bluuebunny/crossref_metadata_2025 huggingface dataset:
Soft governance against superbugs: How effective is the international regime on antimicrobial resistance?
Authors: Heinzel Mirko , Koenig-Archibugi Mathias
Published: September 2023

Antimicrobial resistance (AMR) and the declining effectiveness of antibiotic medicines due to misuse are among the biggest threats to global health and a major challenge for global governance in this century. Since drug-resistant bacteria spread easily across borders, government policies that exacerbate or mitigate AMR affect other countries. International organizations and governments addressed the global public good of maintaining antimicrobial protection by creating a soft governance regime largely devoid of legally binding rules and enforcement mechanisms. This article presents a cross-national empirical assessment of the effectiveness of the international AMR regime combining novel data on national action plans and data on antibiotic consumption in 191 countries between 2000 and 2018. We find that the regime sets ambitious goals and achieves broad participation, substantial implementation, and meaningful change in the use of antibiotics. The involvement of the largest consumers of antibiotics has been crucial for both effectiveness and equity.
Study on the Dyeing Properties of a Novel Reactive Dye with One Vinylsulfone Reactive Group, on Cotton Substrates, Before and After Its Ultrafiltration Treatment
Authors: Lykidou Smaro , Gitsouli Eleftheria , Daniilidis Vasileios , Vouvoudi Evangelia , Nikolaidis Nikolaos F.
Published: September 2023

Reactive dyes are widely used in the textile industry due to their versatility of shades, high wash fastness properties, and the ease of application. Dyeing properties such as exhaustion, substantivity, fixation, time to half dyeing, migration index and effect of metal salts were studied for a novel reactive dye (named RRNa) synthesized with one vinylsulfone as reactive group. The aim of this study is to figure out the influence of the ultrafiltration process this dye went through on its aforementioned properties. It was found that the ultrafiltrated reactive dye shows higher exhaustion, substantivity, dye uptake than the original dye, which is attributed to the purification performed by the ultrafiltration process. The migration index is slightly lower for the ultrafiltrated dye which indicates that its mobility is lower, due to the possible formation of more covalent bonds between the dye and the substrate. The effect of metals (Fe, Co, Cu) was also studied and the color strength of the dyeings in the presence of sulfate salts was compared with the control sample. It was found that Co2+ and Cu2+ have a detrimental effect on the shade obtained, whereas Fe3+ reduces color strength to a lower extent.
Assessment of Wetland Ecosystem’s Health Using Remote Sensing – Case Study: Burullus Wetland – Ramsar Site
Authors: Hotaiba Amira M. , Salem Boshra B. , Halmy Marwa Waseem A.
Published: September 2023

Complex ecosystems as wetlands are very sensitive to changes and disturbances. Human activities causing habitat fragmentation that alter landscapes affect the wetland ecosystems and negatively influence biodiversity. The health of the ecosystem is measured as a homeostasis between the system components and stability or resilience of the system against disturbance; therefore, any anthropogenic disturbances can cause dramatic changes in the balance of wetland ecosystem. Burullus, the second largest of the Egyptian northern coastal wetlands along the Mediterranean coast, has been recognized recently as critically endangered ecosystem according to an assessment using IUCN Red List of ecosystems. The study sought to assess Burullus wetland’s health based on multispectral indicators related to the structure, function, and resilience of the ecosystem. Three indices were calculated to quantify the health of the wetland: the structure index, vigor index, and resilience index. The overall status of the wetland indicates a dynamic state and rapid transformation, which occurred over the study period. The outcomes indicated that Burullus’s health has progressively deteriorated in the recent investigated years of 2016 and 2019 compared to the reference years of 1984 and 1986. The assessed indicators revealed a trend towards more deterioration of its ecological system due to the LULC transformations, anthropogenic interventions, and overexploitation of its natural resources. In addition, the growth in the impervious surfaces by 9% in the recent years due to expansion in urbanization was detected. All of these factors may affect the ecological balance and the health of the wetland to some extent. The fragility of this wetland and the continuous fragmentation of it occurs due to human activities that threaten its important and unique habitats. The integrated framework for the assessment of Burullus wetland’s health based on remotely sensed data and using geospatial techniques can be utilized for the assessment of other similar coastal wetlands at national and regional scales.
Two-sided fault parameter assessment through the utilization of a particle swarm optimizer to different gravity horizontal gradients-orders with application to various cases studies
Authors: Elhussein Mahmoud , Abo-Ezz Eid R. , Gomaa Omar A. , Géraud Yves , Essa Khalid S.
Published: September 2023

Metaheuristic methods are increasingly being implemented to source parameter estimation of gravity anomalies. These approaches have become popular in the geophysical community because of their superior advantages. We emphasize the application of the particle swarm optimizer (PSO), which is motivated by the birds’ behaviors, to elucidate gravity anomalies. Besides, using different horizontal derivative orders for the observed data is valuable in reducing the regional field effect. The current inversion algorithm applied to other synthetic models (a two-sided dipping fault with a third-order regional, a two-sided dipping fault model interfered by a spherical structure model with and without 10% noise, and two neighboring two-sided dipping faults models with and without 10% noise) as well as two real-world cases from the United States and Tunisia. The usefulness of applying these techniques together was demonstrated by providing stable results in executing the buried source parameters and eradicating the regional field effect. Therefore, we recommend the application of these techniques in the model parameter estimation studies performed with potential field anomalies due to mineralized zones.
Dolomitisation favoured by Lewis acidic background compounds in saline fluids
Authors: Vandeginste Veerle , Hocknull Elliot , Fazeli Hossein , Ji Yukun
Published: September 2023

Predicting the type and rate of reactions between minerals and fluids is of utmost importance in many applications. Due to the presence of background ions, natural environments are often much more complex than laboratory experimental conditions that are used to derive mineral dissolution or precipitation rates. Dolomitisation is one of the most important diagenetic processes affecting carbonate rocks. Still, its underlying mechanisms are not yet completely unraveled. Here, we test the impact of background ions in saline solutions on the dolomitisation rate. Using batch reactor experiments at 200 °C and mineralogical characterisation, we demonstrate that the presence of background ions influences the fluid starting pH and specific ion effect, both impacting the dolomitisation rate. The results indicate that ions with a stronger hydration enthalpy correlate with a shorter dolomitisation induction time, and that Lewis acid AlCl3 is more effective than Brønsted acid HCl. Importantly, dolomitisation occurred at a slightly acidic pH, and carbon speciation modelling showed that carbonate ions did not dominate in any of the experiments. Hence, dolomitisation in our experiments is faster in saline, slightly acidic rather than alkaline solutions and the rate is influenced by the solution composition, with specific ion effects influencing dolomite surface charge, interfacial tension and the structure of water. These new insights have implications for interpretations on natural environments, such as deep reservoirs with saline, slightly acidic formation water, and predictions related to geological carbon dioxide storage.
Assessing the role of community participation in integrated watershed management in Dandi Lake watershed Dandi district, West Showa, Oromia, Ethiopia
Authors: Bekele Yobsan , Kebede Birhanu , Kuma Tolera
Published: September 2023

Integrated watershed management is the method of overseeing human exercises and characteristic assets on a water shed basis, taking into consideration social and financial concerns. It is an ever-evolving hone including the administration of arrive, water, biota, and other assets and it requires involvement of strong institutions at the grass root level. Most watershed projects were not successful due to a lack of effective community participation. The objective of this study was to evaluate the contribution of community participation in integrated watershed management schemes in the Dandi lake watershed (Ethiopia) for long-term water resource conservation initiatives and short-term livelihood activities that enables the communities of the study area to meet their needs. Questionnaires, FGD, key informant interviews, personal observation were used as data collection tools. The collected data were organized and categorized according to the intended objectives and analyzed in qualitative and quantitative methods. The result of the study showed that role of community participation in participatory watershed management was examined by involvement in different management phases, 65.1% were involved only in the implementation stage, only 27.6% of respondents confirmed as they involve in all stages, 5.9 and 1.3% of sampled respondents witnessed as they are only involved in planning and mapping stage of watershed management. This study revealed that community participation in water shade management was hindered due to shortage of resources, interest, and previous experience, as well as peer pressure. In the meantime some successful efforts have been made on different land uses meant to reduce natural resource degradation and food security problems. These efforts include, contribution of delivered extension service, infrastructure provision and maintenance. The study also realized and proved the existence of unused development potential to improve the livelihood situation of the watershed community. This study came up with a good managerial implication, typically, it enhances Community engagement status by increasing its visibility and understanding of issues and empowers communities to have a say in decisions that affect their lives, cities and neighborhoods. The watershed management guidelines have to be clear to the community.
Effectiveness of bimetallic ZnO-B2O3 nanoparticles produced by Streptomyces gancidicus as prospective antifungal agents and therapeutic nutrients to enhance pea plant immunity against damping off-causing Pythium irregulare: in vivo and in vitro investigations
Authors: Elkhodary Basma H. , Attia Mohamed S. , El-Sayyad Gharieb S. , Salem Marwa S.
Published: September 2023

Pythium irregulare (P. irregulare) is one of the soil-borne pathogens that is the primary cause of damage to several plants each year. The novelty and originality of this work were the ability of Streptomyces gancidicus (S. gancidicus OR229936) to synthesize bimetallic zinc oxide-boron oxide nanoparticles (ZnO-B2O3 NPs) for reducing P. irregulare growth and safeguarding pea plant from damping off disease. The produced bimetallic ZnO-B2O3 NPs’ XRD results highlighted the ZnO diffraction peaks at 2Ɵ = 27.50°, 31.15°, 45.15°, 56.89°, 67.98°, and 75.25°, which are complemented by the standard card JCPDS number 361451 and correspond to (002), (101), (102), (110), (103), and (201) Bragg’s reflections. Along with the standard card JCPDS number 300019, they additionally include the B2O3 NP diffraction peaks at 2Ɵ = 15.25°, 28.69°, 31.99°, and 41.28°. Bimetallic ZnO-B2O3 NPs were tested against P. irregular for their antifungal activities. The findings indicated that ZnO-B2O3 NPs exhibited potential anti P. irregulare activity, with an inhibition zone of 33 mm at a concentration of 1000 µg/mL and a promising MIC of 0.01 µg/mL. Bimetallic ZnO-B2O3 NPs (0.01 ppm) application appeared to significantly lessen the severity of the pea post-emergence damaging off disease by 10% and to provide significant protection by 88%. In comparison to fungicide (difenoconazole 25%) treatments, all metabolic resistance indicators significantly enhanced after the usage of bimetallic ZnO-B2O3 NPs, ZnO NPs, and B2O3 NPs with ethyl acetate extract of S. gancidicus. The beneficial impacts of the bimetallic ZnO-B2O3 NPs, ZnO NPs, and B2O3 NPs have been broadened to increase the enzyme activities of peroxidase (POD) and polyphenol oxidase (PPO) in both healthy and infected pea plant in comparison to control. Reduction of Malondialdehyde content (MDA) in response to S. gancidius filtrate, bimetallic ZnO-B2O3 NPs, ZnO NPs, B2O3 NPs, and difenoconazole by 41.68%, 36.51%, 26.15, 26.15, and 15.25%, respectively. Also, contents of H2O2 in infected pea plant were diminished by 50%, 45%, 40%, 37.5%, and 22.5% at bimetallic ZnO-B2O3 NPs, S. gancidicus filtrate, ZnO NPs, difenoconazole, and B2O3 NPs comparing to P. irregular-infected pea plant is strong evidence to induce disease recovery. The application of bimetallic ZnO-B2O3 NPs seems to be a significant approach to relieve the toxic influences of P. irregulare on infected pea plant as green and alternative therapeutic nutrients of chemical fungicides.
Improving table detection for document images using boundary
Authors: Liu Yingli , Zheng Jianfeng , Zhang Guangtao , Shen Tao
Published: September 2023

Locating tables in document images is the first step to extracting table information, and high location precision is required. The dominant approach of table detection is based on an object detection algorithm, and the detector defines the prediction task as a regression problem, which inevitably leads to positioning errors. To address this issue, this paper presents an approach called Border Line Correction (BLC) to refine the rough prediction results of the original detector through the table boundary lines extracted from the document image. Our approach transforms the regression task into a classification problem, thus avoiding the inherent regression error of the object detection algorithm. Traditional annotation methods are inadequate for table detection tasks as they fail to capture the completeness and purity of the detection results. Therefore, this study treats the correct position of a table as a tolerance region. Additionally, to overcome the limitations of existing datasets in the materials domain, we collected 1183 samples from scientific literature in the materials field and created the MatTab dataset, annotating the tables with tolerance regions. This paper use Cascade RCNN with Swin Transformer as baseline models, and BLC is utilized to optimize the detection results. Experimental results demonstrate significant improvements with BLC at an IOU of 0.95 on the MatTab, ICDAR2019, and ICDAR2017 datasets. In MatTab, the percentage of correctly detected complete and pure tables increased from 72.3% to 82.1%.
Actor-critic objective penalty function method: an adaptive strategy for trajectory tracking in autonomous driving
Authors: Wang Bo , Bai Fusheng , Zhang Ke
Published: September 2023

Trajectory tracking is a key technology for controlling the autonomous vehicles effectively and stably to track the reference trajectory. How to handle the various constraints in trajectory tracking is very challenging. The recently proposed generalized exterior point method (GEP) shows high computational efficiency and closed-loop performance in solving the constrained trajectory tracking problem. However, the neural networks used in the GEP may suffer from the ill-conditioning issue during model training, which result in a slow or even non-converging training convergence process and the control output of the policy network being suboptimal or even severely constraint-violating. To effectively deal with the large-scale nonlinear state-wise constraints and avoid the ill-conditioning issue, we propose a model-based reinforcement learning (RL) method called the actor-critic objective penalty function method (ACOPFM) for trajectory tracking in autonomous driving. We adopt an integrated decision and control (IDC)-based planning and control scheme to transform the trajectory tracking problem into MPC-based nonlinear programming problems and embed the objective penalty function method into an actor-critic solution framework. The nonlinear programming problem is transformed into an unconstrained optimization problem and employed as a loss function for model updating of the policy network, and the ill-conditioning issue is avoided by alternately performing gradient descent and adaptively adjusting the penalty parameter. The convergence of ACOPFM is proved. The simulation results demonstrate that the ACOPFM converges to the optimal control strategy fast and steadily, and perform well under the multi-lane test scenario.
Sustainable Financial Advice for SMEs
Authors: de Jong Fred , Wagensveld Koos
Published: September 2023

The financial industry can play a significant role in reaching the sustainability goals. But there is a lack of attention to the part financial advisors can or should play. By advising SMEs on sustainability, financial advisors are in the position to make a large impact. To do that, financial advisors must not only advise on creating financial value but also on social and ecological value. By advising on creating multiple value and applying integrated thinking, financial advisors can provide sustainable financial advice to SMEs. And because of the large and diverse number of financial advisors for SMEs, they can make a difference in helping SMEs to become more sustainable. This article focuses on the role financial advisors can play and the impact they can make for SMEs in their challenge to become more sustainable. By combining theory on the value of advice, multiple value creation, and integrated thinking, specifically related to the challenges of SMEs on sustainability, the result is a definition of sustainable financial advice to stimulate the debate on the specific role of financial advisors in reaching the sustainability goals worldwide. Sustainable financial advice is financial advice with integrated thinking about multiple value creation with the aim to reach the sustainability goals.
Retraining investment for Alberta’s oil and gas workers for green jobs in the solar industry
Authors: Meyer Theresa K. , Hunsberger Carol , Pearce Joshua M.
Published: September 2023

If oil sands are to be eliminated from the energy market to protect the global environment, human health and long-term economic welfare, a significant number of workers will be displaced in the transition to renewable energy technologies. This study outlines a cost-effective and convenient path for oil and gas workers in Alberta to be retrained in the burgeoning solar photovoltaic (PV) industry. Many oil and gas workers would be able to transfer fields with no additional training required. This study examines retraining options for the remainder of workers using the most closely matching skill equivalent PV job to minimize retraining time. The costs for retraining all oil sands workers are quantified and aggregated. The results show the total costs for retaining all oil sands workers in Alberta for the PV industry ranges between CAD$91.5 m and CAD$276.2 m. Thus, only 2–6% of federal, provincial, and territorial oil and gas subsidies for a single year would need to be reallocated to provide oil and gas workers with a new career of approximately equivalent pay. The results of this study clearly show that a rapid transition to sustainable energy production is feasible as costs of retraining oil and gas workers are far from prohibitive.
A NAC transcription factor, PpNAC1, regulates the expression of PpMYB10.1 to promote anthocyanin biosynthesis in the leaves of peach trees in autumn
Authors: Meng Junren , Sun Shihang , Li Ang , Pan Lei , Duan Wenyi , Cui Guochao , Xu Juan , Niu Liang , Wang Zhiqiang , Zeng Wenfang
Published: September 2023

Red leaves in autumn are characteristic of a very early-maturing ripening variety of peach (Prunus persica). Analysis of the genetic factors and molecular mechanisms associated with the red-leaf phenotype can help breed peach very early maturing peach varieties. This study investigated the mechanisms underlying the red- and green-leaf phenotypes in autumn. Red compounds accumulated in the older but not younger leaves in the extremely early-maturing peach variety, ‘99-30-33’, and the leaves of the medium-maturing variety, ‘Zhongtao5 (CP5)’. Metabolic analysis showed that cyanidin-3-O-glucoside was the most abundant anthocyanin in the red leaves. The segregation of the progenies obtained from crossing revealed that the red leaves are a unique hereditary phenomenon not in line with Mendel’s law. BSA-seq and RNA-seq analyses suggest that PpNAC1 was essential for enhancing anthocyanin biosynthesis and was highly upregulated in red than in green leaves. Similar to PpNAC1, the anthocyanin activator, PpMYB10.1, was the only gene highly expressed in red leaves. Moreover, the functional genes involved in anthocyanin biosynthesis, such as Prunus persica Flavonoid 3'-hydroxylase (PpF3'H), Prunus persicaDihydroflavonol reductase (PpDFR), Prunus persica Leucoantho-cyanidin dioxygenase (Pp LDOX), Prunus persica Glutathione S-transferase (PpGST), and Prunus persica UDP-glucose, flavonoid-3-O-glucosyltransferase (PpUFGT), were upregulated in the older red leaves of 99-30-33 but downregulated in the younger 99-30-33 and green CP5 leaves. Yeast one-hybrid and dual-luciferase assays further confirmed that PpNAC1, which refers to 'Prunus persica NAC (NAM、A TAF1/2、CUC1/2)' bound to the promoter of PpMYB10.1, PpMYB10.1 stands for 'Prunus persica MYB (v-myb avian myeloblastosis viral) 10.1' and activated its expression along with those of PpGST and PpUFGT. These results provide insights into the mechanisms responsible for the development of red color in peach leaves in autumn.
Ancient Mars May Have Had a Cyclical Climate
Authors: Balakrishnan Vijay
Published: September 2023

Hexagonal structures in sediments are evidence of repeated wet and dry conditions on the Red Planet.
Sparse, Empirically Optimized Quadrature for Broadband Spectral Integration
Authors: Czarnecki Paulina , Polvani Lorenzo , Pincus Robert
Published: September 2023

Broadband (spectrally‐integrated) radiation calculations are dominated by the expense of spectral integration, and many applications require fast parameterizations for computing radiative flux. Here we describe a novel approach using a linear weighted sum of monochromatic calculations at a small set of optimally‐chosen frequencies. The empirically‐optimized quadrature method is used to compute atmospheric boundary fluxes, net flux profiles throughout the atmosphere, heating rate profiles, and top‐of‐the‐atmosphere forcing by CO2, in the longwave for clear skies. We evaluate the method against two modern correlated k‐distribution models and find that we can achieve comparable errors with 32 spectral points. We also examine the effect of minimizing different cost functions, and find that in order to accurately represent heating rates and CO2 forcing, these quantities must be included in the cost function.
Poor response to methylphenidate is associated with a smaller dorsal attentive network in adult Attention-Deficit/Hyperactivity Disorder (ADHD)
Authors: Parlatini Valeria , Radua Joaquim , Solanes Font Aleix , Wichers Rob , Maltezos Stefanos , Sanefuji Masafumi , Dell’Acqua Flavio , Catani Marco , Thiebaut de Schotten Michel , Murphy Declan
Published: September 2023

Stimulants, such as methylphenidate (MPH), are effective in treating attention-deficit/hyperactivity disorder (ADHD), but there is individual variability in response, especially in adults. To improve outcomes, we need to understand the factors associated with adult treatment response. This longitudinal study investigated whether pre-treatment anatomy of the fronto-striatal and fronto-parietal attentional networks was associated with MPH treatment response. 60 adults with ADHD underwent diffusion brain imaging before starting MPH treatment, and response was measured at two months. We tested the association between brain anatomy and treatment response by using regression-based approaches; and compared the identified anatomical characteristics with those of 20 matched neurotypical controls in secondary analyses. Finally, we explored whether combining anatomical with clinical and neuropsychological data through machine learning provided a more comprehensive profile of factors associated with treatment response. At a group level, a smaller left dorsal superior longitudinal fasciculus (SLF I), a tract responsible for the voluntary control of attention, was associated with a significantly lower probability of being responders to two-month MPH-treatment. The association between the volume of the left SLF I and treatment response was driven by improvement on both inattentive and hyperactive/impulsive symptoms. Only non-responders significantly differed from controls in this tract metric. Finally, our machine learning approach identified clinico-neuropsychological factors associated with treatment response, such as higher cognitive performance and symptom severity at baseline. These novel findings add to our understanding of the pathophysiological mechanisms underlying response to MPH, pointing to the dorsal attentive network as playing a key role.
Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database
Authors: Lauritsen Jakob , Sauvé Nicolas , Tryakin Alexey , Jiang Di Maria , Huddart Robert , Heng Daniel Y. C. , Terbuch Angelika , Winquist Eric , Chovanec Michal , Hentrich Marcus , Fankhauser Christian D. , Shamash Jonathan , del Muro Xavier Garcia , Vaughn David , Heidenreich Axel , Sternberg Cora N. , Sweeney Christopher , Necchi Andrea , Bokemeyer Carsten , Bandak Mikkel , Jandari Abolghassem , Collette Laurence , Gillessen Silke , Beyer Joerg , Daugaard Gedske
Published: September 2023

Background

Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate.

Patients and methods

In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT.

Results

A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70–1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem.

Conclusion

Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.
DNA damage response inhibitors enhance tumour treating fields (TTFields) potency in glioma stem-like cells
Authors: Vanderlinden Aurelie , Jones Callum G. , Myers Katie N. , Rominiyi Ola , Collis Spencer J.
Published: September 2023

Background

High-grade gliomas are primary brain cancers with unacceptably low and persistent survival rates of 10–16 months for WHO grade 4 gliomas over the last 40 years, despite surgical resection and DNA-damaging chemo-radiotherapy. More recently, tumour-treating fields therapy (TTFields) has demonstrated modest survival benefit and been clinically approved in several countries. TTFields is thought to mediate anti-cancer activity by primarily disrupting mitosis. However, recent data suggest that TTFields may also attenuate DNA damage repair and replication fork dynamics, providing a potential platform for therapeutic combinations incorporating standard-of-care treatments and targeted DNA damage response inhibitors (DDRi).

Methods

We have used patient-derived, typically resistant, glioma stem-like cells (GSCs) in combination with the previously validated preclinical Inovitro™ TTFields system together with a number of therapeutic DDRi.

Results

We show that TTFields robustly activates PARP- and ATR-mediated DNA repair (including PARylation and CHK1 phosphorylation, respectively), whilst combining TTFields with PARP1 or ATR inhibitor treatment leads to significantly reduced clonogenic survival. The potency of each of these strategies is further enhanced by radiation treatment, leading to increased amounts of DNA damage with profound delay in DNA damage resolution.

Conclusion

To our knowledge, our findings represent the first report of TTFields applied with clinically approved or in-trial DDRi in GSC models and provides a basis for translational studies toward multimodal DDRi/TTFields-based therapeutic strategies for patients with these currently incurable tumours.
SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells
Authors: Yang Shu , Yang Guangyan , Wang Xinyu , Xiang Jiaqing , Kang Lin , Liang Zhen
Published: September 2023

Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-β-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-β signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-β, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.
Engineered small extracellular vesicles loaded with miR-654-5p promote ferroptosis by targeting HSPB1 to alleviate sorafenib resistance in hepatocellular carcinoma
Authors: Sun Jiao , Liu Qi , Jiang Yanfang , Cai Zhihui , Liu Hui , Zuo Huaiwen
Published: September 2023

Sorafenib (sora) is the initial therapy for patients with progressive hepatocellular carcinoma (HCC), but the emergence of drug resistance has seriously impacted its therapeutic efficacy. However, the mechanism of sora resistance remains unclear, and effective strategies to overcome drug resistance are still lacking. By establishing a sora-resistant hepatocellular carcinoma cell line, we found that Heat Shock Protein Family B (small) Member 1 (HSPB1) was markedly upregulated in sora-resistant HCC cells. Further research revealed that the ferroptosis resistance induced by HSPB1 upregulation plays a crucial role in sora resistance. In addition, we confirmed that miR-654-5p enhances sora-induced ferroptosis by binding to HSPB1 and reducing its protein levels. To enhance miRNA stability and delivery efficiency in vivo, we used small extracellular vesicles (sEV) derived from human adipose mesenchymal stem cells as miR-654-5p carriers, creating engineered sEV (m654-sEV). The research demonstrated that m654-sEV effectively delivers miR-654-5p to HCC cells, targeting HSPB1 and enhancing sora-induced ferroptosis. This improves therapeutic effects on sora-resistant HCC cells and xenograft tumors, restoring their sensitivity to sora. In summary, m654-sEV, which targets HSPB1 via miR-654-5p delivery, represents a promising strategy for addressing sora-resistant issue. The combined use of m654-sEV and sora has the potential to significantly enhance therapeutic efficacy for patients with sora-resistant HCC.
Myelination and excitation-inhibition balance synergistically shape structure-function coupling across the human cortex
Authors: Fotiadis Panagiotis , Cieslak Matthew , He Xiaosong , Caciagli Lorenzo , Ouellet Mathieu , Satterthwaite Theodore D. , Shinohara Russell T. , Bassett Dani S.
Published: September 2023

Recent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders.
A CK2 and SUMO-dependent, PML NB-involved regulatory mechanism controlling BLM ubiquitination and G-quadruplex resolution
Authors: Liu Shichang , Atkinson Erin , Paulucci-Holthauzen Adriana , Wang Bin
Published: September 2023

The Boom syndrome helicase (BLM) unwinds a variety of DNA structures such as Guanine (G)-quadruplex. Here we reveal a role of RNF111/Arkadia and its paralog ARKL1, as well as Promyelocytic Leukemia Nuclear Bodies (PML NBs), in the regulation of ubiquitination and control of BLM protein levels. RNF111 exhibits a non-canonical SUMO targeted E3 ligase (STUBL) activity targeting BLM ubiquitination in PML NBs. ARKL1 promotes RNF111 localization to PML NBs through SUMO-interacting motif (SIM) interaction with SUMOylated RNF111, which is regulated by casein kinase 2 (CK2) phosphorylation of ARKL1 at a serine residue near the ARKL1 SIM domain. Upregulated BLM in ARKL1 or RNF111-deficient cells leads to a decrease of G-quadruplex levels in the nucleus. These results demonstrate that a CK2- and RNF111-ARKL1-dependent regulation of BLM in PML NBs plays a critical role in controlling BLM protein levels for the regulation of G-quadruplex.
Fast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9
Authors: Thürkauf Marco , Lin Shuo , Oliveri Filippo , Grimm Dirk , Platt Randall J. , Rüegg Markus A.
Published: September 2023

Molecular screens comparing different disease states to identify candidate genes rely on the availability of fast, reliable and multiplexable systems to interrogate genes of interest. CRISPR/Cas9-based reverse genetics is a promising method to eventually achieve this. However, such methods are sorely lacking for multi-nucleated muscle fibers, since highly efficient nuclei editing is a requisite to robustly inactive candidate genes. Here, we couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery to establish a system for highly effective somatic gene deletions in mice. Using well-characterized genes, we show that local or systemic inactivation of these genes copy the phenotype of traditional gene-knockout mouse models. Thus, this proof-of-principle study establishes a method to unravel the function of individual genes or entire signaling pathways in adult skeletal muscle fibers without the cumbersome requirement of generating knockout mice.
Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Authors: Hong Yun Soo , Battle Stephanie L. , Shi Wen , Puiu Daniela , Pillalamarri Vamsee , Xie Jiaqi , Pankratz Nathan , Lake Nicole J. , Lek Monkol , Rotter Jerome I. , Rich Stephen S. , Kooperberg Charles , Reiner Alex P. , Auer Paul L. , Heard-Costa Nancy , Liu Chunyu , Lai Meng , Murabito Joanne M. , Levy Daniel , Grove Megan L. , Alonso Alvaro , Gibbs Richard , Dugan-Perez Shannon , Gondek Lukasz P. , Guallar Eliseo , Arking Dan E.
Published: September 2023

Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.
Heat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation
Authors: Qi Yadong , He Jiamin , Zhang Yawen , Ge Qiwei , Wang Qiwen , Chen Luyi , Xu Jilei , Wang Lan , Chen Xueqin , Jia Dingjiacheng , Lin Yifeng , Xu Chaochao , Zhang Ying , Hou Tongyao , Si Jianmin , Chen Shujie , Wang Liangjing
Published: September 2023

Declined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc−/−), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/β-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.
Proof-of-concept study linking ex vivo sensitivity testing to neoadjuvant anthracycline-based chemotherapy response in breast cancer patients
Authors: Ladan Marjolijn M. , Meijer Titia G. , Verkaik Nicole S. , de Monye Cecile , Koppert Linetta B. , Oomen-de Hoop Esther , van Deurzen Carolien H. M. , Kanaar Roland , Nonnekens Julie , van Gent Dik C. , Jager Agnes
Published: September 2023

We developed a functional ex vivo anthracycline-based sensitivity test. Surgical resection material of primary breast cancer (BC) was used to determine criteria for the ex vivo sensitivity assay based on morphology, proliferation and apoptosis. Subsequently, a proof-of-concept study was performed correlating results of this assay on primary BC biopsies with in vivo response after treatment with anthracycline-containing neoadjuvant chemotherapy (NAC). Cut off values for the ex vivo anthracycline-based sensitivity test were established based on analysis of 21 primary breast tumor samples obtained after surgery. In the proof-of-concept study based on a new set of tumor biopsies, 41 patients were included. Eight biopsies did not contain tumor cells and three patients could not be biopsied for various reasons. In the remaining 30 biopsies, the success rate of the ex vivo test was 77% (23/30); six out of seven failed tests were due to excessive apoptosis, our pre-specified test criteria. Of the 23 patients with a successful ex vivo test result, three patients did not undergo NAC after the biopsy. Here we report the ex vivo anthracycline-based sensitivity assay is feasible on biopsy material and shows 75% concordance between ex vivo outcomes and in vivo MRI response. Unfortunately, the percentage of unsuccessful tests is rather high. This study provides the foundation for further development of ex vivo sensitivity assays.
Spirometry practice by French general practitioners between 2010 and 2018 in adults aged 40 to 75 years
Authors: Chapron A. , Lemée T. , Pau G. , Jouneau S. , Kerbrat S. , Balusson F. , Oger E.
Published: September 2023

In France, most spirometries are performed by pneumologists. Spirometry is difficult to access due to the distance to medical office and long delays for appointments. This lack of accessibility contributes to the underdiagnosis of chronic obstructive pulmonary disease (COPD) among patients aged between 40 and 75 years. In recent years, general practitioners (GPs) have been performing spirometry in private practice. However, the extent of this practice is unknown. A French retrospective, repetitive transversal study analysed data from the “Système National des Données de Santé” (SNDS) database. The targeted population was GPs in primary care that performed spirometries between 2010 and 2018, in patients aged between 40 and 75 years. Between 2010 and 2018, 302,674 (7.2%) spirometries were performed in France by GPs in private practices, in patients 40 to 75 years old. 5.4% by “expert GPs” (>60 spirometries/year) and 1.8% by “non-expert GPs”. In “non-expert GPs” (2.8% of French GPs in 2018), the annual number of spirometries increased by 701 each year (p < 2.104), the annual number of GPs performing spirometries increased by 114 each year (p < 2.10−5). Overall, 24.9% of the spirometries performed by GPs were referrals from other GPs. The number of spirometries performed by GPs and the number of GPs performing spirometries has gradually increased over time. However, this increase is inadequate considering the need to early detect and follow up respiratory disorders.
Satisfaction with cognitive remediation therapy: its effects on implementation and outcomes using the cognitive remediation satisfaction scale
Authors: Evans Joanne , Tinch-Taylor Rose , Csipke Emese , Cella Matteo , Pickles Andrew , McCrone Paul , Stringer Dominic , Oliver Abigail , Reeder Clare , Birchwood Max , Fowler David , Greenwood Kathryn , Johnson Sonia , Perez Jesus , Ritunnano Rosa , Thompson Andrew , Upthegrove Rachel , Wilson Jon , Kenny Alex , Isok Iris , Joyce Eileen M. , Wykes Til
Published: September 2023

Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach’s alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design.
Assessing immunogenicity barriers of the HIV-1 envelope trimer
Authors: Maliqi Liridona , Friedrich Nikolas , Glögl Matthias , Schmutz Stefan , Schmidt Daniel , Rusert Peter , Schanz Merle , Zaheri Maryam , Pasin Chloé , Niklaus Cyrille , Foulkes Caio , Reinberg Thomas , Dreier Birgit , Abela Irene , Peterhoff David , Hauser Alexandra , Kouyos Roger D. , Günthard Huldrych F. , van Gils Marit J. , Sanders Rogier W. , Wagner Ralf , Plückthun Andreas , Trkola Alexandra
Published: September 2023

Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.