bluuebunny/crossref_metadata_2025 huggingface dataset:
Binning meets taxonomy: TaxVAMB improves metagenome binning using bi-modal variational autoencoder
Authors: Kutuzova Svetlana , Piera Pau , Nor Nielsen Knud , Olsen Nikoline S. , Riber Leise , Gobbi Alex , Forero-Junco Laura Milena , Dougherty Peter Erdmann , Westergaard Jesper Cairo , Christensen Svend , Hansen Lars Hestbjerg , Nielsen Mads , Nissen Jakob Nybo , Rasmussen Simon
Published: October 2024

A common procedure for studying the microbiome is binning the sequenced contigs into metagenome-assembled genomes. Currently, unsupervised and self-supervised deep learning based methods using co-abundance and sequence based motifs such as tetranucleotide frequencies are state-of-the-art for metagenome binning. Taxonomic labels derived from alignment based classification have not been widely used. Here, we propose TaxVAMB, a metagenome binning tool based on semi-supervised bi-modal variational autoencoders, combining tetranucleotide frequencies and contig co-abundances with contig annotations returned by any taxonomic classifier on any taxonomic rank. TaxVAMB outperforms all other binners on CAMI2 human microbiome datasets, returning on average 40% more near-complete assemblies than the next best binner. On real long-read datasets TaxVAMB recovers on average 13% more near-complete bins and 14% more species. When used in a single-sample setup, TaxVAMB on average returns 83% more high quality bins than VAMB. TaxVAMB bins incomplete genomes drastically better than any other tool, returning 255% more high quality bins of incomplete genomes than the next best binner. Our method has immediate research and industrial applications, as well as methodological novelty which can be translated to other biological problems with semi-supervised multimodal datasets.
Agroforestry adoption and its influence on soil quality under smallholder maize production systems in western Kenya
Authors: Nyuma H.T , Njoroge R , Otinga A.N
Published: October 2024

Agroforestry, a sustainable land use practice was-introduced in western Kenya in the early 1990’s as a soil fertility replenishment strategy alongside other multiple benefits. Since then, effect of the practice on soil quality is seldom evidenced. Therefore, a study was conducted in the region to assess the effects of agroforestry adoption on soil quality under small holder maize production systems. A total of 120 soil samples were collected from two land use practices: agroforestry adoption (90) and non-agroforestry adoption (30) at 0-30 cm depth from two locations (Busia and Kakamega counties). On average, adoption of agroforestry significantly improved soil physicochemical properties compared to non-adoption of agroforestry. Bulk density (BD) reduced by 21% (from 1.4 to1.1g cm−3)while SOC increased by 75% (0.8-1.4%), P by 80% (3.0-5.4 mg kg−1), exchangeable K+by 256% (0.3-8.0 Cmolc kg−1), Ca2+by 100% (1.0-2.0 Cmolc kg−1), S by 50%(0.2-0.3 mg kg−1), and Cu by 18% (2.8-3.3 mg kg−1).In reference to the soil environmental requirement for maize production, agroforestry adoption significantly increased K and Cu above the critical thresholds of 0.4 Cmolc kg−1and 1.0 mg kg−1, respectively regardless of the study location or adoption practice. In addition, different agroforestry tree species had variable effect on soil properties. Sesbania and leucaena significantly influenced soil BD, clay, pH, Similarly, soil available P (4.3.-7.0 mg kg−1), exchangeable K+(0.4-0.7 cmolc kg−1), Mg (0.1-0.2 cmolc kg−1), and Mn (13.5 – 25.2 mg kg−1) above non-agroforestry adoption at both locations, while calliandra significantly increased SOC in Kakamega only.
DNA nanodevice for analysis of force-activated protein extension and interactions
Authors: Zhou Kun , Chung Minhwan , Cheng Jing , Powell John T. , Yan Qi , Liu Jun , Xiong Yong , Schwartz Martin A. , Lin Chenxiang
Published: October 2024

Force-induced changes in protein structure and function mediate cellular responses to mechanical stresses. Existing methods to study protein conformation under mechanical force are incompatible with biochemical and structural analysis. Taking advantage of DNA nanotechnology, including the well-defined geometry of DNA origami and programmable mechanics of DNA hairpins, we built a nanodevice to apply controlled forces to proteins. This device was used to study the R1-R2 segment of the talin1 rod domain as a model protein, which comprises two alpha-helical bundles that reversibly unfold under tension to expose binding sites for the cytoskeletal protein vinculin. Electron microscopy confirmed tension-dependent protein extension while biochemical analysis demonstrated enhanced vinculin binding under tension. The device could also be used in pull down assays with cell lysates, which identified filamins as novel tension-dependent talin binders. The DNA nanodevice is thus a valuable addition to the molecular toolbox for studying mechanosensitive proteins.
Decoding the Functional Interactome of Non-Model Organisms with PHILHARMONIC
Authors: Sledzieski Samuel , Versavel Charlotte , Singh Rohit , Ocitti Faith , Devkota Kapil , Kumar Lokender , Shpilker Polina , Roger Liza , Yang Jinkyu , Lewinski Nastassja , Putnam Hollie , Berger Bonnie , Klein-Seetharaman Judith , Cowen Lenore
Published: October 2024

Protein-protein interaction (PPI) networks are a fundamental resource for modeling cellular and molecular function, and a large and sophisticated toolbox has been developed to leverage their structure and topological organization to predict the functional roles of under-studied genes, proteins, and pathways. However, the overwhelming majority of experimentally-determined interactions from which such networks are constructed come from a small number of well-studied model organisms. Indeed, most species lack even a single experimentally-determined interaction in these databases, much less a network to enable the analysis of cellular function, and methods for computational PPI prediction are too noisy to apply directly. We introduce PHILHARMONIC, a novel computational approach that couples deep learningde novonetwork inference with robust unsupervised spectral clustering algorithms to uncover functional relationships and high-level organization in non-model organisms. Our clustering approach allows us to de-noise the predicted network, producing highly informative functional modules. We also develop a novel algorithm called ReCIPE, which aims to reconnect disconnected clusters, increasing functional enrichment and biological interpretability. We perform remote homology-based functional annotation by leveraging hmmscan and GODomainMiner to assign initial functions to proteins at large evolutionary distances. Our clusters enable us to newly assign functions to uncharacterized proteins through “function by association.” We demonstrate the ability of PHILHARMONIC to recover clusters with significant functional coherence in the reef-building coralP. damicornis, its algal symbiontC. goreaui, and the well-annotated fruit flyD. melanogaster. We perform a deeper analysis of theP. damicornisnetwork, where we show that PHILHARMONIC clusters correlate strongly with gene co-expression and investigate several clusters that participate in temperature regulation in the coral, including the first putative functional annotation of several previously uncharacterized proteins. Easy to run end-to-end and requiring only a sequenced proteome, PHILHARMONIC is an engine for biological hypothesis generation and discovery in non-model organisms.

PHILHARMONIC is available athttps://github.com/samsledje/philharmonic
Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors
Authors: Cabezas-Caballero Jose , Huhn Anna , Kutuzov Mikhail A. , Andre Violaine , Shomuradova Alina , van der Merwe P. Anton , Dushek Omer
Published: October 2024

Adoptive T cell therapy using T cells engineered with novel T cell receptors (TCRs) targeting tumor-specific peptides is a promising immunotherapy. However, these TCR-T cells can cross-react with off-target peptides, leading to severe autoimmune toxicities. Current efforts focus on identifying TCRs with reduced cross-reactivity. Here, we show that T cell cross-reactivity can be controlled by the co-signalling molecules CD5, CD8, and CD4, without modifying the TCR. We find the largest reduction in cytotoxic T cell cross-reactivity by knocking out CD8 and expressing CD4. Cytotoxic T cells engineered with a CD8-to-CD4 co-receptor switch show reduced cross-reactivity to random and positional scanning peptide libraries, as well as to self-peptides, while maintaining their on-target potency. Therefore, co-receptor switching generates super selective T cells that reduce the risk of lethal off-target cross-reactivity, and offers a universal method to enhance the safety of T cell immunotherapies for any TCR.

Graphical abstract

One sentence summary

Switching the CD8 for the CD4 co-receptor in cytotoxic T cells reduces the functional cross-reactivity of T cells without modifying the TCR.
Phosphorylation of HP1/Swi6 relieves competition with Suv39/Clr4 on nucleosomes and enables H3K9 trimethyl spreading
Authors: Kennedy Dana R , Lemiere Joel , Tan Catherine , Simental Eric , Braxton Julian , Maxwell Robert A , Amine Ahmed AA , Al-Sady Bassem
Published: October 2024

Heterochromatin formation in Schizosaccharomyces pombe requires the spreading of histone 3 (H3) Lysine 9 (K9) methylation (me) from nucleation centers by the H3K9 methylase, Suv39/Clr4, and the reader protein, HP1/Swi6. To accomplish this, Suv39/Clr4 and HP1/Swi6 have to associate with nucleosomes both nonspecifically, binding DNA and octamer surfaces and specifically, via recognition of methylated H3K9 by their respective chromodomains. However, how both proteins avoid competition for the same nucleosomes in this process is unclear. Here, we show that phosphorylation tunes the nucleosome affinity of HP1/Swi6 such that it preferentially partitions onto Suv39/Clr4’s trimethyl product rather than its unmethylated substrates. Preferential partitioning enables efficient conversion from di-to trimethylation on nucleosomes in vitro and H3K9me3 spreading in vivo. Together, our data suggests that phosphorylation of HP1/Swi6 creates a regime that relieves competition with the “read-write” mechanism of Suv39/Clr4 for productive heterochromatin spreading.
5hmC enhances PARP trapping and restores PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells
Authors: Kharat Suhas S. , Mishra Arun P. , Sengodan Satheesh K. , Dierman Dillon , Fox Stephen D. , Sharan Shyam K.
Published: October 2024

Mutations inBRCA1andBRCA2genes are the leading cause of hereditary breast and ovarian cancer.BRCA1/2-mutant cells are defective in repairing damaged DNA by homologous recombination and are characterized by hypersensitivity to PARP inhibitors. PARP inhibitors can trap PARP proteins on the chromatin, a mechanism that can contribute to the death of BRCA1/2-deficient cells. The FDA has approved multiple PARP inhibitors for the treatment of metastatic breast and ovarian cancers, but despite the success of PARP inhibitors in treatingBRCA1/2-mutant cancers, drug resistance is a major challenge. Here, we report that 5hmC enhances PARP1 trapping on the chromatin in olaparib-treated cells. Elevated PARP trapping generates replication gaps, leading to the restoration of PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells. Our findings suggest that combining 5hmC with olaparib can restore the sensitivity of chemoresistant BRCA1/2-deficient cells.
Sensitivity to photoperiod is a complex trait inCamelina sativa
Authors: Ramirez-Corona Bryan A , Seagren Erin , Sherman Carissa , Imaizumi Takato , Queitsch Christine , Cuperus Josh
Published: October 2024

Day neutrality, or insensitivity to photoperiod (day length), is an important domestication trait in many crop species. Although the oilseed cropCamelina sativahas been cultivated since the Neolithic era, day-neutral accessions have yet to be described. We sought to leverage genetic diversity in existing germplasms to identifyC. sativaaccessions with low photoperiod sensitivity for future engineering of this trait. We quantified variation in the photoperiod response across 161 accessions ofC. sativaby measuring hypocotyl length of four-day-old seedlings grown in long-day and short-day conditions, finding wide variation in photoperiod response. Similarly, soil-grown adult plants from selected accessions showed variation in photoperiod response in several traits; however, photoperiod responses in seedling and adult traits were not correlated, suggesting complex mechanistic underpinnings. Although RNA-seq experiments of the reference accession Licalla identified several differentially regulatedArabidopsissyntelogs involved in photoperiod response, includingCOL2, FT, LHYandWOX4, expression of these genes in the accessions did not correlate with differences in their photoperiod sensitivity. Taken together, we show that all tested accessions show some degree of photoperiod response, and that this trait is likely complex, involving several and separable seedling and adult traits.

Significance Statement

Day neutrality (photoperiod insensitivity) is a common trait in domesticated crops; however, the ancient oilseed cropCamelina sativahas remained photoperiod-sensitive, which likely limits seed yields. Here, we show that photoperiod sensitivity is conserved across manyC. sativacultivars, albeit to different degrees, and we establish that photoperiod sensitivity is a complex trait, which will require genetic engineering to achieve day neutrality.
Dynamic RNA binding and unfolding by nonsense-mediated mRNA decay factor UPF2
Authors: Szeto Jenn-Yeu Alvin , Vivoli Vega Mirella , Mailliot Justine , Orriss George , Sun Lingling , Bufton Joshua C. , Powers Kyle T. , Yadav Sathish K.N. , Berger Imre , Schaffitzel Christiane
Published: October 2024

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance pathway involved in translational control and gene expression regulation. Core NMD factors UPF1, UPF2 and UPF3B are conserved from yeast to humans and essential to target mRNAs with a premature stop codon for decay. UPF2 binding to UPF1 activates UPF1's ATPase and helicase activities, and UPF2 binding to UPF3B is important for its association with the exon-junction complex and efficient NMD. However, UPF2's association with RNA remains largely uncharacterized. Here, we analyze nucleic acid binding, identifying the first and third MIF4G domains of UPF2 as main RNA-/DNA-binding modules. We find that UPF2's MIF4G domain-3 has RNA annealing activity while full-length UPF2 unfolds our reporter hairpin-RNA structure. We show that UPF2 preferentially binds and stabilizes single-stranded RNA (ss-RNA) in a sequence-independent manner. Concomitant to ss-RNA binding, UPF2 undergoes a distinct conformational change in its otherwise highly dynamic structure. UPF2's RNA binding and unfolding activity may support UPF1's helicase and mRNP remodeling activity and, in combination with UPF3B, stabilize UPF1's association with nonsense mRNA.
Deep Learning Prediction of Parkinson’s Disease using Remotely Collected Structured Mouse Trace Data
Authors: Shahriar Zawad Md Rahat , Tumpa Zerin Nasrin , Sollis Lydia , Parab Shubham , Washington Peter
Published: October 2024

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder globally, and current screening methods often rely on subjective evaluations. We developed deep learning-based classification models using mouse trace data collected via a web application. 315 participants (73 PD, 179 non-PD, 63 suspected PD) completed three hand movement tasks: tracing a straight line, spiral, and sinewave. We developed three types of models: (1) engineered features models, (2) computer vision models, and (3) multimodal models. Feature importance was evaluated using Gradient Shapley Additive Explanations (GradShap). The multimodal Visual transformer (ViT) model achieved the highest performance, with F1 scores of 0.8413 ± 0.0336 (PD vs. non-PD), 0.8520 ± 0.0014 (suspected PD vs. non-PD), and 0.7034 ± 0.0017 (PD vs. suspected PD). Image data proved most influential in predicting PD outcomes. These findings suggested that models trained on confirmed PD diagnoses hold significant promise for early-stage PD screening at the population level.
Phage-plasmid borne methionine tRNA ligase mediates epidemiologically relevant antimicrobial persistence
Authors: Tam Yi Ling , De Silva P. Malaka , Barker Clare R. , Li Ruizhe , Batisti Biffignandi Gherard , Santos Leanne , Chong Charlotte E. , Mason Lewis C. E. , Nair Satheesh , Ribeca Paolo , Bayliss Sion C. , Jenkins Claire , Bakshi Somenath , Hall James P.J. , Cowley Lauren , Baker Kate S.
Published: October 2024

Antimicrobial resistance (AMR) is a global public health crisis with few options for control. As such early identification of emerging bacterial strains capable of rapidly evolving AMR is key. Although antimicrobial tolerance and persistence are precursor phenotypes for AMR, little evidence exists to support their importance in real-world settings. Here we used bacterial genome wide association on national genomic surveillance data of the diarrhoeal pathogenShigella sonnei(n=3745) to agnostically identify common genetic signatures among lineages convergently evolving toward AMR (n=15). This revealed an association of an AMR trajectory with a multi- and highly variable second copy ofmetG, borne by a phage-plasmid we called pWPMR2. Further analyses revealed that pWPMR2 was present across clinically relevant enteric pathogens globally, including past and contemporary outbreaks, and that the additional-metGmechanism was present across multiple bacterial phyla. Functional microbiology, experimental evolution, and single-cell physiology studies confirmed that the expression of auxiliarymetG, particularly the mutated version on pWPMR2, created a sub population of persister cells predisposed to survival in, and evolving resistance against, third generation cephalosporins. Thus, we demonstrate a novel mechanism of auxiliarymetGcarriage that predisposes bacteria to AMR with real world impacts. Furthermore, our approach is a timely example of using genomic epidemiology to rapidly guide functional microbiology studies in the era of routine genomic surveillance, and also highlights several deficiencies in current AMR surveillance practices.
A survey on the nationwide prevalence of asbestos-related lung cancer in Japan
Authors: Niino Mariko , Tomizuka Taro , Nishina Yuka , Ichinose Yuichi , Gonoi Wataru , Higashi Takahiro
Published: October 2024

BACKGROUND

An accurate estimate of the nationwide prevalence of asbestos-related lung cancer (ARLC) is necessary to adequately operate a compensation subsidy program for patients with ARLC. Our study aimed to estimate the proportion of patients with ARLC among patients with primary lung cancer, and describe the characteristics and distribution of ARLC.

METHODS

All facilities that treated patients diagnosed with lung cancer in 2016 were requested to submit computed tomography images of 10 patients randomly selected from the national databases of hospital-based cancer registries. ARLC was defined as pleural plaques (PPs) extending over one-quarter of the inner lateral chest wall or existing PPs accompanied by obvious lung fibrosis. We estimated the proportion and distribution of ARLC among primary lung cancer cases and compared the characteristics of ARLC with those of primary lung cancer.

RESULTS

Of 772 facilities that treated at least one patient with lung cancer, 370 provided 3,565 sets of CT images. Of these, 216 (6.1%) had PPs, and 86 (2.4%) met the compensation criteria. After sample weighting, 2.0% of all primary lung cancers were classified as ARLC in Japan. A higher percentage of patients with ARLC were male (94.2% vs. 68.6%;P< .01) and had more advanced-stage disease (stage III: 22.1% vs. 16.0%; stage IV: 44.2% vs. 39.8%;P=.05) than other primary lung cancers. A majority (53.5%) of patients with ARLC were diagnosed at designated cancer hospitals. The proportion of squamous cell carcinoma was higher in ARLC than in those with primary lung cancer (25.6% vs. 18.6%;P< .01).

CONCLUSION

The estimated number of patients with ARLC was larger than expected from the number of applicants in the compensation system for asbestos-related health damages (AHDRS). Consequently, countermeasures are required to accurately identify eligible compensation recipients.

Highlight

The estimated proportion of patients with ARLC among patients with lung cancer was 2%.

The proportion of squamous cell carcinoma was higher in ARLC than in primary lung cancer.

A higher number of ARLC cases than expected from the official reports of AHDRS compensation recipients in Japan was found. More accurate AHDR reports are needed
Motif-induced Subgraph Generative Learning for Explainable Neurological Disorder Detection
Authors: Liu Mujie , Dong Qichao , Wang Chenze , Cheng Xinrui , Febrinanto Falih Gozi , Hoshyar Azadeh Noori , Xia Feng
Published: October 2024

The wide variation in symptoms of neurological disorders among patients necessitates uncovering individual pathologies for accurate clinical diagnosis and treatment. Current methods attempt to generalize specific biomarkers to explain individual pathology, but they often lack analysis of the underlying pathogenic mechanisms, leading to biased biomarkers and unreliable diagnoses. To address this issue, we propose a motif-induced subgraph generative learning model (MSGL), which provides multi-tiered biomarkers and facilitates explainable diagnoses of neurological disorders. MSGL uncovers underlying pathogenic mechanisms by exploring representative connectivity patterns within brain net-works, offering motif-level biomarkers to tackle the challenge of clinical heterogeneity. Furthermore, it utilizes motif-induced information to generate enhanced brain network subgraphs as personalized biomarkers for identifying individual pathology. Experimental results demonstrate that MSGL outperforms baseline models. The identified biomarkers align with recent neuroscientific findings, enhancing their clinical applicability.
Proximity Interactome analyses unveil novel regulators of IRE1α canonical signaling
Authors: Le Goupil Simon , Philippe Céline , Laprade Hadrien , Lode Mathéo , Boniface Rachel , Pelizzari-Raymundo Diana , Dejgaard Kurt , Jansen Gregor , Limia Celia , Hetz Claudio , Mahdizadeh S. Jalil , Negroni Luc , Aubry Marc , Ricci Jean-Ehrland , Eriksson Leif A. , Chevet Eric
Published: October 2024

The unfolded protein response (UPR) is a key adaptive pathway that controls endoplasmic reticulum (ER) homeostasis. The UPR is transduced by three ER-resident sensors of ER homeostasis disruption in the lumen of this compartment. They trigger select downstream signaling pathways in the cytosol and nucleus. Among them, IRE1α (referred to as IRE1 hereafter), a type I transmembrane protein, senses accumulation of improperly folded proteins in the ER lumen and transduces signals through both kinase and endoribonuclease (RNase) activities in the cytosol. IRE1 catalyzesXBP1mRNA unconventional splicing and RNA degradation (Regulated IRE1 Dependent Decay, termed RIDD). Recent studies have reported that IRE1-dependent protein-protein interactions (PPi) drive additional non-canonical IRE1 functions. Herein, we define the IRE1 signalosome as a list of IRE1 binding partners (direct or not) which alter IRE1 signaling towards XBP1 mRNA splicing and RIDD. Here we determined the IRE1in situinteractome using BioID, putatively connecting IRE1 to previously unrecognized cellular functions. In addition, we link the binding of several IRE1 partners to the regulation of its RNase. Furthermore, we identify HNRNPL as an IRE1-interacting partner, previously unrecognized, which stabilizes IRE1 under basal conditions by counteracting ERAD-mediated degradation. Overall, the characterization of the IRE1 signalosome not only reveals the multi-faceted control of IRE1 RNase activity and stability by its interacting partners and allow us to discuss putative additional IRE1 regulators and cellular functions based on the nature of its interactome and its localization.
Chemosensory modulation of eye-body coordination in larval zebrafish
Authors: Sy Samuel K. H. , Chan Danny C. W. , Zhang Jenny J. , Lyu Jing , Feng Crystal , Wang Kui , Mok Vincent C. T. , Wong Kenneth K. Y. , Mu Yu , Randlett Owen , Hu Yu , Ko Ho
Published: October 2024

Coordinated eye-body movements are essential for many animal behaviors, yet the influence of chemosensory inputs on these movements remains underexplored. Here, we enhance the Fish-On-Chips optofluidic platform to reveal that larval zebrafish use coupled saccade-tail flips for chemosensory avoidance, but not pursuit. Spontaneous saccades, which alternate in direction, are closely synchronized with tail flips via anticipatory adjustments in tail flip event rate, directionality, and kinematics. In response to ethologically representative chemosensory cues, this coordination is differentially modulated based on valence. Aversive chemical cues increase saccade frequency and the proportion of saccade-coupled tail flips, while also enhancing the turning intent as the coupling strengthens. Conversely, appetitive chemicals promote more sustained gliding movements without impacting saccades or their tail flip coupling. Brain-wide neuronal activity imaging reveals that the pallium, a cortical homolog in teleosts, strongly represents the sensorimotor transformation of aversive cue-associated coupled saccade-tail flips. Our findings underscore the critical role of chemosensory cues in regulating eye-body coordination in an early vertebrate species, highlighting a deep evolutionary integration of sensory inputs to optimize locomotion.
Revealing mechanisms underlying the collective escape of starling flocks
Authors: Papadopoulou Marina , Hildenbrandt Hanno , Storms Rolf F. , Carere Claudio , Hemelrijk Charlotte K.
Published: October 2024

European starlings perform a great diversity of patterns of collective behaviour when hunted by aerial predators; their large flocks are changing shape, size, and internal structure continuously and rapidly, but how these patterns emerge by self-organization is still unknown. Here, we disentangle the emergence of several interconnected patterns of collective escape in starlings. We combine video footage of starling flocks pursued by a robotic predator, the RobotFalcon, with simulations of large flocks in a new data-driven 3-dimentional agent-based model. Our empirical data show that flock members often differ in their evasive manoeuvres and that several patterns of collective escape arise simultaneously at different parts in the flock. In our computational model, we identify what rules of motion, coordination and escape at the individual level lead to the emergence of group density, internal dynamics, and patterns of collective escape similar to real starling flocks. Overall, our results suggest that the emergence and dynamics of simultaneous patterns of collective escape depend on: the speed with which the escape information propagates from one or few initiators, the positions of the escaping flock members in relation to the predator, and the previous state of the flock (hysteresis).
A circuit model for transsaccadic space updating and mislocalization
Authors: Wang Xiao , Tsien Sophia , Goldberg Michael E. , Zhang Mingsha , Qian Ning
Published: October 2024

We perceive a stable, continuous world despite drastic changes of retinal images across saccades. However, whilepersistentobjects in daily life appear stable across saccades, stimuliflashedaround saccades can be grossly mislocalized. We address this puzzle with our recently proposed circuit model for perisaccadic receptive-field (RF) remapping in LIP and FEF. The model uses center/surround connections to store a relevant stimulus’ retinal location in memory as a population activity. This activity profile is updated across each saccade by directional connections gated by the corollary discharge (CD) of the saccade command. The updating is a continuous backward (against the saccade) shift of the population activity (equivalent to continuous forward remapping of the RFs), whose cumulative effect across the saccade is a subtraction of the saccade vector. The model explains forward and backward translational mislocalization for stimuli flashed around the saccade onset and offset, respectively, as insufficient and unnecessary cumulative updating after the saccade, caused by the sluggish CD time course and visual response latency. We confirm the model prediction that for perisaccadic RFs measured with flashes before the saccades, the final forward remapping magnitudes after the saccades are smaller for later flashes. We discuss the possibility that compressive mislocalization results from a brief reduction of attentional remapping and repulsion. Although many models of RF remapping, transsaccadic updating, and perisaccadic mislocalization have been proposed, our work unifies them into a single circuit mechanism and suggests that the brain uses “unaware” decoders which do not distinguish between different origins of neurons’ activities.
Comprehensive Analysis of Mitochondrial DNA Variation in the Taiwan Biobank: Implications for Complex Traits and Population Genetics
Authors: Chou Ting-Hsuan , Chien Pei-Miao , Chen Pin-Xuan , Lee Ni-Chung , Wang Hurng-Yi , Chang Yi-Cheng , Chen Pei-Lung , Hsu Jacob Shu-Jui
Published: October 2024

This study presents a comprehensive analysis of mitochondrial DNA (mtDNA) variation in the Taiwan Biobank (TWB), providing insights into the genetic characteristics of the Taiwanese population and the implications of mtDNA in complex traits. We performed mtDNA genotyping on 1,492 individuals using whole-genome sequencing data and imputed mtDNA variants for 101,473 participants from microarray data. Our analysis identified 23 confirmed pathogenic mtDNA variants, with approximately 1 in 180 individuals carrying such variants. Further exploration of mtDNA haplogroups and ancestry revealed no direct correlation between nuclear and mitochondrial genomes, which reflects their distinct inheritance patterns and evolutionary histories. In a mitochondrial genome-wide association study across 86 traits and 306 mtDNA variants, we discovered novel associations betweenMT-ND2gene variants and high myopia, as well as 14 mtDNA variants linked to renal function biomarkers. Notably, renal-associated variants clustered into two main groups: ancestral variants of macrohaplogroup M associated with poorer renal function and variants of the B4b sub-haplogroup linked to improved renal function markers. Our findings highlight the importance of population-specific genetic studies, contributing to our understanding of mitochondrial genetics in the Taiwanese population and its implications for health and disease.
Acute Aerobic Exercise Enhances Associative Learning in Active but not Sedentary Individuals
Authors: Gultig Kayleigh Danielle , Boele Cornelis Peter , Roggeveen Lotte E.M , Soong Emily , Koekkoek Sebastiaan K.E , De Zeeuw Chris I , Boele Henk-Jan
Published: October 2024

Physical exercise has repeatedly been reported to have advantageous effects on brain functions, including learning and memory formation. However, objective tools to measure such effects are often lacking. Eyeblink conditioning is a well-characterised method for studying the neural basis of associative learning. As such, this paradigm has potential as a tool to assess to what extent exercise affects one of the most basic forms of learning. Until recently, however, using this paradigm for testing human subjects in their daily life was technically challenging. As a consequence, no studies have investigated how exercise affects eyeblink conditioning in humans. Here we hypothesize that acute aerobic exercise is associated with improved performance in eyeblink conditioning. Furthermore, we explored whether the effects of exercise differed for people with an active versus a sedentary lifestyle. We conducted a case-control study using a smartphone-based platform for conducting neurometric eyeblink conditioning in healthy adults aged between 18-40 years (n = 36). Groups were matched on age, sex, and education level. Our primary outcome measures included the amplitude and timing of conditioned eyelid responses over the course of eyeblink training. As a secondary measure, we studied the amplitude of the unconditioned responses. Acute exercise significantly enhanced the acquisition of conditioned eyelid responses; however, this effect was only true for individuals with an active lifestyle. No statistically significant effects were established for timing of the conditioned responses and amplitude of the unconditioned responses. This study highlights a facilitative role of acute aerobic exercise in associative learning and emphasises the importance of accounting for lifestyle when investigating the acute effects of exercise on brain functioning.
Towards a complete phage tail fiber structure atlas
Authors: Klein-Sousa Victor , Roa-Eguiara Aritz , Kielkopf Claudia S. , Sofos Nicholas , Taylor Nicholas M. I.
Published: October 2024

Bacteriophages use receptor-binding proteins (RBPs) to adhere to bacterial hosts. Understanding the structure of these RBPs can provide insights into their target interactions. Tail fibers, a prominent type of RBP, are typically elongated, flexible, and trimeric proteins, making it challenging to obtain high-resolution experimental data of their full-length structures. Recent advancements in deep learning-based protein structure prediction, such as AlphaFold2-multimer (AF2M) and ESMfold, allow for the generation of high-confidence predicted models of complete tail fibers. In this paper, we introduce RBPseg, a method that combines monomeric ESMfold predictions with a novel sigmoid distance pair (sDp) protein segmentation technique. This method segments the tail fiber sequences into smaller fractions, preserving domain boundaries. These segments are then predicted in parallel using AF2M and assembled into a full fiber model. We demonstrate that RBPseg significantly improves AF2M v2.3.2 in terms of model confidence, running time, and memory usage. To validate our approach, we used single-particle cryo-electron microscopy to analyze five tail fibers from three phages of the BASEL collection. Additionally, we conducted a structural classification of 67 fibers and their domains, which identified 16 well-defined tail fiber classes and 89 domains. Our findings suggest the existence of modular fibers as well as fibers with different sequences and shared structure, indicating possible sequence convergence, divergence, and domain swapping. We further demonstrate that these structural classes account for at least 24% of the known tail fiber universe.
Borrelia burgdorferiloses essential genetic elements and cell proliferative potential during stationary phase in culture but not in the tick vector
Authors: Zhang Jessica , Takacs Constantin N. , McCausland Joshua W. , Mueller Elizabeth A. , Buron Jeline , Thappeta Yashna , Wachter Jenny , Rosa Patricia A. , Jacobs-Wagner Christine
Published: October 2024

The Lyme disease agentBorrelia burgdorferiis a polyploid bacterium with a segmented genome in which both the chromosome and over 20 distinct plasmids are present in multiple copies per cell. This pathogen can survive at least nine months in its tick vector in an apparent dormant state between blood meals, without losing cell proliferative capability when re-exposed to nutrients. CultivatedB. burgdorfericells grown to stationary phase or resuspended in nutrient-limited media are often used to study the effects of nutrient deprivation. However, a thorough assessment of the spirochete’s ability to recover from nutrient depletion has been lacking. Our study shows that starvedB. burgdorfericultures rapidly lose cell proliferative. Loss of genetic elements essential for cell proliferation contributes to the observed proliferative defect in stationary phase. The gradual decline in copies of genetic elements is not perfectly synchronized between chromosomes and plasmids, generating cells that harbor one or more copies of the essential chromosome but lack all copies of one or more non-essential plasmids. This phenomenon likely contributes to the well-documented issue of plasmid loss during in vitro cultivation ofB. burgdorferi. In contrast,B. burgdorfericells from ticks starved for 14 months showed no evidence of reduced cell proliferative ability or plasmid loss. Beyond their practical implications for studyingB. burgdorferi, these findings suggest that the midgut of the tick vector offers a unique environment that supports the maintenance ofB. burgdorferi’s segmented genome and cell proliferative potential during periods of tick fasting.

Importance

Borrelia burgdorfericauses Lyme disease, a prevalent tick-borne illness.B. burgdorferimust survive long periods (months to a year) of apparent dormancy in the midgut of the tick vector between blood meals. Resilience to starvation is a common trait among bacteria. However, this study reveals that in laboratory cultures,B. burgdorferipoorly endures starvation and rapidly loses viability. This decline is linked to a gradual loss of genetic elements required for cell proliferation. These results suggest that the persistence ofB. burgdorferiin nature is likely shaped more by unique environmental conditions in the midgut of the tick vector than by a general innate ability of this bacterium to endure nutrient deprivation.
Synaptic composition, activity, mRNA translation and dynamics in combined single-synapse profiling using multimodal imaging
Authors: Falkovich Reuven , Aryal Sameer , Wang Jasmine , Sheng Morgan , Bathe Mark
Published: October 2024

The function of neuronal circuits, and its perturbation by psychoactive molecules or disease-associated genetic variants, is governed by the interplay between synapse activity and synaptic protein localization and synthesis across a heterogeneous synapse population. Here, we combine in situ measurement of synaptic multiprotein compositions and activation states, synapse activity in calcium traces or glutamate spiking, and local translation of specific genes, across the same individual synapses. We demonstrate how this high-dimensional data enables identification of interdependencies in the multiprotein-activity network, and causal dissection of complex synaptic phenotypes in disease-relevant chemical and genetic NMDAR loss of function that translatein vivo. We show how this method generalizes to other subcellular systems by deriving mitochondrial protein networks, and, using support vector machines, its value in overcoming animal variability in phenotyping. Integrating multiple synapse information modalities enables deep structure-function characterization of synapse populations and their responses to genetic and chemical perturbations.
Cortical Reactivations Modulated by Local Inhibitory Circuits Mediate Memory Consolidation
Authors: Lensjø Kristian Kinden , Nystuen Ingeborg Nymoen , Rogge Frederik Sebastian , Tøndel Kristin , Sugden Arthur , Shurnayte Inga , Grødem Sverre , Malthe-Sørenssen Anders , Hafting Torkel , Andermann Mark L. , Fyhn Marianne
Published: October 2024

Highly salient events activate neurons across various brain regions. During subsequent rest or sleep, the activity patterns of these neurons often correlate with those observed during the preceding experience. Growing evidence suggests that these reactivations play a crucial role in memory consolidation, the process by which experiences are solidified in cortical networks for long-term storage.

Here, we demonstrate that reactivations in the lateral visual cortex are vital for the consolidation of visual association learning. By employing longitudinal two-photon Ca2+imaging alongside paired LFP recordings in the hippocampus and cortex, we show that targeted manipulation of PV+inhibitory neurons in the lateral visual cortexafterdaily training selectively attenuated cue-specific reactivations and learning, with no apparent effect on normal network function during training. In contrast, reactivations in the control group were biased towards salient cues, aligned with learning process and persisted for hours after training had ended. Overall, our results underscore a crucial role for cortical reactivations in memory consolidation.
The Role of Physical Activity in Mitigating Age-Related Changes in the Neuromuscular Control of Gait
Authors: Nuñez-Lisboa M.N. , Dewolf A.H.
Published: October 2024

Exercise is known to induce several neural and muscular adaptations, such as increased muscle mass and functional capacity in older adults. In this study, we investigated its impact on the neuromuscular control of gait among young and older adults, divided into two groups: more active (young: n=15; 5185 ± 1471 MET-min/week; old: n=14; 6481 ± 4846 MET-min/week) and less active participants (young: n=14; 1265 ± 965 MET-min/week; old: n=14; 1473 ± 859 MET-min/week). Maximal isometric tests of ankle and knee extension revealed a reduction in force among older adults, with differences associated with the level of physical activity at the ankle level. Gait mechanics revealed no significant differences between young adults and the more active older adults. In contrast, less active older adults exhibited shorter steps, higher mechanical cost, and greater collision at heel strike. These changes cannot be attributed solely to reductions in muscle strength. Instead, they are likely the result of modifications in neuromuscular control and mechanical properties of muscles in less active older adults. Specifically, wider activation (and greater coactivation) of lumbar and sacral motor pools as well as a different timing of activation were observed. Also, their muscle-tendon stiffness was reduced. In conclusion, our findings highlight that the age-related decline in gait efficiency is exacerbated by a sedentary lifestyle. Even modest increases in physical activity appear to preserve neuromuscular control and improve walking performance. This suggests that interventions aiming to enhance physical activity levels could mitigate age-related declines in gait mechanics.
LYCEUM: Learning to call copy number variants on low coverage ancient genomes
Authors: Yılmaz Mehmet Alper , Ceylan Ahmet Arda , Kaynar Gün , Çiçek A. Ercüment
Published: October 2024

Copy number variants (CNVs) are pivotal in driving phenotypic variation that facilitates species adaptation. They are significant contributors to various disorders, making ancient genomes crucial for uncovering the genetic origins of disease susceptibility across populations. However, detecting CNVs in ancient DNA (aDNA) samples poses substantial challenges due to several factors: (i) aDNA is often highly degraded; (ii) contamination from microbial DNA and DNA from closely related species introduce additional noise into sequencing data; and finally, (iii) the typically low coverage of aDNA renders accurate CNV detection particularly difficult. Conventional CNV calling algorithms, which are optimized for high coverage read-depth signals, underperform under such conditions. To address these limitations, we introduce LYCEUM, the first machine learning-based CNV caller for aDNA. To overcome challenges related to data quality and scarcity, we employ a two-step training strategy. First, the model is pre-trained on whole genome sequencing data from the 1000 Genomes Project, teaching it CNV-calling capabilities similar to conventional methods. Next, the model is fine-tuned using high-confidence CNV calls derived from only a few existing high-coverage aDNA samples. During this stage, the model adapts to making CNV calls based on the downsampled read depth signals of the same aDNA samples. LYCEUM achieves accurate detection of CNVs even in typically low-coverage ancient genomes. We also observe that the segmental deletion calls made by LYCEUM show correlation with the demographic history of the samples and exhibit patterns of negative selection inline with natural selection. LYCEUM is available athttps://github.com/ciceklab/LYCEUM.
Backtracking Metabolic Dynamics in Single Cells Predicts Bacterial Replication in Human Macrophages
Authors: Dramé Mariatou , Ershov Dmitry , Martyn Jessica E. , Tinevez Jean-Yves , Buchrieser Carmen , Escoll Pedro
Published: October 2024

Accurately tracking dynamic state transitions is crucial for modeling and predicting biological outcomes, as it captures heterogeneity of cellular responses. To build a model to predict bacterial infection in single cells, we have monitored in parallel infection progression and metabolic parameters in thousands of human primary macrophages infected with the intracellular pathogenLegionella pneumophila. By combining livecell imaging with a novel tool for classifying cells based on infection outcomes, we were able to trace the specific evolution of metabolic parameters linked to distinct outcomes, such as bacterial replication or cell death. Our findings revealed that early changes in mitochondrial membrane potential (Δψm) and in the production of mitochondrial Reactive Oxygen Species (mROS) are associated with macrophages that will later support bacterial growth. We used these data to train an explainable machine-learning model and achieved 83% accuracy in predictingL. pneumophilareplication in single, infected cells before bacterial replication starts. Our results highlight backtracking as a valuable tool to gain new insights in host-pathogen interactions and identify early mitochondrial alterations as key predictive markers of success of bacterial infection.
Complex system modelling reveals oxalate homeostasis is driven by diverse oxalate-degrading bacteria
Authors: Mukherjee Sromona D. , Batagello Carlos A. , Adler Ava , Agudelo Jose , Zampini Anna , Suryavanshi Mangesh , Nguyen Andrew , Orr Teri , Dearing Denise , Monga Manoj , Miller Aaron W.
Published: October 2024

Decades of research have made clear that host-associated microbiomes touch all facets of health. However, effective therapies that target the microbiome have been elusive given its inherent complexity. Here, we experimentally examined diet-microbe-host interactions through a complex systems framework, centered on dietary oxalate. Using multiple, independent molecular, animal, andin vitroexperimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, administration of the oxalate-degrading specialist,Oxalobacter formigenes,was only effective against a poor oxalate-degrading microbiota background and gives critical new insights into why clinical intervention trials with this species exhibit variable outcomes. Data suggest that, while heterogeneity in the microbiome impacts multiple diet-host-microbe interfaces, metabolic redundancy among diverse microorganisms in specific diet-microbe axes is a critical variable that may impact the efficacy of bacteriotherapies, which can help guide patient and probiotic selection criteria in probiotic clinical trials.