Miracle-dz/UniFAR-FTUs huggingface dataset:
Glutathione catabolism by Enterobacteriaceae species to hydrogen sulphide adversely affects the viability of host systems in the presence of 5′fluorodeoxyuridine

Reduced glutathione (GSH) plays an essential role in relieving oxidative insult from the generation of free radicals via normal physiological processes. However, GSH can be exploited by bacteria as a signalling molecule for the regulation of virulence. We describe findings arising from a serendipitous observation that when GSH and Escherichia coli were incubated with 5′fluorodeoxyuridine (FUdR)‐synchronised populations of Caenorhabditis elegans, the nematodes underwent rapid death. Death was mediated by the production of hydrogen sulphide mainly through the action of tnaA, a tryptophanase‐encoding gene in E. coli. Other Enterobacteriaceae species possess similar cysteine desulfhydrases that can catabolise l‐cysteine‐containing compounds to hydrogen sulphide and mediate nematode killing when worms had been pre‐treated with FUdR. When colonic epithelial cell lines were infected, hydrogen sulphide produced by these bacteria in the presence of GSH was also able to inhibit ATP synthesis in these cells particularly when cells had been treated with FUdR. Therefore, bacterial production of hydrogen sulphide could act in concert with a commonly used genotoxic cancer drug to exert host cell impairment. Hydrogen sulphide also increases bacterial adhesion to the intestinal cells. These findings could have implications for patients undergoing chemotherapy using FUdR analogues that could result in intestinal damage.
Effect of WeChat Messaging on Improving the Quality of Bowel Preparation for Outpatient Colonoscopy

With the most active users of any social media platform in China, WeChat has become the preferred platform for public announcements and is widely used in the fields of medicine and nursing (Hong, Zhou, Fang, & Shi, 2017; Zeng, Deng, Wang, & Liu, 2016). The aim of this study was to evaluate the effect of WeChat messaging on bowel preparation for outpatient colonoscopy. A total of 150 outpatients scheduled for colonoscopy in a Grade III level A hospital were randomly assigned to the experimental group (n = 73) or the control group (n = 72). Both groups received routine guidance from the day of the scheduling appointment through the day of colonoscopy. In addition, the experimental group received colonoscopy-related information and individualized guidance daily through WeChat from the day of the appointment. After the colonoscopy, the diet and medication compliance, satisfaction, anxiety, and bowel cleanliness were compared. Post-intervention, there were significant differences in bowel cleanliness, satisfaction, diet and medication compliance, and anxiety between the two groups. WeChat messaging can help improve diet and medication compliance, patient satisfaction, and the success rate and thoroughness of colonoscopy, as well as alleviate the anxiety of patients scheduled for outpatient colonoscopy.
During Translesion Synthesis, Escherichia coli DinB89 (T120P) Alters Interactions of DinB (Pol IV) with Pol III Subunit Assemblies and SSB, but Not with the β Clamp

Specialized DNA polymerases (Pols) capable of catalyzing translesion synthesis (TLS) generate mutations that contribute to bacterial virulence, pathoadaptation, and antimicrobial resistance. One mechanism by which the bacterial TLS Pol IV gains access to the DNA to generate mutations is by exchanging places with the bacterial Pol III replicase via a Pol III-Pol IV switch. ABSTRACT Translesion synthesis (TLS) by specialized DNA polymerases (Pols) is an evolutionarily conserved mechanism for tolerating replication-blocking DNA lesions. Using the Escherichia coli dinB-encoded Pol IV as a model to understand how TLS is coordinated with the actions of the high-fidelity Pol III replicase, we previously described a novel Pol IV mutant containing a threonine 120-to-proline mutation (Pol IV-T120P) that failed to exchange places with Pol III at the replication fork in vitro as part of a Pol III-Pol IV switch. This in vitro defect correlated with the inability of Pol IV-T120P to support TLS in vivo, suggesting Pol IV gains access to the DNA, at least in part, via a Pol III-Pol IV switch. Interaction of Pol IV with the β sliding clamp and the single-stranded DNA binding protein (SSB) significantly stimulates Pol IV replication and facilitates its access to the DNA. In this work, we demonstrate that Pol IV interacts physically with Pol III. We further show that Pol IV-T120P interacts normally with the β clamp, but is impaired in interactions with the α catalytic and εθ proofreading subunits of Pol III, as well as SSB. Taken together with published work, these results provide strong support for the model in which Pol IV-Pol III and Pol IV-SSB interactions help to regulate the access of Pol IV to the DNA. Finally, we describe several additional E. coli Pol-Pol interactions, suggesting Pol-Pol interactions play fundamental roles in coordinating bacterial DNA replication, DNA repair, and TLS. IMPORTANCE Specialized DNA polymerases (Pols) capable of catalyzing translesion synthesis (TLS) generate mutations that contribute to bacterial virulence, pathoadaptation, and antimicrobial resistance. One mechanism by which the bacterial TLS Pol IV gains access to the DNA to generate mutations is by exchanging places with the bacterial Pol III replicase via a Pol III-Pol IV switch. Here, we describe multiple Pol III-Pol IV interactions and discuss evidence that these interactions are required for the Pol III-Pol IV switch. Furthermore, we describe several additional E. coli Pol-Pol interactions that may play fundamental roles in managing the actions of the different bacterial Pols in DNA replication, DNA repair, and TLS.
Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischaemia

Acute kidney injury is common, with ~13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischaemia, typically following cardiac surgery, renal transplant or severe haemorrhage. We examined the cause of the sustained reduction in renal blood flow (‘no-reflow’), which exacerbates kidney injury even after an initial cause of compromised blood supply is removed. Adult male Sprague-Dawley rats, or NG2-dsRed male mice were used in this study. After 60 min kidney ischaemia and 30–60 min reperfusion, renal blood flow remained reduced, especially in the medulla, and kidney tubule damage was detected as Kim-1 expression. Constriction of the medullary descending vasa recta and cortical peritubular capillaries occurred near pericyte somata, and led to capillary blockages, yet glomerular arterioles and perfusion were unaffected, implying that the long-lasting decrease of renal blood flow contributing to kidney damage was generated by pericytes. Blocking Rho kinase to decrease pericyte contractility from the start of reperfusion increased the post-ischaemic diameter of the descending vasa recta capillaries at pericytes, reduced the percentage of capillaries that remained blocked, increased medullary blood flow and reduced kidney injury. Thus, post-ischaemic renal no-reflow, contributing to acute kidney injury, reflects pericytes constricting the descending vasa recta and peritubular capillaries. Pericytes are therefore an important therapeutic target for treating acute kidney injury.
The evolving role of long noncoding RNA HIF1A-AS2 in diabetic retinopathy: a cross-link axis between hypoxia, oxidative stress and angiogenesis via MAPK/VEGF-dependent pathway

ABSTRACT Background Diabetic retinopathy (DR) signifies a frequent serious diabetic complication influencing retinal structure and function. Dysregulation of lncRNAs drives a wide array of human diseases especially diabetes; thus, we aimed to study lncRNA HIF1A-AS2 role and its interplay with hypoxia, oxidative stress (OS), and angiogenesis in DR. Materials and methods 60 DM patients in addition to 15 healthy subjects. were enrolled. LncRNA HIF1A-AS2 mRNA relative gene expression was assessed. Hypoxia inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), mitogen activated protein kinase (MAPK), and endoglin levels were assessed. Detection of DNA damage using comet assay, and Redox status parameters were also detected. Results LncRNA HIF1A-AS2 expression was significantly increased in diabetic patients with the highest levels in proliferative DR patients. Moreover, HIFα, VEGF, MAPK, and Endogolin levels were significantly higher in the diabetic patients compared to control group with the highest levels in in proliferative DR patients. Significant DNA damage in comet assay was observed to be the highest in this group. Conclusion We observed for the first time the imminent role of long noncoding RNA HIF1A-AS2 in DR throughout its stages and its interplay with hypoxia, OS, and angiogenesis via MAPK/VEGF-dependent pathway.
SNP‐based heritability and selection analyses: Improved models and new results

Complex‐trait genetics has advanced dramatically through methods to estimate the heritability tagged by SNPs, both genome‐wide and in genomic regions of interest such as those defined by functional annotations. The models underlying many of these analyses are inadequate, and consequently many SNP‐heritability results published to date are inaccurate. Here, we review the modelling issues, both for analyses based on individual genotype data and association test statistics, highlighting the role of a low‐dimensional model for the heritability of each SNP. We use state‐of‐art models to present updated results about how heritability is distributed with respect to functional annotations in the human genome, and how it varies with allele frequency, which can reflect purifying selection. Our results give finer detail to the picture that has emerged in recent years of complex trait heritability widely dispersed across the genome. Confounding due to population structure remains a problem that summary statistic analyses cannot reliably overcome. Also see the video abstract here: https://youtu.be/WC2u03V65MQ
Generation of Human Lung Organoid Cultures from Healthy and Tumor Tissue to Study Infectious Diseases

Three-dimensional (3D) human lung organoids reflect the native cell composition of the lung as well as its physiological properties. Human 3D lung organoids offer ideal conditions, such as timely availability in large quantities and high physiological relevance for reassessment and prediction of disease outbreaks of respiratory pathogens and pathogens that use the lung as a primary entry portal. ABSTRACT Respiratory viruses cause mild to severe diseases in humans every year, constituting a major public health problem. Characterizing the pathogenesis in physiologically relevant models is crucial for developing efficient vaccines and therapeutics. Here, we show that lung organoids derived from human primary or lung tumor tissue maintain the cellular composition and characteristics of the original tissue. Moreover, we show that these organoids sustain viral replication with particular infection foci formation, and they activate the expression of interferon-associated and proinflammatory genes responsible for mediating a robust innate immune response. All together, we show that three-dimensional (3D) lung organoids constitute a relevant platform to model diseases and enable the development of drug screenings. IMPORTANCE Three-dimensional (3D) human lung organoids reflect the native cell composition of the lung as well as its physiological properties. Human 3D lung organoids offer ideal conditions, such as timely availability in large quantities and high physiological relevance for reassessment and prediction of disease outbreaks of respiratory pathogens and pathogens that use the lung as a primary entry portal. Human lung organoids can be used in basic research and diagnostic settings as early warning cell culture systems and also serve as a relevant platform for modeling infectious diseases and drug development. They can be used to characterize pathogens and analyze the influence of infection on, for example, immunological parameters, such as the expression of interferon-associated and proinflammatory genes in the context of cancer. In our study, we found that cancer-derived lung organoids were more sensitive to influenza A virus infection than those derived from healthy tissue and demonstrated a decreased innate immune response.
Phase 1/2 trial evaluating the effectiveness and safety of dose-adapted Hypofractionated pelvic radiotherapy for Advanced Cervical cancers INeligible for ChemoTherapy (HYACINCT)

Abstract Background The standard treatment for locally advanced cervical cancer (LACC) is concurrent chemoradiation (CRT) followed by brachytherapy (BRT). The addition of chemotherapy (ChT) to radiotherapy (RT) is associated with a 7.5% improvement in overall survival but with more grade 3–4 acute toxicities (16.4% vs 4.9%, CRT vs RT alone). The risk-benefit ratio could be less favorable in advanced disease with renal dysfunction secondary to tumor-related hydronephrosis; borderline cardiac function; and frail patients. RT alone followed by BRT achieves long-term locoregional control <62%. Hypofractionated RT (HF-RT) using older techniques result in comparable disease control and low late toxicity rates (4–8%). Dose-adapted HF-RT using intensity-modulated RT with nodal simultaneous integrated boost (nSIB) could improve tumor control and toxicity, when ChT is contraindicated. Methods The HYACINCT study is a two-phase study to determine the effectiveness and safety of HF-RT with nSIB in LACC when ChT is contraindicated. Phase 1 is a dose-escalation study using standard 3 + 3 design, to determine the maximum tolerated dose (MTD) for nSIB in combination with pelvic HF-RT (2.67 Gy x 15 fractions). Phase 2 is a single-arm clinical trial using Simon’s two-stage design, to assess the efficacy of HF-RT with nSIB in terms of tumor response. Adult women with biopsy-proven, untreated LACC, with contraindication to ChT will be included in this trial. Discussion For the phase 1, the primary endpoint is dose-limiting toxicity (DLT), or any grade ? 3 acute or sub-acute toxicity. The dose level at which incidence of DLT is ? 33% is defined as the maximum tolerance dose (MTD). For the phase 2, the primary endpoint is complete response at 3 months post-treatment. Secondary outcomes are progression-free and overall survival, acute and late toxicity, and patient-reported outcomes (EPIC, EORTCQLQ C30 + CX24, PGIC, PCIS). Trial registration: NCT05210270
Toward a CRISPR-Cas9-based Gene Drive in the Diamondback Moth Plutella xylostella.

Promising to provide powerful genetic control tools, gene drives have been constructed in multiple dipteran insects, yeast, and mice for the purposes of population elimination or modification. However, it remains unclear whether these techniques can be applied to lepidopterans. Here, we used endogenous regulatory elements to drive Cas9 and single guide RNA (sgRNA) expression in the diamondback moth (DBM), Plutella xylostella, and test the first split gene drive system in a lepidopteran. The DBM is an economically important global agriculture pest of cruciferous crops and has developed severe resistance to various insecticides, making it a prime candidate for such novel control strategy development. A very high level of somatic editing was observed in Cas9/sgRNA transheterozygotes, although no significant homing was revealed in the subsequent generation. Although heritable Cas9-medated germline cleavage as well as maternal and paternal Cas9 deposition were observed, rates were far lower than for somatic cleavage events, indicating robust somatic but limited germline activity of Cas9/sgRNA under the control of selected regulatory elements. Our results provide valuable experience, paving the way for future construction of gene drives or other Cas9-based genetic control strategies in DBM and other lepidopterans.
The impact of physical activity on well-being, lifestyle and health promotion in an era of COVID-19 and SARS-CoV-2 variant

ABSTRACT We must recognize the limitations of the current situation and vaccines where SARS-CoV-2 variants continue to transform and spread and need to build strategies to maintain and promote health in adherence to the suggested recommended action of the WHO. The purpose of this review is to examine the literature and latest research on the effects of physical activity (PA) on health in preparation for the SARS-CoV-2 strain and future infectious diseases era. In addition, it provides some general guidelines for actionable PA. We performed a literature search using Scopus, Riss, MEDLINE, and Google Scholar, this review method was a narrative literature review of the available literature and latest literature regarding health and PA-related factors during the COVID-19 pandemic. As a result, PA suggests opportunities to not only maintain and promote health by strengthening the immune system in an era where the COVID-19 variant is a crisis but also implement opportunities for well-being (WB), healthy lifestyles, and long-term health improvement. In particular, maintaining a regular PA routine outdoors or at home could be an important means to lower infection rates and maintain health during the potential impact of the current COVID-19 crisis and future pandemics (i.e. dramatic moments). The clinical relevance of the present review is crucial to understanding the impact of PA on WB, lifestyle, physical and mental health, maintaining regular PA, and important preventive factor to better prepare for the era of COVID-19 variants and similar pandemics in the future as it is emphasized as a prevention strategy and key strategy for continuous health promotion.
Model Based Design of Fuel Pump Control

This paper presents a co-simulation method to design of speed controller for turbojet fuel pump. Expected fuel pump is used for small turbine engine concept with reducer driven by free turbine. The amount of injected fuel into the combustion chamber is based on the speed of the fuel pump which is controlled by the engine control unit. The final flow of fuel into the combustion chamber is restricted by fuel bypass which constricts the return fuel according to pressure in the nozzles. This back fuel bypass has nonlinear and fixed characteristic determined by its structure. The only way how to control the amount of incoming fuel to the engine is the pump speed control. Effect of the bypass represents a variable component in the fuel pump load and from the view of the speed controller it is a disturbance variable. This paper describes the co-simulation model based on the use of MATLAB/Simulink and MSC Adams environment. This simulation uses interconnection of Simulink controller design and simplified model of the fuel pump dynamics in Adams (without hydraulic modelling).
Clinical electrophysiology of the aging heart

ABSTRACT Introduction Advancements in medical and consumer-grade technologies have made it easier than ever to monitor a patient’s heart rhythm and to diagnose arrhythmias. Octogenarians with symptomatic arrhythmias have unique management challenges due to their frailty, complex drug interactions, cognitive impairment, and competing comorbidities. The management decisions are further complicated by the lack of randomized evidence to guide treatment. Areas Covered A comprehensive literature review was undertaken to outline various tachyarrhythmias and bradyarrhythmias and their management, the role of cardiac implantable electronic devices, cardiac ablations, and specific geriatric arrhythmia considerations as recommended in international guidelines. Expert Opinion Atrial fibrillation (AF) is arguably the most important arrhythmia in the elderly and is associated with significant morbidity and mortality. Early diagnosis of AF, potentially with smart devices (wearables), has the potential to reduce the incidence of stroke, systemic emboli, and the risk of dementia. Bradyarrhythmias have a high incidence in the elderly as well, often requiring implantation of a permanent pacemaker. Leadless pacemakers implanted directly into the right ventricle are great options for gaining traction in elderly patients.
APOE Antibody Inhibits Aβ‐Associated Tau Seeding and Spreading in a Mouse Model

APOE is the strongest genetic factor for late‐onset Alzheimer's disease (AD). A specific conformation of the ApoE protein is present in amyloid‐β (Aβ) containing plaques. Immunotherapy targeting ApoE in plaques reduces brain Aβ deposits in mice. Here, we evaluated the effects of the anti‐human APOE antibody HAE‐4 on amyloid plaques, Aβ‐mediated tau seeding and spreading, and neuritic dystrophy in the 5XFAD amyloid mice expressing human ApoE4. HAE‐4 reduced Aβ plaques as well as Aβ‐driven tau seeding/spreading and neuritic dystrophy. These results demonstrate that HAE‐4 may provide therapeutic effects on amyloid removal and Aβ driven downstream consequences such as tauopathy. ANN NEUROL 2022;91:847–852
Myocardial perfusion by CMR coronary sinus flow shows sex differences and lowered perfusion at stress in patients with suspected microvascular angina

Patients with chest pain may have normal coronary arteries and suffer from microvascular angina (MVA). The aim of this study was to determine if patients with suspected MVA have lower global myocardial perfusion (global MP) during adenosine stress compared with healthy controls and coronary artery disease (CAD) patients and to determine if there are sex differences in global MP.
‘It enables the carers to see the person first’: Qualitative evaluation of point‐of‐care digital management system in residential aged care

Abstract Aims and objectives To evaluate acceptability, efficiency, and quality of a new digital care management system in a residential aged care home (RACH). Background Improving care quality and efficiency in RACH, while simultaneously upgrading data management, is a priority for communities and governments. Design Participatory action research with mixed methods data collection was employed to evaluate a digital care management system implemented at a 169‐bed RACH. This paper reports qualitative findings of the 2‐year evaluation. Methods Qualitative data were collected using focus groups with residents, visitors, nurses, managers, care workers, and consultants; resident/visitor and staff hallway interviews and responses to open‐ended questions in online staff surveys. Data were analysed thematically under the four predetermined study objectives. Reporting adhered to COREQ guidelines. Results 325 data captures from 88 participants, over seven data sources were coded. Findings indicate that the system was acceptable to both residents and staff due to perceptions of time‐saving and improved quality of care. Increased efficiency was perceived through timeliness as well as reduced time spent retrieving and documenting information. Quality of care was improved through care scheduling individualised to resident needs, with reminders to avoid missed care. Relatives were reassured and activities were scheduled to loved one's preferences. The co‐design implementation process was successful through commitment to quality from leadership teams and prioritising the focus on the holistic needs of the residents. Conclusion A strong emphasis on co‐design with care staff in developing and implementing the digital care system contributed to a system that supported nursing and care work, facilitated reporting and documentation, and improved resident care and well‐being including identification of missed care. Relevance to Clinical Practice Nurses, carers, administrators, and advocates can support the co‐design creation of information systems that suit the workflow of an organisation and keep the focus on individualised models of care provision.