bluuebunny/crossref_metadata_2025 huggingface dataset:
Pretransplant HOMA-β Is Predictive of Insulin Independence in 7 Patients With Chronic Pancreatitis Undergoing Islet Autotransplantation
Authors: Beamish Christine A. , Gaber A. Osama , Fraga Daniel W. , Hamilton Dale J. , Sabek Omaima M.
Published: September 2022

Background.

Islet and β-cell function is intrinsic to glucose homeostasis. Pancreatectomy and islet autotransplantation (PIAT) for chronic pancreatitis (CP) treatment is a useful model for assessing islet function in the absence of immune-suppression and to perform extensive presurgical metabolic evaluations not possible from deceased donors. We recently showed that in CP-PIAT patients, preoperative islet identity loss presented with postoperative glycemic loss. Here, we examine presurgical islet function using Homeostatic Model Assessment-Beta Cell Function (%) (HOMA-β) and glycemic variables and compared them with postsurgical insulin independence and their predicted alignment with Secretory Unit of Islet Transplant Objects (SUITO) and beta cell score after transplantation (BETA-2) scores.

Methods.

Seven CP-PIAT patients were assessed for β-cell function metrics, including pretransplant and 6-mo posttransplant HOMA-β using insulin and C-peptide and evaluations of proposed insulin independence by SUITO and BETA-2 graft function equations. These were compared with oral glucose tolerance tests and pancreas histological samples taken at the time of transplant, examined for β-cell maturity markers.

Results.

Pre-PIAT, HOMA-β (60%−100%) associated with post-PIAT insulin independence. This association was only moderately supported by post-PIAT SUITO threshold scores (≥26) but robustly by BETA-2 scores (≥16.2). Appropriate posttransplant oral glucose tolerance test curves were found in those patients with normal pretransplant HOMA-β values. Preoperative low serological β-cell function was displayed by concurrent evidence of β-cell identity alterations including colocalization of insulin and glucagon, loss of urocortin-3, and increased intra-islet vimentin in patients who were insulin-dependent post-PIAT.

Conclusions.

These data encourage HOMA-β assessment before PIAT for estimating posttransplant insulin independence.
Spatial and temporal Variability of bacterial and chemical pollution in marine sediments of the beach of Lattakia city
Authors: AHMAD SHREBA RAMIA , Al Ali Badr , Laika Hussam Eddin
Published: September 2022

This study focuses on evaluation bacterial and chemical contamination of coastal sediments in three sites in the coast of Lattakia during the summer 2021 and winter 2022. It was achieved by determining the concentrations of heavy metals (lead and cadmium) and microbial contamination indicators (Total Bacteria (TB), Fecal Coliform (FC) and Fecal Streptococcus (FS). The source of pollution was determined by the FC/FS ratio. The results showed high values ​​of microbial contamination indicators and concentrations of heavy metals in the studied sites in winter and summer respectively, where TB values ​​were between (1.3-3.75) × 10 5 CFU/100g and (1.55-6.3) × 10 5 CFU/100g and FC Between (2.5-3) × 10 3 CFU/100g, FS (2-2.9) × 10 3 CFU/100g and lead concentration was (37.15-41.69) mg/kg and cadmium concentration was (1.67-3.14) mg/kg.
Key features of pneumococcal isolates recovered in Central and Northwestern Russia in 2011–2018 determined through whole-genome sequencing
Authors: Egorova Ekaterina , Kumar Narender , Gladstone Rebecca A. , Urban Yulia , Voropaeva Elena , Chaplin A.V. , Rumiantseva Elena , Svistunova T. S. , Hawkins Paulina A. , Klugman Keith P. , Breiman Robert F. , McGee Lesley , Bentley Stephen D. , Lo Stephanie W.
Published: September 2022

Invasive pneumococcal disease remains one of the leading causes of morbidity and mortality worldwide. In Russia, 13- valent pneumococcal conjugate vaccine (PCV13) was introduced into the childhood immunization programme nationwide in 2014. As part of the Global Pneumococcal Sequencing Project (GPS), we used genome data to characterize 179 pneumococcal isolates collected from Russia in 2011–2018 to investigate the circulating pneumococcal strains using a standardized genomic definition of pneumococcal lineages (global pneumococcal sequence clusters, GPSCs), prevalent serotypes and antimicrobial resistance profiles.

We observed high serotype and lineage diversity among the 179 isolates recovered from cerebrospinal fluid (n=77), nasopharyngeal swabs (n=99) and other non-sterile site swabs (n=3). Overall, 60 GPSCs were identified, including 48 clonal complexes (CCs) and 14 singletons, and expressed 42 serotypes (including non-typable). Among PCV13 serotypes, 19F, 6B and 23F were the top three serotypes while 11A, 15B/C and 8 were the top three among non-PCV13 serotypes in the collection. Two lineages (GPSC6 and GPSC47) expressed both PCV13 and non-PCV13 serotypes that caused invasive disease, and were penicillin- and multidrug-resistant (MDR), highlighting their potential to adapt and continue to cause infections under vaccine and antibiotic selective pressure. PCV13 serotypes comprised 92 % (11/12) of the CSF isolates from the children aged below 5 years; however, the prevalence of PCV13 serotype isolates dropped to 53 % (31/58) among the nasopharyngeal isolates. Our analysis showed that 59 % (105/179) of the isolates were predicted to be non-susceptible to at least one class of antibiotics and 26 % (46/179) were MDR. Four MDR lineages (GPSC1, GPSC6, GPSC10 and GPSC47) accounted for 65 % (30/46) of the MDR isolates and expressed PCV13 serotypes (93 %, 28/30).

This study provides evidence of high genetic and serotype diversity contributed by a mix of globally spreading and regionally circulating lineages in Russia. The observations suggest that the PCV13 vaccine could be important in reducing both invasive disease and antimicrobial resistance. We also identify potential lineages (GPSC6 and GPSC47) that may evade the vaccine.
Origins of monkeypox viruses and their strains circulating in 2022
Authors: Chen Ji-Ming , Gong Huan-Yu , Chen Rui-Xu , Sun Ming-Hui , Ji Yu-Fei , Li Guo-Hui , Tan Su-Mei , Sun Ying-Xue
Published: September 2022

Monkeypox has spread unprecedentedly to nearly 100 countries and infected more than 51,000 people since 1 May 2022. This large-scale outbreak constituted a public health emergency of international concern (PHEIC), as declared by the World Health Organization. To better recognize and control this outbreak, we explore here through phylogenetic analysis the origins of MPXVs and their strains circulating in 2022, which remain unclear so far. Our results suggest that MPXVs possibly originated from some cowpox viruses and three lineages of MPXVs within Clade IIb circulated in 2022. Our results also suggest that two MPXVs respectively similar to the two MPXVs exported from Nigeria to the USA in 2021, ON676708/USA/2021 and ON676707/USA/2021, evolved into two lineages and sparked the large-scale outbreak in 2022, after their unknown evolutionary and epidemiological journeys possibly in Nigeria, the USA, or other countries before May 2022. This view does not stigmatize any country, because monkeypox is an endemic zoonosis in west Africa with wildlife reservoirs, and its large-scale outbreak in 2022 also resulted from the global decline of population immunity against smallpox due to the cease of vaccination against smallpox decades ago.
BRAin-wide Neuron quantification Toolkit reveals strong sexual dimorphism in the evolution of fear memory
Authors: Franceschini Alessandra , Mazzamuto Giacomo , Checcucci Curzio , Chicchi Lorenzo , Fanelli Duccio , Costantini Irene , Passani Maria Beatrice , Silva Bianca Ambrogina , Pavone Francesco Saverio , Silvestri Ludovico
Published: September 2022

Fear responses are functionally adaptive behaviors that are strengthened as memories. Indeed, a detailed knowledge of the neural circuitry modulating fear and fear memory could be the turning point for the comprehension of this emotion and its pathological states.

A comprehensive understading of the neural circuits mediating memory encoding, consolidation, and retrieval over time presents the fundamental technological challenge of analyzing activity in the entire brain with single-neuron resolution. In this context, we developed the BRAin-wide Neuron quantification Toolkit (BRANT) for mapping whole-brain neuronal activation at micron-scale resolution, combining tissue clearing, high-resolution light-sheet microscopy, and automated 3D image analysis. The robustness and scalability of this method allowed us to quantify the evolution of neuronal activation patterns across multiple phases of memory in mice. This approach highlighted a strong sexual dimorphism in the circuits recruited during memory recall, which had no counterpart in the behaviour. The methodology presented here paves the way for a comprehensive functional characterization of the evolution of fear memory.
Developmental rate displays effects of inheritance but not of sex in inter-population hybrids ofTigriopus californicus
Authors: Healy Timothy M. , Hargadon Alexis Cody , Burton Ronald S.
Published: September 2022

Coevolved interactions between mitochondrial-encoded and nuclear-encoded genes within populations can be disrupted by inter-population hybridization resulting in reduced hybrid fitness. This hybrid breakdown may be an important factor contributing to reproductive isolation between populations or species, and strong selection among hybrids to maintain compatible mitonuclear genotypes occurs in at least some species. Despite potentially differential consequences of mitonuclear incompatibilities in females and males due to maternal inheritance of the mitochondrial genome, the extent to which phenotypic variation associated with hybrid breakdown is sex-specific and heritable remains unresolved. Here we present two experiments investigating variation in developmental rate among reciprocal inter-population hybrids of the intertidal copepodTigriopus californicus. Developmental rate is a proxy for fitness in this species that is substantially influenced by variation in mitonuclear compatibility among hybrids. First, we show that F2hybrid developmental rate is the same in females and males, suggesting that effects of mitonuclear incompatibilities on this trait are likely experienced equally by the two sexes. Second, we demonstrate that variation in developmental rate among F3hybrids is heritable; times to copepodid metamorphosis of F4offspring of fast-developing F3parents (12.25 ± 0.05 d, μ ± SEM) were significantly faster than those of F4offspring of slow-developing parents (14.58 ± 0.05 d). Taken together, these results provide evidence for strong effects of mitonuclear interactions across generations of hybrid eukaryotes with no differences between the sexes, and support key roles of mitonuclear incompatibility in hybrid breakdown and reproductive isolation.
Single-nuclei transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species
Authors: Dimitriadis Athanasios , Zhang Fuquan , Murphy Thomas , Trainer Thomas , Jaunmuktane Zane , Schmidt Christian , Nazari Tamsin , Linehan Jacqueline , Brandner Sebastian , Collinge John , Mead Simon , Viré Emmanuelle
Published: September 2022

Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein (PrP). The most common human form of the disease, sporadic Creutzfeldt-Jakob disease (sCJD), typically presents as a rapidly progressive dementia and has no effective treatments. Prion diseases are transmissible to laboratory rodents affording unprecedented opportunities to understand neurodegeneration in its evolving stages. Murine models are especially useful in prion research as they develop bona fide prion disease and recapitulate all biochemical and neuropathological hallmarks of human prion disease. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. This is at least in part because confounding effects related to brain cellular heterogeneity have not been resolved. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
Platelet phosphatidylserine is the critical mediator of thrombosis in heparin-induced thrombocytopenia
Authors: Zlamal Jan , Singh Anurag , Weich Karoline , Jaffal Hisham , Uzun Günalp , Althaus Karina , Bakchoul Tamam
Published: September 2022

Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated prothrombotic disorder caused by antibodies reactive to complexes of platelet factor 4 and heparin. Platelets (PLTs) and their interaction with different immune cells contribute to prothrombotic conditions in HIT. However, the exact mechanisms and the role of different PLT subpopulations to this prothrombotic enviroment remain poorly understood. In this study, we observed that HIT patient antibodies (Abs) induce relevant changes in PLT phenotype, with the key features being increased P-Selectin expression and procoagulant phosphatidylserine (PS) externalization. Formation of procoagulant PLTs was dependent on engagement of PLT Fc-gamma-RIIA by HIT Abs and resulted in significant increase of thrombin generation on the PLT surface. Using an ex vivo thrombosis model and multi-parameter assessment of thrombus formation, we observed that HIT Ab-induced procoagulant PLTs propagated formation of large PLT aggregates, leukocyte recruitment and most importantly, fibrin network generation. These prothrombotic conditions were prevented via the upregulation of PLTs intracellular cAMP with Iloprost, a clinically approved prostacyclin analogue. Additionally, the functional relevance of high P-Selectin and PS levels on procoagulant PLTs was dissected. While inhibition of P-Selectin did not affect thrombus formation, the specific blockade of PS with Lactadherin prevented HIT Ab-mediated thrombin generation and most importantly procoagulant PLT-mediated thrombus formation ex vivo. Taken together, our findings indicate that procoagulant PLTs are critical mediators of prothrombotic conditions in HIT. Upregulation of cAMP with Iloprost or PS targeting specifc therapeutics could be a promising approach to prevent thromboembolic events in HIT patients.

Key points

- HIT immune complexes drive procoagulant platelet formation

- Phosphatidylserine blockade prevents HIT antibody-induced thrombus formation
A climate-driven compartmental model for fungal diseases in fruit orchards: The impacts of climate change on a brown rot-peach system
Authors: Bevacqua Daniele , Vanalli Chiara , Casagrandi Renato , Gatto Marino
Published: September 2022

As a well-known driving force of diseases in crops, climate change is likely to impact future crop yields. In the present work, we account for climate-related influences on the key parameters of a SIR-type epidemiological model for fungal diseases in stone fruit aimed at simulating different observed epidemic patterns, and, eventually, evaluating the possible impacts of climate change on the disease-induced yield loss. Brown rot disease in peach orchards is used here as a study system. We contrasted simulation results with epidemiological measures collected from an experimental orchard in Avignon (southern France) in two consecutive years, characterized by dissimilar brown rot outbreaks. The capacity of our climate-driven model to adequately reproduce the observed disease patterns suggests temperature and precipitation as key drivers of brown rot epidemics. Overall, the model predicts a potential decrease of brown rot severity under warmer and drier climatic conditions. To comprehensively understand the effect of future climate change on peach yield, alterations of crop phenology must also be accounted for. We thus build a model that considers the synergism between the two factors: vulnerability to the pathogen and varying phenology. Using plausible climate change scenarios, we find that the peach yield in the considered Mediterranean region will be considerably impaired: although brown rot-related yield losses are expected to decrease in warmer and drier climatic conditions, climate change will hinder fruit blooming and consequently the yield because milder winters will impede the achievement of dormancy. By deepening our understanding of climatic impacts on crop fungal infections, the present study may serve as a useful tool to plan and implement suitable adaptation strategies for peach cultivation.
DEGoldS: a workflow to assess the accuracy of differential expression analysis pipelines through gold-standard construction
Authors: Hurtado Mikel , Mora-Márquez Fernando , Soto Álvaro , Marino Daniel , Goicoechea Pablo G. , López de Heredia Unai
Published: September 2022

RNA sequencing (RNA-seq) is a high throughput sequencing method that has become one the most employed tools in transcriptomics. The implementation of optimal bioinformatic analyses required in RNA-seq experiments may be complicated due to the large amounts of data generated by the sequencing platforms, along with the intrinsic nature of these data types. In the last years many programs and pipelines have been developed for differential expression (DE) analyses, but their effectiveness can be reduced when working with non-model species lacking public genomic resources. Moreover, there is not a universal recipe for all the experiments and datasets and the modification of standard RNA-seq bioinformatic pipelines through parameter tuning and the use of alternative software may have a strong impact in the outcome of DE analysis. Therefore, although the selection of the most accurate DE pipeline configuration and the evaluation of how these changes could affect the final DE results in RNA-seq experiments is mandatory to reduce bias, the lack of gold-standard datasets with known expression patterns hampers its implementation. In the present manuscript we present DEGoldS, a workflow consisting on sequential Bash and R scripts to construct gold-standards for simulation-based benchmarking of user selected pipelines for DE analysis and the computation of the accuracy of the pipelines. We validated the workflow with a case study consisting on real RNA-seq libraries of radiata pine, an important forest tree species with no publicly available reference genome. The results showed that slight pipeline modifications produced remarkable differences in the outcome of DE analysis.
A High throughput method for egg size measurement inDrosophila
Authors: Barghi Neda , Ramirez-Lanzas Claudia
Published: September 2022

Life-history traits are used as proxies of fitness in insects includingDrosophila. Egg size is an adaptive and ecologically important trait potentially with genetic variation across different populations. However, the low throughput of manual measurement of egg size has hampered the widespread use of this trait in evolutionary biology and population genetics. We established a method for accurate and high throughput measurement ofDrosophilaegg size using large particle flow cytometry (LPFC). The size estimates using LPFC are accurate and highly correlated with the manual measurements. The measurement of egg size is high throughput (average of 214 eggs measured per minute) and viable eggs of a specific size can be sorted rapidly (average of 70 eggs per minute). Sorting by LPFC does not reduce the survival of eggs making it a suitable approach for sorting eggs for downstream analyses. This protocol can be applied to any organism within the detectable size range (10-1500 μm) of the large particle flow cytometers. We discuss the potential applications of this method and provide recommendations for optimizing the protocol for other organisms.
Sounding the alarm: sex differences in rat ultrasonic vocalizations during Pavlovian fear conditioning and extinction
Authors: Laine MA , Mitchell JR , Rhyner J , Clark R , Kannan A , Keith J , Pikus MC , Bergeron E , Ravaglia I. , Ulgenturk E , Shinde A , Shansky RM
Published: September 2022

Pavlovian fear conditioning is a prevalent tool in the study of aversive learning, which is a key component of stress-related psychiatric disorders. Adult rats can exhibit various threat-related behaviors, including freezing, motor responses and ultrasonic vocalizations (USVs). While these responses can all signal aversion, we know little about how they relate to one another. Here we characterize USVs emitted by male and female rats during cued fear acquisition and extinction and assess the relationship between different threat-related behaviors. To probe the effects of aversive stimulus intensity, we exposed the rats to mild (0.3 mA), moderate (0.5 mA) or strong (1 mA) foot shocks. We found that males consistently emitted more alarm calls than females, and male alarm calls were more closely contingent on shock intensity than were female alarm calls. Furthermore, 25 % of males and 45 % of females did not emit alarm calls. Males that made alarm calls had significantly higher levels of freezing than males who did not, while no differences in freezing were observed between female alarm callers and non-callers. Alarm call emission was also affected by the predictability of the shock; when unpaired from a tone cue, both males and females started emitting alarm calls significantly later. Some rats continued to alarm-call during extinction learning (90% of males, 30% of females) and retrieval (65% of males, 20% of females). Collectively these data suggest sex-dependence in how behavioral readouts relate to innate and conditioned threat responses. Importantly, we suggest that the same behaviors can signal sex-dependent features of aversion.

Significance statement

Behavioral neuroscientists can access various outputs during behavioral tests to draw conclusions about internal states of animals. While freezing is the most common index of rodents feeling threatened, these animals also emit specific ultrasonic vocalizations during aversive situations. Here we record several motor and vocal behaviors to assess how they relate to each other as threat responses, and how such relationships vary across sex. We found robust differences in how much male and female rats engaged in so-called alarm vocalizations. These vocalizations were subject to extinction in both sexes, but correlated with freezing only in males. As the field advances to include more females in preclinical research, it is crucial that we understand how similar-appearing outputs may reflect sex-biased features.
The Evolution of Dynamic and Flexible Courtship Displays That Reveal Individual Quality
Authors: Hollon Sam H. , Ruiz Irene García , Veen Thor , Fawcett Tim W.
Published: September 2022

Sexual selection is a major force shaping morphological and behavioral diversity. Existing theory focuses on courtship display traits such as morphological ornaments whose costs and benefits are assumed be to fixed across individuals’ lifetimes. In contrast, empirically observed displays are often inherently dynamic, as vividly illustrated by the acrobatic dances, loud vocalizations, and vigorous motor displays involved in courtship behavior across a broad range of taxa. One empirically observed form of display flexibility occurs when signalers adjust their courtship investment based on the number of rival signalers. The predictions of established sexual selection theory cannot readily be extended to such displays because display expression varies between courtship events, such that any given display may not reliably reflect signaler quality. Thus, we lack an understanding of how dynamic displays coevolve with sexual preferences and how signalers should tactically adjust their display investment across multiple courtship opportunities. To address these questions, we extended an established model of the coevolution of a female sexual preference and a male display trait to allow for dynamic, flexible displays. We find that a dynamic display can coevolve with a sexual preference away from their naturally selected optima, though display intensity is a weaker signal of male quality than for static ornaments. Furthermore, we find that males evolve to decrease their display investment when displaying alongside more rivals. This research represents a first step towards generalizing the findings of sexual selection theory to account for the ubiquitous dynamism of animal courtship.

Significance Statement

Animal courtship displays are typically costly for survival: songs attract predators; dances are exhausting; extravagant plumage is cumbersome. Because of the trade-off between mating benefits and survival costs, displaying individuals often vary their displays across time, courting more intensely when the potential benefit is higher or the cost is lower. Despite the ubiquity of such adjustment in nature, existing theory cannot account for how this flexibility might affect the coevolution of displays with sexual preferences, nor for the patterns of tactical display adjustment that might result, because those models treat displays as static, with fixed costs and benefits. Generalizing a well-studied model of sexual selection, we find that a static display and a flexible display can evolve under similar conditions. Our model predicts that courtship should be less intense when more competitors are present.
Loss of H3.1K27me1 in Arabidopsis confers resistance to Geminivirus by sequestering DNA repair proteins onto rDNA and defense-related genes
Authors: Wang Zhen , Castillo Gonzalez Claudia M. , Zhao Changjiang , Tong Chun-Yip , Li Changhao , Liu Zhiyang , Xie Kaili , Zhu Jiaying , Wu Zhongshou , Peng Xu , Jacob Yannick , Michaels Scott D. , Jacobsen Steven E. , Zhang Xiuren
Published: September 2022

The H3 methyltransferases ATXR5 and ATXR6 deposit H3.1K27me1 to heterochromatin to prevent genomic instability and transposon reactivation. Here, we report that atxr5 atxr6 mutants displayed robust resistance to Geminivirus. The viral resistance correlated with activation of DNA repair pathways, but not with transposon reactivation or heterochromatin amplification. We identified RAD51 and RPA1A as partners of virus-encoded Rep protein. The two DNA repair proteins showed increased binding to heterochromatic regions and defense-related genes in atxr5 atxr6 vs wild type plants. Consequently, the proteins had reduced interactions to viral DNA in the mutant, thus hampering viral replication. Additionally, RAD51 recruitment to the host genome arose via BRCA1, HOP2 and CYCB1, and this recruitment was essential for viral resistance in atxr5 atxr6. Thus, Geminiviruses adapt to healthy plants by hijacking its DNA repairing pathways for replication, but the host could retain DNA repairing proteins via sacrificing its genome stability to suppress viral infection.
CXCR4 controls movement and degranulation of CD8+T cells in the influenza-infected lung via differential effects on interaction and tissue scanning
Authors: Mrass Paulus , Kinjyo Ichiko , Byrum Janie R. , Torres David , Baker Steven F. , Cannon Judy L.
Published: September 2022

Effector CD8+T cell interactions are critical in controlling viral infection by directly killing infected cells but overabundant or sustained activation also exacerbates tissue damage. Chemokines promote the trafficking of effector CD8+T cells into infected tissues, but we know little about how chemokines regulate the function of CD8+T cells within tissues. Using a murine model of influenza A virus infection, we found that expression of the chemokine receptor CXCR4 by lung-infiltrating cytotoxic T cells correlated with the expression of the degranulation marker CD107a. Inhibition of CXCR4 reduced activation, adhesion, and degranulation of cytotoxic T cellsin vitroandin vivo. Moreover, in live influenza-infected lung tissue, T cells stopped moving in lung regions with high levels of influenza antigen, and CXCR4 was essential for CD8+T cells to execute this arrest signal fully. In contrast, CXCR4 increased the motility of CD8+T cells in low-influenza areas of the lung. We also found that CXCR4 stimulated the effector function of lung-infiltrating cytotoxic T cells even after clearance of influenza virus, and inhibition of CXCR4 expedited the recovery of influenza-infected mice, despite delayed clearance of the replication-competent virus. Our results suggest that CXCR4 promotes the interaction strength of cytotoxic T cells in lung tissue through combined effects on T cell movement and interaction with virally infected target cells in influenza infected-lungs.
Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 co-activation
Authors: Shah Viral , Giotopoulos George , Osaki Hikari , Meyerhöfer Markus , Meduri Eshwar , Schubert Benedict , Yun Haiyang , Horton Sarah J , Agrawal-Singh Shuchi , Haehnel Patricia S , Basheer Faisal , Lugo Dave , Kühn Michael WM , Guezguez Borhane , Theobald Matthias , Kindler Thomas , Gallipoli Paolo , Prinjha Rab K , Huntly Brian JP , Sasca Daniel
Published: September 2022

Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). The main reason for this involves an increased transcriptional plasticity within AML, which allows cells to escape the therapeutic pressure. To study mechanisms of resistance, we investigated immediate epigenetic and transcriptional responses following BET inhibition, and could demonstrate that BET inhibitor-mediated release of BRD4 from chromatin is accompanied by an acute compensatory feedback loop that attenuates inhibition, or even increases expression, of specific transcriptional modules. This adaptation is most marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity by combining BET- and p300- inhibition. p300 activity is required during all steps of adaptation. However, the transcriptional programs that p300 regulates to induce resistance to BETi differ between AML subtypes. Remarkably, in some AMLs, p300 regulates a series of transitional transcriptional patterns that allow homeostatic adjustments during earlier stages of resistance to BET-inhibitors. In consequence, p300 remains crucial throughout all stages of resistance in sensitive AML-subtypes, although its importance declines following the development of chronic resistance to BET inhibitors in some other AMLs. Altogether, our study elucidates the mechanisms that underlie an “acute” state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to become “chronic”. Importantly, however, our data also suggest that a sequential treatment with BET- and p300 inhibition may prevent resistance development, thereby improving outcomes.

Key points

A mechanistic feedback to p300 enables acute tolerance to BET inhibition.

p300 regulates transcriptional networks that lead to chronic resistance to BET inhibition.

Sequential BET-, followed by p300-inhibition, is synthetically lethal in AML, and is optimally deployed during earlier stages of resistance to BET inhibitors.
Topological Links in Predicted Protein Complex Structures Reveal Limitations of AlphaFold
Authors: Hou Yingnan , Xie Tengyu , He Liuqing , Tao Liang , Huang Jing
Published: September 2022

AlphaFold is making great progress in protein structure prediction, not only for single-chain proteins but also for multi-chain protein complexes. When using AlphaFold-Multimer to predict protein–protein complexes, we observed some unusual structures in which chains are looped around each other to form topologically intertwining links at the interface. To our knowledge, such topological links are never observed in the experimental structures deposited in the Protein Data Bank (PDB). Although it is well known and has been well studied that protein structures may have topologically complex shapes such as knots and links, existing methods are hampered by the chain closure problem and show poor performance in identifying topologically linked structures in protein–protein complexes. Therefore, we address the chain closure problem by using sliding windows from a local perspective and propose an algorithm to measure the topological–geometric features that can be used to identify topologically linked structures. An application of the method to AlphaFold-Multimer-predicted protein complex structures finds that approximately 0.7% of the predicted structures contain topological links. The method presented in this work will facilitate the computational study of protein–protein interactions and help further improve the structural prediction of multi-chain protein complexes.
Complete blood count and selected serum parameters of Venus transgenic rabbits
Authors: Biró Bálint , Skoda Gabriella , Hoffmann Orsolya Ivett , Hiripi László , Gócza Elen , Lipták Nándor
Published: September 2022

Green fluorescent protein (GFP) transgenic laboratory animals (mice, rats, rabbits etc.) are commonly used in basic research for modelling human diseases, studying organ development, cell transfer during pregnancy or tissue engineering. The expression of the fluorescent protein can be either ubiquitous or tissue-specific, depending on the transgenic construct and the integration site of the transgene. Despite the wide applications, the data about the physiological parameters of GFP transgenic animals are limited. In most of the transgenic lines, GFP does not induce any detrimental effect, but GFP-induced conditions are also reported. Altered T-lymphopoiesis and low white blood cell (WBC) count were observed in human ubiquitin C promoter-driven GFP transgenic (UBC-GFP) mice due to latent stem cell defect. The aim of the present study was to examine the effects of the Venus fluorescent protein on hematopoiesis and general health of transgenic rabbits, thus, hematology along with selected serum parameters were measured.
Restoring functional D2- to D1-neuron correspondence enables goal-directed action control in long-lived striatal circuits
Authors: Bertran-Gonzalez Jesus , Dinale Caroline , Matamales Miriam
Published: September 2022

Multidisciplinary evidence suggests that instrumental performance is governed by two major forms of behavioural control: goal-directed and autonomous processes. Brain-state abnormalities affecting the striatum, such as ageing, often shift control towards autonomous—habit-like—behaviour, although the neural mechanisms responsible for this shift remain unknown. Here, combining instrumental conditioning with cell-specific functional mapping and manipulation in striatal neurons, we explored strategies that invigorate goal-directed action capacity in aged mice. In animals performing instrumental actions, D2- and D1-neurons of the aged striatum were engaged in a characteristically counterbalanced manner, something that related to the propensity to express autonomous behaviour. Long-lasting, cell-specific desensitisation of D2-neurons in aged transgenic mice recapitulated the uneven D2-to D1-neuron functional correspondence observed in young mice, an effect that enabled successful goal-directed action. Our findings contribute to the understanding of the neural bases of behavioural control and propose neural system interventions that enhance cognitive functioning in habit-prone brains.
Self-supervised deep learning for pan-cancer mutation prediction from histopathology
Authors: Saldanha Oliver Lester , Loeffler Chiara M. L. , Niehues Jan Moritz , van Treeck Marko , Seraphin Tobias P. , Hewitt Katherine Jane , Cifci Didem , Veldhuizen Gregory Patrick , Ramesh Siddhi , Pearson Alexander T. , Kather Jakob Nikolas
Published: September 2022

The histopathological phenotype of tumors reflects the underlying genetic makeup. Deep learning can predict genetic alterations from tissue morphology, but it is unclear how well these predictions generalize to external datasets. Here, we present a deep learning pipeline based on self-supervised feature extraction which achieves a robust predictability of genetic alterations in two large multicentric datasets of seven tumor types.
Widely Distributed Biosynthetic Cassette Is Responsible for Diverse Plant Side-Chain-Cross-Linked Cyclopeptides
Authors: Lima Stella T. , Ampolini Brigitte G. , Underwood Ethan B. , Graf Tyler N. , Earp Cody E. , Khedi Imani C. , Chekan Jonathan R.
Published: September 2022

Cyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome-mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP-domain containing gene clusters. Precursor peptides from these biosynthetic cassettes directly map to both cyclopeptide alkaloids from Ziziphus jujuba and the structurally distinct hibispeptins from Hibiscus syriacus. Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica, which we named arabipeptins. These results expand our understanding of the biosynthetic pathways responsible for diverse plant side chain cross-linked cyclopeptides and suggest the presence of previously unknown natural products or protein post-translational modifications that are widely distributed in eudicots.
SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion
Authors: Christ Wanda , Kapell Sebastian , Sobkowiak Michal J. , Mermelekas Georgios , Evertsson Björn , Sork Helena , Saher Osama , Bazaz Safa , Gustafsson Oskar , Cardenas Eduardo I. , Villa Viviana , Ricciarelli Roberta , Sandberg Johan K. , Bergquist Jonas , Sturchio Andrea , Svenningsson Per , Malm Tarja , Espay Alberto J. , Pernemalm Maria , Lindén Anders , Klingström Jonas , El Andaloussi Samir , Ezzat Kariem
Published: September 2022

The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed the interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogenous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as: APLP1 (amyloid beta precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Additionally, viral amyloid induction led to a dramatic drop in the soluble protein concentration in the CSF. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF and result in soluble protein depletion, and thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.

Significance Statement

Viruses have generally been excluded from the etiology of amyloid pathologies based on the assumption that amyloid formation requires a proteinaceous conformational template (a prion) to form. Here we show that neuroinvasive viruses induce amyloid aggregation of a plethora of proteins in human CSF even after UV inactivation. Our work illustrates that viruses can induce amyloid aggregation of endogenous human proteins in their native environment by acting as physical catalysts of amyloid nucleation and phase transition. Demonstrating this direct mechanistic link, which is independent of templating, can help better understand the link between viruses and neurodegenerative disorders, especially in the post-COVID-19 era.
Genome characterization of monkeypox cases detected in India: Identification of three sub clusters among A.2 lineage
Authors: Shete Anita M. , Yadav Pragya D. , Kumar Abhinendra , Patil Savita , Patil Deepak Y. , Joshi Yash , Majumdar Triparna , Relhan Vineet , Sahay Rima R. , Vasu Meenakshy , Gawande Pranita , Verma Ajay , Kumar Arbind , Dhakad Shivram , Krishnan Anukumar Bala , Chenayil Shubin , Kumar Suresh , Abraham Priya
Published: September 2022

Since May 2022, Monkeypox, a zoonotic Orthopox DNA virus was reported in more than 102 countries indicating expansion of its geographic range. We analyzed the complete genomes sequences of Monkeypox cases from Kerala (n=5 travelled from UAE) and Delhi (n=5 no travel history), India confirmed during July to August 2022. All the retrieved MPXV sequences from India covering 90 to 99% genome belong to A.2 lineage of clade IIb. The A.2 MPXV lineage divided in three sub clusters; first cluster Kerala n=5, Delhi n=2 aligned with the USA-2022 ON674051.1; while second of Delhi n=3 aligned with USA-2022 ON675438.1 and third consists of the UK, USA and Thailand. Recent update in MPXV lineage designated all the five sequences from Kerala as A.2.1. In addition to known 16 single nucleotide polymorphisms (SNPs) along with 13 APOBEC3 cytosine deaminase activity determined specific lineage defining mutations in A.2 lineage, 25 additional APOBEC3 mutations were found in 10 reported sequences. The study emphasizes need of enhancing genomic surveillance to understand the mutation and its linkage.
A highly contiguous genome assembly of red perilla (Perilla frutescens) domesticated in Japan
Authors: Tamura Keita , Sakamoto Mika , Tanizawa Yasuhiro , Mochizuki Takako , Matsushita Shuji , Kato Yoshihiro , Ishikawa Takeshi , Okuhara Keisuke , Nakamura Yasukazu , Bono Hidemasa
Published: September 2022

Perilla frutescens(Lamiaceae) is an important herbal plant with hundreds of bioactive chemicals, among which perillaldehyde and rosmarinic acid are the two major bioactive compounds in the plant. The leaves of red perilla are used as traditional Kampo medicine or food ingredients. However, the medicinal and nutritional uses of this plant could be improved by enhancing the production of valuable metabolites through the manipulation of key enzymes or regulatory genes using genome editing technology. Here, we generated a high-quality genome assembly of red perilla domesticated in Japan. A near-complete chromosome level assembly ofP. frutescenswas generated contigs with N50 of 41.5 Mb from PacBio HiFi reads. 99.2% of the assembly was anchored into 20 pseudochromosomes, among which seven pseudochromosomes consisted of one contig, while the rest consisted of less than six contigs. Gene annotation and prediction of the sequences successfully predicted 86,258 gene models, including 76,825 protein-coding genes. Further analysis showed that potential targets of genome editing for the engineering of anthocyanin pathways inP. frutescensare located on the late-stage pathways. Overall, our genome assembly could serve as a valuable reference for selecting target genes for genome editing ofP. frutescens.
Cell strain energy costs of active control of contractility
Authors: Solowiej-Wedderburn Josephine , Dunlop Carina M.
Published: September 2022

Cell mechanosensing is implicated in the control of a broad range of cell behaviours, with cytoskeletal contractility a key component. Experimentally, it is observed that the contractility of the cell responds to increasing substrate stiffness, showing increased contractile force and changing the distribution of cytoskeletal elements. Here we show using a theoretical model of active cell contractility that upregulation of contractility need not be energetically expensive, especially when combined with changes in adhesion and contractile distribution. Indeed, we show that a feedback mechanism based on maintenance of strain energy would require an upregulation in contractile pressure on all but the softest substrates. We consider both the commonly reported substrate strain energy and active work done. We demonstrate substrate strain energy would select for the observed clustering of cell adhesions on stiffer substrates which also enable an upregulation of total contractile pressure; while localisation of contractility has the greatest impact on the internal work.
Corrosion behavior research and corrosion prediction of structural steel in marine engineering
Authors: Cao Hang , Wang Kangchen , Song Shenyou , Zhang Xiaohu , Gao Qianyu , Liu Yuanyuan
Published: September 2022

Purpose

This paper aims to reveal the corrosion mechanism and corrosion development regulation of marine engineering structural steel in the marine environment and provide constructive suggestions for marine immersed tunnel engineering.

Design/methodology/approach

In this study, marine engineering structural steel’s behavior and corrosion prediction were carried out under the conditions of no cathodic protection and under-protection by artificially adding dissolved oxygen in a simulated seawater solution as a depolarizing agent.

Findings

Marine resources are rich in China. With the development of the economy and the improvement of engineering technology, marine engineering structural steel is used more and more widely. Engineering structural steel has a great risk of corrosion failure for long-term service in seawater, as seawater is a kind of corrosive medium containing various salts. At present, there are few projects and research studies available on the corrosion in the seawater environment of Q390C engineering structural steel, which is used in the Shenzhen–Zhongshan Link immersed tunnel steel shell at home and abroad. It cannot guide the corrosion of immersed tunnel steel shells in the ocean.

Originality/value

In this paper, the corrosion mechanism and corrosion development regulation of marine engineering structural steel in the marine environment are studied by accelerated corrosion test in the laboratory, which is of great significance to ensure the long-life durability of the immersed tunnel in marine engineering.