bluuebunny/crossref_metadata_2025 huggingface dataset:
HSP70 is upregulated after heat but not freezing stress in the freeze-tolerant cricketGryllus veletis
Authors: Adams Victoria E. , van Oirschot Maranda L. , Toxopeus Jantina
Published: November 2024

Heat shock proteins (HSPs) are well known to prevent and repair protein damage caused by various abiotic stressors, but their role in low temperature and freezing stress is not well-characterized compared to other thermal challenges. Ice formation in and around cells is hypothesized to cause protein damage, yet many species of insects can survive freezing, suggesting HSPs may be an important mechanism in freeze tolerance. Here, we studied HSP70 in a freeze-tolerant cricketGryllus veletisto better understand the role of HSPs in this phenomenon. We measured expression of one heat-inducible HSP70 isoform at the mRNA level (using RT-qPCR), as well as the relative abundance of total HSP70 protein (using semi-quantitative Western blotting), in five tissues from crickets exposed to a survivable heat treatment (2 h at 40°C), a 6-week fall-like acclimation that induces freeze tolerance, and a survivable freezing treatment (1.5 h at -8°C). While HSP70 expression was upregulated by heat at the mRNA or protein level in all tissues studied (fat body, Malphigian tubules, midgut, femur muscle, nervous system ganglia), no tissue exhibited HSP70 upregulation within 2 – 24 h following a survivable freezing stress. During fall-like acclimation to mild low temperatures, we only saw moderate upregulation of HSP70 at the protein level in muscle, and at the RNA level in fat body and nervous tissue. Although HSP70 is important for responding to a wide range of stressors, our work suggests that this chaperone may be less critical in the preparation for, and response to, moderate freezing stress.

Highlights

Heat shock protein 70 (HSP70) may not contribute substantially to freeze tolerance

Heat stress caused HSP70 mRNA and protein upregulation in the spring field cricket

Acclimation prior to freezing was correlated with slight HSP70 upregulation

HSP70 was not upregulated after freezing in this freeze-tolerant insect

Further work is needed to determine whether freezing causes protein damage

Graphical abstract
A Modular Layer-by-Layer Nanoparticle Platform for Hematopoietic Progenitor and Stem Cell Targeting
Authors: Dacoba Tamara G. , Nabar Namita , Hammond Paula T.
Published: November 2024

Effective delivery of drug and gene cargos to hematopoietic stem and progenitor cells (HSPCs) is a major challenge. Current therapeutic strategies in genetic disorders or hematological malignancies are hindered by high costs, low accessibility, and high off-target toxicities. Layer-by-Layer nanoparticles (LbL NPs) are modular systems with tunable surface properties to enable highly specific targeting. In this work, we developed LbL NPs that target HSPCs via antibody functionalization with reduced off-target uptake by circulating myeloid cells. NPs layered with poly(acrylic acid), a bioinert polymer, provided more stealth properties in vivo than other tested bioactive polyanions. The additional conjugation of anti-cKit and anti-CD90 antibodies improved NP uptake by 2-to 3-fold in non-differentiated bone marrow cells in vitro. By contrast, anti-CD105 functionalized NPs showed the highest association to HSPCs in vivo, ranging from 3.0–8.5% in progenitor subpopulations. This LbL NP platform was then adapted to target human HSPC receptors, with similar targeting trends in healthy CD34+ human cells. By contrast, anti-CXCR4 functionalization demonstrated the greatest targeting to human B-cell lymphoma and leukemia cells. Taken together, these results underscore the therapeutic potential of this modular LbL NP platform with the capacity to target HSPCs in a disease-dependent context.
Utilizing blood single-cell transcriptomics to integrate intrinsic and systemic immune aging
Authors: Tomusiak Alan , Lore Sierra , Scheibye-Knudsen Morten , Verdin Eric
Published: November 2024

Biomarkers of aging provide insight into the biological effects of interventions and diseases. However, most biomarkers today are based on measurements derived from bulk cell measurements, making it challenging to interpret whether an effect is due to changes in cell type composition (systemic factors) or a cell intrinsic effect. Single-cell RNA sequencing provides a unique platform to simultaneously compare aging-associated changes on both a cellular and bulk level. We first generated a single-cell combined automated human blood cell type and age predictor (clock) for six distinct human T cell subsets. We applied these tools to find acute COVID is associated with a shift in CD8+ cytotoxic cell proportions, while cell type proportions are stable in patients with HIV on long-term ART treatment (HIV+ART). Both COVID and HIV+ART were associated with an increase in naive CD8 T cell transcriptomic age. We further found our single-cell aging biomarker is linked to ribosomal gene expression and has a link to mean cellular transcript length. This study highlights the potential of single cell transcriptomic biomarkers for understanding how the human immune system is impacted by age-associated systemic changes in cell type composition and intrinsic cellular aging.
The NGAGE Model Developed at the Rush Alzheimer’s Disease Research Center: An Approach to Community Engagement and Inclusion in Dementia Research with Diverse Community-Dwelling Older Adults
Authors: Glover Crystal M. , Schneider Julie A. , Bennett David A. , Barnes Lisa L. , Marquez David X. , Aggarwal Neelum T. , Leurgans Sue , Graham Karen L. , Frick Susan , Shah Raj C.
Published: November 2024

Background

One of the biggest challenges in the field of Alzheimer’s disease and related dementias (ADRD) is the severe inequitable inclusion of Black and Latino adults in clinical research studies. Despite consistent and persistent efforts, rates of participation among diverse older adults remain critically low.

Objective

The purpose of this paper is to set forth The NGAGE Model, one developed at the Rush Alzheimer’s Disease Research Center (Rush ADRC) to facilitate community engagement and research participation among diverse older adults.

Methods

The NGAGE Model consists of five steps that are conceptually distinct but overlapping in practice: 1) Networking, 2) Give first, 3) Advocate for research, 4) Give back, and 5) Evaluate. We define and describe each step. For steps 1 through 4, we calculated the number of events, number of attendees for each event, and percentages of attendees by racial and ethnic categorizations annually from July 1, 2011, through June 30, 2023, resulting in data for 12 distinct years, as provided in annual progress reports to the National Institute on Aging. For Step 5, we counted the number of persons and computed percentages of people by racial and ethnic groups who consented to our Data and Specimen Repository and enrolled in a research study.

Results

Over 12 years, the Rush ADRC conducted 5,362 events with 265,794 attendees. Give First activities represented the NGAGE step with both the highest number of events (n=2,247) and the most attendees (n=124,403). Among Black adults, the highest attendee percentage existed for Advocate for Research events (47%), while the highest for Latinos occurred for Give First activities (26%). Furthermore, 2,135 persons consented to the Data and Specimen Repository and 5,905 enrolled in a research study across 12 years. Higher percentages of both Black (37%) and Latino (10%) adults enrolled in research studies compared to the Repository with 21% and 7%, respectively.

Conclusions

The NGAGE Model facilitated community engagement and research inclusion among Black and Latino adults, particularly via Give First and Advocate for Research activities. We discuss the impacts of study milestones, staff resources, and the COVID-19 pandemic on The NGAGE Model activities and outcomes.
Incorporating epidemiological data into the genomic analysis of partially sampled infectious disease outbreaks
Authors: Carson Jake , Keeling Matt , Ribeca Paolo , Didelot Xavier
Published: November 2024

Pathogen genomic data is increasingly being used to investigate transmission dynamics in infectious disease outbreaks. Combining genomic data with epidemiological data should substantially increase our understanding of outbreaks, but this is highly challenging when the outbreak under study is only partially sampled, so that both genomic and epidemiological data are missing for intermediate links in the transmission chains. Here we present a new dynamic programming algorithm to perform this task efficiently. We implement this methodology into the well-established TransPhylo framework to reconstruct partially sampled outbreaks using a combination of genomic and epidemiological data. We use simulated datasets to show that including epidemiological data can improve the accuracy of the inferred transmission links compared to inference based on genomic data only. This also allows us to estimate parameters specific to the epidemiological data (such as transmission rates between particular groups) which would otherwise not be possible. We then apply these methods to two real-world examples. Firstly, we use genomic data from an outbreak of tuberculosis in Argentina, for which data was also available on the HIV status of sampled individuals, in order to investigate the role of HIV co-infection in the spread of this tuberculosis outbreak. Second, we use genomic and geographical data from the 2003 epidemic of avian influenza H7N7 in the Netherlands to reconstruct its spatial epidemiology. In both cases we show that incorporating epidemiological data into the genomic analysis allows us to investigate the role of epidemiological properties in the spread of infectious diseases.
Anticoagulation after hemorrhagic transformation in acute cardioembolic ischemic stroke
Authors: Kim Hyunsoo , An Ye-Eun , Seo Beom-Seok , Kim Jae-Myung , Choi Kang-Ho , Park Man-Seok , Lee Ji Sung , Kim Joon-Tae
Published: November 2024

Background

The safety and efficacy of anticoagulation in the presence of hemorrhagic transformation (HT) in cardioembolic acute ischemic stroke (AIS) remain uncertain.

Methods

This retrospective study enrolled patients presenting with cardioembolic AIS within 48 hours at a tertiary stroke center between January 2011 and August 2023. Patients who developed HT during hospitalization and underwent follow-up imaging were included, focusing on those with hemorrhagic infarction or parenchymal hematoma type 1. Primary outcomes were HT exacerbation on follow-up imaging and 3-month modified Rankin Scale (mRS) distribution shift, comparing anticoagulation therapy (AC), antiplatelet therapy (APT), and drug discontinuation (NM). The safety outcome was symptomatic intracerebral hemorrhage (sICH) occurrence.

Results

Among 763 patients with HT (mean age 74.6±8.9 years, 48.1% male), AC was associated with a higher incidence of HT exacerbation compared to APT (adjusted OR 0.48, 95% CI 0.29-0.80, p-value =0.005). However, AC demonstrated improved 3-month mRS outcomes versus APT (adjusted OR 0.63, 95% CI 0.43-0.92, p-value =0.017) and NM (adjusted OR 0.38, 95% CI 0.26-0.55, p-value <0.001). sICH occurred in 5% of cases overall, with rates of 1.5%, 2.1%, and 11.7% in the AC, APT, and NM groups, respectively (adjusted OR for NM vs. AC: 3.93, 95% CI 1.18-13.16, p-value =0.026).

Conclusion

In cardioembolic AIS patients with HT, excluding those with PH-2, anticoagulation may lead to radiological exacerbation without increasing sICH risk, while potentially improving functional outcomes. These findings suggest that the presence of HT should not necessarily preclude the use of anticoagulation therapy in this patient population.
Specialty palliative care use among cancer patients: A population-based study
Authors: Cassel J. Brian , McClish Donna , Buxton David , Yanni Leanne , Roberts Seth , Skoro Nevena , May Peter , Del Fabbro Egidio , Noreika Danielle
Published: November 2024

Background

Rigorous population-based assessments of the use of specialty palliative care (SPC) in the US are rare.

Settings/subjects

This study examined SPC use among cancer patients in a mid-sized metropolitan area in Southeast US.

Measurements

In this cancer decedent cohort study, data were acquired and linked from the state-wide cancer registry; state-wide hospital discharge dataset; and local SPC providers.

Results

12,030 individuals with cancer were included in this study; only 2,958 (24.6%) used SPC. Of the 9,072 persons who did not use SPC, 3,877 (42.7%) went only to hospitals that did not offer SPC; and 3,517 (38.8%) went to hospitals that offered SPC but did not use it. About half of SPC recipients (1493; 50.5%) first received SPC in the final 30 days of life, including 768 (26.0%) in the final week of life. Characteristics associated with using SPC use included being in an socio-economic status quintile other than the lowest; being younger; being Black; having a solid (versus hematological) cancer; having a shorter survival with cancer; dying in the latter two years of the study; being from an area of low or complete rurality; having a hospital admission in the final 60 days prior to initiation of PC or death; having more days in hospital; and living within 15 miles of a hospital offering SPC.

Conclusions

In this population-based study, only one-quarter of cancer patients used SPC, and for half who did so, it came in the final 30 days of life.

Key Message

This novel population-based study found that about 25% of cancer patients who died 2012-2015 had used of specialty palliative care (SPC). Half of them first received SPC in the final month of life. Characteristics associated with SPC included being Black, younger, and residing within 15 miles of a hospital offering SPC.
Honey bees are resilient to the long-term presence of alcohol in their diet
Authors: Ostap-Chec Monika , Bajorek Daniel , Antoł Weronika , Stec Daniel , Miler Krzysztof
Published: November 2024

Previous studies on various organisms have suggested that low doses of ethanol can have stimulatory effects, while higher doses may lead to toxicity, a response known as hormesis. Low ethanol concentrations occur naturally in the environment, particularly in fermenting fruits and flower nectar, where pollinators such as honey bees may encounter it. This study aimed to investigate the potential hormetic effects of low-level ethanol consumption on honey bees. Bees were divided into three groups: one provided with only sucrose solution, one both with sucrose and 0.5% ethanol in sucrose, and one with only 1% ethanol in sucrose. The bees were exposed to these diets for 14 days, and their performance was assessed through survivorship, flight endurance, body mass, lipid content, and trehalose and ethanol levels in the haemolymph. The results showed no significant differences in most parameters between the groups. However, bees constantly exposed to 1% ethanol had slightly higher trehalose levels compared to the control group, suggesting a possible adaptive response to ethanol exposure. Ethanol levels in the haemolymph differed significantly between groups, with bees exposed to ethanol showing its detectable levels in their system. While no clear hormetic effects were observed in terms of improved performance, the elevated trehalose levels in bees constantly exposed to 1% ethanol may indicate adaptations protecting from ethanol-induced damage. The study provides insights into how honey bees tolerate low-level ethanol exposure and highlights the need for further research on the ecological implications of ethanol consumption in pollinators.
Detecting Special Genes in Marine Symbionts: A Phylogeny-Deviation Approach Identifies Recombination-Enhancing Variants
Authors: Zhou Xiaolin , Li Weijie , Xie Siya , Xia Kang , Xiao Mei , Yang Xiaojing , Li Zhiyuan
Published: November 2024

Different microbes possess special traits that enable adaptation to their specific niches, often through specialized genes. Identifying such species-special genes provides insights into microbial physiology and offers new tools for bioengineering. However, beyond the search for orphan genes, there are few methods for detecting genes that are homologous to those in other species yet contain unusual functional regions. In investigating the extreme recombination frequency of the marine symbiont bacteriumCa. E. kahalalidifaciens, we developed a computational approach to identify vairants that substantially deviate from phylogenetic expectations. This unbiased strategy successfully identified multiple Holliday junctions-related genes inCa. E. kahalalidifaciensas candidates responsible for its exceptional recombination capacity. Heterologous expression of these gene variants inEscherichia colisignificantly enhanced recombination efficiency. These high-efficient variants offer insights into improving tools for genetic manipulations, and our gene-identification approach can be applied broadly for microbial genome mining.
Exploring the latent space of transcriptomic data with topic modeling
Authors: Valle Filippo , Caselle Michele , Osella Matteo
Published: November 2024

The availability of high-dimensional transcriptomic datasets is increasing at a tremendous pace, together with the need for suitable computational tools. Clustering and dimensionality reduction methods are popular go-to methods to identify basic structures in these datasets. At the same time, different topic modeling techniques have been developed to organize the deluge of available data of natural language using their latent topical structure.

This paper leverages the statistical analogies between text and transcriptomic datasets to compare different topic modeling methods when applied to gene expression data. Specifically, we test their accuracy in the specific task of discovering and reconstructing the tissue structure of the human transcriptome and distinguishing healthy from cancerous tissues. We examine the properties of the latent space recovered by different methods, highlight their differences, and the pros and cons of the methods across different tasks. Finally, we show that the latent topic space can be a useful embedding space, where a basic neural network classifier can annotate transcriptomic profiles with high accuracy.
A threshold level of JNK activates damage-responsive enhancers via JAK/STAT to promote tissue regeneration
Authors: Quinn John W. , Lee Mariah C. , Van Hazel Chloe , Wilson Melissa A. , Harris Robin E.
Published: November 2024

Tissue regeneration requires the directed activity of numerous genes, which are often reused from development. Although the identities of many key factors have been established, how their expression is activated and subsequently coordinated over regenerative time remains unclear. One highly conserved signal central to diverse examples of regeneration is the stress activated MAP kinase JNK. InDrosophila, damage-induced JNK signaling promotes expression of multiple genes that direct proliferation, growth and changes in cellular identity. However, how these JNK targets are selectively upregulated in the context of injury, and subsequently expressed in specific patterns responsible for repair is unknown. Our work previously characterized Damage-Responsive, Maturity-Silenced (DRMS) enhancers; regulatory elements that are activated directly by JNK to promote regenerative gene expression. Here we have investigated how the damage-responsive (DR) module of these enhancers are engaged, finding that cell death is entirely dispensable for their activation. We identify JAK/STAT signaling as an additional direct input into DR enhancers downstream of JNK, which acts to broaden DR enhancer activity into the wound periphery where JNK levels are insufficient to promote regenerative gene expression alone. Finally, we demonstrate that a distinct threshold level of JNK activity exists that must be achieved to activate regenerative signaling via DR enhancers, which, alongside input from JAK/STAT, results in their temporally and spatially appropriate expression necessary for regeneration.

Author Summary

Wound healing and regeneration require the activation of multiple genes whose expression must be carefully coordinated to direct the necessary changes in cell division, identity and organ development that promote the restoration of tissue integrity and patterning. TheDrosophilaimaginal disc is a well-established model of regeneration that we have used to better understand spatiotemporal control of reparative gene expression. The response to damage in imaginal discs is primarily mediated thorough the conserved JNK signaling pathway, but how JNK leads to the diversity of gene expression that occurs around a wound is not well understood. Our work previously characterized discrete genomic regions called Damage-Responsive (DR) enhancers that respond to JNK to activate genes of the regeneration program. Here we show that the behavior of these enhancers depends on a threshold level of JNK and that they integrate both JNK and its immediate downstream target JAK/STAT to establish the proper regionality of gene expression, promoting the necessary spread of regenerative signaling around a wound. These findings improve our understanding of how wound patterning is established by discrete regulatory elements that are activated by damage.
Environmental DNA reveals temporal and spatial variability of invertebrate communities in arid-lands ephemeral water bodies
Authors: Hedges Brock A , Beasley-Hall Perry G , Dorey James B , Weinstein Philip , Austin Andrew D , Guzik Michelle T
Published: November 2024

Context

Throughout semi-arid and arid Australia surface freshwater is rare, and where it does occur, it is often ephemeral. This is the case for freshwater granite rock-holes that occur throughout much of southern Australia. Rock-holes support freshwater invertebrate communities, however, the ongoing threat of climate change means that this ecosystem is likely to experience hydrological disruptions. Rock-holes are also likely to be heavily impacted by invasive vertebrates. However, the ecology of this ecosystem is poorly understood despite its relative ecological significance and the extent of its associated threats.

Aims and methods

To provide a baseline ecological understanding of this ecosystem we documented species richness and variability at a series of rock-holes in the Gawler bioregion in South Australia using an environmental DNA approach.

Key results

Metabarcoding recorded invertebrates from 22 orders and 45 families. Community composition varied among rock-holes and throughout the year, with a peak in species richness in winter.

Conclusions and implications

These findings demonstrate the importance of these ecosystems to a range of endemic taxa. We propose establishment of monitoring programs, development of custom barcode reference libraries for the rock-hole ecosystem and future research into the likely impacts of climate change on the communities associated with them.
Environmental DNA and wildlife camera traps uncover complimentary vertebrate visitation patterns at freshwater granite rock-holes
Authors: Hedges Brock Adam , Beasley-Hall Perry G , Berry Tina E , Dawkins Kathryn L , Austin Andrew D , Weinstein Philip , Guzik Michelle T
Published: November 2024

Freshwater ecosystems are in decline globally. In Australia, threatening processes include invasive species, increasing drought frequency, climate change and changes to land use, all of which have been associated with declining vertebrate diversity, particularly in Australia’s arid interior. Efficient monitoring tools are required to effectively monitor and conserve freshwater ecosystems and their associated vertebrate communities. Environmental DNA (eDNA) metabarcoding is one tool that shows promise for monitoring these systems, but knowledge of how eDNA data compares to more established ecological assessment techniques is limited. To address this knowledge gap, we sampled vertebrate eDNA from seven freshwater water bodies of proposed conservation importance in the Australian arid-lands, at three timepoints to measure visitation and compare our findings to camera trapping data at the same locations. Using eDNA we detected 19 species of vertebrates, including native species (such as macropods, wombats and emus) and invasive species (such as feral goats, cats and foxes). In contrast, camera traps detected 32 species, and was much more successful at detecting bird visitation than eDNA. These communities varied both spatially between rock-holes, and temporally, with summer collection periods being distinct from winter-spring. Our results demonstrate the success of eDNA metabarcoding as a tool for monitoring vertebrate visitation to arid-lands freshwater ecosystems that is complementary to more traditional survey methods such as wildlife camera trapping. Finally, we provide conservation recommendations for these vertebrate communities and discuss the efficacy of eDNA for monitoring freshwater resources in arid-lands environments.
Topologically distinct and equivalent multiple efferent arterioles in the human glomeruli
Authors: Li Joshua Jing Xi , Teoh Jeremy Yuen Chun , Lai Hei Ming
Published: November 2024

We revisit the assumption that the human glomerulus consists of a capillary network with one afferent arteriole and only one efferent arteriole. Using three-dimensional tissue imaging, we unambiguously demonstrate the existence of multiple efferent arterioles via total reconstruction of a full human glomerular capillary network. Through graph network analysis, we found these multiple efferent arterioles can be topologically distinct or equivalent with reference to the global glomerular capillary network, and were strategically positioned with respect to the afferent arteriole. We also found the extraglomerular connections between two efferent arterioles may have significant contributions to the redistribution of intraglomerular blood flow. These new findings can provide new paradigms in the regulation and dysfunction of glomerular ultrafiltration, the crosstalk between intra- and extraglomerular factors, and the cross-coupling between nephrons.
ABRpresto: An algorithm for automatic thresholding of the Auditory Brainstem Response using resampled cross-correlation across subaverages
Authors: Shaheen Luke A. , Buran Brad N. , Suthakar Kirupa , Koehler Seth D. , Chung Yoojin
Published: November 2024

The auditory brainstem response (ABR) is an essential diagnostic indicator of overall cochlear health, used extensively in both basic research and clinical studies. A key quantification of the ABR is threshold, the lowest sound level that elicits a response. Because the morphology of ABR waveforms shift with stimulus level and the overall signal-to-noise ratio is low, threshold estimation is not straightforward. Although several algorithmic approaches have been proposed, the current standard practice remains the visual evaluation of ABR waveforms as a function of stimulus level.

We developed an algorithm based on the cross-correlation of two independent averages of responses to the same stimulus. For each stimulus level, the individual responses to each tone-pip are randomly split into two groups. The median waveform for each group is calculated, and then the normalized cross-correlation between these median waveforms is obtained. This process is repeated 500 times to obtain a resampled cross-correlation distribution. For each frequency, the mean values of these distributions are computed for each level and fit with a sigmoid or a power law function to estimate the threshold.

Algorithmic thresholds demonstrated robust and accurate performance, achieving 92% accuracy within ±10 dB of human-rated thresholds on a large pool of mouse data. This performance was better than that of several published algorithms on the same dataset. This algorithm has now fully replaced the manual estimation of ABR thresholds for our preclinical studies, thereby saving significant time and enhancing objectivity in the process.
XPO1 inhibition modulates the Wnt/β-catenin signaling pathway to reduce colorectal cancer tumorigenesis
Authors: Evans Andrew E. , Afroz Sahida , Magstadt Alexa , Dixon Dan A.
Published: November 2024

Colorectal Cancer (CRC) is the second leading cause of cancer-related death in the U.S. and high-risk individuals face a notably higher likelihood of developing CRC based on their genetic background. Hence, there is a compelling need for innovative chemopreventive treatments aimed at minimizing CRC tumorigenesis. Exportin 1 (XPO1; also referred to as CRM1) plays a pivotal role in transporting proteins from the nucleus to the cytoplasm. Various cancers overexpress XPO1, including CRC, and Selective Inhibitors of Nuclear Export (SINE) compounds, such as Eltanexor (KPT-8602), have been developed to target XPO1. Eltanexor demonstrates fewer adverse effects than its precursors and is currently under evaluation in Phase I/II clinical trials. This research evaluates Eltanexor as a chemopreventive agent for CRC. Our findings indicate Eltanexor treatment inhibits expression of the common chemoprevention target in CRC, cyclooxygenase-2 (COX-2). This occurs by Eltanexor-dependent reduction of Wnt/β-catenin signaling. Furthermore, XPO1 inhibition leads to forkhead transcription factor O subfamily member 3a (FoxO3a) nuclear retention, which can modulate β-catenin/TCF transcriptional activity.In vivooral treatment of Eltanexor to Apcmin/+mice (a mouse model for Familial Adenomatosis Polyposis) was well-tolerated andreduced tumor burden by approximately 3-fold, along with decreased tumor size. Drug sensitivity assays using organoids from Apcmin/+micetumors show increased sensitivity to Eltanexor compared to wild-type organoids. Collectively, these findings highlight XPO1 as a potent target for CRC chemoprevention.

SIGNIFICANCE

In this study, we show the XPO1 inhibitor, Eltanexor, reduces COX-2 by modulating the Wnt/β-catenin signaling pathway and acts as an effective chemopreventive agent in the Familial Adenomatous Polyposis (FAP) mouse model, Apcmin/+mice.
The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes
Authors: Wang Jiayi E. , Muralidharan Charanya , Nargis Titli , Enriquez Jacob R. , Anderson Ryan M. , Mirmira Raghavendra G. , Tersey Sarah A.
Published: November 2024

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin producing pancreatic β-cells. Macrophages infiltrate islets early in T1D pathogenesis, preceding the influx of T- and B-lymphocytes. The integrated stress response (ISR), a cellular pathway activated during stress, coordinates adaptive changes in gene expression to maintain cell function and survival. To study the ISR in macrophages, bone-marrow derived macrophages were treated with a pharmacological inhibitor of the ISR (ISRIB) and polarized to a proinflammatory M1-like state. We found a reduction in the number of proinflammatory macrophages as well as a reduction in iNOS mRNA and protein levels with ISRIB treatment. RNA-sequencing revealed a reduction in pathways related to stress responses, including ER stress, reactive oxygen species (ROS) regulation, and autophagy as well as migration pathway genes. ISRIB treatment led to decreased macrophage migration after stimulation in vitro and decreased macrophages to the site of injury after tailfin cut in zebrafish in vivo. Pre-diabetic female non-obese diabetic (NOD) mice administered ISRIB demonstrated an overall reduction in the macrophage numbers in the pancreatic islets. Additionally, the insulitic area of pancreata from ISRIB treated NOD mice had increased PD-L1 levels. Our study provides new insights into ISR signaling in macrophages and demonstrates that the ISR might serve as a potential target for intervention in macrophages during early T1D pathogenesis.
Expression Profile of Human Bitter Taste Receptors in Human Aortic and Coronary Artery Endothelial Cells
Authors: Kochany Paweł , Opiełka Mikołaj , Słonimska Paulina , Gulczynski Jacek , Kostrzewa Tomasz , Łoś Andrzej , Znaniecki Łukasz , Mickiewicz Agnieszka , Iżycka-Świeszewska Ewa , Sachadyn Paweł , Woźniak Michał , Gruchała Marcin , Górska-Ponikowska Magdalena
Published: November 2024

Human bitter taste receptors (TAS2Rs) are G protein-coupled receptors primarily associated with bitter taste perception, in the oral cavity. Many dietary compounds and drugs function as TAS2Rs agonists, activating their intracellular signaling pathways. Emerging evidence indicates TAS2Rs expression in extraoral tissues, including the cardiovascular system, where their functional role remains underexplored.. This study investigates TAS2Rs expression in primary human aortic and coronary artery endothelial cells. Using digital PCR (dPCR), we confirmed the mRNA expression of all 25 TAS2R subtypes in both cell lines. The expression levels were substantially higher in human coronary artery endothelial cells compared to human aortic endothelial cells. We confirmed the protein expression of TAS2R10 and TAS2R38 proteins using Western blot. These findings mark the first identification of TAS2Rs in these endothelial cells, suggesting a potential role in vascular physiology. These findings suggest a potential role for TAS2Rs in vascular physiology, prompting further research into their impact on endothelial function in cardiovascular health and pathology.
Study the Effect of Green Method Synthesis Cu- nanoparticles with Ionization Radiation on Lactate Dehydrogenase (LDH)
Authors: Sih Baydaa T.
Published: November 2024

Copper nanoparticles (Cu-NPs) hold considerable importance in the fields of medicine and pharmacy owing to their pronounced affinity for glucose. These nanoparticles are synthesized utilizing environmentally friendly vitamin C extracted from Iraqi lemons, possessing dimensions of less than 20 nanometers and exhibiting both star and spherical morphologies, which are conducive to efficient cellular penetration.

Optical assessments, including ultraviolet absorption, X-ray diffraction, Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM), have validated that the sizes of Cu-NPs are indeed optimal for applications in biomedicine.

Lactate dehydrogenase (LDH) is an enzymatic protein that plays a pivotal role in cellular respiration. A study conducted on cancer patients undergoing radiotherapy, administered at a total dose of 30 Gy divided into 12 sessions of 2.5 Gy per session, revealed a significant elevation in LDH enzyme levels in both in vivo and in vitro samples, with notable increases up to 7.5 Gy, followed by behavioral alterations observed at dosages of 10 and 15 Gy. The initial doses of irradiation were found to enhance the effectiveness of LDH, thereby facilitating the proliferation of cancer cells.

In an effort to mitigate this effect, Cu-NPs were employed, resulting in a reduction of HDL activity by -36% in the control samples. Nevertheless, exposure to X-ray irradiation modified the characteristics of Cu-NPs, leading to an increase in HDL enzyme values, which may be attributed to alterations in nanostructure or surface interactions.
A Scalable Framework for Identifying Allelic Series from Summary Statistics
Authors: McCaw Zachary R , Gao Jianhui , Dey Rounak , Tucker Simon , Zhang Yiyan ,   insitro Research Team, Gronsbell Jessica , Li Xihao , Fox Emily , O’Dushlaine Colm , Soare Thomas W
Published: November 2024

Genes for which a dose-response relationship exists between mutational severity and phenotypic impact make for logical therapeutic targets, as the effects of pharmacological modulation can be anticipated from the natural variation present in a population. We refer to genes where such a dose-response relationship exists as harboring allelic series, and have introduced the rare coding-variant allelic series test (COAST) for their identification. The original COAST required access to individual-level data. However, such data are often unavailable due to privacy concerns or logistical challenges. Meanwhile, single-variant summary statistics of the type produced by genome-wide association studies are plentiful. Here we introduce COAST-SS, an extension of COAST that accepts summary statistics as input, namely the per-variant effect sizes and standard errors, along with estimates of the minor allele frequency and local linkage disequilibrium (LD). As a running example, we consider identifying allelic series for circulating lipid traits, drawing on data from the UK Biobank, Million Veterans Program, and Trans-Omics of Precision Medicine Program. Through extensive analyses of real and simulated data, we demonstrate that COAST-SS provides p-values effectively equivalent to those from the original COAST. Interestingly, we find that when LD is low, as is expected among rare variants, COAST-SS is robust to misspecification of the LD matrix, providing valid inference even when the LD matrix is set to the identity matrix. We explore several strategies for annotating the pathogenicity of variants supplied to COAST-SS, finding that they often yield similar power for detecting candidate allelic series. Lastly, we employ COAST-SS to screen for lipid trait allelic series in a meta-analyzed cohort of up to 840K subjects. COAST-SS has been incorporated into the publicly availableAllelicSeries Rpackage.
Navigating the Fitness Landscapes of Plasmodium falciparum Dihydrofolate Reductase: Evolutionary Insights into Antifolate Resistance
Authors: Muzata Danny , Sanyal Dwipanjan , Shivram A , Pandey Deeptanshu , Chakraborti Soumyananda , Chivukula Aneesh S. , Jasuja Ravi , Uversky Vladimir N. , Zielinski Daniel , Upadhyay Prajna D. , Albers Mark , Chowdhury Sourav
Published: November 2024

The rapid emergence of drug resistance in malaria parasites poses a significant challenge to the efficacy of antifolate treatments. Traditional drug development approaches, which often rely on empirical screening with limited mechanistic insights, tend to overlook the complex evolutionary mechanisms that enablePlasmodium falciparumto evade drug inhibition while preserving enzyme functionality. In this study, we employed computational techniques to investigate the mutational landscape of dihydrofolate reductase (DHFR), focusing on regions essential for enzyme stability and resistance. Our analysis uncovered conserved residues essential for stability, mutation hotspots that enhance adaptability under drug pressure and co-evolving clusters revealing critical functional interdependencies. Through integrated approaches including mutational scanning, epistatic interaction modeling, and fitness trajectory mapping, we elucidated distinct evolutionary pathways that drive resistance. We were able to track the adaptive paths taken by wild-type residues upon mutation, revealing the steps required to reach high-fitness peaks within the rugged fitness landscape. These findings provide valuable insights into the molecular mechanisms of antifolate resistance. We suggest that future drug design should target co-evolving networks and conserved regions to support the development of next-generation therapies to overcome resistance.
Hybrid Transformer and Neural Network Configuration for Protein Classification Using Amino Acids
Authors: Labiosa Nathan , Kohli Aryan , Chung Christian , Korban Christopher
Published: November 2024

This study introduces a hybrid machine learning model for classifying proteins, developed to address the complexities of protein sequence and structural analysis. Utilizing an architecture that combines a lightweight transformer with a concurrent neural network, the hybrid model leverages both sequential and intrinsic physical properties of proteins. Trained on a comprehensive dataset from the Research Collaboratory for Structural Bioinformatics Protein Data Bank, the model demonstrates a classification accuracy of 95%, outperforming existing methods by at least 15%.

The high accuracy achieved demonstrates the potential of this approach to innovate protein classification, facilitating advancements in drug discovery and the development of personalized medicine. By enabling precise protein function prediction, the hybrid model allows for specialized strategies in therapeutic targeting and the exploration of protein dynamics in biological systems.

Future work will focus on enhancing the model’s generalizability across diverse datasets and exploring the integration of more machine learning techniques to refine predictive capabilities further. The implications of this research offer potential breakthroughs in biomedical research and the broader field of protein engineering.
DGRNA: a long-context RNA foundation model with bidirectional attention Mamba2
Authors: Yuan Ye , Chen Qushuo , Pan Xiaoyong
Published: November 2024

Ribonucleic acid (RNA) is an important biomolecule with diverse functions i.e. genetic information transfer, regulation of gene expression and cellular functions. In recent years, the rapid development of sequencing technology has significantly enhanced our understanding of RNA biology and advanced RNA-based therapies, resulting in a huge volume of RNA data. Data-driven methods, particularly unsupervised large language models, have been used to automatically hidden semantic information from these RNA data. Current RNA large language models are primarily based on Transformer architecture, which cannot efficiently process long RNA sequences, while the Mamba architecture can effectively alleviate the quadratic complexity associated with Transformers. In this study, we propose a large foundational model DGRNA based on the bidirectional Mamba trained on 100 million RNA sequences, which has demonstrated exceptional performance across six RNA downstream tasks compared to existing RNA language models.
Strain softening and hysteresis arising from 3D multicellular dynamics during long-term large deformation
Authors: Tsubota Ken-ichi , Horikoshi Shota , Hiraiwa Tetsuya , Okuda Satoru
Published: November 2024

Living tissues exhibit complex mechanical properties, including viscoelastic and elastoplastic responses, that are crucial for regulating cell behaviors and tissue deformations. Despite their significance, the intricate properties of three-dimensional (3D) multicellular tissues are not well understood and are inadequately implemented in biomaterial engineering. To address this gap, we developed a numerical method to analyze the dynamic properties of multicellular tissues using a 3D vertex model framework. By focusing on 3D tissues composed of confluent homogeneous cells, we characterized their properties in response to various deformation magnitudes and time scales. Stress relaxation tests revealed that large deformations initially induced relaxation in the shapes of individual cells. This process is amplified by subsequent transient cell rearrangements, homogenizing cell shapes and leading to tissue fluidization. Additionally, dynamic viscoelastic analyses showed that tissues exhibited strain softening and hysteresis during large deformations. Interestingly, this strain softening originates from multicellular structures independent of cell rearrangement, while hysteresis arises from cell rearrangement. Moreover, tissues exhibit elastoplastic responses over the long term, which are well represented by the Ramberg–Osgood model. These findings highlight the characteristic properties of multicellular tissues emerging from their structures and rearrangements, especially during long-term large deformations. The developed method offers a new approach to uncover the dynamic nature of 3D tissue mechanics and could serve as a technical foundation for exploring tissue mechanics and advancing biomaterial engineering.
Social inequalities in vaccine coverage and their effects on epidemic spreading
Authors: Manna Adriana , Karsai Márton , Perra Nicola
Published: November 2024

Vaccinations are fundamental public health interventions. Yet, inequalities in vaccines uptake across socioeconomic groups can significantly undermine their impact. Moreover, heterogeneities in vaccination coverage across socioeconomic strata are typically neglected by epidemic models and considered, if at all, only at posteriori. This limitation reduces their ability to predict and assess the effectiveness of vaccination campaigns. Here, we study the impact of socioeconomic inequalities in vaccination uptake on epidemic burden. We consider a modeling framework based on generalized contact matrices that extend traditional age-stratified approaches to incorporate socioeconomic status (SES) variables. We simulate epidemic dynamics under two scenarios. In the first vaccination campaigns are concurrent with epidemics. In the second instead, vaccinations are completed before the onset of infection waves. By using both synthetic and empirical generalized contact matrices, we find that inequalities in vaccine uptake can lead to non-linear effects on disease outcomes and exacerbate disease burden in disadvantaged groups of the population. We demonstrate that simple models ignoring SES heterogeneity produce incomplete or biased predictions of epidemic burden. Additionally, we show how inequalities in vaccine coverage interact with non-pharmaceutical interventions (NPIs) compounding differences across subgroups. Overall, our findings highlight the importance of integrating SES dimensions, alongside age, into epidemic models to inform more equitable and effective public health interventions and vaccination strategies.
Klotho plasma levels are an independent predictor of mortality in women with acute coronary syndrome
Authors: Cortés García Marcelino , Kallmeyer Mayor Andrea , Tarín Nieves , Cristobal Carmen , Pello Lázaro Ana María , Aceña Alvaro , Gutierrez-Landaluce Carlos , Huelmos Ana , Alonso Martín Joaquín , López Bescós Lorenzo , Mahillo-Fernandez Ignacio , Lorenzo Oscar , Gonzalez-Casaus Maria , Egido Jesus , Tuñon Jose
Published: November 2024

INTRODUCTION

Alterations in plasma levels of the components of the mineral metabolism (MM) system (calcidiol, fibroblast growth factor-23 [FGF23], phosphate, parathormone [PTH] and klotho) are related to cardiovascular diseases. However, gender differences of the whole MM system in patients with acute coronary syndrome (ACS) have not been reported so far.

METHODS

We studied 1,230 patients with ACS. At baseline clinical data were collected and plasma levels of MM components were assessed. The primary outcome was a composite of acute ischaemic events, heart failure and all-cause mortality. Secondary outcomes included each component separately.

RESULTS

282 patients (22.9%) were female. At baseline, FGF23, PTH, phosphate, and klotho plasma levels were higher in women than in men. After 5.44 (3.03-7.46) years of follow-up, the primary outcome occurred in 28.0% women and 23.5% men, and death in 10.6% and 9.4% respectively. At multivariate Cox regression analysis, FGF23 levels were associated with incidence of the primary outcome in both, women (Hazard ratio [HR] 1.02 [95%CI:1.01-1.04];p=0.001) and men (HR 1.04 [1.00-1.03];p=0.016), in whom calcidiol levels were also an independent predictor of this outcome. Klotho (HR 0.80 [95%CI:0.67-0.96];p=0.019) and phosphate (HR=2.24 [95%CI: 1.11-4.50];p=0.025) were independent predictors of death in women, while calcidiol (HR=0.84 [95%CI0.72-0.98];p=0.024) and FGF23 levels (HR=1.02 [1.00-1.03];p=0.048) were predictors in men.

CONCLUSIONS

Klotho levels are inversely and independently related to all-cause mortality after an ACS in women, but not in men. Furthermore, the MM profile in ACS patients differs in both genders. Future research should explore the underlying mechanisms of these associations.