up of Intestinal Transplantation for Advanced and Recurrent Nonresectable Pseudomyxoma Peritonei

Abstract: Objective: To report our experience with the combination of radical surgical excision and intestinal transplantation in patients with recurrent Pseudomyxoma Peritonei (PMP) not amenable to further Cytoreductive surgery (CRS). Background: CRS and heated intra-operative peritoneal chemotherapy is an effective treatment for many patients with PMP. In patients with extensive small bowel involvement, or non-resectable recurrence, disease progression results in small bowel obstruction, nutritional failure, fistulation, with resulting abdominal wall failure. Methods: Between 2013-2022, patients with PMP who had nutritional failure and were not suitable for further CRS underwent radical debulking and intestinal transplantation at our centre. Results: 15 patients underwent radical exenteration of affected intra-abdominal organs, and transplantation adapted according to the individual case. Eight patients had isolated small bowel transplantation and seven patients underwent modified multi-visceral transplantation. Additionally, in seven patients with significant abdominal wall tumour involvement, a full thickness vascularized abdominal wall transplant was performed. Two of the 15 patients died within 90 days due to surgically related complications. Actuarial 1-year and 5-year patient survivals were 79% and 55% respectively. The majority of the patients had significant improvement in quality of life after transplantation. Progression/recurrence of disease was detected in 91% of patients followed up for more than six months. Conclusion: Intestinal/multi-visceral transplantation enables a more radical approach to the management of PMP than can be achieved with conventional surgical methods and is suitable for patients for whom there is no conventional surgical option. This complex surgical intervention requires combined skills of both peritoneal malignancy and transplant teams.

Natural Compound-Based Nanoparticles to Target Free Radicals in Cancer

Abstract: Cell proliferation and malignant transformation are enabled by genetic and epigenetic changes. During the malignancy process, malignant cells acquire distinguishing characteristics. Cancer cells have acquired the ability to generate more reactive oxygen species (ROS), resulting in high oxidative stress. ROS-mediated signaling is needed for cancer cell physiology, and high levels of ROS cause oxidative stress-induced cytotoxicity in cancer cells. To avoid ROS-mediated cytotoxicity, cancer cells modulate their redox state through various antioxidant mechanisms and keep their ROS levels below the threshold. Cancer treatment that targets oxidative stress is an appealing option. Many natural oxidative stress modulators and bioactive compounds have been used in the treatment of cancer. Conventional uptake of bioactive molecule is associated with lower bioavailability, solubility, unlikely biodistribution, and side effects. Traditional drug uptake is improved by nanoformulation, making it easier to overcome side effects, improve biodistribution, and extend drug duration time. Natural prooxidant-loaded nanoparticles efficiently carry prooxidant to the tumor site and selectively and efficiently induce oxidative stress-mediated cell death in cancer cells.

Zmiz1 is required for mature β-cell function and mass expansion upon high fat feeding

Abstract: ABSTRACT Genome-wide association studies have identified hundreds of signals for type 2 diabetes (T2D), most of which confer risk through effects on gene expression. We previously identified the transcription factor ZMIZ1 as a probable effector transcript in human islets, but how altered ZMIZ1 expression impacts T2D risk is unknown. We now show that islets from carriers of the T2D-risk alleles have reduced islet insulin content and glucose-stimulated insulin secretion. To elucidate the mechanism for islet-cell dysfunction, we generated β-cell-specific Zmiz1 knockout (Zmiz1 βKO ) mice. Male and female Zmiz1 βKO mice were glucose intolerant with impaired insulin secretion, compared with control littermates. Transcriptomic profiling of Zmiz1 βKO islets identified over 500 differentially expressed genes including those involved in β-cell function and maturity which we confirmed at the protein level. After high fat feeding, Zmiz1 βKO mice fail to expand β-cell mass and become severely diabetic. Thus, Zmiz1 is required for normal glucose homeostasis and may contribute to T2D risk by maintaining a mature β-cell state and allowing islet mass expansion upon metabolic stress.

A Secure Bank Transaction Using Blockchain Computing and Forest Oddity

Abstract: The Indian banking system has progressed from nationalization to liberalization. The banks are the backbone of any country wherever financial support is required. Security is an important factor that must be followed in any organization to protect its user’s confidential data. This paper removes issues using Blockchain Algorithm SHA-256. The aim of the study is to compare the security and privacy features of selected banks. The study further investigates the bank customers’ perception towards security and privacy concern’ regarding the use of e-banking services. The current framework, various following partner issues that break away at projected tasks using Blockchain algorithm SHA-256 which are extremely traditional and effectively accessible for software engineer action within the event that it needs to interrupt. During this paper, we tend to use SHA-256 calculation for message key age and for info encoding utilized upgraded Blowfish algorithm. When the procedure of this is finished, we tend to boot discover the negotiated server in the cloud framework. For replicas, we tend to utilize Cloudsim, a java primarily based check system.

Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression

Abstract: Aims/hypothesis: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycemic traits. However, little is known about the function of the zinc finger transcription factor RREB1 in glucose homeostasis or how changes in its expression and/or function influence diabetes risk. Methods: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 T2D-risk alleles. Results: CRISPR-Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression, and glucose levels. Loss of RREB1 reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells, and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed a dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of T2D-risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with RREB1 regulating islet cell function. Conclusions/interpretation: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.

Intervention of Modern Genetic Tools for Managing Insect Pests of Fruit Crops

Abstract: Merits and demerits of select modern genetic tools as sterile insect technique, repressible dominant lethal, engineering insect pests, transgenic crops, primary resistance management, gene silencing RNA interference, genome-editing-based methods, autocidal insect control techniques, and genomics approaches for pest management have been discussed. Application of these methods to manage insect pests of fruit crops have been dealt with. Finally, new vision to pest control and future prospects in the utilization of molecular genetics-based tools for insect pest management has been presented.

Holistic process integration and optimization: Large-scale hybrid process applications

Abstract: Holistic integration and optimization of chemical processes and consumer product manufacture require the application of holistic systems modeling in process and product design to evaluate the related environmental, socio-ecological, and economic impacts. Market research, impact assessment, and risk management scenarios are used jointly to establish optimization of the business models for sustainability; combining optimal resource efficiency; and process costs with minimal adverse environmental impacts. These aims are satisfied through the incorporation of supply-chain systems that make best use of industrial symbiosis and eco-industrial parks for shared and linked recycle, reuse, and regeneration of utilities, services, and materials.

Stemness and Stromal Niche: Targets in Oxidative Stress–Induced Oral Cancer

Abstract: Oral cancer is the third most prevalent cancer in the world and the most common among males. Despite improvement in therapeutic strategies, the overall prognosis of oral cancer has remained poor. A subpopulation of cancer cells, known as cancer stem cells (CSCs) and its interaction with tumor microenvironment (TME), drives aggressive behavior of cancer. Excess of pro-oxidant components induces oxidative stress in both cancer cells and TME and plays critical roles in the neoplastic outcomes of the oral cavity. However, CSCs have intrinsic ability to maintain low oxidative stress status and metabolic plasticity which allows it to thrive in high oxidative stress conditions. In this chapter, we have discussed the role of oxidative stress in CSCs and stromal microenvironment of oral cancer and available therapeutic options against it.KeywordsOral cancerStemnessOxiadative stressMicroenvironmentO2 metabolism

Facilitation of Insulin Effects by Ranolazine in Astrocytes in Primary Culture

Abstract: Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels; however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins (10-8 M), Rn (10-6 M), and Ins + Rn (10-8 M and 10-6 M, respectively) were added to astrocytes for 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. Rn increased protein expression of Cu/Zn-SOD and the pro-inflammatory protein COX-2 was upregulated by Ins. On the contrary, no significant changes were found in the protein expression of NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. In addition, Rn + Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone.

Examining the Time Headway Distributions on Rural Highways Under Different Traffic Flow Conditions

Abstract: The Time Headway (TH) between vehicles is one of the vital microscopic parameters in traffic engineering. It is influenced by the prevailing traffic flow characteristics of the highway segments. An accurate measure of TH is essential to deal effectively with any given traffic system. The selection of the suitable probability distribution function for a specific condition of traffic remained an open question. This research aims to evaluate the best-fitted TH probability distribution function for different traffic flow levels in multilane-divided rural highways under heterogeneous traffic conditions. The traffic-related data was obtained using a state-of-the-art, non-intrusive Infra-Red (IR) traffic detector system. The IR sensor system was used to collect the traffic data like vehicle class, traffic speed, traffic flow, and TH from the Chennai–Nagapattinam National Highways in India. To interpret and distinguish the driver behavior in maintaining different TH distributions at different traffic flow conditions, the Kolmogorov–Smirnov (K–S) test was used. The descriptive statistical results reveal that the mean TH values under different traffic flow conditions differ from each other, implying that the traffic flow conditions influence the TH distributions. Consequently, the research findings show significant variations in the TH following characteristics for the highway segment under various traffic flow conditions. The estimated TH distributions can be used to build the microscopic traffic simulation models.