bluuebunny/crossref_metadata_2025 huggingface dataset:
Feminization of the precarious at the UNAM: examining obstacles to gender equality
Authors: ciccia lu , Espinosa-Lugo Geraldine , García-Guzmán Graciela , Gasca-Pineda Jaime , Velez Patricia , Espinosa-Asuar Laura
Published: May 2024

In this article we seek a better understanding of the specificities of the gender gap, regarding the reality of women in the different disciplines contained in STEM within Latin America. Specifically, we analyze and compare the situation of women in the Institutes of Mathematics, Ecology and Biology, belonging to the National Autonomous University of Mexico (UNAM). In this novel study, we contribute to deepen in how the phenomena of horizontal and vertical segregation are combined with symbolic and structural obstacles, as well as economic-labor precariousness, within the framework of gender norms. We also analyze the points in common regarding the situation in the Global North. We consider that these facts are fundamental to understand how gender stereotypes are perpetuated in the production of knowledge, and what are the values implied in gender norms that explain the exclusion, and self-exclusion, of women in certain disciplines and statuses. Related to this, we inquired into the relationship between these values and the cultural capital represented in each of the disciplines mentioned and found that the knowledge areas that currently represent the highest cultural capital pose symbolic obstacles for women. Conversely, those areas that less strongly embody values associated with masculinity, and therefore have less cultural capital, present mainly structural obstacles for women.
Model-based deconvolution of a force signal to estimate motor unit twitch parameters under low, moderate and high force isometric contractions
Authors: Rohlén Robin , Celichowski Jan
Published: May 2024

Muscle force generation and human movement are organised by the central nervous system and executed by the peripheral nervous system and the muscle fibres through molecular and electrical mechanisms. Over the last half-century, attempts have been made to elucidate these mechanisms in vivo, primarily focusing on the motor unit (MU) activity because of its role as the smallest voluntarily contractible unit. Although it is firmly established that the nervous system controls muscle force by modulating MU activity, it is yet possible to distinguish between the activities of slow- and fast-twitch MUs non-invasively, which is important for rehabilitation and diagnostic purposes. Although different methods exist to extract MU twitch parameters from a force signal, no method can accurately identify a single MU twitch given a single MU spike train. We addressed this problem by developing a model-based deconvolution method. We evaluated the method using a MU-based recruitment model under isometric contractions and tested it on experimental data. We found that the deconvolution method can provide non-biased average twitch parameter estimates with low variance for the latest recruited MUs, irrespective of contraction level. It can estimate average twitch parameters when the underlying MUs comprise unequal successive twitch profiles, the force signal has lower signal-to-noise ratios, or when the spike train includes missed firings at the cost of slightly increased bias or variance. Finally, the method provides twitch parameter estimates that align with the expected MU recruitment characteristics in experimental conditions. To conclude, the deconvolution method may be used to study slow and fast MUs for rehabilitation and neuromuscular diagnostics.

Author Summary

To generate force voluntarily with a specific muscle, the brain plans and sends signals through the spinal cord via motor neurons, each of which communicates with a set of muscle fibres. Together, these muscle fibres and the motor neuron are called a motor unit. In the literature, the neural signals have received much attention, whereas the mechanical force-generating muscle fibres have received much less due to the limitations of current methods. By extracting the mechanical characteristics of these muscle fibres connected to a specific motor neuron type in vivo, one can use this information for rehabilitation and neuromuscular diagnostics of humans. Here, we proposed a method that can accurately estimate the force profile from each motor unit during low to high contraction levels. This method can be used for rehabilitation and neuromuscular diagnostics purposes.
Adaptive evolutionary trajectories in complexity: repeated transitions between unicellularity and differentiated multicellularity
Authors: Isaksson Hanna , Lind Peter , Libby Eric
Published: May 2024

Multicellularity spans a wide gamut in terms of complexity, from simple clonal clusters of cells to large-scale organisms composed of differentiated cells and tissues. While recent experiments have demonstrated that simple forms of multicellularity can readily evolve in response to different selective pressures, it is unknown if continued exposure to those same selective pressures will result in the evolution of increased multicellular complexity. We use mathematical models to consider the adaptive trajectories of unicellular organisms exposed to periodic bouts of abiotic stress, such as drought or antibiotics. Populations can improve survival in response to the stress by evolving multicellularity or cell differentiation—or both; however, these responses have associated costs when the stress is absent. We define a parameter space of fitness-relevant traits and identify where multicellularity, differentiation, or their combination is fittest. We then study the effects of adaptation by allowing populations to fix mutations that improve their fitness. We find that while the same mutation can be beneficial to phenotypes with different complexity, e.g. unicellularity and differentiated multicellularity, the magnitudes of their effects can differ and alter which phenotype is fittest. As a result, we observe adaptive trajectories that gain and lose complexity. We also show that the order of mutations, historical contingency, can cause some transitions to be permanent in the absence of neutral evolution. Ultimately, we find that continued exposure to a selective driver for multicellularity can either lead to increasing complexity or a return to unicellularity.
Gene regulatory dynamics during the development of a paleopteran insect, the mayflyCloeon dipterum
Authors: Pallarès-Albanell Joan , Ortega-Flores Laia , Senar-Serra Tòt , Ruiz Antoni , Abril Josep F. , Rossello Maria , Almudi Isabel
Published: May 2024

The evolution of insects has been marked by the appearance of key body plan innovations and novel organs that promoted the outstanding ability of this lineage to adapt to new habitats, boosting the most successful radiation in animals. To understand the origin and evolution of these new structures, it is essential to investigate which are the genes and gene regulatory networks participating during the embryonic development of insects. Great efforts have been made to fully understand, from a gene expression and gene regulation point of view, the development of holometabolous insects, in particularDrosophila melanogaster, with the generation of numerous functional genomics resources and databases. Conversely, how hemimetabolous insects develop, and which are the dynamics of gene expression and gene regulation that control their embryogenesis, are still poorly characterized. Therefore, to provide a new platform to study gene regulation in insects, we generated ATAC-seq (Assay for transposase-Accessible Chromatin using sequencing) for the first time during the development of the mayflyCloeon dipterum.This new available resource will allow to better understand the dynamics of gene regulation during hemimetabolan embryogenesis, sinceC. dipterumbelongs to the paleopteran order of Ephemeroptera, the sister group to all other winged insects. These new datasets include six different time points of its embryonic development and identify accessible chromatin regions corresponding to both general and stage-specific promoters and enhancers. With these comprehensive datasets, we characterised pronounced changes in accessible chromatin between stages 8 and 10 of embryonic development, which correspond to the transition from the last stages of segmentation to organogenesis and appendage differentiation. The application of ATAC-seq in mayflies has contributed to identify the epigenetic mechanisms responsible for embryonic development in hemimetabolous insects and it will provide a fundamental resource to understand the evolution of gene regulation in winged insects.
Glycolytic metabolism modulation on spinal neuroinflammation and vital functions following cervical spinal cord injury
Authors: Michel-Flutot Pauline , Mansart Arnaud , Vinit Stéphane
Published: May 2024

High spinal cord injuries (SCIs) often result in persistent diaphragm paralysis and respiratory dysfunction. Chronic neuroinflammation within the damaged spinal cord after injury plays a prominent role in limiting functional recovery by impeding neuroplasticity. In this study, we aimed to reduce glucose metabolism that supports neuroinflammatory processes in an acute preclinical model of C2 spinal cord lateral hemisection in rats. We administered 2-deoxy-D-glucose (2-DG; 200 mg/kg/day s.c., for 7 days) and evaluated the effect on respiratory function and chondroitin sulfate proteoglycans (CSPGs) production around spinal phrenic motoneurons. Contrary to our initial hypothesis, our 2-DG treatment did not have any effect on diaphragm activity and CSPGs production in injured rats, although slight increases in tidal volume were observed. Unexpectedly, it led to deleterious effects in uninjured (sham) animals, characterized by increased ventilation and CSPGs production. Ultimately, our results seem to indicate that this 2-DG treatment paradigm may create a neuroinflammatory state in healthy animals, without affecting the already established spinal inflammation in injured rats. Given the beneficial effects of 2-DG observed in other studies on neuronal activity and inflammation, adjusting 2-DG doses and/or increasing treatment duration should be explored to reduce deleterious inflammatory processes occurring after SCI.
Ebola virus infection of Flt3-dependent, conventional dendritic cells and antigen cross-presentation leads to high levels of T-cell activation
Authors: Niemetz Linda , Bodmer Bianca S. , Olal Catherine , Escudero-Pérez Beatriz , Hoehn Katharina , Bencsik András , Vickers Molly A. , Rodríguez Estefanía , Oestereich Lisa , Hoenen Thomas , Muñoz-Fontela César
Published: May 2024

Severe Ebola virus disease (EVD) is characterized by excess, dysregulated T-cell activation and high levels of inflammation. Previous studies have described that in vitro EBOV infection of monocyte-derived DCs (moDCs) inhibits DC maturation resulting in suppression of T-cell activation. However, it is unknown how other DC subsets distinct from moDCs respond to EBOV infection.

To better understand how DCs initiate T cell activation during EBOV infection, we assessed the response of FMS-like tyrosine kinase 3 (Flt3)-dependent, conventional mouse DCs (cDCs) to EBOV infection, and developed a DC-T-cell co-culture system utilizing a recombinant EBOV expressing the model antigen ovalbumin.

Our findings suggested that, in contrast to moDCs, cDC2 and cDC1 were poorly infected with EBOV, although both infected and bystander cDCs displayed high levels of activation. DCs were able to activate CD8 T cells via cross-presentation of EBOV antigens obtained from cell debris of EBOV-infected cells. Of note, rather than interfering with cross-presentation, EBOV infection enhanced the cross-presentation capacity of DCs.

Our findings indicate that EBOV infection of Flt3-dependent cDCs, results in activation rather than inhibition leading to high levels of CD8 T-cell activation. With that we propose a mechanistic explanation for the excess T-cell activation observed in severe human EVD.
Design and development of a field-deployable water bath for loop-mediated isothermal amplification assay
Authors: Rafiq Nafisa , Verma Mohit S.
Published: May 2024

Nucleic acid testing has become a prominent method for rapid microbial detection. Unlike polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP) is a simple method of nucleic acid amplification where the reaction can be performed at a constant temperature and the output provided in a colorimetric format. A transparent water bath is a desirable instrument to perform the heating and observe the visual results. However, existing methods of heating water are not convenient for loading and unloading the test samples. Here, we developed a field-deployable water bath—an isothermal heater called IsoHeat for short–which is solely dedicated to performing LAMP reactions and can heat the water up to 85°C. Using 3D-printing and laser-cutting technology, we fabricated different parts and mechanically assembled the parts to develop the entire device. Users can commence the heating by pressing the start button on the screen after entering the target temperature. Subsequently, the device heats up the water bath and maintains the target temperature through a PID algorithm-based control system. We demonstrate that IsoHeat can operate in environmental temperatures ranging from 5-33 °C and it can conduct LAMP reactions in liquid format as well as in paper-based devices. IsoHeat is more efficient and user-friendly compared to a commercially available immersion-heating device, which is often used to perform LAMP reactions. This newly developed device would be helpful to detect pathogens conveniently in the field (e.g., at point-of-care for human applications, on farms for plant and animal applications, and in production facilities for food safety applications).
The Precision and Power of Population Branch Statistics in Identifying the Genomic Signatures of Local Adaptation
Authors: Shpak Max , Lawrence Kadee N. , Pool John E.
Published: May 2024

Population branch statistics, which estimate the branch lengths of focal populations with respect to two outgroups, have been used as an alternative to FST-based genome-wide scans for identifying loci associated with local selective sweeps. In addition to the original population branch statistic (PBS), there are subsequently proposed branch rescalings: normalized population branch statistic (PBSn1), which adjusts focal branch length with respect to outgroup branch lengths at the same locus, and population branch excess (PBE), which also incorporates median branch lengths at other loci. PBSn1 and PBE have been proposed to be less sensitive to allele frequency divergence generated by background selection or geographically ubiquitous positive selection rather than local selective sweeps. However, the accuracy and statistical power of branch statistics have not been systematically assessed. To do so, we simulate genomes in representative large and small populations with varying proportions of sites evolving under genetic drift or background selection (approximated using variableNe), local selective sweeps, and geographically parallel selective sweeps. We then assess the probability that local selective sweep loci are correctly identified as outliers by FSTand by each of the branch statistics. We find that branch statistics consistently outperform FSTat identifying local sweeps. When background selection and/or parallel sweeps are introduced, PBSn1 and especially PBE correctly identify local sweeps among their top outliers at a higher frequency than PBS. These results validate the greater specificity of rescaled branch statistics such as PBE to detect population-specific positive selection, supporting their use in genomic studies focused on local adaptation.

Significance Statement

Population branch statistics are widely used in genome-wide scans to identify loci associated with local adaptation. This study finds that branch statistics are more accurate thanFSTat identifying local selective sweeps under a wide range of demographic parameters and models of evolution. It also demonstrates that certain branch statistics have improved ability to distinguish local adaptation from other models of natural selection.
Single-cell RNA-Sequencing Co-Expression Analysis with CFTR in Lung Tissue
Authors: Wang Cheng , Kanagarajah Kayshani , Wong Amy , Ratjen Felix , Strug Lisa J
Published: May 2024

1

Background

While cystic fibrosis is caused by loss-of-function variants in theCystic Fibrosis Transmembrane Conductance Regulator (CFTR), other modifier genes have been shown to associate with disease severity. Co-expression of modifiers with CFTR in normal tissue indicates a cooperative relationship and suggests the potential for compensation in the presence of CFTR dysfunction. We examined the co-expression relationships with CFTR in the lung using single cell RNA sequencing to pinpoint cell types and their modifiers involved in the forced expiratory volume in 1 second (FEV1)-based cystic fibrosis lung phenotype and support target cell-type prioritization for therapy1.

Methods

SmartSeq2 single cell RNA sequencing data from non-cystic fibrosis lung tissue was used for evaluation of co-expression with CFTR and modifier genes. Zero-inflated negative binomial model was used to formally test the co-expression association. 10X Chromium based single cell RNA sequencing data from both cystic fibrosis and non-cystic fibrosis studies were assessed graphically to confirm conclusions from the SmartSeq2 primary analysis.

Results

Differentiating basal, club and alveolar epithelial type 2 cells were found to have high proportions of cells expressing CFTR as well as the greatest number of significant co-expression relationships with the modifiers. In particular, among alveolar epithelial type 2 cells, we observed a strong co-expression trio relationship between CFTR, SLC6A14 and SLC26A9 (p < 0.05).

Conclusions

CFTR-modifier gene co-expression suggests basal, club and alveolar epithelial type 2 cells show coordinated expression. Alveolar epithelial type 2 cells showed strong co-expression evidence with two of the most established cystic fibrosis modifier genes.
CRISPR Double Knockout Library Reveals Synthetic Lethal Gene Pairs in Triple-Negative Breast Cancer
Authors: Shao Shuai , Li Shangjia , Tang Shan , Fan Kunjie , Li Lang
Published: May 2024

Synthetic lethality, a genetic interaction involving two or more genes whose combined loss results in cell death, has emerged as a promising strategy for targeted cancer therapy. By exploiting synthetic lethal interactions, cancer cells can be selectively targeted and eradicated while preserving healthy cells, minimizing off-target effects, and reducing toxicity. The development of PARP inhibitors for ovarian and breast cancer patients with BRCA mutations exemplifies the potential of synthetic lethality-based therapy. Various experimental approaches, including CRISPR/Cas9 screens, have been employed to identify synthetic lethal gene pairs. Our lab has developed a CRISPR double knockout library, leveraging the XDeathDB database for candidate gene selection. This comprehensive platform offers insights into 12 cell death modes and 149 cell death hallmark genes. We aim to construct a cell-death double knock-out library using these genes and perform double knock-out screening on MDA-MB-231, a representative cell line for TNBC chemo poor responders. The identified synergistic lethal gene pairs may serve as potential drug targets for treating TNBC.
11β-hydroxysteroid dehydrogenase type 2 may mediate the stress-specific effects of cortisol on brain cell proliferation in adult zebrafish (Danio rerio)
Authors: Flatt E. Emma , Alderman Sarah L
Published: May 2024

Stress-induced increases in cortisol can stimulate or inhibit brain cell proliferation, but the mechanisms behind these opposing effects are unknown. We tested the hypothesis that 11β-hydroxysteroid dehydrogenase type 2 (Hsd11b2), a glucocorticoid-inactivating enzyme expressed in neurogenic regions of the adult zebrafish brain, mitigates cortisol-induced changes to brain cell proliferation using one of three stress regimes: a single 1-min air exposure (acute stress), two air exposures spaced 24 h apart (repeat acute stress), or social subordination (chronic stress). Plasma cortisol was significantly elevated 15 min after air exposure and recovered within 24 h after acute and repeat stress, whereas subordinate fish exhibited significant and sustained elevations relative to dominant fish for 24 h. Following acute stress, brain hsd11b2 transcript abundance was significantly lower 24 h after a single air exposure but was unchanged by repeat stress or social subordination. A sustained increase in brain Hsd11b2 protein levels occurred after acute stress, but not after repeat or chronic stress. Following acute and repeat stress, brain pcna transcript abundance exhibited a prolonged elevation, but was unaffected by social subordination. Interestingly, the number of telencephalic BrdU+ cells increased in fish after a single air exposure but was unchanged by repeat stress. Following acute and repeat stress, fish expressed lower brain gr and mr transcript abundance while subordinate fish exhibited no changes. Taken together, these results demonstrate stressor-specific regulation of Hsd11b2 in the zebrafish brain that could modulate rates of cortisol catabolism contributing to observed differences in brain cell proliferation.
Correlative multiscale 3D imaging of mouse primary and metastatic tumors by sequential light sheet and confocal fluorescence microscopy
Authors: Zheng Jingtian , Wu Yi-Chien , Cai Xiaoying , Phan Philana , Er Ekrem Emrah , Zhao Zongmin , Lee Steve Seung-Young
Published: May 2024

Three-dimensional (3D) optical microscopy, combined with advanced tissue clearing, permitsin situinterrogation of the tumor microenvironment (TME) in large volumetric tumors for preclinical cancer research. Light sheet (also known as ultramicroscopy) and confocal fluorescence microscopy are often used to achieve macroscopic and microscopic 3D images of optically cleared tumor tissues, respectively. Although each technique offers distinct fields of view (FOVs) and spatial resolution, the combination of these two optical microscopy techniques to obtain correlative multiscale 3D images from the same tumor tissues has not yet been explored. To establish correlative multiscale 3D optical microscopy, we developed a method for optically marking defined regions of interest (ROIs) within a cleared mouse tumor by employing a UV light-activated visible dye and Z-axis position-selective UV irradiation in a light sheet microscope system. By integrating this method with subsequent tissue processing, including physical ROI marking, reversal of tissue clearing, tissue macrosectioning, and multiplex immunofluorescence, we established a workflow that enables the tracking and 3D imaging of ROIs within tumor tissues through sequential light sheet and confocal fluorescence microscopy. This approach allowed for quantitative 3D spatial analysis of the immune response in the TME of a mouse mammary tumor following cancer immunotherapy at multiple spatial scales. The workflow also facilitated the direct localization of a metastatic lesion within a whole mouse brain. These results demonstrate that our ROI tracking method and its associated workflow offer a novel approach for correlative multiscale 3D optical microscopy, with the potential to provide new insights into tumor heterogeneity, metastasis, and response to therapy at various spatial levels.
Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes
Authors: Peng Xianlu Laura , Kharitonova Elena V. , Xu Yi , Kearney Joseph F. , Luan Changfei , Chan Priscilla S. , Hariharan Arthi , McCabe Ian C. , Leary John R. , Morrison Ashley B. , Trembath Hannah E. , LaBella Michelle E. , Herera Loeza Silvia G. , Cliff Ashley , Kim Hong Jin , Belt Brian A. , Panni Roheena Z. , Linehan David C. , Damrauer Jeffrey S , Iuga Alina C. , Kim William Y. , Rashid Naim U. , Yeh Jen Jen
Published: May 2024

Cancer-associated fibroblast (CAF) subpopulations in pancreatic ductal adenocarcinoma (PDAC) have been identified using single-cell RNA sequencing (scRNAseq) with divergent characteristics, but their clinical relevance remains unclear. We translate scRNAseq-derived CAF cell-subpopulation-specific marker genes to bulk RNAseq data, and develop a single- sample classifier, DeCAF, for the classification of clinicallyrestraining andpermissive CAF subtypes. We validate DeCAF in 19 independent bulk transcriptomic datasets across four tumor types (PDAC, mesothelioma, bladder and renal cell carcinoma). DeCAF subtypes have distinct histology features, immune landscapes, and are prognostic and predict response to therapy across cancer types. We demonstrate that DeCAF is clinically replicable and robust for the classification of CAF subtypes in patients for multiple tumor types, providing a better framework for the future development and translation of therapies against permissive CAF subtypes and preservation of restraining CAF subtypes.

Significance

We introduce a replicable and robust classifier, DeCAF, that delineates the significance of the role of permissive and restraining CAF subtypes in cancer patients. DeCAF is clinically tractable, prognostic and predictive of treatment response in multiple cancer types and lays the translational groundwork for the preclinical and clinical development of CAF subtype specific therapies.
In defense of the original Type I functional response: The frequency and population-dynamic effects of feeding on multiple prey at a time
Authors: Novak Mark , Coblentz Kyle E. , DeLong John P.
Published: May 2024

Ecologists differ in the degree to which they consider the linear Type I functional response to be an unrealistic versus sufficient representation of predator feeding rates. Empiricists tend to consider it unsuitably non-mechanistic and theoreticians tend to consider it necessarily simple. Holling’s original rectilinear Type I response is dismissed by satisfying neither desire, with most compromising on the smoothly saturating Type II response for which searching and handling are assumed to be mutually exclusive activities. We derive a “multiple-prey-at-a-time” response and a generalization that includes the Type III to reflect predators that can continue to search when handling an arbitrary number of already-captured prey. The multi-prey model clarifies the empirical relevance of the linear and rectilinear models and the conditions under which linearity can be a mechanistically-reasoned description of predator feeding rates, even when handling times are long. We find support for linearity in 35% of 2,591 compiled empirical datasets and support for the hypothesis that larger predator-prey body-mass ratios permit predators to search while handling greater numbers of prey. Incorporating the multi-prey response into the Rosenzweig-MacArthur population-dynamics model reveals that a non-exclusivity of searching and handling can lead to coexistence states and dynamics that are not anticipated by theory built on the Type I, II, or III response models. In particular, it can lead to bistable fixed-point and limit-cycle dynamics with long-term crawl-by transients between them under conditions where abundance ratios reflect top-heavy food webs and the functional response is linear. We conclude that functional response linearity should not be considered empirically unrealistic but also that more cautious inferences should be drawn in theory presuming the linear Type I to be appropriate.
XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites
Authors: Lin Xiaohui , Leung Kay Sze Karina , Wolfe Kaitlynn F. , Lee Brian J. , Zha Shan
Published: May 2024

Poly-ADP-ribose polymerases 1 and 2 (PARP1 and PARP2) are crucial sensors of DNA-strand breaks and emerging cancer therapy targets. Once activated by DNA breaks, PARP1 and PARP2 generate poly-ADP-ribose (PAR) chains on themselves and other substrates to promote DNA single-strand break repair (SSBR). PARP1 can be activated by diverse DNA lesions, whereas PARP2 specifically recognizes 5’ phosphorylated nicks. They can be activated independently and provide mutual backup in the absence of the other. However, whether PARP1 and PARP2 have synergistic functions in DNA damage response remains elusive. Here, we show that PARP1 and the PAR chains generated by PARP1 recruit PARP2 to the vicinity of DNA damage sites through the scaffold protein XRCC1. Using quantitative live-cell imaging, we found that loss of XRCC1 markedly reduces irradiation-induced PARP2 foci in PARP1-proficient cells. The central BRCT domain (BRCT1) of XRCC1 binds to the PAR chain, while the C-terminal BRCT domain (BRCT2) of XRCC1 interacts with the catalytic domain of PARP2, facilitating its localization near the breaks. Together, these findings unveil a new function of XRCC1 in augmenting PARP2 recruitment in response to PARP1 activation and explain why PARP1, but not PARP2, is aggregated and hyperactivated in XRCC1-deficient cells.
N-Terminal proteomics reveals distinct protein degradation patterns in different types of human atherosclerotic plaques
Authors: Lorentzen Lasse G. , Yeung Karin , Eldrup Nikolaj , Eiberg Jonas P. , Davies Michael J.
Published: May 2024

BACKGROUND

Destabilization and rupture of atherosclerotic plaques is a major cause of acute atherosclerotic cardiovascular events, including heart attack, ischemic stroke and peripheral arterial disease. Plaque destabilization is associated with extracellular matrix (ECM) modification and remodelling involving protease activity. Enzymatic cleavage generates protein fragments with new ‘ends’ (N-termini). We hypothesized that plaques susceptible to rupture would contain elevated levels of fragmented proteins with new N-termini. Identification of active proteases and their target proteins might allow categorization of plaque stability.

METHODS

Plaques from 21 patients who underwent carotid surgery due to symptomatic carotid artery stenosis were examined in an observational/cross-sectional study. The plaques were solubilized, digested, enriched for N-terminal fragments and analyzed by liquid chromatography-mass spectrometry.

RESULTS

The above methodology detected 35349 peptides, with 19543 being N-terminal species; 6561 were subsequently identified and quantified. Multidimensional scaling analysis and hierarchical clustering indicate the presence of three distinct clusters, which correlate with gross macroscopic plaque morphology (soft, mixed, and hard), ultrasound classification (echolucent/echogenic) and presence of hemorrhage/ulceration. Major differences were identified in the complement of peptide fragments, consistent with alternative turnover and degradation pathways dependent on plaque type. Identified peptides include signal and pro-peptides from ECM synthesis/turnover, and many from protein fragmentation. Sequence analysis indicates the targeted proteins (including ECM species) and the proteases (including meprins, cathepsins, matrix metalloproteinases, elastase, kallikreins) involved in fragment generation.

CONCLUSIONS

This study provides a large dataset of peptide fragments and proteases involved in plaque stability, mechanistic insights into remodelling, and possible biomarkers for improved atherosclerosis risk profiling.

GRAPHICAL ABSTRACT
Decoding ruminative states from neurophysiological patterns
Authors: Welkerling Jana , Schneeweiss Patrick , Wolf Sebastian , Rohe Tim
Published: May 2024

Individuals with depression often engage in iterative “rumination” about challenging situations and potential outcomes. Although the state of rumination has been associated with diverse univariate neurophysiological features, the potential to use multivariate patterns to decode it remains uncertain. In this study, we trained linear support vector machines to differentiate state rumination from distraction using patterns in the alpha, beta, and theta bands, as well as inter-channel connectivity. We used validated tasks to induce rumination or distraction for eight minutes in 24 depressed individuals in six runs over three sessions. During inductions, we recorded 64-channel EEG data and measured self-reported levels of rumination. Participants reported strongly increased rumination, and we decoded state rumination from EEG patterns with significant accuracy. However, the informative features were not consistent across participants, demonstrating that while ruminative states can indeed be decoded from EEG data, these states appear to reflect processes unique to each individual.
Anandamide is an Early Blood Biomarker of Hermansky-Pudlak Syndrome Pulmonary Fibrosis
Authors: Cinar Resat , Basu Abhishek , Arif Muhammad , Park Joshua K. , Zawatsky Charles N. , Zuo Ben Long G. , Zuo Mei Xing G. , O’Brien Kevin J. , Behan Molly , Introne Wendy , Iyer Malliga R. , Gahl William A. , Malicdan May Christine V. , Gochuico Bernadette R.
Published: May 2024

Hermansky-Pudlak syndrome (HPS) is a group of rare genetic disorders, with several subtypes leading to fatal adult-onset pulmonary fibrosis (PF) and no effective treatment. Circulating biomarkers detecting early PF have not been identified. We investigated whether endocannabinoids could serve as blood biomarkers of PF in HPS. We measured endocannabinoids in the serum of HPS, IPF, and healthy human subjects and in a mouse model of HPSPF. Pulmonary function tests (PFT) were correlated with endocannabinoid measurements. In a pale ear mouse model of bleomycin-induced HPSPF, serum endocannabinoid levels were measured with and without treatment with zevaquenabant (MRI-1867), a peripheral CB1R and iNOS antagonist. In three separate cohorts, circulating anandamide levels were increased in HPS-1 patients with or without PF, compared to healthy volunteers. This increase was not observed in IPF patients or in HPS-3 patients, who do not have PF. Circulating anandamide (AEA) levels were negatively correlated with PFT. Furthermore, a longitudinal study over the course of 5-14 years with HPS-1 patients indicated that circulating AEA levels begin to increase with the fibrotic lung process even at the subclinical stages of HPSPF. In pale ear mice with bleomycin-induced HpsPF, serum AEA levels were significantly increased in the earliest stages of PF and remained elevated at a later fibrotic stage. Zevaquenabant treatment reduced the increased AEA levels and attenuated progression in bleomycin-induced HpsPF. Circulating AEA may be a prognostic blood biomarker for PF in HPS-1 patients. Further studies are indicated to evaluate endocannabinoids as potential surrogate biomarkers in progressive fibrotic lung diseases.
Stenotrophomonas muris- First discovered as an urgent human pathogen with strong virulence associated with bloodstream infections
Authors: Liu Jiaying , Dong Xu , Yu Yuyun , Wu Tiantian , Xiang Yanghui , Yuan Xin , Cao Dan , Bi Kefan , Zhang Hanyin , Zhu Lixia , Zhang Ying
Published: May 2024

For the first time,Stenotrophomonas muris(S. muris) has been identified to be associated with human infections while studying the virulence ofStenotrophomonas maltophilia(S. maltophilia) clinical isolates. Previously,S. muriswas only isolated from the intestines of mice but its pathogenic potential for humans has never been reported. In this work, the phenotype ofS. murisvirulence, the potential genes that encode higher virulence ofS. muris, and host responses toS. murisinfection were investigated for the first time. It was found that S9 (S. murisno.9, isolated from patient’s bloodstream infection) was more virulent than both S8 (S. murisno.8, isolated from patient’s sputum) and S1 (S. maltophilia), where S8 and S9 were subsequently identified asS. murisby whole genome sequencing analysis. Candidate genes which may encode higher virulence of S9 were identified, includingvirB6, dcm, hlyD, and 14 other genes involved in porphyrin metabolism, pyrimidine metabolism, DNA methylation, two component system, and biofilm formation. Transcriptome analysis of host cells (THP-1 cells) infected by S8 and S9 (S9 with strong virulence over S8 with weak virulence) showed that 12 candidate genes involved in ion transport function and calcium signaling pathway were down-regulated and require special attention. Antibiotic susceptibility testing indicated that compared withS. maltophilia, theS. murisstrains, though more susceptible to minocycline, are highly resistant to last resort antibitoics colistin and polymyxin B and are also resistant to cephalosporin and fluoroquinolone. Because of the above differences in virulence properties and antibiotic susceptibility, it is critical thatS. murisbe distinguished fromS. maltophiliain clinical setting for improved care. This work provides the basis for future studies on pathogenic mechanisms ofS. murisand for developing improved treatment in the future.
Cost-effectiveness of respiratory syncytial virus vaccination strategies for older Canadian adults: a multi-model comparison
Authors: Rudd Monica , Simmons Alison E. , Gebretekle Gebremedhin B. , Tuite Ashleigh R.
Published: May 2024

Background

Two respiratory syncytial virus (RSV) vaccines are currently approved for use in adults aged 60 years and older in Canada. Economic analyses have shown that adult RSV vaccination programs may be cost-effective, particularly when focused on people at increased risk of RSV disease due to increased age or presence of chronic medical conditions (CMCs). We conducted a multi-model comparison to explore the impact of alternate model structural and methodological assumptions on the cost-effectiveness of RSV vaccination programs.

Methods

We compared three static cost-utility models developed by the Public Health Agency of Canada, GSK, and Pfizer using a common set of input parameters. Each model evaluated sequential incremental cost-effectiveness ratios (ICERs) in 2023 Canadian dollars per quality-adjusted life year (QALY) for a set of policy alternatives, with vaccine eligibility determined by combinations of age and CMC status. Results were calculated for each vaccine separately for scenarios assuming two or three years of vaccine protection using the health system perspective and a 1.5% annual discount rate.

Results

The three cost-utility models were broadly concordant across the scenarios modeled. In all scenarios, focusing on vaccination of people with CMCs was preferred over broader age-based policies. RSV vaccination for people with CMCs over the age of 70 years was most commonly identified as the optimal policy when using a cost-effectiveness threshold of $50,000/QALY. When only considering policies based on age criteria, vaccinating people over 80 years was cost-effective at this threshold.

Discussion

A multi-model comparison of Canadian cost-utility models shows that RSV vaccination programs for RSV are likely cost-effective for some groups of older adults in Canada. These findings were consistent across models, despite differences in model structure.
A new lineage nomenclature to aid genomic surveillance of dengue virus
Authors: Hill Verity , Cleemput Sara , Fonseca Vagner , Tegally Houriiyah , Brito Anderson F. , Gifford Robert , Tran Vi Thuy , Kien Duong Thi Hue , Huynh Tuyen , Yacoub Sophie , Dieng Idrissa , Ndiaye Mignane , Balde Diamilatou , Diagne Moussa M. , Faye Oumar , Salvato Richard , Wallau Gabriel Luz , Gregianini Tatiana S. , Godinho Fernanda M.S. , Vogels Chantal B.F. , Breban Mallery I. , Leguia Mariana , Jagtap Suraj , Roy Rahul , Hapuarachchi Chanditha , Mwanyika Gaspary , Giovanetti Marta , Alcantara Luiz C.J. , Faria Nuno R. , Carrington Christine V.F. , Hanley Kathryn A. , Holmes Edward C. , Dumon Wim , de Oliveira Tulio , Grubaugh Nathan D.
Published: May 2024

Dengue virus (DENV) is currently causing epidemics of unprecedented scope in endemic settings and expanding to new geographical areas. It is therefore critical to track this virus using genomic surveillance. However, the complex patterns of viral genomic diversity make it challenging to use the existing genotype classification system. Here we propose adding two sub-genotypic levels of virus classification, named major and minor lineages. These lineages have high thresholds for phylogenetic distance and clade size, rendering them stable between phylogenetic studies. We present an assignment tool to show that the proposed lineages are useful for regional, national and sub-national discussions of relevant DENV diversity. Moreover, the proposed lineages are robust to classification using partial genome sequences. We provide a standardized neutral descriptor of DENV diversity with which we can identify and track lineages of potential epidemiological and/or clinical importance. Information about our lineage system, including methods to assign lineages to sequence data and propose new lineages, can be found at:dengue-lineages.org.
Biomarkers of RV dysfunction in HFrEF identified by direct tissue proteomics: extracellular proteins fibromodulin and fibulin-5
Authors: Běhounek Matěj , Lipcseyová Denisa , Vít Ondřej , Žáček Petr , Talacko Pavel , Husková Zuzana , Kikerlová Soňa , Tykvartová Tereza , Wohlfahrt Peter , Melenovský Vojtěch , Beneš Jan , Petrák Jiří
Published: May 2024

BACKGROUND

Right ventricular dysfunction (RVD) is a commonly accompanying condition in patients with heart failure with reduced ejection fraction (HFrEF), and is associated with poor prognosis. However, no specific biomarker of RVD is available for clinical routine.

METHODS

We performed a label-free proteomic analysis of myocardium from the left and right ventricles of HFrEF patients with and without RVD who underwent heart transplantation (n=20). Concentrations of two extracellular matrix proteins with highest myocardial upregulation in RVD – fibromodulin (FMOD) and fibulin-5 (FBLN5) - were assayed in the blood, compared to controls (n=65) and tested in separate large cohort of HFrEF patients (n=232) to test association of the two proteins with RV function and long-term outcome.

RESULTS

FMOD and FBLN5 plasma concentrations progressively increased with worsening RV function (p = 0.0001 and 0.004), while there was no association with LV dysfunction, BMI or kidney function. In survival analysis, plasma levels of both FMOD and FBLN5 were significantly associated with patient outcome (p = 0.005 and 0.0004). Using reclassification analysis, addition of plasma FBLN5 to right ventricle function assessment led to an improvement in AUC after 4 years compared to RV function assessment only. Similarly, adding plasma fibromodulin to the multi-parametric MAGGIC score showed a significantly higher AUC after 4 years. Importantly, the prognostic value of both biomarkers was additive.

CONCLUSION

Our study proposes that circulating levels of FMOD and FBLN5 may serve as a new biomarkers of RVD in HFrEF patients.
Left and Right Ventricular Diameters Independently Predict Outcome in Intermediate and High-Risk Pulmonary Embolisms
Authors: Spevack Daniel , Bali Atul D. , Kanwal Arjun , Isath Ameesh , Sharma Tanya , Ahsan Syed , Malekan Ramin , Goldberg Joshua B.
Published: May 2024

Background

The right to left ventricular diameter ratio (RV/LV) is a key imaging parameter used in risk stratification of pulmonary embolism. While having RV/LV above a cutoff value of 0.9 is usually attributed to pathological RV dilatation, we hypothesized that increased RV/LV may also be attributable to reduced LV filling. We aimed to examine RV and LV diameters as independent predictors of PE outcomes in patients presenting with intermediate or high-risk PE.

Methods

We measured RV and LV diameters on pre-intervention echocardiograms performed on 164 subjects presenting at or referred to our center for large PE requiring surgical thrombectomy, venoarterial extracorporeal membrane oxygenation (VA-ECMO), or catheter directed thrombectomy.

Results

The primary outcome of death (n=3) or survival of cardiopulmonary resuscitation (CPR) (n=11) was met in 14 subjects. Smaller LV diameter and larger RV diameter were each demonstrated to be independent predictors of the primary outcome. LV diameter of <3.6 cm, RV diameter >5.0 cm, and RV/LV ratio of >1.2 were the cutoff values for each parameter most associated with the primary outcome.

Conclusion

This study demonstrates that, in addition to dilated RV, small LV is an independent risk factor of death or need for CPR in hemodynamically significant PE treated with advanced therapies. This finding suggests that the predictive value of RV/LV for PE outcomes may be attributed to both RV enlargement and reduced LV filling.
Driver gene detection via causal inference on single cell embeddings
Authors: Fu Chengbo , Cheng Lu
Published: May 2024

Driver genes are pivotal in different biological processes. Current methods generally identify driver genes by associative analysis. Leveraging on the development of current large language models (LLM) in single cell genomics, we propose a causal inference based approach called CID to identify driver genes from scRNA-seq data. Through experiments on three different datasets, we show that CID can (1) identify biologically meaningful driver genes that have not been captured by current associative-analysis based methods, and (2) accurately predict the change directions of target genes if a driver gene is knocked out.
Neuronal migration depends on blood flow in the adult brain
Authors: Ogino Takashi , Saito Akari , Sawada Masato , Takemura Shoko , Nagase Jiro , Kawase Honomi , Inada Hiroyuki , Herranz-Pérez Vicente , Mukouyama Yoh-suke , Ema Masatsugu , García-Verdugo José Manuel , Nabekura Junichi , Sawamoto Kazunobu
Published: May 2024

In animal tissues, several cell types migrate along blood vessels, raising the possibility that blood flow influences cell migration. Here, we show that blood flow promotes the migration of new olfactory-bulb neurons in the adult brain. Neuronal migration is facilitated by blood flow, leading to accumulation of new neurons near blood vessels with abundant blood flow. Blood flow inhibition attenuates blood vessel-guided neuronal migration, suggesting that blood contains factors beneficial to neuronal migration. We found that ghrelin, which is increased in blood by hunger, directly influences neuronal migration. Ghrelin signaling promotes somal translocation by activating actin cytoskeleton contraction at the rear of the cell soma. New neurons mature in the olfactory bulb and contribute to the olfactory function for sensing odorants from food. Finally, we show that neuronal migration is increased by calorie restriction, and that ghrelin signaling is involved in the process. This study suggests that blood flow promotes neuronal migration through blood-derived ghrelin signaling in the adult brain, which could be one of the mechanisms that improve the olfactory function for food-seeking behavior during starvation.