bluuebunny/crossref_metadata_2025 huggingface dataset:
MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in
Aspergillus fumigatus
Authors: Thorn Harrison I. , Guruceaga Xabier , Martin-Vicente Adela , Nywening Ashley V. , Xie Jinhong , Ge Wenbo , Fortwendel Jarrod R.
Published: February 2024

Aspergillus fumigatus
is a major invasive mold pathogen and the most frequent etiologic agent of invasive aspergillosis. The currently available treatments for invasive aspergillosis are limited in both number and efficacy. Our recent work has uncovered that the β-glucan synthase inhibitors, the echinocandins, are fungicidal against strains of
A. fumigatus
with defects in septation initiation network (SIN) kinase activity. These drugs are known to be fungistatic against strains with normal septation. Surprisingly, SIN kinase mutant strains also failed to invade lung tissue and were significantly less virulent in immunosuppressed mouse models. Inhibiting septation in filamentous fungi is therefore an exciting therapeutic prospect to both reduce virulence and improve current antifungal therapy. However, the SIN remains understudied in pathogenic fungi. To address this knowledge gap, we characterized the putative regulatory components of the
A. fumigatus
SIN. These included the GTPase, SpgA, it’s two-component GTPase-activating protein, ByrA/BubA, and the kinase activators, SepM and MobA. Deletion of
spgA
,
byrA,
or
bubA
resulted in no overt septation or echinocandin susceptibility phenotypes. In contrast, our data show that deletion of
sepM
or
mobA
largely phenocopies disruption of their SIN kinase binding partners,
sepL
and
sidB
, respectively. Reduced septum formation, echinocandin hypersusceptibility, and reduced virulence were generated by loss of either gene. These findings provide strong supporting evidence that septa are essential not only for withstanding the cell wall disrupting effects of echinocandins but are also critical for the establishment of invasive disease. Therefore, pharmacological SIN inhibition may be an exciting strategy for future antifungal drug development.

IMPORTANCE

Septa are important structural determinants of echinocandin susceptibility and tissue invasive growth for the ubiquitous fungal pathogen
Aspergillus fumigatus
. Components of the septation machinery therefore represent promising novel antifungal targets to improve echinocandin activity and reduce virulence. However, little is known about septation regulation in
A. fumigatus
. Here, we characterize the predicted regulatory components of the
A. fumigatus
septation initiation network. We show that the kinase activators SepM and MobA are vital for proper septation and echinocandin resistance, with MobA playing an essential role. Null mutants of
mobA
displayed significantly reduced virulence in a mouse model, underscoring the importance of this pathway for
A. fumigatus
pathogenesis.
Reconstructing the transcriptional regulatory network of probiotic
L. reuteri
is enabled by transcriptomics and machine learning
Authors: Josephs-Spaulding Jonathan , Rajput Akanksha , Hefner Ying , Szubin Richard , Balasubramanian Archana , Li Gaoyuan , Zielinski Daniel C. , Jahn Leonie , Sommer Morten , Phaneuf Patrick , Palsson Bernhard O.
Published: February 2024

Limosilactobacillus reuteri
, a probiotic microbe instrumental to human health and sustainable food production, adapts to diverse environmental shifts via dynamic gene expression. We applied the independent component analysis (ICA) to 117 RNA-seq data sets to decode its transcriptional regulatory network (TRN), identifying 35 distinct signals that modulate specific gene sets. Our findings indicate that the ICA provides a qualitative advancement and captures nuanced relationships within gene clusters that other methods may miss. This study uncovers the fundamental properties of
L. reuteri
’s TRN and deepens our understanding of its arginine metabolism and the co-regulation of riboflavin metabolism and fatty acid conversion. It also sheds light on conditions that regulate genes within a specific biosynthetic gene cluster and allows for the speculation of the potential role of isoprenoid biosynthesis in
L. reuteri
’s adaptive response to environmental changes. By integrating transcriptomics and machine learning, we provide a system-level understanding of
L. reuteri
’s response mechanism to environmental fluctuations, thus setting the stage for modeling the probiotic transcriptome for applications in microbial food production.

IMPORTANCE

We have studied
Limosilactobacillus reuteri
, a beneficial probiotic microbe that plays a significant role in our health and production of sustainable foods, a type of foods that are nutritionally dense and healthier and have low-carbon emissions compared to traditional foods. Similar to how humans adapt their lifestyles to different environments, this microbe adjusts its behavior by modulating the expression of genes. We applied machine learning to analyze large-scale data sets on how these genes behave across diverse conditions. From this, we identified 35 unique patterns demonstrating how
L. reuteri
adjusts its genes based on 50 unique environmental conditions (such as various sugars, salts, microbial cocultures, human milk, and fruit juice). This research helps us understand better how
L. reuteri
functions, especially in processes like breaking down certain nutrients and adapting to stressful changes. More importantly, with our findings, we become closer to using this knowledge to improve how we produce more sustainable and healthier foods with the help of microbes.
Relationship between consumption of high fat, sugar or sodium (HFSS) food and obesity and non-communicable diseases
Authors: Thapsuwan Sasinee , Phulkerd Sirinya , Chamratrithirong Aphichat , Gray Rossarin Soottipong , Jindarattanaporn Nongnuch , Loyfah Nutnicha , Thongcharoenchupong Natjera , Pattaravanich Umaporn
Published: February 2024

The objective of this study was to investigate the relationship between high in fat, sugar or salt consumption, obesity and non-communicable diseases (NCDs) in the population in Thailand, and other associated factors. This study used data from participants age 15 years or older from the 2021 Health Behaviour of Population Survey. The final analytical sample included 74 894 respondents with complete data. Binary logistic regression analysis was used to investigate the relationship between socio-demographic characteristics, unhealthy food, NCDs and obesity. People with obesity had the significant ORs for sugar-sweetened beverages or SSB (OR 1.208; 95% CI 1.159 to 1.259), high-fat foods (OR 1.162; 95% CI 1.120 to 1.207) and snacks (OR 1.048; 95% CI 1.004 to 1.093), but had the significant protective ORs for meat products (OR 0.964; 95% CI 0.930 to 0.999), instant food (OR 0.903; 95% CI 0.865 to 0.942) and fast food (OR 0.871; 95% CI 0.831 to 0.913). People with any NCDs had the significant protective ORs for meat products (p≤0.001), instant food (p≤0.05) and fast food (p≤0.01). People with diabetes tended not to drink SSB while people with heart disease tended not to consume SSB and snacks. The findings suggest a need for prevention and control strategies such as promoting healthy snacking behaviour, modifying food environments and paying specific attention to the population most at risk of obesity and NCDs.
Assessing trends and variability in outpatient dual testing for chronic kidney disease with urine albumin and serum creatinine, 2009–2018: a retrospective cohort study in the Veterans Health Administration System
Authors: Bhave Nicole M , Han Yun , Steffick Diane , Bragg-Gresham Jennifer , Zivin Kara , Burrows Nilka R , Pavkov Meda E , Tuot Delphine , Powe Neil R , Saran Rajiv
Published: February 2024

Background

Simultaneous urine testing for albumin (UAlb) and serum creatinine (SCr), that is, ‘dual testing,’ is an accepted quality measure in the management of diabetes. As chronic kidney disease (CKD) is defined by both UAlb and SCr testing, this approach could be more widely adopted in kidney care.

Objective

We assessed time trends and facility-level variation in the performance of outpatient dual testing in the integrated Veterans Health Administration (VHA) system.

Design, subjects and main measures

This retrospective cohort study included patients with any inpatient or outpatient visit to the VHA system during the period 2009–2018. Dual testing was defined as UAlb and SCr testing in the outpatient setting within a calendar year. We assessed time trends in dual testing by demographics, comorbidities, high-risk (eg, diabetes) specialty care and facilities. A generalised linear mixed-effects model was applied to explore individual and facility-level predictors of receiving dual testing.

Key results

We analysed data from approximately 6.9 million veterans per year. Dual testing increased, on average, from 17.4% to 21.2%, but varied substantially among VHA centres (0.3%–43.7% in 2018). Dual testing was strongly associated with diabetes (OR 10.4, 95% CI 10.3 to 10.5, p<0.0001) and not associated with VHA centre complexity level. However, among patients with high-risk conditions including diabetes, <50% received dual testing in any given year. As compared with white veterans, black veterans were less likely to be tested after adjusting for other individual and facility characteristics (OR 0.93, 95% CI 0.92 to 0.93, p<0.0001).

Conclusions

Dual testing for CKD in high-risk specialties is increasing but remains low. This appears primarily due to low rates of testing for albuminuria. Promoting dual testing in high-risk patients will help to improve disease management and patient outcomes.
Correlation between allostatic load index and cumulative mortality: a register-based study of Danish municipalities
Authors: Bruun-Rasmussen Neda Esmailzadeh , Napolitano George , Bojesen Stig E , Ellervik Christina , Holmager Therese Lucia Friis , Rasmussen Knud , Lynge Elsebeth
Published: February 2024

Objectives

The aim of this study was to examine population-based allostatic load (AL) indices as an indicator of community health across 14 municipalities in Denmark.

Design

Register-based study.

Setting

Data derived from: the Lolland-Falster Health Study, the Copenhagen General Population Study and the Danish General Suburban Population Study. Nine biomarkers (systolic blood pressure, diastolic blood pressure, pulse rate, total serum cholesterol, high-density lipoprotein cholesterol, waist-to-hip ratio, triglycerides, C-reactive protein and serum albumin) were divided into high-risk and low-risk values based on clinically accepted criteria, and the AL index was defined as the average between the nine values. All-cause mortality data were obtained from Statistics Denmark.

Participants

We examined a total of 106 808 individuals aged 40–79 years.

Primary outcome measure

Linear regression models were performed to investigate the association between mean AL index and cumulative mortality risk.

Results

Mean AL index was higher in men (range 2.3–3.3) than in women (range 1.7–2.6). We found AL index to be strongly correlated with the cumulative mortality rate, correlation coefficient of 0.82. A unit increase in mean AL index corresponded to an increase in the cumulative mortality rate of 19% (95% CI 13% to 25%) for men, and 16% (95% CI 8% to 23%) for women but this difference was not statistically significant. The overall mean increase in cumulative mortality rate for both men and women was 17% (95% CI 14% to 20%).

Conclusions

Our findings indicate the population-based AL index to be a strong indicator of community health, and suggest identification of targets for reducing AL.
Mobile health biometrics to prescribe immediate remote physical activity for enhancing uptake to cardiac rehabilitation (MOTIVATE-CR+): protocol for a randomised controlled feasibility trial
Authors: Crozier Anthony , Cocks Matthew , Hesketh Katie , Miller Gemma , Mcgregor Gordon , Thomas Laura , Jones Helen
Published: February 2024

Introduction

Cardiac rehabilitation (CR) can reduce cardiovascular mortality and improve health-related quality of life. In the United Kingdom, patient uptake of CR remains low (52%), falling well short of the target in the 2019 National Health Service long-term plan (85%). Mobile health (mHealth) technologies, offering biometric data to patients and healthcare professionals, may bridge the gap between supervised exercise and physical activity advice, enabling patients to engage in regular long-term physically active lifestyles. This randomised controlled trial (RCT) will evaluate the feasibility of mHealth technology when incorporated into a structured home-based walking intervention, in people with recent myocardial infarction.

Methods and analysis

This is a feasibility, assessor blinded, parallel group RCT. Participants will be allocated to either CR standard care (control group) or CR standard care+mHealth supported exercise counselling (mHealth intervention group). Feasibility outcomes will include the number of patients approached, screened and eligible; the percentage of patients who decline CR (including reasons for declining), agree to CR and consent to being part of the study; the percentage of patients who enrol in standard CR and reasons for drop out; and the percentage of participants who complete clinical, physical and psychosocial outcomes to identify a suitable primary outcome for a future definitive trial.

Ethics and dissemination

The trial was approved in the UK by the Northwest—Greater Manchester East Research Ethics Committee (22/NW/0301) and is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results will be published in peer-reviewed journals and presented at national and international scientific meetings.

Trial registration numbers

NCT05774587
Community perspectives on the magnitude of Xeroderma pigmentosum and care-seeking practices in Micheweni district, Pemba: a mixed-methods cross-sectional study
Authors: Matemba Lucas E , Shayo Elizabeth H , Masemo Ame , Nassor Nahya K , Ally Mayassa S , Msovela Judith
Published: February 2024

Objectives

To determine the community’s perception on the magnitude of Xeroderma pigmentosum (XP) disease and healthcare-seeking practices in Micheweni, Pemba in response to the public widespread information on the increased burden of the disease.

Design

Mixed-methods cross-sectional study.

Setting

Micheweni district, Pemba.

Participants

211 male and female adults in the household survey, three caretakers/parents of patients with XP in the case study, 20 key community leaders/influential people and health workers in in-depth interviews and 50 community members and other leaders in six focus groups.

Results

This study has revealed that XP disease exists in few families of which some of them have more than one child affected. The record review showed that there were a total of 17 patients who were diagnosed with the disease for the past 3 years, however only 10 were alive during the time of the survey. Findings from the community members revealed that several patients were believed to have XP disease and perceived causes include inheritance, food types, beliefs and other sociocultural practices. Stigma and discrimination were reported by caretakers and religious leaders. However, some cases believed to be XP were identified as other skin conditions when clinical examination was performed by the team of our researchers. There is a great confusion about XP and other skin diseases.

Conclusion

The study has shown that XP affects only few families, hence termed as concentrated rather than a generalised disease. Due to the rareness of the disease, majority of people in the district are unaware of the disease, hence confusing it with other skin conditions. There is a need for the government in collaboration with other stakeholders to provide educational programme to community members about the disease to address the misconception about the magnitude of the disease.
Prevalence and drivers of nurse and physician distress in cardiovascular and oncology programmes at a Canadian quaternary hospital network during the COVID-19 pandemic: a quality improvement initiative
Authors: Jelen Ahlexxi , Rodin Gary , Graham Leanna , Goldfarb Rebecca , Mah Kenneth , Satele Daniel V , Elliot Mary , Krzyzanowska Monika K , Rubin Barry B
Published: February 2024

Objectives

To assess the prevalence and drivers of distress, a composite of burnout, decreased meaning in work, severe fatigue, poor work–life integration and quality of life, and suicidal ideation, among nurses and physicians during the COVID-19 pandemic.

Design

Cross-sectional design to evaluate distress levels of nurses and physicians during the COVID-19 pandemic between June and August 2021.

Setting

Cardiovascular and oncology care settings at a Canadian quaternary hospital network.

Participants

261 nurses and 167 physicians working in cardiovascular or oncology care. Response rate was 29% (428 of 1480).

Outcome measures

Survey tool to measure clinician distress using the Well-Being Index (WBI) and additional questions about workplace-related and COVID-19 pandemic-related factors.

Results

Among 428 respondents, nurses (82%, 214 of 261) and physicians (62%, 104 of 167) reported high distress on the WBI survey. Higher WBI scores (≥2) in nurses were associated with perceived inadequate staffing (174 (86%) vs 28 (64%), p=0.003), unfair treatment, (105 (52%) vs 11 (25%), p=0.005), and pandemic-related impact at work (162 (80%) vs 22 (50%), p<0.001) and in their personal life (135 (67%) vs 11 (25%), p<0.001), interfering with job performance. Higher WBI scores (≥3) in physicians were associated with perceived inadequate staffing (81 (79%) vs 32 (52%), p=0.001), unfair treatment (44 (43%) vs 13 (21%), p=0.02), professional dissatisfaction (29 (28%) vs 5 (8%), p=0.008), and pandemic-related impact at work (84 (82%) vs 35 (56%), p=0.001) and in their personal life (56 (54%) vs 24 (39%), p=0.014), interfering with job performance.

Conclusion

High distress was common among nurses and physicians working in cardiovascular and oncology care settings during the pandemic and linked to factors within and beyond the workplace. These results underscore the complex and contextual aspects of clinician distress, and the need to develop targeted approaches to effectively address this problem.
AI assisted reader evaluation in acute CT head interpretation (AI-REACT): protocol for a multireader multicase study
Authors: Fu Howell , Novak Alex , Robert Dennis , Kumar Shamie , Tanamala Swetha , Oke Jason , Bhatia Kanika , Shah Ruchir , Romsauerova Andrea , Das Tilak , Espinosa Abdalá , Grzeda Mariusz Tadeusz , Narbone Mariapaola , Dharmadhikari Rahul , Harrison Mark , Vimalesvaran Kavitha , Gooch Jane , Woznitza Nicholas , Salik Nabeeha , Campbell Alan , Khan Farhaan , Lowe David J , Shuaib Haris , Ather Sarim
Published: February 2024

Introduction

A non-contrast CT head scan (NCCTH) is the most common cross-sectional imaging investigation requested in the emergency department. Advances in computer vision have led to development of several artificial intelligence (AI) tools to detect abnormalities on NCCTH. These tools are intended to provide clinical decision support for clinicians, rather than stand-alone diagnostic devices. However, validation studies mostly compare AI performance against radiologists, and there is relative paucity of evidence on the impact of AI assistance on other healthcare staff who review NCCTH in their daily clinical practice.

Methods and analysis

A retrospective data set of 150 NCCTH will be compiled, to include 60 control cases and 90 cases with intracranial haemorrhage, hypodensities suggestive of infarct, midline shift, mass effect or skull fracture. The intracranial haemorrhage cases will be subclassified into extradural, subdural, subarachnoid, intraparenchymal and intraventricular. 30 readers will be recruited across four National Health Service (NHS) trusts including 10 general radiologists, 15 emergency medicine clinicians and 5 CT radiographers of varying experience. Readers will interpret each scan first without, then with, the assistance of the qER EU 2.0 AI tool, with an intervening 2-week washout period. Using a panel of neuroradiologists as ground truth, the stand-alone performance of qER will be assessed, and its impact on the readers’ performance will be analysed as change in accuracy (area under the curve), median review time per scan and self-reported diagnostic confidence. Subgroup analyses will be performed by reader professional group, reader seniority, pathological finding, and neuroradiologist-rated difficulty.

Ethics and dissemination

The study has been approved by the UK Healthcare Research Authority (IRAS 310995, approved 13 December 2022). The use of anonymised retrospective NCCTH has been authorised by Oxford University Hospitals. The results will be presented at relevant conferences and published in a peer-reviewed journal.

Trial registration number

NCT06018545.
Improving leadership skills of infection prevention and control teams by psychological empowerment: study protocol for a cluster randomised controlled trial (IP-POWER)
Authors: Keil Valentine , Schaumburg Tiffany , Buchta Frederike , Luz J Katrin , Kolbe-Busch Susanne , Chaberny Iris Freya , von Lengerke Thomas
Published: February 2024

Introduction

Infection prevention and control (IPC) teams are routinely confronted with intense emotions in their daily work, as they are involved in many change processes with front-line medical staff, for example, when promoting compliance with basic IPC measures. In addition, they are confronted with challenges due to their role as intermediaries. Based on former research, this study aims to empower IPC teams to promote clinicians’ compliance through interventions focusing on the IPC teams’ leadership skills.

Methods and analysis

The IP-POWER study (Infection Prevention with head and heart: Psychological empowerment of IPC teams), a multicentre, two-arm, non-blinded, cluster-randomised controlled trial with a parallel waiting control group, is planned to be conducted in Germany as of February to November 2024. A group of 10 voluntary hospitals is going to participate in a multistage intervention programme, including 2 days of intense psychological training; 5 hospitals will be randomly assigned to the waiting control group. After the workshops, there will be a 12-week follow-up period during which the contents learnt within the workshops can be applied and internalised into IPC practice. The proposed outcomes (both self-assessed and other-assessed leadership competencies of IPC team members and their task profiles, perceived workload, motivation to act in order to implement IP measures and goal attainment) are going to be collected with an online questionnaire, followed by an analysis with IBM SPSS (Statistics 29 (or later)) using descriptive analyses and multiple linear regressions. Additionally, as external data sources, hand hygiene compliance rates from the study hospitals’ monitoring systems will be analysed using χ² tests.

Ethics and dissemination

This study was reviewed and approved by the ethics committee of the University of Leipzig (184/23-ek; vote from 4 July 2023). Findings will be disseminated via peer-review publications, and national and international conference presentations.

Trial registration number

DRKS00031879.
Deployment of a human-centred clinical decision support system for pulmonary embolism: evaluation of impact on quality of diagnostic decisions
Authors: Altabbaa Ghazwan , Flemons Ward , Ocampo Wrechelle , Babione Julie Nathalie , Kaufman Jamie , Murphy Sydney , Lamont Nicole , Schaefer Jeffrey , Boscan Alejandra , Stelfox Henry T , Conly John , Ghali William A
Published: February 2024

Pulmonary embolism (PE) is a serious condition that presents a diagnostic challenge for which diagnostic errors often happen. The literature suggests that a gap remains between PE diagnostic guidelines and adherence in healthcare practice. While system-level decision support tools exist, the clinical impact of a human-centred design (HCD) approach of PE diagnostic tool design is unknown.

Design

Before–after (with a preintervention period as non-concurrent control) design study.

Setting

Inpatient units at two tertiary care hospitals.

Participants

General internal medicine physicians and their patients who underwent PE workups.

Intervention

After a 6-month preintervention period, a clinical decision support system (CDSS) for diagnosis of PE was deployed and evaluated over 6 months. A CDSS technical testing phase separated the two time periods.

Measurements

PE workups were identified in both the preintervention and CDSS intervention phases, and data were collected from medical charts. Physician reviewers assessed workup summaries (blinded to the study period) to determine adherence to evidence-based recommendations. Adherence to recommendations was quantified with a score ranging from 0 to 1.0 (the primary study outcome). Diagnostic tests ordered for PE workups were the secondary outcomes of interest.

Results

Overall adherence to diagnostic pathways was 0.63 in the CDSS intervention phase versus 0.60 in the preintervention phase (p=0.18), with fewer workups in the CDSS intervention phase having very low adherence scores. Further, adherence was significantly higher when PE workups included the Wells prediction rule (median adherence score=0.76 vs 0.59, p=0.002). This difference was even more pronounced when the analysis was limited to the CDSS intervention phase only (median adherence score=0.80 when Wells was used vs 0.60 when Wells was not used, p=0.001). For secondary outcomes, using both the D-dimer blood test (42.9% vs 55.7%, p=0.014) and CT pulmonary angiogram imaging (61.9% vs 75.4%, p=0.005) was lower during the CDSS intervention phase.

Conclusion

A clinical decision support intervention with an HCD improves some aspects of the diagnostic decision, such as the selection of diagnostic tests and the use of the Wells probabilistic prediction rule for PE.
Characterization of hydrocarbon degraders from Northwest Passage beach sediments and assessment of their ability for bioremediation
Authors: Lirette Antoine-O. , Chen Ya-Jou , Freyria Nastasia J. , Góngora Esteban , Greer Charles W. , Whyte Lyle G.
Published: February 2024

Global warming-induced sea ice loss in the Canadian Northwest Passage (NWP) will result in more shipping traffic, increasing the risk of oil spills. Microorganisms inhabiting NWP beach sediments may degrade hydrocarbons, offering a potential bioremediation strategy. In this study, the characterization and genomic analyses of 22 hydrocarbon-biodegradative bacterial isolates revealed that they contained a diverse range of key alkane and aromatic hydrocarbon-degradative genes, as well as cold and salt tolerance genes indicating they are highly adapted to the extreme Arctic environment. Some isolates successfully degraded Ultra Low Sulfur Fuel Oil (ULSFO) at temperatures as low as −5 °C and high salinities (3%–10%). Three isolates were grown in liquid medium containing ULSFO as sole carbon source over 3 months and variation of hydrocarbon concentration was measured at three time points to determine their rate of hydrocarbon biodegradation. Our results demonstrate that two isolates ( Rhodococcus sp. R1B_2T and Pseudarthrobacter sp. R2D_1T) possess complete degradation pathways and can grow on alkane and aromatic components of ULSFO under Arctic conditions. Overall, these results demonstrate that diverse hydrocarbon-degrading microorganisms exist in the NWP beach sediments, offering a potential bioremediation strategy in the events of a marine fuel spill reaching the shores of the NWP.
Simulation Research on High-Voltage β-Ga2O3 MOSFET Based on Floating Field Plate
Authors: Wang Wentao , Cai Yuncong , Tian Xusheng , Gao Huhu , Li Wenji , Lei Zhifeng , Zhang Chunfu , Feng Qian , Wang Zhengxing , Hao Yue
Published: February 2024

The simulation model of a depletion-mode (D-mode) β-Ga2O3 metal–oxide–semiconductor field-effect transistor (MOSFET) is constructed by Silvaco ATLAS technology computer-aided design (TCAD) simulation, which employs an epitaxial drift layer grown on a sapphire substrate. On this basis, the floating field plate (F-FP) structure based on the gate-pad-connected field plate (P-FP) is proposed to improve the breakdown characteristics of the device, which is easy to be prepared. The working principle of F-FP is investigated with the help of the device with one F-FP. Based on the principle that the number of floating field plates is increased on an optimized floating field plate structure. Subsequently, the devices with two and three floating field plates are simulated in turn, and the optimal structural parameters of the three F-FPs device are finally obtained, and the breakdown voltage is 3800 V at this time. In addition, it is found that the device breakdown voltage is increased by approximately 500–600 V for each additional floating field plate.
Influence of Al Doping on the Structural, Optical, and Electrical Characteristics of ZnMn2O4
Authors: Heiba Zein K. , Ghannam M. M. , Mohamed Mohamed Bakr , Sanad Moustafa M. S. , El-naggar A. M. , Shaltout Abdallah A.
Published: February 2024

Doped zinc manganite samples were synthesized using the sol-gel method, incorporating varying amounts of aluminum (ZnMn2-xAlxO4, x = 0, 0.03, 0.05, 0.07, 0.1). High quality X-ray diffraction data enabled detection and accurate quantification of the predominant phase ZnMn2O4 (ZMO) and minor phase ZnO. The structure and microstructure of developed phases were investigated applying the Rietveld refinement method. The nanoscale nature of the samples was examined by High-resolution transmission electron microscopy (HRTEM); the incorporation of Al into the ZMO matrix and the oxidation states of various cations were studied through X-ray photoelectron spectroscopy (XPS). The introduction of Al has resulted in a modification of the light-absorption characteristics of the ZMO sample. Specifically, the direct optical band gap energy of ZMO decreased from 2.45 to 2.25 eV with an increase in the amount of Al doping to 0.1. Moreover, an investigation was conducted into the impact of Al doping amount, frequency, and temperature on the dielectric constant, dielectric tangent loss, ac conductivity, complex impedance, and complex electric modulus. It was observed that all samples, except for the sample with x = 0.05, exhibited ferroelectric features. The activation energies for the samples with x = 0, 0.03, 0.05, 0.07, and 0.1 were determined to be 0.274, 0.456, 0.099, 0.103, and 0.152 eV, respectively. The conduction mechanism type in the different samples was identified. The obtained changes of dielectric properties indicated the capability of improving the ZMO characteristics for various applications via controlling the doping content of Al.
Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model
Authors: Kim Min Ji , Lee Hwi-Ho , Kim Choi , Lee Ja Yeon , Chung Kyung-Sook , Lee Kyung-Tae , Lee Jae Yeol
Published: February 2024

Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.
Damage Assessment of Low‐Velocity Impacted Sandwich Composite Structures Using X‐Ray Micro‐Computed Tomography
Authors: Chipanga Tendai , Nemraoui Ouassini , Ismail Fareed
Published: February 2024

Sandwich composite structures offer significant versatility in structural system design but are susceptible to low‐velocity impact damage, impacting their structural robustness. This study focused on nondestructive testing, particularly using X‐ray micro‐computed tomography, to assess damage on these structures, comprised of thin glass fibre reinforced polymer face sheets and a polyvinyl chloride foam core, under low‐velocity impacts. Impacts were induced by a constant mass of 5.61 kg, dropped from various heights, generating impact energies between 2 and 22 J. This resulted in varied damage levels, from indentations to full perforations. The X‐ray micro‐computed tomography technique was chosen for its ability to detect internal damage. However, the system’s efficacy in accurately assessing damage depends on numerous factors like focus‐to‐detector distance, focus‐to‐object distance, and spatial resolution of the detector, among others. The system yielded an approximated resolution range of 10–25 μm for a focal spot size of 4 μm and the resolution range of 11–26 μm for a spot size of 7 μm. To this end, the system was able to reveal damage inflicted across the specimen through captured and reconstructed images. The quality of the reconstructed images was validated using ImageJ2 software by comparing with the processed images. The median filter was found to deliver images that closely resembled the original ones, albeit with a slight reduction in quality. Damage types varied based on impact energies. Low‐level impacts caused matrix cracking and delamination at the foam interface. Medium‐level impacts led to intralaminar and interlaminar damage, fibre fractures, and significant damage to the foam core through shearing and crushing. High‐level impacts resulted in near or full perforations, with more pronounced delamination at the bottom interface, and fibre fractures in the impact zone, displaying a distinctive diamond‐like damage pattern. These findings can be instrumental in developing a predictive impact damage model.
Enhancing Fault Detection and Classification in MMC-HVDC Systems: Integrating Harris Hawks Optimization Algorithm with Machine Learning Methods
Authors: Hazim Hameed Hameed Omar , Kutbay Uğurhan , Rahebi Javad , Hardalaç Fırat , Mahariq Ibrahim
Published: February 2024

Accurate fault detection in high-voltage direct current (HVDC) transmission lines plays a pivotal role in enhancing operational efficiency, reducing costs, and ensuring grid reliability. This research aims to develop a cost-effective and high-performance fault detection solution for HVDC systems. The primary objective is to accurately identify and localize faults within the power system. In pursuit of this goal, the paper presents a comparative analysis of current and voltage characteristics between the rectifier and inverter sides of the HVDC transmission system and their associated alternating current (AC) counterparts under various fault conditions. Voltage and current features are extracted and optimized using a metaheuristic approach, specifically Harris Hawk’s optimization method. Leveraging machine learning (ML) and artificial neural networks (ANN), this technique demonstrates its effectiveness in generating a fault locator with exceptional accuracy. With a substantial volume of data employed for learning and training, the Harris Hawks optimization method exhibits faster convergence compared to other metaheuristic methods examined in this study. The research findings are applied to simulate diverse fault types and unknown fault locations at multiple system points. Evaluating the fault detection system’s effectiveness, quantified through metrics such as specificity, accuracy, F1 score, and sensitivity, yields remarkable results, with percentages of 99.01%, 98.69%, 98.64%, and 98.67%, respectively. This research underscores the critical role of accurate fault detection in HVDC systems, offering valuable insights into optimizing grid performance and reliability.
Higher Oxygen Content Affects Rabbit Meat’s Quality and Fatty Acid Profile in a Modified Atmosphere
Authors: Składanowska-Baryza Joanna , Kmiecik Dominik , Rudzińska Magdalena , Vissio Annalisa , Grygier Anna , Ludwiczak Agnieszka , Stanisz Marek
Published: February 2024

After 7 days of storage, the quality of the meat packed in both systems (MAP and VAC) was satisfactory; however, after 14 and 21 days, there was a noticeable decline in quality, as evidenced by changes in the water percentage and color parameters (L∗, a∗, and b∗). However, muscles stored in the MAP1 had the highest tenderness. The results indicated that as the storage time increased (up to 21 days), the share of C14:0 (P<0.001) and C16:0 (P<0.001) acids in the fat of the LTL muscles decreased. Only the share of C18:0 (P=0.001) and C20:1 (P=0.015) acids was significantly influenced by the packaging method. The highest iodine level was found in MAP1 21 days after packaging (85.68). The ratio of n-6/n-3, PUFA/SFA, AI, and TI indexes, which indicate a higher nutritional quality of fat, varied only with storage time without being affected by the gas mixture (P>0.05). The H/H level differed significantly with the storage time (P<0.001), with no effect of the gas mixture (P=0.133). After the 21-day storage period, the controlled atmosphere led to an increase in the concentration of MUFA and PUFA and a decrease in SFA, according to the study of the fatty acid profile.
Neutrophils Mediate Protection Against Colitis and Carcinogenesis by Controlling Bacterial Invasion and IL22 Production by γδ T Cells
Authors: Carnevale Silvia , Ponzetta Andrea , Rigatelli Anna , Carriero Roberta , Puccio Simone , Supino Domenico , Grieco Giovanna , Molisso Piera , Di Ceglie Irene , Scavello Francesco , Perucchini Chiara , Pasqualini Fabio , Recordati Camilla , Tripodo Claudio , Belmonte Beatrice , Mariancini Andrea , Kunderfranco Paolo , Sciumè Giuseppe , Lugli Enrico , Bonavita Eduardo , Magrini Elena , Garlanda Cecilia , Mantovani Alberto , Jaillon Sebastien
Published: February 2024

Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathologic contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r−/− mice) were used in classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histologic, cellular, and molecular analyses coupled with adoptive cell transfer. We also performed correlative analyses using human datasets. Csf3r−/− mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared with control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r−/− mice reverted the phenotype. In colitis, Csf3r−/− mice showed increased bacterial invasion and a reduced number of healing ulcers in the colon, indicating a compromised regenerative capacity of epithelial cells. Neutrophils were essential for γδ T-cell polarization and IL22 production. In patients with ulcerative colitis, expression of CSF3R was positively correlated with IL22 and IL23 expression. Moreover, gene signatures associated with epithelial-cell development, proliferation, and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL22-dependent tissue repair pathway.
Supplementary Table 4 from EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas
Authors: DuCote Tanner J. , Song Xiulong , Naughton Kassandra J. , Chen Fan , Plaugher Daniel R. , Childress Avery R. , Gellert Abigail R. , Skaggs Erika M. , Qu Xufeng , Liu Jinze , Liu Jinpeng , Li Fei , Wong Kwok-Kin , Brainson Christine F.
Published: February 2024

Supplementary Table 4 shows Gene Set Enrichment Analysis of differentially expressed mRNAs in combination-treated tumors vs. single agent-treated tumors for three major cell sub-clusters in the single cell RNA-sequencing.
Supplementary Figure 4 from EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas
Authors: DuCote Tanner J. , Song Xiulong , Naughton Kassandra J. , Chen Fan , Plaugher Daniel R. , Childress Avery R. , Gellert Abigail R. , Skaggs Erika M. , Qu Xufeng , Liu Jinze , Liu Jinpeng , Li Fei , Wong Kwok-Kin , Brainson Christine F.
Published: February 2024

Supplementary Figure 4 shows additional ChIP-sequencing data from human lung squamous cell carcinoma tumoroids.
Supplementary Figure 1 from EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas
Authors: DuCote Tanner J. , Song Xiulong , Naughton Kassandra J. , Chen Fan , Plaugher Daniel R. , Childress Avery R. , Gellert Abigail R. , Skaggs Erika M. , Qu Xufeng , Liu Jinze , Liu Jinpeng , Li Fei , Wong Kwok-Kin , Brainson Christine F.
Published: February 2024

Supplementary Figure 1 shows changes in NGFR and CD274 (PD-L1) gene and protein expression in human lung cancer cell lines in response to EZH2 inhibitor and interferon-gamma treatment.
FIGURE 6 from EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas
Authors: DuCote Tanner J. , Song Xiulong , Naughton Kassandra J. , Chen Fan , Plaugher Daniel R. , Childress Avery R. , Gellert Abigail R. , Skaggs Erika M. , Qu Xufeng , Liu Jinze , Liu Jinpeng , Li Fei , Wong Kwok-Kin , Brainson Christine F.
Published: February 2024

scRNA-seq highlights neutrophil heterogeneity shifts in response to EZH2 inhibition combined with immunotherapy. A, Annotated UMAP plot showing the 16 different populations within lung tumors of the Lkb1/Pten model of LSCC after treatment with placebo, GSK126, anti-PD1, or combined GSK126 with anti-PD1. B, Percentage of cells per treatment group graphed for all populations, # indicates adjusted P < 0.0012 by proportion z-test. C, GSEA depicting gene sets that are enriched or depleted in Tumor, Macrophage/Dendritic Cells, or Neutrophils in mice treated with EZH2 inhibitor and anti-PD1 contrasted with either treatment alone. Normalized enrichment scores are plotted and bubble sizes estimate FDR. See also Supplementary Table S2. D, Heat maps showing DEGs among tumor, macrophages, and dendritic cells, and neutrophils between GSK126, anti-PD1, and combination treated mice compared with placebo. E, UMAP of five neutrophil populations showing selected genes that are highly expressed in each cluster. See also Supplementary Fig. S6.
FIGURE 1 from EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas
Authors: DuCote Tanner J. , Song Xiulong , Naughton Kassandra J. , Chen Fan , Plaugher Daniel R. , Childress Avery R. , Gellert Abigail R. , Skaggs Erika M. , Qu Xufeng , Liu Jinze , Liu Jinpeng , Li Fei , Wong Kwok-Kin , Brainson Christine F.
Published: February 2024

EZH2 inhibition allows upregulation of MHCI and MHCII in 2D human LSCC cell lines. A, Schematic for proposed mechanism: Inhibition of EZH2 methyltransferase activity by the drugs GSK126 or EPZ6438 will lead to derepression of antigen presentation genes that can then be more effectively activated by IFNγ. B, qRT-PCR in the indicated four human lung cancer cell lines treated for 7 days with vehicle or 5 µmol/L EZH2 inhibition with 20 ng/mL IFNγ added on day 5 for the genes B2M, HLA-A, CIITA, and HLA-DRA, mean ± SEM is graphed, n = 4 individual cultures, *, P < 0.04; **, P < 0.008; ***, P < 0.0009; ****, P < 0.0001 by one-way ANOVA with pairwise comparisons and Holm-Šídák post hoc test. C, Flow cytometry analysis of indicated four human lung cancer cell lines treated for 7 days with vehicle or 5 µmol/L EZH2 inhibition with 20 ng/mL IFNγ added on day 5 for the cell surface proteins HLA-A,B,C and HLA-DR; mean ± SEM is graphed; n = 4 individual cultures; *, P < 0.04; **, P < 0.006; ***, P < 0.0009; ****, P < 0.0001 by one-way ANOVA with pairwise comparisons and Holm-Šídák's post hoc test. Representative histograms from HCC15 cell lines are shown, G = GSK126, E = EPZ6438, I = IFNγ, I+G = IFNγ+GSK126, and I+E = IFNγ+EPZ6438. D, Western blotting of A549 and HCC15 cell lines treated for 7 days with vehicle or 5 µmol/L EZH2 inhibition with 20 ng/mL IFNγ added on day 5 for the proteins B2M, HLA-DR, DQ, DP, EZH2, H3K27me3 and total histone H3. Data are representative of two individual cultures. See also Supplementary Fig. S1.
Identification of a New Enhancer That Promotes Sox9 Expression by a Comparative Analysis of Mouse and Sry-Deficient Amami Spiny Rat
Authors: Hirata Yurie , Mizushima Shusei , Mitsukawa Shoichiro , Kon Masafumi , Kuroki Yoko , Jogahara Takamichi , Shinohara Nobuo , Kuroiwa Asato
Published: February 2024

Introduction: Testis differentiation is initiated by the SRY gene on the Y chromosome in mammalian species. However, the Amami spiny rat, Tokudaia osimensis, lacks both the Y chromosome and the Sry gene and acquired a unique Sox9 regulatory mechanism via a male-specific duplication upstream of Sox9, without Sry. In general mammalian species, the SRY protein binds to a testis-specific enhancer to promote SOX9 gene expression. Several enhancers located upstream of Sox9/SOX9 have been reported in mice and humans. In particular, the binding of SRY to the highly conserved enhancer Enh13 is thought to be a common mechanism underlying testis differentiation and sex determination in mammals. Methods: Sequences of T. osimensis homologues of three Sox9 enhancers that were previously reported in mice, Enh8, Enh14, and Enh13, were determined. We performed in vitro assays to confirm enhancer activity involved in Sox9 regulation in T. osimensis. Results: T. osimensis Enh13 showed enhancer activity when co-transfected with NR5A1 and SOX9. Mouse Enh13 was activated by NR5A1 and SRY; however, T. osimensis Enh13 did not respond to SRY, even though the binding sites of SRY and NR5A1 were conserved. To identify the key sequence that is present in mouse but absent from T. osimensis, we performed reporter gene assays using vectors in which partial sequences of T. osimensis Enh13 were replaced with mouse sequences. For T. osimensis Enh13 in which the second half (approximately 430 bp) was replaced with the corresponding mouse sequence, activity in response to NR5A1 and SRY was recovered. Further, reporter assays revealed that multiple regions in the second half of the mouse Enh13 sequence are required for the response to NR5A1 and SRY. The latter 49 bp was particularly important and contained four binding sites for three transcription factors, POU2F1, HOXA3, and GATA1. Conclusion: We showed that there are unknown sequences responsible for the interaction between NR5A1 and SRY and mEnh13 based on comparative analyses of Sry-dependent and Sry-independent species. Our comparative analyses revealed new molecular mechanisms underlying mammalian sex determination.