bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Methylation Signatures of Cardiovascular Health Provide Insights into Diseases
Authors: Carbonneau Madeleine , Li Yi , Qu Yishu , Zheng Yinan , Wood Alexis C. , Wang Mengyao , Liu Chunyu , Huan Tianxiao , Joehanes Roby , Guo Xiuqing , Yao Jie , Taylor Kent D. , Tracy Russell P. , Peter Durda , Liu Yongmei , Johnson W Craig , Post Wendy S. , Blackwell Tom , Rotter Jerome I. , Rich Stephen S. , Redline Susan , Fornage Myriam , Wang Jun , Ning Hongyan , Hou Lifang , Lloyd-jones Donald , Ferrier Kendra , Min Yuan-I. , Carson April P. , Raffield Laura M. , Teumer Alexander , Grabe Hans J. , Völzke Henry , Nauck Matthias , Dörr Marcus , Domingo-Relloso Arce , Fretts Amanda , Tellez-Plaza Maria , Cole Shelley , Navas-Acien Ana , Wang Meng , Murabito Joanne M. , Heard-Costa Nancy L. , Prescott Brenton , Xanthakis Vanessa , Mozaffarian Dariush , Levy Daniel , Ma Jiantao
Published: November 2024

Background

The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

Methods

We calculated the American Heart Association’s Life’s Essential 8 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with LE8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident CVD, CVD-specific mortality, and all-cause mortality.

Results

We identified 609 CpGs associated with LE8 score at false discovery rate (FDR) < 0.05 in the discovery analysis and at Bonferroni correctedP< 0.05 in the multi-cohort replication stage. Most had low-to-moderate heterogeneity (414 CpGs [68.0%] with I2< 0.2) in replication analysis. Pathway enrichment analyses and phenome-wide association study (PheWAS) search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the EWAS catalog, with 29-fold enrichment for stroke (P= 2.4e-15) and 21-fold for ischemic heart disease (P= 7.4e-38). Two-sample Mendelian randomization (MR) analysis showed significant association between 141 CpGs and ten phenotypes (261 CpG-phenotype pairs) at FDR < 0.05. For example, hypomethylation at cg20544516 (MIR33B;SREBF1) associated with lower risk of stroke (P= 8.1e-6). In multivariable prospective analyses, the CVH DNAm score was consistently associated with clinical outcomes across participating cohorts, the reduction in risk of incident CVD, CVD mortality, and all-cause mortality per standard deviation increase in the DNAm score ranged from 19% to 32%, 28% to 40%, and 27% to 45%, respectively.

Conclusions

We identified new DNAm signatures for CVH across diverse cohorts. Our analyses indicate that immune response-related pathways may be the key mechanism underpinning the association between CVH and clinical outcomes.
Effectiveness of aerobic physical exercise on depression symptoms in adults: A protocol for a systematic review and meta-analysis of randomized clinical trials
Authors: de Souza Larissa Nayara , de Araújo Silvana Medeiros , da Silva Paiva Eva , Eliege da Silva Alícia , da Costa Neto Joel Florêncio , Lima Assis Juvêncio César , dos Santos Isis Kelly , Mesquita Soares Themis Cristina , Pinto Edson Fonseca , da Silva Júnior Roque Ribeiro , Knackfuss Maria Irany
Published: November 2024

Objective

Depression is a chronic condition that affects millions of people and requires effective interventions. Studies suggest that aerobic exercise can improve mental health and reduce depression symptoms, despite variations in exercise type and intensity. The aim of this study will be to analyze the effect of aerobic exercise on reducing depression in adults.

Methods

This is a systematic review protocol, which will follow the PRISMA-P 2020 guidelines and has been registered in PROSPERO (no. CRD42024592700). The study search will be conducted in five databases: PubMed, Embase, Cochrane, BVS, and SPORTDiscus, using MeSH-based descriptors. Studies will be selected independently by two researchers using the Rayyan ‘QCRI’ software. Data extraction will be conducted with specific forms, and the methodological quality of the studies will be assessed using the Cochrane RoB 2.0 method. The certainty of evidence will be evaluated through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).

Conclusions

The systematic review is expected to identify the effective dose-response for reducing depression levels and provide understanding of the mechanisms through which aerobic exercise influences depression.
AZIN2-dependent polyamine metabolism determines adipocyte progenitor fate and protects against obesity and dysmetabolism
Authors: Mund Christine , Sinha Anupam , Aderhold Anika , Mateska Ivona , Hagag Eman , Traikov Sofia , Gercken Bettina , Soto Andres , Pollock Jonathan , Arndt Lilli , Wölk Michele , Werner Natalie , Fodelianaki Georgia , Subramanian Pallavi , Chung Kyoung-Jin , Grossklaus Sylvia , Langner Mathias , Elgendy Mohamed , Grinenko Tatyana , Wielockx Ben , Dahl Andreas , Gericke Martin , Blüher Matthias , Coskun Ünal , Voehringer David , Fedorova Maria , Peitzsch Mirko , Murray Peter J. , Chavakis Triantafyllos , Alexaki Vasileia Ismini
Published: November 2024

Adipose tissue homeostasis plays a critical role in metabolic disease but the metabolic circuitry regulating adipose tissue dynamics remains unclear. In this study, polyamine metabolism emerges as an important regulator of adipose tissue pathophysiology. We identify AZIN2 (Antizyme inhibitor 2), a protein promoting polyamine synthesis and acetylation, as a major regulator of total acetyl-CoA in adipocyte progenitors (APs). AZIN2 deficient APs demonstrate increased H3K27 acetylation marks in genes related to lipid metabolism, cell cycle arrest and cellular senescence, and enhanced adipogenesis compared to wild-type counterparts. Upon high-fat diet (HFD)-induced obesity, global AZIN2 deficiency in mice provokes adipose tissue hypertrophy, AP senescence, lipid storage perturbations, inflammation and insulin resistance. IL4 promotesAzin2expression in APs but not mature adipocytes due to diminished IL4 receptor expression in the latter. In human visceral and subcutaneous adipose tissue,AZIN2expression positively correlates with expression of early progenitor markers and genes associated with protection against insulin resistance, while it negatively correlates with markers of lipogenesis. In sum, AZIN2-driven polyamine metabolism preserves adipose tissue health, a finding that could be therapeutically harnessed for the management of obesity-associated metabolic disease.
Scalable cell-free production of active T7 RNA polymerase
Authors: Rezvani Ryan N. , Aw Rochelle , Chan Wei , Satish Krishnathreya , Chen Han , Lavy Adi , Rimal Swechha , Patel Divyesh A. , Kvam Erik , Karim Ashty S. , Krüger Antje , Kightlinger Weston K. , Jewett Michael C.
Published: November 2024

The SARS-CoV-2 pandemic highlighted the urgent need for biomanufacturing paradigms that are robust and fast. Here, we demonstrate the rapid process development and scalable cell-free production of T7 RNA polymerase, a critical component in mRNA vaccine synthesis. We carry out a one-liter cell-free gene expression (CFE) reaction that achieves over 80% purity, low endotoxin levels, and enhanced activity relative to commercial T7 RNA polymerase. To achieve this demonstration, we implement rolling circle amplification to circumvent difficulties in DNA template generation, and tune cell-free reaction conditions, such as temperature, additives, purification tags and agitation to boost yields. We achieve production of a similar quality and titer of T7 RNA polymerase over more than 4 orders of magnitude reaction volume. This proof of principle positions CFE as a viable solution for decentralized biotherapeutic manufacturing, enhancing preparedness for future public health crises or emergent threats.
Mirages in continuous directed enzyme evolution: A cautionary case study with plantized bacterial THI4 enzymes
Authors: Van Gelder Kristen , Gayen Anuran K. , Hanson Andrew D.
Published: November 2024

Continuous directed evolution (CDE) improves enzyme characteristics by hypermutating the enzyme genein vivoin a microbial platform, linking enzyme activity to growth, and selecting for growth rate. Combined with genome editing, CDE can expand the gene pool for plant breeding. THI4 enzymes, essential for thiamin synthesis, are ideal targets for plant CDE. Plant THI4s are inefficient; their replacement by efficient bacterial THI4s could boost biomass yield by up to 4%. However, bacterial THI4s are O2-sensitive and unsuited to plants. Previous CDE campaigns in the yeast OrthoRep system adapted bacterial THI4s for plant-like conditions, achieving success withMucinivorans hirudinisTHI4 (MhTHI4), which acquired beneficial mutations that improved growth. Here, we increased selection pressure on MhTHI4 by reducing its expression, leading to faster-growing populations with new nonsynonymous and synonymous mutations. Surprisingly, the synonymous mutations appeared largely responsible for the growth rate improvements, providing a cautionary example for other OrthoRep CDE projects.
eDNA replicates, polymerase and amplicon size impact inference of richness across habitats
Authors: Anmarkrud Jarl Andreas , dos Anjos Santa Rosa Fabricio , Thorbek Lisbeth , Schroder-Nielsen Audun , Melo Sviggum Silvana , Ready Jonathan Stuart , de Boer Hugo , Mauvisseau Quentin
Published: November 2024

Environmental DNA-based monitoring has been increasingly used in the last decade to monitor biodiversity in aquatic and terrestrial systems. Molecular-based surveys now allow quick and reliable production of baseline knowledge of species community composition on a large scale, allowing better understanding of ecosystem function and mitigation of stressors linked to anthropogenic activities. Despite this, technical hurdles often remain, and the impact of replicates, PCR polymerases and amplicon size on the recovered species richness is still poorly understood. Here, we conducted a large controlled experiment, with bulk samples collected from terrestrial, marine and freshwater environments to assess the impact of natural and technical replicates, PCR polymerases with different degrees of fidelity or proofreading activity, as well as amplicon size on species richness recovery across habitats. In this study, we consistently found variations in sample species richness depending on PCR polymerase choice. We further demonstrate the dissimilar impacts between natural and technical replicates on species richness recovery, and the necessity of increasing natural replications in eDNA based surveys. We highlight the benefits and limitations of replication strategies, polymerase choice and amplicon size across terrestrial, marine and freshwater habitats, and provide recommendations to increase the reliability of future eDNA-based metabarcoding studies.
SARM1 Activation Promotes Axonal Degeneration Via a Two-Step Liquid-to-Solid Phase Transition
Authors: Wenbin Zhang , Qinyi Zhou , Jun Zhang , Jiachen Wang , Sanduo Zheng , Xiaodong Wang
Published: November 2024

SARM1 protein plays a central role in axonal degeneration, a key process in many neurodegenerative diseases and nerve injuries. It mediates this by depleting axonal NAD+ through its NADase activity, catalyzed by the TIR domain. Normally, this activity is kept in an inactive state and becomes activated in response to various neuronal damage signals. However, the molecular mechanism behind SARM1 activation, particularly how activation is restricted to damaged axons, remains to be fully elucidated. In this study, using a class of pyridine-containing compounds that induce SARM1-dependent cell death and axonal degeneration, we reveal a two-step process of SARM1 activation. The first step involves sub-lethal “priming” activation of SARM1 mediated by the NAD+ precursor NMN, leading to the formation of covalent conjugates between the hydrolyzed product of NAD+, adenosine diphosphate ribose (ADPR), and the compounds catalyzed by the intrinsic base exchange activity of SARM1. In the second step, these ADPR-conjugates act as molecular glues, promoting the formation of self-proliferating superhelical filaments. On these filaments, SARM1’s TIR domains adopt an active NADase configuration. As the superhelical filaments rapidly reach their limit of solubility, they precipitate out of the liquid phase as condensates with stable, fully activated NAD hydrolysis activity. Interestingly, we found that a series of reported SARM1 inhibitors currently under clinical development, which target the TIR enzymatic domain, can paradoxically activate SARM1’s NADase activity via this mechanism. These findings provide new insights into how SARM1 activation is spatially restricted to damaged axons and offer important implications for the development of therapeutics targeting SARM1.
PTBP1 is upregulated by Zika virus infectionviaHIF-1α signal and hijacks NS1 protein to induce NS1 degradation to restrain viral replication
Authors: Rao Menglan , Lei Zhiwei , Liu Shuang , Lin Jiuxiu , Kong Yue , Liang Yicong , Luo Zhen
Published: November 2024

Zika virus (ZIKV), belonging to theFlaviviridaefamily, has been a severe threat to human health since the worldwide outbreak. ZIKV is capable of inducing fetal microcephaly, Guillain-Barré syndrome, and other serious neurological complications. Polypyrimidine tract-binding protein 1 (PTBP1) is a key member of the heterogeneous nuclear ribonucleoproteins (hnRNPs) family, functioning in selective mRNA splicing and gene expression regulation. Our previous study has indicated that the expression of PTBP1 increases in astrocytes upon ZIKV infection, yet the precise regulatory mechanisms underlying its role in viral replication remain elusive. In this study, we elucidated the specific pathway by which ZIKV upregulates PTBP1 expression through the activation of Hypoxia-inducible factor-1α (HIF-1α) expression. Further investigation revealed that overexpression of PTBP1 effectively inhibits viral replication, whereas knockdown of PTBP1 significantly enhances viral replication. Mechanistically, using co-immunoprecipitation assays for protein interaction screening, we identified an interaction between PTBP1 and ZIKV non-structural protein NS1. Detailed studies demonstrated that PTBP1 bound and colocalized with NS1 to lead to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings unveil a novel mechanism underlying that ZIKV infection induces the expression of PTBP1 via the HIF-1α pathway, subsequently the accumulated PTBP1 binds to ZIKV NS1 protein to promote NS1 degradation, thereby effectively inhibiting viral replication. The study illustrates a distinct restricted cellular factor that regulates ZIKV replication, which provides a potential target for the control of the viral replication and pathogenesis during the ZIKV epidemic.

Importance

Since the outbreak of ZIKV infection among human in 2014, a Zika epidemic has caused Zika fever accompanied with fetal microcephaly, Guillain-Barré syndrome, and other neurological symptoms. Emerging evidence reveals that ZIKV infects astrocytes to specially induce the expression of polypyrimidine tract-binding protein 1 (PTBP1), one of hnRNPs members. However, the interplay between PTBP1 and ZIKV replication is highly concerned. Here, we uncover a distinct manner that ZIKV infection induces PTBP1 expression through the activation of hypoxia-inducible factor-1α (HIF-1α) signal. Additionally, activation of HIF-1α signal hinders ZIKV replication relying on PTBP1 accumulation. Further investigations suggest that PTBP1 restrains ZIKV replication by interacting with ZIKV NS1 protein, thereby leading to the degradation of NS1 protein via a lysosomal pathway. Collectively, our findings illustrate a novel restricted cellular factor PTBP1 mediated by HIF-1α that regulates ZIKV replication, which provides a potential therapeutic target of the viral replication and pathogenesis against ZIKV pandemic.
Integrative Metagenomic and Blood Biomarker Analysis Reveals Distinct Metabolic Responses to Aerobic and Anaerobic Interventions in Athletic and Non-Athletic Individuals
Authors: Zielińska Kinga , Michałowska-Sawczyn Monika , Kosciolek Tomasz , Łabaj Paweł P. , Bicakci Barkin , Proia Patrizia , Cięszczyk Paweł , Kochanowicz Andrzej , Mieszkowski Jan , Humińska-Lisowska Kinga
Published: November 2024

Background

The gut microbiome influences physiological responses to exercise through interactions with inflammatory markers and metabolite production. Athletes often exhibit a more diverse gut microbiome that is associated with improved performance, but the mechanisms, particularly in relation to different training modalities, are not fully understood. This study aims to integrate blood serum markers with metagenomic data to explore the interplay between exercise type, gut microbiome, and biochemical responses in athletic and non-athletic individuals.

Methods

Fifty-two male participants (endurance athletes, strength athletes, and controls) underwent two maximal exercise tests: the anaerobic Wingate test and the aerobic Bruce treadmill test. Blood and stool samples were collected at multiple time points for biochemical analysis and metagenomic sequencing. Blood markers were correlated with shifts in microbiome composition and function.

Results

While most biochemical parameters showed similar trends across all groups post-exercise, SPARC and adiponectin levels showed distinct responses depending on the exercise modality. The strength group showed unique microbiome associations with blood markers after the Wingate test. Baseline enrichment of specific bacteria (Clostridium phoceensisandCatenibacterium spp.) was associated with an inhibited response to the Bruce test in strength athletes.

Conclusions

The integration of metagenomic and blood serum analyses reveals that exercise modality and training background elicit complex physiological and biochemical responses mediated by the gut microbiome. These findings suggest that specific microbial species may play significant roles in recovery and adaptation processes following acute exercise. Further research with larger cohorts is needed to validate these findings and explore microbiome-targeted interventions to improve performance and recovery.
A highly conserved sRNA downregulates multiple genes, including a σ54transcriptional activator, in the virulence mode ofBordetella pertussis
Authors: Sim Minji , Nguyen Jeffers , Škopová Karolína , Yoo Kyungyoon , Tai Chin-Hsien , Knipling Leslie , Chen Qing , Kim David , Nolan Summer , Elaksher Rawan , Majdalani Nadim , Lorenzi Hernan , Stibitz Scott , Moon Kyung , Hinton Deborah M.
Published: November 2024

Bacterial sRNAs together with the RNA chaperone Hfq post-transcriptionally regulate gene expression by affecting ribosome binding or mRNA stability. In the human pathogenBordetella pertussis, the causative agent of whooping cough, hundreds of sRNAs have been identified, but their roles inB. pertussisbiology are mostly unknown. Here we characterize a Hfq-dependent sRNA (S17), whose level is dramatically higher in the virulence (Bvg+) mode. We show that transcription from a σA-dependent promoter yields a long form of 190 nucleotides (nts) that is processed by RNase E to generate a shorter, more stable form (S17S) of 67 nts. Using RNA-seq and RT-qPCR, we identify 92 genes whose expression significantly increases in the absence of S17. Of these genes, 70 contain sequences at/near their ribosome binding sites (RBSs) that are complementary to single-stranded (ss) regions (Sites 1 or 2) of S17S. The identified genes include those encoding multiple transporters and 3 transcriptional regulators. Using alacZtranslational reporter system, we demonstrate that S17S directly represses one of these genes,BP2158, a σ54- dependent transcriptional regulator, suggesting the repression of a σ54regulon in the Bvg+mode. We find that the S17S region containing Sites 1 and 2 is 100% conserved throughout various Betaproteobacteria species, and the S17S target sites are often conserved in the homologs of theB. pertussistarget genes. We speculate that S17S regulation represents a highly conserved process that fine-tunes gene expression in the Bvg+mode ofB. pertussisand perhaps under other conditions in related bacteria.

IMPORTANCE

Regulation of gene expression involves controlling transcription, translation, and transcript degradation. sRNAs with short sequences complementary to an mRNA sequence are involved in post-transcriptional regulation by aiding or interfering with either ribosome binding or nuclease attack. In the human pathogenBordetella pertussis, the causative agent of whooping cough, hundreds of sRNA have been identified, but their functions remain largely unknown. We have characterized a sRNA that is abundant in the virulence mode ofB. pertussisand serves to down-regulate multiple genes including transcriptional regulators and various transporters. We demonstrate that this sRNA directly represses a transcriptional factor, suggesting that it influences the regulation of specificB. pertussisregulons. The high conservation of this sRNA and its targets within Betaproteobacteria suggests a conserved pathway for gene regulation.
The “Ocular Response Function” for encoding and decoding oculomotor related neural activity
Authors: Gehmacher Quirin , Schubert Juliane , Kaltenmaier Aaron , Weisz Nathan , Press Clare
Published: November 2024

Oculomotor activity provides critical insights into cognition and health, with growing evidence demonstrating its involvement in various cognitive functions such as attention, memory, and sensory processing. Furthermore, eye movements are emerging as significant indicators of psychopathologies and neurological disorders, including schizophrenia, dementia, depression, and tinnitus. Despite its crucial importance across domains, the role of oculomotion has often been underexplored in neuroimaging studies - largely due to methodological challenges. Eye movements have traditionally been viewed as artefacts in the neural signal, leading to the exclusion of epochs containing them, or correction methods to remove their influence. However, this strategy does not allow us to determine their role in a range of neural effects or mapping between tasks and neural responses. To enable such nuanced investigations in typical function and disease, we introduce what we term “Ocular Response Functions”. We used simultaneous magnetoencephalographic and eye-tracking recordings during the resting-state combined with temporal response functions to precisely map the relationship between oculomotion and neural activity. Our approach allows for the temporally and spatially precise prediction of neural activity based on ocular action, and vice versa. We further validate this method in a passive listening task, highlighting its potential for uncovering cognitive insights in experimental settings. By providing a robust framework for examining the interplay between eye movements and neural processes, our method opens new avenues for both research and clinical applications, potentially advancing early detection and intervention strategies for neurological and psychiatric disorders.
A novel mouse model for developmental and epileptic encephalopathy by Purkinje cell-specific deletion ofScn1b
Authors: Isaac Guillén F. , Geist Mendee A. , Cheng Shao-Ying , Harris Arwen M. , Treviño Martha E. , Brumback Audrey C. , Nishiyama Hiroshi , Howard MacKenzie A.
Published: November 2024

Loss of function variants ofSCN1Bare associated with a range of developmental and epileptic encephalopathies (DEEs), including Dravet syndrome. These DEEs feature a wide range of severe neurological disabilities, including changes to social, motor, mood, sleep, and cognitive function which are notoriously difficult to treat, and high rates of early mortality. While the symptomology ofSCN1B-associated DEEs indicates broad changes in neural function, most research has focused on epilepsy-related brain structures and function. Mechanistic studies ofSCN1B/Scn1bhave delineated diverse roles in development and adult maintenance of neural function, via cell adhesion, ion channel regulation, and other intra- and extra-cellular actions. However, use of mouse models is limited as knockout ofScn1b, globally and even in some cell-specific models (e.g., Parvalbumin+ interneuron-specific knockout) in adult mice, leads to severe and progressive epilepsy, health deterioration, and 100% mortality within weeks. Here, we report findings of a novel transgenic mouse line in whichScn1bwas specifically deleted in cerebellar Purkinje cells. Unlike most existing models, these mice did not show failure to thrive or early mortality. However, we quantified marked decrements to Purkinje cell physiology as well as motor, social, and cognitive dysfunction. Our data indicate that cerebellar Purkinje cells are an important node for dysfunction and neural disabilities inSCN1B-related DEEs, and combined with previous work identify this as a potentially vital site for understanding mechanisms of DEEs and developing therapies that can treat these disorders holistically.
Humans and marmosets share similar face recognition signatures in shape-based visual face discrimination behavior
Authors: Jeon You-Nah , Cho Hector Y. , Green Ashley C. , Issa Elias B.
Published: November 2024

Our ability to identify faces is thought to depend on high-level visual processing in the brain. Nonetheless, studies of face recognition have generally relied on 2D face photographs where low-level strategies relying on texture and appearance cues can be employed to adequately support high face identification performance. Here, we designed a fine face discrimination task under 3D pose and lighting variation that was purely based on shape, a task which challenged state-of-the-art artificial vision systems compared to object recognition tasks. In contrast, humans performed this shape based face task at comparable levels to their object recognition performance. We then tested one of the smallest simian primates on this human-level, machine-difficult visual task, the common marmoset – a small, New World monkey. Marmosets successfully discriminated between face identities across 3D viewing conditions based purely on face shape. Their face recognition performance was on par with their object recognition performance and exhibited face-specific behavioral signatures similar to humans, including lower performance for inverted faces, faces lit from below, and contrast reversed faces. These results demonstrate that a high-level visual behavior, invariant face recognition based purely on geometry and not additional texture and appearance cues, is shared across simian primates from among the smallest to the most advanced, consistent with the presence of common underlying high-level visual brain areas across simian primates.
Uncovering the shared genetic contributors to primary and secondary hypertension using whole genome sequencing in a national disease cohort
Authors: Manoj Megha , Sadeghi-Alavijeh Omid , Gale Daniel P.
Published: November 2024

Introduction

Extreme early-onset hypertension (EEHTN) defines a cohort of patients with a persistent blood pressure above 160/100mmHg under 30 years of age. This cohort is at heightened risk of complications and often undergo a diagnostic odyssey. We used Whole Genome Sequencing (WGS) data provided by the 100,000 Genomes Project (100KGP), to quantify the genetic contributors to EEHTN and to ascertain the diagnostic utility of WGS.

Methods

We performed sequencing-based genome-wide association studies (GWAS) in 901 unrelated EEHTN cases and 20852 ancestry matched unaffected controls. The analysis was inclusive of individuals with diverse genetic ancestry. Enrichment of common, low-frequency minor allele frequency (MAF) > 0.1% and rare (MAF < 0.1%) single-nucleotide variant (SNV), insertion/deletion variants (indels) and rare structural variant (SV) alleles on a genome-wide and per-gene basis was sought using a generalised linear mixed model approach to account for population structure. A validated polygenic risk score (PRS) for hypertension (HTN) was applied to the EEHTN cohort and a primary HTN cohort.

Results

Analysis of rare SNVs and indels revealedPKD1(P=2.70 x 10-13) as significantly associated with EEHTN. This signal was lost when we excluded those with known renal disease. 81.5% of the individuals harbouring qualifyingPKD1variants had known cystic kidney disease (CyKD), this is replicated in the UK Biobank (UKBB). There were no common SNVs or rare SV associations with EEHTN. PRS discriminated between cases and controls (P = 2.2x10-16) but not between patients with PHTN or secondary HTN.

Conclusions

These findings represent a thorough examination of the genetic architecture of a national EEHTN cohort using well-controlled statistical methodology. The low diagnostic yield of WGS in this group brings into question its utility as a population level clinical tool but provides insights into EEHTN biology. The PRS findings suggest shared genetic contributors to early-onset extreme hypertension and primary hypertension ascertained at any age.
Recurrent hyper-motif circuits in developmental programs
Authors: Adler Miri , Medzhitov Ruslan
Published: November 2024

During embryogenesis, homogenous groups of cells self-organize into stereotypic spatial and temporal patterns that make up tissues and organs. These emergent patterns are controlled by transcription factors and secreted signals that regulate cellular fate and behaviors through intracellular regulatory circuits and cell-cell communication circuits. However, the principles of these circuits and how their properties are combined to provide the spatio-temporal properties of tissues remain unclear. Here we develop a framework to explore building-block circuits of developmental programs. We use single-cell gene expression data across developmental stages of the human intestine to infer the key intra- and inter-cellular circuits that control developmental programs. We study how these circuits are joined into higher-level hyper-motif circuits and explore their emergent dynamical properties. This framework uncovers design principles of developmental programs and reveals the rules that allow cells to develop robust and diverse patterns.
Targeted detection of endogenous LINE-1 proteins and ORF2p interactions
Authors: Nielsen Mathias I. , Wolters Justina C. , Rosas Bringas Omar G. , Jiang Hua , Di Stefano Luciano H. , Oghbaie Mehrnoosh , Hozeifi Samira , Nitert Mats J. , van Pijkeren Alienke , Smit Marieke , ter Morsche Lars , Mourtzinos Apostolos , Deshpande Vikram , Taylor Martin S. , LaCava John
Published: November 2024

Background

Both the expression and activities of LINE-1 (L1) retrotransposons are known to occur in numerous cell-types and are implicated in pathobiological contexts such as aging-related inflammation, autoimmunity, and in cancers. L1s encode two proteins that are translated from bicistronic transcripts. The translation product ofORF1(ORF1p) has been robustly detected by immunoassays and shotgun mass spectrometry (MS). Yet, more sensitive detection methods would enhance the use of ORF1p as a clinical biomarker. In contrast, until now, no direct evidence of endogenous L1ORF2translation to protein (ORF2p) has been shown. Instead, assays for ORF2p have been limited to ectopic L1 ORF over-expression contexts and to indirect detection of endogenous ORF2p enzymatic activity, such as by the sequencing ofde novogenomic insertions. Immunoassays for endogenous ORF2p have been problematic, producing apparent false positives due to cross-reactivities, and shotgun MS has not yielded reliable evidence of ORF2p peptides in biological samples.

Results

Here we present targeted mass spectrometry assays, selected and parallel reaction monitoring (SRM and PRM, respectively) to detect and quantify L1 ORF1p and ORF2p at their endogenous abundances. We were able to quantify ORF1p and ORF2p present in our samples down to a range in the low attomoles. Confident in our ability to affinity enrich ORF2p, we describe an interactome associated with endogenous ORF2-containing macromolecular assemblies.

Conclusion

This is the first assay to demonstrate sensitive and robust quantitation of endogenous ORF2p. The ability to assay ORF2p directly and quantitatively will improve our understanding of the developmental and diseased cell states where L1 expression and its activity naturally occur. The ability to simultaneously assay endogenous L1 ORF1p and ORF2p is an important step forward for L1 analytical biochemistry. Endogenous ORF2p interactomes can now be presented with confidence that ORF2p is among the enriched proteins.
Leveraging the power of long reads for targeted sequencing
Authors: Iyer Shruti V. , Goodwin Sara , McCombie William Richard
Published: November 2024

Long-read sequencing technologies have improved the contiguity and, as a result, the quality of genome assemblies by generating reads long enough to span and resolve complex or repetitive regions of the genome. Several groups have shown the power of long reads in detecting thousands of genomic and epigenomic features that were previously missed by short-read sequencing approaches. While these studies demonstrate how long reads can help resolve repetitive and complex regions of the genome, they also highlight the throughput and coverage requirements needed to accurately resolve variant alleles across large populations using these platforms. At the time of this review, whole-genome long-read sequencing is more expensive than short-read sequencing on the highest throughput short-read instruments; thus, achieving sufficient coverage to detect low-frequency variants (such as somatic variation) in heterogenous samples remains challenging. Targeted sequencing, on the other hand, provides the depth necessary to detect these low-frequency variants in heterogeneous populations. Here, we review currently used and recently developed targeted sequencing strategies that leverage existing long-read technologies to increase the resolution with which we can look at nucleic acids in a variety of biological contexts.
High-pressure synthesis and neutron scattering study of tantalum hydride
TaH1.23(5)
and a tantalum polymorph with A15-type structure
Authors: Kuzovnikov Mikhail A. , Hansen Thomas , Ivanov Alexandre S. , Kolesnikov Alexander I. , Kulakov Valery I. , Savvin Stanislav , Tkacz Marek
Published: November 2024

A unique type of tantalum hydride was synthesized by exposing tantalum dihydride to the high hydrogen pressure of 9 GPa and a temperature of 580∘C using toroid-type high-pressure chambers. The samples of this hydride were cooled down to 100 K, recovered to ambient pressure, and studied in a metastable state by hot extraction, powder x-ray and neutron diffraction, and inelastic neutron scattering. X-ray diffraction demonstrated that this hydride had an A15-type crystal structure of metal lattice (space group Pm−3n, Ta atoms at the 2a and 6c Wyckoff positions) and a lattice parameter of a=5.510(5)Å at T=85 K. The hydrogen content determined by hot extraction was H/Ta=1.23(5). Hydrogen desorption during heating the sample in vacuum proceeded in two steps—first, ΔH/Ta=0.2 was desorbed at around −70∘C, and then the rest of the hydrogen was desorbed between 100∘C and 390∘C. The A15-type metal lattice was preserved upon hydrogen removal, leaving a unique polymorph of tantalum. Neutron diffraction of A15−TaH1.23(5) demonstrated that hydrogen atoms occupy the 24k and 16i Wyckoff sites in the crystal structure, and annealing at 250 K resulted in a decrease of the 24k and an increase of the 16i site occupancies. Inelastic neutron scattering revealed four vibrational modes in the fundamental band of A15−TaH1.23(5) at 72, 135, 145, and 166meV, the first three and the last one of which were tentatively assigned to the vibrations of H atoms at the 24k and 16i sites, respectively. No superconductivity was found in A15−TaH1.1 and hydrogen-free A15-Ta at temperatures down to 1.5 K.

Published by the American Physical Society
2024
Electric conductivity of QCD matter and dilepton spectra in heavy-ion collisions
Authors: Rapp Ralf
Published: November 2024

The electric conductivity, σel, is a fundamental transport coefficient of QCD matter that can be related to the zero-energy limit of the electromagnetic (EM) spectral function at vanishing three-momentum in the medium. The EM spectral function is also the central quantity to describe the thermal emission rates and pertinent spectra of photon and dilepton radiation in heavy-ion collisions. Employing a model for dilepton rates that combines hadronic many-body theory with nonperturbative QGP emission constrained by lattice QCD which describes existing dilepton measurements in heavy-ion collisions, I investigate the sensitivity of low-mass dilepton spectra in Pb-Pb collisions at the CERN Large Hadron Collider (LHC) to σel. In particular, I separately evaluate the contributions from QGP and hadronic emission, and identify signatures that can help to extract σel from high-precision experimental data expected to be attainable with future detector systems at the LHC.

Published by the American Physical Society
2024
High precision measurement of the
Tc99β
spectrum
Authors: Paulsen M. , Ranitzsch P. C.-O. , Loidl M. , Rodrigues M. , Kossert K. , Mougeot X. , Singh A. , Leblond S. , Beyer J. , Bockhorn L. , Enss C. , Wegner M. , Kempf S. , Nähle O.
Published: November 2024

Highly precise measurements of the Tc99β spectrum were performed in two laboratories using metallic magnetic calorimeters. Independent sample preparations, evaluation methods, and analyses yielded consistent results and the spectrum could be measured down to less than 1keV. Consistent β spectra were also obtained via cross evaluations of the experimental data sets. An additional independent measurement with silicon detectors in a 4π configuration confirms the spectrum shape above 25keV. Detailed theoretical calculations were performed using the nuclear shell model and including atomic effects. The spectrum shape was found to be sensitive to the effective value of the axial-vector coupling constant. Combining measurements and predictions, we extracted Qβ=295.82(16)keV, gVeff=0.376(5), and gAeff=0.574(36), which seems to solve an inconsistency of the quenched coupling constants between first and higher forbidden nonunique transitions. Furthermore, we derived the mean energy of the β spectrum, E¯β=98.51(23)keV, logf=−0.47660(22), and logft=12.3478(23).

Published by the American Physical Society
2024
Interacting Kerr-Newman electromagnetic fields
Authors: Aghapour Sajad , Andersson Lars , Rosquist Kjell , Smołka Tomasz
Published: November 2024

In this paper, we study some of the properties of the G→0 limit of the Kerr-Newman solution of Einstein-Maxwell equations. Carter noted the near equality between the gyromagnetic ratio, or g-factor, of the Kerr-Newman solution and of the electron. This observation is a consequence of the multipole structure of the Kerr-Newman field. We discuss additional coincidences between the Kerr-Newman multipole structure and the properties of the electron. In contrast to the Coulomb field, this spinning Maxwell field has a finite Lagrangian. Moreover, by evaluating the Lagrangian for the superposition of two such Kerr-Newman electromagnetic fields on a flat background, we are able to find their interaction potential. This yields a correction to the Coulomb interaction due to the spin of the field.

Published by the American Physical Society
2024
Rigorous hydrodynamics from linear Boltzmann equations and viscosity-capillarity balance
Authors: Kogelbauer Florian , Karlin Ilya
Published: November 2024

Exact closure for hydrodynamic variables is rigorously derived from the linear Boltzmann kinetic equation. Our approach, based on spectral theory, structural properties of eigenvectors, and the theory of slow manifolds, allows us to define a unique, optimal reduction in phase space close to equilibrium. The hydrodynamically constrained system induces a modification of entropy that ensures pure dissipation on the hydrodynamic manifold, which is interpreted as a nonlocal variant of Korteweg's theory of viscosity-capillarity balance. The rigorous hydrodynamic equations are exemplified on the Knudsen minimum paradox in a channel flow.

Published by the American Physical Society
2024
Momentum deficit and wake-added turbulence kinetic energy budgets in the stratified atmospheric boundary layer
Authors: Klemmer Kerry S. , Howland Michael F.
Published: November 2024

To achieve decarbonization targets, wind turbines are growing in hub height and rotor diameter, and they are being deployed in new locations with diverse atmospheric conditions not previously seen, such as offshore. Physics-based analytical wake models commonly used for design and control of wind farms simplify atmospheric boundary layer (ABL) and wake physics to achieve computational efficiency. This is accomplished primarily through a simplified model form that neglects certain flow processes, such as atmospheric stability, and through the parametrization of ABL and wake turbulence through a wake spreading rate. In this study, we systematically analyze the physical mechanisms that govern momentum and turbulence within a wind turbine wake in the stratified ABL. We use large-eddy simulation and analysis of the streamwise momentum deficit and wake-added turbulence kinetic energy (TKE) budgets to study wind turbine wakes under neutral and stable conditions. To parse the turbulence in the wake from the turbulent, incident ABL flow, we decompose the flow into the base ABL flow and the deficit flow produced by the presence of a turbine. We then analyze the decomposed flow field budgets to study the effects of changing stability on the streamwise momentum deficit and wake-added TKE. The results demonstrate that stability changes the relative balance of turbulence and advection for both the streamwise momentum deficit and wake-added TKE primarily through the nonlinear interactions of the base flow with the deficit flow. The stable cases are most affected by increased shear and veer in the base flow and the neutral case is most affected by the increased ambient turbulence intensity. These differences in the base flow that arise from stratification are relatively more important than the buoyancy forcing terms in the wake-added TKE budget. The wake-added TKE depends on the ABL stability. An existing wake-added TKE model that neglects the effects of ABL stability yields 15–25% error compared to large-eddy simulation, with errors that are higher in stable conditions than neutral. These results motivate future research to develop fast-running models of wake-added TKE that account for stability effects.

Published by the American Physical Society
2024
Finite Bubble Statistics Constrain Late Cosmological Phase Transitions
Authors: Elor Gilly , Jinno Ryusuke , Kumar Soubhik , McGehee Robert , Tsai Yuhsin
Published: November 2024

We consider first order cosmological phase transitions (PTs) happening at late times below standard model temperatures TPT≲GeV. The inherently stochastic nature of bubble nucleation and the finite number of bubbles associated with a late-time PT lead to superhorizon fluctuations in the PT completion time. We compute how such fluctuations eventually source curvature fluctuations with universal properties, independent of the microphysics of the PT dynamics. Using cosmic microwave background (CMB) and large scale structure measurements, we constrain the energy released in a dark-sector PT. For 0.1  eV≲TPT≲keV this constraint is stronger than both the current bound from additional neutrino species ΔNeff, and in some cases, even CMB-S4 projections. Future measurements of CMB spectral distortions and pulsar timing arrays will also provide competitive sensitivity for keV≲TPT≲GeV.

Published by the American Physical Society
2024
Topologically protected quantized changes of the distance between atoms
Authors: Kopaei Ali Emami , Giergiel Krzysztof , Sacha Krzysztof
Published: November 2024

Thouless pumping enables the transport of particles in a one-dimensional periodic potential if the potential is slowly and periodically modulated in time. The change in the position of particles after each modulation period is quantized and depends solely on the topology of the pump cycle, making it robust against perturbations. Here, we demonstrate that Thouless pumping also allows for the realization of topologically protected quantized changes of the distance between atoms if the atomic s-wave scattering length is properly modulated in time.

Published by the American Physical Society
2024
Recovering detailed shape of phase response curves from the higher harmonics of singularity response
Authors: Masuda Kosaku , Tokuda Isao T. , Fukuda Hirokazu
Published: November 2024

The phase response curve (PRC) is crucial in elucidating the synchronization characteristics of nonlinear oscillators under the influence of external forces. Oscillatory phenomena in nature often consist of an ensemble of multiple oscillators, which complicates the measurement of individual oscillator PRCs. A prior study introduced a technique for estimating individual PRCs from the singularity response (SR)—the reaction of an ensemble of desynchronized oscillators without couplings. However, the utility of this method is somewhat limited, as it considers only the first harmonic of the PRC. The current study demonstrates that the detailed contour of the PRC can be ascertained by employing the higher harmonics of the SR.

Published by the American Physical Society
2024
Differentiable master equation solver for quantum device characterization
Authors: Craig D. L. , Ares N. , Gauger E. M.
Published: November 2024

Differentiable models of physical systems provide a powerful platform for gradient-based algorithms, with particular impact on parameter estimation and optimal control. Quantum systems present a particular challenge for such characterization and control, owing to their inherently stochastic nature and sensitivity to environmental parameters. To address this challenge, we present a versatile differentiable quantum master equation solver facilitating direct computation of steady-state solutions, and incorporate this solver into a framework for device characterization capable of dealing with additional nondifferentiable parameters. Our approach utilizes gradient-based optimization and Bayesian inference to provide estimates and uncertainties in quantum device parameters. To showcase our approach, we consider steady-state charge transport through electrostatically defined quantum dots. Using simulated data, we demonstrate efficient estimation of parameters for a single quantum dot, and model selection as well as the capability of our solver to compute time evolution for a double quantum dot system. Our differentiable solver stands to widen the impact of physics-aware machine learning algorithms on quantum devices for characterization and control.

Published by the American Physical Society
2024
Floating drift on a vibrofluidized relaxing granular slope
Authors: Yamamoto Yuki , Katsuragi Hiroaki
Published: November 2024

For floating on water, low density is the sole necessary factor. However, it has not been clarified how to floatingly drift on fluidized granular matter. Although this problem relates to various natural phenomena such as debris flow and lunar boulder-fall traces, fundamental aspects of the floating drift on granular flow have not been revealed. Therefore, the motion of a sphere on a vibrated granular slope is experimentally investigated in this study. As a result, we find that the sinking depth of the floating sphere can be explained by a modified buoyancy model. In addition, the downstream velocity of the drifting sphere can be understood by a force balance between flow-induced pushing force and frictional resistance force. This force balance results in a nonsteady but stable floating drift on the relaxing granular slope.

Published by the American Physical Society
2024