bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting ZNF638 activates antiviral immune responses and potentiates immune checkpoint inhibition in glioblastoma
Authors: Seetharam Deepa , Chandar Jay , Ramsoomair Christian K. , Desgraves Jelisah F. , Medina Alexandra Alvarado , Hudson Anna Jane , Amidei Ava , Castro Jesus R. , Govindarajan Vaidya , Wang Sarah , Zhang Yong , Sonabend Adam M. , Valdez Mynor J. Mendez , Maric Dragan , Govindarajan Vasundara , Rivas Sarah R. , Lu Victor M. , Tiwari Ritika , Sharifi Nima , Thomas Emmanuel , Alexander Marcus , DeMarino Catherine , Johnson Kory , De La Fuente Macarena I , Nasany Ruham Alshiekh , Noviello Teresa Maria Rosaria , Ivan Michael E. , Komotar Ricardo J. , Iavarone Antonio , Nath Avindra , Heiss John , Ceccarelli Michele , Chiappinelli Katherine B. , Figueroa Maria E. , Bayik Defne , Shah Ashish H.
Published: October 2024

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression and poor immune cell infiltration (CD8+T-cells, dendritic cells). ZNF638 knockdown decreased H3K9-trimethylation, increased cytosolic dsRNA and activated intracellular dsRNA-signaling cascades (RIG-I, MDA5 and IRF3). Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in patient-derived GBM neurospheres and diverse murine models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate interferon signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Finally, we showed that low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in rGBM patients and melanoma patients. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.
Heterosis in crosses between remnant populations of a rare prairie forb: implications for restoration genetics
Authors: Oakley Christopher G. , Turner Isabelle A. , Rojas-Gutierrez Juan Diego , Easter Bob
Published: October 2024

Background and Aims

A major goal in both basic and applied evolutionary genetics is understanding the role of drift in shaping genetic variation with fitness consequences. For organisms amenable to controlled crosses, the increased fitness of progeny from between-relative to within-population crosses (heterosis) provides a useful tool to infer historical fixation of partly recessive deleterious alleles by drift and/or bottlenecks. Additionally, heterosis may also provide a unique benefit in regional admixture provenancing for restorations of rare plant species, but empirical data to directly test this idea is lacking.

Methods

We quantified heterosis in crosses between small remnant populations of a rare prairie forb (Silene regiaSims). We measured early fitness components (seed number per fruit, germination, and juvenile survival) in a controlled environment. Adult fitness components (survival and reproduction) were quantified over two flowering seasons in two different environments, a field common garden simulating the initial stages of a restoration, and a greenhouse. To our knowledge, our study is the first to estimate cumulative fitness for a rare species in conditions of a newly established restoration in the field. Additionally, we provide a unique comparison of heterosis estimated under controlled vs. field conditions.

Key Results

The consequences of between-population crosses for cumulative fitness in the field were strongly positive in two of the populations (132-292% heterosis) and neutral in a third. Heterosis was generally stronger when measured under field conditions and was more likely to be detected for adult fitness components.

Conclusions

Regional admixture provenancing in restorations should be beneficial for this species. We advocate for more research on heterosis in rare species, particularly in restorations. Such restorations can be opportunities for experimental genetics in addition to reestablishing important ecosystem services.
Inhibition Resolves Simon Conflict: Evidence from EEG Decoding
Authors: Lee Yoon Seo , Bae Gi-Yeul , Cho Yang Seok
Published: October 2024

The congruency sequence effect (CSE), a hypothesized marker of top-down cognitive control, refers to a reduced congruency effect after incongruent trials compared to congruent trials. Although this effect has been observed across various distractor interference tasks, the nature of the control processes underlying the CSE remains a topic of active debate. It has been suggested that cognitive control may resolve conflicts in information processing either by (a) enhancing the representation of goal information and/or (b) suppressing the representation of distractor information. The present study aimed to identify the conflict resolution processes within the context of the color Simon task by decoding the goal and distracting information from human scalp EEG signals. For the decoding analysis, models were trained separately for color and location attributes corresponding to goal and distractor information. Additionally, decoding accuracy was calculated in different frequency bands: theta (4-8 Hz), alpha (8-12 Hz), low beta (12-20 Hz), and high beta (20-30 Hz). Results showed that decoding accuracy for distractor information was reduced when cognitive control was activated and this pattern was only observed in the high beta-frequency band (20-30 Hz). In contrast, no such difference was observed for target information. These findings suggest that cognitive control regulates Simon conflict by inhibiting distractor representation in the brain, thereby preventing unwanted distraction-driven behaviors.
Comparative evaluation of methodologies for estimating the effectiveness of non-pharmaceutical interventions in the context of COVID-19: a simulation study
Authors: Ganser Iris , Paireau Juliette , Buckeridge David L , Cauchemez Simon , Thiebaut Rodolphe , Prague Mélanie
Published: October 2024

Numerous studies assessing the effectiveness of non-pharmaceutical interventions (NPIs) against COVID-19 have produced conflicting results, partly due to methodological differences. This study aims to clarify these discrepancies by comparing two frequently used approaches in terms of parameter bias and confidence interval coverage of NPI effectiveness parameters. We compared two-step approaches, where NPI effects are regressed on by-products of a first analysis, such as the effective reproduction numberℛt, with more integrated models that jointly estimate NPI effects and transmission rates in a single-step approach. We simulated datasets with mechanistic and an agent-based models and analyzed them with both mechanistic models and a two-step regression procedure. In the latter,ℛtwas estimated first and then used as the outcome in a linear regression with NPI variables as predictors. Mechanistic models consistently outperformed two-step regressions, exhibiting minimal bias (0-5%) and accurate confidence interval coverage. Conversely, the two-step regression showed up to 25% bias, with significantly lower-than-nominal confidence interval coverage, reflecting challenges in uncertainty propagation. We identified additional challenges in the two-step regression method, such high depletion of susceptibles and time lags in observational data. Our findings suggest caution when using two-step regression methods for estimating NPI effectiveness.
Examining the causal genetic effects of substance use on aging
Authors: Balbona Jared V. , Jeffries Paul , Gorelik Aaron J. , Nelson Elliot C. , Bogdan Ryan , Agrawal Arpana , Johnson Emma C.
Published: October 2024

Substance use shortens lifespan, impedes health, and accelerates the biological aging process. We found widespread genetic correlations between alcohol, tobacco, cannabis, and opioid use and use disorders with indices of aging across the lifespan. There was evidence of tobacco and alcohol use and use disorders causally impacting physical, cognitive, and biological aging, with the effects of alcohol being more dependent on quantity of consumption; evidence of reverse causality was scant.
Depression and the Prefrontal-Hippocampal Pathway - A Pilot Multimodal Neuroimaging Study in Transgender Women
Authors: Jarukasemkit Setthanan , Tam Karen M. , Yoadsanit Seksan , Easley Ty , Modi Hailey , Stahl Lyn , Kampaengtip Adun , Chansakul Thanissara , Janamnuaysook Rena , Hiransuthikul Akarin , Chunharas Chaipat , Bijsterbosch Janine D.
Published: October 2024

This pilot study explored associations between gamma-aminobutyric acid (GABA) spectroscopy and functional magnetic resonance imaging in transgender women with depression. Twenty participants completed mental health surveys and imaging between January and March 2024. Depression severity was measured by Patient Health Questionnaire-9 (PHQ-9) scores. Higher PHQ-9 scores were associated with lower GABA levels in the hippocampus and lower fractional amplitude of low-frequency fluctuations (fALFF) in the dorsolateral prefrontal cortex. These findings revealed interactions between neurotransmitter signaling and functional brain activity of the hippocampal-prefrontal circuit in depression. Future large-scale neuroimaging studies are needed.
Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes
Authors: Atser Michael G. , Wenyonu Chelsea D. , Rowe Elyn M. , Leung Connie L. K. , Cen Haoning Howard , Queathem Eric D. , Liu Leo T. , Moravcova Renata , Rogalski Jason , Perrin David , Crawford Peter , Foster Leonard J. , Alcazar Armando , Johnson James D.
Published: October 2024

Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdownPdk1. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and13C6glucose labelling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation.13C16palmitate tracing of uniformly labelled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 suppressed cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation following palmitic acid treatment, suggesting that effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover inPdk1knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.
16S rRNA gene sequencing for bacterial identification and infectious disease diagnosis
Authors: Li Mei-Na , Han Qiang , Wang Nan , Wang Ting , You Xue-Ming , Zhang Shuai , Zhang Cui-Cui , Shi Yong-Qiang , Qiao Pei-Zhuang , Man Cheng-Lian , Feng Teng , Li Yue-Yue , Zhu Zhuang , Quan Ke-Ji , Xu Teng-Lin , Zhang George Fei
Published: October 2024

16S rRNA gene sequence is the most common housekeeping genetic marker to study bacterial phylogeny and taxonomy. Therefore, 16S rRNA gene sequencing has the potential to identify novel bacteria and diagnose bacteria. This study compared 16S rRNA gene sequencing with conventional PCR for bacterial identification and disease diagnosis. The bacterial community in healthy and diseased hosts was analyzed by 16S rRNA gene sequencing. 16S rRNA gene sequencing is more sensitive than conventional PCR in detecting bacteria. Moreover, 16S rRNA gene sequencing is adequate to identify novel bacteria. 16S rRNA gene sequencing demonstrated that most pathogenic bacteria persist in diseased or healthy hosts in different abundance. Pathogenic bacteria, such as well-known chicken pathogenAvibacterium paragallinarum,Ornithobacterium rhinotracheale, andGallibacterium anatis, were identified as indicator species of diseased samples. Alpha diversity analysis showed that the healthy group species is significantly higher than in the diseased groups. Beta diversity analysis also demonstrated differences between healthy and infected groups. The study concluded that 16S rRNA gene sequencing is a more sensitive method for detecting pathogens, and microbiota analysis can distinguish between healthy and diseased samples. Eventually, 16S rRNA gene sequencing has represented the potential in human and animal clinical diagnosis and novel bacterial identification.
Model-free machine learning-based 3D single molecule localisation microscopy
Authors: Boland Miguel A. , Lightley Jonathan P. E. , Garcia Edwin , Kumar Sunil , Dunsby Chris , Flaxman Seth , Neil Mark A. A. , French Paul M. W. , Cohen Edward A. K.
Published: October 2024

Single molecule localisation microscopy (SMLM) can provide two-dimensional super-resolved image data from conventional fluorescence microscopes, while three dimensional (3D) SMLM usually involves a modification of the microscope, e.g. to engineer a predictable axial variation in the point spread function. Here we demonstrate a 3D SMLM approach (we call“easyZloc”) utilising a lightweight Convolutional Neural Network that is generally applicable, including with “standard” (unmodified) fluorescence microscopes, and which we consider may be practically useful in a high throughput SMLM workflow. We demonstrate the reconstruction of nuclear pore complexes with comparable performance to previously reported methods but with a significant reduction in computational power and execution time. 3D reconstructions of the nuclear envelope and a tubulin sample over a larger axial range are also shown.
Beta-hairpin Mechanism of Autoinhibition and Activation in the Kinesin-2 Family
Authors: Webb Stephanie , Toropova Katerina , Mukhopadhyay Aakash G. , Nofal Stephanie D. , Roberts Anthony J.
Published: October 2024

Members of the kinesin-2 family coordinate with other motors to power diverse physiological processes, but the structural mechanisms regulating kinesin-2 activity have been unknown. Distinctively, kinesin-2s canonically function as heterotrimers of two different motor subunits (e.g. Kif3A and Kif3B) and Kap3, but the role of heterotrimerization has yet to fully emerge. Here, we combine structural, cell biological, and single-molecule approaches to dissect kinesin-2 regulation as a heterodimer, heterotrimer, and quaternary complex with a cargo adaptor (APC). We identify a conserved motif in the tail of kinesin-2s (the beta-hairpin motif) that controls kinesin-2 motility by sequestering the motor domains away from their microtubule track, using striking molecular mimicry. Our data reveal how Kap3 binds via a multipartite interface with Kif3A and Kif3B, and – rather than activating motility directly – provides a platform on which cargo adaptors can engage and occlude the beta-hairpin motif. Together, these data articulate a structural framework for kinesin-2 activation, coordination with dynein, and adaptation for different biological functions.
In vitro inhibition of the CFTR ion channel in the cervix thickens cervical mucus
Authors: Looney Rachel J , Roberts Mackenzie , Markovetz Matthew , Godiah Rachelle , Yao Shan , Golgotiu Kristi , Wei Shuhap , Cellucci Chris , Han Leo
Published: October 2024

Study question: Does the inhibition of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) alter cervical mucus produced by endocervical cells in vitro? Summary answer: Inhibition of CFTR dehydrates and thickens in vitro endocervical secretions. What is known already: Cervical mucus changes throughout the menstrual cycle in response to hormonal fluctuations, helping to regulate fertility and access of pathogens to the reproductive tract. CFTR is an anion channel that plays a critical role in mediating epithelial mucus secretions. Study design, size, duration: In vitro experiments conducted with control and experimental arms. Participants/materials, setting, methods: Primary endocervical cells obtained from rhesus macaques Macaca mulatta were treated with vehicle controls or CFTR inhibitor Inh-172. Hydration and viscosity of secreted mucus was measured through air surface liquid and particle tracking microrheology. Main results and the role of chance: Endocervical cells treated with CFTR inhibitor Inh-172 demonstrated dehydrated, thicker mucus secretions compared to control (p<.01). Limitations, reasons for caution: In vitro models do not fully recapitulate cellular mucus secretions. Wider implications of the findings: Cervical mucus plays an important role in fertility regulation. Our studies suggest that CFTR may be an important mediator of those changes and provide experimental evidence for the infertility phenotype seen in women with cystic fibrosis. Additionally, assays used in these studies are useful endpoints for studying cervical mucus regulation in vitro.
Cataract induction in an arthropod reveals how lens crystallins contribute to the formation of ‘biological glass’
Authors: Mitra Amartya T. , Rathore Shubham , Jester Augusta , Hyland-Brown Ruby , Hassert J , Benoit Joshua B. , Stowasser Annette , Buschbeck Elke K.
Published: October 2024

Lenses are vital components of eyes, crafted through the precise arrangement of proteins to achieve transparency and focusing power, and placed appropriately within the eye for the retina to receive sharp, focused images. Maintaining these states is challenging due to substantial post-embryonic eye and lens growth. Here, we gain insights into required processes by exploring consequences of silencing Lens3, a key lens protein, during growth inThermonectus marmoratussunburst diving beetle larvae. We show thatlens3RNAileads to opaque aggregates reminiscent of vertebrate lens ‘cataracts,’ causing the projection of degraded images which impact behaviour in low light. Our findings uncover how complex biological lenses are constructed and further support that visual input is inconsequential for coordinated eye growth in this clade. We highlight the utility of this insect as a tractable model system to investigate the aetiology of lens cataracts and refractive errors in a sophisticated camera-type eye.

Highlights

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Crystallin protein knockdown induces central cataracts in an insect camera-type eye

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Cataractous lenses project blurry images but have unchanged focal length

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Resulting image degradation impacts behaviour in challenging low light conditions

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Contrary to vertebrates, blurry vision does not affect refractive state
HIF-1α regulates mitochondrial function in bone marrow-derived macrophages, but not in tissue-resident alveolar macrophages
Authors: Woods Parker S. , Cetin-Atalay Rengül , Meliton Angelo Y. , Sun Kaitlyn A. , Shamaa Obada R. , Shin Kun Woo D. , Tian Yufeng , Haugen Benjamin , Hamanaka Robert B. , Mutlu Gökhan M.
Published: October 2024

HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state, but can shift toward glycolysis under hypoxic conditions. Here, using inducible HIF-1α knockout (Hif1a-/-) TR-AMs and bone marrow-derived macrophages (BMDMs) and show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition, but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity inHif1a-/-BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in macrophages.
Physical traits of supercompetitors in cell competition
Authors: Carpenter Logan C. , Banerjee Shiladitya
Published: October 2024

Cell competition is a fitness control mechanism in tissues, where less fit cells are eliminated to maintain tissue homeostasis. Two primary mechanisms of cell elimination have been identified in cell competition studies: contact-dependent cell death and mechanical compression-driven apoptosis. While both occur in tissues, their combined impact on population dynamics is unclear. Here we develop a cell-based computational model to study competition between two cell types with differing physical properties. The model integrates cellular mechanics with cell-cycle dynamics, contact-induced apoptosis, and cell extrusion via mechanical stress. Using this model, we explored how differences in physical traits between cell types influence competitive interactions. Our findings show that differences in cell compressibility alone can drive mechanical competition, with stiffer cells outcompeting softer ones in otherwise identical populations. Surprisingly, mutations that reduce cell stiffness, combined with decreased contact inhibition of proliferation, can create a “soft” super-competitive mutant. We demonstrate that changes in apoptosis sensitivity, cell adhesion, and cell size significantly affect growth potential and susceptibility to apoptosis. Furthermore, mutant cell colonies require a critical colony size, dependent on cell compressibility, to overtake the surrounding wild-type tissue. For colonies below the critical size, the elimination process is stochastic, driven by a protrusive finger-like instability in the interface between two cells that promote invasion of the supercompetitors.
Assessing substrate scope of the cyclodehydratase LynD by mRNA display-enabled machine learning models
Authors: Steude Emma G. , Dieckhaus Henry , Pelton Jarrett M. , Kuhlman Brian , Bowers Albert A.
Published: October 2024

Many of the biosynthetic pathways for ribosomal synthesized and post-translationally modified peptide (RiPP) natural products make use of multi-domain enzymes with separate recruitment and catalysis domains that separately bind and modify peptide substrates. This “division of labor” allows RiPP enzymes to use relatively open and promiscuous active sites to perform chemistry at multiple residues within a peptide substrate seemingly regardless of the surrounding context. Defining, measuring, and predicting the seemingly broad substrate promiscuity of RiPPs necessitates high throughput assays, capable of assessing activity against very large libraries of peptides. Using mRNA display, a high throughput peptide display technology, we examine the substrate promiscuity of the RiPP cyclodehydratase, LynD. The vast substrate profiling that can be done with mRNA display enables the construction of deep learning models for accurate prediction of substrate processing by LynD. These models further inform on epistatic interactions involved in enzymatic processing. This work will facilitate the further elucidation of other RiPP enzymes and enable their use in the modification of mRNA display libraries for selection of modified peptide-based inhibitors and therapeutics.
Differential expression and modulation of presenilin-1 and presenilin-2 in neural cell lines
Authors: Eccles Melissa K. , Woodfield Amy , Milligan Armstrong Ayeisha , Agostino Mark , Groth David M. , Verdile Giuseppe
Published: October 2024

Presenilin proteins, the catalytic components of the γ-secretase enzyme, play a key role in the pathogenesis of Alzheimer’s disease primarily by generating amyloid-β peptides. Although often grouped together, Presenilin-1 (PS1) and Presenilin-2 (PS2) are distinct proteins that contribute differently to γ-secretase activity. This study examines the differential expression of PS1 and PS2 in various neuroblastoma and microglial cell lines, along with compensatory responses following the ablation of one presenilin homologue. Using quantitative immunoblotting, we show that PS1 and PS2 expression levels vary significantly across cell types. Notably, the ablation of PS2 results in increased PS1 expression, particularly in microglial cells, highlighting the importance of PS2. Additionally, neuronal differentiation of two neuroblastoma lines, caused changes in protein expression levels resulting in similar expression profiles of PS1 and PS2, with PS2 levels being higher than PS1. Understanding PS expression profiles is crucial for distinguishing between PS1- and PS2-mediated γ-secretase activity and for developing γ-secretase-targeted therapeutics with improved selectivity.
Telomere-to-telomere assembly by preserving contained reads
Authors: Kamath Sudhanva Shyam , Bindra Mehak , Pal Debnath , Jain Chirag
Published: October 2024

Automated telomere-to-telomere (T2T) de novo assembly of diploid and polyploid genomes remains a formidable task. A string graph is a commonly used assembly graph representation in the assembly algorithms. The string graph formulation employs graph simplification heuristics, which drastically reduce the count of vertices and edges. One of these heuristics involves removing the reads contained in longer reads. In practice, this heuristic occasionally introduces gaps in the assembly by removing all reads that cover one or more genome intervals. The factors contributing to such gaps remain poorly understood. In this work, we mathematically derived the frequency of observing a gap near a germline and a somatic heterozygous variant locus. Our analysis shows that (1) an assembly gap due to contained read deletion is an order of magnitude more frequent in Oxford Nanopore Technologies (ONT) reads than Pacific Biosciences high-fidelity (PacBio HiFi) reads due to differences in their read-length distributions, and (2) this frequency decreases with an increase in the sequencing depth. Drawing cues from these observations, we addressed the weakness of the string graph formulation by developing the repeat-aware fragmenting tool (RAFT) assembly algorithm. RAFT addresses the issue of contained reads by fragmenting reads and producing a more uniform read-length distribution. The algorithm retains spanned repeats in the reads during the fragmentation. We empirically demonstrate that RAFT significantly reduces the number of gaps using simulated data sets. Using real ONT and PacBio HiFi data sets of the HG002 human genome, we achieved a twofold increase in the contig NG50 and the number of haplotype-resolved T2T contigs compared to hifiasm.
Characterizing tandem repeat complexities across long-read sequencing platforms with TREAT andotter
Authors: Tesi Niccoló , Salazar Alex , Zhang Yaran , van der Lee Sven , Hulsman Marc , Knoop Lydian , Wijesekera Sanduni , Krizova Jana , Schneider Anne-Fleur , Pennings Maartje , Sleegers Kristel , Kamsteeg Erik-Jan , Reinders Marcel , Holstege Henne
Published: October 2024

Tandem repeats (TRs) play important roles in genomic variation and disease risk in humans. Long-read sequencing allows for the accurate characterization of TRs; however, the underlying bioinformatics perspectives remain challenging. We presentotterand TREAT:otteris a fast targeted local assembler, cross-compatible across different sequencing platforms. It is integrated in TREAT, an end-to-end workflow for TR characterization, visualization, and analysis across multiple genomes. In a comparison with existing tools based on long-read sequencing data from both Oxford Nanopore Technology (ONT, Simplex and Duplex) and Pacific Bioscience (PacBio, Sequel II and Revio),otterand TREAT achieve state-of-the-art genotyping and motif characterization accuracy. Applied to clinically relevant TRs, TREAT/ottersignificantly identify individuals with pathogenic TR expansions. When applied to a case-control setting, we replicate previously reported associations of TRs with Alzheimer's disease, including those near or withinAPOC1(P= 2.63 × 10−9),SPI1(P= 6.5 × 10−3), andABCA7(P= 0.04) genes. Finally, we use TREAT/otterto systematically evaluate potential biases when genotyping TRs using diverse ONT and PacBio long-read sequencing data sets. We show that, in rare cases (0.06%), long-read sequencing from coverage drops in TRs, including the disease-associated TRs inABCA7andRFC1genes. Such coverage drops can lead to TR misgenotyping, hampering the accurate characterization of TR alleles. Taken together, our tools can accurately genotype TRs across different sequencing technologies and with minimal requirements, allowing end-to-end analysis and comparisons of TRs in human genomes, with broad applications in research and clinical fields.
Global characterization of somatic mutations and DNA methylation changes during vegetative propagation in strawberries
Authors: Hu Shaoqiang , Zeng Xiangguo , Liu Yuguo , Li Yongping , Qu Minghao , Jiao Wen-Biao , Han Yongchao , Kang Chunying
Published: October 2024

Somatic mutations arise and accumulate during tissue culture and vegetative propagation, potentially affecting various traits in horticultural crops, but their characteristics are still unclear. Here, somatic mutations in regenerated woodland strawberry derived from tissue culture of shoot tips under different conditions and 12 cultivated strawberry individuals are analyzed by whole genome sequencing. The mutation frequency of single nucleotide variants is significantly increased with increased hormone levels or prolonged culture time in the range of 3.3 × 10−8–3.0 × 10−6mutations per site. CG methylation shows a stable reduction (0.71%–8.03%) in regenerated plants, and hypoCG-DMRs are more heritable after sexual reproduction. A high-quality haplotype-resolved genome is assembled for the strawberry cultivar “Beni hoppe.” The 12 “Beni hoppe” individuals randomly selected from different locations show 4731–6005 mutations relative to the reference genome, and the mutation frequency varies among the subgenomes. Our study has systematically characterized the genetic and epigenetic variants in regenerated woodland strawberry plants and different individuals of the same strawberry cultivar, providing an accurate assessment of somatic mutations at the genomic scale and nucleotide resolution in plants.
Complete genomes of Asgard archaea reveal diverse integrated and mobile genetic elements
Authors: Valentin-Alvarado Luis E. , Shi Ling-Dong , Appler Kathryn E. , Crits-Christoph Alexander , De Anda Valerie , Adler Benjamin A. , Cui Michael L. , Ly Lynn , Leão Pedro , Roberts Richard J. , Sachdeva Rohan , Baker Brett J. , Savage David F. , Banfield Jillian F.
Published: October 2024

Asgard archaea are of great interest as the progenitors of Eukaryotes, but little is known about the mobile genetic elements (MGEs) that may shape their ongoing evolution. Here, we describe MGEs that replicate in Atabeyarchaeia, a wetland Asgard archaea lineage represented by two complete genomes. We used soil depth–resolved population metagenomic data sets to track 18 MGEs for which genome structures were defined and precise chromosome integration sites could be identified for confident host linkage. Additionally, we identified a complete 20.67 kbp circular plasmid and two family-level groups of viruses linked to Atabeyarchaeia, via CRISPR spacer targeting. Closely related 40 kbp viruses possess a hypervariable genomic region encoding combinations of specific genes for small cysteine-rich proteins structurally similar to restriction-homing endonucleases. One 10.9 kbp integrative conjugative element (ICE) integrates genomically into theAtabeyarchaeum deiterrae-1chromosome and has a 2.5 kbp circularizable element integrated within it. The 10.9 kbp ICE encodes an expressed Type IIG restriction-modification system with a sequence specificity matching an active methylation motif identified by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing. Restriction-modification of Atabeyarchaeia differs from that of another coexisting Asgard archaea, Freyarchaeia, which has few identified MGEs but possesses diverse defense mechanisms, including DISARM and Hachiman, not found in Atabeyarchaeia. Overall, defense systems and methylation mechanisms of Asgard archaea likely modulate their interactions with MGEs, and integration/excision and copy number variation of MGEs in turn enable host genetic versatility.
Generation of Antibody Libraries for Phage Display: Preparation of Helper Phage
Authors: Peng Haiyong , Rader Christoph
Published: October 2024

The generation and selection of antibody libraries by phagemid-based phage display requires three components; namely, phagemid library, host bacterial cells, and helper phage. The use of helper phage is necessary for the selection of phagemid libraries by phage display because it provides all genes needed for production of infectious phage particles. Here, we describe the generation of high-titer helper phage preparations suitable for phagemid-based phage display. The approach is based on helper phage VCSM13, which includes a gene for kanamycin resistance and a mutated packaging signal that, in the presence of a phagemid with an unmutated packaging signal, favors the production of infectious phage particles with phagemid phenotype and genotype.
Generation and Selection of Phage Display Antibody Libraries in Fab Format
Authors: Rader Christoph
Published: October 2024

Monoclonal antibodies (mAbs) have exceptional utility as research reagents and pharmaceuticals. As a complement to both traditional and contemporary single-B-cell cloning technologies, the mining of antibody libraries via display technologies—which mimic and simplify B cells by physically linking phenotype (protein) to genotype (protein-encoding DNA or RNA)—has become an important method for mAb discovery. Among these display technologies, phage display has been particularly successful for the generation of mAbs that bind to a wide variety of antigens with exceptional specificities and affinities. Rather than multivalent whole antibodies, phage display typically uses monovalent antibody fragments, such as “fragment antigen binding” (Fab), as the format of choice. The ∼50-kDa Fab format consists of four immunoglobulin (Ig) domains on two polypeptide chains (light chain and shortened heavy chain), and exhibits its antigen binding site in a natural configuration found in bivalent IgG and other multivalent Ig molecules. The Fab fragment has a high melting temperature and a low tendency to aggregate, and can be readily converted to natural and nonnatural Ig formats without affecting antigen binding properties, which has made it a favored format for phage display for more than three decades. Here, I briefly summarize some of the approaches used for the generation and selection of phage display antibody libraries in Fab format, from human and nonhuman antibody repertoires.
Exchange-enhanced spin-orbit splitting and its density dependence for electrons in monolayer transition metal dichalcogenides
Authors: Rozhansky Igor , Fal'ko Vladimir
Published: October 2024

We show that spin-orbit splitting (SOS) in monolayers of semiconducting transition metal dichalcogenides (TMDs) is substantially enhanced by an electron-electron interaction. This effect, similar to the exchange enhancement of the electron g factor, is most pronounced for conduction band electrons (in particular, in MoS2), and it has a nonmonotonic dependence on the carrier sheet density n. That is, the SOS enhancement is peaked at the onset of filling of the higher-energy spin-split band by electrons, n*, which also separates the regimes of slow (at nn*) spin and valley relaxation of charge carriers. Moreover, this density itself is determined by the enhanced SOS value, making the account of exchange renormalization important for the analysis of the spintronic performance of field-effect transistors based on two-dimensional TMDs.

Published by the American Physical Society
2024
Rift Gaps in Chemical-Wave Network Systems
Authors: Kanimian Tamar , Haroun Lara , Sultan Rabih
Published: October 2024

We carry out experiments in diffusion-precipitation systems in a framework with multiple diffusion sources. The advancing precipitation fronts reach a point where they stop, leaving a rift or gap between the precipitate zones. In a similar setting, fractal metal deposits emerging from various reduction centers were synthesized. They were shown to meander in the medium, but fail to meet or overlap, thus also leaving a gap or rift just like in the precipitation system. The obtained patterns were analyzed by calculating entropy and front velocity for the former system, and fractal dimension for the latter. The observed structures represent chemical analogs of Voronoi diagrams.

Published by the American Physical Society
2024
Universal Time-Entanglement Trade-Off in Open Quantum Systems
Authors: Pocklington Andrew , Clerk Aashish A.
Published: October 2024

We demonstrate a surprising connection between pure steady-state entanglement and relaxation time scales in an extremely broad class of Markovian open systems, where two (possibly many-body) systems, A and B, interact locally with a common dissipative environment. This setup also encompasses a broad class of adaptive quantum dynamics based on continuous measurement and feedback. As steady-state entanglement increases, there is generically an emergent strong symmetry that leads to a dynamical slow-down. Using this, we can prove rigorous bounds on relaxation times set by steady-state entanglement. We also find that this time must necessarily diverge for maximal entanglement. To test our bound, we consider the dynamics of a random ensemble of local Lindbladians that support pure steady states, finding that the bound does an excellent job of predicting how the dissipative gap varies with the amount of entanglement. Our work provides general insights into how dynamics and entanglement are connected in open systems and has specific relevance to quantum reservoir engineering.

Published by the American Physical Society
2024
Synthesis, structures and Hirshfeld surface analyses of 2-hydroxy-N′-methylacetohydrazide and 2-hydroxy-N-methylacetohydrazide
Authors: Vashchenko Oleksandr V. , Khomenko Dmytro M. , Dyakonenko Viktoriya V. , Lampeka Rostyslav D.
Published: October 2024

The structures of the title compounds 2-hydroxy-N′-methylacetohydrazide, 1, and 2-hydroxy-N-methylacetohydrazide, 2, both C3H8N2O2, as regioisomers differ in the position of the methyl group relative to the N atoms in 2-hydroxy-acetohydrazide. In the structure of 1, the 2-hydroxy-acetohydrazide core [OH—C—C(=O)—NH—NH] is almost planar and the methyl group is rotated relative to this plane. As opposed to 1, in the structure of 2 all non-hydrogen atoms lie in the same plane. The hydroxyl and carbonyl groups in structures 1 and 2 are in trans and cis positions, respectively. The methyl amino group and carbonyl group are in the cis position relative to the C—N bond in structure 1, while the amino group and carbonyl group are in the trans position relative to the C—N bond in stucture 2. In the crystal, molecules of 1 are linked by N—H...O and O—H...N intermolecular hydrogen bonds, forming layers parallel to the ab crystallographic plane. A Hirshfeld surface analysis showed that the H...H contacts dominate the crystal packing with a contribution of 55.3%. The contribution of the H...O/O...H interaction is somewhat smaller, amounting to 30.8%. In the crystal, as a result of the intermolecular O—H...O hydrogen bonds, molecules of 2 form dimers, which are linked by N—H...O hydrogen bonds and a three-dimensional supramolecular network The major contributors to the Hirshfeld surface are H...H (58.5%) and H...O/O...H contacts (31.7%).
Crystal structure of (μ2-7-{[bis(pyridin-2-ylmethyl)amino-1κ3
N,N′,N′′]methyl}-5-chloroquinolin-8-olato-2κN;1:2κ2
O)trichlorido-1κCl,2κ2
Cl-dizinc(II)
Authors: Kubono Koji , Tanaka Kanata , Tani Keita , Kashiwagi Yukiyasu
Published: October 2024

The title compound, [Zn2(C22H18ClN4O)Cl3], is a dinuclear zinc(II) complex with three chlorido ligands and one pentadentate ligand containing quinolin-8-olato and bis(pyridin-2-ylmethyl)amine groups. One of the two ZnII atom adopts a tetrahedral geometry and coordinates two chlorido ligands with chelate coordination of the N and O atoms of the quinolin-8-olato group in the ligand. The other ZnII atom adopts a distorted trigonal–bipyramidal geometry, and coordinates one chlorido-O atom of the quinolin-8-olato group and three N atoms of the bis(pyridin-2-ylmethyl)amine unit. In the crystal, two molecules are associated through a pair of intermolecular C—H...Cl hydrogen bonds, forming a dimer with an R
2
2(12) ring motif. Another intermolecular C—H...Cl hydrogen bond forms a spiral C(8) chain running parallel to the [010] direction. The dimers are linked by these two intermolecular C—H...Cl hydrogen bonds, generating a ribbon sheet structure in ac plane. Two other intermolecular C—H...Cl hydrogen bonds form a C(7) chain along the c-axis direction and another C(7) chain generated by a d-glide plane. The molecules are cross-linked through the four intermolecular C—H...Cl hydrogen bonds to form a three-dimensional network.
Secret professional deviance: the case of the independence rule
Authors: Picard Claire-France , Courtois Cynthia , Durocher Sylvain , Malo Angélique
Published: October 2024

Purpose

This paper examines how rank-and-file practitioners react to and negotiate uniformized professional standards imposed by the elites of their profession in order to embody their professional ideal.

Design/methodology/approach

We explore this topic through the specific case of the Canadian independence rule. We mobilize Freidson’s and Becker’s conceptual tools to make sense of our data, generated through 55 interviews with rank-and-file practitioners.

Findings

We found that most rank-and-file practitioners override the (spirit of the) independence rule and engage in a process of secret deviance to pursue their professional ideal of accompanying their client in their business. Specifically, our analysis underlines how they find pleasure in fulfilling their professional ideal, seek to protect the secrecy that allows them to pursue this ideal while avoiding sanctions, and convince themselves of the morality of breaking the (spirit of the) rule in order to embody their conception of professionalism.

Research limitations/implications

Our analysis expands fieldwork on rank-and-file practitioners by offering an analysis of struggles they experienced in their daily practice and by bringing to light their path to secret “professional” deviance.

Practical implications

Our study points to the necessity for better consideration of the realities of professional segments when developing rules or standards.

Originality/value

Our study develops a distinctive conceptual construct – the professionalism conception gap – to explain how secret “professional” deviance can unfold within a profession. This construct could be mobilized to further understand the divergences that can exist within broader professional spheres.
Affirmative action and government initiatives to improve gender equality in India: a retrospective view
Authors: Sahoo Debashish Kumar , Lenka Usha
Published: October 2024

Purpose

This paper discusses the problems of gender equality in society, the workplace and the household in the specific context of India. It explicates the past and the present gender diversity initiatives by government machinery to bring gender equality through affirmative action.

Design/methodology/approach

The design, methodology and approach involve a general review.

Findings

Developed countries have taken initiatives for gender equality almost in the pre-20th century and were partially successful. Despite gender diversity and affirmative action and legislation, bias still prevails in varied forms. In the case of India, the movement for gender equality started post-independence (1947). Still, there is a high disparity between men and women in society as well as in various occupations, as it is evident through a huge difference in salary, responsibilities, perquisites, recognition and promotions offered to men and women. India needs more transformation in the culture, statutory bodies and the mindset of patriarchal societies, to achieve gender equality. The legislative changes have faced resistance in their implementation due to social, cultural and religious issues, and the expectations and perceptions toward females have not been changed by the patriarchal society.

Originality/value

This paper deciphers the gender equality movement in developing countries like India, and how the planning commission of India focuses on women’s development and government machinery tries to bring down the gender gap through affirmative action. Why, in spite of all these efforts, India is not able to minimize the gender gap and concludes with reasons and implications.
The impact of social determinants of health on international migrants’ health outcomes: a bibliometric analysis
Authors: Sweileh Waleed
Published: October 2024

Purpose

The aim of this study is to conduct an in-depth exploration of the research landscape concerning the impact of social determinants of health (SDH) on the health outcomes of international migrants.

Design/methodology/approach

Leveraging the extensive Scopus database, this study retrieved a total of 2,255 articles spanning the years 1993–2023. The framework for analysis used the SDH categories outlined by the World Health Organization.

Findings

The research landscape exhibited an apparent increase in the number of publications, but not a net increase in the research productivity. The USA emerged as the leading contributor to research output, with the Journal of Immigrant and Minority Health emerging as the most prolific publication venue, and the University of Toronto ranking as the most prolific institution. The SDH category that received the highest number of publications was the “community and social context”. Migrants from different regions in Asia (East, Central and South Asia) and those from Latin America and the Caribbean region appeared to be the most commonly researched. Highly cited articles predominantly delved into mental health outcomes arising from discrimination and migration policies.

Research limitations/implications

The findings proffer valuable insights for shaping future research endeavors, accentuating the imperative for diversified studies encompassing underrepresented domains, broader health outcomes and the inclusion of migrant populations from different world regions in investigative pursuits.

Originality/value

This study delivers a comprehensive analysis of the research landscape, unveiling critical trends in the realm of SDH and migrant health outcomes.