bluuebunny/crossref_metadata_2025 huggingface dataset:
Vowel Harmony in Austronesian Languages
Authors: Gasser Emily
Published: October 2024

This chapter describes patterns of vowel harmony (VH) in the Austronesian languages. While not as pervasive or archetypal as that found in families such as Turkic, VH is nonetheless far more widespread in Austronesian than is generally recognized. Documented patterns spread [ATR] or laxness, height, backness, rounding, and/or nasality. While the domain of harmony is frequently limited to a two-syllable window, it can be as large as the prosodic word or even the Intonational Phrase, and its application can be influenced by stress, syllable shape, and the surrounding consonants. VH is most common in the western part of the Austronesian world, but is attested in central and eastern languages as well. Comprising roughly one sixth of the world’s languages, Austronesian is a large and diverse family, and it would not be surprising if further language documentation were to uncover more VH patterns of varying kinds across the group.
Kant’s Criticism of Metaphysics
Authors: Watkins Eric
Published: October 2024

This chapter presents a novel interpretation of one line of Kant’s critique of the claims of traditional metaphysics. In its first section, it presents a series of conditions on cognition, according to which cognition requires not only that the object to be cognized must be given in intuition and thought through concepts (the givenness and thought conditions), but also that it be possible to show that the positive properties thought through the relevant concepts are exhibited by the object given in intuition so that an object we are aware of is thereby rendered intelligible (the real possibility, positive content, and subjective sources conditions). In the second section, it shows how Kant argues that even if the most important objects of traditional metaphysics—the soul, God, and freedom—might be thought to satisfy the givenness and thought conditions, they cannot satisfy the other conditions. For it turns out that of the objects of which we can be aware (e.g. by them being given in intuition), we cannot be aware of them as exhibiting the positive properties represented by the concepts of the objects of traditional metaphysics, for there is a fundamental mismatch between how we represent objects that are given to us and the content represented in the concepts of the objects of traditional metaphysics.
Kant on Virtue
Authors: Hills Alison
Published: October 2024

Kant’s moral theory has often been portrayed as a paradigm of a rule-based moral theory, consisting of strict obligations with no role for a conception of virtue. But Kant does have an interest in the reasons for action as well as the action itself, in the evaluation of a person (as a good will), and in an underlying moral disposition (the Gesinnung or ‘metamaxim’), all of which are similar to ideas of virtue. Moreover, Kant does have a conception of virtue, developed in the Metaphysics of Morals, according to which virtue is the strength to carry out our moral obligations, in the face of temptations from ‘the beloved self’ to do otherwise.
Kant on Cognition and Knowledge
Authors: Kohl Markus
Published: October 2024

This chapter discusses the difference and the connections between Kant’s notions of cognition (Erkenntnis) and knowledge (Wissen). Unlike knowledge, cognition is a representational state which need not have the propositional structure of a judgment. Even cognitions that have such a structure need not coincide with knowledge, because they might rather have the doxastic status of opinion or faith, or they might be false (whereas knowledge is a certain recognition of truth). The chapter argues that while Kant distinguishes between many different species of cognition, he uses the term ‘knowledge’ univocally across his theoretical and practical philosophy. All knowledge is based upon some kind of cognition that provides the sufficient objective, certain ground for a knowing assent to a proposition. However, not all knowledge must be based upon the demanding type of cognition that is central to Kant’s overall argument in the first Critique, which requires a synthesis of concepts and sensible intuition. We have a lot of determinate knowledge, including knowledge that we possess transcendental freedom of will, that is based upon purely conceptual practical cognition. We can also have some indeterminate philosophical knowledge (e.g. knowledge that there are non-sensible, noumenal beings) that is based upon purely conceptual theoretical cognition.
Kant on Logic
Authors: Bader Ralf M.
Published: October 2024

Immanuel Kant developed a highly systematic and nuanced conception of logic that differs significantly from, and is in important respects superior to, the logics developed by his predecessors and contemporaries, as well as those in use nowadays. Whilst his logic plays a crucial role in both his theoretical and practical philosophy, it is unfortunately widely misunderstood, leading to deep-rooted misinterpretations of the Critical philosophy. This chapter provides an account of the logical forms of judgment in general and transcendental logic, spelling out the different ways in which concepts can be synthesized to form categorical judgments and the ways in which categorical judgments can be synthesized to form hypothetical and disjunctive judgments.
Alternative metrics and social impact of research about Social Sciences in Cuba
Authors: Ortiz Núñez Roelvis , Jaillier Castrillón Érika
Published: October 2024

The evaluation of the social impact of research is a critical concern for both the scientific and social communities. This study aims to describe the social impact of scientific research outcomes in the field of Social Sciences in Cuba. Five dimensions of analysis and 16 alternative indicators were utilized, employing altmetric tools and data sources. The data for the study were collected from the Scopus database and the altmetric data provider PlumX Metrics. Statistical techniques for trend and correlation analysis between indicators, along with data visualization, were used for the analysis. The results indicate that the most prominent indicators were citations in Scopus and CrossRef, Views Count, Full Text Views, Abstract Views, Readers in Mendeley Captures, and social network metrics from Facebook and Twitter. The research findings with the greatest social impact pertained to climate change and environmental policy, scientific production related to COVID-19, higher education, sustainable development, gender studies, legislation, and tourism.
KCNB1‐Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus
Authors: Forzisi‐Kathera‐Ibarra Elena , Jo Chanmee , Castillo Leonard , Gaur Anika , Lad Prachi , Bortolami Alessandro , Roser Christian , Venkateswaran Srinidi , Dutto Stefania , Selby Matthew , Sampath Harini , Pan Ping‐Yue , Sesti Federico
Published: October 2024

The neurons of the melanocortin system regulate feeding and energy homeostasis through a combination of electrical and endocrine mechanisms. However, the molecular basis for this functional heterogeneity is poorly understood. Here, a voltage‐gated potassium (Kv+) channel named KCNB1 (alias Kv2.1) forms stable complexes with the leptin receptor (LepR) in a subset of hypothalamic neurons including proopiomelanocortin (POMC) expressing neurons of the Arcuate nucleus (ARHPOMC). Mice lacking functional KCNB1 channels (NULL mice) have less adipose tissue and circulating leptin than WT animals and are insensitive to anorexic stimuli induced by leptin administration. NULL mice produce aberrant amounts of POMC at any developmental stage. Canonical LepR‐STAT3 signaling—which underlies POMC production—is impaired, whereas non‐canonical insulin receptor substrate PI3K/Akt/FOXO1 and ERK signaling are constitutively upregulated in NULL hypothalami. The levels of proto‐oncogene c‐Fos—that provides an indirect measure of neuronal activity—are higher in arcuate NULL neurons compared to WT and most importantly do not increase in the former upon leptin stimulation. Hence, a Kv channel provides a molecular link between neuronal excitability and endocrine function in hypothalamic neurons.
Effectiveness of recombinant follicle-stimulating hormone treatment in patients with oligo-asthenospermia at different levels of DNA fragmentation index: A phase II clinical trial
Authors: Soltani Salman , Tafazoli Nooshin , Emadzadeh Maryam , Aghaee Atena , Ebrahiminia Milani Soheila , Seyedi Vostakolaee Seyed Mohsen , Akhavan Rezayat Alireza
Published: October 2024

Objective

This study aimed to perform an evaluation of changes in spermogram parameters after follicle-stimulating hormone (FSH) therapy in infertile males having oligo-asthenospermia at different levels of DNA fragmentation index (DFI).

Materials and methods

Infertile men with oligo-asthenospermia, no underlying urogenital disease (such as varicocele), and medically fertile partners were enrolled over 1 year. Semen parameters, FSH, luteinizing hormone, and testosterone levels were determined; also, a Sperm DNA Fragmentation Assay Kit (Hamun Teb Pishro, Tehran, Iran) was used for determining sperm DFI at baseline .Participants were categorized into three groups based on DFI: DFI <15% (group 1), DFI of 15%–30% (group 2), and DFI >30% (group 3). All participants received subcutaneous recombinant FSH (150 mg every other day) for 6 months. Sperm specimens were tested 6 months after intervention (a single sperm control test).

Results

Sixty males whose average age was 28.4 years were enrolled. Only group 3 (poor fertility) exhibited a significant rise in sperm concentration (p = 0.001) and motility (p < 0.05) after FSH treatment. Group 1 (DFI <30 fertility) and group 2 (DFI of 15%–30%) showed increased mean sperm concentration and motility postintervention, although these alterations were not significantly different. Follicle-stimulating hormone levels increased significantly in all three groups after FSH administration. Serum luteinizing hormone and testosterone levels were not significantly increased in any of the groups.

Conclusions

FSH treatment improves sperm concentration and motility in men with oligo-asthenospermia, with significant improvements observed in men with DFI >30%. DNA fragmentation index can be a predictive indicator of response to FSH treatment in such patients.
SCREENING AND MONITORING OF DIABETIC RETINOPATHY IN COMMUNITY CARE
Authors: He Xin , Deng Xinchen , Lin Zhong , Wen Liang , Zhou Weihe , Xu Xiang , Hu Shiqi , Liang Yuanbo , Wang Yu , Qu Jia , Ye Cong
Published: October 2024

Purpose:

This study aimed to evaluate the effectiveness of single-field fundus photography for diabetic retinopathy (DR) screening and monitoring versus six-field imaging in community settings.

Methods:

Adults aged ≥30 years with Type 2 diabetes from 15 communities in Northeast China were recruited for this prospective cohort study (n = 2,006 at baseline and n = 1,456 at follow-up). Participants underwent both single-field and six-field digital fundus photography at baseline and follow-up visits (mean duration of 21.2 ± 3.2 months). Photographs were graded using international standards. Agreement in DR severity grading, referral recommendations, and detection of DR progression were compared between single-field and six-field fundus photography.

Results:

Single-field grading showed substantial agreement with multifield grading in classifying DR severity (81.9% identical at baseline, 80.6% at follow-up, Gwet AC1 0.79 and 0.77). For referring eyes with moderate nonproliferative DR or worse, single-field grading had ∼70% sensitivity and 100% specificity compared with six-field grading. Single-field grading identified 74.9% or 79.7% of eyes progressing or regressing by six-field grading, respectively.

Conclusion:

Single-field fundus photography demonstrated reasonable effectiveness for DR screening and monitoring in a community setting, supporting its use for improving access to DR detection. However, reduced sensitivity compared with multifield imaging should be acknowledged.
A good bug gone bad? Whole genome sequence and phenotypic characterisation of a soil organism, Bacillus paralicheniformis MB647, isolated from an infected orthopaedic implant.
Authors: Abbas Sidra , Figueroa-Chavez Wendy , Yasmin Azra , Welch Martin
Published: October 2024

An isolate of a rod-shaped, endospore-forming Gram-positive facultative anaerobe was recovered from infected orthopaedic implant samples collected from a hospital in Islamabad, Pakistan. The isolate was motile and displayed optimal growth at 37°C (pH 7.0). The whole genome sequence of strain showed 97% similarity with the Bacillaceae family and 90% with Bacillus paralicheniformis. This species is only rarely associated with diseases in humans, and to the best of our knowledge, this is the first report of Bacillus paralicheniformis MB647 being isolated from an infected orthopaedic implant. To understand better why MB647 might cause infections in humans, we carried out whole genome sequencing. This revealed a number of antibiotic resistance mechanisms (conferring resistance to tetracycline, bicyclomycin, bacitracin, erythromycin, and various β-lactams). Several virulence factors were identified in the genome, including genes linked to biofilm formation, hemolysins production and the secretion of proteolytic enzymes such as proteases and gelatinases, which may contribute to the pathogenic potential of MB647 in implant associated infections. Based on the consensus of whole genome sequencing, multi-locus sequencing typing (MLST) and phenotypic analyses, we conclude that this strain represents a novel lineage with a unique sequence type (ST48) within the genus Bacillus.
Model-based fed-batch cultivation ofViola odorataplant cells exhibiting antimalarial and anticancer activity
Authors: Babu R , Veeramani Manokaran , Wallepure Aadinath , Muthuvijayan Vignesh , Singh Shailja , Srivastava Smita
Published: October 2024

Viola odoratais used in the indigenous medicine to treat respiratory tract disorders and is limited in availability. Bioprocess principles can be applied to develop sustainable methods to produce high-qualityV. odoratabiomass. To this effect, a modified stirred tank reactor and a balloon-type bubble column reactor were used to improve biomass production. Nutrient feeding strategies were developed using first principle-based mathematical modelling to achieve higher cell density in the reactor. Experimental validation of the fed-batch model-predicted strategy resulted in a two-fold enhancement in biomass production (32.2 g DW L-1) at the bioreactor level. Also, bioreactor-cultivated biomass extracts were tested forin vitrohemolytic, cytotoxic, anti-inflammatory, andin vivoantiplasmodial activities. This is the first report on fed-batch cultivation in bioreactors and the antiplasmodial activity ofV. odorata. Overall, the bioactive potential of thein vitro-generated biomass extracts is found to be similar to that in the natural plant biomass extracts.

Highlights

Cultivation ofV. odoratacell suspension culture using a modified stirred tank and balloon-type bubble column bioreactors.

Batch kinetic models were developed and extrapolated into a fed-batch model.

Enhanced biomass production (32.2 g DW L-1) in bioreactors using a nutrient-feeding strategy.

Extracts showed anti-inflammatory effects and up to 80 % inhibition of parasite growth, with no hemolytic activity.

Confirmed antiplasmodial activityin vivo, effective alongside artesunate.

In vitro-generated biomass extracts showed comparable bioactive potential to that of natural plants.

Graphical Abstract
Reducing flight time during running decreases tibial-fibular strains: a finite element analysis
Authors: Khassetarash Arash , Nigg Benno. M. , Edwards W. Brent
Published: October 2024

Purpose

Reducing strains within the tibia and fibula during running may reduce the risk of stress fractures. We examined the effect of reduced flight time during running (i.e., grounded running) on finite-element predicted bone strains within the tibia-fibula complex.

Methods

Nine physically active males ran on an instrumented treadmill at 2.2 m/s using a preferred and reduced flight time technique in a randomized order. Three-dimensional force and motion capture data were recorded during running and a computed tomography image was subsequently acquired for the participant’s left leg. An inverse-dynamics-based musculoskeletal modeling workflow was used to calculate bone-on-bone contact and muscle forces during the stance phase of running. These forces served as inputs to a participant-specific finite-element model to estimate peak bone strains and strained volume (i.e., the volume of bone experiencing strains above a specific threshold) within the tibia-fibula complex.

Results

Guided attempts to reduce flight time was successful with an 18 ms (95% CI: 12 ms, 25 ms; p<0.001) reduction in flight time. Reducing flight time was associated with significant reductions in peak tibial/fibular strains (17% lower; 95% CI: -7.1%, -25.0%; p=0.002) and strained volume (35% lower; 95% CI: -13.57%, -50.87%; p=0.007).

Conclusion

We conclude that guided attempts to reduce flight time significantly reduces strains in the tibia and fibula during treadmill running at a fixed speed. These results suggest that grounded running may be a viable technique to reduce musculoskeletal loading and stress fracture risk, particularly in slow runners and those runners coming back from injury.
Establishment of a locally adaptive allele in multidimensional continuous space
Authors: Sakamoto Takahiro
Published: October 2024

Local adaptation is widely seen when species adapt to spatially heterogeneous environments. Although many theoretical studies have investigated the dynamics of local adaptation using two-population models, there remains a need to extend the theoretical framework to continuous space settings, reflecting the real habitats of species. In this study, we use a multidimensional continuous space model and mathematically analyze the establishment process of local adaptation, with a specific emphasis on the relative roles of mutation and migration. First, the role of new mutations is evaluated by deriving the establishment probability of a locally adapted mutation using a branching process and a diffusion approximation. Next, the contribution of immigrants from a neighboring region with similar environmental conditions is considered. Theoretical predictions of the local adaptation rate agreed with the results of Wright–Fisher simulations in both mutation-driven and migration-driven cases. Evolutionary dynamics depend on several factors, including the strength of migration and selection, population density, habitat size, and spatial dimensions. These results offer a theoretical framework for assessing whether mutation or migration predominantly drives convergent local adaptation in spatially continuous environments in the presence of patchy regions with similar environmental conditions.
Prey attraction in a generalist microbial predator,Dictyostelium discoideum
Authors: Shreenidhi P. M. , McCabe Rachel I. , Queller David C. , Strassmann Joan E.
Published: October 2024

Generalist predators often live in environments that vary in the type and abundance of prey species. The prey species in turn vary in their susceptibility and suitability to predation. How do generalists navigate this variation in prey abundance and profitability and seek out their preferred prey? We investigated this in the soil protistDictyostelium discoideum, a generalist predator of many species of bacteria. Despite their generalist diet, amoebas experience considerable variation in growth rate on their prey bacteria. We tested if amoebas innately prefer the more profitable prey bacteria. We found that the levels of chemoattraction of naïve amoebas towards prey bacteria increased with increasing growth rate of the amoebas on those bacteria. This suggests thatD. discoideumamoebas have an innate prey preference that is adaptive. Next, we tested how experience with prey bacteria affects chemoattraction in amoebas. Given the number of bacterial species in soil, learning from experience should be advantageous. However, we found no evidence for learning; instead amoeba preference in learning experiments was partially explained by innate attractiveness of the prey bacteria. Our results suggest that generalist amoebas are innately attracted to the more profitable prey bacteria and this innate attraction cannot be overridden by recent experience.
lucie: An Improved Python Package for Loading Datasets from the UCI Machine Learning Repository
Authors: Ge Kenneth , Nguyen Phuc , Arnaout Ramy
Published: October 2024

The University of California–Irvine (UCI) Machine Learning (ML) Repository (UCIMLR) is consistently cited as one of the most popular dataset repositories, hosting hundreds of high-impact datasets. However, a significant portion, including 28.4% of the top 250, cannot be imported via theucimlrepopackage that is provided and recommended by the UCIMLR website. Instead, they are hosted as .zip files, containing nonstandard formats that are difficult to import without additional ad hoc processing. To address this issue, here we presentlucie—loadUniversityCalifornia Irvineexamples—a utility that automatically determines the data format and imports many of these previously non-importable datasets, while preserving as much of a tabular data structure as possible.luciewas designed using the top 100 most popular datasets and benchmarked on the next 130, where it resulted in a success rate of 95.4% vs. 73.1% forucimlrepo. lucieis available as a Python package on PyPI with 98% code coverage.
A Measure of Event-Related Potentials (ERP) Indices of Motivation During Cycling
Authors: Renoud-Grappin Rémi , Gabriel Damien , Broussard Emmanuelle , Mourot Laurent , Giustiniani Julie , Pazart Lionel
Published: October 2024

Although motivation is a central aspect of the practice of a physical activity, it is a challenging endeavour to predict an individual’s level of motivation during the activity. The objective of this study was to assess the feasibility of measuring motivation through brain recording methods during physical activity, with a specific focus on cycling. The experiment employed the Effort Expenditure for Reward Task (EEfRT), a decision-making task based on effort and reward, conducted under two conditions: one involving cycling on an ergometer at moderate intensity and the other without cycling. The P300, an event-related potential linked to motivation, was recorded using electroencephalography.

A total of 20 participants were recruited to complete the EEfRT, which involved making effort-based decisions of increasing difficulty in order to receive varying levels of monetary reward. The results demonstrated that the P300 amplitude was influenced by the act of cycling, exhibiting a reduction during the cycling session. This reduction may be explained by a reallocation of cognitive resources due to the exertion of physical effort, which is consistent with the transient hypofrontality theory. In terms of behaviour, participants demonstrated a tendency to make more challenging choices when the potential rewards were higher or the probability of gaining them was lower. This pattern was observed in both the cycling and non-cycling conditions. A positive correlation was identified between P300 amplitude and the proportion of difficult choices, particularly under conditions of low reward probability. This suggests that P300 may serve as a neural marker of motivation.

The study demonstrates the feasibility of using electroencephalography to monitor motivation during exercise in real-time, with potential applications in rehabilitation settings. However, further research is required to refine the design and explore the effects of different exercise types on motivation.
Prefrontal Cortical Deficits are a Putative Susceptibility Factor for PTSD
Authors: Nalloor Rebecca , Shanazz Khadijah , Vazdarjanova Almira
Published: October 2024

A subset of people who experience a traumatic event develop Post-Traumatic Stress Disorder (PTSD) suggesting that there are susceptibility factors influencing PTSD pathophysiology. While post trauma sequelae factors are extensively studied, susceptibility factors are difficult to study and therefore poorly understood. To address this gap, we previously developed an animal model - Revealing Individual Susceptibility to PTSD-like phenotype (RISP). RISP allows studying susceptibility factors by identifying, before trauma, rats that are likely to develop a PTSD-like phenotype after trauma. Hypofunctioning prefrontal cortex has been reported in people with PTSD, however, it is unclear if it is a susceptibility factor, sequalae factor, or both. Using RISP, we tested the hypothesis that altered medial prefrontal cortical (mPFC) function is a putative susceptibility factor. Susceptible male rats showed altered expression of plasticity-related immediate early genes (ArcandHomer1a) in the Prelimbic and Infralimbic subregions of the mPFC following spatial learning. Susceptible rats also showed deficits in attentional set shifting task when task demands increased. These findings suggest that Susceptible rats have mPFC deficits both at the cellular and functional level before trauma. Consistent with the findings in rats, military personnel who showed pre-trauma deficits in cognitive tasks involving mPFC developed PTSD post-trauma. Combined, these findings suggest that mPFC deficits are a putative susceptibility factor for PTSD and enhancing mPFC function in susceptible individuals before trauma may confer resilience to developing PTSD.

A subset of people who experience a traumatic event develop Post-Traumatic Stress Disorder (PTSD) suggesting that there are susceptibility factors influencing (PTSD) pathophysiology. While post trauma sequelae factors are extensively studied, susceptibility factors are difficult to study and therefore poorly understood. In the manuscript, we report data from both an animal model of susceptibility to a PTSD-like phenotype, and from military personnel, which is consistent with the hypothesis that deficits in prefrontal cortex function exist in susceptible individuals before PTSD-inducing trauma. The reported experiments include both a cellular molecular technique (Arc/Homer 1acatFISH), based on the expression of effector immediate-early genes necessary for consolidation of learning-induced plasticity, as well as behavioral experiments for assessing cognitive function in rats and humans.
Rapid microfluidic perfusion system enables controlling dynamics of intracellular pH regulated by Na+/H+exchanger NHE1
Authors: Tran Quang D. , Bouret Yann , Noblin Xavier , Jarretou Gisèle , Counillon Laurent , Poët Mallorie , Cohen Céline
Published: October 2024

pH regulation of eukaryotic cells is of crucial importance and influences different mechanisms including chemical kinetics, buffer effects, metabolic activity, membrane transport and cell shape parameters. In this study, we develop a microfluidic system to rapidly and precisely control a continuous flow of ionic chemical species to acutely challenge the intracellular pH regulation mechanisms and confront predictive models. We monitor the intracellular pH dynamics in real-time using pH-sensitive fluorescence imaging and establish a robust mathematical tool to translate the fluorescence signals to pH values. By varying flow rate across the cells and duration for rinsing process, we manage to tweak the dynamics of intracellular pH from a smooth recovery to either an overshooting state, where the pH goes excitedly to a maximum value before decreasing to a plateau, or an undershooting state where the pH is unable to recover to ∼ 7. We believe our findings will provide more insight into intracellular regulatory mechanisms and promote the possibility of exploring cellular behavior in the presence of strong gradients or fast changes in homogeneous conditions.
Phosphorus availability as the primary determinant of nutrient limitation in temperate biodiverse herbaceous vegetation
Authors: Van Sundert Kevin , van Diggelen Rudy , D’Haese Jos , Aggenbach Camiel J.S. , Dammers Enrico , Findeisen Sophia , Kotowski Wiktor , Kozub Lucasz , Kranenburg Richard , van der Bij Arrie , Emsens Willem-Jan
Published: October 2024

Understanding whether nitrogen (N), phosphorus (P) or potassium (K) (co)limit productivity across biodiverse herbaceous habitats is crucial to guide management. Therefore, we investigated for 386 plots representing 13 nutrient-limited habitat types across Europe whether community N:P:K stoichiometry and limitation types differ along wide-ranging gradients in soil development, moisture and pH. Results indicate P/P+N as frequent as N limitation. K/K+N limitation occurs not where K availability is minimal, but in species-impoverished habitats with excess N and P. Overall, P emerges as primary driver of stoichiometry, strongly driven by the environment: at optimal pH of 6, N:P and P/P+N limitation are minimal and N limitation maximal, despite also good conditions for N availability. At pH<5 and >7, N:P is high and P/P+N limitation common. Our findings emphasize soil pH control on nutrient limitation through influence on P. Studies reporting widespread K (co)limitation in temperate herbaceous vegetation likely sampled anthropogenically P/N-enriched communities.
CryoLike: A python package for cryo-electron microscopy image-to-structure likelihood calculations
Authors: Tang Wai Shing , Soules Jeff , Rangan Aaditya , Cossio Pilar
Published: October 2024

Extracting conformational heterogeneity from cryo-electron microscopy (cryo-EM) images is particularly challenging for flexible biomolecules, where traditional 3D classification approaches often fail. Over the past few decades, advancements in experimental and computational techniques have been made to tackle this challenge, especially Bayesian-based approaches that provide physically interpretable insights into cryo-EM heterogeneity. To reduce the computational cost for Bayesian approaches, we introduce CryoLike, a computationally efficient algorithm for evaluating image-to-structure (or image-to-volume) likelihoods across large image datasets, which is built on Fourier-Bessel representations of the images and packaged in a user-friendly Python workflow.
Complementary evaluation of computational methods for predicting single residue effects on peptide binding specificities
Authors: Ayyildiz Merve , Noske Jakob , Gisdon Florian J. , Kynast Josef P. , Höcker Birte
Published: October 2024

Understanding the interactions that make up protein-protein or protein-peptide interfaces is a crucial step towards applications in biotechnology. The ability to discriminate between different partners defines the specificity of a binding protein and is equally important as its affinity to the target. Whereas many established computational methods provide an estimate of binding or non-binding, comparing similar ligands is still significantly more challenging. Here we evaluated the capability of predicting ligand binding specificity using three established but conceptually different physics-based methods for protein design. As a model system, we analyzed the binding of peptides to designed armadillo repeat proteins, where a single residue of the peptide was changed systematically, and compared the results with an experimental reference data set. The mutation of a single residue can have a strong impact on binding affinity and specificity, which is difficult to capture in sampling and scoring. We critically assessed the prediction accuracy of the computational methods and found that the prediction performance of each method is differently affected, suggesting the use of a complementary approach of the evaluated methods.

Author Summary

Proteins have to recognize other proteins and peptides in the cell with high specificity. To be able to predict such interactions with high precision would be immensely useful for medical and biotechnological applications. Here we tested three computational methods that use physics-based force fields on an experimental dataset and evaluated how well these predictions can be used to discriminate binding pockets on a single residue level. The predicted values of each method and the experimentally determined specificities correlated well, even though each approach had its biases. Therefore, we correlated the predictions with each other to complement the strengths and weaknesses of all approaches.
Reenacting a mouse genetic evolutionary arms race in yeast reveals SLXL1/SLX compete with SLY1/2 for binding to Spindlins
Authors: Arlt Martin F. , Kruger Alyssa N. , Swanepoel Callie M. , Mueller Jacob L.
Published: October 2024

The house mouse X and Y chromosomes have recently acquired high copy number, rapidly evolving gene families representing an evolutionary arms race. This arms race between proteins encoded by X-linkedSlxl1/Slxand Y-linkedSlygene families can distort male offspring sex ratio, but how these proteins compete remains unknown. Here, we report howSlxl1/SlxandSlyencoded proteins compete in a protein family-specific and dose-dependent manner using yeast. Specifically, SLXL1 competes with SLY1 and SLY2 for binding to the Spindlin SPIN1. Similarly, SLX competes with SLY2 for binding the Spindlin SSTY2. These competitions are driven by the N-termini of SLXL1, SLX, SLY1, and SLY2 binding to the third Tudor domains of SPIN1 and SSTY2. SLY1 and SLY2 form homo- and heterodimers, suggesting the competition is between complex multimers. Residues under positive selection mapping to the interaction domains and rapid exon gain/loss are consistent with competition between the X- and Y-linked gene families. Our findings support a model in which dose-dependent competition of these X- and Y-linked encoded proteins to bind Spindlins occurs in haploid X- and Y-spermatids to influence X-versus Y-sperm fitness and thus sex ratio.

Significance Statement

In house mouse, an evolutionary arms race between proteins encoded by the X-linkedSlxl1/Slxand Y-linkedSlygene families during spermatogenesis can distort male offspring sex ratio, but how these proteins compete remains unknown. We report how SLXL1/SLX competes with SLY1/SLY2 by demonstrating their dose-dependent competitive binding to Spindlins, the key protein domains and rapidly evolving residues and exons that drive the competition, and how the competition is likely between complex multimers. Our findings have broad implications for the mechanics of evolutionary arms and how competition between sex chromosomes influences X-versus Y-sperm fitness and sex ratio.
Academic Success and Mental Health: The Paradox of Frontoparietal-Default Mode Network Coupling among Children Facing Poverty
Authors: Pacheco Selina , Bunge Silvia A. , Ellwood-Lowe Monica E.
Published: October 2024

Childhood family income is a powerful predictor of academic achievement and mental health. Here, we ask whether children living in poverty who succeed academically are subsequently protected from, or at risk for, internalizing symptoms. Prior research indicates that children in poverty with better academic performance tend to have higher temporal coupling between the Lateral Frontoparietal Network (LFPN) and Default Mode Network (DMN) than lower-performing children in poverty. An open question is whether higher LFPN-DMN coupling has maladaptive long-term consequences for mental health for this population. In this pre-registered longitudinal study, we analyzed data from 10,829 children (1,931 in poverty) in the ABCD study across four time points (ages 9-13). Higher grades correlated with fewer internalizing symptoms; this association was more pronounced for children below poverty. Longitudinally, LFPN-DMN connectivity correlated positively with internalizing symptoms across both groups and timepoints. Thus, although higher academic performance was associated with better mental health outcomes for all children, the specific pattern of LFPN-DMN connectivity that supports academic resilience among children in poverty may be a risk factor for developing internalizing symptoms. These findings highlight the complex nature of academic resilience in the context of structural inequity.

Highlights

High grades linked to fewer internalizing symptoms, especially for kids in poverty.

High LFPN-DMN connectivity predicts higher internalizing symptoms in children.

Neural correlates of academic resilience may predispose children to internalizing.

Children below poverty had higher internalizing symptoms.
ALDH1 subtype-specific inhibitor targets key cancerous epithelial cell populations in aggressive subtypes of breast cancer
Authors: Pequerul Raquel , Constantinescu Andrada , Janji Bassam , Kumar Akinchan , Parés Xavier , Palacios Oscar , Colignon Delphine , Berrou Axelle , Fournet Guy , Berchard Paul , Martin Guillaume , Ceylan Ismail , Rebollido-Ríos Rocio , Farrés Jaume , Perez-Alea Mileidys
Published: October 2024

Aggressive breast cancer subtypes, particularly triple-negative breast cancer (TNBC), lack effective targeted therapies, requiring novel approaches. This study focuses on the aldehyde dehydrogenase 1A (ALDH1A) subfamily, comprising ALDH1A1, ALDH1A2, and ALDH1A3, and their roles in tumor biology and the tumor microenvironment. Comprehensive transcriptomic and single-cell analyses revealed subtype- and cell-specific expression patterns of ALDH1A isoforms, withALDH1A3predominantly expressed in epithelial cancer cells of basal-like tumors, whileALDH1A1andALDH1A2were expressed in stromal and immune-associated subpopulations. Guided by these findings, we developed ABD0171, a selective ALDH1A3 inhibitor that demonstrated potent isoform-specific activity. ABD0171 effectively disrupted key pathways in TNBC cellsin vitro, including IL6/JAK/STAT3, tPA and Src/FAK, and exhibited superior selectivity, robust antitumor and antimetastatic effects, and a favorable safety profilein vivo. These results establish ALDH1A3 as a promising therapeutic target and validate ABD0171 as a candidate to address current challenges in aggressive breast cancers.
Scale-free flocking and giant fluctuations in epithelial active solids
Authors: Shen Yuan , O’Byrne Jérémy , Schoenit Andreas , Maitra Ananyo , Mege Rene-Marc , Voituriez Raphael , Ladoux Benoit
Published: October 2024

The collective motion of epithelial cells is a fundamental biological process which plays a significant role in embryogenesis, wound healing and tumor metastasis. While it has been broadly investigated for over a decade bothin vivoandin vitro, large scale coherent flocking phases remain underexplored and have so far been mostly described as fluid. In this work, we report a mode of large-scale collective motion for different epithelial cell types in vitro with distinctive new features. By tracking individual cells, we show that cells move over long time scales coherently not as a fluid, but as a polar elastic solid with negligible cell rearrangements. Our analysis reveals that this solid flocking phase exhibits signatures of long-range polar order, unprecedented in cellular systems, with scale-free correlations, anomalously large density fluctuations, and shear waves. Based on a general theory of active polar solids, we argue that these features result from massless Goldstone modes, which, in contrast to polar fluids where they are generic, require the decoupling of global rotations of the polarity and in-plane elastic deformations in polar solids. We theoretically show and consistently observe in experiments that the fluctuations of elastic deformations diverge for large system size in such polar active solid phases, leading eventually to rupture and thus potentially loss of tissue integrity at large scales.

Significance statement

During embryonic development and wound healing, epithelial cells usually display in-plane polarity over large spatial scales and move coherently. However, over years, mostin vitrostudies have examined the fluid-like chaotic dynamics of epithelial cells, in which collective cellular flows self-organize into recurring transient vortices and jets similar to those observed in classical fluid turbulence. Little is known about the large-scale coherent dynamics of epithelial cells. We demonstrate that such coherent motions are not simply turbulent-like flows with larger correlation lengths, but a new mode of collective motion with a solid-like behavior, accompanied by an emergent global order, scale-free correlations, anomalous density fluctuations and propagating Goldstone modes. Our work suggests that such a collective motion of epithelial cells falls outside the scope of traditional active fluids, which may shed new light on the current studies of collective cell migration as well as active matter physics.
Admixed populations in the neighbor-joining algorithm: a geometric analysis with five taxa
Authors: Zhang Joy Z. , ‘Jack’ Lo Wai Tung , Stillman Michael , Kim Jaehee
Published: October 2024

The Neighbor-Joining (NJ) algorithm is a widely used method for constructing phylogenetic trees from genetic distances. While NJ is known to perform well with tree-like data, its behavior under admixture remains understudied. In this work, we present a geometric framework for analyzing the NJ algorithm under a linear admixture model. We focus on three key properties related to clustering order, distance, and topological path length in the resulting NJ trees involving five taxa. Our approach leverages polyhedral geometry to define NJ cones, which correspond to distinct cherry-picking orders and partition the space of dissimilarity vectors. We project dissimilarity vectors with admixture into a lower-dimensional space without admixture, defining polyhedral regions induced by NJ cones that satisfy specified properties. We compute the exact probabilities that these properties hold by directly calculating the volumes of the induced NJ cones and compare them with Monte Carlo integration and standard NJ simulation methods. Our results show that the property on clustering order is always satisfied, while the other properties are highly probable but depend on the admixture fraction. We also prove that certain induced NJ cones have zero volume, indicating that the corresponding NJ tree topologies are infeasible under admixture. We have implemented our methods as a publicly available moduleNeighborJoiningwithinMacaulay2, providing an efficient tool for analyzing NJ cones and their properties. This work provides new insights into the geometric structure inherent to the NJ algorithm in the presence of admixture, identifying the conditions under which admixture influences the resulting phylogenetic trees.
Structural compromise in spiking cortex and connected networks
Authors: Sahlas Ella , Avigdor Tamir , Ngo Alexander , Royer Jessica , Larivière Sara , Chen Judy , Xie Ke , Wang Yezhou , Lam Jack , Rodríguez-Cruces Raúl , Arafat Thaera , Pana Raluca , Bernasconi Andrea , Bernasconi Neda , Frauscher Birgit , Bernhardt Boris C.
Published: October 2024

INTRODUCTION

Epilepsy is increasingly conceptualized as a network disorder, and advancing methods for its diagnosis and treatment requires characterizing both the epileptic generator and related networks. We combined multimodal magnetic resonance imaging (MRI) and high-density electroencephalography (HD-EEG) to interrogate alterations in cortical microstructure, morphology, and intrinsic local function within and beyond spiking tissue in focal epilepsy.

METHODS

We studied 25 patients with focal epilepsy (12F, mean ± SD age = 31.28 ± 9.30 years) and 55 age- and sex-matched healthy controls, subdivided into a group of 30 for imaging feature normalization (15F, 31.40 ± 8.74 years) and a group of 25 for replication (12F, 31.04 ± 5.65 years). The 3T MRI acquisition included T1-weighted, diffusion, quantitative T1 relaxometry, and resting-state functional imaging. Open-access MRI processing tools derived cortex-wide maps of morphology and microstructure (cortical thickness, mean diffusivity, and quantitative T1 relaxometry) and intrinsic local function and connectivity (timescales, connectivity distance, and node strength) for all participants. Multivariate approaches generated structural and functional alteration scores for each cortical location. Using HD-EEG electrical source imaging, the most prominent spike type was localized and we quantified MRI alterations within spike sources, as well as in proximal and connected networks.

RESULTS

Regions harboring spike sources showed increased structural MRI alterations compared to the rest of the brain in patients. Structural compromise extended to all regions with close functional coupling to spike sources, but not to anatomical neighbors of spike sources. This finding was replicated using average control functional and anatomical matrices instead of patient-specific matrices.

CONCLUSION

Spiking regions contain more marked alterations in microstructure and morphology than the remaining cortex, and combining imaging with neurophysiology techniques may ultimately help identify the epileptogenic zone non-invasively. There are nevertheless broader networks effects, which may relate to a cascading of structural changes to functionally connected cortices. These results underscore the utility of combining high-definition MRI and EEG approaches for characterizing epileptogenic tissue and assessing distributed network effects.
Ultrastructural viscoelastic behavior of collagen identified by AFM nano-dynamic mechanical analysis
Authors: Asgari Meisam , Mirzarazi Elahe , Vali Hojatollah , Frisina Robert D. , Espinosa Horacio D.
Published: October 2024

Soft tissues exhibit predominantly time-dependent mechanical behavior critical for their biological function in organs like the lungs and aorta, as they can deform and stretch at varying rates depending on their function. Collagen type I serves as the primary structural component in these tissues. The viscoelastic characteristics of such tissues, stemming from diverse energy dissipation mechanisms across various length scales, remains poorly characterized at the nanoscale. Furthermore, prior experimental investigations have predominantly centered on analyzing tissue responses largely attributed to interactions between cells and fibers. Despite many studies on tissue viscoelasticity from scaffolds to single collagen fibrils, the time-dependent mechanics of collagen fibrils at the sub-fibrillar level remain poorly understood. This pioneering study employs atomic force microscopy (AFM) nano-rheometry to examine the viscoelastic characteristics of individual collagen type I fibrils at the ultrastructural level within distinct topographical zones, specifically focusing on gap and overlap regions. Our investigation has unveiled that collagen fibrils obtained viain-vitrofibrillogenesis from human placenta display a viscoelastic response that replicates the mechanical behavior of the tissue at the macroscale. Further, our findings suggest a distinct viscoelastic behavior between the gap and overlap regions, likely stemming from variances in molecular organization and cross-linking modalities within these specific sites. The results of our investigation furnish unequivocal proof of the temporal dependence of mechanical properties and provides unique data to be compared to atomistic models, laying a foundation for refining the precision of macroscale models that strive to capture tissue viscoelasticity across varying length scales.