bluuebunny/crossref_metadata_2025 huggingface dataset:
Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial cancer
Authors: Nikkola Jussi , Ryyppö Lauri , Vuorinen Juuso , Moilanen Lauri , Ahtiainen Maarit , Pylvänäinen Kirsi , Selin Hanna , Virtanen Tuomo , Nykter Matti , Veitonmäki Thea , Mecklin Jukka-Pekka , Seppälä Toni T. , Annala Matti
Published: December 2024

Lynch syndrome (LS) is a hereditary condition characterized by defective DNA mismatch repair (MMR) and high incidence of several cancers, including urothelial cancers (UC) of the upper urinary tract and bladder. We set out to study the somatic landscape of LS-associated urothelial cancer (LS-UC) by analyzing 41 surgical tumor samples and 3 urine DNA samples from 34 LS-UC patients. We show that telomerase reverse transcriptase (TERT) promoter mutations found in 83% of sporadic UC are almost completely absent (5%) in LS-UC (p < 0.00001). Instead, all LS-UC carried a 5-methylcytosine deamination (CG>TG) and microsatellite instability driven mutation landscape characterized by highly frequentARID1A(82%),FGFR3(80%), and KMT2D (78%) mutations, as well as preferential usage of CG>TG mutation hotspots. We propose that the scarcity ofTERTpromoter mutations in LS-UC is due to inability to create the necessary GABP binding motif (5’-GGAA) through CG>TG mutation or microsatellite instability. Our data shows that LS-UC represents a disease entity with unique genomic characteristics.
Multiple full-length homozygous IGH haplotypes from Mauritian cynomolgus macaques
Authors: Olubo Simone , Gibson William S. , Prall Trent M , Karl Julie , Wiseman Roger W. , O'Connor David H , Douek Danny , Schramm Chaim A
Published: December 2024

Background: Nonhuman primates are frequent experimental models for human disease pathology and vaccine design. However, the vast and mostly uncatalogued immunogenomic diversity of typical species adds complexity to the interpretation of experiments and hinders reproducibility. Mauritian cynomolgus macaques (MCM) offer a unique opportunity to circumvent these difficulties, due to their restricted genetic diversity. Results: We assembled high-quality immunoglobulin heavy chain (IGH) haplotypes from long-read genomic sequencing of 13 MCM. Four animals were homozygous for IGH, yielding 3 distinct haplotypes. IGH haplotype H1 was observed in two of the homozygotes and 5 additional heterozygous animals, accounting for half of the assemblies recovered. The 3 homozygous haplotypes exhibited considerable variation, including a 125 kilobase region that was duplicated twice in H3. Furthermore, H1 shares only 83% average sequence identity with the IGH locus of the rhesus macaque reference genome, in addition to numerous large structural variations. We annotated the IG gene content from all complete MCM IGH assemblies and found 298 functional IGHV alleles, of which 94 (32%) were not in existing databases. We also identified 69 functional IGHD alleles, 11 functional IGHJ alleles, and 38 functional constant gene alleles across all 5 isotypes. Conclusions: In total, we identified multiple common and genetically diverse IGH haplotypes within MCM and provide high-quality reference assemblies and annotations for these to facilitate future work with this important animal model.
Identification of genetic variation in genes linked to buparvaquone resistance in Theileria sp infecting dairy cattle in India.
Authors: Musale Pankaj , Khilari Ajinkya , Gade Rohini , Dhanikachalam Velu , Jadhav Santoshkumar , Bajpai Manali , Turakani Bhagya , Joshi Akshay , Prajapati Amar , Srivastava Anand , Swaminathan Marimutthu , Joshi Sachin , Shanmugam Dhanasekaran
Published: December 2024

Buparvaquone (BQO) is used for treatment of bovine theileriosis, a tickborne disease caused by parasites of the heileria genus. Studies on T. annulata have linked the mechanism of BQO resistance predominantly to genetic variations in the parasite cytochrome b (cytb) gene. In addition, cryptic mechanisms of resistance involving the parasite peptidyl-prolyl isomerase (pin1) and dihydroorotate dehydrogenase (dhodh) genes require assessment. In India, where bovine theileriosis is endemic, and BQO is widely used for treatment, monitoring and establishing the link between genetic variations in cytb, dhodh and pin1 genes and BQO resistance is essential. In this study, multiplexed PCR amplification and nanopore sequencing approaches were used for genotyping the complete gene loci of the target genes. Analysis of 420 T. annulata field samples collected from seven different states of India revealed the presence of previously reported variations S129G, A146T and P253S in cytb and A53P in pin1, which are linked to BQO resistance. The role of A146T, a highly prevalent variation which mostly co-occurred with I203V, in BQO resistance needs to be evaluated. From 60 samples having T. orientalis infection, the genetic variations identified from the three genes were found to be mostly natural variations based on the reference genotypes and were distinct from T. annulata variations. This study has revealed the presence of BQO resistance-linked cytb gene mutations in T. annulata infecting dairy cattle in India and establishes a nanopore sequencing method for molecular surveillance of genetic variation in field samples.
Microtubule stiffening by doublecortin-domain protein ZYG-8 contributes to spindle orientation duringC. eleganszygote division
Authors: Cueff Louis , Pastezeur Sylvain , Huet Ewen , Coquil Méline , Savary Titouan , Pécréaux Jacques , Bouvrais Hélène
Published: December 2024

To address the role of microtubule flexural rigidity in spindle positioning during cell division, we used theCaenorhabditis eleganszygote. We showed that ZYG-8DCLK1, its unique Doublecortin-family member, rigidifies microtubules, as evidenced by more bent microtubules when targeting this protein. Microtubules also exhibited larger maximal curvatures and increased tortuosity. Functionally, we observed increased amplitudes of anaphase spindle-pole oscillations followingzyg-8(RNAi)and even greater inzyg-8(or484ts)mutants preventing microtubule binding. Interestingly, the mutants exhibited incorrect final spindle position and orientation. Overly soft microtubules impaired spindle centring force, upsetting the pulling versus pushing force balance. We strengthened these findings by depleting PTL-1Tau, a protein that rigidifies microtubules. In conclusion, sufficient microtubule rigidity is essential during mitosis to ensure effective cortical pushing, thereby accurately orienting the spindle and guaranteeing correct daughter cell fates. Microtubule rigidity is likely controlled in human mitoses as well, consistent with reported DCLK1 and Tau deregulations in various cancers.
The mycobacterial nucleoid-associated protein NapM exhibits stress-induced septal localization and modulates cell envelope gene expression
Authors: Milcarz Kornel , Hołówka Joanna , Pawełczyk Jakub , Paściak Mariola , Lavrynchuk Yaroslav , Płociński Przemysław , Zakrzewska-Czerwińska Jolanta
Published: December 2024

The bacterial chromosome is organized in a hierarchical and dynamic manner to facilitate various DNA transactions. Nucleoid-associated proteins (NAPs) are the most abundant small-scale chromosomal organizers, playing roles in maintaining chromosomal DNA integrity, gene regulation, DNA replication, and DNA repair. In this study, we characterize the recently identified mycobacterial NAP, NapM inMycobacterium smegmatis. Our study shows that NapM exhibits a distinctive septal localization in response to stress affecting cell envelope integrity and modulates the expression of approximately one-third ofM. smegmatisgenes, including those involved in cell envelope biosynthesis. Our findings suggest that NapM regulates mycobacterial cell division under stress, enabling this saprophyte to adapt to constantly changing environmental conditions.
Thermodynamic Parameter Estimation for Modified Oligonucleotides Using Molecular Dynamics Simulations
Authors: Park Soon Woo , Lee Junehawk , Park Jung Woo , Kim Moon Ki , Seo Sangjae
Published: December 2024

This study investigates the thermodynamic parameters of 1,300 RNA/DNA hybrid duplexes, including both natural and chemically modified forms, using molecular dynamics (MD) simulations. Modified duplexes consist of phosphorothioate (PS) backbones and 2′-O-methoxyethyl (MOE) modifications, both commonly used in therapeutic oligonucleotides. Hybridization enthalpy and entropy were calculated from MD trajectories using molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalized Born surface area (MMGBSA) approaches. To address discrepancies with experimental data, we established empirical relationships by comparing calculated values with known experimental results of natural hybrid duplexes, then extended these relationships to the entire dataset. The corrected parameters were subsequently used to generate nearest-neighbor (NN) models, allowing for experimentally reliable melting temperature predictions. In this process, MMGBSA demonstrated superior predictive performance with high convergence and consistency for both natural and modified duplexes. Specifically, MMGBSA captured the stabilizing effects of the MOE modification with minimal bias, while MMPBSA exhibited greater variability and limited reliability. These findings highlight the potential of MMGBSA for accurate thermodynamic modeling of both natural and modified nucleic acids, providing a robust framework and experimentally meaningful insights for applications in nucleic acid-based therapeutic design and biotechnology.
Normative models reveal distinct cortical abnormalities to dimensions of psychopathologies in preadolescents
Authors: Deng Qingkun , Levitis Elizabeth , Adams Rick A , Altmann Andre
Published: December 2024

Background

Evidence suggests a non-specific mapping between psychiatric disorders and underlying neurobiological substrates. A dimensional psychopathology framework may prove useful for organizing observed neurobiological alterations along broad psychopathological dimensions.

Methods

We applied latent class analysis, with an additional constraint on classification uncertainty, to identify clinical cohorts of symptomatic homogeneity to represent the high-risk end of specific psychopathological dimensions (i.e., internalizing/externalizing,p-factor), using baseline data (N= 11860) from the Adolescent Brain and Cognitive Development (ABCD) Study. These cohorts were compared against neurotypical individuals in deviations from the normality of cortical development, quantified using autoencoder-based normative models, to reveal cortical abnormalities.

Results

We identified cortical thickness related to psychopathologies in the ABCD data, particularly to externalizing syndromes, and revealed distinct structural abnormalities to broad psychopathological dimensions.

Conclusion

This study highlights the value of person-centered analytic techniques, combined with normative modeling, to complement traditional associational methodologies in revealing neurobiological correlates of dimensional psychopathologies.
Purinergic Receptor P2Y13Controls Activation and Mode of Division in Subependymal Adult Neural Stem Cells
Authors: Paniagua-Herranz Lucía , Serrano-López Julia , Llorente-Sáez Celia , Pérez-Sanz Marina Leonor , de Agustín-Durán David , Duart-Abadia Pere , Domingo-Muelas Ana , Vincelle-Nieto África , Bragado Paloma , Manzano-Franco Diana , Arribas-Blázquez Marina , Olivos-Oré Luis Alcides , Gascón Sergio , Gutierrez-Uzquiza Álvaro , Pérez-Sen Raquel , Delicado Esmerilda G. , Gómez-Villafuertes Rosa , Reyes-Palomares Armando , Artalejo Antonio R. , Fariñas Isabel , Ortega Felipe
Published: December 2024

The subependymal zone (SEZ) of the mammalian brain is the most active germinal area that continues to generate newborn neurons throughout life. This area harbors a population of neural stem cells (NSCs) that can be found in different states of activation, each differing in proliferative capacity and molecular signature: quiescent NSCs (qNSCs), primed NSCs (pNSCs), and activated NSCs (aNSCs). There is currently a void in terms of the specific markers available to effectively discern between these transient states. Likewise, the molecular signaling mechanisms controlling the transition from quiescence to activation remain largely unexplored, as do the factors influencing the decision between differentiation and self-renewal during NSC division. Here, we present evidence that the metabotropic P2Y13purinergic receptor plays a critical role in regulating adult neurogenesis. We found that P2Y13is specifically expressed in NSCs within the adult SEZ and that its levels can be used to distinguish qNSCs from aNSCs. Functionally, P2Y13signaling promotes NSC activation, enhancing lineage progression, while dampening their self-renewal capacity. Conversely, pharmacological blockade or genetic silencing of the P2Y13receptor favors NSC quiescence. Thus, we identified the metabotropic P2Y13purinergic receptor as a pivotal modulator of NSC dynamics, influencing both the balance between NSC quiescence and activation and the mode of NSC division at the subependymal zone.
Mapping Chromatin Interactions of ZBP1 and ADAR1 Z-Alpha Domains: A ChIP-Seq Based Comparison
Authors: Hamrick Dennis , Sharma Manjita , Grow Edward
Published: December 2024

The DNA double helix typically exists in the canonical B-form conformation, but this structure often can adopt the unique alternative form known as Z-DNA. In Z-DNA, the DNA helix winds to the left in a zigzag pattern instead of the right-handed B-DNA form. Z-DNA is thought to play a key role in transcription, but it is unclear whether is a positive or negative regulator of RNA polymerase activity. Additionally, several studies have shown how Z-DNA contributes to DNA damage or genome instability. However, the precise role of Z-DNA in the genome remains unclear. To address this question, we mapped Z-DNA using a ChIP-Seq assay with two Z-DNA biosensors: Zaa-Zbp1, comprised of a dimerized Z-alpha Z-DNA binding domains from Z-DNA binding protein 1 (Zbp1), and Zaa-Adar1, comprised of dimerized Z-alpha domains from Adenosine deaminase acting on RNA 1 (Adar1). We found that these Zaa probes possessed similar binding profiles when analyzed with motif analysis, but gene ontology analysis revealed that these Z-alpha domains bound to heterogeneous genes, with Zaa-Zbp1 most strongly binding to genes in the RHOQ-GTPase pathway and Zaa-Adar1 binding to genes involved in the M phase of the cell cycle.
Global Cancer Burden Attributable to Dietary Risks: Trends, Regional Disparities, and Future Projections (1990-2050)
Authors: Liang Jinghao , Lin Yijian , Huang Zishan , Ni Jingchun , Lin Hongmiao , Cai Yiwen , Qi Jihao , Yao Liangyi , Yang Luoyao , Lin Dianhan , Guo Zhihua , Yin Weiqiang , He Jianxing
Published: December 2024

Cancer remains a leading global cause of death, with its burden increasingly shaped by demographic shifts and dietary factors. This study utilized the Global Burden of Disease (GBD) 2021 database to evaluate cancer burdens attributable to dietary risks from 1990 to 2021, accounting for differences by age, gender, region, and socioeconomic level, and projected trends through 2050 using a Bayesian Age-Period-Cohort model. The global disability-adjusted life years (DALYs) attributable to dietary risks declined from 302.48 to 189.62 per 100,000 population (AAPC: −1.49%) over three decades, yet disparities remain prominent across Socio-Demographic Index (SDI) regions. High-SDI countries, such as Luxembourg, achieved substantial reductions, while low-SDI nations like Lesotho and Zimbabwe experienced rising burdens, driven by inadequate dietary quality and limited health resources. Key dietary risks, including low intake of whole grains, milk, and red meat, demonstrated improvement in high-income countries but worsening trends in many low- and middle-income regions. Projections suggest a continued global decline in cancer burden attributable to dietary factors by 2050, with high-income regions benefiting most, while Latin America, the Caribbean, North Africa, and the Middle East may experience slower progress or transient increases. Additionally, the burden of poor dietary practices is expected to rise sharply among individuals aged 75 years and older, underscoring the compounding effects of aging populations. These findings highlight the urgent need for culturally tailored dietary interventions and evidence-based policies to address disparities, reduce cancer burdens, and improve outcomes for vulnerable populations globally.
Impact of a transient neonatal visual deprivation on the development of the ventral occipito-temporal cortex in humans
Authors: Mattioni Stefania , Rezk Mohamed , Gao Xiaoqing , Nam Junghyun , Liu Zhong-Xu , Gau Remi , Goffaux Valérie , Constantino Andrea I. , de Beeck Hans Op , Lewis Terri , Maurer Daphne , Collignon Olivier
Published: December 2024

How does experience shape the development of visual brain regions? We demonstrate that a transient period of visual deprivation early in life in humans leads to permanent alteration in the function of the early visual cortex (EVC), while leaving the categorical coding of downstream ventral occipito-temporal cortex (VOTC) mostly unaffected. We used fMRI to characterize the brain response to five categories (faces, bodies, objects, buildings and words) in a rare group of cataract-reversal individuals who experienced a transient period of blindness early in life, and in matched participants with typical visual development. We show that the encoding of low-level visual properties is impaired in EVC in cataract-reversal participants, while the categorical response in the VOTC is preserved. When altering the visual properties of our stimuli to mimic in controls the deficit of EVC response of the cataract, we observe a cascading alteration of the categorical coding from EVC to VOTC that is not observed in the cataract-reversal group. Our results show that a typical visual categorical organization develops in VOTC despite a period of visual deprivation early in life and in the presence of impaired processing in EVC. A deep neural network exposed to a visual diet that emulates the experience of our participants reproduced our brain observations within an artificial system. These findings emphasize how specific visual regions are differently affected by a period of visual deprivation early in life, with information encoded in EVC being permanently affected, while the categorical coding in VOTC shows resilience to deprivation.
Emotion processing in mothers with bonding disorder during the first year postpartum: Results of an adapted fMRI emotional GoNoGo Task
Authors: Eckstein Monika , Krauch Marlene , Brenner Ines , Zietlow Anna-Lena , Ditzen Beate
Published: December 2024

Maternal bonding refers to the unique emotional connection between a mother and her baby that gradually develops during the pre- and postpartum period. However, 3-24% of women report bonding disorders (BD), often accompanied by constraints for the mother-infant relationship with consequences for child development. The underlying neural patterns are not clarified yet. Our present study investigates the neural and behavioral patterns that underlie the processing of emotional infant stimuli over the 1 year postpartum. Mothers with and without BD (N = 45) completed an adapted (newly developed) Emotional Infant GoNoGo Task while fMRI scanning at 3, 6 and 12 months postpartum. Our results show that response inhibition towards emotional infant faces elicits stronger results than towards adult faces in all mothers. While behavioral performance in BD is impaired, the neural responses to emotional infant faces as compared to neutral faces are increased at 3 months postpartum in limbic structures such as the anterior cingulate and insula, as well as nucleus caudatus. At 6 and 12 months behavioral reactions assimilate in BD to those of healthy controls, while differences in neural reactions between BD and healthy controls increase at 6 months and decrease again at 12 months. These effects are independent of depressive symptoms. Our findings point to an experience-based adaptive process of emotion processing and responses to infants’ affect during the first year postpartum as a specific characteristic of clinical bonding disorder and thus might point to potential or future therapeutic interventions targeting emotion processing and regulation in mothers with BD.

Key Findings

⍰ We present an adapted version of an Emotional GoNoGo Task for fMRI with infant stimuli: Behavioral inhibition towards emotional infant faces leads to increased activity in emotion regulation networks compared to adult faces in women during the 1styear postpartum.

⍰ Women with postpartum bonding disorder (BD) show increased neural reactions (ACC, NCl Caudate, Insula) towards emotional baby faces (not adult faces, irrespectively of instructed inhibition and of valence) compared to a healthy control group (CG) at 3 months postpartum.

⍰ On a behavioural level, women with BD show increased reaction times to positive emotional adult faces and higher error rates during the inhibition of reaction towards emotional baby faces at 3 months.

⍰ Differences in neural reactions to emotional baby faces between BD and CG increase at 6 months and decrease again at 12 months, while behavioral reactions in BD assimilate to those of CG
Network-based drug repurposing for psychiatric disorders using single-cell genomics
Authors: Gupta Chirag , Kalafut Noah Cohen , Clarke Declan , Choi Jerome J. , Arachchilage Kalpana Hanthanan , Khullar Saniya , Xia Yan , Zhou Xiao , Gerstein Mark , Wang Daifeng
Published: December 2024

Neuropsychiatric disorders lack effective treatments due to a limited understanding of underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data and analyzed cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, and autism (23 cell classes/subclasses). Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural networks on those modules to prioritize novel risk genes and leveraged them in a network-based drug repurposing framework to identify 220 drug molecules with the potential for targeting specific cell types. We found evidence for 37 of these drugs in reversing disorder-associated transcriptional phenotypes. Additionally, we discovered 335 drug-associated cell-type eQTLs, revealing genetic variation’s influence on drug target expression at the cell-type level. Our results provide a single-cell network medicine resource that provides mechanistic insights for advancing treatment options for neuropsychiatric disorders.
Effects of Vascular Endothelial Growth Factor Family on Macular Pucker:cis-Mendelian Randomization and Colocalization Analyses
Authors: Gao Qi , Guo Jinglong
Published: December 2024

Background

Vascular endothelial growth factor (VEGF) family and its receptors (VEGFR) could be implicated in macular pucker (MP) pathogenesis. We usedcis-Mendelian randomization (cis-MR) and Bayesian colocalization with summary-level genome-wide association study (GWAS) data to explore causal relationships.

Methods

Genetic variants associated with soluble VEGFR2 (sVEGFR2), sVEGFR3, VEGF-A, VEGF-C, or VEGF-D levels were selected from a GWAS of protein quantitative trait loci with 35,559 Icelanders. MP GWAS (3,974 cases, 376,650 controls) was sourced from the FinnGen. We employedcis-MR using invariance-weighted median, supplemented by other methods. Bayesian colocalization validatedcis-MR findings. Pleiotropy, reverse causality, and heterogeneity were assessed.

Findings

Cis-MR suggested that genetically predicted higher levels of sVEGFR2 were associated with reduced MP risk (Odds ratio (OR) 0.82, 95% confidence interval (CI) 0.75-0.89, P=9.20 × 10-6). Colocalization supported shared genetic variants in theVEGFR2gene region between sVEGFR2 and MP (posterior probability of hypothesis 4 (PPH4) =0.94), reinforcing sVEGFR2’s protective role in MP. Althoughcis-MR suggested an inverse relationship between sVEGFR3 levels and MP risk (OR 0.71, 95% CI 0.57-0.89, P=2.64 × 10-3), colocalization analysis did not confirm direct causality (PPH4=0.03). VEGF-A, VEGF-C and VEGF-D levels were not associated with MP risk in MR analyses. No evidence of pleiotropy, reverse causality, and heterogeneity was found across our MR analyses.

Interpretation

Our study suggested that sVEGFR2 has causally protective effects against MP and could serve as a potential drug target. Further research is necessary to elucidate its protective mechanisms and validate its translational implications.
Efficacy of Melflufen in Patients with Relapsed/Refractory Multiple Myeloma and Mutated or DeletedTP53
Authors: Acs Klara , Miettinen Juho J. , Sergeev Philipp , Heckel Tobias , Diao Yumei , Witt-Mulder Kristina , Thureson Marcus , Bischler Thorsten , Huppunen Maiju-Emilia , Obermüller Jakob , Munawar Umair , Slipicevic Ana , Bargou Ralf C. , Lehmann Fredrik , Gelius Stefan Svensson , Norin Stefan , Schjesvold Fredrik , Sonneveld Pieter , Stühmer Thorsten , Heckman Caroline A.
Published: December 2024

Background

Patients with relapsed/refractory multiple myeloma (RRMM) and high-risk genetic abnormalities such as del(17p) andTP53mutation have poor response to standard therapies and shorter survival compared to patients without these aberrations. Here, we investigated the activity and mechanism of action of peptide-drug conjugate melphalan flufenamide (melflufen) inTP53wild type (TP53wt) and mutant (TP53mut) myeloma models and assessed the efficacy of melflufen in patients with del(17p) and/orTP53mutation.

Methods

We evaluated melflufen activityex vivoin 24 myeloma bone marrow (BM) samples and explored indicators of response from single cell RNA sequencing (scRNAseq) profiles. The efficacy of melflufenvs.control treatments was further investigated inTP53−/−and parentalTP53wt myeloma cell lines. DNA damage, apoptosis kinetics, mitochondrial function, plus transcriptomic and metabolic data were analyzed to understand the mechanisms responsible for melflufen activity in the absence of p53. Patient outcome data from the OCEAN phase III clinical trial (NCT03151811), which investigated the clinical activity of melflufen in RRMM, were statistically analyzed to assess the impact of del(17p) andTP53mutation on clinical response.

Results

BM plasma cell (PC) response to melflufen was independent ofTP53mutation status, with melflufen active in del(17p),TP53mut, andTP53wt samples. Differential analysis of scRNAseq data demonstrated that melflufen sensitive PCs had lower expression of p53 target genes and higher expression of genes associated with DNA damage repair and cell cycle checkpoints. Analysis ofTP53−/−andTP53wt cell lines showed superior efficacy of melflufen in comparison to melphalan or cyclophosphamide. In the presence and absence of functional p53, melflufen robustly induced apoptosis, DNA damage, and mitochondrial dysfunction. InTP53−/−cells, melflufen treatment led to distinct changes in expression of genes associated with cell cycle checkpoint and apoptosis, which were not observed with melphalan treatment. Notably, post-hoc analysis of the OCEAN trial del(17p) patient population demonstrated favorable progression free survival in the del(17p) subgroup treated with melflufen plus dexamethasone compared to the pomalidomide plus dexamethasone arm.

Conclusions

Our insights into the molecular mechanisms of melflufen activity inTP53mut myeloma support its clinical efficacy and application in the del(17p) andTP53mut patient population.

Trial registration

NCT03151811, registration 2017-05-09.
Inferring disease progression stages in single-cell transcriptomics using a weakly supervised deep learning approach
Authors: Wehbe Fabien , Adams Levi , Babadoudou Jordan , Yuen Samantha , Kim Yoon-Seong , Tanaka Yoshiaki
Published: December 2024

Application of single-cell/nucleus genomic sequencing to patient-derived tissues offers potential solutions to delineate disease mechanisms in humans. However, individual cells in patient-derived tissues are in different pathological stages, and hence, such cellular variability impedes subsequent differential gene expression analyses. To overcome such a heterogeneity issue, we present a novel deep learning approach, scIDST, that infers disease progression levels of individual cells with weak supervision framework. The disease progression–inferred cells display significant differential expression of disease-relevant genes, which cannot be detected by comparative analysis between patients and healthy donors. In addition, we demonstrate that pretrained models by scIDST are applicable to multiple independent data resources and are advantageous to infer cells related to certain disease risks and comorbidities. Taken together, scIDST offers a new strategy of single-cell sequencing analysis to identify bona fide disease-associated molecular features.
The rate and spectrum of new mutations in mice inferred by long-read sequencing
Authors: López-Cortegano Eugenio , Chebib Jobran , Jonas Anika , Vock Anastasia , Künzel Sven , Keightley Peter D. , Tautz Diethard
Published: December 2024

All forms of genetic variation originate from new mutations, making it crucial to understand their rates and mechanisms. Here, we use long-read sequencing from Pacific Biosciences (PacBio) to investigate de novo mutations that accumulated in 12 inbred mouse lines derived from three commonly used inbred strains (C3H, C57BL/6, and FVB) maintained for 8 to 15 generations in a mutation accumulation (MA) experiment. We built chromosome-level genome assemblies based on the MA line founders’ genomes and then employed a combination of read and assembly-based methods to call the complete spectrum of new mutations. On average, there are about 45 mutations per haploid genome per generation, about half of which (54%) are insertions and deletions shorter than 50 bp (indels). The remainder are single-nucleotide mutations (SNMs; 44%) and large structural mutations (SMs; 2%). We found that the degree of DNA repetitiveness is positively correlated with SNM and indel rates and that a substantial fraction of SMs can be explained by homology-dependent mechanisms associated with repeat sequences. Most (90%) indels can be attributed to microsatellite contractions and expansions, and there is a marked bias toward 4 bp indels. Among the different types of SMs, tandem repeat mutations have the highest mutation rate, followed by insertions of transposable elements (TEs). We uncover a rich landscape of active TEs, notable differences in their spectrum among MA lines and strains, and a high rate of gene retroposition. Our study offers novel insights into mammalian genome evolution and highlights the importance of repetitive elements in shaping genomic diversity.
Impact of beam asymmetries at the Future Circular Collider
e+e−
Authors: Kicsiny Peter , Buffat Xavier , Le Nguyen Nguyen Khoi , Pieloni Tatiana , Seidel Mike
Published: December 2024

In this paper, we present detailed simulations with asymmetric initial beam settings in the context of the proposed Future Circular Collider e+e− (FCC-ee) using the framework. We compare simulated equilibrium bunch sizes and luminosities against an already existing analytical model, which shows remarkably good agreement for realistic small perturbations. We investigate the longitudinal top-up injection, the currently preferred injection scheme for the FCC-ee, using self-consistent simulations featuring beam-beam collisions with beamstrahlung and the injection process for the first time. We present and assess the sensitivity and required precision of the nominal beam parameters in a potential real-life operation by providing first estimates of the tolerances in the initial asymmetry of several machine parameters, with respect to the 3D flip-flop mechanism, obtained from parameter scan simulations.

Published by the American Physical Society
2024
New analytical formula on the Touschek lifetime of the polarized electron beam in electron storage rings
Authors: Fu Hongjin , Duan Zhe , Wang Jiuqing
Published: December 2024

Several analytical formulas have been developed to calculate the Touschek lifetime of beam in electron storage rings under different assumptions. Among them, Piwinski’s formula is the most general and precise for unpolarized beams, widely applied in the mainstream accelerator simulation software. Lee’s formula is conventionally adopted to evaluate the influence of beam polarization on the Touschek lifetime, but it is less general than Piwinski’s formula when applied to unpolarized beams. In this paper, a new formula for the Touschek lifetime of ultrarelativistic polarized beams is derived in the theoretical framework of Piwinski. Its applications to several lattices of electron storage rings reveal that the influence of beam polarization on the Touschek lifetime is weaker than that estimated with Lee’s formula especially when the vertical emittance is large.

Published by the American Physical Society
2024
Double pole structures of
X1(2900)
as the
P
-wave
D¯*K*
resonances
Authors: Wang Jun-Zhang , Lin Zi-Yang , Wang Bo , Meng Lu , Zhu Shi-Lin
Published: December 2024

We reveal the double pole structures of the manifestly exotic tetraquark state X1(2900) in the scenario of P-wave D¯*K* dimeson resonance. We find that the observed enhancement signal associated with X1(2900) in B+→D+D−K+ by LHCb contains two P-wave poles denoted as Tcs1−(2900) and Tcs1−′(2900), respectively. After considering the channel couplings among the D¯K, D¯*K, D¯K* and D¯*K* and the width of the K* meson, the masses and widths of the S-wave pole Tcs0+(2900) and two P-wave poles Tcs1−(2900) and Tcs1−′(2900) coincide with those of the X0(2900) and X1(2900) remarkably, which provides strong support for identifying X0(2900) and X1(2900) as D¯(*)K(*) dimeson states. Furthermore, we extensively calculate all S-wave and P-wave D¯(*)K(*) systems up to J=3 and predict four new isoscalar charmed-strange dimeson-type tetraquark states: an S-wave state Tcs1+(2900) with quantum number JP=1+, three P-wave states Tcs1−(2760) with JP=1−, Tcs0−(2760) with JP=0− and Tcs2−(2900) with JP=2−. These near-threshold poles can be searched for at LHCb, Belle II and BESIII.

Published by the American Physical Society
2024
Potential of light-cone sum rules without semiglobal quark-hadron duality
Authors: Carvunis A. , Mahmoudi F. , Monceaux Y.
Published: December 2024

This work addresses the calculation of local form factors involved in the theoretical predictions of semileptonic B-meson decays at low q2. We present a new approach to the method of QCD light-cone sum rule with B-meson light-cone distribution amplitudes. In our strategy, we bypass the semiglobal quark-hadron duality (QHD) approximation which usually contributes an unknown and potentially large systematic error to the prediction of form factors. We trade this improvement for an increased reliance on higher-order contributions in perturbation theory. Unlike the systematic error from semiglobal QHD, truncation errors are assessable and systematically improvable, hence allowing robust predictions of form factors. For the transitions B→π,ρ,K(*), our predictions agree with the literature for all form factors at q2=0.

Published by the American Physical Society
2024
Axions in Andromeda: Searching for minicluster-neutron star encounters with the Green Bank Telescope
Authors: Walters Liam , Shroyer Jordan E. , Edenton Madeleine , Agrawal Prakamya , Johnson Bradley , Kavanagh Bradley J. , Marsh David J. E. , Visinelli Luca
Published: December 2024

The QCD axion and axionlike particles are compelling candidates for galactic dark matter. Theoretically, axions can convert into photons in the presence of a strong external magnetic field, which means it is possible to search for them experimentally. One approach is to use radio telescopes with high-resolution spectrometers to look for axion-photon conversion in the magnetospheres of neutron stars. In this paper, we describe the results obtained using a novel approach where we used the Green Bank Telescope (GBT) to search for radio transients produced by collisions between neutron stars and dark matter clumps known as axion miniclusters. We used the versatile GBT astronomical spectrometer and the X-band receiver (8–10 GHz) to observe the core of Andromeda. Our measurements are sensitive to axions with masses between 33 and 42  μeV with Δma=3.8×10−4  μeV. This paper gives a description of the search method we developed, including observation and analysis strategies. Given our analysis algorithm choices and the instrument sensitivity (∼2  mJy in each spectral channel), we did not find any candidate signals greater than 5σ. We are currently implementing this search method in other spectral bands.

Published by the American Physical Society
2024
Quantum-corrected anti–de Sitter spacetime
Authors: Thompson Jacob C. , Winstanley Elizabeth
Published: December 2024

We study the backreaction of a quantum scalar field on anti–de Sitter (AdS) spacetime. The renormalized expectation value of the stress-energy tensor operator for a massless, conformally coupled quantum scalar field on global AdS spacetime in four space-time dimensions acts as a source term on the right-hand side of the Einstein equations for the quantum-corrected metric. We solve the quantum-corrected Einstein equations numerically and find deviations from pure AdS which increase as the temperature of the quantum scalar field state increases. We interpret these quantum-corrected metrics as asymptotically AdS solitons, and study the mass of these solitons as a function of the temperature of the quantum scalar field.

Published by the American Physical Society
2024
Modular invariance as completeness
Authors: Benedetti Valentin , Casini Horacio , Kawahigashi Yasuyuki , Longo Roberto , M. Magán Javier
Published: December 2024

We review the physical meaning of modular invariance for unitary conformal quantum field theories in d=2. For quantum field theory models, while T invariance is necessary for locality, S invariance is not mandatory. S invariance is a form of completeness of the theory that has a precise meaning as Haag duality for arbitrary multi-interval regions. We present a mathematical proof as well as derive this result from a physical standpoint using Renyi entropies and the replica trick. For rational conformal field theories (CFTs), the failure of modular invariance or Haag duality can be measured by an index, related to the quantum dimensions of the model. We show how to compute this index from the modular transformation matrices. The index also appears in a limit of the Renyi mutual information. Cases of infinite index are briefly discussed. Part of the argument can be extended to higher dimensions, where the lack of completeness can also be diagnosed using the CFT data through the thermal partition function and measured by an index.

Published by the American Physical Society
2024
Generalized symmetry resolution of entanglement in conformal field theory for twisted and anyonic sectors
Authors: Das A. , Molina-Vilaplana J. , Saura-Bastida P.
Published: December 2024

A comprehensive symmetry resolution of the entanglement entropy in (1+1)-d rational conformal field theories with categorical noninvertible symmetries is presented. This amounts to symmetry resolving the entanglement with respect to the generalized twisted and anyonic charged sectors of the theory. The anyonic sectors label the irreducible representations of a modular fusion category defining the symmetry and can be understood through the (2+1)-d symmetry topological field theory that encodes the symmetry features of the conformal field theory. Using this, we define the corresponding generalized boundary-dependent charged moments necessary for the symmetry resolution of the entanglement entropy and find that, contrary to the case of invertible symmetries, the entanglement equipartition between different charged sectors at the next-to-leading order in the ultraviolet cutoff, is broken.

Published by the American Physical Society
2024
Celestial strings: Field theory, conformally soft limits, and mapping the worldsheet onto the celestial sphere
Authors: Castiblanco Lina , Giribet Gaston , Marin Gabriel , Rojas Francisco
Published: December 2024

We compute the celestial correlators corresponding to tree-level 5-gluon amplitudes in the type I superstring theory. Since celestial correlation functions are obtained by integrating over the full range of energies, there is no obvious analog of the α′→0 limit in this basis. This is manifestly shown by a factorization of the α′ dependence in the celestial string amplitudes. Consequently, the question arises as to how the field theory limit is recovered from string theory in the celestial basis. This problem has been addressed in the literature for the case of 4-gluon amplitudes at tree level, where the forward scattering limit of the stringy factor was identified as a limit in which celestial Yang-Mills 4-point function is recovered. Here, we extend the analysis to the case with five gluons, for which the string moduli space allows for more types of limits, thus allowing us to investigate this aspect in more detail. Based on celestial data only, we study the regime in which one arrives at the correct celestial field theory limit. We also study other properties of the celestial string amplitudes, namely, the conformally soft theorem, effective field theory expansion in the conformal basis, and a map that arises in the regime of high-energy/large-scaling dimension that connects the punctured string world sheet to the insertion of primary operators in the celestial CFT for the massless n-point string amplitude.

Published by the American Physical Society
2024
Real time dynamics of large
N
models
Authors: Popov Fedor K.
Published: December 2024

We analyze the real-time dynamics of the large N vector model, focusing on heavy states with energies of the order N. In this regime, we demonstrate that interactions become sufficiently strong to produce nonzero condensate of the Hubbard-Stratonovich field σ, which, in turn, induces particle production. This process leads to a significant transformation of the initial state and potential thermalization. For homogeneous perturbations, our results show that the equations become integrable, yet can still lead to thermalization in the continuum limit. Furthermore, we calculate the energies of these heavy states and their contributions to the thermal free energy, thereby determining the free energy of the critical O(N) model by operator counting.

Published by the American Physical Society
2024
Melancholia states of the Atlantic Meridional Overturning Circulation
Authors: Lohmann Johannes , Lucarini Valerio
Published: December 2024

The Atlantic Meridional Overturning Circulation (AMOC) is a much studied component of the climate system, because its suspected multistability is associated with tipping behavior yielding potentially large regional and global climatic impacts. In this paper we investigate the global stability properties of the system using an ocean general circulation model. We construct an unstable AMOC state, i.e., an unstable solution of the flow that resides between the stable regimes of a vigorous and collapsed AMOC. Such a solution, also known as a melancholia or edge state, is a dynamical saddle embedded in the boundary separating the competing basins of attraction. It is physically relevant since it lies on the most probable path of a noise-induced transition between the two stable regimes, and because tipping occurs when one of the attractors and the melancholia state collide. Its properties may thus give hints towards physical mechanisms and predictability of the critical transition. We find that while the AMOC melancholia state as viewed from its upper ocean properties lies between the vigorous and collapsed regimes, it is characterized by an Atlantic deep ocean that is fresher and colder compared to both stable regimes. The melancholia state has higher dynamic enthalpy than either stable state, representing a state of higher potential energy that is in good agreement with the dynamical landscape view on metastability.

Published by the American Physical Society
2024
Nonperturbative Effects in Energy Correlators: From Characterizing Confinement Transition to Improving
αs
Extraction
Authors: Lee Kyle , Pathak Aditya , Stewart Iain W. , Sun Zhiquan
Published: December 2024

Energy correlators provide a powerful observable to study fragmentation dynamics in QCD. We demonstrate that the leading nonperturbative corrections for projected N-point energy correlators are described by the same universal parameter for any N, which has already been determined from other event shape fits. Including renormalon-free nonperturbative corrections substantially improves theoretical predictions of energy correlators, notably the transition into the confining region at small angles. Nonperturbative corrections are shown to have a significant impact on αs extractions.

Published by the American Physical Society
2024
Tunable Generation of Spatial Entanglement in Nonlinear Waveguide Arrays
Authors: Raymond A. , Zecchetto A. , Palomo J. , Morassi M. , Lemaître A. , Raineri F. , Amanti M. I. , Ducci S. , Baboux F.
Published: December 2024

Harnessing high-dimensional entangled states of light presents a frontier for advancing quantum information technologies, from fundamental tests of quantum mechanics to enhanced computation and communication protocols. In this context, the spatial degree of freedom stands out as particularly suited for on-chip integration. But while traditional demonstrations produce and manipulate path-entangled states sequentially with discrete optical elements, continuously coupled nonlinear waveguide systems offer a promising alternative where photons can be generated and interfere along the entire propagation length, unveiling novel capabilities within a reduced footprint. Here we exploit this concept to implement a compact and reconfigurable source of path-entangled photon pairs based on parametric down-conversion in semiconductor nonlinear waveguide arrays. We use a double-pump configuration to engineer the output quantum state and implement various types of spatial correlations, exploiting a quantum interference effect between the biphoton state generated in each pumped waveguide. This demonstration, at room temperature and telecom wavelength, illustrates the potential of continuously coupled systems as a promising alternative to discrete multicomponent quantum circuits for leveraging the high-dimensional spatial degree of freedom of photons.

Published by the American Physical Society
2024
Strong-Field Theory of Attosecond Tunneling Microscopy
Authors: Ma Boyang , Krüger Michael
Published: December 2024

Attosecond observations of coherent electron dynamics in molecules and nanostructures can be achieved by combining conventional scanning tunneling microscopy (STM) with ultrashort femtosecond laser pulses. While experimental studies in the subcycle regime are under way, a robust strong-field theory description has remained elusive. Here we devise a model based on the strong-field approximation. Valid in all regimes, it provides a surprising analogy to the standard model of STM. We show that the intuitive three-step model of attosecond science directly emerges from our model and we also describe the optimal conditions for attosecond STM experiments.

Published by the American Physical Society
2024