bluuebunny/crossref_metadata_2025 huggingface dataset:
Solubilizer tag effect on PD-L1/inhibitor binding properties for m-terphenyl derivatives
Authors: Surmiak Ewa , Ząber Julia , Plewka Jacek , Wojtanowicz Grzegorz , Kocik-Krol Justyna , Kruc Oskar , Muszak Damian , Rodríguez Ismael , Musielak Bogdan , Skalniak Lukasz , Magiera-Mularz Katarzyna , Holak Tad A. , Kalinowska-Tłuścik Justyna
Published: May 2023

Although heavily studied, the subject of anti-PD-L1 small molecular inhibitors is still elusive. Here, we present a systematic overview of principles behind the successful anti-PD-L1 small molecule inhibitor design on the example of the m-terphenyl scaffold with a particular focus on the neglected influence of the solubilizer tag on the overall affinity towards PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation in HTRF and cell-based assays. The affinity is also explained based on the crystal structure of the inhibitor itself, its co-structure with PD-L1 as well as molecular modeling study. Our results structuralize the knowledge related to the strong pharmacophore feature of the m-terphenyl scaffold preferential geometry and the more complex role of the solubilizer tag in PD-L1 homodimer stabilization.
Construction of Crushed Brick Column Reinforcement as A Sustainable Ground Improvement Technique
Authors: Ng Jun Shen , Hasan Muzamir , Low Yong Ler
Published: May 2023

This researcher investigates the efficiency of crushed brick for reinforcing the soft kaolin by applying the stone column technique. The use of this material complies with sustainability concept and it is cost-effective. The construction of stone column can be done using the vibro-replacement method, where the researchers demonstrated the combination of crushed brick into the soft clay soil. Related geotechnical laboratory works were implemented for determining the properties of crushed brick and kaolin clay. The shear strength parameters were accessed from Unconfined Compression Test (UCT) using 21 samples at different design. Each design has 3 samples, including control sample used, three (3) samples of 10 mm diameter, three (3) samples of 16 mm diameter crushed brick column and they were analysed in different height comprising 60 mm, 80 mm, and 100 mm respectively. The results of shear strength improvement from diameter of 10 mm column with height penetrating ratio of 1.0, 0.6 and 0.8 were 13.33%, 12.31% and 9.79% respectively. While for 16 mm column diameter with height penetrating ratio of 1.0 showing the highest, 16.10% followed by 0.6 and 0.8 indicating 13.49% and 11.35% respectively. Conclusively, the improvement of shear strength of kaolin clay relies on the design of crushed brick column reinforcement.
Revision Total Knee replacement finances: a detailed cost-analysis of operative practice at a regional tertiary referral centre
Authors: Alexiadis Aris , Reynolds Patrick , Al-Mouazzen Louay , Toms Andrew , Phillips John , Waterson Ben
Published: May 2023

Background:
The revision knee complexity classification (RKCC) stratifies knee revision operations depending on their level of complexity from simple revisions (R1) to highly complex cases (R3). Current financial codes used for calculation of reimbursement for knee revision services provided at the Trust, rely on patients’ comorbidities. However, previous research has demonstrated that this approach may not yield an accurate financial account of knee revision arthroplasty cost. This is a single centre study from a secondary and tertiary revision unit, with work previously presented by the authors demonstrating that the majority of complex revision knee replacement within the region, take place in this unit. The aims of this study were to illustrate the current cost profile and renumeration service currently in place for revision knee and show the differences in cost based on complexity of the operation.
Methods:
In this retrospective study, 89 cases who underwent revision knee operations in 2019 were analysed. Data was obtained from a tertiary referral centre where the episodes had occurred. Mean cost, tariff, and subsequent deficit were calculated for the R1, R2 and R3 episodes.
Results:
R2 and R3 episodes were significantly more expensive than R1 episodes. The increase in cost between R3 and R2 episodes was not significant. The total cost of the revision operations was £1,162,343. Tariffs received for R2 and R3 revision operations were significantly more expensive than R1 operations. However, the increase in tariffs received for R3 operations was not significant in relation to R2 operations. The total amount of tariffs received by the Trust was £ 770,996 generating a net deficit of - £ 391,347.
Conclusion
Current financial coding for revision knee does not accurately predict costs associated with revision knee surgery. Net deficit varies depending on the RKCC grade of the knee revision episode with more complex operations resulting in a higher mean net deficit. Implementation of the RKCC could prove to be a useful tool in generating an accurate prediction of the cost associated with knee revision surgery.
Examining the Relationship Between Borderline Personality Traits and Eating Attitudes, and Guilt and Shame
Authors: FARAJI Haydeh , Oğur Songül
Published: May 2023

Background:This study examines the relationship between borderline personality traits, eating attitudes, and guilt and shame.In the literature, although there are separate studies on borderline personality traits, eating attitudes, guilt, and shame, examining the relationship between the three concepts is limited. Therefore, this study aims to address this gap and is considered critical scientific data for mental health professionals in the clinical field.Method: The research was conducted among 213 female (53.1%) and 187 male (46.8%) undergraduate students aged 18-24 studying in Istanbul. Participants were informed about the study, and their informed consent was obtained. Participants were selected by convenience sampling method. The research was shared with the participants face-to-face and via Google Forms. "Socio-Demographic Information Form," "Borderline Personality Questionaire (BPQ)," "Offence-Related Shame and Guilt Scale (ORSGS)," and "Eating Attitude Test Short Form (EAT-26)" were used within the scope of the study. Statistical analyses were transferred to the SPSS 25 program. "Pearson Correlation Analysis," "Independent Groups T-Test," and “ANOVA” were used in the analysis of the data obtained. PROCESS 3.5 was used for mediator role analysis.Results:A significant positive correlation was found between shame and borderline personality traits, affect indecision, self-image, sense of emptiness, and intense anger. A significant positive correlation was found between bulimia and preoccupation with eating and borderline personality traits impulsivity sub-variables.Conclusions:At the end of the study, it was seen that the borderline personality traits, shame, and guilt variables were significantly related to each other. Borderline personality traits and eating attitudes have been found to have a semi-intermediate role in their relationship with shame. It is recommended that clinicians assess self-conscious emotions in clients with eating disorders and explore the possible origin and significance of these effects. This recommendation will likely facilitate the therapy and treatment process.
Efficient and fast screening and separation based on computer aided screening and complex chromatography method for 5-lipoxygenase inhibitors from Poria cocos
Authors: Wu Tong , Hou Wanchao , Li Sainan , Liu Chunming , Zhang Yuchi
Published: May 2023

Poria cocos (Schw.) Wolf (P. cocos) is a traditional Chinese medicinal materia that medicine food homologyl. In this study, based on the β-Amyloid deposition hypothesis of AD, a fast and efficient methods that ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) and molecular docking were developed for the rapid screening and identification of anti-5-lipoxygenase (anti-5-LOX) enzyme active ingredient of P. cocos ethyl acetate extract. Continuous counter-current chromatography (CCC) combined with semi-preparative high performance liquid chromatography (Semi-preparative HPLC) was developed for targeted separation of active components. Five potential 5-LOX inhibitors were screened by ultrafiltration affinity assay in P. cocos. The molecular docking simulation results are consistent with the ultrafiltration experimental results, which further verifies the accuracy of the experiment. Subsequently, five high-purity active ingredients (Tumulosic acid, Polyporenic acid C, 3-Epi-dehydrotumulosic acid, Pachymic acid and Dehydrotrametenolic acid) could be isolated by the established separation method, with the purities of 95.86%, 96.35%, 97.22%, 98.43% and 99.00%, respectively. The established continuous countercurrent chromatography can effectively improve the yield and purity of low content active ingredients in traditional Chinese medicine, and provide ideas and methods for the targeted separation of active ingredients. The methods of screening and isolating active ingredients established in this paper will be helpful for the development of new therapeutic drugs for Alzheimer's disease (AD).
The prognostic nutritional index predicts prognosis after liver resection in elderly patients with early-stage hepatocellular carcinoma
Authors: Hu YaFei , Ma Wen-Jie , Gu Han-Fei , Hu Hai-Jie , Wang Jun-Ke , Liu Fei , Lv Tian-Run , Yang SiQi , Dai Yu-Shi , Zou Rui-Qi , Li Fu-Yu
Published: May 2023

Aims
We aimed to determine the value of the preoperative prognostic nutritional index (PNI) and establish new nomograms to predict recurrence-free and overall survival (RFS and OS) in elderly patients with early-stage hepatocellular carcinoma (HCC).
Methods
Elderly patients (≥ 60 years of age) with very early-stage HCC (CNLC IA-IIA) after curative surgical resection were identified. PNI was calculated by [10 × serum albumin level (gr/dL)] + [0.005 × total lymphocyte count (per mm3)]. Univariate and multivariate Cox analysis was used to screen the variables and construct the nomogram model. ROC and calibration curves were used for model evaluation.
Results
The PNI-high was defined as ≥ 49.5 and ≥ 49.05 for RFS and OS, respectively. The 5-year-RFS rate was 34.1% in the PNI-low group versus 57.4% in the PNI-high group (P = 0.014). The 5-year OS rate in the PNI-low group was significantly lower than that in the PNI-high groups (68.2% vs. 84.4%, P = 0.033). The nomogram prediction models for patients’ RFS and OS were built by incorporating the same three independent survival predictors, including PNI-low, tumor presence of vascular invasion, and low differentiation. These two prediction models demonstrated good calibration and discrimination, with all C‑indexes greater than 0.72. The calibration plots basically coincide with the diagonal, indicating that the observed RFS and OS were close to the predicted outcomes.
Conclusions
The PNI-low, tumor presence of vascular invasion, and low differentiation can be adopted as a decision aid to predict the long-term RFS and OS for elderly patients with resected HCC.
Self-determination: A utopia in frail older people with decreased cognition?
Authors: Hammar Isabelle Andersson , Westgård Theresa , Dahlin-Ivanoff Synneve , Wilhelmson Katarina
Published: May 2023

Background
Self-determination in old age is essential for people’s experiences of good subjective health and quality of life. The knowledge concerning how frail older people with decreased cognition perceive their ability to be self-determined in the different dimension in daily life is, however, limited. The aim of this study was therefore to explore the relationship of self-determination and cognition in frail older people.
Methods
This study was a cross-sectional secondary data analysis using baseline data from a larger CGA-Swed randomized control trial with frail people 75≥. In this study, a total of 119 people responded to the self-determination assessment Impact on Participation and Autonomy-Older persons (IPA-O). The data was analysed with the Fisher’s exact test to test differences in proportions of perceived self-determination. Decreased cognition was broadly defined as a score below 25 points on the Mini Mental State Examination (MMSE). The Relative Risk (RR) with a 95% Confidence Interval (CI) was used to explore the risk of perceiving reduced self-determination.
Results
High degree of self-determination was identified in Financial situation, 94 per cent among participants with intact cognition respectively 92 per cent among those with decreased cognition. Regardless of cognition, approximately a third of the sample perceived low levels of self-determination in Mobility and in Social relationships. For people with decreased cognition, the relative risk for perceiving reduced self-determination was statistically significant higher in activities related to Self-care (item 6, p = 0.044, RR = 2.38), and in Social relationship (item 16, p = 0.041, RR = 3.71) when comparing with the participants with intact cognition.
Conclusion
Perceiving self-determination when being old, frail and having decreased cognition is possible but is dependent upon which activities that are involved. For increased perceptions of self-determination, healthcare needs should be carried out according to older people’s wants and wishes. Frail older people with decreased cognition should be treated as being experts in their own lives, and healthcare professionals should be enablers in supporting the older people to navigate them in reaching their desired direction.
Trial registration:
ClinicalTrials.gov, NCT02773914. Retrospectively registered 16 May 2016.
Synergistic efficacy of repetitive peripheral magnetic stimulation on central intermittent theta burst stimulation for upper limb function in patients with chronic stroke: a double-blinded, randomized controlled trial
Authors: Chang Chi-Shou , Chen Chia-Ling , Chen Rou-Shayn , Chen Hsieh-Ching , Chen Chung-Yao , Chung Chia-Ying , Wu Pei-Hsuan , Wu Ching-Yi , Lin Keh-Chung
Published: May 2023

Background: Non-invasive techniques such as central intermittent theta burst stimulation (iTBS) and repetitive peripheral magnetic stimulation (rPMS) have shown promise to improve motor function for stroke patients. However, the combined efficacy of rPMS and central iTBS has not been extensively studied. This randomized controlled trial aimed to investigate the synergistic effects of rPMS on central iTBS in patients with stroke.
Method: In this study, 28 stroke patients were randomly allocated to receive either 1200 pulses of real or sham rPMS on the radial nerve of the affected limb, followed by 1200 pulses of central iTBS on the ipsilesional hemisphere. The patients received the intervention for 10 sessions over two weeks. The primary outcome measures were the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and the Action Research Arm Test (ARAT). Secondary outcomes for activities and participation included the Functional Independence Measure-Self care (FIM-Self care) and the Stroke Impact Scale (SIS). The outcome measures were assessed before and after the intervention.
Results: Both groups showed significant improvement in FMA-UE and FIM-Self care after the intervention, (p<0.05). Only the rPMS + iTBS group had significant improvement in ARAT-Grasp, SIS-Strength and SIS-ADL (p<0.05). However, the change scores in all outcome measures did not differ between two groups.
Conclusions: Overall, the study's findings support that rPMS may have synergistic effects on central iTBS to improve grasp function and participation. In conclusion, these findings highlight the potential of rPMS as an adjuvant therapy for central iTBS in stroke rehabilitation. Further long-term studies are needed to fully investigate the synergistic effects of rPMS on central iTBS.
Trial registration: This trial was registered under ClinicalTrials.gov ID No. NCT04265365, retrospectively registered, on February 11, 2020.
Effect of Higher Glycated Hemoglobin (HbA1c) Levels on rheumatoid arthritis Risk:A Mendelian Randomization Study
Authors: Liu Tuodong , Zhang Qing , Deng Chao , Ni Jiangdong
Published: May 2023

Introduction：Published studies have suggested a potential association between diabetes mellitus (DM) and RA, with glycated hemoglobin (HbA1c) serving as an important biomarker for DM. The purpose of this study was to investigate the causal relationship between HbA1c levels and RA risk using Mendelian randomization (MR) analysis.
methods：A two-sample Mendelian randomization (MR) study was conducted using genetic variants as instrumental variables (IVs) related to HbA1c. Summary statistics from genome-wide association studies (GWAS) were obtained from the publicly accessible Integrative Epidemiology Unit (IEU) OpenGWAS database. A systematic selection process was employed to identify high-quality instrumental single-nucleotide polymorphisms (SNPs) strongly associated with the exposure. Various MR methodologies, such as inverse-variance weighted (IVW) and MR-Egger, were implemented to determine causal effects. The MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were used to evaluate horizontal pleiotropy, heterogeneities, and stability of the association. Odds ratios (OR) and 95% confidence intervals (CI) were computed.
Results：A total of 9 SNPs were identified as final IVs. The MR analysis demonstrated a significant causal relationship between elevated HbA1c levels and an increased risk of seronegative RA [odds ratio (OR) = 1.358, 95% confidence interval (CI), 1.044-1.767]. However, no significant evidence of a causal relationship was observed between HbA1c and seropositive RA [OR = 1.033, 95% CI, 0.850-1.257] or overall RA [OR = 1.093, 95% CI, 0.935-1.278]. Sensitivity analyses supported the robustness of the findings, with no significant evidence of heterogeneity or bias and no potential SNPs affecting the causal link.
Conclusions:This study provides evidence of a causal relationship between HbA1c levels and seropositive RA risk, emphasizing the importance of closely monitoring and managing HbA1c levels in patients. Further research is needed to elucidate shared pathophysiological mechanisms between DM and RA, which may lead to novel therapeutic strategies.
Mechanism study of oleanolic acid derivative, K73-03, inducing cell apoptosis in hepatocellular carcinoma
Authors: Wang Jiaqi , Ma Chuchu , Tang Zhongyuan , Sun Zhengwu , Qaed Eskandar , Chi Xinming , Wang Jun , Jamalat Yazeed , Geng Zhaohong , Tang Zeyao , Yao Qiying
Published: May 2023

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. We found that K73-03 could significantly inhibit the cell viability, migration and colony formation of SMMC-7721 and HepG2 cells in a dose-dependent manner, having a stronger effect on HepG2 cells. Excess ROS was produced when treated with K73-03 compared with the control group. After adding a reactive oxygen scavenger, N-acetyl-L-cysteine (NAC), the expression of ROS was downregulated. For mitochondrial dysfunction, K73-03 could reduce Mitochondrial membrane potential (∆Ψm) and inhibit cell respiration. In mechanism studies, the ratio of Bax/Bcl-2 and the expressions of cleaved-caspase9 and cleaved-caspase3 in HepG2 cells were upregulated after K73-03 treatment, while the ratio of LC3B-II/I and the expression of Beclin1 were also increased. The protein expressions of p-JAK2, p-STAT3, COX-2, p65 and p-65 in K73-03 treated HepG2 cells were downregulated and the nuclear translocation of p65 was inhibited. In our study, K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway.
A resistivity-based experimental compaction model for Yunnan laterite
Authors: PENG Guangcan , XU Xingqian , ZHAO Xi , QU Xin , WANG Haijun
Published: May 2023

Soil resistivity can effectively reflect the variation in structural characteristics of soils. The changes in soil resistivity can indirectly represent the degree of soil compaction, which is of great significance for the rapid evaluation of soil compaction. Yunnan laterite, in China, has widely been used as a building material in foundations, roadbeds, and dams due to its high strength and low compression. In this work, we tested the vertical and lateral resistivity of laterite during consolidation compression through an improved consolidation compression resistivity tester to discuss the variations in resistivity structural characteristic parameters (structural factor, shape factor, and anisotropy coefficient). A comprehensive index of resistivity structure characteristics was proposed to create a compactness evaluation model of laterite. The results showed that the vertical resistivity, lateral resistivity, average structural factor, and average shape factor of laterite gradually increased with continuous multi-stage vertical loading; however, the anisotropy coefficient decreased first, and then slowly increased to a stable state. The comprehensive index of resistivity structure characteristics could indirectly reflect the water content and pore content of the laterite, and the lateral resistivity was predicted from the vertical resistivity. Considering the influence of saturation and porosity on the resistivity structure characteristics, the evaluation model of compaction for laterite was finally established based on resistivity characteristics and this model had high accuracy, with small model verification error and good applicability. The proposed prediction model could serve as a theoretical reference for the application of the high-density electrical method in the convenient detection of compaction for laterite rolling engineering.
Vertebral venous plexus abnormalities in a young Poodle causing chronic lameness
Authors: Vedel Tanja , Heidemann Pernille Lindholm , Koch Bodil Cathrine , Leifsson Páll S. , McEvoy Fintan J. , Gredal Hanne
Published: May 2023

Background

Chronic progressive lameness in young dogs which do not show abnormalities on initial, survey imaging, is diagnostically challenging. The present case had undergone extensive diagnostics without definitive diagnosis until magnetic resonance imaging (MRI) allowed lesion detection and localization to the vertebral venous system. Abnormalities of the vertebral venous system have only previously been reported once in veterinary medicine.

Case presentation

A 1-year-old intact male Standard Poodle was referred with a history of chronic and progressive right thoracic limb lameness. A full work up which included routine haematology, serum biochemistry, radiography, and native computed tomography (CT) of the affected thoracic limb was performed at the referring veterinarian and reported as normal. Management including conventional pain medication, laser treatment, and physiotherapy had been attempted unsuccessfully. Treatment with meloxicam (0.1 mg/kg per os daily) did, however, have some effect on the dog’s pain according to the owner. At our hospital the right thoracic limb lameness was confirmed. A pain reaction was found on manipulation of both shoulders, and a marked muscle atrophy was noted around the right shoulder. On neurological examination, the right thoracic limb had decreased muscle tone and a decreased withdrawal reflex localizing the problem to a right-sided C6-T2 myelopathy or radiculopathy. MRI of the cervicothoracic spine and both brachial plexuses was performed. This showed enlarged internal vertebral venous plexuses especially on the right side from the level of C6 -T2 vertebrae together with marked contrast enhancement of the nerve roots in this region, suggesting nerve root compression secondary to the enlarged venous system. Further analgetic medical management was attempted but due to progression of the dog’s clinical signs, euthanasia was elected 5 months later. Post-mortem investigations confirmed imaging findings and found loss of neurons and swelling of the axons at the compressive sites on histopathology.

Conclusions

Based on the imaging findings a diagnosis of venous plexus abnormalities with secondary radiculopathy was considered most likely. This was confirmed by the post-mortem investigation. Venous plexus abnormalities are rare but should be considered in young dogs with progressive signs of lameness and regional muscle atrophy in which the underlying cause is not identified with conventional diagnostics.
Impacts of Improved Horizontal Resolutions in the Simulations of Mean and Extreme Precipitation using CMIP6 HighResMIP Models over West Africa
Authors: Ajibola Felix Olabamiji , Afolayan Stella Abosede
Published: May 2023

We analyzed 16 historical simulations from High-Resolution Model Intercomparison Project (HighResMIP) within the framework of Coupled Model Intercomparison Project (CMIP) Phase 6 (CMIP6). The simulations comprise high and low-resolution simulations. The aim is to examine the effect of improved horizontal resolution models on mean and extreme precipitation over West Africa from 1985 – 2014. Observation shows southeast and southwest regions are the most active in precipitation, consistent with simulations of HighResMIP. The impact of improved horizontal resolutions is felt in the simulation of orographic-induced rainfall over the high grounds and the intensification of precipitation in most of the metrics employed. The observed highest 1-day precipitation shows most of the Guinea coast region had 1-day rainfall greater than 100 mm, which was over-estimated (under-estimated) by high (low) resolution simulations. Also, improvement in horizontal resolution seems to improve the capacity of high-resolution models to reproduce the observed pattern of heavy precipitation (R10mm) days and very heavy rainfall (R20mm) days. The spatio-temporal analysis showed the presence of uncertainty in the simulation of both the high and low resolutions simulations in reproducing the extreme precipitation over West Africa. Due to this, a bias correction approach was employed.
Proteomic analysis of mesenchymal stromal cells secretome in comparison to leukocyte- and platelet-rich fibrin
Authors: Al-Sharabi Niyaz , Gruber Reinhard , Sanz Mariano , Mohamed-Ahmed Samih , Kristoffersen Einar K , Mustafa Kamal , Shanbhag Siddharth
Published: May 2023

Secretomes of mesenchymal stromal cells (MSC) are emerging as a novel growth factor (GF)-based strategy for periodontal and bone regeneration. The objective of this study was to compare the secretome of human bone marrow MSC (BMSC) to that of leukocyte- and platelet-rich fibrin (L-PRF), an established GF-based therapy, in the context of wound healing and regeneration. Conditioned media from human BMSC (BMSC-CM) and L-PRF (LPRF-CM) were subjected to quantitative proteomic analysis using liquid chromatography with tandem mass spectrometry. Global profiles, gene ontology (GO) categories, differentially expressed proteins (DEPs), and gene set enrichment (GSEA) were identified using bioinformatic methods. Concentrations of selected proteins were determined using a multiplex immunoassay. Among the proteins identified in BMSC-CM (2157 proteins) and LPRF-CM (1420 proteins), 1283 proteins were common. GO analysis revealed similarities between the groups in terms of biological processes (cellular organization, protein metabolism) and molecular functions (cellular-/protein-binding). Notably more DEPs were identified in BMSC-CM (n=550) compared to LPRF-CM (n=118); these included several key GF, cytokines, and extracellular matrix (ECM) proteins involved in wound healing. GSEA revealed enrichment of ECM (especially bone-ECM) related processes in BMSC-CM and immune-related processes in LPRF-CM. Similar trends for inter-group differences in protein detection were observed in the multiplex analysis. Thus, while the secretomes of both BMSC and L-PRF are favourable for wound healing, BMSC-CM is additionally enriched for proteins/processes relevant for periodontal and bone regeneration.
Limit Theorem for a Rough Differential Equation with a Negative Long-Range Random Coefficient
Authors: Bedhiafi Mounir , Gaidi Mohamed
Published: May 2023

We consider an ordinary differential equation driven by rough paths, in the T. Lyons sense \cite{Ly}, depending on a small parameter and with a negative long-range random coefficient. We establish sufficient conditions under which the solution of this ordinary differential equation converges to the solution of a stochastic differential equation driven by a fractional Brownian motion with Hurst parameter \(H\in( \frac{1}{4},\frac{1}{2})\), depends on the asymptotic behavior of the covariance function of the random coefficient.
Cardiopulmonary physiological effects of diuretic therapy in preterm infants with chronic pulmonary hypertension
Authors: Zhu Faith , Rios Daniel Ibarra , Joye Sebastien , Baczynski Michelle , Rios Danielle , Giesinger Regan , McNamara Patrick , Jain Amish
Published: May 2023

Objective
Using targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH).
Study Design
Retrospective study comparing TNE indices pre- and ≤ 2 weeks (post) of initiating diuretic therapy in infants born < 32 weeks gestational age with cPH.
Results
Twenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0±2.8 weeks, 859±294 grams, and 7.8±3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p=0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p<0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05).
Conclusion
Primary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance.
FSP1 and NRF2 independently contribute to ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma
Authors: KIM JongWoo , Kim Min-Ju , Han Tae-Hee , Lee Ji-Yoon , Kim Sangok , Kim Hyerin , Oh Kyoung-Jin , Kim Won-Kon , Han Baek-Soo , Bae Kwang-Hee , Ban Hyun Seung , Bae Soo Han , Lee SC , Lee Haeseung , Lee Eun-woo
Published: May 2023

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1),was identified as the gene most significantly correlatedwith ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis independent of NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.
Microbial Upcycling of Polyethylene into Recombinant Proteins
Authors: Connor Alexander , Lamb Jessica , Delferro Massimiliano , Koffas Mattheos , Zha Runye
Published: May 2023

Herein, we report the development of a new strain of Pseudomonas bacteria capable of upcycling deconstructed polyethylene into high value bespoke recombinant protein products. Using hexadecane, a proxy for depolymerized polyethylene, as a sole carbon nutrient source, we optimized media compositions that facilitate robust biomass growth, with results suggesting the benefits of lower hydrocarbon concentrations and the use of NH4Cl as a nitrogen source. We genomically integrated recombinant genes for green fluorescent protein and spider dragline-inspired silk protein, and we showed their expression in Pseudomonas aeruginosa, reaching titers of approximately 10 mg/L when hexadecane was used as the sole carbon source. Lastly, we demonstrated that chemically depolymerized polyethylene, comprised of a mixture of branched and unbranched alkanes, could be upcycled into silk protein by Pseudomonas aeruginosa at titers of 11.3 ± 1.1 mg/L. Thus, this work establishes a versatile microbial platform for valorizing recalcitrant plastic waste.
Limited water outflux from the subducted slab serpentinite via Mariana arc-basin magmatism
Authors: Zhao Si-Yu , Zhou Zhiyuan , Tamura Yoshihiko , Ma Jinlong , Xu Yi-Guang , Zhang Shao-Wei , Zhao Tai-Ping , Yang Alexandra Yang
Published: May 2023

The water cycle between Earth’s surface and interior controls the long-term stability of sea level. The discovery of ~24-km thick serpentinized mantle in the Pacific plate outside of the Mariana Trench suggests that water influx by plate subduction could be three times greater than previous estimates. However, the extent to which water hosted in the slab serpentinite is released by magmatism remains unclear. Here we present new boron isotopic data on Mariana frontal- and rear-arc volcanics, along with literature data on d11B, halogens and water, to examine the role of slab serpentinite in Mariana arc-basin magmatism. Our results indicate that the contribution of slab serpentinite occurs only in rear-arc volcanics, but is largely invisible in other Mariana arc-basin volcanics. Additionally, quantitative calculations suggest that the water influx of slab crust is sufficient to account for the water outflux through Mariana arc-basin magmatism, demonstrating a limited role of slab serpentinite. Given the extensive slab serpentinization inferred from well-developed bending faults throughout the entire Mariana arc system in the subducting plate, subduction of the 24-km slab serpentinite could potentially carry ~80% of bound water in the subducted slab to the mantle outside of the typical subduction zone region.
Factors affecting hemorrhagic events in patients with advanced lung cancer: from the Rising-VTE/NEJ037 study
Authors: Kawakado Keita , Tsubata Yukari , Hotta Takamasa , Yamasaki Masahiro , Ishikawa Nobuhisa , Fujitaka Kazunori , Kubota Tetsuya , Kobayashi Kunihiko , Isobe Takeshi
Published: May 2023

Background: Despite the occurrence of various hemorrhagic events during the treatment of advanced lung cancer, few studies have reported on their risk factors. In addition, the development of cancer-related thromboembolism indicates the use of anticoagulants. However, adverse events such as bleeding should be monitored. This study aimed to identify the factors that influence the onset of hemorrhagic events in patients with advanced lung cancer.
Methods: The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study. A total of 1008patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Multivariate analysis using a Cox proportional hazard model was performed to compare the outcomes of the time to the onset of hemorrhagic events for 2 years after registration.
Results: Hemorrhagic events occurred in 115 patients (11.4%), of which 35 (30.4%) had major bleeding events. The factors that significantly increased the risk of hemorrhagic events were venous thromboembolism (VTE) and an Eastern Cooperative Oncology Performance Status score of 1. The factors that significantly reduced the risk of hemorrhagic events were female sex and M1a status.
Conclusion: VTE is a risk factor for hemorrhagic events in patients with advanced lung cancer, and risks associated with anticoagulant therapy should be considered.
Molecular Function Validation and Prognostic Value Analysis of the Cuproptosis-Related Gene Ferredoxin 1 in Colon Cancer
Authors: Feng Ranran , Chen Yong , Shi Lei , Tian Ziying , Yan Shiqi , Jiang Su , Zhang Wenling
Published: May 2023

Background
Cuproptosis is the most recently discovered form of regulated cell death (RCD) induced by intracellular copper. Growing evidence has indicated that cuproptosis plays a considerable role in tumorigenesis among various cancers. However, the role of cuproptosis in the development of colon cancer (CC) and its prognostic value remains to be investigated.
Methods
Five independent cohorts with CC were included in this study. Comprehensive bioinformatics analyses were used to explore the expression, molecular function, and prognostic value of the pivotal regulator of cuproptosis, ferredoxin 1 (FDX1). Correlation analyses and least absolute shrinkage and selection operation (LASSO) regression analyses were utilized to screen the optimal combination of cuproptosis-related genes for constructing a Cox proportional hazards model, and the cuproptosis-related risk score (CRRS) was calculated to stratify CC patients in prognosis. The immunology, tumor stemness index, and drug sensitivity of the CRRS-based subgroups were also investigated. Moreover, the expression and biological functions of FDX1 were validated in vitro.
Results
Results showed that FDX1 was significantly downregulated in CC and its lower expression indicated poorer outcomes. Seven cuproptosis-associated genes were selected to construct the prognostic model. CRRS displayed good performance in predicting prognosis compared with clinical features. Moreover, CRRS could significantly enhance the prognostic prediction precision of the classic tumor, nodes, and metastases (TNM) staging system. The high-CRRS group showed an obvious immunosuppressive microenvironment and a lower stemness index compared with the low-CRRS group. The difference in FDX1 expression between CC and normal tissues was verified in vitro. Overexpression of FDX1 promoted cell death and inhibited cell proliferation and migration.
Conclusions
Our results suggest that CRRS can function as a good prognostic indicator for CC patients and may help guide treatment management. Our findings provide new insights into cuproptosis-targeted therapies for CC patients.
Association between dried fruit intake and DNA methylation: A Multivariable Mendelian Randomization Analysis
Authors: Wu Lingling , Pei Hua , Zhang Yanyan , Zhang Xingxing , Feng Minhua , Yuan Lin , Guo Meixiang , Wei Yuanhao , Tang Zhen , xiang xiqiao
Published: May 2023

Background
Observational studies have reported associations between dried fruit intake and DNA methylation(DNAm). However, inherent flaws in observational study designs make them susceptible to confounding and reverse causality bias. Consequently, it is unclear whether a causal association exists. In the present study, we aimed to investigate the causal associations between dried fruit intake and DNAm.
Methods
We performed two-sample Mendelian randomization (MR) using the IEU Open GWAS database aggregated data. Forty-three single nucleotide polymorphisms (SNPs) associated with dried fruit intake as instrumental variables (IVs) were selected as exposure. DNAm outcomes include Gran (estimated granulocyte proportions); AgeAccelGrim(GrimAge acceleration); Hannum (Hannum age acceleration); IEAA(Intrinsic epigenetic age acceleration), AgeAccelPheno( PhenoAge acceleration), and DNAmPAIadjAge (DNAm-estimated plasminogen activator inhibitor-1 levels). Inverse variance weighted (IVW) method was the primary method for MR analysis, complemented by four other MR methods to ensure the stability and reliability of the results. Additional sensitivity analyses were also performed. The direct effects of dried fruit intake on DNAm were estimated using multivariable mendelian randomization (MVMR).
Results
Univariate MR results showed that for each standard deviation increase in dried fruit intake, the risk of AgeAccelGrim was reduced by 77.7% [odds ratio (OR) = 0.223, 95% confidence interval (CI) = 0.081–0.612; PIVW=3.588×10− 3], and the risk of AgeAccelPheno was reduced by 81.7% (OR = 0.183, 95%CI = 0.054–0.621, PIVW=6.426×10− 3). However, the effects on Gran(PIVW=0.264), Hannum(PIVW=0.299), IEAA(PIVW=0.700), and DNAmPAIadjAge(PIVW=0.051) were not statistically significant. MVMR results adjusting for the potential effects of confounders showed that the causal relationship between dried fruit intake and AgeAccelGrim (PIVW=2.482×10− 2) persisted, but the effect on AgeAccelPheno (PIVW=0.052) was not statistically significant. Sensitivity analysis showed that our results were stable and reliable.
Conclusion
Our MR findings suggest that increased dried fruit intake is associated with slower AgeAccelGrim, providing a promising avenue for exploring the beneficial effects of dried fruit intake on lifespan extension.
Byzantine Roof Tiles from Chersonesos (Crimea, Ukraine): A techno-morphological approach
Authors: Moisieiev Dmitriy , Klenina Elena
Published: May 2023

The present paper provides an overview of the building ceramic material used during the functioning of a Byzantine Christian complex with a five-apse church and of a dwelling housein Chersonesos. The aim of this work is to broaden our knowledge of Byzantine ceramic construction material based on an in-depth analysis of items discovered during the excavation of block LV in the western part of Chersonesos using the techno-morphological method. Our investigation was carried out to clarify the origin and dating of some subgroups and variants of flanged tiles. This work makes a significant contribution to the study of Byzantine building ceramics, constituting the first attempt to construct a relative chronology of building periods in the history of the important Byzantine provincial town of Chersonesos in Crimea. It is based on a comprehensive and comparative analysis of building ceramics found during the excavation of blocks XLV and LV. Earlier similar analyses of roof tiles did not yield significant results due to the inaccurate dating of the material. The present study is expected to contribute to our understanding of the technological specifics of tile production in the Byzantine provinces and its chronology. The research provides a relevant insight into the specific shapes, context distribution and the associated chronology of Byzantine tiles.
Exploring the potential of Bacillus subtilis as cell factory for food ingredients and special chemicals
Authors: Chen Taichi , BRUL STANLEY , Hugenholtz Jeroen
Published: May 2023

Background Bacillus subtilis has been established as model microorganism for fundamental research in the laboratory on protein production/secretion and sporulation and as model bacterium for controlling spoilage in the food industry. It has also been used for production of (commercial) enzymes and several secondary metabolites such as vitamins. However, this doesn’t fully reflect the potential of B. subtilis as a cell-factory. Here, various strains of B. subtilis, including food-grade, spore-deficient strains and industrially-used strains, were compared for their growth and metabolic potential. Industry-relevant parameters were analyzed for all strains under various aeration regimes, under anaerobic conditions, in various nutritious and nutrient-limited cultivation media, with and without organic nitrogen sources, and with and without sugar.Results Practical experiments were conducted to compare industrial relevant properties like growth rates, intracellular components and extracellular metabolite profile of different B. subtilis strains. Based on growth flexibility in different media, we found that some unconventional strains like NCIB3610 and DSM1092 are adapted to inorganic or organic nitrogen source utilization, which is highly relevant when considering a biorefinery approach using various cheap and abundant waste/sidestreams. Secondly, spore-deficient strains such as 3NA, 168S and PY79S, showed advantages in microbial protein and acetolactate pathway expression, which is associated with applications in food industry for protein supplement and diacetyl production. Lastly, WB800 and PY79S exhibited potential for fermentative production of Dipicolinic acid, 2,3-Butanediol and Lactic acid that could serve as precursors for biopolymers.Conclusion This study demonstrates the broad potential for more extensive industrial use of Bacillus subtilis in the (biobased) chemical industry for use of sidestreams, in the personal care industry, in the food industry for food additive production, and in the bio-sustainable industry for biofuel and bio-degradable plastic precursors production. In addition, selecting different B. subtilis strains for specific purposes makes full use of the diversity of this species and increases the potential of B. subtilis in its contribution to the bio-based economy.
Multi-armed Bandit Algorithms for Cournot Games
Authors: Taywade Kshitija , Goldsmith Judy , Harrison Brent , Bagh Adib
Published: May 2023

We investigate using a multi-armed bandit (MAB) setting for modeling repeated Cournot oligopoly games. Agents interact with separate bandit problems. An agent can choose from a set of arms/actions representing discrete production quantities; here, the action space is ordered. Agents are independent and autonomous and cannot observe anything from the environment; they can only see their own rewards after taking action and only work towards maximizing these rewards. We first study Cournot models with stationary market demand where random entry or exit from the market is not allowed. We propose two novel approaches that take advantage of the fact that the action space is ordered: ϵ-greedy+HL and ϵ-greedy+EL. These are based on the ϵ-greedy approach as an underlying mechanism because the ϵ-greedy method does not require any knowledge of even the priors of the reward distributions, unlike other popular methods like UCB or Thompson sampling. Our proposed approaches help firms focus on more profitable actions by eliminating less profitable choices and are designed to optimize the exploration. However, in real-world scenarios, market demands evolve over a product’s lifetime for a myriad of reasons. Therefore, we also investigate repeated Cournot games with non-stationary demand such that firms/agents face independent instances of the non-stationary multi-armed bandit problem. We propose a novel algorithm Adaptive with Weighted Exploration (AWE) ϵ-greedy that is loosely based on the ϵ-greedy approach. We use computer simulations to study the emergence of various equilibria in the outcomes and empirically analyze joint cumulative regrets. Using our proposed method, agents are able to swiftly change their course of action according to the changes in demand. In most of the simulations, firms overall produce collusive outcomes, i.e., outcomes better than the Nash equilibrium.