bluuebunny/crossref_metadata_2025 huggingface dataset:
Conditional Assistance: Entrapment Concerns and Individual-Level Support for US Alliance Partners
Authors: Justwan Florian , Berejikian Jeffrey D
Published: September 2023

In this paper, we explore how concerns about entrapment influence mass attitudes about armed support for an alliance partner. We focus on two separate dimensions of entrapment: allied crisis instigation and the risk of direct entanglement in a nuclear conflict. Our empirical analysis is based on US experimental survey data, collected in 2021. Our data analysis reveals two main findings. First, people are less likely to endorse military action in support of another country if that state is perceived as the instigator of a given military crisis. However, we find that allied crisis instigation only reduces individual-level support for certain types of military operations (cruise missile and nuclear strikes) but not others. Furthermore, even where significant, the substantive effect of our experimental vignette is fairly limited. This implies that US voters are not particularly sensitive to the potential for offensive entrapment in the US–South Korean alliance. Second, we find that nuclear deterrence threats from international rivals sap public support for military action. However, this is only true (1) for conventional military attacks and (2) if the US President does not provide a substantive justification for military intervention. As soon as leaders offer a detailed rationale for military action, the negative effect of foreign nuclear threats on support for the use of force disappears.
Referral to Adolescent Weight Management Interventions: Qualitative Perspectives From Providers
Authors: Darling Katherine E , Warnick Jennifer , Guthrie Kate M , Santos Melissa , Jelalian Elissa
Published: September 2023

Objective

Current guidelines for treatment of obesity in adolescence include screening and referring youth with obesity to appropriate weight management (WM) care. However, prior work has not explored the referral process to adolescent WM programs, especially for youth from lower-income backgrounds, who are at increased risk of obesity and related negative health outcomes. This qualitative study sought to understand pediatricians’ current practices regarding referrals to adolescent WM interventions with a focus on adolescents from lower-income backgrounds.

Methods

Individual interviews were conducted with 11 medical providers that had referred at least 5 adolescents from low-income backgrounds to WM interventions. Applied thematic analysis was used for data analysis.

Results

Identified themes included weight-related discussions with adolescents as potentially fraught, as providers want to address weight-related health concerns while being thoughtful about potential harm. Providers also noted varied factors affecting their decision to refer to WM programs, including health implications, perceived motivation of the patient and family, and availability of programs. Providers identified that many families experience shame or guilt around referral to WM. Few themes were identified regarding impact of income on weight-related conversations with adolescents.

Conclusion

Findings were novel in regard to discussions of weight in adolescents with obesity leading to WM referral. Despite being a primary focus of the present study, few themes were identified regarding specific considerations for adolescents from low-income backgrounds. Future clinical research should focus on provider-focused interventions to increase sensitivity regarding weight-related discussions and attention to diversity, equity, and inclusion.
General Regulatory Factor7 regulates innate immune signalling to enhance Verticillium wilt resistance in cotton
Authors: Liu Fujie , Cai Sheng , Wu Peng , Dai Lingjun , Li Xinyi , Ai Nijiang , Feng Guoli , Wang Ningshan , Zhou Baoliang
Published: September 2023

Sessile growing plants are always vulnerable to microbial pathogen attacks throughout their lives. To fend off pathogen invasion, plants have evolved a sophisticated innate immune system that consists of cell surface receptors and intracellular receptors. Somatic embryogenesis receptor kinases (SERKs) belong to a small group of leucine-rich repeat receptor-like kinases (LRR-RLKs) that function as co-receptors regulating diverse physiological processes. GENRAL REGULATORY FACTOR (GRF) proteins play an important role in physiological signalling transduction. However, the function of GRF proteins in plant innate immune signalling remains elusive. Here, we identified a GRF gene, GauGRF7, that is expressed both constitutively and in response to fungal pathogen infection. Intriguingly, silencing of GRF7 compromised plant innate immunity, resulting in susceptibility to Verticillium dahliae infection. Both transgenic GauGRF7 cotton and transgenic GauGRF7 Arabidopsis lines enhanced the innate immune response to V. dahliae infection, leading to high expression of two helper NLRs (hNLR) genes (ADR1 and NRG1) and pathogenesis-related genes, and increased ROS production and salicylic acid level. Moreover, GauGRF7 interacted with GhSERK1, which positively regulated GRF7-mediated innate immune response in cotton and Arabidopsis. Our findings revealed the molecular mechanism of the GRF protein in plant immune signaling and offer potential opportunities for improving plant resistance to V. dahliae infection.
ACNPs in the U.S. Army—Medical Force Multipliers for Large-Scale Combat Operations
Authors: Grabowski Robert L , Stene Edward C , Armen Scott B , Boyer Matthew C
Published: September 2023

Operations in the Middle East have slowed, and near-peer tensions escalate. The U.S. Military has directed its attention from combating insurgencies toward preparedness for large-scale combat operations (LSCOs). The threat of LSCO demands a dramatic shift in strategy and resource and has raised questions about how the military will pivot from the counter-insurgency operations of the previous two decades. Innovation and change are needed to adequately receive, treat, hold, and transport the high volume of anticipated casualties in LSCO. Review of the current deployed medical structure has identified needs to increase emergency medical capabilities near the point of injury, increase patient holding capacity (particularly in critical care) in field hospitals and expeditionary medical facilities, and address likely delayed and prolonged medical evacuation. To address these new challenges, the authors offer recommendations for the addition of Acute Care Nurse Practitioners (ACNPs) to the U.S. Army Medical Department. ACNPs are advanced practice providers, specialized in acute and critical care. ACNPs are a potential medical force multiplier not currently utilized in the U.S. Army. If adapted, ACNPs could contribute significantly to meeting the demands of LSCO medical needs via multiple roles. Recommendations are provided by the authors, such as utilizing the ACNP within the Forward Resuscitative Surgical Detachment, Field Hospital intensive care unit, aeromedical evacuation, and/or Prolonged Care Augmentation Detachment. With support from the U.S. Army Nurse Corp and Army Medical Department, ACNPs could be integrated into the Army healthcare model, emulating the civilian standard of care for every soldier deployed. Furthermore, use of ACNPs in theater could advance deployed medical capabilities and help conserve the fighting force of the U.S. Military and its partners.
IllustrisTNG in the HSC-SSP: image data release and the major role of mini mergers as drivers of asymmetry and star formation
Authors: Bottrell Connor , Yesuf Hassen M , Popping Gergö , Omori Kiyoaki Christopher , Tang Shenli , Ding Xuheng , Pillepich Annalisa , Nelson Dylan , Eisert Lukas , Gao Hua , Goulding Andy D , Kalita Boris S , Luo Wentao , Greene Jenny E , Shi Jingjing , Silverman John D
Published: September 2023

At fixed galaxy stellar mass, there is a clear observational connection between structural asymmetry and offset from the star-forming main sequence, ΔSFMS. Herein, we use the TNG50 simulation to investigate the relative roles of major mergers (stellar mass ratios μ ≥ 0.25), minor (0.1 ≤ μ < 0.25), and mini mergers (0.01 ≤ μ < 0.1) in driving this connection amongst star-forming galaxies (SFGs). We use dust radiative transfer post-processing with SKIRT to make a large, public collection of synthetic Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP) images of simulated IllustrisTNG (TNG) galaxies over 0.1 ≤ z ≤ 0.7 with log (M⋆/M⊙) ≥ 9 (∼750 k images). Using their instantaneous star formation rates (SFRs), known merger histories/forecasts, and HSC-SSP asymmetries, we show (1) that TNG50 SFGs qualitatively reproduce the observed trend between ΔSFMS and asymmetry and (2) a strikingly similar trend emerges between ΔSFMS and the time-to-coalescence for mini mergers. Controlling for redshift, stellar mass, environment, and gas fraction, we show that individual mini merger events yield small enhancements in SFRs and asymmetries that are sustained on long time-scales (at least ∼3 Gyr after coalescence, on average) – in contrast to major/minor merger remnants which peak at much greater amplitudes but are consistent with controls only ∼1 Gyr after coalescence. Integrating the boosts in SFRs and asymmetries driven by μ ≥ 0.01 mergers since z = 0.7 in TNG50 SFGs, we show that mini mergers are responsible for (i) 55 per cent of all merger-driven star formation and (ii) 70 per cent of merger-driven asymmetric structure. Due to their relative frequency and prolonged boost time-scales, mini mergers dominate over their minor and major counterparts in driving star formation and asymmetry in SFGs.
Autoactivation of mycorrhizal symbiosis signaling through gibberellin deactivation in orchid seed germination
Authors: Miura Chihiro , Furui Yuki , Yamamoto Tatsuki , Kanno Yuri , Honjo Masaya , Yamaguchi Katsushi , Suetsugu Kenji , Yagame Takahiro , Seo Mitsunori , Shigenobu Shuji , Yamato Masahide , Kaminaka Hironori
Published: September 2023

Orchids parasitically depend on external nutrients from mycorrhizal fungi for seed germination. Previous findings suggest that orchids utilize a genetic system of mutualistic arbuscular mycorrhizal (AM) symbiosis, in which the plant hormone gibberellin (GA) negatively affects fungal colonization and development, to establish parasitic symbiosis. Although GA generally promotes seed germination in photosynthetic plants, previous studies have reported low sensitivity of GA in seed germination of mycoheterotrophic orchids where mycorrhizal symbiosis occurs concurrently. To elucidate the connecting mechanisms of orchid seed germination and mycorrhizal symbiosis at the molecular level, we investigated the effect of GA on a hyacinth orchid (Bletilla striata) seed germination and mycorrhizal symbiosis using asymbiotic and symbiotic germination methods. Additionally, we compared the transcriptome profiles between asymbiotically and symbiotically germinated seeds. Exogenous GA negatively affected seed germination and fungal colonization, and endogenous bioactive GA was actively converted to the inactive form during seed germination. Transcriptome analysis showed that B. striata shared many of the induced genes between asymbiotically and symbiotically germinated seeds, including GA metabolism- and signaling-related genes and AM-specific marker homologs. Our study suggests that orchids have evolved in a manner that they do not use bioactive GA as a positive regulator of seed germination and instead autoactivate the mycorrhizal symbiosis pathway through GA inactivation to accept the fungal partner immediately during seed germination.
LRRK2 G2019S and Parkinson’s disease: insight from Neuroinflammation
Authors: Yao Xiao-Yan , Guan Li-Na , Chen Qi , Ren Chao
Published: September 2023

The multiple hypothesis holds that the pathogenesis of Parkinson’s disease (PD) requires many factors such as heredity, environment and ageing. Mutations in Leucine-rich repeat kinase 2 (LRRK2) are recognized the risk factors of PD, and closely related to sporadic and familial PD and can regulate a variety of cellular pathways and processes. An Increasing number of studies has shown that glial hyperactivation-mediated neuroinflammation participates in dopaminergic neuron degeneration and pathogenesis of PD. LRRK2 is essential to the regulaton of chronic inflammation, especially for the central nervous system. The review spotlights on the novel development of LRRK2 on microglia and astrocytes, and explore their potential therapeutic targets, in order to provide a new insights in PD.

Key messages: What is already known on this topic The G2019S mutation of LRRK2 is now recognised as a pathogenic mutation in PD. Previous studies have focused on the relationship between neurons and LRRK2 G2019S. What this study adds Neuroinflammation mediated by LRRK2 G2019S of glial cells affects the progress and development of PD and attention must be paid to the role of LRRK2 G2019S in glial cells in PD. How this study might affect research, practice or policy Developing anti-inflammatory drugs from the perspective of LRRK2 G2019S of glial cells is a new direction for the treatment of PD.
Polymath: to be or not to be?
Authors: Kapsetaki Marianna Evangelia
Published: September 2023

Is it best to achieve excellence in one or multiple fields? Is it better to be a medical doctor reading only medical textbooks all your life or is it better to also tour around the world as a concert pianist and investigate the mysteries of the brain by conducting research projects? As a medical doctor, classical pianist, and neuroscientist, I discuss the advantages, disadvantages, opportunities, and challenges of pursuing multiple careers, drawing from my own experience and from polymaths of the past.
Nanotoxicity of multifunctional stoichiometric cobalt oxide nanoparticles (SCoONPs) with repercussions toward apoptosis, necrosis, and cancer necrosis factor (TNF-α) at nano-biointerfaces
Authors: Kumar Rajiv , Chhikara Bhupender S , Er Zeybekler Simge , Gupta Dhruv Sanjay , Kaur Ginpreet , Chhillar Mitrabasu , Aggarwal Anil K , Rahdar Abbas
Published: September 2023

Introduction

Apoptosis, necrosis, and cancer necrosis factor (TNF-a) are all impacted by the nanotoxicity of multifunctional stoichiometric cobalt oxide nanoparticles (SCoONPs) at nano-biointerfaces. The creation of multi-functional nanoparticles has had a considerable impact on the transport of drugs and genes, nanotheranostics (in-vivo imaging, concurrent diagnostics), interventions for external healing, the creation of nano-bio interfaces, and the instigation of desired changes in nanotherapeutics.

Objectives

The quantitative structure-activity relationships, chemical transformations, biological interactions as well as toxicological analyses are considered as main objectives. Discrete dimensions of SCoNPs-cell interaction interfaces, their characteristic physical features (size, shape, shell structure, and surface chemistry), impact on cell proliferation and differentiation are the key factors responsible for nanotoxicity.

Methods

The development of multi-functional nanoparticles has been significant in drug/gene delivery, nanotheranostics (in-vivo imaging, coinciding diagnostics), and external healing interventions, designing a nano-bio interface, as well as inciting desired alterations in nanotherapeutics. Every so often, the cellular uptake of multi-functional cobalt [Co, CoO, Co2(CO)8 and Co3O4] nanoparticles (SCoONPs) influences cellular mechanics and initiates numerous repercussions (oxidative stress, DNA damage, cytogenotoxicity, and chromosomal damage) in pathways, including the generation of dysregulating factors involved in biochemical transformations.

Results

The concerns and influences of multifunctional SCoNPs on different cell mechanisms (mitochondria impermeability, hydrolysis of ATP, the concentration of Ca2+, impaired calcium clearance, defective autophagy, apoptosis, and necrosis), and interlinked properties (adhesion, motility, and internalization dynamics, role in toxicity, surface hydrophilic and hydrophobicity, biokinetics and biomimetic behaviors of biochemical reactions) have also been summarized. SCoONPs have received a lot of interest among the nanocarriers family because of its advantageous qualities such as biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity.

Conclusion

Various applications, such as bio-imaging, cell labeling, gene delivery, enhanced chemical stability, and increased biocompatibility, concerning apoptosis, necrosis, and nano-bio interfaces, along with suitable examples. In this analysis, the multi-functional cobalt [Co, CoO, Co2(CO)8 and Co3O4] nanoparticles (SCoNPs) intricacies (cytogenotoxicity, clastogenicity, and immunomodulatory), nanotoxicity, and associated repercussions have been highlighted and explained.
Voluntary thermal maximum of grassland vipers (Vipera spp.): environmental drivers and local adaptation
Authors: Radovics Dávid , Sos Tibor , Mebert Konrad , Üveges Bálint , Budai Mátyás , Rák Gergő , Szabolcs Márton , Lengyel Szabolcs , Mizsei Edvárd
Published: September 2023

The thermal tolerance of ectotherms is a critical factor that influences their distribution, physiology, behaviour, and, ultimately, survival. Understanding the factors that shape thermal tolerance in these organisms is, therefore, of great importance for predicting their responses to forecasted climate warming. Here, we investigated the voluntary thermal maximum (VTmax) of nine grassland viper taxa and explored the factors that influence this trait. The small size of these vipers and the open landscape they inhabit render them particularly vulnerable to overheating and dehydration. We found that the VTmax of grassland vipers is influenced by environmental temperature, precipitation, short-wave flux, and individual body size, rather than by phylogenetic relatedness. Vipers living in colder environments exhibited a higher VTmax, contradicting the hypothesis that environmental temperature is positively related to VTmax. Our findings emphasize the importance of considering local to regional adaptations and environmental conditions when studying thermal physiology and the evolution of thermal tolerance in ectotherms.
Food fraud: insights from investigating a near-fatal poisoning with global implications
Authors: Cao Zhao , Yemets Masha , Muneem Sadia , Shannon Kyle , Gowher Fatima , Malloy Jennifer , Kafka Erin , Mitchell Clifford , King Joshua , Urban Sinisa
Published: September 2023

Risks of food fraud have been exacerbated by ongoing supply-chain shortages and reduced regulatory oversight caused by the COVID19 pandemic. Since food fraud cases involve adulterants that are deliberately disguised, resulting poisonings are especially difficult to investigate and treat. We encountered a near-fatal poisoning with “weight-loss candlenuts” that are readily available online. We leveraged state-of-the-art high-resolution mass spectrometry (HRMS) and discovered that commonly used spectral libraries and toxin/poison standards panels do not contain the materials needed to identify the causative agents of this nearly lethal poisoning. By building new methods, we ultimately found ‘Nuez de la India’ contain high levels of uncommon cardiac glycosides, while deploying HRMS as a novel ‘chemical fingerprinting’ tool revealed them to be mislabeled yellow oleander seeds. Our work presents a rapid investigative strategy to empower future investigations, and provides guiding principles to food safety programs for treating, and indeed preventing, these potentially fatal poisonings that are increasing worldwide.
The Patient Safety Curriculum: An Interventional Study on the Effectiveness of Patient Safety Education for Jordanian Nursing Students
Authors: Al-Nawafleh Ahmad H. , Musleh Sultan , Nawafleh Nofal
Published: September 2023

The purpose of the study was to assess the effectiveness of the World Health Organization’s (WHO) patient safety curriculum (PSC) in improving the patient safety education for nursing students in Jordanian higher education programmes.

Methods

An interventional design adopting a pre-test and post-test was used. A questionnaire survey was administered to 373 nursing students before and after the curriculum. Students were asked to complete pre-test and post-test questionnaires on self-awareness of patient safety.

Results

students had moderate knowledge of factors that influence patient safety and scored as the highest, (mean 3.45, SD 0.94). The greatest improvement was in the role of the health organisation in error reporting (the mean difference was 0.97, P=0.001). Taking into consideration the essential measurements, the results obtained after the post-test regarding the two patient safety topics showed a significant increase after completing the training, demonstrating that the patient safety course was effective.

Conclusion

the study highlights the importance of developing a curriculum in nursing schools that incorporates patient safety education. The WHO PSC guide can be a great start in this domain.
Estimating the distribution of reedPhragmites australisin Britain demonstrates challenges of remotely sensing rare land cover types at large spatial scales
Authors: Davies Jacob G. , Dytham Calvin , Robinson Robert A , Beale Colin M.
Published: September 2023

ReedPhragmites australisis important for biodiversity, for ecosystem services, and as a resource for humans. Already one of the mostly widely distributed wetland plants globally, reed has recently expanded outside of its native range, modifying ecosystems. However, like most wetland plant communities, reedbed has rarely been mapped at large geographical scales, restricting the information available to ecologists and resource managers. Using Sentinel-2 data and machine learning in open-source software, we produce the first remotely-sensed reedbed map of Britain. A random forest was trained on 79.2 ha of reedbed and 2,719.2 ha of non-reedbed land cover, using free online imagery. Accuracy was high within the training area (AUC > 0.998); however, field validation accuracy was much lower (AUC = 0.671), with many false positives (commission error of 93.4%). A similar workflow carried out in Google Earth Engine, using nearly an order of magnitude more images, gave a lower commission error but a disproportionately higher omission error. Due to the classification error, our map is more useful for a non-spatial estimate of the overall reedbed extent in Britain, rather than for the spatial location of reedbeds in Britain. Using the known commission and omission error, we estimate that in 2015 - 2017 c. 7800 ha of Britain was reedbed. Our study highlights the issues that present enduring barriers to accurate land cover classification at large spatial scales, perhaps suggesting fruitful areas for technological innovation. Even with a ‘big data’ approach and even if technological issues are resolved, ecological factors such as confusion land cover types and geographical variation in temporal reflectance function will probably continue to impose upper limits on the size of area for which land cover can be classified accurately, and therefore on the utility of remote sensing to resource managers.
Pre-zygotic mate selection affects progeny fitness and is only partially correlated with the expression ofNaS-like RNases
Authors: Baraniecka Patrycja , Seibt Wibke , Groten Karin , Kessler Danny , McGale Erica , Gase Klaus , Baldwin Ian T. , Pannell John R.
Published: September 2023

Nicotiana attenuatastyles preferentially select pollen from accessions with corresponding expression patterns ofNaS-like-RNases (SLRs), and the post-pollination ethylene burst (PPEB) is an accurate predictor of seed siring success. However, the ecological consequences of mate selection, its effect on the progeny, and the role of SLRs in the control of ethylene signaling are still not well understood.

We explored the link between the magnitude of the ethylene burst and transcript and protein abundance of the SLRs in a set of recombinant inbred lines (RILs) and investigated the fitness consequences of mate selection for the next generation. Genome Wide Association Study (GWAS) identified novel candidate genes potentially involved in the control of mate selection.

We found that high levels of PPEB are associated with the absence of SLR2 but not with the expression of SLR1 in most of the tested RILs. Maternal genotypes that favor certain pollen produce offspring with longer roots when pollinated with these donors, but the selection for beneficial traits is abolished when the maternal genotype selects only against certain pollen donors.

We conclude that mate selection mechanisms affect the offspring number and performance in ways that might be adaptive.
NanoLAS: a Comprehensive Nanobody Database with Data Integration, Consolidation, and Application
Authors: Xiong Shuchang , Liu Zhengwen , Yi Xin , Liu Kai , Huang Bingding , Wang Xin
Published: September 2023

Nanobodies, a unique subclass of antibodies first discovered in camelid animals, are composed solely of a single heavy chain’s variable region (VHH). Their significantly reduced molecular weight, in comparison to conventional antibodies, confers numerous advantages in the treatment of various diseases. As research and applications involving nanobodies expand, the quantity of identified nanobodies is also rapidly growing. However, the existing antibody databases are deficient in type and coverage, failing to satisfy the comprehensive needs of researchers and thus, impeding progress in nanobody research.

In response to this, we have amalgamated data from multiple sources to successfully assemble a new and comprehensive nanobody database. This database has currently included the latest nanobody data, provides researchers with an excellent search and data display interface, thus facilitating the progression of nanobody research and their application in disease treatment.

In summary, the newly constructed Nanobody Library and Archive System (NanoLAS) may significantly enhance the retrieval efficiency and application potential of nanobodies. We envision that NanoLAS will serve as an accessible, robust, and efficient tool for nanobody research and development, propelling advancements in the field of biomedicine.

Database URL

https://www.nanolas.cloud
Gel-Shrink Softlithography: Enabling 3D Tissue Culture Microstructure Miniaturization and Tacky Super-Soft Material Molding
Authors: Huang Cheng-Kuang , Lim Chwee Teck
Published: September 2023

In this study, we introduce an innovative hydrogel soft lithography technique that leverages the significant volume change of hydrogels during hydration. Through a systematic desiccation process applied to hydrogels containing microfeatures, we achieved a remarkable 2-fold reduction in feature dimensions. These shrunken hydrogel structures were then readily molded using standard soft lithography methods. Furthermore, we demonstrated the technique’s utility in rectifying surface imperfections commonly found in 3D printed structures, offering promising prospects in fields like tissue engineering. Additionally, our study discovered a unique capability of hydrated hydrogel molds in molding super-soft, tacky elastomeric materials, exemplified by CY25-276 and low cross-linker ratio PDMS. This development opens doors to studying cellular forces through traction force microscopy to a broader spectrum of 3D structural contexts. In support of our efforts in microfabrication advancement, we explored multicellular responses to surface curvatures of diminishing dimensions. Our findings reveal a curvature-dependent alignment pattern: cells residing on convex surfaces align with the direction of least curvature, while those in concave regions align with the direction of the strongest curvature. These results underscore the critical influence of geometric complexity in biological systems and highlight the need for continuously improving methods to replicate geometric qualities relevant to these environments.
Cognitive tasks, anatomical MRI, and functional MRI data evaluating the construct of self-regulation
Authors: Bissett Patrick G. , Eisenberg Ian W. , Shim Sunjae , Rios Jaime Ali H. , Jones Henry M. , Hagen Mckenzie P. , Enkavi A. Zeynep , Li Jamie K. , Mumford Jeanette A. , MacKinnon David P. , Marsch Lisa A. , Poldrack Russell A.
Published: September 2023

We describe the following shared data from N=103 healthy adults who completed a broad set cognitive tasks, surveys, and neuroimaging measurements to examine the construct of self-regulation. The neuroimaging acquisition involved task-based fMRI, resting fMRI, and structural MRI. Each subject completed the following ten tasks in the scanner across two 90- minute scanning sessions: attention network test (ANT), cued task switching, Columbia card task, dot pattern expectancy (DPX), delay discounting, simple and motor selective stop signal, Stroop, a towers task, and a set of survey questions. Subjects also completed resting state scans. The dataset is shared openly through the OpenNeuro project, and the dataset is formatted according to the Brain Imaging Data Structure (BIDS) standard.
Mechanisms analysis for Formononetin counteracted-Osimertinib resistance in Non-small-cell lung cancer cells: from the insight into the gene transcriptional level
Authors: Yin Runyang , Gao Jing , Liu Yang
Published: September 2023

Backgrounds

Osimertinib resistance in Non-Small-Cell Lung Cancers (NSCLC) is a difficult problem to be solved in clinic. Formononetin is one of the main isoflavone components, which has strong anti-cancer effects in NSCLC. However, the potential effects and the mechanisms of Formononetin to counteract the Osimertinib resistant in NSCLC is remain to be uncovered.

Methods

Osimertinib-resistant NSCLC cell line (H1975_OR) was generated by increasingly adding of Osimertinib in H1975 cell culture medium. The Formononetin was used to induce H1975_OR cell apoptosis an to inhibit cell proliferation and clonal formation. The RNA-sequencing was used to study the potential mechanisms for Formononetin to counteract the Osimertinib resistant in NSCLC.

Results

Formononetin could significantly induced cell apoptosis, whereas, dramatically inhibited cell proliferation and clinal formation in H1975_OR cells. Formononetin induced tremendous alterations of gene expression in H1975_OR cells and these genes can be clustered into unique GO, KEGG and GSEA pathways.

Conclusion

Our results preliminarily uncovered the underlying mechanisms for Formononetin counteracted Osimertinib-resistance in NSCLC cells and provided a potential treatment method for Osimertinib resistant NSCLC patients.
Whole-cell multi-target single-molecule super-resolution imaging in 3D with microfluidics and a single-objective tilted light sheet
Authors: Saliba Nahima , Gagliano Gabriella , Gustavsson Anna-Karin
Published: September 2023

Multi-target single-molecule super-resolution fluorescence microscopy offers a powerful means of understanding the distributions and interplay between multiple subcellular structures at the nanoscale. However, single-molecule super-resolution imaging of whole mammalian cells is often hampered by high fluorescence background and slow acquisition speeds, especially when imaging multiple targets in 3D. In this work, we have mitigated these issues by developing a steerable, dithered, single-objective tilted light sheet for optical sectioning to reduce fluorescence background and a pipeline for 3D nanoprinting microfluidic systems for reflection of the light sheet into the sample. This easily adaptable novel microfluidic fabrication pipeline allows for the incorporation of reflective optics into microfluidic channels without disrupting efficient and automated solution exchange. By combining these innovations with point spread function engineering for nanoscale localization of individual molecules in 3D, deep learning for analysis of overlapping emitters, active 3D stabilization for drift correction and long-term imaging, and Exchange-PAINT for sequential multi-target imaging without chromatic offsets, we demonstrate whole-cell multi-target 3D single-molecule super-resolution imaging with improved precision and imaging speed.
Quantification of Human Papillomavirus cell - free DNA from low volume blood plasma samples by digital PCR
Authors: Rosing Fabian , Meier Matthias , Schroeder Lea , Laban Simon , Hoffmann Thomas , Kaufmann Andreas , Siefer Oliver , Würdemann Nora , Klußmann Jens Peter , Rieckmann Thorsten , Alt Yvonne , Faden Daniel , Waterboer Tim , Höfler Daniela
Published: September 2023

The incidence rate of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is increasing in many countries with high human development index. HPV cell-free DNA (cfDNA) isolated from relatively large amounts of blood plasma (typically 3-4 ml) has been successfully used for therapy surveillance of HPV-OPC patients. A currently highly discussed application of HPV-cfDNA is early detection of HPV-OPC in symptom-free individuals. This requires particularly sensitive and specific cfDNA detection methods as viral copy numbers can be very low. To study the predictive power of pre-diagnostic HPV-cfDNA, archived samples from epidemiological cohorts with limited plasma volume are an important source.

To establish a cfDNA detection workflow optimized for low plasma volumes we compared two cfDNA purification methods (MagNA Pure 96 and QIAamp ccfDNA/RNA) and two digital PCR systems (Biorad QX200 and QIAGEN QIAcuity One). Final assay validation included 65 low volume plasma samples from OPC patients with defined HPV status (34 HPV16+, 1 HPV33+, 2 HPV58+, 28 HPV-negative) stored for 2-9 years.

MagNA Pure 96 yielded a 28% higher cfDNA isolation efficiency in comparison to the QIAamp ccfDNA/RNA kit. Both digital PCR systems showed comparable analytic sensitivity (limit of detection 6-17 copies for both HPV16 and HPV33), but the higher multiplexing capacity allowed the QIAcuity to detect both HPV types in the same assay. In the validation set, the assay had a sensitivity of 80% (n=28/35) for detecting HPV16 and HPV33, and a specificity of 97% (n=29/30). In samples with ≥750 µl plasma available, the sensitivity was 85% (n=17/20), while in samples with <750 µl plasma the sensitivity was 73% (n=11/15).

Despite the expected drop in sensitivity with decreased plasma volume, the assay is sensitive and highly specific even in low volume samples, and thus suited for studies exploring HPV-cfDNA as an early HPV-OPC detection marker in low volume archival material.
Seizure Event Detection Using Intravital Two-Photon Calcium Imaging Data
Authors: Stern Matthew A. , Cole Eric R. , Gross Robert E. , Berglund Ken
Published: September 2023

Significance

Genetic cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure activity, with newfound potential to understand epilepsy. Although many methods exist to measure seizure-related activity in traditional electrophysiology, few yet exist for calcium imaging.

Aim

To demonstrate an automated algorithmic framework to detect seizure-related events using calcium imaging – including the detection of pre-ictal spike events, propagation of the seizure wavefront, and terminal spreading waves for both population-level activity and that of individual cells.

Approach

We developed an algorithm for precise recruitment detection of population and individual cells during seizure-associated events, which broadly leverages averaged population activity and high-magnitude slope features to detect single-cell pre-ictal spike and seizure recruitment. We applied this method to data recorded using awakein vivotwo-photon calcium imaging during pentylenetetrazol induced seizures in mice.

Results

We demonstrate that our detected recruitment times are concordant with visually identified labels provided by an expert reviewer and are sufficiently accurate to model the spatiotemporal progression of seizure-associated traveling waves.

Conclusions

Our algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging.
The unreasonable effectiveness of the total quasi-steady state approximation, and its limitations
Authors: Eilertsen Justin , Schnell Santiago , Walcher Sebastian
Published: September 2023

In this note, we discuss the range of parameters for which the total quasi-steady-state approximation of the Michaelis–Menten reaction mechanism holds validity. We challenge the prevalent notion that total quasi-steady-state approximation is “roughly valid” across all parameters, showing that its validity cannot be assumed, even roughly, across the entire parameter space — when the initial substrate concentration is high. On the positive side, we show that the linearized one-dimensional equation for total substrate is a valid approximation when the initial reduced substrate concentrations0/KMis small. Moreover, we obtain a precise picture of the long-term time course of both substrate and complex.
Toxin-mediated depletion of nicotinamide dinucleotides drives persister formation in a human pathogen
Authors: Santi Isabella , Dias Teixeira Raphael , Manfredi Pablo , Spiess Daniel , Mas Guillaume , Klotz Alexander , Zamboni Nicola , Hiller Sebastian , Jenal Urs
Published: September 2023

Toxin-antitoxin (TA) systems are widespread in bacteria and are implicated in genome stability, virulence, phage defense and persistence. Although TA systems encompass a large variety of molecular activities and cellular targets, their physiological role and regulatory mechanisms are often unclear1,2. Here, we show that a RES domain TA system increases the survival of the human pathogenP. aeruginosaduring antibiotic treatment by generating a subpopulation of highly drug-tolerant persisters. The NatT toxin is an NAD phosphorylase, which leads to strong depletion of NAD and NADP in a subpopulation of cells. Actively growingP. aeruginosacells effectively compensate for toxin-mediated NAD deficiency by inducing the NAD salvage path-way. In contrast, under nutrient-limited conditions, NatT generates NAD-depleted cells that give rise to drug tolerant persisters during outgrowth. Structural and biochemical analyses of active and inactive NatR-NatT complexes reveal how changes in NatR-NatT interaction controls toxin activity and autoregulation. Finally, we show that the NAD precursor nicotinamide blocks NatT activity and eliminates persister formation, exposing powerful metabolic feedback control of toxin activity. The findings that patient isolates containnatTgain-of-function alleles and that NatT increasesP. aeruginosavirulence, argue that NatT contributes toP. aeruginosafitness during infections. These studies provide mechanistic insight into how a TA system promotes pathogen persistence by disrupting essential metabolic pathways during nutrient stress.
The neurovascular coupling in the attention during visual working memory
Authors: Zhang Hao , Hu Yiqing , Li Yang , Li Dongwei , Liu Hanli , Li Xiaoli , Song Yan , Zhao Chenguang
Published: September 2023

How to focus attention during visual working memory (vWM) depends on one’s ability to filter out distractors and expand the scope of targets. Although the spatiotemporal properties of attention processes in WM are well documented, it is still unclear how the mechanisms of neurovascular coupling (NVC) between electroencephalographic (EEG) signals and hemodynamic activity of attention during vWM. To investigate the NVC mechanism underlying attention during vWM, we recorded simultaneous functional near-infrared spectroscopy (fNIRS) and EEG data when humans were performing cued change-detection tasks. The multimodal data showed that the control and scope processes during vWM were involved in similar temporal profiles of frontal theta event-related synchronization (ERS) and posterior contralateral delay activities (CDA), and revealed similar distributions of hemodynamic activation within the frontal eye fields (FEF) and superior parietal lobule (SPL). These task-related features have a common NVC outcome across individuals: the higher EEG features (theta ERS or CDA amplitude), the greater the increment of local oxygenated hemoglobin (HbO) signals within the FEF and SPL. Moreover, when distractors should be filtered out, EEG-informed NVC is involved in a broader range of brain regions in the frontoparietal network (FPN). These results provided unique neurovascular evidence for the mechanisms of attention scope and control in vWM. Interestingly, there might be a negative relationship between behavioral metrics and theta-informed NVC strengths within the FEF for attention control. On a dynamic basis, the NVC features had higher discriminatory power for predicting behavior than EEG features and fNIRS features alone. Together, these results highlight what multimodal approaches can advance our understanding of the role of attention in vWM and how the fluctuations of NVC are associated with actual behavior.
Impossible ecologies: Interaction networks and stability of coexistence in ecological communities
Authors: Meng Yu , Horvát Szabolcs , Modes Carl D. , Haas Pierre A.
Published: September 2023

Does an ecological community allow stable coexistence? Identifying the general principles that determine the answer to this question is a central problem of theoretical ecology. Random matrix theory approaches have uncovered the general trends of the effect of competitive, mutualistic, and predator-prey interactions between species on stability of coexistence. However, an ecological community is determined not only by the counts of these different interaction types, but also by their network arrangement. This cannot be accounted for in a direct statistical description that would enable random matrix theory approaches. Here, we therefore develop a different approach, of exhaustive analysis of small ecological communities, to show that this arrangement of interactions can influence stability of coexistence more than these general trends. We analyse all interaction networks ofN⩽ 5 species with Lotka–Volterra dynamics by combining exact results forN⩽ 3 species and numerical exploration. Surprisingly, we find that a very small subset of these networks are “impossible ecologies”, in which stable coexistence is non-trivially impossible. We prove that the possibility of stable coexistence in general ecologies is determined by similarly rare “irreducible ecologies”. By random sampling of interaction strengths, we then show that the probability of stable coexistence varies over many orders of magnitude even in ecologies that differ only in the network arrangement of identical ecological interactions. Finally, we demonstrate that our approach can reveal the effect of evolutionary or environmental perturbations of the interaction network. Overall, this work reveals the importance of the full structure of the network of interactions for stability of coexistence in ecological communities.
Personalised Regional Modelling Predicts Tau Progression in the Human Brain
Authors: Chaggar Pavanjit , Vogel Jacob , Pichet Binette Alexa , Thompson Travis B. , Strandberg Olof , Mattsson-Carlgren Niklas , Karlsson Linda , Stomrud Erik , Jbabdi Saad , Magon Stefano , Klein Gregory ,   the Alzheimer’s Disease Neuroimaging Initiative, Hansson Oskar , Goriely Alain
Published: September 2023

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer’s disease, and its accumulation exhibits a rich spatio-temporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatio-temporal process is orchestrated – namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimer’s disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics on two independent cohorts, with subjects in early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathologic tau seeds, and subjects in late stage disease (Braak stage 3/4 onwards) characterised primarily by local production of tau. Furthermore, we demonstrate that the model can accurately predict subject-specific longitudinal tau accumulation at a regional level, potentially providing a new clinical tool to monitor and classify patient disease progression.

Teaser

A mechanistic model reveals tau protein dynamics in Alzheimer’s, showing stage-specific shifts in transport and local production.
An antimicrobial drug recommender system using MALDI-TOF MS and dual-branch neural networks
Authors: De Waele Gaetan , Menschaert Gerben , Waegeman Willem
Published: September 2023

Timely and effective use of antimicrobial drugs can improve patient outcomes, as well as help safeguard against resistance development. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently routinely used in clinical diagnostics for rapid species identification. Mining additional data from said spectra in the form of antimicrobial resistance (AMR) profiles is, therefore, highly promising. Such AMR profiles could serve as a drop-in solution for drastically improving treatment efficiency, effectiveness, and costs.

This study endeavours to develop the first machine learning models capable of predicting AMR profiles for the whole repertoire of species and drugs encountered in clinical microbiology. The resulting models can be interpreted as drug recommender systems for infectious diseases. We find that our dual-branch method delivers considerably higher performance compared to previous approaches. In addition, experiments show that the models can be efficiently fine-tuned to data from other clinical laboratories. MALDI-TOF-based AMR recommender systems can, hence, greatly extend the value of MALDI-TOF MS for clinical diagnostics.

All code supporting this study is distributed on PyPI and is packaged under:https://github.com/gdewael/maldi-nn
B cell directed CAR-T cell therapy results in activation of CD8+ cytotoxic CAR-negative bystander T cells in both non-human primates and patients
Authors: Kaminski James , Fleming Ryan A. , Alvarez-Calderon Francesca , McGuckin Connor , Ho Emily E. , Eng Fay , Rui Xianliang , Keskula Paula , Cagnin Lorenzo , Charles Joanne , Zavistaski Jillian , Margossian Steven P. , Kapadia Malika A. , Rottman James B. , Lane Jennifer , Baumeister Susanne H.C. , Tkachev Victor , Shalek Alex K. , Kean Leslie S. , Gerdemann Ulrike
Published: September 2023

There is growing appreciation for the emergence of CARnegbystander T cells after CAR-T cell infusion. However, their phenotypic and transcriptomic hallmarks and mechanisms of activation remain uncertain. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T cells to interrogate CARnegT cells following B cell targeted CAR-T cell therapy. In a NHP model, we observed a distinct population of activated CD8+ CARnegT cells emerging during CAR-T cell expansion. These bystander CD8+ CARnegT cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisangelecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T cells. These T cells efficiently killed leukemic cells through a TCR-independent mechanism. Together, these data identify bystander CD8+ T cells as a novel mechanism by which CAR-T cell infusion can induce further anti-leukemic activity, measurable in both NHP and in patients.

Statement of Significance

We have deeply interrogated CARnegbystander CD8+ T cells during CAR-T cell expansion in non­human primates and patients receiving Tisangelecleucel to identify the unique transcriptomic signature defining these cells, and to determine that IL-2-and IL-15-induced cytotoxic bystander T cells are capable of killing in a TCR-independent manner. These data highlight the potential of bystander T cells for leukemia control and provide a critical foundation for their future analysis.