bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flow interactions lead to self-organized flight formations disrupted by self-amplifying waves
Authors: Newbolt Joel W. , Lewis Nickolas , Bleu Mathilde , Wu Jiajie , Mavroyiakoumou Christiana , Ramananarivo Sophie , Ristroph Leif 
Published: April 2024

AbstractCollectively locomoting animals are often viewed as analogous to states of matter in that group-level phenomena emerge from individual-level interactions. Applying this framework to fish schools and bird flocks must account for visco-inertial flows as mediators of the physical interactions. Motivated by linear flight formations, here we show that pairwise flow interactions tend to promote crystalline or lattice-like arrangements, but such order is disrupted by unstably growing positional waves. Using robotic experiments on “mock flocks” of flapping wings in forward flight, we find that followers tend to lock into position behind a leader, but larger groups display flow-induced oscillatory modes – “flonons” – that grow in amplitude down the group and cause collisions. Force measurements and applied perturbations inform a wake interaction model that explains the self-ordering as mediated by spring-like forces and the self-amplification of disturbances as a resonance cascade. We further show that larger groups may be stabilized by introducing variability among individuals, which induces positional disorder while suppressing flonon amplification. These results derive from generic features including locomotor-flow phasing and nonreciprocal interactions with memory, and hence these phenomena may arise more generally in macroscale, flow-mediated collectives.
High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue
Authors: Zhang Ning , Harbers Luuk , Simonetti Michele , Diekmann Constantin , Verron Quentin , Berrino Enrico , Bellomo Sara E. , Longo Gabriel M. C. , Ratz Michael , Schultz Niklas , Tarish Firas , Su Peng , Han Bo , Wang Wanzhong , Onorato Sofia , Grassini Dora , Ballarino Roberto , Giordano Silvia , Yang Qifeng , Sapino Anna , Frisén Jonas , Alkass Kanar , Druid Henrik , Roukos Vassilis , Helleday Thomas , Marchiò Caterina , Bienko Magda , Crosetto Nicola 
Published: April 2024

AbstractSomatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we perform multi-region, single-cell DNA sequencing to characterize the SCNA landscape across tumor-rich and normal tissue in two male patients with localized prostate cancer. We identify two distinct karyotypes: ‘pseudo-diploid’ cells harboring few SCNAs and highly aneuploid cells. Pseudo-diploid cells form numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones. In contrast, aneuploid cells do not form subclones and are detected throughout the prostate, including normal tissue regions. Highly localized pseudo-diploid subclones are confined within tumor-rich regions and carry deletions in multiple tumor-suppressor genes. Our study reveals that SCNAs are widespread in normal and tumor regions across the prostate in localized prostate cancer patients and suggests that a subset of pseudo-diploid cells drive tumorigenesis in the aging prostate.
Scalable computation of anisotropic vibrations for large macromolecular assemblies
Authors: Lam Jordy Homing , Nakano Aiichiro , Katritch Vsevolod 
Published: April 2024

AbstractThe Normal Mode Analysis (NMA) is a standard approach to elucidate the anisotropic vibrations of macromolecules at their folded states, where low-frequency collective motions can reveal rearrangements of domains and changes in the exposed surface of macromolecules. Recent advances in structural biology have enabled the resolution of megascale macromolecules with millions of atoms. However, the calculation of their vibrational modes remains elusive due to the prohibitive cost associated with constructing and diagonalizing the underlying eigenproblem and the current approaches to NMA are not readily adaptable for efficient parallel computing on graphic processing unit (GPU). Here, we present eigenproblem construction and diagonalization approach that implements level-structure bandwidth-reducing algorithms to transform the sparse computation in NMA to a globally-sparse-yet-locally-dense computation, allowing batched tensor products to be most efficiently executed on GPU. We map, optimize, and compare several low-complexity Krylov-subspace eigensolvers, supplemented by techniques such as Chebyshev filtering, sum decomposition, external explicit deflation and shift-and-inverse, to allow fast GPU-resident calculations. The method allows accurate calculation of the first 1000 vibrational modes of some largest structures in PDB ( > 2.4 million atoms) at least 250 times faster than existing methods.
EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition
Authors: Romero Pierre , Richart Laia , Aflaki Setareh , Petitalot Ambre , Burton Megan , Michaud Audrey , Masliah-Planchon Julien , Kuhnowski Frédérique , Le Cam Samuel , Baliñas-Gavira Carlos , Méaudre Céline , Luscan Armelle , Hamza Abderaouf , Legoix Patricia , Vincent-Salomon Anne , Wassef Michel , Holoch Daniel , Margueron Raphaël 
Published: April 2024

AbstractMutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.
DenRAM: neuromorphic dendritic architecture with RRAM for efficient temporal processing with delays
Authors: D’Agostino Simone , Moro Filippo , Torchet Tristan , Demirağ Yiğit , Grenouillet Laurent , Castellani Niccolò , Indiveri Giacomo , Vianello Elisa , Payvand Melika 
Published: April 2024

AbstractNeuroscience findings emphasize the role of dendritic branching in neocortical pyramidal neurons for non-linear computations and signal processing. Dendritic branches facilitate temporal feature detection via synaptic delays that enable coincidence detection (CD) mechanisms. Spiking neural networks highlight the significance of delays for spatio-temporal pattern recognition in feed-forward networks, eliminating the need for recurrent structures. Here, we introduce DenRAM, a novel analog electronic feed-forward spiking neural network with dendritic compartments. Utilizing 130 nm technology integrated with resistive RAM (RRAM), DenRAM incorporates both delays and synaptic weights. By configuring RRAMs to emulate bio-realistic delays and exploiting their heterogeneity, DenRAM mimics synaptic delays and efficiently performs CD for pattern recognition. Hardware-aware simulations on temporal benchmarks show DenRAM’s robustness against hardware noise, and its higher accuracy over recurrent networks. DenRAM advances temporal processing in neuromorphic computing, optimizes memory usage, and marks progress in low-power, real-time signal processing
Large-scale cross-ancestry genome-wide meta-analysis of serum urate
Authors: Cho Chamlee , Kim Beomsu , Kim Dan Say , Hwang Mi Yeong , Shim Injeong , Song Minku , Lee Yeong Chan , Jung Sang-Hyuk , Cho Sung Kweon , Park Woong-Yang , Myung Woojae , Kim Bong-Jo , Do Ron , Choi Hyon K. , Merriman Tony R. , Kim Young Jin , Won Hong-Hee 
Published: April 2024

AbstractHyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.
Whole-cortex in situ sequencing reveals input-dependent area identity
Authors: Chen Xiaoyin , Fischer Stephan , Rue Mara C. P. , Zhang Aixin , Mukherjee Didhiti , Kanold Patrick O. , Gillis Jesse , Zador Anthony M. 
Published: April 2024

Abstract
The cerebral cortex is composed of neuronal types with diverse gene expression that are organized into specialized cortical areas. These areas, each with characteristic cytoarchitecture1,2, connectivity3,4 and neuronal activity5,6, are wired into modular networks3,4,7. However, it remains unclear whether these spatial organizations are reflected in neuronal transcriptomic signatures and how such signatures are established in development. Here we used BARseq, a high-throughput in situ sequencing technique, to interrogate the expression of 104 cell-type marker genes in 10.3 million cells, including 4,194,658 cortical neurons over nine mouse forebrain hemispheres, at cellular resolution. De novo clustering of gene expression in single neurons revealed transcriptomic types consistent with previous single-cell RNA sequencing studies8,9. The composition of transcriptomic types is highly predictive of cortical area identity. Moreover, areas with similar compositions of transcriptomic types, which we defined as cortical modules, overlap with areas that are highly connected, suggesting that the same modular organization is reflected in both transcriptomic signatures and connectivity. To explore how the transcriptomic profiles of cortical neurons depend on development, we assessed cell-type distributions after neonatal binocular enucleation. Notably, binocular enucleation caused the shifting of the cell-type compositional profiles of visual areas towards neighbouring cortical areas within the same module, suggesting that peripheral inputs sharpen the distinct transcriptomic identities of areas within cortical modules. Enabled by the high throughput, low cost and reproducibility of BARseq, our study provides a proof of principle for the use of large-scale in situ sequencing to both reveal brain-wide molecular architecture and understand its development.
Optical clocks at sea
Authors: Roslund Jonathan D. , Cingöz Arman , Lunden William D. , Partridge Guthrie B. , Kowligy Abijith S. , Roller Frank , Sheredy Daniel B. , Skulason Gunnar E. , Song Joe P. , Abo-Shaeer Jamil R. , Boyd Martin M. 
Published: April 2024

AbstractDeployed optical clocks will improve positioning for navigational autonomy1, provide remote time standards for geophysical monitoring2 and distributed coherent sensing3, allow time synchronization of remote quantum networks4,5 and provide operational redundancy for national time standards. Although laboratory optical clocks now reach fractional inaccuracies below 10−18 (refs. 6,7), transportable versions of these high-performing clocks8,9 have limited utility because of their size, environmental sensitivity and cost10. Here we report the development of optical clocks with the requisite combination of size, performance and environmental insensitivity for operation on mobile platforms. The 35 l clock combines a molecular iodine spectrometer, fibre frequency comb and control electronics. Three of these clocks operated continuously aboard a naval ship in the Pacific Ocean for 20 days while accruing timing errors below 300 ps per day. The clocks have comparable performance to active hydrogen masers in one-tenth the volume. Operating high-performance clocks at sea has been historically challenging and continues to be critical for navigation. This demonstration marks a significant technological advancement that heralds the arrival of future optical timekeeping networks.
PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells
Authors: Lacher Sebastian B. , Dörr Janina , de Almeida Gustavo P. , Hönninger Julian , Bayerl Felix , Hirschberger Anna , Pedde Anna-Marie , Meiser Philippa , Ramsauer Lukas , Rudolph Thomas J. , Spranger Nadine , Morotti Matteo , Grimm Alizee J. , Jarosch Sebastian , Oner Arman , Gregor Lisa , Lesch Stefanie , Michaelides Stefanos , Fertig Luisa , Briukhovetska Daria , Majed Lina , Stock Sophia , Busch Dirk H. , Buchholz Veit R. , Knolle Percy A. , Zehn Dietmar , Dangaj Laniti Denarda , Kobold Sebastian , Böttcher Jan P. 
Published: April 2024

AbstractCancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1–4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5–9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2–EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
Antisense oligonucleotide therapeutic approach for Timothy syndrome
Authors: Chen Xiaoyu , Birey Fikri , Li Min-Yin , Revah Omer , Levy Rebecca , Thete Mayuri Vijay , Reis Noah , Kaganovsky Konstantin , Onesto Massimo , Sakai Noriaki , Hudacova Zuzana , Hao Jin , Meng Xiangling , Nishino Seiji , Huguenard John , Pașca Sergiu P. 
Published: April 2024

AbstractTimothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2–6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Single-cell analysis reveals context-dependent, cell-level selection of mtDNA
Authors: Kotrys Anna V. , Durham Timothy J. , Guo Xiaoyan A. , Vantaku Venkata R. , Parangi Sareh , Mootha Vamsi K. 
Published: April 2024

AbstractHeteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the ‘sign’ of the effect is wholly dependent on the environment.
Structures of human γδ T cell receptor–CD3 complex
Authors: Xin Weizhi , Huang Bangdong , Chi Ximin , Liu Yuehua , Xu Mengjiao , Zhang Yuanyuan , Li Xu , Su Qiang , Zhou Qiang 
Published: April 2024

AbstractGamma delta (γδ) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology1–3. The γδ T cell receptor (TCR), which is generated by γδ T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex2. The γδ TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy4. Here we report the structures of two prototypical human Vγ9Vδ2 and Vγ5Vδ1 TCR–CD3 complexes5,6, revealing two distinct assembly mechanisms that depend on Vγ usage. The Vγ9Vδ2 TCR–CD3 complex is monomeric, with considerable conformational flexibility in the TCRγ–TCRδ extracellular domain and connecting peptides. The length of the connecting peptides regulates the ligand association and T cell activation. A cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signalling. The Vγ5Vδ1 TCR–CD3 complex displays a dimeric architecture, whereby two protomers nestle back to back through the Vγ5 domains of the TCR extracellular domains. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the Vγ5Vδ1 TCR is essential for T cell activation. These findings reveal organizing principles of the γδ TCR–CD3 complex, providing insights into the unique properties of γδ TCR and facilitating immunotherapeutic interventions.
JAK-STAT signaling maintains homeostasis in T cells and macrophages
Authors: Fortelny Nikolaus , Farlik Matthias , Fife Victoria , Gorki Anna-Dorothea , Lassnig Caroline , Maurer Barbara , Meissl Katrin , Dolezal Marlies , Boccuni Laura , Ravi Sundar Jose Geetha Aarathy , Akagha Mojoyinola Joanna , Karjalainen Anzhelika , Shoebridge Stephen , Farhat Asma , Mann Ulrike , Jain Rohit , Tikoo Shweta , Zila Nina , Esser-Skala Wolfgang , Krausgruber Thomas , Sitnik Katarzyna , Penz Thomas , Hladik Anastasiya , Suske Tobias , Zahalka Sophie , Senekowitsch Martin , Barreca Daniele , Halbritter Florian , Macho-Maschler Sabine , Weninger Wolfgang , Neubauer Heidi A. , Moriggl Richard , Knapp Sylvia , Sexl Veronika , Strobl Birgit , Decker Thomas , Müller Mathias , Bock Christoph 
Published: April 2024

AbstractImmune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice—but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wild-type mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcriptional state and helps prepare these cells for rapid response to immune stimuli.
De novo identification of CD4+ T cell epitopes
Authors: Zdinak Paul M. , Trivedi Nishtha , Grebinoski Stephanie , Torrey Jessica , Martinez Eduardo Zarate , Martinez Salome , Hicks Louise , Ranjan Rashi , Makani Venkata Krishna Kanth , Roland Mary Melissa , Kublo Lyubov , Arshad Sanya , Anderson Mark S. , Vignali Dario A. A. , Joglekar Alok V. 
Published: April 2024

AbstractCD4+ T cells recognize peptide antigens presented on class II major histocompatibility complex (MHC-II) molecules to carry out their function. The remarkable diversity of T cell receptor sequences and lack of antigen discovery approaches for MHC-II make profiling the specificities of CD4+ T cells challenging. We have expanded our platform of signaling and antigen-presenting bifunctional receptors to encode MHC-II molecules presenting covalently linked peptides (SABR-IIs) for CD4+ T cell antigen discovery. SABR-IIs can present epitopes to CD4+ T cells and induce signaling upon their recognition, allowing a readable output. Furthermore, the SABR-II design is modular in signaling and deployment to T cells and B cells. Here, we demonstrate that SABR-IIs libraries presenting endogenous and non-contiguous epitopes can be used for antigen discovery in the context of type 1 diabetes. SABR-II libraries provide a rapid, flexible, scalable and versatile approach for de novo identification of CD4+ T cell ligands from single-cell RNA sequencing data using experimental and computational approaches.