bluuebunny/crossref_metadata_2025 huggingface dataset:
The bibliometric analysis of most cited 100 papers in anesthesia-induced neurotoxicity
Authors: Ocmen Elvan , Erdost Hale Aksu , Hanci Volkan
Published: December 2023

Anesthesia-induced neurotoxicity is a major concern for anesthetists for more than 20 years. Many experimental and clinical studies have been conducted on this topic since late 1990s. However, bibliometric analysis of these papers has not been reported. In this study, we aimed to analyze the 100 most cited articles on anesthesia-induced neurotoxicity. It was planned as cross-sectional study. On January 30, 2023, we searched the “Web of Science (WOS)” database for anesthesia-induced neurotoxicity and most cited 100 papers about this topic were obtained. Data such as authors’ names, year of publication, name of the journal, type of paper, and citation numbers were analyzed. The most cited 100 papers were read by the investigators, and the anesthetic, animal type in experimental studies, any protective agent and the method for detecting neurotoxicity used in the studies were also noted. There were 75 articles and 22 reviews in the 100 most cited articles. We found that most of the papers in most cited 100 list were published between 2010 to 1024. Most of the papers (11%) were from Harvard University and almost half of the papers (49%) were published in Anesthesiology. A great number of studies were performed in newborns or early childhood (85.5%) and inhalational anesthetics (54.7%) were the most studied anesthetic type. Most of the most cited 100 papers were published in Q1 journals (P = .012) and the continent of the most journals in this list was America (P = .014). The median total and annual citation numbers of funded papers were statistically significantly higher (P < .001 and P < .001 respectively). Anesthesia-induced neurotoxicity is very important, especially for pediatric anesthetists. This study is the first to conduct a bibliometric analysis of the most cited 100 publications on this field. Although there was a gap in the publications about this topic during COVID-19 pandemic, we believe that there will be many more publications on anesthesia-induced neurotoxicity since the mechanism, outcome and possible protection are still unknown.
Causal relationship between obesity and meniscal injuries: Two-sample Mendelian randomization
Authors: Deng Gaung-hua
Published: December 2023

To investigate the causal relationship between obesity and meniscal injuries using Mendelian randomization (MR). Genetic loci independently associated with obesity and meniscal injuries in people of European origin were selected as instrumental variables using pooled data from genome-wide association studies. Three MR analyses, MR-Egger, weighted median and inverse variance weighting, were used to investigate the causal relationship between obesity and meniscal injuries. The results were tested for robustness by heterogeneity and multiplicity tests, and sensitivity analyses were performed using the “leave-one-out” method. The inverse variance weighting results showed an OR (95% CI) of 1.13 (1.04–1.22), P = .003, indicating a causal relationship between obesity and the occurrence of meniscal injuries. And no heterogeneity and multiplicity were found by the test and sensitivity analysis also showed robust results. In this study, genetic data were analyzed and explored using 2-sample MR analysis, and the results showed that obesity is a risk factor for meniscal injuries.
Supraspinal control of motoneurons after paralysis enabled by spinal cord stimulation
Authors: Balaguer Josep-Maria , Prat-Ortega Genis , Verma Nikhil , Yadav Prakarsh , Sorensen Erynn , de Freitas Roberto , Ensel Scott , Borda Luigi , Donadio Serena , Liang Lucy , Ho Jonathan , Damiani Arianna , Grigsby Erinn , Fields Daryl P. , Gonzalez-Martinez Jorge A. , Gerszten Peter C. , Fisher Lee E. , Weber Douglas J. , Pirondini Elvira , Capogrosso Marco
Published: December 2023

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons.
Association of Alcohol Intake with the Incidence of Atrial Fibrillation in Persons ≥65 Years Old in the Atherosclerosis Risk in Communities (ARIC) Cohort
Authors: Li Louis Y , Li Linzi , Chen Lin Yee , Soliman Elsayed Z , Alonso Alvaro
Published: December 2023

Background

The association of alcohol intake with incident atrial fibrillation (AF) remains controversial, particularly among older individuals at higher risk of AF. This study explores the association of alcohol intake with incident AF in persons ≥65 years old in the Atherosclerosis Risk in Communities (ARIC) cohort.

Methods

Data were obtained from ARIC, a community-based cohort aiming to identify risk factors for cardiovascular disease. Alcohol intake was assessed through interviewer-administered questionnaires. Incident AF was ascertained between the 2011-2013 visit and 2019. Participants were classified as current, former, or never drinkers. Former drinkers were further categorized on weekly alcohol consumption: light, moderate, heavy. Covariates included demographic characteristics, prevalent cardiovascular disease, and other risk factors. The association between drinking characteristics and incident AF was analyzed using Cox proportional hazard models.

Results

There were 5,131 participants with mean (SD) age 75.2 (5.0) years, 41% male, 23% Black, and 739 (14%) cases of incident AF. Current (HR 1.04, 95% CI 0.83-1.29) and former (HR 1.16, 95% CI 0.93-1.45) drinkers had a similar risk of incident AF compared to never drinkers. Incident AF was similar across categories of alcohol consumption in former drinkers (heavy drinkers [HR 1.14, 95% CI 0.84-1.55], moderate drinkers [HR 1.15, 95% CI 0.75-1.78) compared to light drinkers). Risk of AF did not differ per 5-year increase in years of abstinence (HR 1.00, 95% CI 0.96-1.03). There was an increase in the risk per 5-year increase in years of drinking (HR 1.07, 95% CI 0.96-1.19).

Conclusion

We did not find consistent evidence supporting an increased risk of AF associated with alcohol intake in persons aged 65 and older, highlighting the need to further explore this relationship in older populations.
A combined frequency domain near infrared spectroscopy and diffuse correlation spectroscopy system for comprehensive metabolic monitoring of inspiratory muscles during loading
Authors: Gómez Carlos A. , Brochard Laurent , Goligher Ewan C. , Rozenberg Dmitry , Reid W. Darlene , Roblyer Darren
Published: December 2023

Significance

Mechanical ventilation (MV) is a cornerstone technology in the intensive care unit as it assists with the delivery of oxygen in critical ill patients. The process of weaning patients from MV can be long, and arduous and can lead to serious complications for many patients. Despite the known importance of inspiratory muscle function in the success of weaning, current clinical standards do not include direct monitoring of these muscles.

Aim

The goal of this project was to develop and validate a combined frequency domain near infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) system for the noninvasive characterization of inspiratory muscle response to a load.

Approach

The system was fabricated by combining a custom digital FD-NIRS and DCS system. It was validated via liquid phantom titrations and a healthy volunteer study. The sternocleidomastoid (SCM), an accessory muscle of inspiration, was monitored during a short loading period in fourteen young healthy volunteer. Volunteers performed two different respiratory exercises, a moderate and high load, which consisted of a one-minute baseline, a one-minute load, and a six-minute recovery period.

Results

The system has low crosstalk between absorption, reduced scattering, and flow when tested in a set of liquid titrations. Faster dynamics were observed for changes in blood flow index (BFi), and metabolic rate of oxygen (MRO2) compared to hemoglobin + myoglobin (Hb+Mb) based parameters after the onset of loads in males. Additionally, larger percent changes in BFi, and MRO2were observed compared to Hb+Mb parameters in both males and females. There were also sex differences in baseline values of oxygenated Hb+Mb, total Hb+Mb, and tissue saturation.

Conclusion

The dynamic characteristics of Hb+Mb concentration and blood flow were distinct during loading of the SCM, suggesting that the combination of FD-NIRS and DCS may provide a more complete picture of inspiratory muscle dynamics.
The impact of CSF-filled cavities on scalp EEG and its implications
Authors: Piai Vitória , Oostenveld Robert , Schoffelen Jan Mathijs , Piastra Maria-Carla
Published: December 2023

Previous studies have found EEG amplitude and scalp topography differences between neurotypical and neurological/neurosurgical groups, being interpreted at the cognitive level. However, these comparisons are invariably accompanied by anatomical changes. Critical to EEG are the so-called volume currents, which are affected by the spatial distribution of the different tissues in the head. We investigated the effect of CSF-filled cavities on simulated EEG scalp data. We simulated EEG scalp potentials for known sources using different volume conduction models: a reference model (i.e., unlesioned brain) and models with realistic CSF-filled cavities gradually increasing in size. We used this approach for a single source close or far from the CSF-lesion cavity, and for a scenario with a distributed configuration of sources (i.e., a “cognitive ERP effect”). Magnitude and topography error between the reference and lesion models were quantified. For the single-source simulation close to the lesion, the CSF-filled lesion modulated signal amplitude with more than 17% magnitude error, and topography with more than 9% topographical error. Negligible modulation was found for the single source far from the lesion. For the multi-source simulations of the cognitive effect, the CSF-filled lesion modulated signal amplitude with more than 6% magnitude error, and topography with more than 16% topography error in a non-monotonic fashion. In conclusion, the impact of a CSF-filled cavity cannot be neglected for scalp-level EEG data. Especially when group-level comparisons are made, any scalp-level attenuated, aberrant, or absent effects are difficult to interpret without considering the confounding effect of CSF.

Impact statement

Previous studies have found EEG amplitude and scalp topography differences between neurotypical and neurological/neurosurgical groups (whose brain damage leads to the presence of a CSF-filled cavity), being interpreted at the cognitive level. Via simulations of scalp-level EEG patterns, we show that attenuated, aberrant, or absent effects in these comparisons are difficult to interpret without considering the confounding effect of CSF.

Funding

This study was partly supported by grants from the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO]) to V. P. (451-17-003 and VI.Vidi.201.081) and to the Language in Interaction Consortium (024-001-006).

CRediT

VP:Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

RO:Conceptualization, Methodology, Software, Writing – review & editing

JMS:Conceptualization, Methodology, Software, Writing – review & editing

MCP:Conceptualization, Investigation, Methodology, Visualization, Writing – review & editing
From lichens to crops: Pathogenic potential ofPseudomonas syringaefromPeltigeralichens is similar to world-wide epidemic strains
Authors: Ramírez Natalia , Caullireau Emma , Sigurbjörnsdóttir Margrét Auður , Vandelle Elodie , Vilhelmsson Oddur , Morris Cindy E.
Published: December 2023

The presence of bacteria belonging to thePseudomonas syringaecomplex (P. syringae) in the natural vegetation of several Icelandic habitat types has been recently reported, raising questions about the risk to Icelandic crops, particularly given the expected increase in agricultural activity due to climate warming. This study takes advantage of Iceland’s unique characteristics and the discovery ofP. syringaeinPeltigeralichens to gain a better understanding of the potential risk posed by this newly discovered ecological niche. The main objective is to evaluate the pathogenic potential and fitness in crops ofP. syringaestrains isolated fromPeltigeralichen sampled in Iceland, focusing on strains that belong to phylogroups 1 and 2, which commonly contain epidemic strains. The results indicate thatP. syringaeisolated from IcelandicPeltigeralichen have a comparable fitness to epidemic strains in eight out of ten tested plant species. Furthermore, pathogenicity assessment on three plant species highlighted that certain strains also caused similar symptoms and disease severity compared to epidemic strains. These findings provide valuable insights into the potential risks posed byP. syringaefrom Icelandic natural habitats and illustrate how strains from these habitats have a wide pathogenic potential to crops without having encountered these crops in the last several thousand years of their presence in Iceland.
Diagnostic images for mild cognitive impairment reveal biomarker status and abnormal scene processing
Authors: Bai Yuetong , Peters Oliver , Freiesleben Silka Dawn , Fenski Friederike , Priller Josef , Spruth Eike Jakob , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Bartels Claudia , Rostamzadeh Ayda , Glanz Wenzel , Teipel Stefan , Kilimann Ingo , Laske Christoph , Munk Matthias H. , Spottke Annika , Roy-Kluth Nina , Brosseron Frederic , Wagner Michael , Frommann Ingo , Lüsebrink Falk , Ramirez Alfredo , Dechent Peter , Hetzer Stefan , Scheffler Klaus , Yakupov Renat , Jessen Frank , Düzel Emrah , Bainbridge Wilma A.
Published: December 2023

Research on the impairment of episodic memory in Alzheimer’s disease often focuses on the processes of memory rather than the content of the specific images being remembered. We recently showed that patients with mild cognitive impairment (MCI), Stage 3 of Alzheimer’s disease, can memorize certain images quite well, suggesting that episodic memory is not uniformly impaired. Certain images, on the other hand, could not be memorized by MCI patients and were instead diagnostic for distinguishing MCI from healthy older adults. In this study, we investigate whether poor memory for diagnostic images is related to impaired neural processing in specific brain regions due to Alzheimer’s biomarker pathology. 64 healthy controls and 48 MCI participants in the DELCODE dataset performed a visual scene memory task during fMRI, with CSF Alzheimer’s disease biomarker data collected (i.e., amyloid and tau biomarkers). We found that diagnostic images have larger behavior-biomarker correlations for total tau, phospho-tau, Aβ42/Aβ40, Aβ42/phospho-tau compared to non-diagnostic images, suggesting that memory for these specific images are more affected by Alzheimer’s disease pathology. The fMRI data revealed an interaction effect between group membership (healthy control / MCI) and image diagnosticity (diagnostic / non-diagnostic scene images), with MCI participants having higher activation in scene processing regions (parahippocampal place area, retrosplenial cortex and occipital place area) for diagnostic images than non-diagnostic images. In contrast, healthy controls showed no differences in processing between diagnostic and non-diagnostic images. These results suggest that MCI individuals may engage in inefficiently heightened encoding activation for these diagnostic images. Our results show that special “diagnostic” images exist that can reveal amyloid and tau pathology and differences in neural activity in scene regions.
Bidirectional Energy Flow in the Photosystem II Supercomplex
Authors: Leonardo Cristina , Yang Shiun-Jr , Orcutt Kaydren , Iwai Masakazu , Arsenault Eric A. , Fleming Graham R.
Published: December 2023

The water splitting capability of Photosystem II (PSII) of plants and green algae requires the system to balance efficient light harvesting along with effective photoprotection against excitation in excess of photosynthetic capacity1,2, particularly under the naturally fluctuating sunlight intensity. The comparatively flat energy landscape of the multi-component structure, inferred from spectra of the individual pigment-protein complexes and the rather narrow and featureless absorption spectrum, is well known3–7. However, how the combination of the required functions emerge from the interactions among the multiple components of the PSII supercomplex (PSII-SC) cannot be inferred from the individual pigment-protein complexes. In this work, we investigate the energy transfer dynamics of the C2S2-type PSII-SC with a combined spectroscopic and modeling approach. Specifically, two-dimensional electronic-vibrational (2DEV) spectroscopy8,9provides enhanced spectral resolution and the ability to map energy evolution in real space, while the quantum dynamical simulation allows complete kinetic modeling of the 210 chromophores. We demonstrate that additional pathways emerge within the supercomplex. In particular, we show that excitation energy can leave the vicinity of the charge separation components, the reaction center (RC), faster than transferring to it. This enables activatable quenching centers in the periphery of the PSII-SC to be effective in removing excessive energy in cases of over-excitation2. Overall, we provide a quantitative description of how the seemingly contradictory functions of PSII-SC arise from the combination of its individual components. This provides a fundamental understanding that will allow further improvement of artificial solar energy devices and bioengineering processes for increasing crop yield10.
Exploring the Brain Characteristics of Structure-informed Functional Connectivity through Graph Attention Network
Authors: Wang Zifan , Toussaint Paule-J , Evans Alan C , Jiang Xi
Published: December 2023

Independent brain regions in neuroanatomy achieve a specific function through connections. As one of the significant morphological features of the cerebral cortex, previous studies have found significant differences in the structure and function of the cerebral gyri and sulci, which provides a basis for us to study the functional connectivity differences between these two anatomic parts. Previous studies using fully connected functional connectivity (FC) and structural connectivity (SC) matrices found significant differences in the perspective of region or connection in gyri and sulci. However, a clear issue is that previous studies have only analyzed the differences through either FC or SC, without effectively integrating both. Meanwhile, another nonnegligible issue is that the subcortical areas, involved in various tasks, have not been systematically explored with cortical regions. Due to the strong coupling between FC and SC, we use SC-informed FC to systematically explore the functional characteristics of gyri/sulci and subcortical regions by combining deep learning method with magnetic resonance imaging (MRI) technology. Specifically, we use graph attention network (GAT) to explore the important connections in the SC-informed FC through the Human Connectome Project (HCP) dataset. With high classification results of above 99%, we have successfully discovered important connections under different tasks. We have successfully explored the importance of different types of connections. In low threshold, gyri-gyri are the most important connections. With the threshold increasing, sub-sub become the most important. Gyri have a higher importance in functional connectivity than sulci. In the seven task states, these connections are mainly distributed among the front, subcortical, and occipital. This study provides a novel way to explore the characteristics of functional connectivity at the whole brain scale.
Patterns and correlates in the distribution, design and management of garden ponds along an urban-rural gradient
Authors: Hamer Andrew J. , Barta Barbara , Márton Zsuzsanna , Vad Csaba F. , Szabó Beáta , Tornero Irene , Horváth Zsófia
Published: December 2023

Urbanisation results in the loss and alteration of natural wetlands and ponds. However, garden ponds in cities and towns can act as rich reservoirs of aquatic biodiversity and stepping stones for dispersal. Homeowners with a range of different motivations, including biodiversity values, install garden ponds. Here, our main aim was to study whether the design and management choices of garden pond owners was dependent on the location of ponds (capital city vs. countryside), when ponds were installed (pond age), or whether fish were introduced. We surveyed 834 garden pond owners across Hungary using a citizen science questionnaire, asking questions on pond size, location, construction date and materials, vegetation structure, introduction of fish and management practices. From 753 validated responses, we found that the introduction of fish into ponds and high urbanisation were strongly associated with local features and management practices, especially large ponds with a water circulation feature, irrespective of pond age. A typical garden pond in Hungary is ∼20 m2, <10 years old, made of rubber (PVC) lining, contains fish, aquatic vegetation and circulating water, and is actively managed. There was a spatial separation of ponds based on local features between ponds in the capital city (Budapest) and elsewhere. These findings suggest that garden pond owners in cities are likely to make different choices in pond design and management compared to owners in regional areas. Our results also suggest that pond owners may primarily select management practices to improve habitat quality for ornamental fish. Our findings have important implications for maintaining aquatic biodiversity in urban areas, where garden ponds may be the only aquatic habitat available.

RESEARCH HIGHLIGHTS

Hungarian garden ponds ≤ 200 m2occur in both large cities and small villages

Most garden ponds we sampled in Hungary were built in the last decade

Pond design and management differs between Budapest and regional areas

Pond design and management practices are influenced by ornamental fish stocking

Pond owners frequently drain ponds to remove sediment and leaves and use algaecides
High Impact: Wikipedia sources and edit history document two decades of the climate change field
Authors: Benjakob Omer , Jouveshomme Louise , Collet Matthieu , Augustoni Ariane , Aviram Rona
Published: December 2023

Since being founded in 2001, Wikipedia has grown into a trusted source of knowledge online, feeding Google search results and serving as training data for ChatGPT. Understanding the accuracy of its information, the sources behind its articles and their role in the transference of knowledge to the public are becoming increasingly important questions. Meanwhile, climate change has moved to the forefront of scientific and public discourse after years of warnings from the scientific community. Therefore, to understand how it was represented on English Wikipedia, we deployed a mixed-method approach on the article for “Effects of climate change” (ECC), its edit history and references, as well as hundreds of associated articles dealing with climate change in different ways. Using automated tools to scrape data from Wikipedia, we saw new articles were created as climatology-related knowledge grew and permeated into other fields, reflecting a growing body of climate research and growing public interest. Our qualitative textual analysis shows how specific descriptions of climatic phenomena became less hypothetical, reflecting the real-world public debate. The Intergovernmental Panel on Climate Change (IPCC) had a big impact on content and structure, we found using a bibliometric analysis, and what made this possible, we also discovered through a historical analysis, was the impactful work of just a few editors. This research suggests Wikipedia’s articles documented the real-world events around climate change and its wider acceptance - initially a hypothesis that soon became a regretful reality. Overall, our findings highlight the unique role IPCC reports play in making scientific knowledge about climate change actionable to the public, and underscore Wikipedia’s ability to facilitate access to research. This work demonstrates Wikipedia can be researched using both computational and qualitative methods to better understand transference of scientific information to the public and the history of contemporary science.
Internally-consistent and fully-unbiased multimodal MRI brain template construction from UK Biobank: Oxford-MM
Authors: Arthofer Christoph , Smith Stephen M. , Douaud Gwenaëlle , Bartsch Andreas , Alfaro-Almagro Fidel , Andersson Jesper , Lange Frederik J.
Published: December 2023

Anatomical MRI templates of the brain are essential to group-level analyses and image processing pipelines, as they provide a reference space for spatial normalisation. While it has become common for studies to acquire multimodal MRI data, many templates are still limited to one type of modality, usually either scalar or tensor-based. Aligning each modality in isolation does not take full advantage of the available complementary information, such as strong contrast between tissue types in structural images, or axonal organisation in the white matter in diffusion tensor images. Most existing strategies for multimodal template construction either do not use all modalities of interest to inform the template construction process, or do not use them in a unified framework.

Here, we present multimodal, cross-sectional templates constructed from UK Biobank data: the OMM-1 template, and age-dependent templates for each year of life between 45 to 81. All templates are fully unbiased to represent the average shape of the populations they were constructed from, and internally consistent through jointly informing the template construction process with T1, T2-FLAIR and DTI data. The OMM-1 template was constructed with a multi-resolution, iterative approach using 240 individuals in the 50-55 year age range. The age-dependent templates were estimated using a Gaussian Process, which describes the change in average brain shape with age in 37,330 individuals.

All templates show excellent contrast and alignment within and between modalities. The global brain shape and size is not preconditioned on existing templates, although maximal possible compatibility with MNI-152 space was maintained through rigid alignment. We showed benefits in registration accuracy across two datasets (UK Biobank and HCP), when using the OMM-1 as the template compared with FSL’s MNI-152 template, and found that the use of age-dependent templates further improved accuracy to a small but detectable extent. All templates are publicly available and can be used as a new reference space for uni- or multimodal spatial alignment.
Visual social information use in collective foraging
Authors: Mezey David , Deffner Dominik , Kurvers Ralf HJM , Romanczuk Pawel
Published: December 2023

Collective dynamics emerge from individual-level decisions, yet we still poorly understand the link between individual-level decision-making processes and collective outcomes in realistic physical systems. Using collective foraging to study the key trade-off between personal and social information use, we present a mechanistic, spatially-explicit agent-based model that combines individual-level evidence accumulation of personal and (visual) social cues with particle-based movement. Under idealized conditions without physical constraints, our mechanistic framework reproduces findings from established probabilistic models, but explains how individual-level decision processes generate collective outcomes in a bottom-up way. In clustered environments, groups performed best if agents reacted strongly to social information, while in uniform environments, individualistic search was most beneficial. Incorporating different real-world physical and perceptual constraints profoundly shaped collective performance, and could even buffer maladaptive herding by facilitating self-organized exploration. Our study uncovers the mechanisms linking individual cognition to collective outcomes in human and animal foraging and paves the way for decentralized robotic applications.

Significance statement

Finding and collecting rewards in heterogeneous environments is key for adaptive collective behavior in humans, animals and machines. We present an open agent-based simulation framework to study how social information use shapes collective foraging from the bottom up. Our model combines individual evidence accumulation with spatially explicit movement. Our results connect individual-level decisions to collective dynamics in realistic physical environments, highlighting the key role of real-world constraints, thereby bringing us closer to embodied collective intelligence. Our work introduces a flexible platform to study the interplay between individual cognitive and perceptual biases, agents’ physical environment and the resulting collective dynamics and thus paves the way for fully decentralized mobile robot applications.
Single-Site Phosphorylation Elicits Structural, Dynamic, and Accessibility Changes in Proteins at both Proximal and Distal Regions to the Phosphosite
Authors: Subhadarshini Seemadri , Tandon Himani , Srinivasan Narayanaswamy , Sowdhamini Ramanathan
Published: December 2023

Phosphorylation, a fundamental cellular mechanism, intricately regulates protein function and signaling pathways. Our study employs extensive computational analyses on a curated dataset of phosphorylated and unphosphorylated protein structures to explore the multifaceted impact of phosphorylation on protein conformation. Our findings reveal that phosphorylation induces not only local changes at the phosphorylation site but also extensive alterations in distant regions, showcasing its far-reaching influence on protein structure-dynamics. Using Normal Mode Analysis (NMA), we investigate changes in protein flexibility post-phosphorylation, highlighting an enhanced level of structural dynamism. Through in-depth case studies on Polyubiquitin-B and Glycogen Synthase Kinase-3 Beta, we elucidate how phosphorylation at distinct sites leads to variable structural and dynamic modifications, potentially dictating functional outcomes. While phosphorylation largely preserves residue motion correlation, it significantly disrupts low-frequency global modes, presenting a dualistic impact on protein dynamics. We also explore alterations in the total accessible surface area (ASA), emphasizing region-specific changes around phosphorylation sites. This study sheds light on phosphorylation-induced conformational changes, dynamic modulation, and surface accessibility alterations, contributing to a comprehensive understanding of cellular regulation and suggesting promising avenues for therapeutic interventions.
Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases
Authors: Song Feizhi , Kovac Valerija , Mohammadi Behnam , Littau Lisa , Scharfenberg Franka , Angles Andreu Matamoros , Vanni Ilaria , Shafiq Mohsin , Orge Leonor , Galliciotti Giovanna , Djakkani Salma , Linsenmeier Luise , Černilec Maja , Hartman Katrina , Jung Sebastian , Tatzelt Jörg , Neumann Julia E. , Damme Markus , Tschirner Sarah K. , Lichtenthaler Stefan F. , Schmitz Matthias , Zerr Inga , Puig Berta , Tolosa Eva , Ferrer Isidro , Magnus Tim , Rupnik Marjan S. , Sepulveda-Falla Diego , Matschke Jakob , Šmid Lojze M. , Bresjanac Mara , Andreoletti Olivier , Krasemann Susanne , Foliaki Simote T. , Nonno Romolo , Becker-Pauly Christoph , Monzo Cecile , Crozet Carole , Haigh Cathryn L. , Glatzel Markus , Serbec Vladka Curin , Altmeppen Hermann C.
Published: December 2023

Proteolytic cell surface release (‘shedding’) of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal andin vitromodels. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated for the human body thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer’s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregates of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2
Authors: Ghose Ritobrata , Das Shubhamay , Urgel-Solas Julia , Pezzano Fabio , Datta Debayan , Ghose Upamanyu , Zapater Antoni Ganez , Lorente Natalia Pardo , Calvo Lorena Espinar , Garcia Laura , Cannata Chiara , Ruprecht Verena , Janic Ana , Sdelci Sara
Published: December 2023

Metastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in up to 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC proliferation and metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NFκB, TNFα and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis.

GRAPHICAL SUMMARY
Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival
Authors: Tzouanas Constantine N. , Sherman Marc S. , Shay Jessica E.S. , Rubin Adam J. , Mead Benjamin E. , Dao Tyler T. , Butzlaff Titus , Mana Miyeko D. , Kolb Kellie E. , Walesky Chad , Pepe-Mooney Brian J. , Smith Colton J. , Prakadan Sanjay M. , Ramseier Michelle L. , Tong Evelyn Y. , Joung Julia , Chi Fangtao , McMahon-Skates Thomas , Winston Carolyn L. , Jeong Woo-Jeong , Aney Katherine J. , Chen Ethan , Nissim Sahar , Zhang Feng , Deshpande Vikram , Lauer Georg M. , Yilmaz Ömer H. , Goessling Wolfram , Shalek Alex K.
Published: December 2023

Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi-omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi-omic computational gene regulatory inference framework and humanin vitroand mousein vivogenetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.
Understanding and exploitation of host stress responses to protein production using novel transcriptomic analytics
Authors: Rode Christoffer , Beulig Felix , Jönsson Mathias , Jahn Leonie J. , Nørholm Morten H. H. , Palsson Bernhard O. , Özdemir Emre , Yang Lei
Published: December 2023

Predictable expression of heterologous genes in a production host is a fundamental challenge in biotechnology. While traditional methods focus on manipulating expression and the property of the heterologous gene, a systems biology approach can complement with designs to improve the host itself. Previously, Independent Component Analysis (ICA) of the RNAseq data helped reveal independently modulated gene sets (iModulons) in bacteria. This was later applied to identify common stress responses related to heterologous gene expression forEscherichia coli. In this study, we expand this analysis with additional non-enzymatic proteins and apply our findings to design novel protein production optimization. By leveraging the Precise-1K transcriptomics knowledge base, we identify three iModulons as novel transcriptional responses to protein production stress; Cold Shock, gcvB sRNA, and the uncharacterized UC-9 iModulons. By studying the gene membership in the UC-9 iModulon, we discover effective novel design targets for improving protein production. This study demonstrates the value of big data analytics and systems understanding of host responses for designing novel strategies to optimize protein production.
Fetal lung vascular development is disrupted by mechanical compression and rescued by administration of amniotic fluid stem cell extracellular vesicles via regulation of the Hippo signaling pathway
Authors: Figueira Rebeca L. , Khalaj Kasra , Antounians Lina , Doktor Fabian , Gaffi Maria Sole , Obed Mikal , Gandhi Sree , Zani Augusto
Published: December 2023

Postnatal pulmonary hypertension is the biggest treatment challenge and major determinant for poor outcome in infants with congenital diaphragmatic hernia (CDH). CDH lungs are hypoplastic and exhibit vascular remodeling, whose pathogenesis remains poorly understood. Using a novel micro-static compression system, herein we found that mechanical compression induces vascular remodeling and downregulation of key angiogenic markers in rat and human fetal lung models, with similar features observed in CDH fetal lung autopsy samples. These fetal lung vascular changes are reversed back to normal upon administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs), a regenerative approach previously shown to restore lung branching morphogenesis and epithelial differentiation in CDH models. Exploring pathways that are dysregulated in CDH lungs and involved in mechanotransduction, we found that compressed fetal lungs had altered expression of Hippo signaling factors that was restored upon AFSC-EV administration. We found that AFSC-EV cargo contains some miRNAs involved in lung vascular development and Hippo pathway, indicating that AFSC-EV regenerative effects is associated with the delivery of specific miRNAs. This study uncovers the role of mechanical compression that herniated organs exert on CDH fetal lungs and proposes a new cell-free strategy to restore normal fetal lung vascular development.
Climate-smart prioritisation of tropical Key Biodiversity Areas for protection in response to widespread temperature novelty
Authors: Trew Brittany T. , Lees Alexander C. , Edwards David P. , Early Regan , Maclean Ilya M. D.
Published: December 2023

Key Biodiversity Areas (KBAs) are a cornerstone of 21stcentury area-based conservation targets. In tropical KBAs, biodiversity is potentially at high risk from climate change, because most species reside within or beneath the canopy, where small increases in temperature can lead to novel climate regimes. We quantify novelty in temperature regimes by modelling hourly temperatures below the forest canopy across tropical KBAs between 1990 and 2019. We find that up to 66% of KBAs with tropical forest are likely to have transitioned to novel temperature regimes. Nevertheless, 34% of KBAs are providing refuge from novelty, 58% of which are not protected. By conducting the first pan-tropical analyses of changes in below-canopy temperatures, we identify KBAs that are acting as climate refugia and should be prioritised as candidates for expansion of the conservation network in response to the post-2020 Global Biodiversity Framework target to conserve 30% of land area by 2030.
A novel druggable DYRK3/CAMKV signaling module for Neuroblastoma tumor growth inhibition
Authors: Rozen Esteban J. , Wgglesworth Kim , Shohet Jason
Published: December 2023

High-risk Neuroblastoma is a very aggressive and deadly pediatric cancer, accounting for over 15% of all childhood cancer mortality. Therefore, novel therapeutic strategies for the treatment of neuroblastoma are urgently sought for. Here, we identified the DYRK3 kinase as a critical mediator of neuroblastoma cell proliferation andin vivotumor growth. Our data suggest a role for DYRK3 as a regulator of the neuroblastoma-specific protein CAMKV, which is also required for neuroblastoma cell proliferation. We show that CAMKV is phosphorylated by DYRK3, and that inhibition of DYRK3 kinase activity induces CAMKV aggregation, probably mediated by its highly disordered C-terminal half. Importantly, we provide evidence that the DYRK3/CAMKV signaling module could play an important role in the regulation of the mitotic spindle during cell division, supporting the idea that inhibition of DYRK3 and/or CAMKV in neuroblastoma cells could constitute an innovative and highly specific intervention to fight against this dreadful pediatric cancer.
Emergence of multiphase condensates from a limited set of chemical building blocks
Authors: Chen Fan , Jacobs William M.
Published: December 2023

Biomolecules composed of a limited set of chemical building blocks can co-localize into distinct, spatially segregated compartments known as biomolecular condensates. Although recent studies of intracellular condensates have shown that coexisting, immiscible condensates can form spontaneously via phase separation, it has remained unclear how coexisting and multiphase condensates assemble from chemical building blocks with limited specificity. Here we establish a connection between the interdependencies among biomolecular interactions and the thermodynamic stability of multiphase condensates. We then introduce an inverse design approach for computing the minimum interaction specificity required to assemble condensates with prescribed molecular compositions in a multicomponent biomolecular mixture. As a proof of principle, we apply our theory to design mixtures of model heteropolymers using a minimal number of distinct monomer types, and we use molecular simulations to verify that our designs produce coexisting condensates with the target molecular compositions. Our theoretical approach explains how multiphase condensates arise in naturally occurring biomolecular mixtures and provides a rational algorithm for engineering complex artificial condensates from simple chemical building blocks.
TRAIL pathway suppression of cancer cell growth and immune cell-mediated tumor cell-killing in a senescent fibroblast-constructed tumor microenvironment
Authors: Zhang Shengliang , Huntington Kelsey E. , Zhou Lanlan , Seyhan Attila A. , Kun Bianca , Carneiro Benedito A. , Kreiling Jill , Sedivy John M. , El-Deiry Wafik S.
Published: December 2023

Cellular senescence and the associated secretory phenotype (SASP) promote cancer in the aging population. During aging or upon chemotherapy exposure, cellular and molecular changes occur in non-cancerous cells and alter responses to cancer therapy, primarily via modifications in the tumor microenvironment (TME) and immune response. Targeting senescent cells through removal, modulation of the SASP, or cellular reprogramming represent promising therapeutic avenues for treating cancer. We elucidate an interplay between cancer cells, immune cells, and senescent fibroblasts and describe the impact of fibroblast senescence on tumor growth and response to cancer therapy. Cytokine profiling reveals dynamic changes in SASP production during etoposide-induced senescence in IMR90 fibroblasts. We show that SASP is partially regulated by p21 (WAF1; CDKN1A), leading to the downregulation of anti-tumorigenic cytokines and upregulation of pro-tumorigenic cytokines. Senescent fibroblasts promote bystander cancer cell growth via a p21-driven SASP. These results provide strategies to target the p21-driven SASP in the TME during cancer therapy. Treatment with TRAIL or TRAIL-inducing Dordaviprone (TIC10/ONC201) reduces cell viability of tumor cells co-cultured with senescent or proliferating fibroblasts and promotes immune-mediated tumor cell-killing in co-culture with senescent IMR90 fibroblasts. ONC201 combined with senolytic drugs (e.g., Navitoclax, Lamivudine) synergizes towards tumor suppression. These results indicate that senolytic therapies may be combined with cancer therapies to target senescence-associated changes in the TME including for modulation of the senescent cytokine landscape.