bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring for fisheries or for fish? Declines in monitoring of salmon spawners continue despite a conservation crisis
Authors: Atkinson Emma M. , Carturan Bruno S. , Atkinson Clare P. , Bateman Andrew W. , Connors Katrina , Hertz Eric , Peacock Stephanie J.
Published: December 2024

Monitoring of salmon in Pacific Canada has been declining for decades. Spawner timeseries enable researchers to quantify impacts of local stressors, identify when and where management interventions are required to avoid extirpations, and evaluate the efficacy of recovery efforts. These data are more important now than ever, as uniquely adapted spawning populations underlie salmon resilience and their ability to adapt to climate change, and fine-scale data can inform terminal fisheries being revitalized by First Nations. We revisit the state of spawner data from the Yukon to southern BC. Almost two-thirds of salmon populations that were historically monitored have no reported estimates in 2013-2022 – the worst decade for data since monitoring programs began in the 1950s. We found strong correlations between the number of populations monitored and catch for each species, suggesting that monitoring is primarily motivated by commercial fisheries management. We recommend clarifying monitoring objectives and strategic investments to improve monitoring outcomes for salmon and communities. We emphasize data stewardship, as ensuring access to these baseline data is a cornerstone for rebuilding wild Pacific salmon.
An Investigation into Mechanomyography for Signal Extraction and Classification of Human Lower Limb Activity
Authors: Bai Yu , Guan Xiao Rong , Zhang Rui , Cheng Shi , Wang zheng
Published: December 2024

To mitigate the difficulties associated with the extraction of Mechanomyography (MMG) signals from raw Accelerometer (ACC) data and the subsequent classification of human lower limb activities based on MMG signals, the Feature Mode Decomposition (FMD) algorithm has been utilized for the isolation of the MMG signal. Simultaneously, surface Electromyography (sEMG) signals were recorded to perform correlation analyses, thereby validating the effectiveness of the extracted Mechanomyography (MMG) signals. The results demonstrate that the envelope entropy derived from the FMD was the lowest among the observed values, and the composite signal obtained via FMD displayed the highest correlation with the sEMG signal. This indicates that FMD is capable of efficiently isolating the MMG signal while maintaining the maximal quantity of muscle contraction data. To address the challenge of classifying human lower limb activities, a comprehensive feature extraction procedure was implemented, resulting in the derivation of 448 unique features from multi-channel mechanomyography (MMG) signals. Subsequently, Kernel Principal Component Analysis (KPCA) was employed to diminish the feature set’s dimensionality. This was succeeded by the deployment of a Temporal Convolutional Network integrated with an Attention mechanism (TCN-Attention) to train the classification model. Additionally, an enhanced Northern Goshawk Optimization Algorithm was leveraged for optimization purposes. The findings indicate that FMD exhibited the minimum envelope entropy value of 8.13, concurrently attaining the maximum correlation coefficient of 0.87 between MMG and sEMG signals. Significantly, the SCNGO-TCN-Attention model demonstrated superior classification accuracy, attaining an exceptional accuracy rate of 98.44%.
Multi-omic profiling identifies malignant subpopulations and a hypoxia-driven angiogenic axis as therapeutic vulnerabilities in sinonasal squamous cell carcinoma
Authors: You Chaelin , Park Jaewoo , Jang Jung Yeon , Yu Myeong Sang , Chung Yoo-Sam , Kang Keunsoo , Park Jihwan , Kim Ji Heui , Kang Kyuho
Published: December 2024

Sinonasal squamous cell carcinoma (SNSCC) is a rare and aggressive malignancy with limited treatment options, necessitating comprehensive molecular characterization to uncover actionable therapeutic targets. Here, we integrate bulk and single-cell transcriptomics, epigenomics, and DNA methylation profiling to construct a detailed molecular and cellular landscape of SNSCC. Our analysis identifies five transcriptionally and epigenetically distinct malignant subpopulations, including hypoxic (TC1) and proliferative (TC2) clusters, with TC1 showing significant association with poor clinical outcomes. We uncover a hypoxia-driven angiogenic axis, wherein TC1 cells secrete adrenomedullin (ADM), MIF, and VEGFA to activate endothelial tip cells, fostering tumor angiogenesis. Epigenetic reprogramming, characterized by alterations in DNA methylation and chromatin accessibility, underpins these transcriptional programs, with AP-1 transcription factors emerging as key regulators. Notably, ADM expression is epigenetically controlled, correlates with advanced clinical stage, and predicts reduced survival in head and neck cancer patients. This multi-omic study highlights the tumor heterogeneity and microenvironmental interactions driving SNSCC progression, revealing epigenetically regulated pathways as promising therapeutic targets for future intervention.
Household clusters of SARS-CoV-2 Omicron subvariants contemporaneously sequenced from dogs and their owners
Authors: Ferreira Francisco C. , Auckland Lisa , Busselman Rachel , Davila Edward , Tang Wendy , Lim Ailam , Sarbo Nathan , Yaglom Hayley Danielle , Centner Heather , Mead Heather , Tao Ying , Castro Juan , Li Yan , Zhang Jing , Wang Haibin , Malapati Lakshmi , Cook Peter , Retchless Adam , Tong Suxiang , Zecca Italo , Ghai Ria , Barton Behravesh Casey , Fischer Rebecca , Hamer Gabriel L. , Hamer Sarah
Published: December 2024

Monitoring the zoonotic potential of emerging SARS-CoV-2 variants in animals is a critical tool to protect public health. We conducted a longitudinal study in 47 households reporting people with COVID-19 in Texas in January-July 2022, during the first Omicron wave. We evaluated 105 people and 100 of their companion animals by RT-qPCR for SARS-CoV-2 at three sequential sampling events 1-2 weeks apart, starting 0-5 days after the first reported diagnosis of COVID-19 in the house. Of 47 households that reported people with COVID-19, SARS-CoV-2 was detected in 43, with 68% of people testing positive by RT-qPCR; 95.5% of people had antibodies to SARS-CoV-2. Dogs were the only animal species positive by RT-qPCR (5.4%; 3/55). Viral copies were consistently lower in dogs than household members, and no infectious virus was recovered in cell culture. Whole genome sequencing revealed household clusters of Omicron subvariants BA.1.1, BA.2.3.4 and BA.5.1.1 in people, dogs and a food bowl, confirming human-to-dog transmission within households, with no evidence of onward transmission from the infected dogs. Eleven dogs (n = 55) and two cats (n = 26) had neutralizing antibodies against SARS-CoV-2. Infection was not associated with clinical signs in pets; only two animals that tested negative for SARS-CoV-2 were reported to be sick. Nearly one-third (30.2%) of households with active COVID-19 had pets exposed to SARS-CoV-2, similar to our pre-Omicron studies, yet incidence of infection in cats was lower compared to pre-Omicron. These differences suggest that the zoonotic transmission dynamics in households may differ based on variant.
MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets inNUP98-Rearranged Acute Myeloid Leukemia
Authors: Michmerhuizen Nicole L. , Heikamp Emily B. , Iacobucci Ilaria , Umeda Masayuki , Arthur Bright , Mishra Vibhor , Di Giacomo Danika , Hiltenbrand Ryan , Gao Qingsong , Radko-Juettner Sandi , Lott Josi , Martucci Cynthia , Subramanyam Varsha , Hatton Charlie , Baviskar Pradyuamna , Portola Pablo , Claquin Aurelie , Chandra Bappaditya , Baggett David W. , Khalighifar Ali , Huang Hongling , Zhou Peipei , Long Lingyun , Shi Hao , Sun Yu , Papachristou Evangelia K. , Chilamakuri Chandra Sekhar Reddy , Vitorino Francisca N. de L. , Gongora Joanna M. , Janke Laura , Kentsis Alex , D’Santos Clive S. , Garcia Benjamin A. , Kriwacki Richard W. , Chi Hongbo , Klco Jeffery M. , Armstrong Scott A. , Mullighan Charles G.
Published: December 2024

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies inNUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition ofMozandHbo1impairsNUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at theMeis1locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 inhibition decreased leukemic burden in multipleNUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies inNUP98-r AML.

SIGNIFICANCE STATEMENT

MOZ and HBO1 associate with NUP98 fusion oncoprotein condensates to drive leukemogenesis. Inhibition of their histone acetyltransferase activity is an effective therapeutic strategy inNUP98-rearranged leukemias, including those resistant to Menin inhibition. Moreover, combined MOZ/HBO1 and Menin inhibition is synergistic, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.
The Speech Reception Threshold Can be Estimated Using EEG Electrodes In and Around the Ear
Authors: Borges Heidi Bliddal , Zaar Johannes , Alickovic Emina , Christensen Christian Bech , Kidmose Preben
Published: December 2024

Objective: Previous studies have demonstrated that the speech reception threshold (SRT) can be estimated using scalp electroencephalography (EEG), referred to as SRTneuro. The present study assesses the feasibility of using ear-EEG, which allows for discreet measurement of neural activity from in and around the ear, to estimate the SRTneuro. Such an estimate can be highly useful e.g. for continuously adjusting noise-reduction algorithms in hearing aids or for logging the SRT in the user's natural environment. Approach: Twenty young normal-hearing participants listened to audiobook excerpts at varying signal-to-noise ratios (SNRs) whilst wearing a 66-channel EEG cap and 12 ear-EEG electrodes. A linear decoder was trained on different electrode configurations to estimate the envelope of the audio excerpts from the EEG recordings. The reconstruction accuracy was determined by calculating the Pearson's correlation between the actual and the estimated envelope. A sigmoid function was then fitted to the reconstruction-accuracy-vs-SNR data points, with the midpoint of the sigmoid serving as the SRTneuro estimate for each participant. Main results: Using only in-ear electrodes, the estimated SRTneuro was within 3 dB of the behaviorally measured SRT (SRTbeh) for 6 out of 20 participants (30%). With electrodes placed both in and around the ear, the SRTneuro was within 3 dB of the SRTbeh for 19 out of 20 participants (95%) and thus on par with the reference estimate obtained from full-scalp EEG. Using only electrodes in and around the ear from the right side of the head, the SRTneuro remained within 3 dB of the SRTbeh for 19 out of 20 participants. Significance: These findings suggest that the SRTneuro can be reliably estimated using ear-EEG, especially when combining in-ear electrodes and around-the-ear electrodes.
Do morphologically distinct groups correspond to reproductively isolated species? A case study inMyrmicaants from Switzerland
Authors: Lavanchy Guillaume , Galkowski Christophe , Jecha Kristine , Freitag Anne , Avril Amaury , Dépraz Aline , Schwander Tanja
Published: December 2024

The most widely used definition of a species is that it is reproductively isolated from other populations. Yet, most species are described on the basis of morphological criteria, and reproductive isolation is seldom tested. Using the ant genusMyrmicaLatreille (Hymenoptera, Formicidae) as a model, we ask whether species described as distinct based on (often subtle) morphological differences indeed form reproductively isolated lineages. We collected and morphologically identified 918Myrmicaants from a 3212 km2area in Switzerland. We then combined DNA barcoding (based on COI) and RAD sequencing to identify genetically isolated lineages. Out of the 14 morphological species identified, 13 formed genetically differentiated lineages, while the last one was not supported by our genetic data. Overall, the morphological identification was congruent with genetic lineage delineation for 94.9% of individuals. Our dataset also allowed us to screen for cryptic lineages in the five most frequent species, including inM. scabrinodiswhere cryptic lineages were previously suggested, but we found no evidence for cryptic species. Overall, our results indicate that morphology parallels genetic isolation in the studied species. However, an integrative approach combining morphological identification with nuclear marker genotyping is necessary for confident species identification of all individuals. Finally, our results provide a library of validated COI barcodes for futureMyrmicaspecimen identification.
RNA Binding of GAPDH Controls Transcript Stability and Protein Translation in Acute Myeloid Leukemia
Authors: Shamloo Sama , Schloßhauer Jeffrey L. , Tiwari Shashank , Fischer Kim Denise , Ghebrechristos Yohana , Kratzenberg Lisa , Bejoy Aathma Merin , Aifantis Ioannis , Wang Eric , Imig Jochen
Published: December 2024

Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukemia (AML) RBPs are key regulators of tumor proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear. Given the inherent complexity of targeting AML broadly, our goal was to uncover potential ncRBP candidates critical for AML survival using a CRISPR/Cas-based screening. We identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a pro-proliferative factor in AML cells. Based on cross-linking and immunoprecipitation (CLIP), we are defining the global targetome, detecting novel RNA targets mainly located within 5’UTRs, including GAPDH, RPL13a, and PKM. The knockdown of GAPDH unveiled genetic pathways related to ribosome biogenesis, translation initiation, and regulation. Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML.
Designing a multi-serotype Dengue virus vaccine: anin silicoapproach to broad-spectrum immunity
Authors: Singh Ankita , Glushchenko Oksana , Ustiugova Alina , Alawi Khadija M , Korzinkin Mikhail , Zhavronkov Alex , Castiglione Filippo
Published: December 2024

Dengue virus infection represents a major global health issue, with four distinct serotypes complicating the challenge of developing a vaccine due to the need for balanced, long-lasting immunity against all serotypes. Current vaccines have limitations, including an increased risk of severe dengue in seronegative individuals and moderate efficacy, highlighting the need for more effective solutions. Our study aimed to design a multi-serotype Dengue virus vaccine using a computational approach to achieve broad-spectrum immunity. We employed advanced computational tools and algorithms to predict B-cell and T-cell epitopes, ensuring the selection of antigenic targets that provide comprehensive protection against all four serotypes. The methodology included tools for B-cell epitope prediction, tools for MHC class II and I peptide predictions, and tools for toxicity and allergenicity screening to ensure the safety of the vaccine candidates. Our results identified 21 B-cell epitopes, 15 CTL peptides, and 12 HTL peptides, validated for safety regarding toxicity and allergenic potential. The vaccine construct incorporated the adjuvant β-defensin-3 and specific linkers to enhance immunogenicity and stability. Tertiary structure prediction, Ramachandran plot analysis, and stereochemical examination confirmed the stability and quality of the vaccine model.

These findings demonstrate the potential of computational methods in addressing the complex challenges of Dengue virus vaccine development. Our computational approach offers a novel pathway for vaccine design, potentially accelerating the development of effective multi-serotype vaccines. This study provides a promising foundation for future research and clinical validation, marking a significant step forward in dengue vaccine development.
ROSLT: An Improved Raspberry-Pi Open-Source Live Voluntary-Wheel Running Tracker Method and Resource
Authors: Sanosa Patrick , Marrow Jade P. , Malicki Amelia R. , Brunt Keith R. , Simpson Jeremy A.
Published: December 2024

Background

Exercise promotes health and has therapeutic effects on disease. Over time, the body improves its maximal exercise capacity through training adaptations such as an increase in VO2 max. In mice, voluntary wheel running allows for a natural setting to test spontaneous running behaviour under non-stressed conditions. There is a need to design sensitive animal-based assay that improves resolution for differentiating exercise performance from a regular cyclometer (which presents a single value from a summary of dynamic data collected over time) and offer circadian analyses. The purpose of this work is to examine the exercise behaviours of mice with a focus on circadian rhythm of running. We hypothesize the pi cyclometer (ROSLT) will mirror VDO M2.1 behaviors, enhancing circadian rhythm insights.

Methods

Using a hand-built cyclometer programmed through the Raspberry Pi computer, voluntary wheel running behaviours in CD-1 mice (∼8-10 weeks) were recorded for 6 consecutive days. This features a Hall Effect sensor and neodymium magnets attached on the running wheels that will detect changes to wheel rotation, speed, acceleration, and distance (continuously) and publish the data to a server in real-time. To compare capabilities, running wheels will also be equipped with the VDO M2.1 WR Cycling Computer to track distance which will be manually recorded once a day. Accuracy from both devices were mechanically validated.

Results

The main findings include that voluntary wheel running distance over 6 days produces inaccuracies by the VDO. The VDO showed fluctuations in distance over the last 3 days, while ROSLT showed consistent measurements.

Conclusion

This comparison shows that ROSLT expands on the running activity of mice each day while maintaining accuracy and precision. This novel dynamic circadian cyclometer will advance our research abilities and can be used in differentiating exercise performance in applications such as doping.
Navigating Medication Safety with Electronic Medical Records: Insights from a Dual-Phase Implementation in Paediatric, Neonatal and Maternity Care
Authors: Mordaunt Dylan A , Johnson Nichola , Verghese Santosh , Parker Rhys , Gibb Katy , Palmer Lyle J
Published: December 2024

Objective

EMR implementations can lead to changes in medication safety events due to the disruption of clinical activities by the implementation. The current study aimed to evaluate the impact of an Electronic Medical Record (EMR) implementation on medication safety events within women’s and children’s services of a large tertiary public hospital.

Methods

This Real-World Evidence (RWE) study utilised a differences-in-differences analysis with negative binomial regression to accommodate overdispersion in medication safety event counts. We compared change over time in key outcomes between areas where the EMR was activated and areas where it was not activated. Data were collected from January 2020 to February 2024 from the enterprise incident management system, spanning periods before and after two separate EMR system activations in 2021 and 2023.

Results

There was an initial rise in minor and near-miss incidents immediately following activation, with no overall increase in events in groups not activated. The observed rise in incidents was in the time immediately around the activation and was not sustained over the longer term. There were no significant changes in trend over time.

Conclusions

Our findings suggest that the implementation of the EMR system was not associated with a change in the occurrence of medication safety events over the longer term. Our study highlights the potential of EMR systems to be integrated into healthcare settings without worsening medication safety outcomes; implementation also doesn’t appear to have improved rates.
Nurses’ Fall Risk Judgements - Cognitive Biases and Contextual Factors Explaining Variability: A multi-centre cross-sectional study
Authors: Takase Miyuki , Kisanuki Naomi , Yoko Sato , Mitsunaka Kazue , Yamamoto Masako
Published: December 2024

Background

Assessing fall risk is a complex process requiring the integration of diverse information and cognitive strategies. Despite this complexity, few studies have explored how nurses make these judgements. Moreover, existing research suggests variability in nurses’ fall risk assessments, but the reasons for this variation and its appropriateness remain unclear.

Objective

This study aimed to investigate how nurses judge fall risk, and the factors associated with their judgements.

Methods

Using purposive sampling, 335 nurses from six hospitals in western Japan participated in an online survey. The participants rated the likelihood of falls in 18 patient scenarios and completed measures of base-rate neglect, belief bias, and availability bias. A linear mixed-effects regression tree was used to identify factors related to their judgements, and a linear mixed-effects regression model examined associations between judgement variability, cognitive biases, and clinical specialty.

Results

Nurses’ fall risk assessments were primarily influenced by whether patients called for assistance, followed by the use of sleeping pills, the presence of a tube or drain, and patient mobility status. Judgement variability was linked to nurses’ gender, education, clinical specialty, and susceptibility to availability bias.

Conclusion

Variability in clinical judgement may be justified when reflecting personalised, context-specific care. However, inconsistencies arising from cognitive biases are problematic. Healthcare organisations should offer targeted training to enhance contextual expertise and reduce the influence of cognitive biases on fall risk assessments.
Isotopic tracing inMycobacterium tuberculosis-infected alveolar epithelial cells indicates metabolic specificity to their virulence and drug-resistance status
Authors: Akram Subia , Masakapalli Shyam Kumar , Nanda Ranjan Kumar
Published: December 2024

Mycobacterium tuberculosis(Mtb), the causative organism of tuberculosis (TB), infects different host cells; however, studies on its metabolic impact on the type 2 alveolar epithelial cells are limited. In this study, comparative metabolic insights of A549 cells infected with laboratory (H37RV, H37Ra) and clinical isolates (drug-resistant: S6, S11 and sensitive: S4, S5) were derived from read out of the13C-based proteinogenic amino acid kinetics. Mtb H37Rv (virulent) exhibited higher growth kinetics within A549 cells compared to H37Ra (avirulent), whereas drug-resistant clinical isolate S6 showed the highest intracellular growth. The viability of H37Rv-infected A549 cells was significantly low. Interestingly, the drug-resistant clinical Mtb isolates maintained better cell viability over time. A [13C6] glucose tracer and mass isotopomer distributions revealed that A549 cells infected with virulent Mtb strains exhibited higher dependency on the central carbon metabolism like glycolysis, the pentose phosphate pathway and the tricarboxylic acid cycle forde novoamino acid biosynthesis. Drug-resistant Mtb isolates infected A549 cells showed robust13C incorporation in the proteinogenic Threonine, Methionine and Lysine, derived from the tricarboxylic acid cycle. A549 cells infected with Mtb, irrespective of their drug resistance status, showed13C incorporation in the essential amino acids (lysine, methionine, threonine, valine), underlining the dependencies of the pathogen on thede novohost metabolic precursors. These findings elucidate the importance of deciphering the strain-specific host-pathogen metabolic interactions to develop targeted therapies against drug-resistant Mtb infections.
CD226+adipose tissue macrophages arise from MDP-derived monocytes and regulate lipid metabolism
Authors: Gallerand Alexandre , Caillot Zakariya , Terekhova Marina , Castiglione Alexia , Leporati Lorlana , Giacchero Margaux , Pilot Thomas , Chang Michael , Dolfi Bastien , Zair Fairouz N. , Goës Eloïse , Bennetot Audrey , Mlamla Zandile , Mass Elvira , Ginhoux Florent , Voehringer David , Mack Matthias , Dombrowicz David , Williams Jesse W. , Masson David , Artyomov Maxim N. , Bertola Adeline , Ivanov Stoyan
Published: December 2024

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their functions are in part dictated by their origin. We previously observed robust monocyte recruitment and contribution to the macrophage pool in brown adipose tissue. In particular, monocytes were predicted to give rise to two phenotypically distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. We found that bone marrow monocytes highly contributed to the CD226+macrophage population while the CD206+population contained mainly yolk sac-derived cells. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226+macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226+macrophages. Using meta-analysis of single cell RNA-sequencing data, we found that MDP-derived CD226+macrophages were present in several tissues including peritoneal cavity, adrenal glands and all adipose depots, with a particular enrichment in beige and brown fat. A similar macrophage subset was identified in humans. Functionally, while depletion of CD206+macrophages using anti-CD115 blocking antibodies led to decreased adipose triglyceride content, genetic depletion of CD226+macrophages caused the opposite phenotype. We thus identify CD226+MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.
Narcissistic and Antisocial Personality Traits are both encoded in the Triple Network: Connectomics evidence
Authors: Jornkokgoud Khanitin , Bakiaj Richard , Wongupparaj Peera , Job Remo , Grecucci Alessandro
Published: December 2024

The neural bases of narcissistic and antisocial traits are still under debate. One intriguing question is whether these traits are encoded within the so-called triple network e.g. the default mode (DMN), salience (SN), and fronto-parietal (FPN) networks, and whether these traits affect the same networks in a similar manner. Connectome-based analyses were conducted on resting-state scans from 183 participants, examining regional and global graph-theoretic metrics in the DMN, SN, and FPN, with the visual and sensorimotor networks as controls. Our findings revealed a clear involvement of the triple network in narcissistic and antisocial traits, confirming a shared neural substrate for the two traits. Both traits were negatively predicted by the anterior cingulate cortex of the SN, possibly indicating less awareness of dangers and more proneness to engage in risky behaviors. Additionally, both traits were positively predicted by the lateral prefrontal cortex of the FPN, suggesting augmented strategic thinking to manipulate others and increased planning skills to achieve personal goals. Besides similarities, there were also some differences. Specific hubs of the DMN were positively associated with narcissism but negatively related with antisocials, possibly explaining their differences in self-reflection and thinking about the self, largely present in the former, but usually reduced in the latter. These results extend previous findings on the involvement of the triple network in personality disorders and suggest both common and different mechanisms underlying narcissistic and antisocial traits. As such, these findings could pave the way for developing potential biomarkers of personality pathology and identify neurostimulation intervention targets.
PTX3 Governs Fibroblast-Epithelial Dynamics in Lung Injury and Repair
Authors: Bammert Marie-Therese , Kollak Ines , Hoffmann Jan , Peter Eva , Schlüter Holger , Li Jun , Campos Alexandre R. , Viollet Coralie , Gantner Florian , Lizé Muriel , Thomas Matthew J. , Le Huy Q.
Published: December 2024

Dysfunctional interactions between fibroblasts and epithelial cells contribute to the progression of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In this study, we utilized a coculture model of human small airway epithelial cells and fibroblasts to investigate intercellular communication during disease progression. Our transcriptomic and proteomic profiling reveal that fibroblasts repair epithelial cells in acute injury by boosting epithelial fatty acid metabolism; conversely, they exacerbate epithelial damage in chronic injury scenarios. By delineating regulators involved in these responses, we identified pentraxin 3 (PTX3) as a key antifibrotic factor secreted by fibroblasts in response to acute epithelial injury. Importantly, PTX3 levels are decreased in bronchoalveolar lavage (BAL) samples from IPF patients compared to non-fibrotic controls, indicating a potential link between diminished PTX3 levels and fibrosis progression. Furthermore, adding PTX3 to chronically injured epithelial-fibroblast cocultures mitigated the pro-fibrotic response and restored the epithelial barrier integrity. These findings highlight the dual roles of fibroblasts and the critical function of PTX3 in lung injury and repair, offering insights for therapeutic strategies.
Identification of novel inhibitors targeting serine acetyltransferase fromNeisseria gonorrhoeae
Authors: Oldham Keely E.A. , Jiao Wanting , Prentice Erica , Hicks Joanna L.
Published: December 2024

Neisseria gonorrhoeaeis an obligate human pathogen and the etiological agent of the sexually transmitted infection, gonorrhoea. The rapid emergence of extensively antimicrobial-resistant strains, including those resistant to all frontline antibiotics, has led toN. gonorrhoeaebeing labelled a priority pathogen by the World Health Organization, highlighting the need for new antimicrobial treatments. Given its absence in humans, targetingde novocysteine biosynthesis has been identified as a promising avenue for developing new antimicrobials against drug-resistant bacteria. The biosynthesis of cysteine is catalyzed by two enzymes; serine acetyltransferase (SAT/CysE) which catalyzes the first step andO-acetylserine sulfhydrylase (OASS/CysK) that catalyzes the second step incorporating sulfur to form L-cysteine. CysE is reported to be essential for bacterial survival in several bacterial pathogens includingN. gonorrhoeae. Here, we have conducted virtual inhibitor screening of commercially available compound libraries against SAT fromN. gonorrhoeae(NgSAT). We have identified a hit compound with an IC50of 13.9 µM and analyzed its interactions with the enzyme’s active site. This provides a platform for the identification and development of novel SAT inhibitors to combat drug-resistant bacterial pathogens.
Frustration in the Protein-Protein interface Plays a Central Role in the Cooperativity of PROTAC Ternary Complexes
Authors: Ma Ning , Bhattacharya Supriyo , Muk Sanychen , Jandova Zuzana , Schmalhorst Philipp S , Ghosh Soumadwip , Le Keith M , Diers Emelyne , Trainor Nicole , Farnaby William , Roy Michael J , Kofink Christiane , Greb Peter , Weinstabl Harald , Ciulli Alessio , Bader Gerd , Sanker Kyra , Bergner Andreas , Vaidehi Nagarajan
Published: December 2024

Targeted protein degradation of a protein of interest (POI) by Proteolysis Targeting Chimeras (PROTACs) is an attractive approach for dealing with formerly undruggable protein targets. PROTACs are heterobifunctional molecules that connect a POI-binding and an E3-ligase (E3) binding motif with a linker. The simultaneous binding and formation of a ternary POI::PROTAC::E3 complex (TC) induces proximity between the POI and the E3, allowing for POI-ubiquitination and subsequent induction of proteasomal degradation. Despite the availability of many three-dimensional structures of TCs, unveiling the structure-function relationships for the design of PROTACs remains a challenge. This is because the TCs can be dynamic with a complex conformational landscape that individual crystal structures may not capture. In this work, we used SMARCA2 as the POI and VHL as the E3-ligase and solved the X-ray crystal structures of the respective ternary complexes with four different PROTACs. Molecular dynamics (MD) simulations were used to show that the SMARCA2-VHL interface is flexible with multiple energy minima. The protein-protein (POI-E3) interactions are largely formed by residues located in structurally disordered loops in both VHL and SMARCA2. The residue pairs in the SMARCA2-VHL interface are 'frustrated', i.e., adopt a suboptimal energetic state. The number of frustrated residue pairs averaged over the MD ensemble shows a positive correlation with the experimentally determined cooperativity of the PROTACs. This indicates that protein-protein interface frustration can play an important role in PROTAC function. The TC ensembles of VHL, SMARCA2 and 11 different PROTACs were modeled by comparative modeling followed by MD. The frustration was subsequently calculated from the MD trajectories and correlated with the cooperativity. We found that identification of the dynamic protein-protein contacts and frustrated residue pairs in the interface can provide a rational framework for the structure-based design of PROTACs.
Mastering the Manu – How humans create large splashes
Authors: Rohilla Pankaj , Choi Daehyun , Wallace Halley , Yung Kai Lauren , Deora Juhi , Lele Atharva , Bhamla Saad
Published: December 2024

Manu jumping, a popular water diving style amongst Māori people in New Zealand, focuses on creating large splashes. Divers perform aerial maneuvers such as the “utkatasana” pose, entering the water in a V-shape, and executing underwater maneuvers to maximize the splash size. Our study explores the underlying fluid dynamics of Manu jumping and demonstrates how two key parameters, the V-angle and the timing of body opening, can maximize the Worthington jet formation. To accurately replicate human manu jumping, we studied water entry of both passive solid objects with varying V angles and an active body opening robot (Manubot). The analysis revealed that a 45-degree V angle is optimal for maximizing Worthington jet formation, consistent with human diving data. This angle balances a large cavity size and a deep pinch-off depth. The body opening within a timing window ofsynchronizes the robot’s potential energies to be timely transferred to the cavity formation, producing the strongest and most vertical, i.e., ideal, Worthington jets. Based on our experimental findings, we propose optimal parameters for generating the largest Manu splashes. These insights offer engineering perspectives on how to modulate underwater cavity dynamics using both passive and active body formations.
Simple One-step Vial-based Pretreatment for Deep Single-cell Proteomics and Its Application to Oocyte Aging
Authors: Zhang Hui , Zhang Hailu , Huang Chuanxi , Zeng Qing , Tian Chunyan , He Fuchu , Yang Yun
Published: December 2024

Single-cell proteomics is a pivotal technology for studying cellular phenotypes, offering unparalleled insights into cellular heterogeneity and dynamic functions. Technical improvement in mass spectrometry instrument and sample preparation has made single-cell proteomics feasible in recent years. Yet, developing a simple and robust sample preparation method to enable deep proteomics profiling of single cells remains a significant challenge. Herein, we developed a simple one-step vial-based pretreatment (SOViP) for deep label-free single-cell proteomics. SOViP integrates all sample preparation procedures into a single step in autosampler vials, yet it is highly efficient and high-throughput. SOViP can be finished within ∼2 h, with hands-on time limited to merely a few minutes. We show that on average over 6,500 can be quantified from a single mouse oocyte using SOViP. In total 6,983 protein groups were identified from single mouse oocytes across an entire reproductive lifespan, offering a valuable proteomics resource for oocyte aging. Unique molecular characteristics of oocytes at different ages were revealed, and a classifier consisting of ten proteins demonstrated accurate age-group classification and fertility-level prediction. Although demonstrated using mouse oocytes in this study, SOViP is adaptable to rare cell samples and other large cells, including follicles and preimplantation embryo cells, among others.
A novelCandida glabrataprotein regulated by mating signalling pathway shapes inter-species interaction
Authors: Parnandi Venkata Anand , Trivedi Parth M. , Panchal Harshita , Patkar Rajesh N.
Published: December 2024

During mixed-species invasive candidiasis - an emerging threat in healthcare - presence ofCandida albicansis near-essential for host colonisation byC. glabrata. However, the molecular communication underlying such intriguing inter-species interaction is largely unexplored. Here, we show thatC. glabratasecretes a unique small protein Yhi1 that induces hyphal growth inC. albicans, which is essential for host tissue invasion. Notably, this Yhi1-based inter-species interaction is specific toC. glabrataandC. albicans, when compared with other common species ofCandida.

Our structure-function analyses reveal a novel functional pentapeptide motif (AXVXH) required for the function of Yhi1. Interestingly, Yhi1 expression and efflux are regulated through the mating MAPK signalling pathway and the pheromone transporterCgSte6, respectively, inC. glabrata, despite its preferred asexual reproduction. Our findings shed light on howC. glabratamating signalling pathway is repurposed to interact withC. albicans, and highlight the potential of Yhi1 as a biomarker and a template for a synthetic novel antifungal peptide.
Early-life stress impairs development of functional interactions and neuronal activity within prefrontal-amygdala networksin vivo
Authors: Donati Angelica , Vedele Francescangelo , Hartung Henrike
Published: December 2024

Early-life stress (ELS), such as parental neglect or abuse, predisposes an individual to develop mental disorders. Disease hallmarks include heightened amygdala reactivity and impaired prefrontal cortex-amygdala functional interactions, already during childhood and adolescence. However, which cellular and circuit mechanisms underlie these hallmarks, as well as the altered developmental trajectory of prefrontal-amygdala networks, is poorly understood. Here we performed simultaneousin vivolocal-field potential and multi-unit recordings under light urethane anaesthesia in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of male and female juvenile or adolescent mice, exposed to a resource scarcity model of ELS. We find a developmentally transient low-theta (3-5 Hz) oscillatory hypercoupling within mPFC-BLA networks in juvenile ELS males which seems to result from a precocious development of coupling strength after ELS. In the mPFC, neuronal spiking activity was decreased in juvenile males and the local theta entrainment of spike firing disrupted. In BLA, both sexes showed an increase in firing activity in a subpopulation of neurons after ELS, also confirmed by an increase in ΔFosB-positive neurons in BLA, which we identified to be non-GABAergic. Directed interactions, i.e. the ability to entrain spike firing in mPFC to the theta rhythm in BLA and vice versa, were also impaired predominantly in juvenile males after ELS, while females showed a milder phenotype. These early sex-dependent impairments in the functional development of prefrontal-amygdala circuits may promote abnormal fear learning and anxiety after ELS and may predispose to a disease phenotype later on.
A major entomoparasite interferes with Chikungunya transmission byAedes albopictus
Authors: Martin Edwige , Chanfi An-nah , Viginier Barbara , Raquin Vincent , Moro Claire Valiente , Minard Guillaume
Published: December 2024

The Asian tiger mosquito,Aedes albopictus, spreads diseases like Chikungunya and has caused outbreaks worldwide. Studies show that mosquitoes-associated microbes can affect how well they spread diseases. One of those microbes, the parasiteAs. taiwanensis, is common in older mosquito populations but rare in newer ones. We found that this parasite slows down the spread of Chikungunya within the mosquito and decreases its transmission rate by half. Unparasitized mosquitoes spread the virus more easily, suggesting that changes in mosquito microbes could impact disease outbreaks and public health.
Revealing rhythm categorization in human brain activity
Authors: Barbero Francesca M. , Lenc Tomas , Jacoby Nori , Polak Rainer , Varlet Manuel , Nozaradan Sylvie
Published: December 2024

Humans across cultures show an outstanding capacity to perceive, learn, and produce musical rhythms. These skills rely on mapping the infinite space of possible rhythmic sensory inputs onto a finite set of internal rhythm categories. What are the brain processes underlying rhythm categorization? We used electroencephalography (EEG) to measure brain activity as human participants listened to a continuum of rhythmic sequences characterized by repeating patterns of two inter-onset intervals. Using frequency and representational similarity analyses, we show that brain activity does not merely track the temporal structure of rhythmic inputs, but, instead, automatically produces categorical representation of rhythms. Surprisingly, despite this automaticity, these rhythm categories do not arise in the earliest stages of the ascending auditory pathway, but show strong similarity between implicit neural and overt behavioral responses. Together, these results and methodological advances constitute a critical step towards understanding the biological roots and diversity of musical behaviors across cultures.
BEVA2.0: Modular Assembly of Golden Gate-Compatible Vectors with Expanded Utility for Genetic Engineering
Authors: Geddes Barney A. , Williamson Riley , Schumacher Jake , Ardi Ahmad , Levin Garrett , Červenka Emily , Huang Rui , diCenzo George C.
Published: December 2024

This expansion for the modular vector assembly platform BEVA (Bacterial Expression Vector Archive) introduces 11 new BEVA parts including two new cloning site variants, two new antibiotic resistance modules, three new origins of replication, and four new accessary modules. As a result, the modular system is now doubled in size and expanded in its capacity to produce diverse replicating plasmids. Furthermore, it is now amenable to genetic engineering methods involving genome-manipulation of target strains through deletions or integrations. In addition to introducing the new modules, we provide several BEVA-derived Golden Gate cloning plasmids that are used to validate parts and that may be useful for genetic engineering of proteobacteria and other bacteria. We also introduce new parts to allow compatibility with the CIDAR MoClo parts libraries.
Rational engineering of allosteric protein switches byin silicoprediction of domain insertion sites
Authors: Wolf Benedict , Shehu Pegi , Brenker Luca , von Bachmann Anna , Kroell Ann-Sophie , Southern Nicholas , Holderbach Stefan , Eigenmann Joshua , Aschenbrenner Sabine , Mathony Jan , Niopek Dominik
Published: December 2024

Domain insertion engineering is a powerful approach to juxtapose otherwise separate biological functions, resulting in proteins with new-to-nature activities. A prominent example are switchable protein variants, created by receptor domain insertion into effector proteins. Identifying suitable, allosteric sites for domain insertion, however, typically requires extensive screening and optimization.

We present ProDomino, a novel machine learning pipeline to rationalize domain recombination, trained on a semi-synthetic protein sequence dataset derived from naturally occurring intradomain insertion events. ProDomino robustly identifies domain insertion sites in proteins of biotechnological relevance, which we experimentally validated inE. coliand human cells. Finally, we employed light- and chemically regulated receptor domains as inserts and demonstrate the rapid, model-guided creation of potent, single-component opto- and chemogenetic protein switches. These include novel CRISPR-Cas9 and -Cas12a variants for inducible genome engineering in human cells. Our work enables one-shot domain insertion engineering and substantially accelerates the design of customized allosteric proteins.
Generation of iPSC line ERCi004-A from human dermal fibroblasts of a patient with maturity-onset diabetes of the young type 3 caused by a heterozygous mutation in theHNF1Agene
Authors: Bastrich Asya , Antonov Daniil , Podzhilkova Aleksandra , Petrova Darya A. , Pylina Svetlana V. , Laptev Dmitriy N. , Sechko Elena A. , Kuznetsov Sergey N. , Vetchinkina Ekaterina A. , Mokrysheva Natalia G.
Published: December 2024

Maturity-onset diabetes of the young type 3 (MODY3) disorder is characterized by an autosomal dominant type of inheritance and highly heterogeneous clinical phenotype influenced by type and position of mutation in theHNF1Agene. We reprogrammed dermal fibroblasts derived from a patient with MODY3 carrying a heterozygous mutation in the site encoding the transactivation domain of the HNF1A protein (c. 864delGinsCC, p.Gly292ArgfsTer25) into iPSCs using transfection with self-replicating RNA vector. Obtained iPSCs (ERCi004-A line) proliferate in dense monolayer cell colonies, have a normal karyotype (46,XX), express pluripotency markers (OCT4, SOX2, TRA-1-60). The functional pluripotency of iPSCs was confirmed by their ability to form embryoid bodies and differentiate into the three germ layers (ecto-, endo-, and mesoderm). Sanger sequencing of iPSCs confirmed the presence of pathogenic heterozygous mutation in theHNF1Agene. This cell line could be useful to modeling of MODY3 pathology to improve understanding of the mechanism of the transactivation domain mutation, as well as a potential source for autologous cell-based therapy.