bluuebunny/crossref_metadata_2025 huggingface dataset:
Behaviour settings, situated action and complexity theory
Authors: Heft Harry
Published: August 2024

In spite of the fact that Roger Barker’s groundbreaking research was acclaimed sixty years ago by his contemporaries, it has all been but forgotten among recent generations of psychologists. However, in the wake of developments in dynamical systems and complexity theory, its value for understanding psychological processes in everyday life should be recognized anew. Barker’s naturalistic studies of children’s daily behaviours in their community revealed that their actions which initially seemed only marginally predictable at the level of individual interaction were, in fact, reliably context-dependent. These results led to the discovery that there are nested structures operating in human habitats as there are throughout the natural world. Barker’s discovery of emergent eco-psychological structures, behaviour settings, that are generated from interdependent actions among individuals in the course of everyday life has yet to be fully appreciated because of the continuing dominance of linear, mechanistic models. His recognition of nested systems operating in human habitats is finally coming into its own with the current metatheoretical shift in psychology embracing dynamical models. Additionally, new understanding arises from the consideration of convergent individual developmental histories of situated action and their role in maintaining the historical dimensions of behaviour settings.

This article is part of the theme issue ‘People, places, things and communities: expanding behaviour settings theory in the twenty-first century’.
Behaviour settings as a way to order types of situations for the study of speech aids
Authors: Zieliński Konrad , Rączaszek-Leonardi Joanna
Published: August 2024

This article revisits the notion of behaviour settings, coined by Roger G. Barker (Barker 1968,
Ecol. Psychol
.
28
, 39–55 (
10.1080/10407413.2016.1121744
)), as a useful concept for the analysis of situations and communicative needs of persons after larynx removal surgery (laryngectomy). We claim that behaviour settings offer a way to characterize types of situations and types of participation, which, in turn, helps to identify aspects of communication where compensation is needed; these steps are crucial in the design process of reliable and context-sensitive speech aids. Moreover, we advocate complementing the behaviour setting concept as a unit of analysis with modern developments in the cognitive sciences, such as conversational analysis of co-operative actions (Goodwin 2017,
Co-operative action (learning in doing: social, cognitive and computational perspectives)
. Cambridge: Cambridge University Press (
10.1017/9781139016735
)) and the analysis of multi-perspectival experience (De Jaegher 2021,
Phenomenol. Cogn. Sci
.
20
, 847–870 (
10.1007/s11097-019-09634-5
)). Such an integration of macro- and micro-level patterns should help discover the relevant relations and values in particular situations. We illustrate our claims with examples from Barker’s own work and from our ongoing analyses of the everyday life of persons after laryngectomy.

This article is part of the theme issue ‘People, places, things, and communities: expanding behaviour settings theory in the twenty-first century’.
Behaviour setting transformation methodology, filling in the gaps of the conventional architectural design process
Authors: Awamleh Zaid
Published: August 2024

This article recounts 6 years of empirical research in a humanitarian context on spatial behaviour using the behaviour settings theory. This research journey details the shortcomings of conventional architectural processes and the subsequent development of a human-centred behaviour setting methodology that drives behaviour change for adaptable spaces. The research work puts Barker’s theory of behaviour settings into practice to show its significant methodological abilities in shaping behaviours through spaces. While the original theory was solely an analytical account of existing behaviours in certain settings, this study marks the first pragmatic exploration of the theory into both residential and refugee contexts. The methodology that is subsequently proposed is a complementary tool to account for the deficiencies of conventional architectural design processes. A method that enables one to fully immerse themselves in the environment, recognize specific architectural interventions, assess their effects and reiterate. It is a proposal for humanizing architecture, sympathizing its processes and personalizing its results for the users of any space.

This article is part of the theme issue ‘People, places, things, and communities: expanding behaviour settings theory in the twenty-first century’.
Enabling spaces for (varied) co-existence
Authors: Pedersen Sofie , Nielsen Emma
Published: August 2024

For people in homelessness, access to social services may appear difficult and alienating, which often contributes to poor health and a risk of accelerated marginalization. Historically, day centres for people in homelessness have been characterized by an emphasis on providing refuge and momentary restitution, accommodating urgent basic needs. In this article, we present a case study of the design of a new day centre in Denmark that aspires to move beyond the historical
place-for-being
. Rather, the new day centre is to be a
place-for-being-and-becoming
, focusing on
bridging
the varied needs of people in homelessness with easy access to social services at the day centre. This article explores the creation of new behaviour settings along with the challenges and considerations in designing enabling spaces for people in societally marginalized positions, concurrently offering and supporting a sense of inclusion, the possibility to develop one’s agency and experience of lived citizenship.

This article is part of the theme issue ‘People, places, things, and communities: expanding behaviour settings theory in the twenty-first century’.
Structures of human PTP1B variants reveal allosteric sites to target for weight loss therapy
Authors: Perdikari Aliki , Woods Virgil A. , Ebrahim Ali , Lawler Katherine , Bounds Rebecca , Singh Nathanael I. , Mehlman Tamar (Skaist) , Riley Blake T. , Sharma Shivani , Morris Jackson W. , Keogh Julia M. , Henning Elana , Smith Miriam , Farooqi I. Sadaf , Keedy Daniel A.
Published: August 2024

Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal precise mechanisms to target for weight loss therapy. We selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from UK Biobank. Seven of 12 variants impaired PTP1B function by increasing leptin-stimulated STAT3 phosphorylation in cells. Using room-temperature X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, and computational modeling, we determined that human variants modulate the 3-dimensional structure of PTP1B through distinct allosteric conduits that energetically link distal, highly ligandable structural regions to the active site. These studies inform the design of allosteric PTP1B inhibitors for the treatment of obesity.
Shared Neural Dynamics of Facial Expression Processing
Authors: Ely Madeline Molly , Ambrus Géza Gergely
Published: August 2024

The ability to recognize and interpret facial expressions is fundamental to human social cognition, enabling navigation of complex interpersonal interactions and understanding of others’ emotional states. The extent to which neural patterns associated with facial expression processing are shared between observers remains unexplored, and no study has yet examined the neural dynamics specific to different emotional expressions. Additionally, the neural processing dynamics of facial attributes such as sex and identity in relation to facial expressions have not been thoroughly investigated.

In this study, we investigated the shared neural dynamics of emotional face processing using an explicit facial emotion recognition task, where participants made two-alternative forced choice (2AFC) decisions on the displayed emotion. Our data-driven approach employed cross-participant multivariate classification and representational dissimilarity analysis on EEG data. The results demonstrate that EEG signals can effectively decode the sex, emotional expression, and identity of face stimuli across different stimuli and participants, indicating shared neural codes for facial expression processing.

Multivariate classification analyses revealed that sex is decoded first, followed by identity, and then emotion. Emotional expressions (angry, happy, sad) were decoded earlier when contrasted with neutral expressions. While identity and sex information were modulated by image-level stimulus features, the effects of emotion were independent of visual image properties. Importantly, our findings suggest enhanced processing of face identity and sex for emotional expressions, particularly for angry faces and, to a lesser extent, happy faces.
From solo to collaborative: the global increase in neuroscience authors over two decades
Authors: Segreti Mariella , Paul Ann , Pani Pierpaolo , Genovesio Aldo , Brunamonti Emiliano
Published: August 2024

The increase in the number of authors per article is a well-documented phenomenon across various academic disciplines. While prior studies have examined this trend in specific fields and countries, they in most cases did not compare the increase in the number of authors between countries. While it has previously shown that the number of authors in neuroscience publications has risen in the G10 countries, no study has yet addressed whether it reflects a global trend in the field. To address this gap, we quantified the global trend in the number of authors in neuroscience publications from 2001 to 2022.

Our findings reveal a consistent increase in authorship across nearly all the countries examined. Italy ranks highest in terms of average authorship per article, while Ukraine ranks the lowest. On the other hand, China shows the largest increase in authorship over the years, followed by Norway and Egypt. South Korea is the only country showing a slight decreasing trend rather than growth. These results contribute to a better understanding of authorship patterns in neuroscience, and can stimulate further investigations on the reasons behind such an increase in terms of socio-economic factors, the need for collaborative efforts in some fields, or, on the negative side, the effect of utilitarian reasons to meet career evaluation criteria.
Identifying Causal Relations between Gut Microbiome, Metabolic Dysfunction-Associated Fatty Liver Disease and the Novel Mediators of Blood Metabolites
Authors: Yi Xinghao , Zhu Haoxue , He Mengyu , Zhong Ling , Gao Shan , Li Ming
Published: August 2024

Background

Research has established connection between gut microbiome and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the causal relationships and the roles of potential mediating factors, such as blood metabolites, remain unclear.

Methods

We conducted a bidirectional and mediation Mendelian randomization (MR) study using the genome-wide summary statistics of gut microbial taxa (Dutch Microbiome Project, n = 7,738), blood lipids (UK Biobank, n =8,299), and the largest MAFLD GWAS data (1,483 cases and 17,781 controls). We used the inverse-variance weighted estimation method as our primary approach. The multivariable Mendelian randomization (MVMR) and two-step MR approaches were used to prioritize the most likely causal metabolites as mediators. Additionally, we conducted linkage disequilibrium score regression (LDSC) analyses to assess genetic correlations, and downstream gene-based analyses to investigate the shared biological mechanism.

Results

By testing the causal effects of 205 bacterial pathways and 207 taxa on MAFLD, we identified 5 microbial taxa causally associated with MAFLD, notably the species Parabacteroides merdae (OR [95%CI] = 1.191[1.022-1.388],p= 0.025). Among 1,399 blood metabolites, 53 showed causal associations with MAFLD, with pregnenetriol sulfate identified as a mediator for genus Parabacteroides on MAFLD (proportion mediated = 16.30%). LDSC analysis also provided suggestive evidence for a potential genetic correlation between them (rg= 2.124,p=0.009).

Conclusions

The study suggested a novel causal relationship between gut microbial taxa and MAFLD, especially the genus Parabacteroides merdae and blood metabolite pregnenetriol sulfate might mediate this relationship.

Importance

Our study reveals novel insights into how the intersection of microorganisms living in the human gut, known as the gut microbiome, influences the development of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a condition increasingly recognized as a major global health concern. By identifying specific gut microbiome taxa and metabolites that contribute to the onset and progression of MAFLD, our findings enhance comprehension of this prevalent condition and unveil promising prospects for its prevention and intervention. We discovered that certain gut bacteria can affect the levels of blood metabolites, which in turn impact the liver’s health. This work carries significant implications for novel strategies for MAFLD prevention and treatment, including interventions aimed at modifying the gut microbiome. Our research underscores the gut-liver connection and its implications for metabolic diseases, contributing to future therapeutic developments that could improve public health worldwide.

Graphic abstract
Evolutionary rates of nuclear and organellar genomes are linked in land plants
Authors: Asar Yasmin , Sauquet Hervé , Ho Simon Y. W.
Published: August 2024

Plants carry genetic material in three compartments, the nuclear, mitochondrial, and chloroplast genomes. These genomes interact with each other to various degrees and are subject to shared evolutionary drivers exerted by their host organisms. However, it is not clear whether the three plant genomes display covarying evolutionary signals.

We tested for correlated evolutionary rates between nuclear and organellar genomes using extensive data sets from the major clades of land plants (Embryophyta), including mosses, ferns, gymnosperms, and angiosperms. To examine the evolutionary dynamics in parasitic angiosperms, which are under distinctive selective pressures, we analysed data sets from mistletoes, broomrapes, sandalwoods, and rafflesias.

Evolutionary rates of nuclear and organellar genomes were positively linked in land plants, except in the parasitic angiosperms. We also found similar positive correlations for rates of nonsynonymous and synonymous change between nuclear and organellar genomes. Our results also reveal extensive evolutionary rate variation across land plant taxa.

Overall, we find that nuclear, mitochondrial, and chloroplast genomes in land plants share similar drivers of mutaNon rates, despite considerable variaNon in life history, morphology, and genome sizes among clades. Our findings lay the foundaNon for further exploraNon of the impact of co-evoluNonary interacNons on shared evoluNonary rates between genomes.
Predicting purification process fit of monoclonal antibodies using machine learning
Authors: Maier Andrew , Cha Minjeong , Burgess Sean , Wang Amy , Cuellar Carlos , Kim Soo , Rajan Neeraja Sundar , Neyyan Josephine , Sengupta Rituparna , O’Connor Kelly , Ott Nicole , Williams Ambrose
Published: August 2024

0

In early stage development of therapeutic monoclonal antibodies, assessment of ease of purification process development typically requires extensive experimentation. However, upstream protein expression and downstream purification experiments are often in conflict with timeline pressures and material constraints, limiting the number of molecules and process conditions that can reasonably be assessed. Recently, high-throughput batch-binding screen data along with improved molecular descriptors have enabled development of robust quantitative structure-property relationship (QSPR) models which predict monoclonal antibody chromatographic binding behavior from the amino acid sequence. This work describes a QSPR strategy forin silicomonoclonal antibody purification process fit assessment. Principal Component Analysis is applied to extract a one-dimensional basis for comparison of molecular chromatographic binding behavior from multi-dimensional high-throughput batch-binding screen data. Kernel Ridge Regression is employed to predict the first principal component for new molecular sequences. This workflow is demonstrated with a set of 97 monoclonal antibodies for five chromatography resins in two salt types across a range of pH and salt concentrations. Model development benchmarks four descriptor sets from biophysical structural models and protein language models. The investigation illustrates the value QSPR models can provide to purification process fit assessment, and selection of resins and operating conditions from sequence alone.
Interpretable Solutions for Stochastic Dynamic Programming
Authors: Ferrer-Mestres Jonathan , Dietterich Thomas G. , Buffet Olivier , Chadès Iadine
Published: August 2024

In conservation of biodiversity, natural resource management and behavioural ecology, stochastic dynamic programming, and its mathematical framework, Markov decision processes (MDPs), are used to inform sequential decision-making under uncertainty. Models and solutions of Markov decision problems should be interpretable to derive useful guidance for managers and applied ecologists. However, MDP solutions that have thousands of states are often difficult to understand. Difficult to interpret solutions are unlikely to be applied, and thus we are missing an opportunity to improve decision-making. One way of increasing interpretability is to decrease the number of states.

Building on recent artificial intelligence advances, we introduce a novel approach to compute more compact representations of MDP models and solutions as an attempt at improving interpretability. This approach reduces the size of the number of states to a maximum numberKwhile minimising the loss of performance compared to the original larger number of states. The reduced MDP is called aK-MDP. We present an algorithm to computeK-MDPs and assess its performance on three case studies of increasing complexity from the literature. We provide the code as a MATLAB package along with a set of illustrative problems.

We found thatK-MDPs can achieve a substantial reduction of the number of states with a small loss of performance for all case studies. For example, for a conservation problem involving Northern Abalone and Sea Otters, we reduce the number of states from 819 to 5 states while incurring a loss of performance of only 1%. For a dynamic reserve selection problem with seven dimensions, while an impressive reduction in the number of states was achieved, interpreting the optimal solutions remained challenging.

Modelling problems as Markov decision processes requires experience. While several models may represent the same problem, reducing the number of states is likely to make solutions and models more interpretable and facilitate the extraction of meaningful recommendations. We hope that this approach will contribute to the uptake of stochastic dynamic programming applications and stimulate further research to increase interpretability of stochastic dynamic programming solutions.
Infants and adults neurally represent the perspective of others like their own perception
Authors: Tebbe Anna-Lena , Rothmaler Katrin , Köster Moritz , Grosse Wiesmann Charlotte
Published: August 2024

Preverbal infants already seem to consider the perspective of others, even when it differs from their own. Similarly, adults take the perspective of others very quickly, in parallel to other cognitively demanding tasks. This raises the question of how multiple perspectives are processed efficiently, and even before higher cognitive capacities develop. To test whether and how others’ perspectives are neurally represented, we presented 12-14-months-old infants and adults with objects flickering at 4 Hz, which evoked neural oscillations at the exact same frequency. Remarkably, both in infants and adults, this same highly specific neural signature of visual object processing was also present when their view was blocked and only another observer saw the object. These results provide strong evidence that we process what others see as if we saw it ourselves, revealing a neural mechanism for efficient perspective taking, present from infancy.
Modeling the effects of vaccination against multiple strains of porcine reproductive and respiratory syndrome at the barn level
Authors: Kennedy Faith , Cardenas Nicolas , Galvis Jason A. , Corzo Cesar , Machado Gustavo
Published: August 2024

Porcine reproductive and respiratory syndrome (PRRSV) remains costly for the swine industry. Measures intended to irradicate or reduce the prevalence of PRRSV have limited effectiveness. Vaccination, the primary control strategy for PRRSV, has yet to be thoroughly investigated to ensure an optimal strategy is being implemented. Due to insufficient cross-immunity between strains, it is prudent to administer the most influential vaccine for the most dominant or threatening PRRSV strain in circulation at a given time. With this in mind, we demonstrated the benefits of targeted vaccination using metapopulation-based modeling. By using up-to-date data describing real farms to simulate the effects of variable vaccine efficacy in both a single and a double strain system, we showed that tailoring vaccines to prevalent PRRSV strains reduces infections, but using multiple vaccines may be more effective if strains vary in vaccine response. Therefore, the impact of the strain-specific effectiveness of market vaccines, paired with computational methods that allow tracking the effects on PRRVS dissemination at individual barns.
Hybrid Protocells based on Coacervate-Templated Fatty Acid Vesicles combine Improved Membrane Stability with Functional Interior Protocytoplasm
Authors: Lee Jessica , Cakmak Fatma P. , Booth Richard , Keating Christine D.
Published: August 2024

Prebiotically-plausible compartmentalization mechanisms include membrane vesicles formed by amphiphile self-assembly and coacervate droplets formed by liquid-liquid phase separation. Both types of structures form spontaneously and can be related to cellular compartmentalization motifs in today’s living cells. As prebiotic compartments, they have complementary capabilities, with coacervates offering excellent solute accumulation and membranes providing superior boundaries. Herein, we describe protocell models constructed by spontaneous encapsulation of coacervate droplets by mixed fatty acid/phospholipid and by purely fatty acid membranes. Coacervate-supported membranes formed over a range of coacervate and lipid compositions, with membrane properties impacted by charge-charge interactions between coacervates and membranes. Vesicles formed by coacervate-templated membrane assembly exhibited profoundly different permeability than traditional fatty acid or blended fatty acid/phospholipid membranes without coacervate interiors, particularly in the presence of Mg2+ions. While fatty acid and blended membrane vesicles were disrupted by addition of 25 mM MgCl2, the corresponding coacervate-supported membranes remained intact and impermeable to externally-added solutes even in the presence of MgCl2. With the more robust membrane, fluorescein diacetate (FDA) hydrolysis, which is commonly used for cell viability assays, could be performed inside the protocell model due to the simple diffusion of FDA and then following with the coacervate-mediated abiotic hydrolysis to fluorescein.
TBK1 and IKKε protect target cells from IFNγ-mediated T cell killing via an inflammatory apoptotic mechanism
Authors: Sun Nicholas D. , Carr Allison R. , Krogman Erica N. , Chawla Yogesh , Zhong Jun , Guttormson Matthew C. , Chan Mark , Hsu Michelle A. , Dong Haidong , Bogunovic Dusan , Pandey Akhilesh , Rogers Laura M. , Ting Adrian T.
Published: August 2024

Cytotoxic T cells produce interferon gamma (IFNγ), which plays a critical role in anti-microbial and anti-tumor responses. However, it is not clear whether T cell-derived IFNγ directly kills infected and tumor target cells, and how this may be regulated. Here, we report that target cell expression of the kinases TBK1 and IKKε regulate IFNγ cytotoxicity by suppressing the ability of T cell-derived IFNγ to kill target cells. In tumor targets lacking TBK1 and IKKε, IFNγ induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1, to trigger RIPK1-dependent apoptosis, largely in a target cell-autonomous manner. Unexpectedly, IFNγ, which is not known to signal to NFκB, induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. TBK1 and IKKε suppress IKKα/β activity and in their absence, IFNγ induces elevated NFκB-dependent expression of inflammatory chemokines and cytokines. Apoptosis is thought to be non-inflammatory, but our observations demonstrate that IFNγ can induce an inflammatory form of apoptosis, and this is suppressed by TBK1 and IKKε. The two kinases provide a critical connection between innate and adaptive immunological responses by regulating three key responses: (1) phosphorylation of IRF3/7 to induce type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these functions such that their inhibition by pathogens attempting to block type I IFN expression would enable IFNγ to trigger apoptosis accompanied by an alternative inflammatory response. Our findings show that loss of TBK1 and IKKε in target cells sensitizes them to inflammatory apoptosis induced by T cell-derived IFNγ.

Short Summary

In the absence of TBK1 and IKKε, target cells are killed by T cells in an IFNγ-dependent manner. In TBK1 and IKKε-deficient cells, IFNγ induces RIPK1-dependent death, as well as hyper-induction of NFκB-dependent inflammatory genes. This suggests that any inhibition of TBK1/IKKε to block type I IFN expression will result in the demise of the cell accompanied by an alternate inflammatory program.

Graphical Abstract
Optics-free Spatial Genomics for Mapping Mouse Brain Aging
Authors: Abdulraouf Abdulraouf , Jiang Weirong , Xu Zihan , Zhang Zehao , Isakov Samuel , Raihan Tanvir , Zhou Wei , Cao Junyue
Published: August 2024

Spatial transcriptomics has revolutionized our understanding of cellular network dynamics in aging and disease by enabling the mapping of molecular and cellular organization across various anatomical locations. Despite these advances, current methods face significant challenges in throughput and cost, limiting their utility for comprehensive studies. To address these limitations, we introduceIRISeq(ImagingReconstruction using IndexedSequencing), a optics-free spatial transcriptomics platform that eliminates the need for predefined capture arrays or extensive imaging, allowing for the rapid and cost-effective processing of multiple tissue sections simultaneously. Its capacity to reconstruct images based solely on sequencing local DNA interactions allows for profiling of tissues without size constraints and across varied resolutions. ApplyingIRISeq, we examined gene expression and cellular dynamics in thirty brain regions of both adult and aged mice, uncovering region-specific changes in gene expression associated with aging. Further cell type-centric analysis further identified age-related cell subtypes and intricate changes in cell interactions that are distinct to certain spatial niches, emphasizing the unique aspects of aging in different brain regions. The affordability and simplicity ofIRISeqposition it as a versatile tool for mapping region-specific gene expression and cellular interactions across various biological systems.

One Sentence Summary:IRISeq, an innovative optics-free spatial transcriptomics method, uncovers aging-related changes in spatial gene expression and focal cell interactions in brain aging.
Sertad1 is elevated and plays a necessary role in synaptic loss, neuron death and cognitive impairment in a model of Alzheimer’s disease
Authors: Ambareen Naqiya , Gharami Kusumika , Biswas Subhas C.
Published: August 2024

Dysfunctional autophagy is a primary characteristic of Alzheimer’s disease (AD) pathogenesis. How autophagic impairment leads to cellular changes that contributes to AD pathogenesis remains unclear. To study this further, we assessed levels of autophagy related proteins in 5xFAD mice brain at different ages and found their robust upregulation in cortex and hippocampus suggesting increased induction of autophagy with disease progression but failed clearance. We have identified a transcriptional coregulator Sertad1, as a key mediator of dysfunctional autophagy in AD mice. We found a progressive elevation in Sertad1 levels in 5xFAD mice with age compared to wild-type (WT) mice. Sertad1 knockdown in 5xFAD mice brain lowered levels of autophagy related proteins and lysosome marker, LAMP1 suggesting its role in autophagy flux modulation. FoxO3a is an important transcriptional regulator of the autophagy network and lies at the nexus of autophagy-apoptosis cross-talk. We found that Sertad1 knockdown blocked nuclear translocation of FoxO3a along with a restoration in Akt activity. Further, we showed that knockdown of Sertad1 in 5xFAD mice brain improved cognitive functions along with a remarkable restoration in synaptic health and dendritic spine density. Taken together, our results demonstrated that autophagy is robustly induced with disease progression but it is impaired; Sertad1 knockdown restored autophagy defects, synaptic loss and improved learning and memory in AD models. Thus, we propose that Sertad1 acts in a multimodal manner regulating crucial cell death pathways including apoptosis and autophagy and could be an excellent target for therapeutic intervention to combat a multifactorial disorder such as AD.
Machine learning, molecular docking and simulation studies reveal Lomitapide, Lodipamide, Zafirlukast, Netupitant and Salmon Calcitonin as potent drug molecules against Chagas disease
Authors: Singh Kavya , Kaur Navjeet , Prabhu Ashish
Published: August 2024

Trypanosoma cruzi(T.cruzi), a protozoan parasite, is the pathogen that causes the hazardous disease Chagas, sometimes referred to as American trypanosomiasis. Currently, there are just two drugs commercially available to treat this fatal condition. So, there is an urgent requirement to create novel, safer and efficient anti-Tc drugs. In this study, we introduce a robust experimental strategy that integrates machine learning with molecular docking and simulation studies to identify the most potential drug candidates from the DrugBank dataset for treating the Chagas disease. In a machine learning method, different classifiers (Naïve Bayes, Random Forest, SMO, and C4.5) were used to train the model on the PubChem dataset and the most effective model (C4.5 algorithm) was then chosen and tested on the DrugBank dataset (containing FDA-approved and investigational drugs). The C4.5 algorithm-based machine learning model with an accuracy of 65% predicts the possible drug candidates (a total of 280 drugs were predicted). AutoDock4.2 software was then used to dock the predicted compounds that had a confidence interval of 80% and above. As a result, 47 predicted drugs were docked, and the best of the 5 drugs based on their docking score were chosen for performing the MD simulation studies. MD simulations (100 ns) were conducted for each of the protein-ligand complexes, which produces an average RMSD score (2.23 Å). The RMSF value of the cruzain (Cys25) binding pocket, after interaction with the five compounds were found to be less than 3.0 Å. Therefore, based on the molecular docking and simulation studies, we found out that Lomitapide, Lodipamide, Zafirlukast, Netupitant and Salmon Calcitonin have shown a stronger binding affinity with the crystal structure of cruzain (Cyst25) molecule, making them potential effective inhibitors. Hence, we could anticipate that our five computationally validated drugs will soon be available at the clinical trial stage and eventually be made accessible to the necessary Chagas disease patients.
Global invasion patterns and dynamics of disease vector mosquitoes
Authors: Pabst Rebecca , Sousa Carla A , Essl Franz , Garcia-Rodriguez Adrian , Liu Daijun , Lenzner Bernd , Schertler Anna , Zezere Jose Luis , Capinha Cesar
Published: August 2024

Mosquitoes are regarded as the most dangerous creatures on earth, spreading deadly pathogens through their bites. Human activities are driving range expansions of many mosquito species by unintentionally introducing them beyond their native ranges. Despite the often dire consequences for human health, a global picture of the introduction trends and the resulting range expansions of mosquitoes is missing. Here, we describe the global invasion patterns of mosquitoes that are vectors of human diseases and analyze the drivers shaping them. In addition, we provide the dataset compiled for these analyses which represent the most up-to-date standardized information on first records for this taxonomic group at a regional level. Our findings reveal that a total of 45 mosquito species have hitherto been introduced into regions outside their native range worldwide, representing 24% of those known to transmit human pathogens in the wild (i.e., outside experimental conditions), with 27 species successfully established. There has been a steep increase in introductions of emerging non-native mosquito species since the mid-20th century when 28 species (62% of all introduced species) were recorded for the first time. In just the last two decades, 12 new species have been identified. The geography of introductions largely mirrors global trade and transportation flows. Initially, most introduced species were native to Africa, but over time, Asian species have become more dominant. North America, Australia and Europe have consistently been the primary recipients. Our results provide a foundation for addressing the increasing threat of non-native vector mosquitoes globally, emphasizing the need for international cooperation and comprehensive control measures to mitigate their impact on public health.
Immunological response against bovine viral diarrhoea virus (BVDV) types 1 and 2 after vaccination with DIVENCE®, measured by ELISA and serum neutralisation on serum and milk samples
Authors: Montbrau C. , Gibert M. , Taberner E. , Tapiolas M. , Teixeira R. , Prenafeta A.
Published: August 2024

Background

A novel subunit vaccine, DIVENCE®, comprises different bovine respiratory and reproductive antigens, including BVDV-1 E2 recombinant glycoprotein and BVDV-2 E2 recombinant glycoprotein. This study evaluated the immune response against BVDV-1 and 2 generated by DIVENCE® over the long term in different strains.

Methods

Two different studies were conducted to assess the immune response induced by DIVENCE®. In the first study, 20 seronegative young calves (55-104 days of age) were randomly distributed into the vaccinated or control group. All animals were given four intramuscular doses (D0, D21, D204 and D570) of 2 mL DIVENCE® or phosphate-buffered saline (PBS). Blood samples were collected to assess BVDV serum antibodies (ELISA) and neutralising antibodies (SN) against BVDV-1 and BVDV-2. In the second trial, heifers (from 10 months of age until calving) and cows (between first and seventh calving) were included and assigned to the vaccinated and control groups. Three different farms were enrolled in the study. The administration regimen was the same as described in the first study. Blood samples were collected from 32 random animals on each farm (16 vaccinated and 16 control animals). Additionally, bulk tank milk samples from each farm were obtained at different time-points and individual milk samples were obtained from vaccinated and control animals. The immune response against BVDV was analysed in serum and milk samples using different ELISA kits. Neutralising antibodies induced by DIVENCE® against different BVDV isolates from Europe and the Americas were also assessed in this trial.

Results

Overall, DIVENCE® induced high levels of total antibodies (ELISA) and neutralising antibodies against BVDV-1 and BVDV-2. These values were significantly (p<0.05) greater than the control group from 21 days after the second dose (D42) until the end of the study (D591). The high antibody levels, particularly after the third dose, were similar to those that described efficacy against experimental challenges of BVDV-1 and 2 in pregnant animals. In the field trial, similar results were observed in terms of total antibodies (ELISA) against BVDV, and no induction of anti-p80 antibodies was observed in vaccinated animals at any time. Additionally, analyses on individual and bulk tank milk samples also confirmed that no anti-p80 antibodies were induced in vaccinated animals. Furthermore, high levels of neutralising antibodies were observed against different BVDV isolates from Europe and the Americas.

Conclusion

The DIVENCE® vaccine induced a strong immune response against BVDV-1 and BVDV-2, and this response allows infected and vaccinated animals to be differentiated (DIVA vaccine).
Repeated activation of preoptic area-recipient neurons in posterior paraventricular nucleus mediates chronic heat-induced negative emotional valence and hyperarousal states
Authors: Cao Zhiping , Yung Wing-Ho , Ke Ya
Published: August 2024

Mental and behavioral disorders are associated with extended period of hot weather as found in heatwaves, but the underlying neural circuit mechanism is poorly known. The posterior paraventricular thalamus (pPVT) is a hub for emotional processing and receives inputs from the hypothalamic preoptic area (POA), the well-recognized thermoregulation center. The present study was designed to explore whether chronic heat exposure leads to aberrant activities in POA recipient pPVT neurons and subsequent changes in emotional states. By devising an air heating paradigm mimicking the condition of heatwaves and utilizing emotion-related behavioral tests, viral track tracing,in vivocalcium recordings, optogenetic manipulations and electrophysiological recordings, we found that chronic heat exposure for 3 weeks led to negative emotional valence and hyperarousal states in mice. The pPVT neurons receive monosynaptic excitatory and inhibitory innervations from the POA. These neurons exhibited a persistent increase in neural activity following chronic heat exposure, which was essential for chronic heat-induced emotional changes. Notably, these neurons were also prone to display stronger neuronal activities associated with anxiety responses to stressful situations. Furthermore, we observed saturated neuroplasticity in the POA-pPVT excitatory pathway after chronic heat exposure that occluded further potentiation. Taken together, long-term aberration in the POA to pPVT pathway offers a neurobiological mechanism of emotional and behavioral changes seen in extended periods of hot weather like heatwaves.
Nano-org, a functional resource for single-molecule localisation microscopy data
Authors: Shirgill S. , Nieves D.J. , Pike J.A. , Ahmed M.A. , Baragilly M.H.H. , Savoye K. , Worboys J. , Hazime K.S. , Garcia A. , Williamson D.J. , Rubin-Delanchy P. , Peters R. , Davis D.M. , Henriques R. , Lee S.F. , Owen D.M.
Published: August 2024

We present a publicly accessible, curated, and functional resource, termed “nano-org”, containing single-molecule localisation microscopy (SMLM) data representing the nanoscale distributions of proteins in cells. Nano-org is searchable by comparing the statistical similarity of the datasets it contains. This unique functionality allows the resource to be used to understand the relationships of nanoscale architectures between proteins, cell types or conditions, enabling a new field of spatial nano-omics.
Single-nucleus transcriptomics resolves differentiation dynamics between shoot stem cells and primary stem
Authors: Moreno Sebastián R. , Lenz Martin O. , Meyerowitz Elliot M , Locke James CW , Jönsson Henrik
Published: August 2024

The shoot apical meristem (SAM), located at the plant apex, is accountable for the formation of above-ground organs such as leaves, stem and flowers. Although transcriptional profiling has elucidated some cell-types observed within stems or flowers, the differentiation transcriptional dynamics from shoot stem cells to multiple cell identities remain unknown. We employed a single-nucleus RNA-sequencing approach to assess the transcriptional heterogeneity and cell differentiation processes within the SAM. By collecting dissected inflorescence meristems, we constructed an inflorescence single-nucleus SAM atlas fromArabidopsis thaliana. Our analysis unveiled regulatory elements for most previously known cell types such as the boundary domain, vasculature, early primordia, epidermis and internal stem cells. We also identified previously unobserved transcriptional profiles, revealing that the stem cortex is defined early within forming primordia. Moreover, trajectory inference analysis allowed us to capture spatial control of S-phase machinery by floral homeotic genes and differentiation gene expression dynamics from internal shoot stem cells toward internal layers such as cortex, cambium, xylem and phloem. The results advance our understanding of the cellular and transcriptional heterogeneity underlying the cell-fate transcriptional dynamics shaping shoot organs and architecture.
Controlling DNA-RNA strand displacement kinetics with base distribution
Authors: Ratajczyk Eryk J. , Bath Jonathan , Šulc Petr , Doye Jonathan P.K. , Louis Ard A. , Turberfield Andrew J.
Published: August 2024

DNA-RNA hybrid strand displacement underpins the function of many natural and engineered systems. Understanding and controlling factors affecting DNA-RNA strand displacement reactions is necessary to enable control of processes such as CRISPR-Cas9 gene editing. By combining multi-scale modelling with strand displacement experiments we show that the distribution of bases along the displacement domain of an invading strand has a very strong effect on reaction kinetics. Merely by redistributing bases within a displacement domain of fixed base composition, we are able to design sequences whose reaction rates span more than two orders of magnitude. We characterize this effect in reactions involving the invasion of dsDNA by an RNA strand and invasion of a hybrid duplex by a DNA strand. We show that oxNA, a recently introduced coarse-grained model of DNA-RNA hybrids, can reproduce trends in experimentally observed reaction rates. We also develop a kinetic model for predicting strand displacement rates. On the basis of these results, we argue that base distribution effects are likely to play an important role in the function of the guide RNAs that direct CRISPR-Cas systems.
Ecosystem dynamics in wet heathlands: spatial and temporal effects of environmental drivers on the vegetation
Authors: Damgaard Christian
Published: August 2024

To understand and estimate the effects of environmental drivers on wet heathland vegetation, pin-point cover data from 42 sites sampled during a 15-year period was regressed onto environmental variables (nitrogen deposition, soil pH, soil C-N ratio, soil type, precipitation and grazing) in a spatio-temporal structural equation model using a Bayesian hierarchical model structure with latent variables to model the effect of measurement and sampling uncertainties.

The results suggest that the modelled environmental variables have various regulating effects on the large-scale spatial variation as well as plant community dynamics in wet heathlands. Most noticeably, nitrogen deposition and yearly precipitation had relatively large and opposite effects on the characteristic speciesErica tetralixandMolinia caerulea, where nitrogen deposition had negative effects onE. tetralixand positive effects onM. caerulea. The results of this study differed in important qualitative aspects from the findings of an earlier study where comparable data from a shorter time-series (7 years instead of 15 years) were analyzed with a similar model, which suggests that relatively long time-series are needed for studying ecosystem dynamics. Furthermore, it was concluded that the effect of nitrogen deposition on plant community dynamics mainly was through direct effects, whereas the effect of soil type on plant community dynamics was both direct and indirect mediated by the effect of soil type on soil pH.

It was concluded that the modeled environmental variables are sufficient for predicting theaverageplant community dynamics of wet heathlands. However, caution are required if the fitted model is used for generating local ecological predictions as input to a process of generating adaptive management plans for specific wet heathland sites. Moreover, the results suggest that the ratio between the two speciesE. tetralixandM. caeruleamay be used as an indicator for the conservation status of wet heathlands.
Microglia determine ß-amyloid plaque burden but are non-essential for downstream pathology
Authors: Li Mosi , Holt Kris , Ridley Katherine , Qiu Jing , Haddow Kirsty , Vasoya Deepali , He Xin , Tulloch Jane , King Declan , Hume David A , Pridans Clare , Dando Owen R , Spires-Jones Tara L , Hardingham Giles E
Published: August 2024

Evidence points to a role for microglia in Alzheimer’s disease (AD) risk, although their position in the pathological cascade is incompletely understood, prompting us to generate a model of ß-amyloidopathy lacking microglia. We find evidence that microglia promote plaque formation and creation of an Aß fibril-rich zone surrounding the plaque core. However, plaque-proximal reactive astrogliosis, synapse loss, and neurite dystrophy are still observed in the absence of microglia.
Single-egg Comet Assay: a protocol to quantify DNA damage in aquatic dormant stages
Authors: Salimraj Rejin , Perotti Alessio , Wojewodzic Marcin W. , Frisch Dagmar
Published: August 2024

The comet assay (CA) was originally developed as toxicity test and quantifies DNA integrity from the distribution of DNA across an electric field. Compromised DNA moves across electric fields faster than intact DNA strands, leaving a quantifiable signature that resembles a comet tail. The dimensions of this comet tail reflect relative DNA damage.

We optimized the CA protocol for individual dormant propagules (Single-egg Comet Assay or SE-CA) to inform downstream analyses such as DNA sequencing, of the DNA quality contained in natural genetic archives of past populations. As a model we used dormant eggs of the microcrustaceanDaphnia.

We tested the SE-CA protocol on impact of processing and storage conditions for dormant eggs and used it to assess DNA damage related to aging of eggs retrieved from recently deposited to centuries-old lake sediment. The SE-CA successfully determined the degree of DNA damage in individual eggs frozen in liquid nitrogen, or at -80°C as well as damage caused by bleaching and historical egg age.

In conclusion, our protocol provides a cost-effective method of assessing DNA damage in sedimentary propagules such as dormantDaphniaeggs. More generally, the SE-CA can be applied to test DNA integrity in individual propagules prior to genome sequencing or to quantify environmental impacts on natural sedimentary biobanks.