bluuebunny/crossref_metadata_2025 huggingface dataset:
BrainACTIV: Identifying visuo-semantic properties driving cortical selectivity using diffusion-based image manipulation
Authors: Garcia Cerdas Diego , Sartzetaki Christina , Petersen Magnus , Roig Gemma , Mettes Pascal , Groen Iris I.A.
Published: October 2024

The human brain efficiently represents visual inputs through specialized neural populations that selectively respond to specific categories. Advancements in generative modeling have enabled data-driven discovery of neural selectivity using brain-optimized image synthesis. However, current methods independently generate one sample at a time, without enforcing structural constraints on the generations; thus, these individual images have no explicit point of comparison, making it hard to discern which image features drive neural response selectivity. To address this issue, we introduce Brain Activation Control Through Image Variation (BrainACTIV), a method for manipulating a reference image to enhance or decrease activity in a target cortical region using pretrained diffusion models. Starting from a reference image allows for fine-grained and reliable offline identification of optimal visuo-semantic properties, as well as producing controlled stimuli for novel neuroimaging studies. We show that our manipulations effectively modulate predicted fMRI responses and agree with hypothesized preferred categories in established regions of interest, while remaining structurally close to the reference image. Moreover, we demonstrate how our method accentuates differences between brain regions that are selective to the same category, and how it could be used to explore neural representation of brain regions with unknown selectivities. Hence, BrainACTIV holds the potential to formulate robust hypotheses about brain representation and to facilitate the production of naturalistic stimuli for neuroscientific experiments.
Self-Documenting Plasmids
Authors: Hernandez Sarah I. , Peccoud Samuel J. , Berezin Casey-Tyler , Peccoud Jean
Published: October 2024

Summary

Plasmids are the workhorse of biotechnology. These small DNA molecules are used to produce recombinant proteins and to engineer living organisms. They can be regarded as the blueprints of many biotechnology products. It is, therefore, critical to ensure that the sequences of these DNA molecules match their intended designs. Yet, plasmid verification remains challenging. To secure the exchange of plasmids in research and development workflows, we have developed self-documenting plasmids that encode information about themselves in their own DNA molecules. Users of self-documenting plasmids can retrieve critical information about the plasmid without prior knowledge of the plasmid identity. The insertion of documentation in the plasmid sequence does not adversely affect their propagation in bacteria and does not compromise protein expression in mammalian cells. This technology simplifies plasmid verification, hardens supply chains, and has the potential to transform the protection of intellectual property in the life sciences.
Structural-Functional Brain Network Coupling During Task Performance Reveals Intelligence-Relevant Communication Strategies
Authors: Popp Johanna L. , Thiele Jonas A. , Faskowitz Joshua , Seguin Caio , Sporns Olaf , Hilger Kirsten
Published: October 2024

Intelligence is a broad mental capability influencing human performance across tasks. Individual differences in intelligence have been linked to characteristics of structural and functional brain networks. Here, we consider their alignment, the structural-functional brain network coupling (SC-FC coupling) during resting state and during active cognition, to predict general intelligence. Using DWI and fMRI data from 764 participants of the Human Connectome Project (Replication:N1=126,N2=180), we modelled SC-FC coupling with similarity and communication measures that capture functional interactions unfolding on top of structural brain networks. By accounting for variations in brain region-specific neural signaling strategies, we show that individual differences in SC-FC coupling patterns predict individual intelligence scores. Most accurate predictions resulted from cognitively demanding tasks and task combinations. Our study suggests the existence of an intrinsic SC-FC coupling organization enabling fine-drawn intelligence-relevant adaptations that support efficient information processing by facilitating brain region-specific adjustment to external task demands.
Vimentin molecular linkages with nesprin-3 enhance nuclear deformations by cell geometric constraints
Authors: Swoger Maxx , Thanh Minh Tri Ho , Byfield Fitzroy J. , Dam Van , Williamson Jessica , Frank Bronson , Hehnly Heidi , Conway Daniel , Patteson Alison E.
Published: November 2024

The nucleus is the organelle of the cell responsible for controlling protein expression, which has a direct effect on cellular biological functions. Here we show that the cytoskeletal protein vimentin plays an important role in increasing cell-generated forces transmitted to the cell nucleus, resulting in increased nuclear deformations in strongly polarized cells. Using micropatterned substrates to geometrically control cell shape in wild-type and vimentin-null cells, we show vimentin increases polarization and deformation of the cell nucleus. Loss of nesprin-3, which physically couples vimentin to the nuclear envelope, phenotypically copies the loss of vimentin, suggesting vimentin transmits forces to the cell nucleus through direct molecular linkages. Use of a fluorescence resonance energy transfer (FRET) sensor that binds to the nuclear envelope through lamin-A/C suggests vimentin increases the tension on the nuclear envelope. Our results indicate that nuclear shape and deformation can be modified by the vimentin cytoskeleton and its specific crosslinks to the cell nucleus.
Seasonal and daily variation in indoor light and temperature associate with sleep disturbance in dementia
Authors: Skeldon Anne C , Rodriguez Garcia Thalia ,   Centre for Care Research & Technology, Soreq Eyal , Walsh Chloe , Dijk Derk-Jan
Published: November 2024

Mechanisms regulating human sleep and physiology have evolved in response to rhythmic variation in environmental variables driven by the Earth’s rotation around its axis and the sun. To what extent these mechanisms are operable in vulnerable people who are primarily exposed to the indoor environment remains unknown. We analysed 26,523 days of data from environmental sensors and a contactless behaviour-and-physiology sensor tracking bed occupancy, heart and breathing rate in 70 people living with dementia (PLWD). Indoor light and temperature, sleep timing, duration and fragmentation as well as the timing of the heart rate minimum all varied across seasons. Beyond the effects of season, higher bedroom temperature and less bright indoor daytime light associated with more disrupted sleep and higher respiratory rate. This sensitivity of sleep and physiology to ecologically relevant variations in indoor environmental variables implies that implementing approaches to control indoor light and temperature can improve sleep.
Exploring Intersectionality of Race and Newcomer Status with Material and Social Deprivation in Ontario Census Data: A Comparative Analysis of the ON-MARG Deprivation Index and Machine-Learning Derived Demographic Clusters
Authors: Calderon Anyosa Renzo , Anderson Geoffrey
Published: November 2024

Background

The Ontario Marginalization Index (ON-MARG) is widely used to assess health inequalities in Ontario by measuring four dimensions of marginalization at the dissemination area (DA) level. However, averaging these dimensions into an overall deprivation score can obscure important information, in particular information on intersectionality of material and social deprivation and race and immigrant status.

Objective

To use machine learning algorithms to uncover relationships among the four ON-MARG dimensions across DAs as demographic clusters and to compare the use of these clusters to understand and map marginalization and to describe health inequities.

Methods

We applied K-means clustering to 2021 ON-MARG data on the four On-MARG dimensions — Households and Dwellings (HD), Material Resources (MR), Age and Labour Force (AL), and Racialized and Newcomer Populations (RN) across 20,123 DAs. We then compared these clusters to ON-MARG average index scores in terms of mapping marginalization in Toronto and examined how these clusters were associated with inequities in mental health service as compared specific dimensions of the ON-MARG index.

Results

We identified four clusters: (1) Advantaged White Canadians, (2) Disadvantaged White Canadians, (3) Advantaged Visible Minorities and Immigrants, and (4) Disadvantaged Visible Minorities and Immigrants. The clustering approach revealed nuanced patterns not captured by the ON-MARG summary scores alone. Disadvantaged White Canadians exhibited the highest outpatient mental health visit rates, particularly among females (250–300 visits per 100,000). Disadvantaged Visible Minorities and Immigrants followed with elevated rates, while both advantaged clusters showed significantly lower utilization. The clusters provided better discrimination of health service disparities than ON-MARG quintiles alone, highlighting that disadvantaged groups, regardless of racial composition, had higher rates of mental health service use.

Conclusions

Combining ON-MARG with machine learning clustering offers a more comprehensive understanding of marginalization’s intersectionality, revealing disparities in health service utilization not apparent from the index alone. This approach underscores the need for targeted, intersectional policies to address the specific needs of diverse populations, ultimately contributing to more equitable healthcare interventions in Ontario.
Touch to text: Spatiotemporal evolution of braille letter representations in blind readers
Authors: Teng Santani , Cichy Radoslaw , Pantazis Dimitrios , Oliva Aude
Published: November 2024

Visual deprivation does not silence the visual cortex, which is responsive to auditory, tactile, and other nonvisual tasks in blind persons. However, the underlying functional dynamics of the neural networks mediating such crossmodal responses remain unclear. Here, using braille reading as a model framework to investigate these networks, we presented sighted (N=13) and blind (N=12) readers with individual visual print and tactile braille alphabetic letters, respectively, during MEG recording. Using time-resolved multivariate pattern analysis and representational similarity analysis, we traced the alphabetic letter processing cascade in both groups of participants. We found that letter representations unfolded more slowly in blind than in sighted brains, with decoding peak latencies ∼200 ms later in braille readers. Focusing on the blind group, we found that the format of neural letter representations transformed within the first 500 ms after stimulus onset from a low-level structure consistent with peripheral nerve afferent coding to high-level format reflecting pairwise letter embeddings in a text corpus. The spatiotemporal dynamics of the transformation suggest that the processing cascade proceeds from a starting point in somatosensory cortex to early visual cortex and then to inferotemporal cortex. Together our results give insight into the neural mechanisms underlying braille reading in blind persons and the dynamics of functional reorganization in sensory deprivation.
A hierarchical coordinate system for sequence memory in human entorhinal cortex
Authors: Shpektor Anna , Bakermans Jacob J. W. , Baram Alon B. , Sarnthein Johannes , Ledergerber Debora , Imbach Lukas , Müller-Seydlitz Emma , Barron Helen C. , Behrens Timothy E. J.
Published: October 2024

Grid cells in rodent entorhinal cortex (EC) support a coordinate system for space, enabling robust memory and powerful flexibility in spatial behaviour. This coordinate system is abstract - with the same grid cells encoding position across different sensory environments; and hierarchical - with grid modules of increasing spatial scale occupying increasingly ventral locations in the EC. Recent theories suggest that a similar abstract coordinate system could offer the same benefits to general memories that are not sequences drawn from a 2D surface. Here we show that an abstract hierarchical coordinate system supports arbitrary sequences in the human medial temporal lobe (MTL). In single-unit recordings from MTL, we find abstract, coordinate-like coding of a simple sequential memory task. In an fMRI experiment with more complex hierarchical sequences, we discover an abstract hierarchical representation in EC: the coordinate representations at distinct levels in the hierarchy are arranged on an anatomical gradient along the EC’s anterior-posterior axis, homologous to the ventro-dorsal axis in rodents. These results therefore mirror the anatomical gradient of grid cells in the rodent EC but now for arbitrary non-spatial sequences. Together they suggest that memories are scaffolded on a hierarchical coordinate system using common neuronal coding principles, aligned to preserved anatomy, across domains and species.
Diminished placental Factor XIIIA1 expression associates with pre-conception antiretroviral treatment and preterm birth in pregnant people living with HIV
Authors: Ojwach Doty , Annels Nicola , Sunshine Sunny , Simpkin Daniel , Duruanyanwu Justin , Webber Tariq , Alinde Berenice , Ikumi Nadia , Zulu Michael , Madlala Hlengiwe , Myer Landon , Malaba Thoko , Newell Marie-Louise , Campagnolo Paolo , Gordon Siamon , Jaspan Heather , Gray Clive M. , Martinez Estrada Fernando
Published: November 2024

We previously showed a link between maternal vascular malperfusion and pre-term birth (PTB) in pregnant people living with HIV (PPLH) initiating antiretroviral treatment (ART) before pregnancy, indicating poor placental vascularisation. After measuring antenatal plasma angiogenic factors to seek mechanistic insights, low levels of plasma Factor XIIIA1 (FXIIIA1) and vascular-endothelial-growth-factor (VEGF) was significantly associated with PTB at the time closest to delivery (median 34 weeks) in PPLH initiating ART before pregnancy. Knowing that FXIIIA1 is crucial for haemostasis, angiogenesis, implantation and pregnancy maintenance and that expression is found on placental macrophages (Hofbauer cells), we examined placentae at delivery from matching participants who either initiating ART before pregnancy or during gestation. Highest FXIIIA1 expression was on Hofbauer cells but was significantly lower in PTB regardless of HIV infection, but was significantly lower in PPLH in PTB from women who initiated ART before pregnancy. To test the hypothesis that antiretroviral drugs may disrupt vascularisation in the placenta, we used a human umbilical vein endothelial cell (HUVEC) matrigel angiogenesis assay. We identified that addition of pre-treated FXIIIA1-expressing MCSF-and IL-10-induced placenta-like macrophages with physiological concentrations of tenofovir, 3TC, and efavirenz resulted in significantly inhibited angiogenesis; akin to the inhibition observed with titratable concentrations of ZED1301, an inhibitor of FXIIIA1. Overall, an efavirenz-containing ART combination inhibits vasculogenesis without causing toxicity and likely does so through inhibition of a FXIIIA1-mediated-placental macrophage pathway.
IL-17A Alters Human Cortical Development in a 3D Ex Vivo Model of Maternal Immune Activation
Authors: Assir Muhammad Z. K. , Yanakiev Mario , Gim Do Hyeon , Valkila Sara S. M. , Muscolino Paola , Peng Liu , Fowler Paul A. , Berg Daniel A. , Kang Eunchai
Published: October 2024

Human brain development depends on the coordinated interaction of diverse cell types and extracellular matrix (ECM) components, which are essential for proper neurogenesis and cortical organization. Epidemiological and animal studies have demonstrated that maternal immune activation (MIA) disrupts brain development, leading to impaired neurogenesis and increased risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and schizophrenia. However, the cellular and molecular mechanisms by which MIA impacts human cortical development remain poorly understood. Here we introduce a 3D ex vivo culture system, termed ‘cerebroids,’ derived from dorsolateral prefrontal cortex of human fetal brain tissue, which faithfully preserves key developmental processes, along with critical cellular diversity and structural integrity of the developing human cortex. Using this platform, we show that IL-17A, a cytokine strongly implicated in NDDs, induces premature cortical folding, increases cortical thickness, and accelerates neurogenesis and neuronal maturation. Transcriptomic and proteomic analyses reveal significant dysregulation of ECM-related pathways, including the upregulation of proteoglycans such as brevican and versican. Notably, treatment with the anti-inflammatory agent parthenolide, an inhibitor of NF-κB and HDAC1 pathways, reverses IL-17A-induced cortical abnormalities, restoring normal cortical thickness, folding, and neurogenesis. These findings provide valuable insights into how IL-17A disrupts human cortical development during MIA, advancing our understanding of NDD-associated structural cortical alterations.
Will a large complex system form Turing patterns?
Authors: Piskovsky Vit , Maini Philip K.
Published: October 2024

From atomic spins in magnets to galaxies, and from embryonic development to patchy vegetation in arid environments, the physical world is filled with complex systems that spontaneously form spatial patterns. In the context of reaction-diffusion systems, pattern formation can be explained by the Turing mechanism, which postulates that diffusion can destabilise spatially uniform steady states. However, the resulting Turing patterns have only been analyzed in systems with a small number of diffusing variables, even though the physical systems they aim to describe are highly complex. In this study, we utilize ideas from random matrix theory to explore how spontaneously formed Turing patterns emerge in random complex systems with many variables. Crucially, we find that diffusion-driven instability is not sufficient to explain pattern formation. Nevertheless, modifications of the Turing mechanism that include various forms of local and non-local attraction and repulsion are shown to reliably promote pattern formation in large complex systems. Altogether, this study assesses the robustness of multiple pattern-forming mechanisms in large complex systems, providing a guide for recognising which mechanisms might be important for pattern formation in empirical studies.
AlphaFold 2, but not AlphaFold 3, predicts confident but unrealistic β-solenoid structures for repeat proteins
Authors: Pratt Olivia S. , Elliott Luc G. , Haon Margaux , Mesdaghi Shahram , Price Rebecca M. , Simpkin Adam J. , Rigden Daniel J.
Published: October 2024

AlphaFold 2 has revolutionised protein structure prediction but, like any new tool, its performance on specific classes of targets, especially those potentially under- represented in its training data, merits attention. Prompted by a highly confident prediction for a biologically meaningless, scrambled repeat sequence, we assessed AF2 performance on sequences comprised perfect repeats of random sequences of different lengths. AF2 frequently folds such sequences into β-solenoids which, while ascribed high confidence, contain unusual and implausible features such as internally stacked and uncompensated charged residues. A number of sequences confidently predicted as β-solenoids are predicted by other advanced methods as intrinsically disordered. The instability of some predictions is demonstrated by Molecular Dynamics. Importantly, other Deep Learning-based structure prediction tools predict different structures or β-solenoids with much lower confidence suggesting that AF2 alone has an unreasonable tendency to predict confident but unrealistic β-solenoids for perfect repeat sequences. The potential implications for structure prediction of natural (near-)perfect sequence repeat proteins are also explored.
Acetylation of RORβ by histone acetyltransferase p300 and deacetylation by SIRT1 modulates receptor stability, turnover and transcriptional activity
Authors: O’Leary Timothy , Shutin Denis , Edwards Dean P. , Griffin Patrick R. , Chang Mi Ra
Published: October 2024

RORβ is an understudied nuclear receptor recently implicated in numerous pathologies. Using immunoprecipitation mass spectrometry, the transcription factor coregulatory protein and histone acetyltransferase p300 (EP300) was identified as a direct interacting protein of RORβ. Crosslinking mass spectrometry (XL-MS) confirmed that p300 interacts with the DNA binding domain (DBD), hinge region, and ligand binding domain (LBD) of RORβ. Both p300 and SIRT1 impact the turnover rate and transcriptional activity of RORβ. p300-dependent acetylation sites were found to be constrained to the DBD and hinge region of RORβ and were deacetylated by SIRT1. Sites that were ubiquitinated in the presence of p300 and SIRT1 were also discovered, with some sites sensitive to proteasome inhibitor. A constitutively acetylated mimic at K176 in the hinge prevented ubiquitination of RORβ at distal sites. Uncovering regulatory mechanisms of RORβ via protein interactions and PTMs will provide strategies for development of therapeutics targeting the receptor.

Teaser

p300 and SIRT1 work in concert to coordinate posttranslational modifications of the nuclear receptor RORβ.

Graphical Abstract
Different serotonergic neurons regulate appetite for sucrose and hunger for proteins
Authors: Dorn Katharina , Gompert Magdalena , He Jianzheng , Scholz Henrike
Published: October 2024

For the organism it is important to replenish internal energy storages selectively and selective appetite for nutrients might uncover internal energy requirements. How is the selective uptake of a specific nutrient regulated? Here we show that inDrosophila melanogasterdifferent sets of serotonergic neurons regulate appetite for sucrose and hunger for proteins. Increased neuronal activity in specific subsets of serotonergic neurons and interfering with serotonin reuptake using a mutated serotonin transporter reduced the appetite for sucrose selectively, but not the hunger for proteins. The insulin receptor together with the serotonin transporter regulates the selective sucrose appetite. We provide evidence that the cellular location of the serotonin transporter depends on the insulin receptor. This mechanism might allow optimizing nutrient intake and in turn might prevent overconsumption by repressing appetite for sucrose. Given the conserved nature of the molecules involved it is likely that the mechanism is conserved in higher organisms.
Denoising complex-valued diffusion MR images using a two-step non-local principal component analysis approach
Authors: Ye Xinyu , Ma Xiaodong , Pan Ziyi , Zhang Zhe , Guo Hua , Uğurbil Kâmil , Wu Xiaoping
Published: October 2024

Purpose

to propose a two-step non-local principal component analysis (PCA) method and demonstrate its utility for denoising diffusion tensor MRI (DTI) with a few diffusion directions.

Methods

A two-step denoising pipeline was implemented to ensure accurate patch selection even with high noise levels and was coupled with data preprocessing for g-factor normalization and phase stabilization before data denoising with a non-local PCA algorithm. At the heart of our proposed pipeline was the use of a data-driven optimal shrinkage algorithm to manipulate the singular values in a way that would optimally estimate the noise-free signal. Our approach’s denoising performances were evaluated using simulation and in-vivo human data experiments. The results were compared to those obtained with existing local-PCA-based methods.

Results

In both simulation and human data experiments, our approach substantially enhanced image quality relative to the noisy counterpart, yielding improved performances for estimation of relevant DTI metrics. It also outperformed existing local-PCA-based methods in reducing noise while preserving anatomic details. It also led to improved whole-brain tractography relative to the noisy counterpart.

Conclusion

The proposed denoising method has the utility for improving image quality for DTI with reduced diffusion directions and is believed to benefit many applications especially those aiming to achieve quality parametric mapping using only a few image volumes.
Modeling Protein Conformations by Guiding AlphaFold2 with Distance Distributions. Application to Double Electron Electron Resonance (DEER) Spectroscopy
Authors: Wu Tianqi , Stein Richard A. , Kao Te-Yu , Brown Benjamin , Mchaourab Hassane S.
Published: November 2024

We describe a modified version of AlphaFold2 that incorporates experiential distance distributions into the network architecture for protein structure prediction. Harnessing the OpenFold platform, we fine-tuned AlphaFold2 on a small number of structurally dissimilar proteins to explicitly model distance distributions between spin labels determined from Double Electron-Electron Resonance (DEER) spectroscopy. We demonstrate the performance of the modified AlphaFold2, referred to as DEERFold, in switching the predicted conformations guided by experimental or simulated distance distributions. Remarkably, the intrinsic performance of AlphaFold2 substantially reduces the number and the accuracy of the widths of the distributions needed to drive conformational selection thereby increasing the experimental throughput. The blueprint of DEERFold can be generalized to other experimental methods where distance constraints can be represented by distributions.
Genome-wide investigation of outer membrane protein families under mosaic evolution inEscherichia coli
Authors: Cao Xin , Cao Cuihua , Chen Zefan , Li Jialin , Zheng Yidong , Wu Jinjin , Li Zeling , Hu Yueming , Hao Gaofeng , Zhu Guoqiang , Köster Wolfgang , White Aaron P. , Wang Yejun
Published: November 2024

Several genes in Gram-negative bacteria encoding outer membrane proteins (OMPs) have been reported to show patterns of mosaic evolution featured by mixture of negative selection and local recombination. Here, we proposed a strategy, and applied it to screen OMPs under mosaic evolution inEscherichia coliin the genome level. In total, 21 OMP families, including 16 new ones, were detected with the typical patterns of mosaic evolution. An abosolute majority of the protein families are conserved inE. colifor the composition, genomic loci and the overall structures. Highly Variable Regions (HVRs) can be recognized, which are frequently located extracellularly within the protruding loops. There are only limited number of major HVR sequence types, within which positively selected sites can be detected ocassionally. Based on the simulated results of multiple models, the OMPs under mosaic evolution are often with good antigenicity, with HVRs of various sequence types coinciding with the B-cell epitopes of the strongest immunogenicity. The study futher broadened our understanding of the characteristics of mosaic evolution and the functions of OMPs in Gram-negative bacteria, laying an important foundation for their potential translational applications.

Importance

It is important to understand the evolutionary mechanisms of bacterial OMP-encoding genes, which would facilitate the development of anti-bacterial reagents. This study made the first genome-wide screening of bacterial OMPs under mosaic evolution, and increased the list of candidate OMP families by 3 folds inE. coli, far more than we expected. The study further confirmed the hypothesis about the evolutionary, micro-evolutionary and structural features of these OMPs, and facilitated the functional theory of mosaic evolution. Moreover, the findings of limited HVR sequence types and strong immunogenicity of HVRs paved important foundation for application of these OMPs and their HVRs in development of antibodies or other anti-bacterial treatment.
Structural and Functional Relevance of Charge Based Transient Interactions inside Intrinsically Disordered Proteins
Authors: Wohl Samuel , Gilron Yishai , Zheng Wenwei
Published: November 2024

Intrinsically disordered proteins (IDPs) perform a wide range of biological functions without adopting stable, well-defined, three-dimensional structures. Instead, IDPs exist as dynamic ensembles of flexible conformations, traditionally thought to be governed by weak, nonspecific interactions, which are well described by homopolymer theory. However, recent research highlights the presence of transient, specific interactions in several IDPs, suggesting that factors beyond overall size influence their conformational behavior. In this study, we investigate how the spatial arrangement of charged amino acids within IDP sequences shapes the prevalence of transient, specific interactions. Through a series of model peptides, we establish a quantitative empirical relationship between the fraction of transient interactions and a novel sequence metric, termed effective charged patch length, which characterizes the ability of charged patches to drive these interactions. By examining IDP ensembles with varying levels of transient interactions, we further explore their heteropolymeric structural behavior in phase-separated condensates, where we observe the formation of a condensate-spanning network structure. Additionally, we perform a proteome-wide scan for charge-based transient interactions within disordered regions of the human proteome, revealing that approximately 10% of these regions exhibit such charge-driven transient interactions, leading to heteropolymeric behaviors in their conformational ensembles. Finally, we examine how these charge-based transient interactions correlate with molecular functions, identifying specific biological roles in which these interactions are enriched.
Practice beyond performance stabilization increases the use of online adjustments to unpredictable perturbations in an interceptive task
Authors: Couto Crislaine Rangel , Leite Cláudio Manoel Ferreira , Campos Carlos Eduardo , Portes Leonardo Luiz , Matos Cíntia de Oliveira , Santos Suziane Peixoto , Ambrósio Natália Fontes Alves , Yehia Hani Camille , Ugrinowitsch Herbert
Published: November 2024

In recent decades, research has focused on motor adjustments in interception tasks within predictable environments. However, emerging studies suggest that continued practice beyond performance stabilization enhances the ability to adapt to unpredictable events. The objective of this study was to investigate the effects of practicing until performance stabilization versus extended practice through superstabilization on the ability to adjust to unpredictable perturbations in intercepting a moving target. We hypothesized superstabilization would better facilitate motor adjustments in response to unpredictable perturbations. Forty participants engaged in an interception task until they achieved either performance stabilization or superstabilization. Subsequently, both stabilization and superstabilization groups were tested in an unpredictable environment, where, in certain trials, the target’s velocity unexpectedly changed after the onset of the movement. The findings revealed that the superstabilization group made more adjustments in response to these perturbations than the stabilization group, attributed to their developed capacity to use online feedback as a control mechanism more efficiently. In contrast, the practice until performance stabilization did not foster this adaptive mechanism. These results support the notion that learning is a dynamic process that extends beyond the point of performance stabilization, emphasizing the benefits of continued practice for mastering complex motor tasks in variable contexts.
Antigenic imprinting dominates humoral responses to new variants of SARS-CoV-2 in a hamster model of COVID-19
Authors: Degryse Joran , Maas Elke , Lassaunière Ria , Geerts Katrien , Kumpanenko Yana , Weynand Birgit , Maes Piet , Neyts Johan , Thibaut Hendrik Jan , Alpizar Yeranddy A. , Dallmeier Kai
Published: November 2024

The emergence of SARS-CoV-2 variants escaping immunity challenges the efficacy of current vaccines. Here, we investigated humoral recall responses and vaccine-mediated protection in Syrian hamsters immunized with the third-generation Comirnaty® Omicron XBB.1.5-adapted COVID-19 mRNA vaccine, followed by infection with either antigenically closely (EG.5.1) or distantly related (JN.1) Omicron subvariants. Vaccination with YF17D vector encoding a modified Gamma spike (YF-S0*) served as a control for pre-Omicron SARS-CoV-2 immunity. Our results show that both Comirnaty® XBB.1.5 and YF-S0* induce robust, however, poorly cross-reactive, neutralizing antibody (nAb) responses. In either case, total antibody and nAb levels increased following infection. Intriguingly, the specificity of these boosted nAbs did not match the respective challenge virus but was skewed towards the primary antigen used for immunization, suggesting a marked impact of antigenic imprinting; confirmed by antigenic cartography. Furthermore, limited cross-reactivity and rapid decline of nAbs induced by Comirnaty® XBB.1.5 with EG.5.1 and, more concerning, JN.1. raises doubts about sustained vaccine efficacy against recent circulating Omicron subvariants. Future vaccine design may have to address two major issues: (i) to overcome original antigenic sin that limits the breadth of a protective response towards emerging variants, and (ii) to achieve sustained immunity that lasts for at least one season.
A designed Zn2+sensor domain transmits binding information to transmembrane histidine kinases
Authors: Hatstat A. Katherine , Kormos Rian , Xu Vee , DeGrado William F.
Published: November 2024

Generating stimulus-responsive, allosteric signalingde novois a significant challenge in protein design. In natural systems like bacterial histidine kinases (HKs), signal transduction occurs when ligand binding initiates a signal that is amplified across biological membranes over long distances to induce large-scale rearrangements and phosphorylation relays. Here, we ask whether our understanding of protein design and multi-domain, intramolecular signaling has progressed sufficiently to enable engineering of a HK with tunablede novocomponents. We generatedde novometal-binding sensor domains and substituted them for the native sensor domain of a transmembrane HK, affording chimeras that transduce signals initiated from ade novosensor. Signaling depended on the designed sensor’s stability and the interdomain linker’s phase and length. These results show the usefulness ofde novodesign to elucidate biochemical mechanisms and principles for design of new signaling systems.
Predicted constrained accessible regions mark regulatory elements and causal variants
Authors: Tomizuka Kohei , Koido Masaru , Suzuki Akari , Yoshino Soichiro , Tanaka Nao , Ishikawa Yuki , Liu Xiaoxi , Koyama Satoshi , Ishigaki Kazuyoshi , Murakawa Yasuhiro ,   Immune transcript/enhancer consortium (ITEC), Yamamoto Kazuhiko , Terao Chikashi
Published: November 2024

Open chromatin regions (OCRs) provide genome-wide DNA elements in a cell-type-specific manner at high resolution but do not always mark active regulatory regions, hampering pinpointing causal functional variants in genetic association studies. Here, we developed a new scoring system, CAMBUS (Chromatin Accessibility Mutation Burden Score), to find active and constraint OCRs via machine-learning predictions of OCRs from surrounding DNA sequences. CAMBUS predicted 66,043 active and constrained OCRs in 29 immune cell types. These OCRs were highly constrained and enriched in known enhancers and super-enhancers. By exploiting the resolution of OCRs, we identified regulatory elements overlapping with known regulatory pathogenic variants of immune-mediated diseases and experimentally-proven or putative causal variants of complex traits, especially leukocyte-related traits, even for rare variants. In summary, our approach can derive hidden constrained and functional OCRs in a cell-type-dependent manner, thus informing non-coding causal genetic factors to human diseases at high resolution.
Multiscale Quantification of Hemispheric Asymmetry in Cortical Maps Using Geometric Eigenmodes
Authors: Milloz Alicia , Vogel Jacob , Olsen Anders , Pang James C , Strandberg Olof , Anijärv Toomas Erik , Stomrud Erik , Palmqvist Sebastian , Spotorno Nicola , Ossenkoppele Rik , Van De Ville Dimitri , Hansson Oskar , Behjat Hamid
Published: October 2024

Hemispheric asymmetry is a universal property of brain organization with wide implications into brain function and structure, and diseases. This study presents a laterality index for characterizing hemispheric asymmetries that underlie cortical maps using geometric eigenmodes derived from human cortical surfaces.We develop a generalized design to quantify asymmetries across various cortical spatial scales. While the design is individual-specific, we implement normalization steps to enable unbiased comparisons across individuals. As a proof of concept, we validated the method on cortical maps of 545 subjects across two datasets, using fMRI maps of healthy individuals and tau-PET maps of patients across the Alzheimer’s disease continuum. Our results reveal that cortical regions in different canonical functional networks have connectivity patterns that entail different degrees of hemispheric asymmetry. Moreover, aggregates of the pathological tau protein manifest subtle asymmetries at varying spatial scales along the disease continuum.
Phage-encoded small RNA hijacks host replication machinery to support the phage lytic cycle
Authors: Silverman Aviezer , Nashef Raneem , Bruner Reut , Noy Tamar , Melamed Sahar
Published: November 2024

Bacteriophages (phages) significantly influence bacterial populations in their natural environment. However, one aspect that has not been thoroughly explored in the context of phage-bacteria interactions is the post-transcriptional regulation of gene expression, despite growing recognition of its importance in bacterial physiology over the past two decades. Important players in this process are small RNAs (sRNAs) that regulate target mRNAs via base-pairing, typically using RNA chaperones like Hfq to facilitate this regulation. Here, we apply RIL-seq to mapin-vivothe sRNA-RNA network inEscherichia coliupon lambda phage infection. We highlight changes in the bacterial transcriptome and sRNA interactome while uncovering a novel phage-encoded sRNA that regulates key genes inE. coli. We decipher the molecular mechanism of the sRNA-mediated regulation and illustrate how the sRNA hijacks the host replication machinery and helps the infection cycle. Overall, we uncover an RNA-level regulatory layer that shapes theE. coli- lambda interactions.
A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein
Authors: Abu-Shmais Alexandra A. , Guo Luqiang , Khalil Ahmed Magady , Miller Rose J. , Janke Alexis K. , Vukovich Matthew J. , Bass Lindsay E. , Suresh Yukthi P. , Rush Scott A. , Wolters Rachael M. , Kose Nurgun , Carnahan Robert H. , Crowe James E. , Bonami Rachel H. , Mousa Jarrod J. , McLellan Jason S. , Georgiev Ivelin S.
Published: November 2024

Human respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are frequent drivers of morbidity and mortality in susceptible populations, most often infantile, older adults, and immunocompromised. The primary target of neutralizing antibodies is the fusion (F) glycoprotein on the surface of the RSV and hMPV virion. As a result of the structural conservation between RSV and hMPV F, three antigenic regions are known to induce cross-neutralizing responses: sites III, IV, and V. Leveraging LIBRA-seq, we identify five RSV/hMPV cross-reactive human antibodies. One antibody, 5-1, potently neutralizes all tested viruses from the major subgroups of RSV and hMPV and provides protection against RSV and hMPV in a mouse challenge model. Structural analysis reveals that 5-1 utilizes an uncommon genetic signature to bind an epitope that spans sites Ø, II and V, defining a new mode of antibody cross-reactivity between RSV and hMPV F. These findings highlight the molecular and structural elements influencing RSV and hMPV cross-reactivity as well as the potential of antibody 5-1 for translational development.
Awakening of the RuMP cycle for partial methylotrophy in the thermophileParageobacillus thermoglucosidasius
Authors: Paredes-Barrada Miguel , Mathissen Annemieke , van der Molen Roland A. , Jiménez-Huesa Pablo J. , Polano Machiel Eduardo , Donati Stefano , Abele Miriam , Ludwig Christina , van Kranenburg Richard , Claassens Nico J.
Published: November 2024

Given sustainability and scalability concerns of using sugar feedstocks for microbial bioproduction of bulk chemicals, widening the feedstock range for microbial cell factories is of high interest. Methanol is a one-carbon alcohol that stands out as an alternative feedstock for the bioproduction of chemicals, as it is electron-rich, water-miscible and can be produced from several renewable resources. Bioconversion of methanol into products under thermophilic conditions (>50°C) could be highly advantageous for industrial biotechnology. Although progress is being made with natural, thermophilic methylotrophic microorganisms, they are not yet optimal for bioproduction and establishing alternative thermophilic methylotrophic bioproduction platforms can widen possibilities. Hence, we set out to implement synthetic methanol assimilation in the emerging thermophilic model organismParageobacillus thermoglucosidasius.We engineeredP. thermoglucosidasiusto be strictly dependent for its growth on methanol assimilation via the core of the highly efficient ribulose monophosphate (RuMP) cycle, while co-assimilating ribose. Surprisingly, this did not require heterologous expression of RuMP enzymes. Instead, by laboratory evolution we awakened latent, native enzyme activities to form the core of the RuMP cycle. We obtained fast methylotrophic growth in which ∼17% of biomass was strictly obtained from methanol. This work lays the foundation for developing a versatile thermophilic bioproduction platform based on renewable methanol.
Chromatin-associated lncRNA-splicing factor condensates regulate hypoxia responsive RNA processing of genes pre-positioned near nuclear speckles
Authors: Song You Jin , Shinn Min Kyung , Bangru Sushant , Wang Yu , Sun Qinyu , Hao Qinyu , Chaturvedi Pankaj , Freier Susan M. , Perez-Pinera Pablo , Nelson Erik R. , Belmont Andrew S. , Guttman Mitchell , Prasanth Supriya G. , Kalsotra Auinash , Pappu Rohit V. , Prasanth Kannanganattu V.
Published: November 2024

Hypoxia-induced alternative splicing (AS) regulates tumor progression and metastasis. Little is known about how such AS is controlled and whether higher-order genome and nuclear domain (ND) organizations dictate these processes. We observe that hypoxia-responsive alternatively spliced genes position near nuclear speckle (NS), the ND that enhances splicing efficiency. NS-resident MALAT1 long noncoding RNA, induced in response to hypoxia, regulates hypoxia-responsive AS. MALAT1 achieves this by organizing the SR-family of splicing factor, SRSF1, near NS and regulating the binding of SRSF1 to pre-mRNAs. Mechanistically, MALAT1 enhances the recruitment of SRSF1 to elongating RNA polymerase II (pol II) by promoting the formation of phase-separated condensates of SRSF1, which are preferentially recognized by pol II. During hypoxia, MALAT1 regulates spatially organized AS by establishing a threshold SRSF1 concentration near NSs, potentially by forming condensates, critical for pol II-mediated recruitment of SRSF1 to pre-mRNAs.
Genome-wide analysis of fitness determinants ofStaphylococcus aureusduring growth in milk
Authors: Mårli Marita Torrissen , Nordraak Anne Olsdatter Ohren , de Bakker Vincent , Winther Anja Ruud , Liu Xue , Veening Jan-Willem , Porcellato Davide , Kjos Morten
Published: November 2024

Staphylococcus aureusis a major concern in the dairy industry due to its significance as a pathogen causing bovine mastitis as well as a source of food poisoning. The nutrient-rich milk environment supports bacterial growth, but the specific genetic determinants that facilitateS. aureusproliferation and persistence in milk are poorly understood. In this study, we conducted a genome-wide CRISPR interference sequencing (CRISPRi-seq) screen to identify fitness determinants essential forS. aureusgrowth and survival in milk. We identified 282 milk-essential genes, including those with key roles in DNA replication, protein synthesis, and metabolism. Comparative analysis with brain heart infusion (BHI) as growth medium, revealed 79 genes with differential fitness, highlighting specific adaptations required for growth in milk. Notably, we found that purine biosynthesis, folate cycle pathways, and metal acquisition were particularly important in this environment. Based on this, we further demonstrate thatS. aureusis more sensitive to the folate inhibitors trimethoprim-sulfamethoxazole (TMP-SMX) in milk and identify several genes whose knockdown results in hypersensitivity to TMP-SMX in milk. Additionally, our analysis showed a relatively reduced importance of cell wall components, such as teichoic acids, forS. aureusfitness in milk, which is also reflected in reduced efficiency of antimicrobials targeting teichoic acids. Together, these findings provide new insights into the genetic basis ofS. aureusfitness and antibiotic susceptibility in milk, offering directions for novel treatment strategies against bovine mastitis.
Influenza A Virus H7 nanobody recognizes a conserved immunodominant epitope on hemagglutinin head and confers heterosubtypic protection
Authors: Chen Zhao-Shan , Huang Hsiang-Chi , Wang Xiangkun , Schön Karin , Jia Yane , Lebens Michael , Besavilla Danica F. , Murti Janarthan R. , Ji Yanhong , Sarshad Aishe A. , Deng Guohua , Zhu Qiyun , Angeletti Davide
Published: November 2024

Influenza remains a persistent global health challenge, largely due to the virus’ continuous antigenic drift and shift, which impede the development of a universal vaccine. To address this, the identification of broadly neutralizing antibodies and their epitopes is crucial. Nanobodies, with their unique characteristics and binding capacity, offer a promising avenue to identify such epitopes. Here, we isolated and purified a hemagglutinin (HA)-specific nanobody that recognizes an H7 subtype of influenza A virus. Notably, the nanobody, named E10, exhibited broad-spectrum binding, cross-group neutralization andin vivoprotection across various influenza A subtypes. Through phage display andin vitrocharacterization, we demonstrated that E10 specifically targets an epitope on HA head. This epitope is part of the conserved lateral patch of HA head and proved to be highly immunodominant upon H7 infection. Importantly, immunization with a peptide including the E10 epitope elicited cross-reactive antibodies and mediated partial protection from lethal viral challenge. Our data highlight the potential of E10 and its associated epitope as a candidate for future influenza prevention strategies.