bluuebunny/crossref_metadata_2025 huggingface dataset:
Living in Endemic Area for Infectious Diseases is Associated to Differences in Immunosenescence Signatures
Authors: Coelho Monique Macedo , Moreira Felipe Caixeta , Zuccherato Luciana Werneck , Ventura Lucas Haniel de Araújo , Camatta Giovanna Caliman , Starling-Soares Bernardo , Torres Lícia , Durso Danielle Fernandes , Sato Hugo Itaru , da Costa Murilo Soares , Guimarães Henrique Cerqueira , Barbuto Rafael Calvão , O. Júnior Mauro Lúcio , Speziali Elaine , Tupinambas Unaí , Teixeira Santuza Maria Ribeiro , Silveira-Nunes Gabriela , Teixeira-Carvalho Andrea , Maioli Tatiani Uceli , Faria Ana Maria Caetano
Published: December 2024

Research on aged individuals from developed countries show that lifestyle factors such as diet, physical activity, stress, smoking, and sleep quality impact aging. However, other relevant factors may influence aging in less-studied populations, such as Brazilian cohorts. This study aimed to analyze immunosenescence profile of individuals living in an endemic area for several infectious diseases in Brazil. We showed that these individuals exhibited accelerated epigenetic aging and increased production of IL-12p70, IL-17A, and IL-9. Production of inflammatory mediators IL-12p70, IL-6, IL-1β, IL-2, and IL-1ra in individuals with flu-like symptoms and those with COVID-19 was higher among residents in endemic areas than in residents from a control non-endemic area. Furthermore, residents of the endemic area had a more prominent inflammatory profile during viral infection and a different pattern of plasma mediators when compared to residents of a non-endemic area. It suggests that these two cohorts had specific immune signatures regardless of the presence or the type of infection at study. Therefore, we demonstrated that there were distinct patterns of immune responses and epigenetic aging depending on the environment the individuals live in. These observations add a layer of diversity to the studies of human aging by including less represented individuals.
Changes in Muscle Synergy Structure and Activation Patterns Underlie Force Field Adaptation, Retention, and Generalization
Authors: Herzog Michael , Berger Denise J. , Russo Marta , d’Avella Andrea , Stein Thorsten
Published: December 2024

1

Humans can adapt their motor commands in response to errors when they perform reaching movements in new dynamic conditions, a process called motor adaptation. They acquire knowledge about the new dynamics, which they can use when they are re-exposed and, limitedly, generalize to untrained reaching directions. While force field adaptation, retention, and generalization have been thoroughly investigated at a kinematic and kinetic task level, the underlying coordination at a muscular level remains unclear. Many studies propose that the central nervous system uses low- dimensional control, i.e., coordinates muscles in functional groups: so-called muscle synergies. Accordingly, we hypothesized that changes in muscle synergy structure and activation patterns represent the acquired knowledge underlying force field adaptation, retention, and generalization. To test this, 36 male humans practiced reaching to a single target in a viscous force field and were tested for retention and generalization to new directions, while we simultaneously measured muscle activity from 13 upper-body muscles. We found that muscle synergies used for unperturbed reaching cannot explain the muscle patterns when adapted. Instead, muscle synergies specific to this adapted state were necessary, alongside a novel four-phasic pattern of muscle synergy activation. Furthermore, these structural changes and patterns were also evident during retention and generalization. Our results suggest that reaching in an environment with altered dynamics requires structural changes to muscle synergies compared to unperturbed reaching, and that these changes facilitate retention and generalization. These findings provide new insights into how the central nervous system coordinates the muscles underlying motor adaptation, retention, and generalization.

2

Significance Statement

Humans can adapt their reaching movements to new dynamic conditions. They acquire knowledge about the new dynamics and can use it not only when re-exposed to these conditions but also, in part, to generalize unpracticed reaching directions. While adaptation, retention, and generalization in a force field with new dynamics have been thoroughly investigated at a kinematic and kinetic task level, coordination of the underlying muscles remains elusive. Our results show how muscle synergies - functional groupings of co-activated muscles - underlie adaptation, retention, and generalization. In particular, we observed structural changes in the muscle synergies after adaptation compared to unperturbed reaching. These changes facilitate retention and spatial generalization. Thus, muscle synergies provide new insights into human motor adaptation.
Natural speech re-synthesis from direct cortical recordings using a pre-trained encoder-decoder framework
Authors: Li Jiawei , Guo Chunxu , Chang Edward F. , Li Yuanning
Published: December 2024

Reconstructing perceived speech stimuli from neural recordings is not only advancing the understanding of the neural coding underlying speech processing but also an important building block for brain-computer interfaces and neuroprosthetics. However, previous attempts to directly re-synthesize speech from neural decoding suffer from low re-synthesis quality. With the limited neural data and complex speech representation space, it is hard to build decoding model that directly map neural signal into high-fidelity speech. In this work, we proposed a pre-trained encoder-decoder framework to address these problems. We recorded high-density electrocorticography (ECoG) signals when participants listening to natural speech. We built a pre-trained speech re-synthesizing network that consists of a context-dependent speech encoding network and a generative adversarial network (GAN) for high-fidelity speech synthesis. This model was pre-trained on a large naturalistic speech corpus and can extract critical features for speech re-synthesize. We then built a light-weight neural decoding network that mapped the ECoG signal into the latent space of the pre-trained network, and used the GAN decoder to synthesize natural speech. Using only 20 minutes of intracranial neural data, our neural-driven speech re-synthesis model demonstrated promising performance, with phoneme error rate (PER) at 28.6%, and human listeners were able to recognize 71.6% of the words in the re-synthesized speech. This work demonstrates the feasibility of using pre-trained self-supervised model and feature alignment to build efficient neural-to-speech decoding model.
GenePioneer: A Comprehensive Python Package for Identification of Essential Genes and Modules in Cancer
Authors: Taheri Golnaz , Haerianardakani Amirhossein
Published: December 2024

We propose a network-based unsupervised learning model to identify essential cancer genes and modules for 12 different cancer types, supported by a Python package for practical application. The model constructs a gene network from frequently mutated genes and biological processes, ranks genes using topological features, and detects critical modules. Evaluation across cancer types confirms its effectiveness in prioritizing cancer-related genes and uncovering relevant modules. The Python package allows users to input gene lists, retrieve rankings, and identify associated modules. This work providing a robust method for gene prioritization and module detection, along with a user-friendly package to support research and clinical decision-making in cancer genomics.

Availability

GenePioneeris released as an open-source software under the MIT license. The source code is available on GitHub athttps://github.com/Golnazthr/ModuleDetection

Contact

golnazt@kth.seandhaerian.amirhossein@gmail.com
Distinct representational properties of cues and contexts shape fear learning and extinction
Authors: Bouyeure Antoine , Pacheco Daniel , Fellner Marie-Christin , Jacob George , Kobelt Malte , Rose Jonas , Axmacher Nikolai
Published: December 2024

Extinction learning does not erase previously established memories but inhibits the expression of fear by the formation of new memory traces that are strongly context-dependent. Previous human neuroimaging studies using representational similarity analysis revealed several core properties of memory traces during fear learning, including their tendency to generalize beyond the initial context – a process described as “cue generalization” – and their reliance on sensory rather than conceptual representational formats. How fear memories are altered during extinction learning, however, remains largely unknown. To address this question, we used a novel experimental paradigm involving multiple cues and contexts in each experimental phase, which allowed us to disentangle the effect of contingency changes (i.e., reversal learning) from the disappearance of unconditioned stimuli during extinction learning. Our data show that contingency changes during reversal induce memory traces with distinct representational geometries characterized by stable activity patterns across repetitions in the precuneus, which interact with specific context representations in medial and lateral prefrontal cortex. The representational geometries of these traces differ strikingly from the generalized patterns established during initial fear learning and persist in the absence of an unconditioned stimulus during extinction. Interestingly, increased levels of prefrontal context specificity predict the subsequent reinstatement of fear memory traces, providing a possible mechanistic explanation for the clinical phenomenon of fear renewal. Our findings show that contingency changes induce novel memory traces with distinct representational properties that are reminiscent to those observed during episodic memory formation and contrast with the generalized representations of initial fear memories. These results shed new light on the neural mechanisms underlying the malleability of memories that support cognitive flexibility, and contribute to conceptual frameworks of extinction learning during the treatment of anxiety disorders.
WITHDRAWN: CPP Translocation in Haptophyte Species
Authors: Gorrie David
Published: December 2024

Withdrawal Statement

The authors have withdrawn this manuscript because it requires extensive revision before submission (see "shortcomings" section). Additionally, some of those acknowledged insist on authorship. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, don’t hesitate to contact the corresponding author.
In silico discovery of potential inhibitors targeting the MEIG1-PACRG complex for male contraceptive development
Authors: Hasse Timothy , Zhang Zhibing , Huang Yu-ming M.
Published: December 2024

The interaction between meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) is a critical determinant of spermiogenesis, the process by which round spermatids mature into functional spermatozoa. Disruption of the MEIG1-PACRG complex can impair sperm development, highlighting its potential as a therapeutic target for addressing male infertility or for the development of non-hormonal contraceptive methods. This study used virtual screening, molecular docking, and molecular dynamics (MD) simulations to identify small molecule inhibitors targeting the MEIG1-PACRG interface. MD simulations provided representative protein conformations, which were used to virtually screen a library of over 800,000 compounds, resulting in 48 high-ranking candidates for each protein. PACRG emerged as a favorable target due to its flexible binding pockets and better docking scores compared to MEIG1. Key binding residues with compounds included W50, Y68, N70, and E74 on MEIG1, and K93, W96, E101, and H137 on PACRG. MD simulations revealed that compound stability in MEIG1 complexes is primarily maintained by hydrogen bonding with E74 and π-π stacking interactions with W50 and Y68. In PACRG complexes, compound stabilization is facilitated by hydrogen bonding with E101 and π-π interactions involving W96 and H137. These findings highlight distinct molecular determinants of ligand binding for each protein. Our work provides mechanistic insights and identifies promising compounds for further experimental validation, establishing a foundation for developing MEIG1-PACRG interaction inhibitors as male contraceptives.
Formulation, Characterization, andin vivoImmunogenicity of Heat-Stabilized Dissolvable Microneedles Containing a Novel VLP Vaccine
Authors: Leyba Aidan , Francian Alexandra , Razjmoo Mohammad , Bierle Amelia , Janardhana Ranjith , Jackson Nathan , Chackerian Bryce , Muttil Pavan
Published: December 2024

Since its introduction, vaccination has heavily improved health outcomes. However, implementing vaccination efforts can be challenging, particularly in low and middle-income countries with warmer climates. Microneedle technology has been developed for its simple and relatively painless applications of vaccines. However, no microneedle vaccine has yet been approved by the FDA. A few hurdles must be overcome, including the need to evaluate the safety and biocompatibility of the polymer used to fabricate these microneedles. Additionally, it is important to demonstrate reliable immune responses comparable to or better than those achieved through traditional administration routes. Scalability in manufacturing and the ability to maintain vaccine potency during storage and transportation are also critical factors. In this study, we developed vaccine-loaded dissolvable microneedles that showed preclinical immunogenicity after storage in extreme conditions. We developed our microneedles using the conventional micromolding technique with polyacrylic acid (PAA) polymer, incorporating a novel virus-like particle (VLP) vaccine targeting arboviruses. We performed characterization studies on these microneedles to assess needle sharpness, skin insertion force, and VLP integrity. We also investigated the thermostability of the vaccine after storing the microneedles at elevated temperatures for approximately 140 days. Finally, we evaluated the immunogenicity of this vaccine in mice, comparing transdermal (microneedle) with intramuscular (hypodermic needle) administration. We successfully fabricated and characterized VLP-loaded microneedles that could penetrate the skin and maintain vaccine integrity even after exposure to extreme storage conditions. These microneedles also elicited robust and long-lasting antibody responses similar to those achieved with intramuscular administration.
Genome sequence of the ornamental plantAquilegia vulgarisreveals the flavonoid biosynthesis gene repertoire
Authors: Friedhoff Ronja , Wolff Katharina , Pucker Boas
Published: December 2024

Aquilegia vulgarisis a widespread ornamental plant. The species is well known for a huge variation of different flower colors and can even be considered as a model species for the evolution of flower morphology. Anthocyanins are a major pigment group responsible for pigmentation of flowers inA. vulgarisand many plant species. Here, we report a highly continuous genome sequence of a EuropeanAquilegia vulgarisplant displaying purple flowers. The corresponding annotation facilitates research on flower color and morphology evolution. Candidate genes for all steps in the core anthocyanidin biosynthesis were identified and investigated with respect to their expression in different seedling parts. The discovery of a flavonoid 3’5’ hydroxylase (F3’5’H), a gene required for the biosynthesis bluish delphinidin derivatives, matches previous reports about metabolites and transcripts inA. vulgaris.
Capturing the Conformational Heterogeneity of HSPB1 Chaperone Oligomers at Atomic Resolution
Authors: Berkeley Raymond F. , Plonski Alexander P. , Phan Tien , Grohe Kristof , Becker Lukas , Wegner Sebastian , Herzik Mark A. , Mittal Jeetain , Debelouchina Galia T.
Published: December 2024

Small heat shock proteins (sHSPs), including HSPB1, are essential regulators of cellular proteostasis that interact with unfolded and partially folded proteins to prevent aberrant misfolding and aggregation. These proteins fulfill a similar role in biological condensates, where they interact with intrinsically disordered proteins to modulate their liquid-liquid and liquid-to-solid phase transitions. Characterizing sHSP structure, dynamics, and client interactions is challenging due to their partially disordered nature, their tendency to form polydisperse oligomers, and their diverse range of clients. In this work, we leverage various biophysical methods, including fast1H-based magic angle spinning (MAS) NMR spectroscopy, molecular dynamics (MD) simulations and modeling, to shed new light on the structure and dynamics of HSPB1 oligomers. Using split-intein mediated segmental labeling, we provide unambiguous evidence that in the oligomer context the N-terminal domain (NTD) of HSPB1 is rigid and adopts an ensemble of heterogenous conformations, the α-crystallin domain (ACD) forms dimers and experiences multiple distinct local environments, while the C-terminal domain (CTD) remains highly dynamic. Our computational models suggest that the NTDs participate in extensive NTD-NTD and NTD-ACD interactions and are sequestered within the oligomer interior. We further demonstrate that HSPB1 higher order oligomers disassemble into smaller oligomeric species in the presence of a client protein and that an accessible NTD is essential for HSPB1 partitioning into condensates and interactions with client proteins. Our integrated approach provides a high-resolution view of the complex oligomeric landscape of HSPB1 and sheds light on the elusive network of interactions that underly HSPB1 function in biological condensates.

Significance statement

HSPB1 is a ubiquitous cellular chaperone that helps prevent the aberrant aggregation of intrinsically disordered proteins involved in biological condensates and neurodegenerative diseases. Despite its central role in this process, many aspects of HSPB1’s structure and interactions with clients are not well understood due to its tendency to form polydisperse oligomeric structures and to function in heterogeneous condensate environments. Here, we present an integrated approach that includes segmental labeling, fast MAS NMR spectroscopy, and computational tools to characterize the structure and dynamics of HSPB1 in its oligomeric form and within client condensates at high resolution. Our approach, which is applicable to other complex biological systems, highlights the important role of HSPB1’s N-terminal domain in oligomeric assembly and interactions with clients.
Confinement stress with movement restriction suppresses male courtship inDrosophilathrough dopamine-dependent neuroplasticity
Authors: Sato Tomohito , Toyama Rana , Kitamoto Toshihiro , Sakai Takaomi
Published: December 2024

Stress disturbs the physiological and psychological balance in animals, leading to changes in brain function. Here, we show that stress in a small space with movement restriction (SS stress) suppresses male courtship inDrosophilaand that alterations in dopamine signaling induced by SS stress are responsible for the persistence of this suppression after the stress experience. We found that SS stress activates numerous dopamine neurons in the brain. Pharmacological and genetic analyses revealed that dopamine synthesis, release, and reception are essential for the persistence of SS-stress-induced courtship suppression. A specific subset of dopamine neurons projects to the mushroom body (MB), a brain region where various sensory inputs are integrated. We identified that SS-stress-induced dopamine release plastically depresses the activity of a subset of MB neurons, and this neuronal depression contributes to the sustained suppression of male courtship behavior following stress exposure. This novel stress model usingDrosophilaprovides valuable insights into dopamine-mediated stress mechanisms, particularly those related to confined spaces.
Dual roles of IQCG, a novel microtubule nucleation factor rapidly evolving in humans
Authors: Liu Xingtang , Wu Yongzhen , He Xia , Shen Yuan , Fu Wenxiang , Hu Haiyang , Yu Haijing
Published: December 2024

The centrosome serves as the main microtubule-organizing structure, playing crucial roles in animal development. Uncovering new components and elucidating their functions helps to understand the regulation of cell maintenance and division by the centrosome. In this study, through a combination of genetic analyses and cell biological characterizations, we identify IQ Motif Containing G (IQCG) as a novel microtubule nucleation factor with a dual role involved in both centrosomal microtubule organization and mitotic spindle formation. IQCG interacts with GSK3β via its N2 region, enhancing its centrosomal accumulation in interphase; subsequently, IQCG disperses into the spindle to promote microtubule generation during mitosis and ensure robust cell division. Furthermore, our analyses indicate that theIQCGgene has undergone accelerated evolution within the human lineage, with positive selection acting on the variable N2 region. This adaptation may confer advantages to human cells by augmenting central regulatory control over cellular activities through the centrosome. Our findings offer novel insights into the functional mechanisms and evolutionary significance of the human centrosome associated with human evolution.

Summary blurb

The cellular functions of the novel microtubule nucleation factor IQCG, which enhances centrosomal microtubule organization and cell division robustness, are implicated in human evolution.
Automated abstraction of clinical parameters of multiple myeloma from real-world clinical notes using large language models
Authors: Del Campo Alana O’Brien , Lituiev Dmytro , Varma Gowtham , Manoharan Mithun , Ravi Sunil Kumar , Aman Avinash , Kansagra Ankit , Greshock Joel , Venkatakrishnan AJ , Batavia Ashita
Published: December 2024

Background

Real-world evidence (RWE) is increasingly recognized as a valuable type of oncology research but extracting fit-for-purpose real-world data (RWD) from electronic health records (EHRs) remains challenging. Manual abstraction from free-text clinical documents, although the gold standard for information extraction, is resource-intensive. RWD generation using natural language processing (NLP) has been limited by performance ceilings and annotation requirements, which recent LLMs improve on. We evaluate new NLP workflows in abstracting multiple myeloma (MM) information from de-identified EHRs.

Methods

NLP workflows (BERT and Llama-based using various prompt types) were developed for 12 MM-specific data fields and evaluated with manually curated data from 125 clinical notes. The best Llama-based workflow for three data fields was applied to all recent notes in selected charts to generate patient journey timelines.

Results

Average F1for the best Llama and BERT workflows was 0.82 and 0.65 respectively. Best workflow performance ranged across the data fields (F1= 0.59–0.99). Statistical analysis of the results showed model size, inter-rater reliability (IRR), variable type, and prompt design significantly predicted workflow performance, in descending order of significance (p< 0.05).

Conclusion

The overall performance improvements seen with larger LLMs and chain-of-thought prompting was greater in ambiguous data fields. IRR can be used to prioritize NLP resources and increase efficiency of RWD generation without sacrificing data quality.
HieVi: Protein Large Language Model for proteome-based phage clustering
Authors: Panigrahi S. , Ansaldi M. , Ginet N.
Published: December 2024

Viral taxonomy is a challenging task due to the propensity of viruses for recombination. Recent updates from the ICTV and advancements in proteome-based clustering tools highlight the need for a unified framework to organize bacteriophages (phages) across multiscale taxonomic ranks, extending beyond genome-based clustering. Meanwhile, self-supervised large language models, trained on amino acid sequences, have proven effective in capturing the structural, functional, and evolutionary properties of proteins. Building on these advancements, we introduce HieVi, which uses embeddings from a protein language model to define a vector representation of phages and generate a hierarchical tree of phages. Using the INPHARED dataset of 24,362 complete and annotated viral genomes, we show that in HieVi, a multi-scale taxonomic ranking emerges that aligns well with current ICTV taxonomy. We propose that this method, unique in its integration of protein language models for viral taxonomy, can encode phylogenetic relationships, at least up to the family level. It therefore offers a valuable tool for biologists to discover and define new phage families while unraveling novel evolutionary connections.
Comparative atlas of genome-wide chromatin-associated protein co-occupancy
Authors: White Shannon M. , Moyers Belle A. , Wang Tao , Mackiewicz Mark , Weimer Annika K. , Grubert Fabian , Ramalingam Vivekanandan , Luo Jay X. J. , Jiang Lixia , Shi Minyi , Yang Xinqiong , Chou Tristan , Zhai Jie , Von Kraut Konor , Adrian Jessika , Partridge E. Christopher , Paul Kristina , Kundaje Anshul , Mendenhall Eric M. , Myers Richard M. , Snyder Michael P.
Published: December 2024

Accurate transcriptional regulation and chromatin dynamics requires the coordination and activity of chromatin-associated proteins (CAPs) at distinct loci. While the combinatorial activity of a select set of CAPs has been previously examined, these studies are limited by the underrepresentation of proteins and cell types explored, making it difficult to identify the global associations as well as the conservation of these associations across different cell types. Here, we performed 270 CAP chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) experiments in both K562 and HepG2 cancer cell lines and explored the relationship between cell identity and CAP co-association using three distinct approaches. We employed a machine learning algorithm to organize the genome-wide binding profiles into 56 and 70 interpretable co-association modules for HepG2 and K562 cell lines, respectively. We found CAP co-association modules are mostly cell type-specific, however those present in both cell lines are largely comprised of TFs from a single TF family and anchor to unique loci via lineage-specific factors. While enhancer-associated co-binding modules were largely composed of cell type-specific CAPs, we found regulatory activity at promoter-enhancer module contacts to be enriched for chromatin remodeling proteins. Additionally, we used colocalization information derived from co-association models in conjunction with neural network models of transcription factor (TF) activity to identify high-confidence candidate TF cooperative pairs. Finally, through comparing CAP enrichment in high occupancy target (HOT) regions in K562 and HepG2 cell lines, we found cell type-specific HOT sites, but not common HOT sites, are selectively enriched at high copy number loci. Overall, this study uncovers principles of sequence-level and large-scale CAP genomic organization and demonstrates how this contributes to cell type-specific regulatory mechanisms and cellular functions.
Lost to science for 126 years: Indigenous Knowledge and Camera Trapping Document the Critically Endangered Black-Naped Pheasant-PigeonOtidiphaps insularis
Authors: Gregg Jason J. , Boersma Jordan , Nason Doka , Malesa Elimo , Le Breton Cosmo , Ketaloya Serena , Iova Bulisa , Mittermeier John C.
Published: December 2024

We combined questionnaires collecting local ecological knowledge with passive and directed camera trapping and bird surveys to scientifically document the Black-Naped Pheasant-PigeonOtidiphaps insularisfor the first time since 1896. This species is endemic to Fergusson Island, in eastern Papua New Guinea, and is New Guinea’s most endangered terrestrial bird species. Indigenous subsistence-based hunters who participated in this research as informants had high levels of local bird knowledge and helped direct camera trapping for one of two successful camera trap captures. Local participants also shared traditional ecological knowledge about the Black-Naped Pheasant-Pigeon, including legends, chants, and a local name for this taxon, Auwo. The scarcity of observations over the course of a month-long expedition, its obscurity to the majority of local respondents interviewed, and prevalent threats from habitat destruction and introduced alien species further support its current Red List status (CR). Our results provide a case study for leveraging local ecological knowledge in combination with standardized survey techniques and may be an especially effective strategy for determining the status of other undocumented or data-deficient species in the southwest Pacific.
CD38 biallelic loss is a recurrent mechanism of resistance to anti-CD38 antibodies in multiple myeloma
Authors: Diamond Benjamin , Baughn Linda , Poorebrahim Mansour , Poos Alexandra M. , Lee Holly , Kaddoura Marcella , Wiedmeier-Nutor J. Erin , Durante Michael , Otteson Gregory , Jevremovic Dragan , Tang Hongwei , Fröhling Stefan , Baertsch Marc A. , Papadimitriou Marios , Ziccheddu Bachisio , Jelinek Tomas , Lemoine Cendrine , Rak Alexey , Green Damian J. , Landgren Ola , Neri Paola , Bergsagel Leif , Braggio Esteban , Kumar Shaji , Raab Marc S. , Fonseca Rafael , Bahlis Nizar , Weinhold Niels , Maura Francesco
Published: December 2024

Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of theCD38gene locus. Here, by using whole genome and whole exome sequencing data from 701 newly diagnosed patients, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse following anti-CD38 antibodies. We report a loss of CD38 in 20% (10/50) of patients post-CD38 therapy, three of which exhibited a loss of both copies. Two of these cases showed convergent evolution where distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that two variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies Daratumumab and Isatuximab. However, a third mutation, R140G, conferred selective resistance to Daratumumab, while retaining sensitivity to Isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies following disease progression and these data support a role for next generation sequencing to guide treatment selection.
All-at-once RNA folding with 3D motif prediction framed by evolutionary information
Authors: Karan Aayush , Rivas Elena
Published: December 2024

Structural RNAs exhibit a vast array of recurrent short 3D elements involving non-Watson-Crick interactions that help arrange canonical double helices into tertiary structures. We present CaCoFold-R3D, a probabilistic grammar that predicts these RNA 3D motifs (also termed modules) jointly with RNA secondary structure over a sequence or alignment. CaCoFold-R3D uses evolutionary information present in an RNA alignment to reliably identify canonical helices (including pseudoknots) by covariation. We further introduce the R3D grammars, which also exploit helix covariation that constrains the positioning of the mostly non-covarying RNA 3D motifs. Our method runs predictions over an almost-exhaustive list of over fifty known RNA motifs (everything). Motifs can appear in any non-helical loop region (including 3-way, 4-way and higher junctions) (everywhere). All structural motifs as well as the canonical helices are arranged into one single structure predicted by one single joint probabilistic grammar (all-at-once). Our results demonstrate that CaCoFold-R3D is a valid alternative for predicting the all-residue interactions present in a RNA 3D structure. Furthermore, CaCoFold-R3D is fast and easily customizable for novel motif discovery.

Availability

The source code can be downloaded from the websiterivaslab.org, the githttps://github.com/EddyRivasLab/R-scape, as well as from the supplementary materials associated to this manuscript.

Supplementary information

Supplementary materials (data and code) are provided with this manuscript, and atrivaslab.org.
Assessment of cortical excitability in awake rhesus macaques with transcranial magnetic stimulation: translational insights from recruitment curves
Authors: Padányi Anna , Knakker Balázs , Lendvai Balázs , Hernádi István
Published: December 2024

Background and objectives

Cortical excitability (CE) is commonly assessed by recording motor evoked potentials (MEPs) in response to single-pulse transcranial magnetic stimulation (sp-TMS). While the motor threshold (MT) remains the most widely used measure of CE, it provides a one-dimensional, criterion-based assessment. In contrast, the recruitment curve (RC) offers a more comprehensive characterization of the full dynamics of cortical recruitment. Yet, only a few preclinical studies involving translationally relevant non-human primates were conducted, and most were under anaesthesia. Hence, we aimed to characterise CE in awake rhesus macaques by recording traditionally defined MT and RCs.

Methods

Traditional MT with a 100 µV MEP criterion (‘tradMT’) was measured in 8 awake adult male rhesus macaques using C-B65 coil and MagVenture stimulator. RCs were recorded at nine relative intensity levels (0.5 – 1.5 × tradMT) in 4 macaques. A sigmoid function was fitted to obtain key CE parameters: the inflection point, lower ankle point, and plateau.

Results

TradMT values were stable and replicable, and aligned most closely with the inflection point of the RC. The lower ankle points were found around at 0.9 × tradMT, marking the transition from a constant to a logarithmic phase, representing a physiologically relevant threshold. Plateau MEP amplitudes were substantially smaller compared to those reported in humans.

Conclusion

Fitted RC parameters revealed a distinction between tradMT and the physiologically relevant threshold. The overall RC shape was consistent with human data, suggesting similar recruitment processes, leading to high translational validity. However, the marked difference in maximal MEP magnitude emphasises the importance of species-specific adaptations.
Temporally overlapping mechanisms diversify clonal B cell responsesin vivo
Authors: Skinner Oliver P. , Asad Saba , Moreira Marcela L. , Lee Hyun Jae , Williams Cameron G. , Li Shihan , Jin Wang , Steiner Thiago M. , Asatsuma Takahiro , Lim Jorene , Ruan Zheng , Soon Megan S.F. , Engel Jessica A. , Khoury David S. , Tuong Zewen Kelvin , King Hamish W. , Haque Ashraful
Published: December 2024

Single naive B cells amplify and diversify their responses when activated by cognate antigen, via Myc-dependent clonal expansion, immunoglobulin class switch recombination (CSR), phenotypic variation, and somatic hypermutation (SHM). Whether these mechanisms act combinatorially in vivo to diversify clonal responses to a single complex pathogen remains unclear. Since diversity in the antigenic targets, functional classes, and production kinetics of parasite-specific antibodies influences immunity to malaria, we test here whether individual B cell clones diversify over time during Plasmodium infection and treatment. During the first week of infection, amid widespread Type I Interferon (IFN)-mediated, bystander activation, CSR initiates soon after Myc up-regulation. CSR then overlaps with clonal expansion, resulting in isotype variegation amongst certain clones. In the second week of infection, expanded clones seeding germinal centres (GC) both bifurcate into extra-follicular plasmablasts and exhibit isotype variegation, revealing substantial intra-clonal diversification. Over the following month, GC clones undergo SHM at approximately four mutations per week, with IgG mutational diversity and IgM+cells preserved in GCs over time. Anti-malarial intervention does not impede SHM, but instead exerts quantitative limits on GC size, plasma cell emergence and circulating antibody titres. Finally, we reveal a contemporaneous B cell developmental pathway that relocates from bone marrow to the spleen during infection and treatment. Thus, multiple temporally overlapping mechanisms combine in vivo to amplify, diversify, and safeguard humoral immune responses.

Graphical abstract

Highlights

Early temporal overlap of CSR with clonal expansion leads to isotype variegation in clones.

Clones seeding GCs bifurcate into plasmablasts and exhibit isotype variegation.

GC B cells accrue mutations at rates unaffected by anti-malarials.

Plasmodiuminfection triggers antigen-independent Type I IFN-mediated bystander activation.

B cell development is preserved in malaria by shifting from bone marrow to spleen.
Lotus japonicusVIH2 is an inositol pyrophosphate synthase that regulates arbuscular mycorrhiza
Authors: Raj Kiran , Gaugler Verena , Lu Mengsi , Schädel Maren , Gaugler Philipp , Grothaus Charlotte M. M. , Jochimsen Ulrike A. , Liu Guizhen , Harings Michael , Jessen Henning J. , Schaaf Gabriel , Ried-Lasi Martina K.
Published: December 2024

Plant yield is often maximized by the extensive use of mineral fertilizers, which, however, has severe environmental consequences. Phosphate is particularly problematic, as it represents a globally limited resource, and its runoff and soil erosion threaten open water bodies. Many crops engage in arbuscular mycorrhizal (AM) symbiosis with nutrient-acquiring fungi, aiding in the uptake of phosphate and other mineral nutrients. However, AM colonization is strongly reduced under high soil phosphate levels. A mechanistic understanding of phosphate sensing, phosphate starvation responses, and their connection to AM remains enigmatic. Here, we show that inLotus japonicus, low-abundant, energy-rich inositol pyrophosphates act as master regulators of AM, orchestrating the crosstalk between phosphate starvation responses and plant root endosymbiosis. These findings hold promise for breeding nutrient-efficient crops.
The invasions ofAedes aegyptiandAedes albopictusin Cyprus: current situation, risk modelling and public health implications for the wider Eastern Mediterranean region
Authors: Caminade Cyril , Vasquez Marlen I. , Herodotou Herodotos , Notarides Gregoris , Pavlou Costas , Fayad Filip , Papakonstantinou Apostolos , Violaris Marios , Petric Dusan , Mamai Wadaka , Tompkins Adrian M. , Bouyer Jeremy
Published: December 2024

The Asian tiger mosquito,Aedes albopictusand the yellow fever mosquito,Aedes aegyptihave been spreading worldwide and are reshaping the distribution of arboviruses. BothAedesspecies have recently been observed in densely populated cities of Cyprus, a touristic island that is a historic bridge between Europe and Asia. Given the high public health stakes for Cyprus and the wider East Mediterranean region, the objectives of this study are three-fold. First, we present a novel delimitation strategy using spatially dense networks of ovitraps deployed in 500×500m cells in Limassol and Larnaca following the detection ofAedesspecies. Second, we use a dynamical vector model to estimate the potential of both species to spread further over Cyprus. Finally, we employ a basic reproduction number (R0) model to assess the potential transmission risk of arboviruses for the wider East Mediterranean region. Our results underline our delimitation strategy’s usefulness in delineatingAe. albopictuspopulations in Limassol and indicate the need for increased surveillance efforts forAe. aegyptiin Larnaca. Our vector model reveals that cities such as Nicosia, Paphos and Ayia Napa are climatically suitable for the establishment of bothAe. aegyptiandAe. albopictus. Finally, the R0model captures historical hotspots of dengue transmission over the East Mediterranean region, with large R0values simulated over Cyprus, Greece, Turkey, southern Italy and southern Spain. We recommend stringent vector surveillance at entry points in Greece and a rapid elimination in Cyprus to prevent the return ofAe. aegyptito the European continent.
Pro-Inflammatory Molecules Implicated in Multiple Sclerosis Divert the Development of Human Oligodendrocyte Lineage Cells
Authors: Blaszczyk Gabriela J. , Mohammadnia Abdulshakour , Piscopo Valerio E. C. , Sirois Julien , Cui Qiao-Ling , Yaqubi Moein , Durcan Thomas M. , Schneider Raphael , Antel Jack P.
Published: December 2024

Background and Objectives

Oligodendrocytes (OL) and their myelin-forming processes are targeted and lost during the disease course of Multiple Sclerosis (MS), targeted by infiltrating leukocytes and their effector cytokines. Myelin repair is considered to be dependent on recruitment and differentiation of oligodendrocyte precursor cells (OPCs). The basis of failure of re-myelination during the disease course of MS remains to be defined. The aim of this study is to determine the impact of pro-inflammatory molecules tumor necrosis factor ⍰ (TNF⍰) and interferon gamma (IFNγ) on the differentiation of human OPCs.

Methods

We generated human OPCs from induced pluripotent stem cells with a reporter gene under the OL-specific transcription factor SOX10. We treated the cellsin vitrowith TNF⍰ or IFNγand evaluated effects in terms of cell viability, expression of OL-lineage markers, and co- expression of astrocyte markers. To relate our findings to the molecular properties of OPCs as found in the MS brain we re-analyzed publicly available single nuclear RNAseq datasets.

Results

Our analysis indicated that both TNF⍰ and IFNγdecreased the proportion of cells differentiating into the OL-lineage; consistent with previous reports. We now observe the TNF⍰ effect is linked to aberrant OPC differentiation. A subset of O4+, reporter-positive cells co- expressed the astrocytic marker Aquaporin-4 (AQP4). On the transcriptomic level, the cells acquire an astrocyte-like signature alongside a conserved reactive phenotype. Analysis of single- nuclear RNAseq datasets from human MS brain revealed a subset of OPCs expressing an astrocytic signature.

Discussion

In the context of MS, these results imply that OPCs are present but inhibited from differentiating along the OL-lineage, with a subset acquiring a reactive and stem-cell like phenotype, reducing their capacity to contribute towards repair. These findings help define a potential basis for the impaired myelin repair in MS and provide a prospective route for regenerative treatment.
In vitrobiofilm formation only partially predicts beneficialPseudomonas fluorescensprotection against rhizosphere pathogens
Authors: Liu Yang , Gates Alexandra D. , Liu Zhexian , Duque Quinn , Chen Melissa Y. , Hamilton Corri D. , O’Toole George A. , Haney Cara H.
Published: December 2024

Plant roots form associations with both beneficial and pathogenic soil microorganisms. While members of the rhizosphere microbiome can protect against pathogens, the mechanisms are poorly understood. We hypothesized that the ability to form a robust biofilm on the root surface is necessary for the exclusion of pathogens; however, it is not known if the same biofilm formation components requiredin vitroare necessaryin vivo. Pseudomonas fluorescensWCS365 is a beneficial strain that is phylogenetically closely related to an opportunistic pathogenP. fluorescensN2C3 and confers robust protection againstP. fluorescensN2C3 in the rhizosphere. We used this plant-mutualist-pathogen model to screen collections ofP. fluorescensWCS365 increasedattachmentmutants (iam) andsurfaceattachmentdefective (sad) transposon insertion mutants that form increased or decreased levels of biofilm on an abiotic surface, respectively. We found that while theP. fluorescensWCS365 mutants had altered biofilm formationin vitro, only a subset of these mutants, including those involved in large adhesion protein (Lap) biosynthesis, flagellin biosynthesis and O-antigen biosynthesis, lost protection againstP. fluorescensN2C3. We found that the inability ofP. fluorescensWCS365 mutants to growin planta, and the inability to suppress pathogen growth, both partially contributed to loss of plant protection. We did not find a correlation between the extent of biofilm formedin vitroand pathogen protectionin plantaindicating that biofilm formation on abiotic surfaces may not fully predict pathogen exclusionin planta. Collectively, our work provides insights into mechanisms of biofilm formation and host colonization that shape the outcomes of host-microbe-pathogen interactions.
De novoevolution of antibiotic resistance to Oct-TriA1
Authors: Chowdhury Farhan R. , Mercado Laura Domínguez , Kharitonov Katya , Findlay Brandon L.
Published: December 2024

The rise of antimicrobial resistance as a global health concern has led to a strong interest in compounds able to inhibit the growth of bacteria without detectable levels of resistance evolution. A number of these compounds have been reported in recent years, including the tridecaptins, a small family of lipopeptides typified by the synthetic analogue octyl-tridecaptin A1. Hypothesizing that prior reports of negligible resistance evolution have been due in part to limitations in the laboratory evolution systems used, we have attempted to select for resistant mutants using a soft agar gradient evolution (SAGE) system developed by our lab. Following optimization of the media conditions by incorporation of the anti-synaeresis agent xanthan gum into the agar matrix, we successfully evolved high-level resistance to both octyl-tridecaptin A1as well as the challenging lipopeptide antibiotic polymyxin B. Decreased tridecaptin susceptibility was linked to mutations in outer membrane proteinsompC,lptDandmlaA, with the effect of these genes confirmed through a mix of allelic replacement and knockout studies. Overall, this work demonstrates the robust evolutionary potential of bacteria, even in the face of challenging antimicrobial agents.
Predictive Modeling of Gene Expression and Localization of DNA Binding Site Using Deep Convolutional Neural Networks
Authors: Karshenas Arman , Röschinger Tom , Garcia Hernan G.
Published: December 2024

Despite the sequencing revolution, large swaths of the genomes sequenced to date lack any information about the arrangement of transcription factor binding sites on regulatory DNA. Massively Parallel Reporter Assays (MPRAs) have the potential to dramatically accelerate our genomic annotations by making it possible to measure the gene expression levels driven by thousands of mutational variants of a regulatory region. However, the interpretation of such data often assumes that each base pair in a regulatory sequence contributes independently to gene expression. To enable the analysis of this data in a manner that accounts for possible correlations between distant bases along a regulatory sequence, we developed the Deep learning Adaptable Regulatory Sequence Identifier (DARSI). This convolutional neural network leverages MPRA data to predict gene expression levels directly from raw regulatory DNA sequences. By harnessing this predictive capacity, DARSI systematically identifies transcription factor binding sites within regulatory regions at single-base pair resolution. To validate its predictions, we benchmarked DARSI against curated databases, confirming its accuracy in predicting transcription factor binding sites. Additionally, DARSI predicted novel unmapped binding sites, paving the way for future experimental efforts to confirm the existence of these binding sites and to identify the transcription factors that target those sites. Thus, by automating and improving the annotation of regulatory regions, DARSI generates experimentally actionable predictions that can feed iterations of the theory-experiment cycle aimed at reaching a predictive understanding of transcriptional control.