bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetics of cellulase-free endo xylanase hyper-synthesis by Aspergillus Niger using wheat bran as a potential solid substrate
Authors: Ali Sikander , Noor Pakeeza , Ahmad Muhammad Usman , Khan Qaiser Farid , William Kaynat , Liaqat Iram , Shah Tawaf Ali , Alsahli Abdulaziz Abdullah , Younous Youssouf Ali , Bourhia Mohammed
Published: September 2024

The present study deals with the production of cellulase-free endoxylanase by Aspergillus niger ISL-9 using wheat bran as a solid substrate. Endoxylanase was produced under a solid-state fermentation. Various growth parameters were optimized for the improved production of the enzyme. The Substrate level of 15 g was optimized as it provided the fungus with balanced aeration and nutrition. Among the six moisture contents investigated, Moisture Content 5 (MC5) was optimized (g/l: malt extract, 10; (NH4)2HPO4, 2.5; urea, 1.0) and 10 mL of MC5 was found to give the highest production of endoxylanase. The pH and time of incubation were optimized to 6.2 and 48 h respectively. The Inoculum size of 2 mL (1.4 × 106 spores/mL) gave the maximum enzyme production. After optimization of these growth parameters, a significantly high endoxylanase activity of 21.87 U/g was achieved. Very negligible Carboxymethylcellulase (CMCase) activity was observed indicating the production of cellulase-free endoxylanase. The notable finding is that the endoxylanase activity was increased by 1.4-fold under optimized conditions (p ≤ 0.05). The overall comparison of kinetic parameters for enhanced production of endoxylanase by A. niger ISL-9 under Solid State Fermentation (SSF) was also studied. Different kinetic variables which included specific growth rate, product yield coefficients, volumetric rates and specific rates were observed at 48, 72 and 96 h incubation time and were compared for MC1 and MC5. Among the kinetic parameters, the most significant result was obtained with volumetric rate constant for product formation (Qp) that was found to be optimum (1.89 U/h) at 72 h incubation period and a high value of Qp i.e.1.68 U/h was also observed at 48 h incubation period. Thus, the study demonstrates a cost-effective and environmentally sustainable process for xylanase production and exhibits scope towards successful industrial applications.
Exploring early- and mid-career academic work wellbeing challenges through a diversity and inclusion lens
Authors: Piano Marianne , Jarden Rebecca J. , Hastings-Ison Tandy , Lawford Belinda J. , Diemer Kristin , Hui Flora , Kefalianos Elaina , McKibbin Gemma
Published: September 2024

Background

Early- to mid-career academics (EMCAs) represent a core component of the Australian higher education workforce. These academics experience major challenges to their wellbeing, driving a strong desire to leave academia.

Objectives

Determine (1) EMCA awareness of, and engagement with, previous University- and Faculty-level diversity and inclusion events/initiatives and (2) opportunities and solutions to address previously reported diversity and inclusion issues experienced in the workplace.

Methods

114 EMCAs in medicine, dentistry and health sciences completed an electronic cross-sectional survey. The survey contained a list of University- and Faculty-provided diversity and inclusion initiatives and sought respondent ratings of interest, awareness (knowing/hearing about) and engagement (attending/applying/participating). Two in-person focus groups comprising participants who opted in during the survey or who responded to broader advertising were conducted. Both groups explored opportunities and solutions to address diversity and inclusion issues reported in an earlier organisation-wide survey.

Results

Whilst early- and mid-career academics reported high interest in diversity and inclusion events, they also reported limited awareness and engagement with these events, feeling unsupported to engage or perceiving consequences for workload. Focus groups identified five themes related to opportunities and solutions to address diversity and inclusion issues experienced in the workplace (1) enhanced relational support for career progression, (2) clear and transparent processes for efficient working, (3) reducing structural barriers to create opportunity, (4) improved financial renumeration, and (5) improved transitions and pathways.

Conclusion

Early- and mid-career academics often felt unable to engage with activities outside of their immediate work responsibilities, such as events about diversity and inclusion, due to feelings of high workload. A systems approach to deploying targeted strategies to address these wellbeing challenges is recommended to sustain and retain this critical workforce.
Benefits of using virtual reality in cariology teaching
Authors: Hamama Hamdi , Harrison Ka Yan , Murbay Sukhdeep
Published: September 2024

Background

Virtual Reality (VR) has been widely used as an useful educational tool in modern dentistry and is considered as an alternative training tool adjunct to conventional training methods.

Objective

This study was designed to investigate the effectiveness of VR haptic-enhanced simulators for training undergraduate dental students during practical cariology pre-clinical caries excavation sessions.

Methods

A total number of 76 students were recruited for this study. Students were randomly divided into 2 groups (38 students each). The experimental group (VR-Start group), students performed caries removal at the VR haptic-enhanced simulator prior to practicing on natural extracted teeth. Conversely, the control group (Natural Tooth-Start Group), students exposed to VR simulation training after practicing on extracted natural teeth. An evaluation questionnaire was disseminated among students to evaluate their self-confidence, perceived clinical skills and their perception of providing better care to patients in the future. They were also invited to express their opinions on the usefulness of VR simulator in comparison with conventional learning methods.

Results

The outcome of Chi-square test showed no significant difference in students’ response among this study groups (p > 0.05). Moreover, the outcome of this study revealed that both student groups considered virtual reality as a useful learning tool. Majority of students (90%) superiorly ranked experience gained from practicing on natural carious teeth. They also clearly stated that virtual reality allowed them to practice more and improve their self-confidence level as well as eye-hand coordination.

Conclusions

Virtual reality simulator is a useful learning tool which can benefit undergraduate dental students at their pre-clinical stage; but, it cannot totally replace the conventional caries excavation.
MCQs in-training examination scores of the surgical residency program in Thailand: the relationship between medical school vs public health-based training institutions
Authors: Orrapin Saritphat , Homchan Ob-Uea , Chotirosniramit Narain , Jirapongcharoenlap Tidarat , Ditsatham Chagkrit
Published: September 2024

Background

This study aims at investigating and evaluating the categorical knowledge of residency using an internet-based examination.

Methods

All in-training examinees from 32 Thailand’s general surgery residency training institutions participating in the online examination. One hundred fifty Multiple Choice questions (MCQs) were selected for this examination from a pool of previous MCQs used for board certification examinations. Baseline chracteristic of the examinee including residency year, training institution (medical schools and public health-based training institutions), regional-based area of the institution, overall test score, scoring by subcategory, total time to complete the examination, and the length of accredited as a training centre time were collected and analysed.

Results

Total 613 examinees. The mean total score of 1st and 3rd year residency of a public health hospital institution differed from those with medical school-based training. On average, the scores in 4 out of 10 categories of residency from medical school training institutions were higher. However, residency from institutions with over 7 years of experience tended to score higher in the Liver, Biliary and Pancreas category.

Conclusions

The average scores of MCQs exams which reflect the medical knowledge for general surgical residency training at medical schools do not significantly differ from those of individuals undergoing public health training. Additionally, the mean scores of MCQs exams did not differ between high-experience training institutions and recent accredited training centers.
Lipoprotein(a) and risk-weighted apolipoprotein B: a novel metric for atherogenic risk
Authors: Rehman Michaela B. , Tudrej Benoit V.
Published: September 2024

Background

Retention of apolipoprotein B (apoB)-containing lipoproteins within the arterial wall plays a major causal role in atherosclerotic cardiovascular disease (ASCVD). There is a single apoB molecule in all apoB-containing lipoproteins. Therefore, quantitation of apoB directly estimates the number of atherogenic particles in plasma. ApoB is the preferred measurement to refine the estimate of ASCVD risk. Low-density lipoprotein (LDL) particles are by far the most abundant apoB-containing particles. In patients with elevated lipoprotein(a) (Lp(a)), apoB may considerably underestimate risk because Mendelian randomization studies have shown that the atherogenicity of Lp(a) is approximately 7-fold greater than that of LDL on a per apoB particle basis. In subjects with increased Lp(a), the association between LDL-cholesterol and incident CHD (coronary heart disease) is increased, but the association between apoB and incident CHD is diminished or even lost. Thus, there is a need to understand the mechanisms of Lp(a), LDL-cholesterol and apoB-related CHD risk and to provide clinicians with a simple practical tool to address these complex and variable relationships. How can we understand a patient’s overall lipid-driven atherogenic risk? What proportion of this risk does apoB capture? What proportion of this risk do Lp(a) particles carry? To answer these questions, we created a novel metric of atherogenic risk: risk-weighted apolipoprotein B.

Methods

In nmol/L: Risk-weighted apoB = apoB - Lp(a) + Lp(a) x 7 = apoB + Lp(a) x 6. Proportion of risk captured by apoB = apoB divided by risk-weighted apoB. Proportion of risk carried by Lp(a) = Lp(a) × 7 divided by risk-weighted apoB.

Results

Risk-weighted apoB agrees with risk estimation from large epidemiological studies and from several Mendelian randomization studies.

Conclusions

ApoB considerably underestimates risk in individuals with high Lp(a) levels. The association between apoB and incident CHD is diminished or even lost. These phenomena can be overcome and explained by risk-weighted apoB.
The link between gut microbiome, nutraceuticals, diet, and diabetes mellitus: a bibliometric and visual analysis of research and emerging trends from 2012 to 2022
Authors: Sarkar Aparajita , Khan Anfal Sher , Kaul Ridhima , Lee Surin , Kamal Ibtihal H. , Paul Pradipta , Laws Sa’ad , Chaari Ali
Published: September 2024

Purpose

The increasing prevalence of diabetes mellitus (DM) worldwide is a cause for global concern. Recent evidence suggests that the interaction between one’s diet and the gut microbiome are key modifiers of diabetes, highlighting the potential role of microbiome-modulating nutraceuticals. This bibliometric analysis examines literature published between 2012 and 2022 to explore trends in the latest research, with additional discussion on major takeaways and future directions.

Methods

We selected and analyzed 640 articles from an initial pool of 4,099 from Web of Science using Microsoft Excel 2016 and VOSviewer software (version 1.6.19).

Results

Our exploration uncovered the most commonly associated and influential journals, countries, study designs, experimental subjects, types of DM, organisms and nutraceuticals studied, and the most cited articles. We also noted the most cited publications across journals, organizations, and countries, along with the collaborative networks among authors, organizations and countries, and the co-occurrence of author keywords from the selection.

Conclusion

It is evident from the increasing number of publications each year that this field has attracted growing attention over the last decade. Nonetheless, continued research is essential to sustain this trend. Our overarching study of diabetes research marks steady progress in understanding the role—and potentially discovering applications—microbiome modulation to enhance metabolic pathways and health outcomes. Advancements in this field may lead to potential therapeutic applications for specific diets and nutraceuticals that modulate the gut microbiota in DM.
NX210c drug candidate peptide strengthens mouse and human blood-brain barriers
Authors: Greene Chris , Rebergue Nicolas , Fewell Gwen , Janigro Damir , Godfrin Yann , Campbell Matthew , Lemarchant Sighild
Published: September 2024

Background

Alterations of blood-brain barrier (BBB) and blood-spinal cord barrier have been documented in various animal models of neurodegenerative diseases and in patients. Correlations of these alterations with functional deficits suggest that repairing barriers integrity may represent a disease-modifying approach to prevent neuroinflammation and neurodegeneration induced by the extravasation of blood components into the parenchyma. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo.

Methods

In vitro, bEnd.3 endothelial cell (EC) monolayers and two different primary human BBB models containing EC, astrocytes and pericytes, in static and microfluidic conditions, were treated with NX210c (1-100 µM), or its vehicle, for 4 h and up to 5 days. Tight junction (TJ) protein levels, permeability to dextrans and transendothelial electrical resistance (TEER) were evaluated. In vivo, young and old mice (3- and 21-month-old, respectively) were treated daily intraperitoneally with NX210c at 10 mg/kg or its vehicle for 5 days and their brains collected at day 6 to measure TJ protein levels by immunohistochemistry.

Results

NX210c induced an increase in claudin-5 protein expression after 24-h and 72-h treatments in mouse EC. Occludin level was also increased after a 24-h treatment. Accordingly, NX210c decreased by half the permeability of EC to a 40-kDa FITC-dextran and increased TEER. In the human static BBB model, NX210c increased by ∼ 25% the TEER from 3 to 5 days. NX210c also increased TEER in the human 3D dynamic BBB model after 4 h, which was associated with a reduced permeability to a 4-kDa FITC-dextran. In line with in vitro results, after only 5 days of daily treatments in mice, NX210c restored aging-induced reduction of claudin-5 and occludin levels in the hippocampus, and also in the cortex for occludin.

Conclusions

In summary, we have gathered preclinical data showing the capacity of NX210c to strengthen BBB integrity. Through this property, NX210c holds great promises of being a disease-modifying treatment for several neurological disorders with high unmet medical needs.
A living critical interpretive synthesis to yield a framework on the production and dissemination of living evidence syntheses for decision-making
Authors: Mansilla Cristián , Wang Qi , Piggott Thomas , Bragge Peter , Waddell Kerry , Guyatt Gordon , Sweetman Arthur , Lavis John N.
Published: September 2024

Background

The COVID-19 pandemic has had an unprecedented impact in the global research production and has also increased research waste. Living evidence syntheses (LESs) seek to regularly update a body of evidence addressing a specific question. During the COVID-19 pandemic, the production and dissemination of LESs emerged as a cornerstone of the evidence infrastructure. This critical interpretive synthesis answers the questions: What constitutes an LES to support decision-making?; when should one be produced, updated, and discontinued?; and how should one be disseminated?

Methods

Searches included the Cochrane Library, EMBASE (Ovid), Health Systems Evidence, MEDLINE (Ovid), PubMed, and Web of Science up to 23 April 2024 and included articles that provide any insights on addressing the compass questions on LESs. Articles were selected and appraised, and their insights extracted. An interpretive and iterative coding process was used to identify relevant thematic categories and create a conceptual framework.

Results

Among the 16,630 non-duplicate records identified, 208 publications proved eligible. Most were non-empirical articles, followed by actual LESs. Approximately one in three articles were published in response to the COVID-19 pandemic. The conceptual framework addresses six thematic categories: (1) what is an LES; (2) what methodological approaches facilitate LESs production; (3) when to produce an LES; (4) when to update an LES; (5) how to make available the findings of an LES; and (6) when to discontinue LES updates.

Conclusion

LESs can play a critical role in reducing research waste and ensuring alignment with advisory and decision-making processes. This critical interpretive synthesis provides relevant insights on how to better organize the global evidence architecture to support their production.

Trial registration

PROSPERO registration: CRD42021241875.
Electroacupuncture inhibited carrageenan-induced pain aversion by activating GABAergic neurons in the ACC
Authors: Zhu Yichen , Sun Haiju , Xiao Siqi , Shen Zui , Zhu Xixiao , Wang Yifang , He Xiaofen , Liu Boyi , Jiang Yongliang , Liang Yi , Fang Janqiao , Shao Xiaomei
Published: September 2024

Pain aversion is an avoidance response to painful stimuli. Previous research has indicated that the anterior cingulate cortex (ACC) is involved in pain aversion processing. However, as interneurons, the role of GABAergic neurons in the ACC (GABAACC neurons) in pain aversion is still unclear. Electroacupuncture (EA) has been shown to ameliorate pain aversion, but the mechanism is not clarified. The present study provided evidence that inhibition of GABAACC neurons contributed to pain aversion. EA alleviated pain aversion by activating GABAACC neurons in an intensity-dependent manner. Specifically, 0.3 mA EA stimulation showed better effects on pain aversion than 0.1 mA stimulation, which could be reversed by chemical genetic inhibition of GABAACC neurons. These results provide a novel mechanism by which EA alleviates pain aversion by reversing GABAACC neurons.
The OBS UK Dashboard: an interactive tool for representative trial site selection to facilitate equality and diversity in maternity research
Authors: Elsmore Amy , Rai Tanvi , Pallmann Philip , Townson Julia , Kotecha Sarah , Black Mairead , Sanders Julia , Collis Rachel , Collins Peter , Karunakaran Bala , Wu Pensee , Bell Sarah , Parry-Smith William
Published: September 2024

Background

Obstetric Bleeding Study UK (OBS UK) (award ID: 152057) is a National Institute for Health and Care Research (NIHR)-funded stepped wedge cluster randomised controlled trial of a complex intervention for postpartum haemorrhage. This was developed in Wales and evaluated in a feasibility study, with improvements in maternal outcomes observed. Generalisability of the findings is limited by lack of control data and limited ethnic diversity in the Welsh obstetric patient population compared to the United Kingdom (UK): 94% of the Welsh population identifies as White, versus 82% in the UK. Non-White ethnicity and socioeconomic deprivation are linked to increased risk of adverse maternal outcomes. Traditionally, decisions regarding site selection are based on desire to complete trials on target in ‘tried and tested’ research active institutions. To ensure widespread applicability of the results and investigate the impact of ethnicity and social deprivation on trial outcomes, maternity units were recruited that represent the ethnic diversity and social deprivation profiles of the UK.

Method

Using routinely collected, publicly available data, an interactive dashboard was developed that demonstrates the demographics of the population served by each maternity unit in the UK, to inform site recruitment. Data on births per year, ethnic and socioeconomic group of the population for each maternity unit, across the UK, were integrated into the dashboard.

Results

The dashboard demonstrates that OBS UK trial sites reflect the ethnic and socioeconomic diversity of the UK (study vs UK population ethnicity: White 79.2% vs 81.7%, Asian 10.5% vs 9.3%, Black 4.7% vs 4.0%, Mixed 2.5% vs 2.9%, Other 3.0% vs 2.1%) with variation in site demography, size and location. Missing data varied across sites and nations and is presented.

Conclusion

The NIHR equality, diversity and inclusion strategy states studies must widen participation, facilitating individuals from all backgrounds to engage. The development of this novel interactive dashboard demonstrates an innovative way of achieving this. National Health Service (NHS) maternity researchers should consider using this tool to enhance diversity in research, address health disparities and improve generalisability of findings. This approach could be applied to healthcare settings beyond maternity care and across different global populations.

Trial registration

ISRCTN 17679951. Registered on August 30, 2023.
Mind the intention-behavior gap: a qualitative study of post-myocardial infarction patients’ beliefs and experiences with long-term supervised and self-monitored physical exercise
Authors: Svenningsen Alexander , Söderström Sylvia , Bucher Sandbakk Silvana , Gullestad Lars , Bønaa Kaare Harald , Wisløff Ulrik , Hollekim-Strand Siri Marte
Published: September 2024

Background

Many post-myocardial infarction (MI) patients struggle with physical activity behavior change (BC) for life-long secondary prevention. There is limited knowledge about factors influencing long-term physical activity BC among post-MI patients. This qualitative study aimed to explore the beliefs and experiences related to post-MI patients’ physical activity BC process following a year’s participation in a supervised and self-monitored exercise program: the Norwegian Trial of Physical Exercise After MI (NorEx).

Methods

We conducted a qualitative study, performing in-depth semi-structured interviews with a randomly selected sample of NorEx participants when they were scheduled for cardiopulmonary exercise testing after one year of participation. Interviews were transcribed verbatim and the data was analyzed by applying reflexive thematic analysis.

Results

Seventeen participants (n = 4 female [24%]; median age, 61 years; median time since index MI, 4 years) were recruited and interviewed once. Analysis resulted in four main themes (nine sub-themes): (1) Personal responsibility to exercise (Exercise is safe, Health benefits, Habitual exercise); (2) Peer social support for a sense of safety and belonging (Social exercise, Supervision is preferred); (3) Research participation transformed exercise beliefs (High-intensity exercise is superior, Personal Activity Intelligence (PAI) promotes exercise adherence); and (4) Mind the intention-behavior gap (Initial anxiety, Lack of continued follow-up).

Conclusions

Several participants reported that they were able to maintain exercise BC during a year’s participation in NorEx. Nevertheless, a perceived lack of continued and individualized follow-up made some participants struggle with motivation and self-regulation, leading to an intention-behavior gap. Therefore, our findings suggest there is a need for individualized and continued social support and supervision from health and exercise professionals to maintain long-term exercise BC for secondary prevention among post-MI patients.

Trial registration

The NorEx study has been registered at ClinicalTrials.gov (NCT04617639, registration date 2020-10-21).
Aerobic exercise and cognitive function in chronic severe traumatic brain injury survivors: a within-subject A-B-A intervention study
Authors: López Lidia Pérez , Coll-Andreu Margalida , Torras-Garcia Meritxell , Font-Farré Manel , Oviedo Guillermo R. , Capdevila Lluis , Guerra-Balic Myriam , Portell-Cortés Isabel , Costa-Miserachs David , Morris Timothy P.
Published: September 2024

Background

Following acute and sub-acute rehabilitation from severe traumatic brain injury (TBI), minimal to no efficacious interventions to treat ongoing cognitive deficits are available. Aerobic exercise is a non-invasive behavioral intervention with promise to treat cognitive deficits in TBI populations.

Methods

Six individuals, aged 24–62 years, with chronic (> 8 months since injury) severe (Glasgow Coma Scale of 3–8) TBI were recruited from two outpatient rehabilitation centers. In an A-B-A study design, 20-weeks of supervised aerobic exercise interventions were delivered three times per week (phase B) in addition to participants typical rehabilitation schedules (phases A). The effect of phase B was tested on a trail making test part B (primary outcome measure of executive function) as well as objective daily physical activity (PA), using both group level (linear mixed effect models) and single subject statistics.

Results

Five of six participants increased trail-making test part B by more than 10% pre-to-post phase B, with three of six making a clinically meaningful improvement (+ 1SD in normative scores). A significant main effect of time was seen with significant improvement in trail-making test part B pre-to-post exercise (phase B). No significant effects in other planned comparisons were found. Statistically significant increases in daily moderate-to-vigorous PA were also seen during phase B compared to phase A with three of six individuals making a significant behaviour change.

Conclusions

The addition of supervised aerobic exercise to typical rehabilitation strategies in chronic survivors of severe TBI can improve executive set shifting abilities and increase voluntary daily PA levels.

Trial registration

Retrospective trial registration on July 11 2024 with trial number: ISRCTN17487462.
Osthole attenuates asthma-induced airway epithelial cell apoptosis and inflammation by suppressing TSLP/NF-κB-mediated inhibition of Th2 differentiation
Authors: Li Yanli , Zhou Yushan , Liu Liqiong , Yang Yunfeng , Liu Yanhong , Yan Dailing , Chen Juyan , Xiao Yi
Published: September 2024

Objective

The aim of this study was to investigate the influence of osthole (OS) on asthma-induced airway epithelial cell apoptosis and inflammation by restraining Th2 differentiation through suppressing TSLP/NF-κB.

Methods

An asthma mouse model and an inflammation cell model were constructed with ovalbumin (OVA) and lipopolysaccharide (LPS), respectively. CD4 + T cells were treated with IL-4 to induce Th2 differentiation. Model mice were treated with OS (15,40 mg/kg) for 7 days, and 10 µg/mL OS was added to cell treatment groups. The levels of relevant indices were detected by RT‒qPCR, HE and Masson staining, Western blotting, ELISA and flow cytometry.

Results

In a mouse asthma model, TSLP expression was elevated, and the NF-κB pathway was activated. Therefore, OS could restrain the apoptosis and inflammation of airway epithelial cells. Downstream mechanistic studies revealed that OS can suppress Th2 differentiation by restraining the level of TSLP and NF-κB nuclear translocation, thus facilitating the proliferation of airway epithelial cells, restraining their apoptosis and inflammation, and alleviating airway inflammation in asthmatic mice.

Conclusion

OS can inhibit Th2 differentiation by inhibiting the TSLP and NF-κB pathways, which can reduce the apoptosis and inflammation of airway epithelial cells caused by asthma.
Development and characterization of reverse genetics systems of feline infectious peritonitis virus for antiviral research
Authors: Gu Guoqian , Fung To Sing , Hung Wong Tsz , Osterrieder Nikolaus , Go Yun Young
Published: September 2024

Feline infectious peritonitis (FIP) is a lethal, immune-mediated disease in cats caused by feline infectious peritonitis virus (FIPV), a biotype of feline coronavirus (FCoV). In contrast to feline enteric coronavirus (FECV), which exclusively infects enterocytes and causes diarrhea, FIPV specifically targets macrophages, resulting in the development of FIP. The transmission and infection mechanisms of this complex, invariably fatal disease remain unclear, with no effective vaccines or approved drugs for its prevention or control. In this study, a full-length infectious cDNA clone of the wild-type FIPV WSU79-1149 strain was constructed to generate recombinant FIPV (rFIPV-WT), which exhibited similar growth kinetics and produced infectious virus titres comparable to those of the parental wild-type virus. In addition, the superfold green fluorescent protein (msfGFP) and Renilla luciferase (Rluc) reporter genes were incorporated into the rFIPV-WT cDNA construct to generate reporter rFIPV-msfGFP and rFIPV-Rluc viruses. While the growth characteristics of the rFIPV-msfGFP virus were similar to those of its parental rFIPV-WT, the rFIPV-Rluc virus replicated more slowly, resulting in the formation of smaller plaques than did the rFIPV-WT and rFIPV-msfGFP viruses. In addition, by replacing the S, E, M, and ORF3abc genes with msfGFP and Rluc genes, the replicon systems repFIPV-msfGFP and repFIPV-Rluc were generated on the basis of the cDNA construct of rFIPV-WT. Last, the use of reporter recombinant viruses and replicons in antiviral screening assays demonstrated their high sensitivity for quantifying the antiviral effectiveness of the tested compounds. This integrated system promises to significantly streamline the investigation of virus replication within host cells, enabling efficient screening for anti-FIPV compounds and evaluating emerging drug-resistant mutations within the FIPV genome.
New insights into honey bee viral and bacterial seasonal infection patterns using third-generation nanopore sequencing on honey bee haemolymph
Authors: Van Herzele Cato , Coppens Sieglinde , Vereecke Nick , Theuns Sebastiaan , de Graaf Dirk C. , Nauwynck Hans
Published: September 2024

Honey bees are rapidly declining, which poses a significant threat to our environment and agriculture industry. These vital insects face a disease complex believed to be caused by a combination of parasites, viruses, pesticides, and nutritional deficiencies. However, the real aetiology is still enigmatic. Due to the conventional analysis methods, we still lack complete insights into the honey bee virome and the presence of pathogenic bacteria. To fill this knowledge gap, we employed third-generation nanopore metagenomic sequencing on honey bee haemolymph to monitor the presence of pathogens over almost a year. This study provides valuable insights into the changes in bacterial and viral loads within honey bee colonies. We identified different pathogens in the honey bee haemolymph, which are not included in honey bee screenings. These pathogens comprise the Apis mellifera filamentous virus, Apis rhabdoviruses, and various bacteria such as Frischella sp. and Arsenophonus sp. Furthermore, a sharp contrast was observed between young and old bees. Our research proposes that transgenerational immune priming may play a role in shaping infection patterns in honey bees. We observed a significant increase in pathogen loads in the spring, followed by a notable decrease in pathogen presence during the summer and autumn months. However, certain pathogens seem to be able to evade this priming effect, making them particularly intriguing as potential factors contributing to mortality. In the future, we aim to expand our research on honey bee transgenerational immune priming and investigate its potential in natural settings. This knowledge will ultimately enhance honey bee health and decrease colony mortality.
Colchicine, serotobenine, and kinobeon A: novel therapeutic compounds in Carthamus tinctorius L. for the management of diabetes
Authors: Hanif Samina , Shahzadi Zainab , Anjum Irfan , Yousaf Zubaida , Aftab Arusa , Javed Sana , Maqboo Zainab , Ullah Riaz , Iqbal Zafar , Raza Muhammad Ahmer
Published: September 2024

Diabetes, a global health concern, poses increasing mortality risks. The pathogenesis of diabetes involves multiple mechanisms, with oxidative stress being one of the key contributors. As synthetic drugs have various side effects, which can be minimized by using herbal plants. This study focuses on the In vitro antioxidant potential, α-amylase inhibition potential, identification of bioactive compounds, and hub genes in diabetes treatment mechanism by using C. tinctorius Extraction of C. tinctorious lead and flower was performed using different solvents (Distilled water, methanol, chloroform, and Dimethyl ether). After extraction different concentrations range from 25–200 mg/mL) was made and checked against activities. The antioxidant potential was assessed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH), total phenolic contents (TPC), and total antioxidant capacity (TAC) assays, while antidiabetic activity was evaluated through α-amylase inhibition assay. Phytochemicals was identified by GC–MS analysis, followed by ADMET screening and network pharmacology analysis using Swiss Target Prediction, Gene Card, DesGeNet, DAVID, STRING, Cytoscape, and drug revitalization databases. Results revealed positive correlations with DPPH, TAC, and TPC. Methanol extract exhibited the highest inhibitory concentration. Screening of 46 compounds was performed by studying their pharmacokinetic properties which revealed 9 compounds effective against 204 diabetes targets. Moreover, their network analysis identified four hub genes, including AKT1, JUN, EGFR, and MMP9. These genes found highly associated with drugs like Colchicine and Serotobenine. Revitalization analysis also highlighted four genes (EGFR, PTGS2, AKT1, and MMP9) strongly correlated with FDA-approved drugs. The study suggests C. tinctorius methanol extract is a potential source for novel drugs.

Graphical Abstract
Targeting hepcidin in colorectal cancer triggers a TNF-dependent-gasdermin E-driven immunogenic cell death response
Authors: Di Grazia Antonio , Franzè Eleonora , Frascatani Rachele , Laudisi Federica , Pacifico Teresa , Tomassini Lorenzo , Di Fusco Davide , Formica Vincenzo , Sica Giuseppe , Stolfi Carmine , Monteleone Ivan , Monteleone Giovanni
Published: September 2024

Interactions between colorectal cancer (CRC) cells and the noncancerous cells in the tumor microenvironment (TME) induce mechanisms for the escape of tumor cells from immune attack. Hepcidin, a peptide that controls immune cell functions, is overproduced by CRC cells. This study aimed to evaluate whether hepcidin acts as a regulator of anti-tumor immunity in CRC. Hepcidin silencing in CRC cells was followed by enhanced TNF-driven caspase-dependent cleavage of GSDM E and death. Mice engrafted with hepcidin-deficient CT26 cells developed fewer and smaller tumors than control mice as a result of the action of tumor-infiltrating CD8+ T lymphocytes and were protected from the development of tumors in a vaccination model and exhibited long-lasting tumor protection. Additionally, hepcidin deficiency enhanced the response of mice bearing CT26-derived tumors to anti-PD-1 therapy. These results suggest that targeting hepcidin in CRC cells enhances the production of TNF thereby triggering a caspase/GSDM E-driven lytic cell death with the downstream effect of boosting a robust immune response against tumor antigens.
Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment
Authors: Lenk Hasan Çağın , Koch Elise , O’Connell Kevin S. , Smith Robert Løvsletten , Akkouh Ibrahim A. , Djurovic Srdjan , Andreassen Ole A. , Molden Espen
Published: September 2024

Background

Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively.

Results

We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively.

Conclusions

We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.
Functional heterogeneity of cancer-associated fibroblasts with distinct neoadjuvant immunotherapy plus chemotherapy response in esophageal squamous cell carcinoma
Authors: Jiang Jun , Xu Chao , Han Donghui , Lu Yuan , Yang Fa , Wang Jiawei , Yan Xiaolong , Mu Xiaorong , Zhang Jipeng , Jia Chenghui , Xu Xinyao , Liu Kui , Liu Zhenhua , Gong Li , Wan Yi , Lu Qiang
Published: September 2024

Novel neoadjuvant immunotherapy combined with chemotherapy (neoICT) has improved outcomes for patients with esophageal squamous-cell carcinoma (ESCC), but challenges persist in low response rates and therapy resistance. Little is known about the intra-tumoral heterogeneity in the ESCC tumor microenvironment (TME) that underlies differential responses to neoadjuvant therapy. We applied single-cell RNA sequencing (scRNA-seq) profiling and multiplexed immunofluorescence staining to thoroughly decipher the TME in ESCC specimens from a neoadjuvant anti-PD1 combination therapy clinical trial. The cancer-associated fibroblasts (CAFs) population showed the significant alteration in abundance following neoadjuvant therapy. Specifically, IL6 + CCL2 + immunomodulatory CAFs and a novel CD248 + mechanoresponsive CAFs subset exhibited increasing infiltration. Mechanistically, CD248 + mechanoresponsive CAFs approached and lined the tumor nest to physically block the infiltration of CD8 + T cells and drug delivery, while IL6 + CCL2 + immunomodulatory CAFs induced therapeutic resistance with distinct IL-6 expression. Among patients treated with neoICT, we observed prominent CAF-T cell interactions. In particular, the NECTIN2-TIGIT ligand-receptor pair was enriched in treated samples, and TIGIT was identified as the major inhibitory checkpoint of T cells. Our findings demonstrate distinct alterations in TME constituent responses to neoadjuvant immunotherapy and identify functional phenotypes of CAFs associated with unfavorable therapeutic responses in patients. This provides potential targets to enhance responses to neoadjuvant therapy in ESCC.
Spatial distribution characteristics of Tibetan Buddhism principal-subordinate monastery systems in the Hehuang region
Authors: Li Weijia , Liu Tongtong , Liu Huanjie , Li Yuan , Li Shuangying , Zhang Yue
Published: September 2024

Tibetan Buddhist monasteries constitute significant cultural heritages of ethnic minorities, evolving into the Principal-Subordinate Monastery System (PSMS) with profound historical and cultural significance. This system exhibits an integrated hierarchical structure in terms of religious dominance, political administration, and cultural diffusion. Existing research primarily focuses on internal humanistic factors such as governance patterns, while there is not any research focused on its patterns and manifestations in spatial distribution. This study aims to elucidate the spatial distribution characteristics of the PSMS in Hehuang region, including the Tibetan Buddhist monasteries from all sects in the Hehuang region since the Song Dynasty It establishes a hierarchical PSMS database based on the affiliation relationships, aimed at storing spatial and property information related to PSMS. The database standardizes the naming and coding of monasteries, and classifies them through hierarchical relationships to ensure data consistency and usability. Finally, the classified and coded monastery data were analyzed by GIS tools to form the PSMS spatial distribution characterisation framework. Results reveal that (1) Monasteries demonstrate notable spatial clustering patterns from both holistic and sectarian perspectives, with density being influenced by the principal monastery’s position. (2) Almost every PSMS exhibits a spatial pattern centered around the principal monastery, with subordinate monasteries clustering within a defined range correlated with the administrative region of the principal monastery. (3) PSMS scale variations are controlled by principal monasteries, exhibiting positive correlations in hierarchical structure, control quantity, and distribution range. (4) The spatial orientation of PSMS correlates with river distribution, while the relationships among mountain ranges require further investigation. These findings provide initial insights into the spatial distribution characteristics of PSMS, confirming the spatial influence of the principal monastery. Besides, this study established an innovative spatial research framework for heritage clusters with multiple types and hierarchies. Thus, this study offers new insights into the spatial distribution of Tibetan Buddhist monastery heritage and presents a framework for further examining the spatial distribution of the Tibetan Buddhist monastery heritage in other regions, as well as other heritage clusters where connected and clustered through religious and cultural ties.
Predicting intradialytic hypotension in critically ill patients undergoing intermittent hemodialysis: a prospective observational study
Authors: da Hora Passos Rogério , Coelho Fernanda Oliveira , Caldas Juliana Ribeiro , dosde Santos GalvãoMelo Erica Batista , de Carvalho Farias Augusto Manoel , Messeder Octávio Henrique Coelho , Macedo Etienne
Published: September 2024

Background

Hypotension during dialysis arises from vasomotor tone alterations and hypovolemia, with disrupted counterregulatory mechanisms in acute kidney injury (AKI) patients. This study investigated the predictive value of preload dependency, assessed by the passive leg raising (PLR) test, and arterial tone, measured by dynamic elastance (Eadyn), for intradialytic hypotension (IDH).

Methods

In this prospective observational study conducted in a tertiary hospital ICU, hemodynamic parameters were collected from critically ill AKI patients undergoing intermittent hemodialysis using the FloTrac/Vigileo system. Baseline measurements were recorded before KRT initiation, including the PLR test and Eadyn calculation. IDH was defined as mean arterial pressure (MAP) < 65 mmHg during dialysis. Logistic regression was used to identify predictors of IDH, and Kaplan–Meier analysis assessed 90-day survival.

Results

Of 187 patients, 27.3% experienced IDH. Preload dependency, identified by positive PLR test, was significantly associated with IDH (OR 8.54, 95% CI 5.25–27.74), while baseline Eadyn was not predictive of IDH in this cohort. Other significant predictors of IDH included norepinephrine use (OR 16.35, 95% CI 3.87–68.98) and lower baseline MAP (OR 0.96, 95% CI 0.94–1.00). IDH and a positive PLR test were associated with lower 90-day survival (p < 0.001).

Conclusions

The PLR test is a valuable tool for predicting IDH in critically ill AKI patients undergoing KRT, while baseline Eadyn did not demonstrate predictive value in this setting. Continuous hemodynamic monitoring, including assessment of preload dependency, may optimize patient management and potentially improve outcomes. Further research is warranted to validate these findings and develop targeted interventions to prevent IDH.
Obstacle avoidance shape control of deformable linear objects with online parameters adaptation based on differentiable simulation
Authors: Ying Changjian , Yamazaki Kimitoshi
Published: September 2024

The manipulation of deformable linear objects (DLOs) such as ropes, cables, and hoses by robots has promising applications in various fields such as product assembly and surgical suturing. However, DLOs are more difficult to manipulate than rigid objects because their shape changes during manipulation. Furthermore, preventing a DLO from colliding with the environment is important to prevent it from becoming entangled and causing shape control to fail. In this paper, we proposed an obstacle avoidance and shape control scheme for DLOs based on differentiable simulation that does not require prior data or a specialized controller. First, we established a dynamic model of the DLO that allows for both forward dynamics transfer and error backpropagation to obtain gradients. Then, we employed model predictive control to optimize the embedded neural network for predicting the actions that would manipulate the DLO. Finally, the control scheme was made applicable to DLOs with different material properties by allowing online adaptation of the model parameters essential to deformation during manipulation. Simulations and real-world experiments demonstrate that the proposed control scheme could manipulate the DLO stably and accurately to avoid obstacles and achieve the goal state. In addition, the online adaptation of parameters helped mitigate the sim-to-real gap.