bluuebunny/crossref_metadata_2025 huggingface dataset:
Inheritance bias of deletion-harbouring mtDNA in yeast: the role of copy number and intracellular selection
Authors: Kashko Nataliia D. , Karavaeva Iuliia , Glagoleva Elena S. , Logacheva Maria D. , Garushyants Sofya K. , Knorre Dmitry A.
Published: September 2024

Eukaryotic cells contain multiple copies of mitochondrial DNA (mtDNA) molecules that replicate independently. Cell mtDNA content and variability contributes to the overall cell fitness. During sexual reproduction, fungi usually inherit mtDNA from both parents, however, the distribution of the mtDNA in the progeny can be biased toward some mtDNA variants. For example, crossingSaccharomyces cerevisiaestrain carrying wild type (rho+) mtDNA with the strain carrying mutant mtDNA variant with large deletion (rho−) can produce up to 99-100% ofrho−diploid progeny. Two factors could contribute to this phenomenon. First,rho−cells may accumulate more copies of mtDNA molecules per cell than wild-type cells, makingrho−mtDNA a prevalent mtDNA molecule in zygotes. This consequently leads to a high portion ofrho−diploid cells in the offspring. Second,rho−mtDNA may have a competitive advantage within heteroplasmic cells, and therefore could displacerho+mtDNA in a series of generations, regardless of their initial ratio. To assess the contribution of these factors, we investigated the genotypes and phenotypes of twenty tworho−yeast strains. We found that indeedrho−cells have a higher mtDNA copy number per cell thanrho+strains. Using anin silicomodelling of mtDNA selection and random drift in heteroplasmic yeast cells, we assessed the intracellular fitness of mutant mtDNA variants. Our model indicates that both higher copy numbers and intracellular fitness advantage of therho-mtDNA contribute to the biased inheritance ofrho−mtDNA.
Biofabrication of Small Vascular Graft with Acellular Human Amniotic Membrane: A Proof-of-Concept Study in Pig
Authors: Aung O , Rossi Peter J , Dyer Mitchell R , Stellpflug Austin , Zhai Yingnan , Kenneth Allen , Wang Xiaolong , Chang Jackie , Chen Yiliang , Tefft Brandon , Wu Rongxue , Gu Lingxia , Wang Bo
Published: September 2024

Synthetic vascular grafts, such as expanded polytetrafluoroethylene (ePTFE), are commonly used for large vessel surgeries [internal diameter (ID) ≥ 10 mm] but present significant challenges in medium to small vessels (ID < 10 mm) due to increased risks of thrombosis, stenosis, and infection. In this study, we developed a small-diameter vascular graft using decellularized human amniotic membrane (DAM graft) (ID = 6 mm) and transplanted it into porcine carotid arteries, comparing it with ePTFE grafts to assess inflammation, biocompatibility, patency, and overall function. One-week post-implantation, ultrasound imaging confirmed blood patency in both graft types. However, after one-month, gross examination revealed pronounced neointimal hyperplasia in ePTFE grafts, while DAM grafts maintained open lumens without signs of stenosis or thrombosis. Histological analysis showed extensive fibrous tissue formation in ePTFE grafts, resulting in luminal narrowing, whereas DAM grafts displayed sustained lumen patency and vascular integration. Immunofluorescence confirmed reduced inflammation and improved tissue organization in DAM grafts, characterized by lower macrophage infiltration and better cellular architecture. These findings suggest that DAM grafts offer superior biocompatibility and significantly lower risks of neointimal hyperplasia, making them a promising alternative for small-diameter vascular surgeries compared to ePTFE grafts.
A ChatGPT Assisted Reading Protocol for Undergraduate Research Students
Authors: Sambar Marcus , Vázquez Gonzalo R. , Vázquez Anne V. , Vázquez Frank X.
Published: September 2024

A major challenge for undergraduate students is reading scientific literature. This is especially true in biophysics, where many of the concepts may not have been covered in undergraduate courses. Students can become overwhelmed, which may lead to less overall engagement with the scientific literature. In response, we have developed a guided reading protocol that combines pre-reading strategies, structured notetaking, and ChatGPT to help students clarify unfamiliar concepts in an interactive way. To test the protocol, participants in this study were given an initial survey to determine their experience with reading scientific literature. After this they were given an abridged biophysics paper and the protocol. The ChatGPT transcripts were analyzed using open coding and the students were given a post-study survey. We found most students did not appear to regularly engage with the literature, possibly due to content barriers they encountered. Analyzing their transcripts, we observed that students asked for definitions, explanations, summaries, and simplifications. Overall, students reported that using ChatGPT was a positive experience and they expected to use ChatGPT in the future. From this work, we expect this new protocol may be a way to keep novice students from becoming discouraged when reading scientific papers and keep them engaged with the current literature.
Multiple Functions of Cerebello-Thalamic Neurons in Learning and Offline Consolidation of a Motor Skill in mice
Authors: Varani Andres P , Mailhes-Hamon Caroline , Sala Romain W , Fouda Sarah , Frontera Jimena L , Léna Clément , Popa Daniela
Published: September 2024

Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum via the ventral and intralaminar thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.
An updated AL-Base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis
Authors: Morgan Gareth , Nau Allison N. , Wong Sherry , Spencer Brian H. , Shen Yun , Hua Axin , Bullard Matthew J. , Sanchorawala Vaishali , Prokaeva Tatiana
Published: September 2024

Background

Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences lead to amyloid deposition could facilitate faster diagnosis and lead to new treatments.

Methods

Light chain sequences are collected in the Boston University AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties.

Results

AL-Base now contains 2,193 monoclonal light chain sequences from plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes,IGKV1-16andIGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated κ light chains harbored significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated λ light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data.

Conclusions

Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.
Cross-sectional brain age assessments are limited in predicting future brain change
Authors: Korbmacher Max , Vidal-Pineiro Didac , Wang Meng-Yun , van der Meer Dennis , Wolfers Thomas , Nakua Hajer , Eikefjord Eli , Andreassen Ole A. , Westlye Lars T. , Maximov Ivan I.
Published: September 2024

The concept of brain age (BA) describes an integrative imaging marker of brain health, often suggested to reflect ageing processes. However, the degree to which cross-sectional MRI features, including BA, reflect past, ongoing and future brain changes across different tissue types from macro-to microstructure remains controversial (Vidal-Pineiro et al. 2021). Here, we advance these findings by using multimodal imaging data of39, 325UK Biobank participants, aged44 − 82years at baseline and2, 520follow-ups within1.12 − 6.90years. In concordance with the original findings, we find insufficient evidence that BA reflects the rate of brain ageing. However, modality-specific differences in brain ages reflected the state of the brain, highlighting diffusion and multimodal MRI brain age as potentially useful cross-sectional markers.
Tissue-specific metabolomic signatures for adoublesexmodel of reduced sexual dimorphism
Authors: Coig Rene , Harrison Benjamin R. , Johnson Richard S. , MacCoss Michael J. , Promislow Daniel E.L.
Published: September 2024

Sex has a major effect on the metabolome. However, we do not yet understand the degree to which these quantitative sex differences in metabolism are associated with anatomical dimorphism and modulated by sex-specific tissues. In the fruit fly,Drosophila melanogaster, knocking out thedoublesex(dsx) gene gives rise to adults with intermediate sex characteristics. Here we sought to determine the degree to which this key node in sexual development leads to sex differences in the fly metabolome. We measured 91 metabolites across head, thorax and abdomen inDrosophila, comparing the differences between distinctly sex-dimorphic flies with those of reduced sexual dimorphism:dsxnull flies. Notably, in the reduced dimorphism flies, we observed a sex difference in only 1 of 91 metabolites, kynurenate, whereas 51% of metabolites (46/91) were significantly different between wildtype XX and XY flies in at least one tissue, suggesting thatdsxplays a major role in sex differences in fly metabolism. Kynurenate was consistently higher in XX flies in both the presence and absence of functioningdsx. We observed tissue-specific consequences of knocking outdsx. Metabolites affected by sex were significantly enriched in branched chain amino acid metabolism and the mTOR pathway. This highlights the importance of considering variation in genes that cause anatomical sexual dimorphism when analyzing sex differences in metabolic profiles and interpreting their biological significance.
Tenascin C Deletion Impairs Tendon Healing and Functional Recovery After Rotator Cuff Repair
Authors: Tashjian Robert Z. , Zitnay Jared , Kazmers Nikolas H. , Veerabhadraiah Shivakumar R. , Zelada Antonio C. , Honeggar Matthew , Smith Matthew C. , Chalmers Peter N. , Henninger Heath B. , Jurynec Michael J.
Published: September 2024

The biological factors that affect healing after rotator cuff repair (RCR) are not well understood. Genetic variants in the extracellular matrix protein Tenascin C (TNC) are associated with impaired tendon healing and it is expressed in rotator cuff tendon tissue after injury, suggesting it may have a role in the repair process. The purpose of the current study was to determine the role of TNC on tendon healing after RCR in a murine model. The supraspinatus tendon was transected and repaired on the left shoulder of Wild-Type (WT-RCR),Tenascin Cnull (Tnc−-RCR) andTncheterozygous (Tnc+/−-RCR) mice. Controls included the unoperated, contralateral shoulder of WT-RCR,Tnc—RCR,Tnc+/−-RCR mice and unoperated shoulders from age and genotype matched controls. We performed histologic, activity testing, RNA-seq, and biomechanical analyses. At 8-weeks post-RCR,Tnc−andTnc+/−mice had severe bone and tendon defects following rotator cuff repair.Tnc−-RCR mice had reduced activity after rotator cuff repair including reduced wheel rotations, wheel duration, and wheel episode average velocity compared with WT-RCR. Loss ofTncfollowing RCR altered gene expression in the shoulder, including upregulation of sex hormone and WNT pathways and a downregulation of inflammation and cell cycle pathways.Tnc−mice had similar biomechanical properties after repair as WT. Further research is required to evaluate tissue specific alterations ofTnc, the interactions ofTncand sex hormone and inflammation pathways as well as possible adjuvants to improve enthesis healing in the setting of reduced TNC function.
Challenging the Chronic Perverse Bias in Prosthetic Valve Design: A Pathway Opens for Advanced Mechanical Valves
Authors: Scotten Lawrence N. , Goode Dylan , Siegel Rolland , Blundon David J. , Dutton James W. , Mohammadi Hadi
Published: September 2024

Objective

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In vitro evaluation of several prototype mechanical valves compared to present-day controls.

Method

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simulated normal cardiac pressures and flows

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gravity pressure head column tester flows.

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recorded valve hydrodynamics and kinematics

Results

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valves superior in performance to clinical controls

Conclusions

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Prototype MHV candidates outperform the closing performance of present day SAVR prosthetic valves, including bioprosthetic control.

Competing Interests

None declared

Financial Disclosure

This research was performed on a pro bono basis by indicted coauthors*, in part, to assist coauthor and Ph.D. candidate Dylan Goode.

CENTRAL MESSAGE

In-vitro dynamics of optimized prototype mechanical heart valves (MHVs) outperformed those of current clinical prosthetic SAVR valves. -Achieving the objective of an anticoagulation-free and durable MHV is directly related to mitigation of detrimental valve closing hydrodynamics and kinematics.

PERSPECTIVE

Improvements in prosthetic valve performance and durability notwithstanding, the objective of an anti-coagulation free device with durability exceeding the projected life expectancy of all recipients has not been achieved. Our work identifies a design and development void that may have significantly delayed progress toward this objective.

SIGNIFICANCE

Our results challenge a longstanding bias in valve design, shifting the focus towards crucial behavior during valve closure. This study paves the way for advanced mechanical valves bringing us closer to the elusive goal of anticoagulation-free performance—a long-awaited milestone in the evolution of prosthetic valves.
Gut-Brain Nexus: Mapping Multi-Modal Links to Neurodegeneration at Biobank Scale
Authors: Shafieinouri Mohammad , Hong Samantha , Schuh Artur , Makarious Mary B. , Sandon Rodrigo , Lee Paul Suhwan , Simmonds Emily , Iwaki Hirotaka , Hill Gracelyn , Blauwendraat Cornelis , Escott-Price Valentina , Qi Yue A. , Noyce Alastair J. , Reyes-Palomares Armando , Leonard Hampton L. , Tansey Malu , Singleton Andrew , Nalls Mike A. , Levine Kristin S , Bandres-Ciga Sara
Published: September 2024

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are influenced by genetic and environmental factors. Using data from UK Biobank, SAIL Biobank, and FinnGen, we conducted an unbiased, population-scale study to: 1) Investigate how 155 endocrine, nutritional, metabolic, and digestive system disorders are associated with AD and PD risk prior to their diagnosis, considering known genetic influences; 2) Assess plasma biomarkers’ specificity for AD or PD in individuals with these conditions; 3) Develop a multi-modal classification model integrating genetics, proteomics, and clinical data relevant to conditions affecting the gut-brain axis. Our findings show that certain disorders elevate AD and PD risk before AD and PD diagnosis including: insulin and non-insulin dependent diabetes mellitus, noninfective gastro-enteritis and colitis, functional intestinal disorders, and bacterial intestinal infections, among others. Polygenic risk scores revealed lower genetic predisposition to AD and PD in individuals with co-occurring disorders in the study categories, underscoring the importance of regulating the gut-brain axis to potentially prevent or delay the onset of neurodegenerative diseases. The proteomic profile of AD/PD cases was influenced by comorbid endocrine, nutritional, metabolic, and digestive systems conditions. Importantly, we developed multi-modal prediction models integrating clinical, genetic, proteomic and demographic data, the combination of which performs better than any single paradigm approach in disease classification. This work aims to illuminate the intricate interplay between various physiological factors involved in the gut-brain axis and the development of AD and PD, providing a multifactorial systemic understanding that goes beyond traditional approaches. Further, we have developed an interactive resource for the scientific community [https://gut-brain-nexus.streamlit.app/] where researchers can investigate components of the predictive model and can investigate feature effects on a sample level.

Teaser

Co-occurring disorders of the gut-brain axis combined with genetic and proteomic data can better predict neurodegenerative risk.
Clinical management, epidemiology, and recurrence of human cystic echinococcosis in a secondary care level hospital in an endemic area of the Andes in Sicuani, Cusco, Peru
Authors: Pineda-Reyes Roberto , Cabada Miguel M , Bold Bolor , Morales Maria Luisa , Hattendorf Jan , Vergaray Paola , Bascope Ruben , Zinsstag Jakob
Published: September 2024

Peru has the highest incidence of human cystic echinococcosis (CE) in South America and most cases are reported in the Central and Southern Peruvian Andes, including the Cusco region. We reviewed medical records of patients with CE admitted between 2010-2019 to a level 2 Hospital in Sicuani, to collect data on the surgical management and disease recurrence in the Canchis province of Cusco. Records of 115 patients were analyzed in detail. The median age was 25 years (IQR, 16-46) and 60% were female. Most patients (68.7%) presented with a single liver cyst. The Gharbi classification was used in 75/107 (70.1%) patients with an ultrasound and 91/142 cysts (64.8%). Thirty one (34.1%) were classified as Gharbi I, 33 (36.3%) Gharbi II, 21 (23.1%) Gharbi III, and 6 (6.6%) Gharbi IV. Pre-surgical complications were reported in 41.7%. One hundred two patients underwent surgery. In 46.1%, one cyst spillage prevention measure was documented, 5.9% had two, and one had the three recommended measures. Post-surgical cyst recurrence was reported in 16.5% at a median 32.3 months (IQR, 3.9-46.6) and readmissions in 12.7%. In the multivariable analysis, having ≥3 cysts (OR 9.5, 95% CI 1.3-85.5), having two pre-surgical complications (OR 12.6, 95% CI 1.8-125.6), and receiving pre-surgical albendazole (OR 5.2, 95% CI 1.3-23.9) were associated with cyst recurrence. Advanced and complicated CE disease and post-surgical recurrence were common in Sicuani. Standardization of ultrasound staging-guided clinical management along with surgical spillage prevention measures could effectively decrease the disease burden linked to clinical care, improving outcomes and decreasing costs.
Using Genomic Context Informed Genotype Data and Within‐model Ancestry Adjustment to Classify Type 2 Diabetes
Authors: Barnett Eric J , Zhang-James Yanli , Hess Jonathan , Glatt Stephen J , Faraone Stephen V
Published: September 2024

Despite high heritability estimates, complex genetic disorders have proven difficult to predict with genetic data. Genomic research has documented polygenic inheritance, cross-disorder genetic correlations, and enrichment of risk by functional genomic annotation, but the vast potential of that combined knowledge has not yet been leveraged to build optimal risk models. Additional methods are likely required to progress genetic risk models of complex genetic disorders towards clinical utility. We developed a framework that uses annotations providing genomic context alongside genotype data as input to convolutional neural networks to predict disorder risk. We validated models in a matched-pairs type 2 diabetes dataset. A neural network using genotype data (AUC: 0.66) and a convolutional neural network using context-informed genotype data (AUC: 0.65) both significantly outperformed polygenic risk score approaches in classifying type-2 diabetes. Adversarial ancestry tasks eliminated the predictability of ancestry without changing model performance.
Development of a Novel Dynamic Leak Model to Simulate Leak for Performance Testing of Manual Neonatal Resuscitation Devices. Does Leak Matter? A Bench Study
Authors: Morakeas Stephanie , Hinder Murray , Drevhammar Thomas , Gruber Viktoria , Mcewan Alistair , Tracy Mark
Published: September 2024

Background: Newborn resuscitation is commonly performed in the presence of face mask leak. Leak is highly variable, pressure dependent and often unrecognised. The effectiveness of resuscitation devices to deliver adequate inflations in the presence of leak is unknown. Bench models simulating continuous leak have disadvantages of not accurately reflecting leak occurring during clinical resuscitation. A dynamic leak model based on pressure release valves was thus developed. Aim: To assess self-inflating bag (SIB) and T-piece resuscitator (TPR) ventilation performance in the presence of dynamic (DLM) compared to continuous (CLM) leak models in a bench study. Method: Five predefined leak levels were tested for each leak model (0-87%). Resuscitation devices were connected to a test lung (compliance 0.6 mL/cmH2O) and respiratory parameters were measured using respiratory function monitors before (patient interface) and after (actual) an induced leak at 40, 60, 80 inflations/min. Results: 3,600 inflations were analysed. DLM showed a decrease in actual tidal volumes from 0%-87% leak with tidal volume differences (SIB 4.8mL, TPR 2.9mL), contrasting to minimal change for CLM (SIB -0.6mL, TPR 0.3mL). CLM demonstrated larger differences between patient interface and actual leak. The absolute difference at 60 inflations/min at 87% leak were SIB 37.5%, TPR 18.2% for CLM compared to SIB 4.6%, TPR 1.4% for DLM. Conclusion: CLM may underestimate the impact of resuscitation device performance with poor correlation between patient interface and actual delivered volume. DLM demonstrates several advantages with more accurate representation of face mask leak and will prove useful in modelling all systems delivering PPV.
Optimizing Large Language Models for Discharge Prediction: Best Practices in Leveraging Electronic Health Record Audit Logs
Authors: Zhang Xinmeng , Yan Chao , Yang Yuyang , Li Zhuohang , Feng Yubo , Malin Bradley A. , Chen You
Published: September 2024

Electronic Health Record (EHR) audit log data are increasingly utilized for clinical tasks, from workflow modeling to predictive analyses of discharge events, adverse kidney outcomes, and hospital readmissions. These data encapsulate user-EHR interactions, reflecting both healthcare professionals' behavior and patients' health statuses. To harness this temporal information effectively, this study explores the application of Large Language Models (LLMs) in leveraging audit log data for clinical prediction tasks, specifically focusing on discharge predictions. Utilizing a year's worth of EHR data from Vanderbilt University Medical Center, we fine-tuned LLMs with randomly selected 10,000 training examples. Our findings reveal that LLaMA-2 70B, with an AUROC of 0.80 [0.77-0.82], outperforms both GPT-4 128K in a zero-shot, with an AUROC of 0.68 [0.65-0.71], and DeBERTa, with an AUROC of 0.78 [0.75-0.82]. Among various serialization methods, the first-occurrence approach — wherein only the initial appearance of each event in a sequence is retained — shows superior performance. Furthermore, for the fine-tuned LLaMA-2 70B, logit outputs yield a higher AUROC of 0.80 [0.77-0.82] compared to text outputs, with an AUROC of 0.69 [0.67-0.72]. This study underscores the potential of fine-tuned LLMs, particularly when combined with strategic sequence serialization, in advancing clinical prediction tasks.
Dual-format attentional template during preparation in human visual cortex
Authors: Chen Yilin , Liu Taosheng , Jia Ke , Theeuwes Jan , Gong Mengyuan
Published: September 2024

Goal-directed attention relies on forming internal templates of key information relevant for guiding behavior, particularly when preparing for upcoming sensory inputs. However, evidence on how these attentional templates is represented during preparation remains controversial. Here, we combine functional magnetic resonance imaging (fMRI) with an orientation cueing task to isolate preparatory activity from stimulus-evoked responses. Using multivariate pattern analysis, we found decodable information of the to-be-attended orientation during preparation; yet preparatory activity patterns were different from those evoked when actual orientations were perceived. When perturbing the neural activity by means of a visual impulse (‘pinging’ technique), the preparatory activity patterns in visual cortex resembled those associated with perceiving these orientations. The observed differential patterns with and without the impulse perturbation suggest a predominantly non-sensory format and a latent, sensory-like format of representation during preparation. Furthermore, the emergence of the sensory-like template coincided with enhanced information connectivity between V1 and frontoparietal areas and was associated with improved behavioral performance. This dual-format mechanism suggests that during preparation the brain encodes more detailed template information beyond its immediate use, potentially providing advantages for adaptive attentional control. Consistent with recent theories of non-veridical, ‘good-enough’ attentional template for initial guidance, our findings established a neural basis for implementing two representational formats in different functional states during preparation: a predominantly non-sensory format for guidance and a latent sensory-like format for prospective stimulus processing.
Convpaint - Universal framework for interactive pixel classification using pretrained neural networks
Authors: Hinderling Lucien , Witz Guillaume , Schwob Roman , Stojiljkovic Ana , Dobrzynski Maciej , Vladymyrov Mykhailo , Frei Joel , Graedel Benjamin , Frismantiene Agne , Pertz Olivier
Published: September 2024

We develop Convpaint, a universal computational framework for interactive pixel classification. Convpaint utilizes pretrained convolutional neural networks (CNNs) or vision transformers (ViTs) for feature extraction and enables easy segmentation across a wide variety of tasks. Available within the Python-based napari software ecosystem, Convpaint integrates seamlessly with other plugins into image processing pipelines, which we demonstrate with three workflows across different data modalities.
Track-A-Worm 2.0: A Software Suite for Quantifying Properties ofC. elegansLocomotion, Bending, Sleep, and Action Potentials
Authors: Vedantham Kiranmayi , Niu Longgang , Ma Ryan , Connelly Liam , Nagella Anusha , Wang Sijie Jason , Wang Zhao-Wen
Published: September 2024

Comparative analyses of locomotor behavior and cellular electrical properties between wild-type and mutantC. elegansare crucial for exploring the gene basis of behaviors and the underlying cellular mechanisms. Although many tools have been developed by research labs and companies, their application is often hindered by implementation difficulties or lack of features specifically suited forC. elegans.Track-A-Worm 2.0addresses these challenges with three key components:WormTracker,SleepTracker, andAction Potential (AP) Analyzer.WormTrackeraccurately quantifies a comprehensive set of locomotor and body bending metrics, reliably distinguish between the ventral and dorsal sides, continuously tracks the animal using a motorized stage, and seamlessly integrates external devices, such as a light source for optogenetic stimulation.SleepTrackerdetects and quantifies sleep-like behavior in freely moving animals.AP Analyzerassesses the resting membrane potential, afterhyperpolarization level, and various AP properties, including threshold, amplitude, mid-peak width, rise and decay times, and maximum and minimum slopes. Importantly, it addresses the challenge of AP threshold quantification posed by the absence of a pre-upstroke inflection point.Track-A-Worm 2.0is potentially a valuable tool for manyC. elegansresearch labs due to its powerful functionality and ease of implementation.
Condensin loop extrusion properties, roadblocks, and role in homology search in S. cerevisiae
Authors: Piveteau Vinciane , Salari Hossein , Dumont Agnes , Savocco Jerome , Dupont Chloe , Jost Daniel , Piazza Aurele
Published: September 2024

The in vivo mechanism, regulations by cis-acting roadblocks, and biological functions of loop extrusion by eukaryotic SMC complexes are incompletely defined. Here, using Hi-C, we identified two condensin-dependent contact stripes at the Recombination Enhancer (RE) and the rDNA in S. cerevisiae. We show that oriented, unidirectional loop extrusion proceeds from these sites with an estimated processivity ~170 kb and a density ~0.04-0.18 that varies across the cell cycle. Centromeres and highly-transcribed RNA PolII-dependent genes are permeable condensin roadblocks. Other positionally labile elements such as replication forks and Smc5/6 complexes bound to substrates generated in the absence of Top2 also hinder loop extrusion by condensin. Cohesin is not an obstacle for condensin. Finally, a DNA double-strand break at MAT blocks condensin, which results in the rapid establishment of a long-range RE-MAT loop that juxtaposes the recombination machinery with its HMLα donor target. Hence, all budding yeast SMCs are involved in recombinational DNA repair. We propose a revised model for donor selection during MAT switching that exploits specific properties of loop extrusion by condensin. It can serve as a paradigm for the establishment of other types of selective interactions along chromosomes.
Microglia-specific NF-κB signaling is a critical regulator of prion-induced glial inflammation and neuronal loss
Authors: Hay Arielle J. D. , Popichak Katriana A. , Mumford Genova , Shirley Payton , Bian Jifeng , Wolfrath Lauren , Lei Samantha , Eggers Michael , Nicholson Eric M. , Tjalkens Ronald B. , Zabel Mark D. , Moreno Julie A.
Published: September 2024

Prion diseases are a group of rare and fatal neurodegenerative diseases caused by the cellular prion protein, PrPC, misfolding into the infectious form, PrPSc, which forms aggregates in the brain. This leads to activation of glial cells, neuroinflammation, and irreversible neuronal loss, however, the role of glial cells in prion disease pathogenesis and neurotoxicity is poorly understood. Microglia can phagocytose PrPSc, leading to the release of inflammatory signaling molecules, which subsequently induce astrocyte reactivity. Animal models show highly upregulated inflammatory molecules that are a product of the Nuclear Factor-kappa B (NF-κB) signaling pathway, suggesting that this is a key regulator of inflammation in the prion-infected brain. The activation of the IκB kinase complex (IKK) by cellular stress signals is critical for NF-κB-induced transcription of a variety of genes, including pro-inflammatory cytokines and chemokines, and regulators of protein homeostasis and cell survival. However, the contribution of microglial IKK and NF-κB signaling in the prion-infected brain has not been evaluated. Here, we characterize a primary mixed glial cell model containing wild-type (WT) astrocytes and IKK knock-out (KO) microglia. We show that, when exposed to prion-infected brain homogenates, NF-κB-associated genes are significantly downregulated in mixed glial cultures containing IKK KO microglia. Mice with IKK KO microglia show rapid disease progression when intracranially infected with prions, including an increase in microglia and reactive astrocytes, and accelerated loss of hippocampal neurons and associated behavioral deficits. These animals display clinical signs of prion disease early and have a 22% shorter life expectancy compared to infected wild-type mice. Intriguingly, PrPScaccumulation was significantly lower in the brains of infected animals with IKK KO microglia compared to age-matched controls, suggesting that accelerated disease is independent of PrPScaccumulation, highlighting a glial-specific pathology.

Conversely, primary mixed glia with IKK KO microglia have significantly more PrPScaccumulation when exposed to infected brain homogenates. Together, these findings present a critical role in NF-κB signaling from microglia in host protection suggesting that microglial IKK may be involved in sufficient clearance of prions.
Intranasal parainfluenza virus-vectored vaccine expressing SARS-CoV-2 spike protein of Delta or Omicron B.1.1.529 induces mucosal and systemic immunity and protects hamsters against homologous and heterologous challenge
Authors: Park Hong-Su , Matsuoka Yumiko , Santos Celia , Luongo Cindy , Liu Xueqiao , Yang Lijuan , Kaiser Jaclyn A , Duncan Eleanor F , Johnson Reed F , Teng I-Ting , Kwong Peter D , Buchholz Ursula J , Le Nouën Cyril
Published: September 2024

The continuous emergence of new SARS-CoV-2 variants requires that COVID vaccines be updated to match circulating strains. We generated B/HPIV3-vectored vaccines expressing 6P-stabilized S protein of the ancestral, B.1.617.2/Delta, or B.1.1.529/Omicron variants as pediatric vaccines for intranasal immunization against HPIV3 and SARS-CoV-2 and characterized these in hamsters. Following intranasal immunization, these B/HPIV3 vectors replicated in the upper and lower respiratory tract and induced mucosal and serum anti-S IgA and IgG. B/HPIV3 expressing ancestral or B.1.617.2/Delta-derived S-6P induced serum antibodies that effectively neutralized SARS-CoV-2 of the ancestral and B.1.617.2/Delta lineages, while the cross-neutralizing potency of B.1.1.529/Omicron S-induced antibodies was lower. Despite the lower cross-neutralizing titers induced by B/HPIV3 expressing S-6P from B.1.1.529/Omicron, a single intranasal dose of all three versions of B/HPIV3 vectors was protective against matched or heterologous WA1/2020, B.1.617.2/Delta or BA.1 (B.1.1.529.1)/Omicron challenge; hamsters were protected from challenge virus replication in the lungs, while low levels of challenge virus were detectable in the upper respiratory tract of a small number of animals. Immunization also protected against lung inflammatory response after challenge, with mild inflammatory cytokine induction associated with the slightly lower level of cross-protection of WA1/2020 and B.1.617.2/Delta variants against the BA.1/Omicron variant. Serum antibodies elicited by all vaccine candidates were broadly reactive against 20 antigenic variants, but the antigenic breadth of antibodies elicited by B/HPIV3-expressed S-6P from the ancestral or B.1.617.2/Delta variant exceeded that of the S-6P B.1.1.529/Omicron expressing vector. These results will guide development of intranasal B/HPIV3 vectors with S antigens matching circulating SARS-CoV-2 variants.
Protonation/deprotonation-driven switch for the redox stability of low-potential [4Fe-4S] ferredoxin
Authors: Wada Kei , Kobayashi Kenji , Era Iori , Isobe Yusuke , Kamimura Taigo , Marukawa Masaki , Nagae Takayuki , Honjo Kazuki , Kaseda Noriko , Motoyama Yumiko , Inoue Kengo , Sugishima Masakazu , Kusaka Katsuhiro , Yano Naomine , Fukuyama Keiichi , Mishima Masaki , Kitagawa Yasutaka , Unno Masaki
Published: September 2024

Ferredoxin is a small iron-sulfur protein and acts as an electron carrier. Low-potential ferredoxins harbor [4Fe-4S] cluster(s), which play(s) a crucial role as the redox center. Low-potential ferredoxins are able to cover a wide range of redox potentials (−700 to −200 mV); however, the mechanisms underlying the factors which control the redox potential are still enigmatic. Here, we determined the neutron structure of ferredoxin fromBacillus thermoproteolyticus, and experimentally revealed the exact hydrogen-bonding network involving the [4Fe-4S] cluster. The density functional theory calculations based on the hydrogen-bonding network revealed that protonation states of the sidechain of Asp64 close to the [4Fe-4S] cluster critically affected the stability of the reduced state in the cluster. These findings provide the first identification of the intrinsic control factor of redox potential for the [4Fe-4S] cluster in low-potential ferredoxins.
Targeted memory reactivation elicits temporally compressed reactivation linked to spindles
Authors: Abdellahi Mahmoud E. A. , Rakowska Martyna , Treder Matthias S. , Lewis Penelope A.
Published: September 2024

Memories reactivate during sleep, however the properties of such reactivation and its relationship to encoding strength and subsequent memory performance are not well understood. We set out to examine memory reactivations associated with a serial reaction time task (SRTT). 48 human participants performed the SRTT, and then slept in the lab while we deliberately induced reactivation in Slow Wave Sleep (SWS) using a Targeted Memory Reactivation (TMR) design. We detected reactivation after TMR cues using multiclass classification that adapted to sleep data by using sleep activity for training and wake activity for testing. We then examined the temporal properties of reactivation in relation to behavioural performance and sleep spindles. In keeping with the rodent literature, the observed reactivation was 3 to 20 times faster than waking activity. Furthermore, we report an inverted-U shaped relationship between TMR-related behavioural improvement and encoding strength, with very strong and very weak memories benefiting little from cueing while medium-strength memories benefit the most. Finally, reactivation was more frequently observed in trials with high sigma power, supporting the idea that sleep spindles are associated with memory reactivation during sleep. These findings bring us closer to understanding the characteristics of human memory reactivation after TMR, demonstrate when cueing is effective, and provide evidence for the positive relationship between the detectability of reactivation and memory consolidation.
Mitochondrial Fatty Acid Oxidation is Stimulated by Red Light Irradiation
Authors: Herrera Manuel Alejandro , Caldeira da Silva Camille C. , Baptista Mauricio S. , Kowaltowski Alicia J.
Published: September 2024

The skin is our largest organ, and also the most exposed to solar radiation. As mitochondria within skin cells are rich in endophotosensitizers such as NADH, FADH2, and cytochromes, we studied the effects of different UV and visible light wavelengths on metabolic fluxes in keratinocytes, the main cell type in the epidermis. We find that 36 J/cm2of UV light (λmaxat 365 nm) leads to a complete inhibition of oxidative phosphorylation. The same light dose at other wavelengths (blue light, 450 nm, and green light, 517 nm) did not affect metabolic fluxes, but reduced cell viability, probably by photosensitizing oxidation. Strikingly, red light (660 nm) not only did not decrease cell viability, but also enhanced cell proliferation as well as basal and maximal oxygen consumption rates for up to two days after irradiation. To uncover the mechanisms in which this unexpected long-lived metabolic enhancement occurred, we measured quantities of oxidative phosphorylation-related proteins and oxygen consumption in permeabilized cells, which were unchanged. This result is indicative of a modulation of cytosolic metabolic processes by red light. Subsequently, we measured glycolytic, glutamine-dependent, and fatty-acid supported metabolic fluxes and determined that red light specifically activates fatty acid oxidation by mitochondria. Overall, our results demonstrate that light modulates oxidative phosphorylation with different effects at distinct wavelengths. Interestingly, we uncover a novel and highly specific effect of red light modulating fatty acid oxidation in keratinocytes, providing a novel mechanistic explanation for the metabolic effects of photobiomodulation.

Highlights

Different UV and visible light wavelengths affect keratinocytes distinctly: UV leads to cell death and metabolic flux inhibition, while green light decreases viability without affecting oxygen consumption.

Surprisingly, red light increases intact cell oxygen consumption up to two days post exposure.

Red light exposure does not change the quantity or activity of components of oxidative phosphorylation in mitochondria.

Increased mitochondrial respiration and ATP synthesis promoted by red light is fueled by enhanced fatty acid oxidation.
Behavioral Evidence for Two Modes of Attention
Authors: Gupta Akanksha , Matthews Tomas E. , Penhune Virginia B. , Morillon Benjamin
Published: September 2024

Attention modulates sensory gain to select and optimize the processing of behaviorally relevant events. It has been hypothesized that attention can operate in either a rhythmic or continuous mode, depending on the nature of sensory stimulation. Despite this conceptual framework, direct behavioral evidence has been scarce. Our study explores when attention operates in a rhythmic mode through a series of nine interrelated behavioral experiments with varying stream lengths, stimulus types, attended features, and tasks. The rhythmic mode optimally operates at approximately 1.5 Hz and is prevalent in perceptual tasks involving long (> 7 s) auditory streams. Our results are supported by a model of coupled oscillators, illustrating that variations in the system’s noise level can induce shifts between continuous and rhythmic modes. Finally, the rhythmic mode is absent in syllable categorization tasks. Overall, this study provides empirical evidence for two modes of attention and defines their conditions of operation.
Distinct basal ganglia decision dynamics under conflict and uncertainty
Authors: Ging-Jehli Nadja R. , Cavanagh James F. , Ahn Minkyu , Segar David J. , Asaad Wael F. , Frank Michael J.
Published: September 2024

The basal ganglia (BG) play a key role in decision-making, preventing impulsive actions in some contexts while facilitating fast adaptations in others. The specific contributions of different BG structures to this nuanced behavior remain unclear, particularly under varying situations of noisy and conflicting information that necessitate ongoing adjustments in the balance between speed and accuracy. Theoretical accounts suggest that dynamic regulation of the amount of evidence required to commit to a decision (a dynamic “decision boundary”) may be necessary to meet these competing demands. Through the application of novel computational modeling tools in tandem with direct neural recordings from human BG areas, we find that neural dynamics in the theta band manifest as variations in a collapsing decision boundary as a function of conflict and uncertainty.

We collected intracranial recordings from patients diagnosed with either Parkinson’s disease (n=14) or dystonia (n=3) in the subthalamic nucleus (STN), globus pallidus internus (GPi), and externus (GPe) during their performance of a novel perceptual discrimination task in which we independently manipulated uncertainty and conflict. To formally characterize whether these task and neural components influenced decision dynamics, we leveraged modified diffusion decision models (DDMs). Behavioral choices and response time distributions were best characterized by a modified DDM in which the decision boundary collapsed over time, but where the onset and shape of this collapse varied with conflict. Moreover, theta dynamics in BG structures predicted the onset and shape of this collapse but differentially across task conditions. In STN, theta activity was related to a prolonged decision boundary (indexed by slower collapse and therefore more deliberate choices) during high-conflict situations. Conversely, rapid declines in GPe theta during low conflict conditions were related to rapidly collapsing boundaries and expedited choices, with additional complementary decision bound adjustments during high uncertainty situations. Finally, GPi theta effects were uniform across conditions, with increases in theta prolonging the collapse of decision bounds. Together, these findings provide a nuanced understanding of how our brain thwarts impulsive actions while nonetheless enabling behavioral adaptation amidst noisy and conflicting information.
Mindfulness-based Neurofeedback: A Systematic Review of EEG and fMRI studies
Authors: Treves Isaac N. , Greene Keara D. , Bajwa Zia , Wool Emma , Kim Nayoung , Bauer Clemens C.C. , Bloom Paul A. , Pagliaccio David , Zhang Jiahe , Whitfield-Gabrieli Susan , Auerbach Randy P.
Published: September 2024

Neurofeedback concurrent with mindfulness meditation may reveal meditation effects on the brain and facilitate improved mental health outcomes. Here, we systematically reviewed EEG and fMRI studies of mindfulness meditation with neurofeedback (mbNF) and followed PRISMA guidelines. We identified 10 fMRI reports, consisting of 177 unique participants, and 9 EEG reports, consisting of 242 participants. Studies of fMRI focused primarily on downregulating the default-mode network (DMN). Although studies found decreases in DMN activations during neurofeedback, there is a lack of evidence for transfer effects, and the majority of studies did not employ adequate controls, e.g. sham neurofeedback. Accordingly, DMN decreases may have been confounded by general task-related deactivation. EEG studies typically examined alpha, gamma, and theta frequency bands, with the most robust evidence supporting the modulation of theta band activity. Both EEG and fMRI mbNF have been implemented with high fidelity in clinical populations. However, the mental health benefits of mbNF have not been established. In general, mbNF studies would benefit from sham-controlled RCTs, as well as clear reporting (e.g. CRED-NF).
Homoploid Hybridization Resolves the Origin of Octoploid Strawberries
Authors: Fan Zhen , Liston Aaron , Soltis Douglas , Soltis Pamela , Ashman Tia-Lynn , Hummer Kim , Whitaker Vance M.
Published: September 2024

The identity of the diploid progenitors of octoploid cultivated strawberry (Fragaria × ananassa) has been subject to much debate. Past work identified four subgenomes and consistent evidence forF. californica(previously namedF. vescasubsp.bracteata) andF. iinumaeas donors for subgenomes A and B, respectively, with conflicting results for the origins of subgenomes C and D. Here, reticulate phylogeny and admixture analysis support hybridization betweenF. viridisandF. vescain the ancestry of subgenome A, and betweenF. nipponicaandF. iinumaein the ancestry of subgenome B. Using an LTR-age-distribution-based approach, we estimate that the octoploid and its intermediate hexaploid and tetraploid ancestors emerged approximately 0.8, 2, and 3 million years ago, respectively. These results provide an explanation for previous reports ofF. viridisandF. nipponicaas donors of the C and D subgenomes and unify conflicting hypotheses about the evolutionary origin of octoploidFragaria.