bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic and immune‐related gene signatures: Predictive stratification and prognostic implications in gastric cancer
Authors: Shao Jian , Zhang Wenjia , Li Yiguang , Tang Yi , Fan Lihong
Published: November 2023

Background

Gastric cancer, marked by its heterogeneous nature, showcases various molecular subtypes and clinical trajectories. This research delves into the significance of metabolic and immune‐driven pathways in gastric cancer, constructing a prognostic signature derived from differentially expressed metabolic and immune‐correlated genes (DE‐MIGs).

Methods

Metabolic and immune‐associated gene were sourced from the GeneCards database. Differential expression analysis on the TCGA‐STAD dataset was executed using the limma package, unveiling 51 DE‐MIGs that underwent functional enrichment scrutiny. The LASSO Cox regression methodology guided the creation of the prognostic signature, and individual patient risk scores were determined. Assessment tools like CIBERSORT, ESTIMATE and ssGSEA were deployed to study the immune microenvironment, while mutation profiles, genomic stability, resistance to chemotherapy and immunotherapy responsiveness were scrutinized across distinct signature categorizations.

Results

Among the identified DE‐MIGs, 26 were significantly tied to the overall survival of gastric cancer patients. The developed prognostic signature proficiently differentiated patients into high‐risk and low‐risk cohorts, with the latter showing markedly better outcomes. The study underscored the centrality of the immune microenvironment in influencing gastric cancer outcomes. Key pathways such as TGF‐Beta, TP53 and NRF2 dominated the high‐risk group, whereas the LRTK−RAS and WNT pathways characterized the low‐risk group. Interestingly, the low‐risk segment also manifested a heightened tumor mutation burden and enhanced susceptibility to immunotherapy.

Conclusions

Our findings introduce a pivotal prognostic signature, rooted in DE‐MIGs, that effectively segregates gastric cancer patients into distinct risk‐based segments. Insights into the influential role of the immune microenvironment in gastric cancer progression pave the way for more refined therapeutic interventions.
Early‐Life Exposure to Dietary Large Phospholipid‐Coated Lipid Droplets Improves Markers of Metabolic and Immune Function in Adipose Tissue Later in Life in a Mouse Model
Authors: Klein Hazebroek Marlou , Baars Annemarie , Mischke Mona , Oosting Annemarie , van Schothorst Evert M. , Schipper Lidewij
Published: November 2023

Scope

Human milk (HM) is considered optimal nutrition for infants, beneficially programming adult health outcomes including reduced obesity risk. Early life exposure to infant formula with lipid droplets closely resembling the structural properties of HM lipid globules (Nuturis) attenuated white adipose tissue (WAT) accumulation in mice upon adult western‐style diet (WSD) feeding. Here, the study aims to elucidate underlying mechanisms.

Methods and results

Mice are raised on control or Nuturis diets between postnatal days 16–42 followed by either standard diet or WSD for 16 weeks. While the adult body composition of mice on a standard diet is not significantly affected, Nuturis reduced adiposity in mice on WSD. Morphologically, mean adipocyte size is reduced in Nuturis‐raised mice, independent of adult diet exposure, and WAT macrophage content is reduced, albeit not significantly. Transcriptomics of epididymal WAT indicate potential beneficial effects on energy metabolism and macrophage function by Nuturis.

Conclusion

Reduced adult adiposity by early life exposure to Nuturis appears to be associated with smaller adipocytes and alterations in WAT immune and energy metabolism. These results suggest that early modulation of WAT structure and/or function may contribute to the protective programming effects of the early‐life Nuturis diet on later‐life adiposity.
Transrectal ultrasound vector projectile imaging for time‐resolved visualization of flow dynamics in the male urethra: A clinical pilot study
Authors: Ishii Takuro , Yamanishi Tomonori , Kamasako Tomohiko , Shibata Chiharu , Fuse Miki , Kaga Mayuko , Kaga Kanya , Nahas Hassan , Yiu Billy Y. S. , Yu Alfred C. H. , Saijo Yoshifumi
Published: November 2023

Background

Quantitative and comprehensive visualization of urinary flow dynamics in the urethra is crucial for investigating patient‐specific mechanisms of lower urinary tract symptoms (LUTS). Although some methods can evaluate the global properties of the urethra, it is critical to assess the local information, such as the location of the responsible lesion and its interactions with urinary flow in relation to LUTS. This approach is vital for enhancing personalized and focal treatments. However, there is a lack of such diagnostic tools that can directly observe how the urethral shape and motion impact urinary flow in the urethra.

Purpose

This study aimed to develop a novel transrectal ultrasound imaging modality based on the contrast‐enhanced urodynamic vector projectile imaging (CE‐UroVPI) framework and validate its clinical applicability for visualizing time‐resolved flow dynamics in the urethra.

Methods

A new CE‐UroVPI system was developed using a research‐purpose ultrasound platform and a custom transrectal linear probe, and an imaging protocol for acquiring urodynamic echo data in male patients was designed. Thirty‐four male patients with LUTS participated in this study. CE‐UroVPI was performed to acquire ultrasound echo signals from the participant's urethra and urinary flow at various voiding phases (initiation, maintenance, and terminal). The ultrasound datasets were processed with custom software to visualize urinary flow dynamics and urethra tissue deformation.

Results

The transrectal CE‐UroVPI system successfully visualized the time‐resolved multidirectional urinary flow dynamics in the prostatic urethra during the initiation, maintenance, and terminal phases of voiding in 17 patients at a frame rate of 1250 fps. The maximum flow speed measured in this study was 2.5 m/s. In addition, when the urethra had an obstruction or an irregular partial deformation, the devised imaging modality visualized complex flow patterns, such as vortices and flow jets around the lesion.

Conclusions

Our study findings demonstrate that the transrectal CE‐UroVPI system developed in this study can effectively image fluid‐structural interactions in the urethra. This new diagnostic technology has the potential to facilitate quantitative and precise assessments of urethral voiding functions and aid in the improvement of focal and effective treatments for patients with LUTS.
Existential distress among family caregivers of patients with advanced cancer: A systematic review and meta‐analysis
Authors: Walbaum Charlotte , Philipp Rebecca , Oechsle Karin , Ullrich Anneke , Vehling Sigrun
Published: November 2023

Objective

Caregiving for a loved one is challenging and requires significant resources. Existential distress in family caregivers may include hopelessness, demoralization, fear of death, pre‐loss grief, or a sense of not being emotionally prepared. The aim of this systematic review is to synthesize the quantitative literature on existential distress among family caregivers of patients with advanced cancer, focusing on its prevalence, association with mental disorders, as well as with sociodemographic, disease, and treatment‐related factors.

Methods

We systematically searched electronic databases for quantitative studies of the above‐described existential distress concepts in family caregivers of patients with advanced cancer. Two independent reviewers extracted data and evaluated study quality. Data were analyzed using random‐effects meta‐analysis.

Results

We retrieved 17.587 records, of which 31 studies fulfilled inclusion criteria. 63% of the studies (n = 20) provided sufficient data for meta‐analysis for 5558 patients. We found an overall pooled prevalence of 30.6% for existential distress, 95% CI [24.2–37.0]. For existential distress subconcepts, prevalence rates were 57.0%, 95% CI [37.8–76.2], for death anxiety, 13.9%, 95% CI [10.8–17.0], for demoralization, 24.0%, 95% CI [18.0–30.0], for pre‐loss grief, 18.4%, 95% CI [4.0–32.7], for hopelessness, 35.2%, 95% CI [28.2–42.2], for loneliness, and 35.6%, 95% CI [13.0–58.3], for emotional unpreparedness.

Conclusions

Approximately one third of the respondents were affected by high levels of existential distress. The review provides evidence for further development of support services that can reduce existential distress, focused on death anxiety, and improve the quality of life for family caregivers of patients with advanced cancer.
Observer‐based event‐triggered consensus control for multi‐agent systems with nonlinearity and unknown inputs
Authors: Weng Weijie , Zhu Fanglai
Published: November 2023

This article investigates observer‐based consensus issues for a class of Lipschitz nonlinear multi‐agent systems (MASs) with unknown input. To address the challenges because of the unmeasurable states and the unknown input of each agent system, an interval observer is utilized to design an unknown input observer (UIO). The UIO possesses the capability of generating asymptotically the estimations of both the system states and unknown input simultaneously. Subsequently, a distributed control protocol scheme is put forwarded. The distributed controller for each agent is designed by using the state estimation and the unknown input reconstruction (UIR). The unknown input is compensated thanks for the introduction of the UIR into the controller, and thus leads to a better control performance. Besides, the event‐triggered strategy is also considered such that agents communicate with each other discontinuously. In this way, an observer‐based event‐triggered distributed control protocol scheme is developed, and under the scheme, the asymptotic convergent MASs consensus is accomplished. Finally, the effectiveness of the proposed methods is verified by a simulation example.
Off‐policy model‐based end‐to‐end safe reinforcement learning
Authors: Kanso Soha , Jha Mayank Shekhar , Theilliol Didier
Published: November 2023

Safety and stability considerations play a crucial role in the development of learning based strategies for control design of systems that require high levels of safety. Safe reinforcement learning (RL) based approaches traditionally seek learning of the control laws that are optimal with respect to system performance whilst ensuring system stability and safety. In this article, an off‐policy safe RL based approach is proposed for nonlinear systems affine in control in continuous time. In this novel work, safety and stability are guaranteed during initialization and exploration phases by adjusting the control input with the solution of a quadratic programming problem combining both input to state stable‐control Lyapunov function and robust control barrier function (R‐CBF) conditions. Moreover, the safety of the learned policy is assured by augmenting the cost function with a CBF to maintain safety and optimize performance simultaneously. Novel mathematically rigorous proofs are provided to establish the stability and safety guarantees, offering a sound theoretical foundation for the approach. To demonstrate the effectiveness of the algorithm, two examples are presented: engine surge and stall dynamics, and an unstable nonlinear system.
On‐farm evaluations of overhead irrigation sprinkler packages at full and reduced rates
Authors: Holt Jonathan , Yost Matt , Creech Earl , Winward Dean , Barker Burdette
Published: November 2023

Irrigation is a critical resource in meeting the global demand for food, feed, fiber, and fuel. One water optimization method with high potential and interest is the use of more efficient irrigation systems. In many areas where pivots are used, the most common sprinkler package is mid‐elevation sprinkler application (MESA), which typically has application efficiencies near 80%. Low‐energy precision application (LEPA) and mobile drip irrigation (MDI) can have greater than 95% application efficiency. The objective of this research was to evaluate the ability of LEPA and MDI to maintain crop yield and quality in alfalfa (Medicago sativa L.) and silage corn (Zea mays L.), at similar and reduced irrigation rates as MESA. The intent of the reduced rate was to determine if the decreased application losses with LEPA and MDI could result in sustained crop production with a 20% irrigation rate reduction. Actual reductions ranged from 5% to 55% depending on system and site due to equipment constraints. Data from two farms in Utah during 2018–2020 provided evidence that these systems can often maintain yield and forage quality with 5%–55% less applied water. However, there were also many instances where yield was reduced by LEPA and MDI, even with similar application rates to MESA. This indicates that the two higher efficiency systems will not save water in all cases and that the application system must be carefully evaluated in small on‐farm trials over multiple years for its ability to succeed in specific field conditions.
Control of Luminescence and Interfacial Properties as Perspective for Upconversion Nanoparticles
Authors: Schroter Alexandra , Hirsch Thomas
Published: November 2023

Near‐infrared (NIR) light is highly suitable for studying biological systems due to its minimal scattering and lack of background fluorescence excitation, resulting in high signal‐to‐noise ratios. By combining NIR light with lanthanide‐based upconversion nanoparticles (UCNPs), upconversion is used to generate UV or visible light within tissue. This remarkable property has gained significant research interest over the past two decades. Synthesis methods are developed to produce particles of various sizes, shapes, and complex core–shell architectures and new strategies are explored to optimize particle properties for specific bioapplications. The diverse photophysics of lanthanide ions offers extensive possibilities to tailor spectral characteristics by incorporating different ions and manipulating their arrangement within the nanocrystal. However, several challenges remain before UCNPs can be widely applied. Understanding the behavior of particle surfaces when exposed to complex biological environments is crucial. In applications where deep tissue penetration is required, such as photodynamic therapy and optogenetics, UCNPs show great potential as nanolamps. These nanoparticles can combine diagnostics and therapeutics in a minimally invasive, efficient manner, making them ideal upconversion probes. This article provides an overview of recent UCNP design trends, highlights past research achievements, and outlines potential future directions to bring upconversion research to the next level.
Exact confidence intervals for the difference of two proportions based on partially observed binary data
Authors: Yu Chongxiu , Wang Weizhen , Zhang Zhongzhan
Published: November 2023

In a matched pairs experiment, two binary variables are typically observed on all subjects in the experiment. However, when one of the variables is missing on some subjects, we have so called the partially observed binary data that consist of two parts: a multinomial from the subjects with a pair of observed variables and two independent binomials from the subjects with only one observed variable. The goal of this paper is to construct exact confidence intervals for the difference of two (success) proportions of the two binary variables. We first derive a new test by combining two score tests for the two parts of the data and invert it to an asymptotic confidence interval. Since asymptotic intervals do not achieve the nominal level, this interval and three other existing intervals are improved to be exact by the general
‐function method. We compare the infimum coverage probability and average interval length of these intervals and recommend the exact intervals that are improved from the newly proposed interval. Two real data sets are used to illustrate the intervals.
Accidental ketamine administration in a horse supposed to undergo general anaesthesia for tenovaginoscopy: Errors and the need of Morbidity and Mortality Rounds in veterinary medicine
Authors: Medina‐Bautista Francisco , Navarro‐Altuna Victoria , Aßmann Anton D. , Bettschart‐Wolfensberger Regula
Published: November 2023

An 11‐year‐old, 500 kg, healthy mare was admitted for tenovaginoscopy. A jugular venous catheter was inserted to administer detomidine for diagnostic imaging and for anaesthesia‐related drug administration. The horse was premedicated with intramuscular acepromazine and intravenous flunixin. For sedation, 7.5 mL of a solution, presumed to be xylazine 2%, was drawn up in a syringe and labelled with a sticker. Two minutes after injection of 7.5 mL from xylazine‐labelled syringe, the horse showed severe ataxia and fell. Nystagmus and catatonia appeared while one person sat on its neck, to prevent it from rising. After 8 minutes, the horse could not be kept down and took several uncoordinated attempts to stand, still showing nystagmus and ataxia for several minutes. The xylazine‐labelled syringes were analysed. They contained pure ketamine. This case report should raise awareness about clinical errors, a healthy error culture and use of Morbidity and Mortality Rounds to improve patient and personnel care.
Interdisciplinary Rendez-Vous Approach in Endovascular Stroke Treatment: A New Concept to Accelerate Mechanical Thrombectomy in Primary Stroke Centers
Authors: Krug Nadja , Braun Holger , Knez Andreas , Auerbach Holger , Bodenberger Stephen , Eglseder Bettina , Kirschke Jan , Boeckh-Behrens Tobias , Wunderlich Silke , Henninger Julia , Boy Sandra , Renz Martin , Sepp Dominik , Zimmer Claus , Maegerlein Christian
Published: November 2023

Purpose

Prompt endovascular treatment of patients with stroke due to intracranial Large Vessel Occlusion (LVO) is a major challenge in rural areas because neurointerventionalists are usually not available. As a result, treatment is delayed, and clinical outcomes are worse compared with patients primarily treated in comprehensive stroke centers (CSC). To address this problem, we present a concept in which interdisciplinary, on-site endovascular treatment is performed in a Primary Stroke Center (PSC) by a team of interventional neuroradiologists and cardiologists: the Rendez-Vous approach.

Methods

Thirty-five patients with LVO who underwent interdisciplinary thrombectomy on-site at the PSC as part of the Rendez-Vous concept were compared with 72 patients who were transferred from a PSCs to the CSC for thrombectomy when diagnosed with LVO in terms of temporal sequences and clinical outcomes.

Results

Patients treated on-site at the PSC as part of the Rendez-Vous approach were managed as successfully and without an increase in complication rates compared with patients treated secondarily at a CSC (91.7% successful interventions in Rendez-Vous vs. 87.3% in control group, p = 0.57). The time from diagnosis of LVO to groin puncture was reduced by mean 74.3 min with the Rendez-Vous concept (p < 0.01). Regarding the clinical outcome, a functionally independent status was achieved in 45.5% in the Rendez-Vous group and in 22.6% in the control group (p = 0.029).

Conclusion

Thanks to interdisciplinary teamwork between cardiology and interventional neuroradiology in local PSCs, times to successful reperfusion can be reduced. This has a potentially positive impact on the clinical outcome of stroke patients.

Graphical Abstract
Enzymatic vitamin A2 production enables red-shifted optogenetics
Authors: Gerhards Johanna , Volkov Leo I. , Corbo Joseph C. , Malan Daniela , Sasse Philipp
Published: November 2023

Optogenetics is a technology using light-sensitive proteins to control signaling pathways and physiological processes in cells and organs and has been applied in neuroscience, cardiovascular sciences, and many other research fields. Most commonly used optogenetic actuators are sensitive to blue and green light, but red-light activation would allow better tissue penetration and less phototoxicity. Cyp27c1 is a recently deorphanized cytochrome P450 enzyme that converts vitamin A1 to vitamin A2, thereby red-shifting the spectral sensitivity of visual pigments and enabling near-infrared vision in some aquatic species.

Here, we investigated the ability of Cyp27c1-generated vitamin A2 to induce a shift in spectral sensitivity of the light-gated ion channel Channelrhodopsin-2 (ChR2) and its red-shifted homolog ReaChR. We used patch clamp to measure photocurrents at specific wavelengths in HEK 293 cells expressing ChR2 or ReaChR. Vitamin A2 incubation red-shifted the wavelength for half-maximal currents (λ50%) by 6.8 nm for ChR2 and 12.4 nm for ReaChR. Overexpression of Cyp27c1 in HEK 293 cells showed mitochondrial localization, and HPLC analysis showed conversion of vitamin A1 to vitamin A2. Notably, the λ50% of ChR2 photocurrents was red-shifted by 10.5 nm, and normalized photocurrents at 550 nm were about twofold larger with Cyp27c1 expression. Similarly, Cyp27c1 shifted the λ50% of ReaChR photocurrents by 14.3 nm and increased normalized photocurrents at 650 nm almost threefold.

Since vitamin A2 incubation is not a realistic option for in vivo applications and expression of Cyp27c1 leads to a greater red-shift in spectral sensitivity, we propose co-expression of this enzyme as a novel strategy for red-shifted optogenetics.
Revisiting landslide risk terms: IAEG commission C-37 working group on landslide risk nomenclature
Authors: Corominas Jordi , Guzzetti Fausto , Lan Hengxing , Macciotta Renato , Marunteranu Cristian , McDougall Scott , Strom Alexander
Published: November 2023

Significant effort has been devoted during the last few decades to the development of methodologies for landslide hazard and risk assessment. All of this work requires harmonization of the methodologies and terminology to facilitate communication within the landslide community, as well as with stakeholders and researchers from other disciplines. Currently, glossaries, and methodological recommendations exist for preparing landslide hazard and risk studies. Nevertheless, there is still debate on the usage of some terms and their implementation in practice.

In 2016, the IAEG commission C-37 established a working group with the objective of preparing a standard multilingual glossary of landslide hazard and risk terms. The glossary aims for the international harmonization of the terms and definitions with those used in associated disciplines (e.g., seismology, hydrology) while considering landslides specifically. The glossary is based on previously published glossaries, including those prepared by ISSMGE TC32, FedIGS, JTC1, and UNISDR. This article presents comments on the meaning of some of the terms that have required further discussion. The English version of the glossary is also included.
Utilisation of semantic technologies for the realisation of data-driven process improvements in the maintenance, repair and overhaul of aircraft components
Authors: Gill Milapji Singh , Fay Alexander
Published: November 2023

Aircraft components are subject to numerous, complex and often manual maintenance, repair and overhaul (MRO) procedures to ensure long operating cycles. In order to remain competitive in the long term, in spite of increased cost pressure, MRO service providers must improve the efficiency of their processes through the targeted use of internal knowledge sources. Techniques from the fields of Artificial Intelligence (AI) and Data Mining (DM) have already proven their potential in diverse domains. However, the application of such data-driven approaches is also associated with some hurdles that need to be eliminated in advance. Data are generated at the business process level, known as Information Technology (IT, e.g. Enterprise Resource Planning (ERP) systems), as well as at the equipment level, known as Operational Technology (OT, e.g. test equipment). The integration of both forms the basis for improving the maintenance activities of diagnostics and maintenance scheduling. However, creating a unified view and understanding of the manifold data related to the maintenance process is a major problem due to the heterogeneous data sources and formats included. In this context, the use of Semantic Technologies (ST) can be helpful to overcome these challenges and provide the foundation for improved data management. The objective of this contribution is to introduce an ontology that delineates fundamental domain concepts, facilitating the augmentation of maintenance process data for individual aircraft components with pertinent contextual information. The result is being applied within the scope of a proof of concept aimed at supporting the coherent digital services diagnostics and short-term maintenance planning.
Disaster Preparedness of Nursing Students in Northern Cyprus: Descriptive Cross-Sectional Study
Authors: Imdat Tulay , Tastan Sevinc
Published: November 2023

Objective:

This study aims to evaluate disaster preparedness of undergraduate nursing students.

Methods:

This descriptive cross-sectional study included 302 voluntary nursing students from a university in Northern Cyprus. Data were collected through an online survey using Google Forms, which included a descriptive information form and the General Disaster Preparedness Belief Scale (GDPBS).

Results:

The mean age of the participants was 20.64 ± 2.02 years. Among the participants, 41.7% had prior experience with disasters, and 77.2% expressed a need for disaster education. The average GDPBS total score was high, and the mean score of the sub-dimensions was moderate. Nursing students who expressed a need for disaster education had higher scores on the severity and self-efficacy subscales of the GDPBS (p<0.05).

Conclusion:

The level of disease preparedness was moderate in nursing students in Northern Cyprus. Therefore, education based on the health belief model, which assumes that positive health behaviors are affected by knowledge and attitudes, may be useful to improve disaster preparedness in nursing students.
The effectiveness of note taking through exposure to L2 input: A meta-analysis
Authors: Jin Zhouhan , Webb Stuart
Published: November 2023

There has been increasing interest in the effects of note taking in second language (L2) research. However, no meta-analysis has been conducted to examine the relationship between note taking and learning through exposure to L2 input. We retrieved 28 effect sizes from 21 studies (N = 1992) to explore the overall effects of note taking as well as to examine the extent to which the effectiveness of note taking is likely to vary as a function of a set of potential moderators (i.e., learner variables, treatment variables, note-taking features, learning target, and measurement type). Results revealed that note taking had a small to medium positive overall effect on learning through exposure to L2 input (g = 0.56, 95% CI: 0.24–0.88). Subsequent moderator analyses revealed that variability in the size of note-taking effects across studies was explained by learner variables (context, region, orthographic scripts, institutional level), treatment variables (mode of input, material type), note-taking features (note-taking behavior, number of note-taking sessions, provision and type of note-taking strategy instruction, total length of instruction, opportunity to review notes), learning target, and measurement type. Based on the obtained findings, teachers are recommended to incorporate note taking in L2 classrooms. Pedagogical suggestions and directions for future research are also provided.
Manipulating the nonlinearity of transition-metal dichalcogenide polaritons
Authors: Hwang Min-Soo , Park Hong-Gyu
Published: November 2023

The lithographically designed potential wells in monolayer WS2 microcavities are utilized to manipulate nonlinear transition-metal dichalcogenide polaritons and enhance the polariton-reservoir interaction strength.
A blockchain-based information market to incentivise cooperation in swarms of self-interested robots
Authors: Van Calck Ludéric , Pacheco Alexandre , Strobel Volker , Dorigo Marco , Reina Andreagiovanni
Published: November 2023

Robot swarms are generally considered to be composed of cooperative agents that, despite their limited individual capabilities, can perform difficult tasks by working together. However, in open swarms, where different robots can be added to the swarm by different parties with potentially competing interests, cooperation is but one of many strategies. We envision an information market where robots can buy and sell information through transactions stored on a distributed blockchain, and where cooperation is encouraged by the economy itself. As a proof of concept, we study a classical foraging task, where exchanging information with other robots is paramount to accomplish the task efficiently. We illustrate that even a single robot that lies to others—a so-called Byzantine robot—can heavily disrupt the swarm. Hence, we devise two protection mechanisms. Through an individual-level protection mechanism, robots are more sceptical about others’ information and can detect and discard Byzantine information, at the cost of lower efficiency. Through a systemic protection mechanism based on economic rules regulating robot interactions, robots that sell honest information acquire over time more wealth than Byzantines selling false information. Our simulations show that a well-designed robot economy penalises misinformation spreading and protects the swarm from Byzantine behaviour. We believe economics-inspired swarm robotics is a promising research direction that exploits the timely opportunity for decentralised economies offered by blockchain technology.
Neuronal transcription of autism gene PTCHD1 is regulated by a conserved downstream enhancer sequence
Authors: Pastore Stephen F. , Muhammad Tahir , Stan Cassandra , Frankland Paul W. , Hamel Paul A. , Vincent John B.
Published: November 2023

Patched domain-containing 1 (PTCHD1) is a well-established susceptibility gene for autism spectrum disorder (ASD) and intellectual disability (ID). Previous studies have suggested that alterations in the dosage of PTCHD1 may contribute to the etiology of both ASD and ID. However, there has not yet been a thorough investigation regarding mechanisms that regulate PTCHD1 expression. We sought to characterize the Ptchd1 promoter in a mouse neuronal model, as well as to identify and validate cis regulatory elements. We defined specific regions of the Ptchd1 promoter essential for robust expression in P19-induced neurons. Evolutionarily-conserved putative transcription factor binding sites within these regions were subsequently identified. Using a pairwise comparison of chromatin accessibility between mouse forebrain and liver tissues, a candidate regulatory region, ~ 9.1 kbp downstream of the Ptchd1 stop codon was defined. This region harbours two ENCODE-predicted enhancer cis-regulatory elements. Further, using DNase footprint analysis, a putative YY1-binding motif was also identified. Genomic deletion of the entire 8 kbp downstream open chromatin region attenuated Ptchd1 transcription by over 60% in our neuronal model, corroborating its predicted regulatory function. This study provides mechanistic insights related to the expression of PTCHD1, and provides important context to interpret genetic and genomic variation at this locus which may influence neurodevelopment.
Fractal complexity of daily physical activity and cognitive function in a midlife cohort
Authors: Blodgett Joanna M. , Ahmadi Matthew , Stamatakis Emmanuel , Rockwood Kenneth , Hamer Mark
Published: November 2023

High stability of fluctuation in physiological patterns across fixed time periods suggest healthy fractal complexity, while greater randomness in fluctuation patterns may indicate underlying disease processes. The importance of fractal stability in mid-life remains unexplored. We quantified fractal regulation patterns in 24-h accelerometer data and examined associations with cognitive function in midlife. Data from 5097 individuals (aged 46) from the 1970 British Cohort Study were analyzed. Participants wore thigh-mounted accelerometers for seven days and completed cognitive tests (verbal fluency, memory, processing speed; derived composite z-score). Detrended fluctuation analysis (DFA) was used to examine temporal correlations of acceleration magnitude across 25 time scales (range: 1 min–10 h). Linear regression examined associations between DFA scaling exponents (DFAe) and each standardised cognitive outcome. DFAe was normally distributed (mean ± SD: 0.90 ± 0.06; range: 0.72–1.25). In males, a 0.10 increase in DFAe was associated with a 0.30 (95% Confidence Interval: 0.14, 0.47) increase in composite cognitive z-score in unadjusted models; associations were strongest for verbal fluency (0.10 [0.04, 0.16]). Associations remained in fully-adjusted models for verbal fluency only (0.06 [0.00, 0.12]). There was no association between DFA and cognition in females. Greater fractal stability in men was associated with better cognitive function. This could indicate mechanisms through which fractal complexity may scale up to and contribute to cognitive clinical endpoints.
A novel approach to microsurgical teaching in head and neck surgery leveraging modern 3D technologies
Authors: Weber Manuel , Backhaus Joy , Lutz Rainer , Nobis Christopher-Philipp , Zeichner Samuel , Koenig Sarah , Kesting Marco , Olmos Manuel
Published: November 2023

The anatomically complex and often spatially restricted conditions of anastomosis in the head and neck region cannot be adequately reproduced by training exercises on current ex vivo or small animal models. With the development of a Realistic Anatomical Condition Experience (RACE) model, complex spatial-anatomical surgical areas and the associated intraoperative complexities could be transferred into a realistic training situation in head and neck surgery. The RACE model is based on a stereolithography file generated by intraoperative use of a three-dimensional surface scanner after neck dissection and before microvascular anastomosis. Modelling of the acquired STL file using three-dimensional processing software led to the model’s final design. As a result, we have successfully created an economical, sustainable and realistic model for microsurgical education and provide a step-by-step workflow that can be used in surgical and general medical education to replicate and establish comparable models. We provide an open source stereolithography file of the head-and-neck RACE model for printing for educational purposes. Once implemented in other fields of surgery and general medicine, RACE models could mark a shift in medical education as a whole, away from traditional teaching principles and towards the use of realistic and individualised simulators.
Lower serum cholesterol levels as a risk factor for critical illness polyneuropathy: a matched case–control study
Authors: Zulehner Gudrun , Seidel Stefan , Polanz Alexander , Schörgenhofer Christian , Rommer Paulus , Merrelaar Marieke , Roth Dominik , Herkner Harald , Behrens Sybille , Kienbacher Calvin Lukas
Published: November 2023

Critical illness polyneuropathy (CIP) is a frequent and underdiagnosed phenomenon among intensive care unit patients. The lipophilic nature of neuronal synapses may result in the association of low serum cholesterol levels with a higher rate of CIP development. We aimed to investigate this issue in critically ill patients. All cases diagnosed with CIP in our tertiary care hospital between 2013 and 2017 were 1:1 matched with controls without the condition by age, sex, and ICD diagnoses. The main risk factors examined were the differences in change between initial and minimum serum total cholesterol levels, and minimum serum total cholesterol levels between matched pairs. Other predictors were serum markers of acute inflammation. We included 67 cases and 67 controls (134 critically ill patients, 49% female, 46% medical). Serum total cholesterol levels decreased more profoundly in cases than controls (median: −74 (IQR −115 to −24) vs. −39 (IQR −82 to −4), median difference: −28, 95% CI [−51, −5]), mg/dl). Minimum serum total cholesterol levels were lower in the cases (median difference: −24, 95% CI [−39, −9], mg/dl). We found significant median differences across matched pairs in maximum serum C-reactive protein (8.9, 95% CI [4.6, 13.2], mg/dl), minimum albumin (−4.2, 95% CI [−6.7, −1.7], g/l), decrease in albumin (−3.9, 95% CI [−7.6, −0.2], g/l), and lowest cholinesterase levels (−0.72, 95% CI [−1.05, −0.39], U/l). Subsequently, more pronounced decreases in serum total cholesterol levels and lower minimum total cholesterol levels during critical care unit hospitalizations may be a risk factor for CIP.
Mutation at the entrance of the quinone cavity severely disrupts quinone binding in respiratory complex I
Authors: Yi Jason Tae , Wang Panyue , Stuchebrukhov Alexei A.
Published: November 2023

In all resolved structures of complex I, there exists a tunnel-like Q-chamber for ubiquinone binding and reduction. The entrance to the Q-chamber in ND1 subunit forms a narrow bottleneck, which is rather tight and requires thermal conformational changes for ubiquinone to get in and out of the binding chamber. The substitution of alanine with threonine at the bottleneck (AlaThr MUT), associated with 3460/ND1 mtDNA mutation in human complex I, is implicated in Leber's Hereditary Optic Neuropathy (LHON). Here, we show the AlaThr MUT further narrows the Q-chamber entrance cross-section area by almost 30%, increasing the activation free energy barrier of quinone passage by approximately 5 kJ mol−1. This severely disrupts quinone binding and reduction as quinone passage through the bottleneck is slowed down almost tenfold. Our estimate of the increase in free energy barrier is entirely due to the bottleneck narrowing, leading to a reduction of the transition state entropy between WT and MUT, and thus more difficult quinone passage. Additionally, we investigate details of possible water exchange between the Q-chamber and membrane. We find water exchange is dynamic in WT but may be severely slowed in MUT. We propose that LHON symptoms caused by 3460/ND1 mtDNA mutation are due to slowed quinone binding. This leads to an increased production of reactive oxidative species due to upstream electron backup at the FMN site of complex I, thus resulting in a mt bioenergetic defect.
Long-term outcomes of periprocedural coronary dissection and perforation for patients undergoing percutaneous coronary intervention in a Japanese multicenter registry
Authors: Kuno Toshiki , Ohata Takanori , Nakamaru Ryo , Sawano Mitsuaki , Kodaira Masaki , Numasawa Yohei , Ueda Ikuko , Suzuki Masahiro , Noma Shigetaka , Fukuda Keiichi , Kohsaka Shun
Published: November 2023

Long-term outcomes of iatrogenic coronary dissection and perforation in patients undergoing percutaneous coronary intervention (PCI) remains under-investigated. We analyzed 8,721 consecutive patients discharged after PCI between 2008 and 2019 from Keio Cardiovascular (KiCS) PCI multicenter prospective registry in the Tokyo metropolitan area. Significant coronary dissection was defined as persistent contrast medium extravasation or spiral or persistent filling defects with complete distal and impaired flow. The primary outcome was a composite of all-cause death, acute coronary syndrome, heart failure, bleeding, stroke requiring admission, and coronary artery bypass grafting two years after discharge. We used a multivariable Cox hazard regression model to assess the effects of these complications. Among the patients, 68 (0.78%) had significant coronary dissections, and 61 (0.70%) had coronary perforations at the index PCI. Patients with significant coronary dissection had higher rates of the primary endpoint and heart failure than those without (25.0% versus 14.3%, P = 0.02; 10.3% versus 4.2%, P = 0.03); there were no significant differences in the primary outcomes between the patients with and without coronary perforation (i.e., primary outcome: 8.2% versus 14.5%, P = 0.23) at the two-year follow-up. After adjustments, patients with coronary dissection had a significantly higher rate of the primary endpoint than those without (HR 1.70, 95% CI 1.02–2.84; P = 0.04), but there was no significant difference in the primary endpoint between the patients with and without coronary perforation (HR 0.51, 95% CI 0.21–1.23; P = 0.13). For patients undergoing PCI, significant coronary dissection was associated with poor long-term outcomes, including heart failure readmission.
Harnessing selenium nanoparticles (SeNPs) for enhancing growth and germination, and mitigating oxidative stress in Pisum sativum L.
Authors: Tendenedzai Job T. , Chirwa Evans M. N. , Brink Hendrik G.
Published: November 2023

Selenium, an essential micronutrient for plants and animals, can cause selenium toxicity as an oxyanion or at elevated doses. However, the toxic selenite (SeO32−) oxyanion, can be converted into less harmful elemental nano-selenium (Se0), with various practical applications. This research aimed to investigate two methods for reducing SeO32−: abiotic reduction using cell-free extract from Enterococcus spp. (abiotic-SeNPs) and chemical reduction involving L-ascorbic acid (chemical-SeNPs). Analysis with XPS confirmed the presence of Se0, while FTIR analysis identified surface functional groups on all SeNPs. The study evaluated the effects of SeO32−, abiotic-SeNPs, and chemical-SeNPs at different concentrations on the growth and germination of Pisum sativum L. seeds. SeO32− demonstrated detrimental effects on germination at concentrations of 1 ppm (germination index (GI) = 0.3). Conversely, both abiotic- and chemical-SeNPs had positive impacts on germination, with GI > 120 at 10 ppm. Through the DPPH assay, it was discovered that SeNPs exhibited superior antioxidant capabilities at 80 ppm, achieving over 70% inhibition, compared to SeO32− (less than 20% inhibition), therefore evidencing significant antioxidant properties. This demonstrates that SeNPs have the potential to be utilized as an agricultural fertilizer additive, benefiting seedling germination and development, while also protecting against oxidative stress.
Extracellular vesicles of human glial cells exert neuroprotective effects via brain miRNA modulation in a rat model of traumatic brain injury
Authors: Salikhova Diana I. , Timofeeva Angelika V. , Golovicheva Victoria V. , Fatkhudinov Timur Kh. , Shevtsova Yulia A. , Soboleva Anna G. , Fedorov Ivan S. , Goryunov Kirill V. , Dyakonov Alexander S. , Mokrousova Victoria O. , Shedenkova Margarita O. , Elchaninov Andrey V. , Makhnach Oleg V. , Kutsev Sergey I. , Chekhonin Vladimir P. , Silachev Denis N. , Goldshtein Dmitry V.
Published: November 2023

Stem cell-based therapeutic approaches for neurological disorders are widely studied. Paracrine factors secreted by stem cells in vitro and delivered intranasally might allow bypassing the disadvantages associated with a surgical cell delivery procedure with likely immune rejection of a transplant. In this study, we investigated the therapeutic effect of the extracellular vesicles secreted by glial progenitor cells (GPC-EV) derived from human induced pluripotent stem cell in a traumatic brain injury model. Intranasal administration of GPC-EV to Wistar rats for 6 days improved sensorimotor functions assessed over a 14-day observation period. Beside, deep sequencing of microRNA transcriptome of GPC-EV was estimate, and was revealed 203 microRNA species that might be implicated in prevention of various brain pathologies. Modulation of microRNA pools might contribute to the observed decrease in the number of astrocytes that inhibit neurorecovery processes while enhancing neuroplasticity by decreasing phosphorylated Tau forms, preventing inflammation and apoptosis associated with secondary damage to brain tissue. The course of GPC-EV administration was promoted the increasing protein levels of NF-κB in studied areas of the rat brain, indicating NF-κB dependent mechanisms as a plausible route of neuroprotection within the damaged area. This investigation showed that GPC-EV may be representing a therapeutic approach in traumatic brain injury, though its translation into the clinic would require an additional research and development.
Optimization of extraction-free protocols for SARS-CoV-2 detection using a commercial rRT-PCR assay
Authors: Kang Minhee , Jeong Eunjung , Kim Ji-Yeon , Yun Sun Ae , Jang Mi-Ae , Jang Ja-Hyun , Kim Tae Yeul , Huh Hee Jae , Lee Nam Yong
Published: November 2023

In the ongoing global fight against coronavirus disease 2019 (COVID-19), the sample preparation process for real-time reverse transcription polymerase chain reaction (rRT-PCR) faces challenges due to time-consuming steps, labor-intensive procedures, contamination risks, resource demands, and environmental implications. However, optimized strategies for sample preparation have been poorly investigated, and the combination of RNase inhibitors and Proteinase K has been rarely considered. Hence, we investigated combinations of several extraction-free protocols incorporating heat treatment, sample dilution, and Proteinase K and RNase inhibitors, and validated the effectiveness using 120 SARS-CoV-2 positive and 62 negative clinical samples. Combining sample dilution and heat treatment with Proteinase K and RNase inhibitors addition exhibited the highest sensitivity (84.26%) with a mean increase in cycle threshold (Ct) value of + 3.8. Meanwhile, combined sample dilution and heat treatment exhibited a sensitivity of 79.63%, accounting for a 38% increase compared to heat treatment alone. Our findings highlight that the incorporation of Proteinase K and RNase inhibitors with sample dilution and heat treatment contributed only marginally to the improvement without yielding statistically significant differences. Sample dilution significantly impacts SARS-CoV-2 detection, and sample conditions play a crucial role in the efficiency of extraction-free methods. Our findings may provide insights for streamlining diagnostic testing, enhancing its accessibility, cost-effectiveness, and sustainability.
Modelling the effectiveness of surveillance based on metagenomics in detecting, monitoring, and forecasting antimicrobial resistance in livestock production under economic constraints
Authors: Apenteng Ofosuhene O. , Aarestrup Frank M. , Vigre Håkan
Published: November 2023

Current surveillance of antimicrobial resistance (AMR) is mostly based on testing indicator bacteria using minimum inhibitory concentration (MIC) panels. Metagenomics has the potential to identify all known antimicrobial resistant genes (ARGs) in complex samples and thereby detect changes in the occurrence earlier. Here, we simulate the results of an AMR surveillance program based on metagenomics in the Danish pig population. We modelled both an increase in the occurrence of ARGs and an introduction of a new ARG in a few farms and the subsequent spread to the entire population. To make the simulation realistic, the total cost of the surveillance was constrained, and the sampling schedule was set at one pool per month with 5, 20, 50, or 100 samples. Our simulations demonstrate that a pool of 20–50 samples and a sequencing depth of 250 million fragments resulted in the shortest time to detection in both scenarios, with a time delay to detection of change of $$>\hspace{0.17em}$$

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15 months in all scenarios. Compared with culture-based surveillance, our simulation indicates that there are neither significant reductions nor increases in time to detect a change using metagenomics. The benefit of metagenomics is that it is possible to monitor all known resistance in one sampling and laboratory procedure in contrast to the current monitoring that is based on the phenotypic characterisation of selected indicator bacterial species. Therefore, overall changes in AMR in a population will be detected earlier using metagenomics due to the fact that the resistance gene does not have to be transferred to and expressed by an indicator bacteria before it is possible to detect.