bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal Trends in Thromboembolic Event Hospitalizations in Patients with Atrial Fibrillation in the United States
Authors: Vasquez Moises A. , Yan Crystal Lihong , Lambrakos Litsa K. , Velasquez Alex , Goldberger Jeffrey J. , Mitrani Raul D.
Published: July 2024

Background

Direct oral anticoagulants and percutaneous left atrial appendage occlusion (LAAC) devices were approved for use in 2010 and 2015, respectively. It is unknown to what extent, if any, these new stroke preventive therapies have impacted hospitalizations for thromboembolic (TE) events in the United States.

Methods

We used the National Inpatient Sample database to describe trends over time in AF-related hospitalizations for acute ischemic stroke (AIS), transient ischemic attacks (TIA), and systemic embolic events (SEE) between 2010 and 2021. Trends in anticoagulation use (AC) and percutaneous LAAC procedures among hospitalized patients with AF were also analyzed.

Results

A total of 1,692,373 hospitalizations for TE were identified between 2010 and 2021: 798,413 from 2010 to 2015 (mean age 78.9 [standard deviation (SD) 10.7] years; 57.8% female) and 893,960 from 2016 to 2021 (mean age 77.5 [SD 10.9] years; 53.1% female). There was a significant increase in rates of AC use (21.2% of inpatients with AF in 2010 vs 42.4% of inpatients with AF in 2021; Ptrend<0.001) and rates of percutaneous LAAC procedures (0.1/100,000 US adults vs to 17.7/100,000 US adults Ptrend<0.001) among inpatients with AF. Between 2010 to 2021, age-adjusted AIS hospitalizations increased (30.8 hospitalizations /100,000 US adults vs 35.9 hospitalizations/ 100,000 US adults; Ptrend<0.001) and peaked in 2019. Age-adjusted SEE hospitalizations (2.5 hospitalizations /100,000 US adults vs 1.3 hospitalizations/ 100,000 US adults; Ptrend<0.001) and TIA hospitalization(8.5 hospitalizations /100,000 US adults vs 4.3 hospitalizations/ 100,000 US adults; Ptrend<0.001) peaked in 2011 and then decreased. Between 2016 and 2021, age-adjusted AIS hospitalizations plateaued (37.7 hospitalizations/100,000 US adults vs 35.9 hospitalizations/100,000 US adults; APC −4.7%; Ptrend= 0.197). The total of all TE hospitalizations remained stable (41.8 hospitalizations/100,000 US adults vs 41.5 hospitalizations/100,000 US adults; Ptrend0.689).

Conclusion

Despite increased anticoagulant and the initial use of percutaneous LAAO, AF-associated TE event hospitalizations in the US have remained stable from 2010 to 2021. Hospitalizations for AF-related TIA and SEE consistently decreased from 2010 to 2021 while AF-related AIS hospitalizations increased from 2010 to 2015 and then plateaued from 2016 to 2021.
No evidence for causal effects of C-reactive protein (CRP) on chronic pain conditions: a Mendelian randomization study
Authors: Suri Pradeep , Tsepilov Yakov A. , Elgaeva Elizaveta E. , Williams Frances M. K. , Freidin Maxim B. , Stanaway Ian B.
Published: July 2024

Objective

We conducted a Mendelian randomization (MR) study to examine causal associations of C-reactive protein (CRP) with (1) spinal pain; (2) extent of multisite chronic pain; and (3) chronic widespread musculoskeletal pain.

Design

Two-sample MR study.

Setting/Subjects

We used summary statistics from publicly available genome-wide association studies (GWAS) conducted in multiple cohorts and biobanks. Genetic instrumental variables were taken from an exposure GWAS of CRP (n=204,402). Outcome GWASs examined spinal pain (n=1,028,947), extent of multisite chronic pain defined as the number of locations with chronic pain (n=387,649), and chronic widespread pain (n=249,843).

Methods

We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis and sensitivity analyses using other methods. We calculated odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values, using a Bonferroni correction (p<0.0166) to account for 3 primary comparisons.

Results

Greater serum CRP (mg/L) was not significantly causally associated with spinal pain (OR=1.04, 95% CI 1.00-1.08; p=0.07) in IVW analysis. Greater serum CRP also showed no significant causal association with extent of multisite chronic pain in IVW analysis (beta coefficient= 0.014, standard error=0.011; p=0.19). CRP also showed no significant causal association with chronic widespread pain in IVW analysis (OR=1.00, 95% CI 1.00-1.00; p=0.75). All secondary and sensitivity analyses also showed no significant associations.

Conclusions

This MR study found no causal association of CRP on spinal pain, the extent of chronic pain, or chronic widespread pain. Future studies examining mechanistic biomarkers for pain conditions should consider other candidates besides CRP.
Boosting LLM-Assisted Diagnosis: 10-Minute LLM Tutorial Elevates Radiology Residents’ Performance in Brain MRI Interpretation
Authors: Kim Su Hwan , Schramm Severin , Wihl Jonas , Raffler Philipp , Tahedl Marlene , Canisius Julian , Luiken Ina , Endrös Lukas , Reischl Stefan , Marka Alexander , Walter Robert , Schillmaier Mathias , Zimmer Claus , Wiestler Benedikt , Hedderich Dennis M.
Published: July 2024

Purpose

To evaluate the impact of a structured tutorial on the use of a large language model (LLM)-based search engine on radiology residents’ performance in LLM-assisted brain MRI differential diagnosis.

Materials & Methods

In this retrospective study, nine radiology residents determined the three most likely differential diagnoses for three sets of ten brain MRI cases with a challenging yet definite diagnosis. Each set of cases was assessed 1) with the support of conventional internet search, 2) using an LLM-based search engine (© Perplexity AI) without prior training, or 3) with LLM assistance after a structured 10-minute tutorial on how to effectively use the tool for differential diagnosis. The tutorial content was based on the results of two studies on LLM-assisted radiological diagnosis and included a prompt template. Reader responses were rated using a binary and numeric scoring system. Reading times were tracked and confidence levels were recorded on a 5-point Likert scale. Binary and numeric scores were analyzed using chi-square tests and pairwise Mann-Whitney U tests each. Search engine logs were examined to quantify user interaction metrics, and to identify hallucinations and misinterpretations in LLM responses.

Results

Radiology residents achieved the highest accuracy when employing the LLM-based search engine following the tutorial, indicating the correct diagnosis among the top three differential diagnoses in 62.5% of cases (55/88). This was followed by the LLM-assisted workflow before the tutorial (44.8%; 39/87) and the conventional internet search workflow (32.2%; 28/87). The LLM tutorial led to significantly higher performance (binary scores: p = 0.042, numeric scores: p = 0.016) and confidence (p = 0.006) but resulted in no relevant differences in reading times. Hallucinations were found in 5.1% of LLM queries.

Conclusion

A structured 10-minute LLM tutorial increased performance and confidence levels in LLM-assisted brain MRI differential diagnosis among radiology residents.

Clinical Relevance Statement

Our findings highlight the considerable benefits that even low-cost, low-effort educational interventions on LLMs can provide. Integrating LLM education in radiology training programs could augment practitioners’ capacity to harness AI technologies effectively.
Bladder-resident bacteria associated with increased risk of recurrence after electrofulguration in women with antibiotic-recalcitrant urinary tract infection
Authors: Gadhvi Jashkaran G. , Kenee Parker R.M. , Lutz Kevin C. , Khan Fatima , Li Qiwei , Zimmern Philippe E. , De Nisco Nicole J.
Published: July 2024

Background

Antibiotic-recalcitrant recurrent urinary tract infection (rUTI) is has become increasingly observed in postmenopausal women. Therefore, when standard antibiotic therapies have failed, some elect electrofulguration (EF) of areas of chronic cystitis when detected on office cystoscopy. EF is thought to remove tissue-resident bacteria that have been previously detected in the bladder walls of postmenopausal women with rUTI. We hypothesized that increased bladder bacterial burden may be associated with incomplete rUTI resolution following EF.

Methods

Following IRB approval, bladder biopsies were obtained from 34 consenting menopausal women electing EF for the advanced management of rUTI. 16S rRNA FISH was performed using both universal andEscherichiaprobes and tissue-resident bacterial load was quantified. Time to UTI relapse after EF was recorded during a six-month follow-up period and the association of bladder bacterial burden and clinical covariates with UTI relapse was assessed.

Results

We observed bladder-residentEscherichiain 52% of all participants and in 92% of participants with recentE. coliUTI. Time-to-relapse analysis revealed that women with high bladder bacterial burden as detected by the universal probe had a significantly (p=0.035) higher risk of UTI within six months of EF (HR=3.15, 95% CI: 1.09-9.11). Interestingly, bladder-residentEscherichiawas not significantly associated (p=0.26) with a higher risk of UTI relapse (HR= 2.14, 95% CI: 0.58-7.90).

Conclusions

We observed that total bladder bacterial burden was associated with a 3.1x increased risk of rUTI relapse within six months. Continued analysis of the relationship between bladder bacterial burden and rUTI outcomes may provide insight into the management of these challenging patients.
PGAP3 regulates human bronchial epithelial cell mRNAs present in asthma and respiratory virus reference data sets
Authors: Leslie Eric , Miller Marina , Lafuze Allison , Svyatskaya Sofya , Choi Gil-Soon , Broide David H.
Published: July 2024

PGAP3 is a glycosylphosphatidylinositol (GPI) phospholipase gene localized within chromosome 17q12-21, a region highly linked to asthma. Although much is known about the function of other chromosome 17q12-21 genes expressed at increased levels in bronchial epithelium such as ORMDL3 and GSDMB, little is known about the function of increased PGAP3 expression in bronchial epithelium in the context of asthma. The aim of this study was therefore to determine whether increased PGAP3 expression in human bronchial epithelial cells regulated expression of mRNA pathways important to the pathogenesis of asthma by utilizing RNA-sequencing and bioinformatic analysis. We performed RNA-sequencing on normal human bronchial epithelial cells transfected with PGAP3 for 24 and 48 hours. PGAP3 regulated genes were compared to asthma and respiratory virus (influenza A, rhinovirus, respiratory syncytial virus) reference data sets to identify PGAP3 target genes and pathways. Approximately 9% of the upregulated PGAP3-induced genes were found in an asthma reference data set, 41% in a rhinovirus reference data set, 33% in an influenza A reference data set, and 3% in a respiratory syncytial virus reference data set. PGAP3 significantly upregulated the expression of several genes associated with the innate immune response and viral signatures of respiratory viruses associated with asthma exacerbations. Two of the highest expressed genes induced by PGAP3 are RSAD2, OASL, and IFN-λ, which are anti-viral genes associated with asthma. PGAP3 also upregulated the antiviral gene BST2, which like PGAP3 is a GPI-anchored protein. We conclude that PGAP3 expression in human bronchial epithelial cells regulates expression of genes known to be linked to asthma, and also regulates the bronchial epithelial expression of genes pertinent to the pathogenesis of respiratory viral triggered asthma exacerbations.
Female fruit flies use social cues to make egg clustering decisions
Authors: Churchill Emily R. , Fowler Emily K. , Friend Lucy A. , Archetti Marco , Yu Douglas W. , Bourke Andrew F. G. , Chapman Tracey , Bretman Amanda
Published: July 2024

Background

The ability to respond plastically to environmental variation is a key determinant of fitness. Females may use cues to strategically place their eggs, for example adjusting the number or location of eggs according to whether other females are present, driving the dynamics of local competition or cooperation. The expression of plasticity in egg laying patterns within individual patches, i.e., in contact clusters or not, represents an additional, under-researched and potentially important opportunity for fitness gains. Clustered eggs might benefit from increased protection or defence, and clustering could facilitate cooperative feeding. However, increased clustering is also expected to increase the risk of over-exploitation through direct competition. These potential benefits and costs likely covary with the number of individuals present, hence egg clustering behaviour within resource patches should be socially responsive. We investigate this new topic using the fruit flyDrosophila melanogaster.

Results

Our mathematical model, parameterised by data, verified that females cluster their eggs non-randomly, and increase clustering as group size increases. We also showed that, as the density of adult females increased, females laid more eggs, laid them faster, and laid more eggs in clusters. Females also preferred to place eggs within existing clusters. Most egg clusters were of mixed maternity.

Conclusions

Collectively, the results reveal that females actively express plasticity in egg clustering according to social environment cues and prefer to lay in clusters of mixed maternity, despite the potential for increased competition. These findings are consistent with egg clustering plasticity being selected due to public goods-related benefits.
Alzheimer’s Disease Knowledge Graph Enhances Knowledge Discovery and Disease Prediction
Authors: Yang Yue , Yu Kaixian , Gao Shan , Yu Sheng , Xiong Di , Qin Chuanyang , Chen Huiyuan , Tang Jiarui , Tang Niansheng , Zhu Hongtu
Published: July 2024

Background

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, continues to increase in prevalence without any effective treatments to date. In this context, knowledge graphs (KGs) have emerged as a pivotal tool in biomedical research, offering new perspectives on drug repurposing and biomarker discovery by analyzing intricate network structures. Our study seeks to build an AD-specific knowledge graph, highlighting interactions among AD, genes, variants, chemicals, drugs, and other diseases. The goal is to shed light on existing treatments, potential targets, and diagnostic methods for AD, thereby aiding in drug repurposing and the identification of biomarkers.

Results

We annotated 800 PubMed abstracts and leveraged GPT-4 for text augmentation to enrich our training data for named entity recognition (NER) and relation classification. A comprehensive data mining model, integrating NER and relationship classification, was trained on the annotated corpus. This model was subsequently applied to extract relation triplets from unannotated abstracts. To enhance entity linking, we utilized a suite of reference biomedical databases and refine the linking accuracy through abbreviation resolution. As a result, we successfully identified 3,199,276 entity mentions and 633,733 triplets, elucidating connections between 5,000 unique entities. These connections were pivotal in constructing a comprehensive Alzheimer’s Disease Knowledge Graph (ADKG). We also integrated the ADKG constructed after entity linking with other biomedical databases. The ADKG served as a training ground for Knowledge Graph Embedding models with the high-ranking predicted triplets supported by evidence, underscoring the utility of ADKG in generating testable scientific hypotheses. Further application of ADKG in predictive modeling using the UK Biobank data revealed models based on ADKG outperforming others, as evidenced by higher values in the areas under the receiver operating characteristic (ROC) curves.

Conclusion

The ADKG is a valuable resource for generating hypotheses and enhancing predictive models, highlighting its potential to advance AD’s disease research and treatment strategies.
ZIP13 regulates lipid metabolism by changing intracellular iron and zinc balance
Authors: Fukunaka Ayako , Tanaka Gen , Kimura Toru , Hengphasatporn Kowit , Saito Daisuke , Shigeta Mayo , Shibata Hiroshi , Ichinose Takayuki , Abe Ichitaro , Shimura Mari , Sato Takashi , Nakagawa Yuko , Horii Takuro , Hatada Izuho , Kajimura Shingo , Kiyonari Hiroshi , Sakurai Hiroyuki , Shigeta Yasuteru , Watada Hirotaka , Fukada Toshiyuki , Fujitani Yoshio
Published: July 2024

Metabolic diseases are caused by a prolonged energy imbalance, and adipose tissue is known to be the main contributor. We previously reported that ZIP13, an Slc39a transporter whose deficiency causes Ehlers-Danlos syndrome spondylocheirodysplastic type 3 associated with lipoatrophy, inhibits the adipocyte browning pathway by modulating intracellular zinc status. The precise mechanisms of how ZIP13 regulates the homeostasis of adipose tissue remain unclear and therefore, we investigated the role of ZIP13 in mature adipocytes using adipocyte-specificZip13-deficient mice. We herein demonstrate that these mice show accelerated lipolysis and reduced respiratory exchange ratio. In addition, abundance of iron and zinc balance were altered during differentiation in normal adipocytes, whereas iron distribution was substantially affected inZip13-deficient adipocytes, which downregulated PDE activity and enhanced β-adrenergic receptor signaling pathways. Importantly, we confirmed that ZIP13 could transport both zinc and iron, using theXenopusoocyte transport system andin silicostructural dynamics simulations, and that the defect in iron distribution perturbs proper lipolysis. Together, these results illustrate that ZIP13 acts as a key regulator for lipolysis in adipocytes via the proper use of metals, and that the ZIP13-iron axis plays an important role in regulation of lipid metabolism.
The SmARTR pipeline: a modular workflow for the cinematic rendering of 3D scientific imaging data
Authors: Macrì Simone , Di-Poï Nicolas
Published: July 2024

Advancements in non-invasive surface and internal imaging techniques, along with computational methods, have revolutionized 3D visualization of organismal morphology. These breakthroughs not only enhance research and medical anatomical analysis, but also facilitate the preservation and digital archiving of scientific specimens. We introduce the SmARTR pipeline (Small Animal Realistic Three-dimensional Rendering), a comprehensive workflow integrating wet lab procedures, 3D data acquisition, and processing to produce photorealistic 3D scientific data through cinematic rendering. This versatile pipeline supports multi-scale visualizations, from tissue-level to whole-organism details across diverse living organisms and is adaptable to various imaging sources and platforms. Its modular design and customizable rendering scenarios, provided by detailed SmARTR networks in a free software environment, make it a powerful tool for 3D data analysis. Accessible to a broad audience, SmARTR serves as a valuable resource not only for multiple fields of research in life sciences but also for education, diagnosis, outreach, and artistic endeavors.
Life Cycle and Morphogenetic Differentiation in Heteromorphic Cell Types of a Cosmopolitan Marine Microalga
Authors: Bousquet Laurie , Fainsod Shai , Decelle Johan , Murik Omer , Chevalier Fabien , Gallet Benoit , Templin Rachel , Schwab Yannick , Avrahami Yoav , Koplovitz Gil , Ku Chuan , Frada Miguel
Published: July 2024

Gephyrocapsa huxleyi is a prevalent, bloom-forming phytoplankton species in the oceans. It exhibits a complex haplo-diplontic life cycle, featuring a diploid-calcified phase, a haploid phase, and a third 'decoupled' phase produced during viral infection. Decoupled cells display a haploid-like phenotype, but are diploid. Here, we investigated the fate of decoupled cells during culture observations and we compared the transcriptome profiling and the cellular architecture in three dimensions of the three cell types. We found that decoupled cells can revert to the calcified form in the absence of viral pressure, revealing the transient nature of this cell type. Ultrastructural analyses showed distinct nuclear organisation with variations in chromatin volume. Transcriptomic analyses revealed gene expression patterns specific to each life phase. These included multiple regulatory functions in chromatin remodelling, broader epigenetic mechanisms and life cycling, which likely contributed to cell differentiation. Finally, the exploration of available host-virus transcriptomes supports life cycle transition during viral infection. This study provides cellular and molecular foundations for nuclear remodelling and cell differentiation in coccolithophores and the identification of gene markers for studying coccolithophore life cycles in natural populations.
TLR9 signaling requires ligand-induced phosphorylation of two specific tyrosine residues by EGFR and Syk
Authors: Veleeparambil Manoj , Wang Chenyao , Kessler Patricia M , Willard Belinda , Sen Ganes C , Chattopadhyay Saurabh
Published: July 2024

Toll-like receptors (TLRs) are transmembrane proteins required for recognizing microbial components or cellular danger signals to activate intracellular signaling pathways leading to induction of anti-microbial and inflammatory genes. Inactive TLRs require ligand-induced activation to recruit adaptor proteins, e.g., MyD88, to trigger the synthesis of cytokines and interferons. TLR9 is an endosomal membrane-bound protein, which binds to CpG-containing microbial DNA or endogenous signals from dead cells or tissue damage. We showed that TLR9 activation requires EGFR, a tyrosine (Tyr) kinase, which interacts with and phosphorylates the cytoplasmic domain of TLR9. Blocking EGFR activity pharmacologically, or knocking out EGFR gene in myeloid cells, suppressed lethal TLR9-induced hepatotoxicity. Here, we reveal that TLR9 required two Src family of kinases, Syk and Lyn, which, together with EGFR, led to phosphorylation and activation of TLR9. Lack of either of these kinases inhibited TLR9-MyD88 interaction, thereby inhibiting TLR9-mediated gene induction. Unlike EGFR, which constitutively binds TLR9, activated Syk interacted with TLR9 in a CpG-dependent manner. Activated Syk interacted with TLR9 and was critical for activating TLR9-bound EGFR. Quantitative mass spectrometric analyses revealed TLR9 was phosphorylated, sequentially, on Tyr870and Tyr980by Syk and EGFR, respectively. Mutation of either of these tyrosines led to complete loss of TLR9-induced cytokine production. For activation, Syk was phosphorylated by Lyn, which was activated by CpG-mediated scavenger-receptor A, and surprisingly, independent of TLR9. In summary, our results uncovered the molecular details of TLR9 activation by its Tyr-phosphorylation, which is critical for TLR9-mediated intracellular signaling.
Simultaneous dual-color calcium imaging in freely-behaving mice
Authors: Dong Zhe , Feng Yu , Diego Keziah , Baggetta Austin M. , Sweis Brian M. , Pennington Zachary T. , Lamsifer Sophia I. , Zaki Yosif , Sangiuliano Federico , Philipsberg Paul A. , Morales-Rodriguez Denisse , Kircher Daniel , Slesinger Paul , Shuman Tristan , Aharoni Daniel , Cai Denise J.
Published: July 2024

Miniaturized fluorescence microscopes (miniscopes) enable imaging of calcium events from a large population of neurons in freely behaving animals. Traditionally, miniscopes have only been able to record from a single fluorescence wavelength. Here, we present a new open-source dual-channel Miniscope that simultaneously records two wavelengths in freely behaving animals. To enable simultaneous acquisition of two fluorescent wavelengths, we incorporated two CMOS sensors into a single Miniscope. To validate our dual-channel Miniscope, we imaged hippocampal CA1 region that co-expressed a dynamic calcium indicator (GCaMP) and a static nuclear signal (tdTomato) while mice ran on a linear track. Our results suggest that, even when neurons were registered across days using tdTomato signals, hippocampal spatial coding changes over time. In conclusion, our novel dual-channel Miniscope enables imaging of two fluorescence wavelengths with minimal crosstalk between the two channels, opening the doors to a multitude of new experimental possibilities.

Teaser

Novel open-source dual-channel Miniscope that simultaneously records two wavelengths with minimal crosstalk in freely behaving animals.
Restoration of locus coeruleus noradrenergic transmission during sleep
Authors: Sima Jiao , Zhang Yuchen , Farriday Declan , Ahn Andy Young-Eon , Lopez Eduardo Ramirez , Jin Chennan , Harrell Jade , Darmohray Dana , Silverman Daniel , Dan Yang
Published: July 2024

Sleep is indispensable for health and wellbeing, but its basic function remains elusive. The locus coeruleus (LC) powerfully promotes arousal by releasing noradrenaline. We found that noradrenaline transmission is reduced by prolonged wakefulness and restored during sleep. Fiber-photometry imaging of noradrenaline using its biosensor showed that its release evoked by optogenetic LC neuron activation was strongly attenuated by three hours of sleep deprivation and restored during subsequent sleep. This is accompanied by the reduction and recovery of the wake-promoting effect of the LC neurons. The reduction of both LC evoked noradrenaline release and wake-inducing potency is activity dependent, and the rate of noradrenaline transmission recovery depends on mammalian target of rapamycin (mTOR) signaling. The decline and recovery of noradrenaline transmission also occur in spontaneous sleep-wake cycles on a timescale of minutes. Together, these results reveal an essential role of sleep in restoring transmission of a key arousal-promoting neuromodulator.
A chromosome-level genome assembly ofDracaena cambodianaand comparative genomics analysis highlights the distinct biological features of two resource species of dragon’s blood
Authors: Xu Yanhong , Peng Junxiang , Li Sipeng , Liu Yang , Wen Dong , Jiang Jiemei , Rong Mei , Wei Wei , Wang Qiuling , Jin Yue , Yang Shuwen , Wang Siyu , Wei Jian-he
Published: July 2024

This study reports a chromosome-level genome forDracaena cambodiana, one of two typical dracaena species in China. This work will help to deepen the understanding of the dracaena species and the conservation and development of plant resources. The final assembly consisted of 54 scaffolds, spanning 1.08 Gb, with a scaffold N50 size of 52.29 Mb, encoded 36860 predicted protein-coding genes. A total of 1,064,810,157 bp of genome sequences were located on 20 chromosomes (2n = 40), accounting for 98.46%. We investigate the possible mechanisms of the longevity of dracaena, the longest-lived plant in the world, which involve DNA repair and post-translational modification. We also performed comparative genomic analysis of the previously assembled genome ofDracaena cochinchinesiswith this genome, and found that the two involved interaction of plant−pathogen interaction and ubiquitin mediated proteolysis, which may reveal why Dracaena has environmental adaptability and longevity characteristics.
Polyelectrolyte mannan from diatoms reshapes sunlit ocean microbiome
Authors: Krull J. , Crawford C.J. , Sidhu C. , Solanki V. , Bligh M. , Rößler L. , Singh R.K. , Huang G. , Robb C.S. , Teeling H. , Seeberger P.H. , Schweder T. , Hehemann J-H.
Published: July 2024

Algae catalyze half of the global solar powered reduction of carbon dioxide to organic molecules. While this organic synthesis shapes genomes of heterotrophic microbiota globally, many corresponding structures remain elusive. We show that diatoms release a mannan polyelectrolyte selecting for bacteria with a specifically adapted enzymatic cascade. NMR spectroscopy, chromatography, automated glycan assembly and enzymatic dissection resolved the structure of a C6 sulfated α-1,3-mannan with exceptional simplicity for a sulfated polysaccharide from algae. Biochemical, physiological and structural analyses demonstrated that some bacteria can hydrolyze this mannan with a cascade of just four enzymes. Circumnavigation metagenome data revealed corresponding genes in Atlantic, Pacific, Southern and Indian Ocean surface waters. We show that this sulfated mannan may exert substantial selection pressure on marine microbiota around the globe.
Mechanobiochemical finite element model to analyze impact-loading-induced cell damage, subsequent proteoglycan loss, and anti-oxidative treatment effects in articular cartilage
Authors: Kosonen Joonas P. , Eskelinen Atte S.A. , Orozco Gustavo A. , Coleman Mitchell C. , Goetz Jessica E. , Anderson Donald D. , Grodzinsky Alan J. , Tanska Petri , Korhonen Rami K.
Published: July 2024

Joint trauma often leads to articular cartilage degeneration and post-traumatic osteoarthritis (PTOA). Pivotal determinants include trauma-induced excessive tissue strains that damage cartilage cells. As a downstream effect, these damaged cells can trigger cartilage degeneration via oxidative stress, cell death, and proteolytic tissue degeneration. N-acetylcysteine (NAC) has emerged as antioxidant capable of inhibiting oxidative stress, cell death, and cartilage degeneration post-impact. However, temporal effects of NAC are not fully understood and remain difficult to assess solely by physical experiments. Thus, we developed a computational framework to simulate a drop tower impact of cartilage with finite element analysis in ABAQUS, and model subsequent oxidative stress-related cell damage, and NAC treatment upon cartilage proteoglycan content in COMSOL Multiphysics, based on priorex vivoexperiments. Model results provide evidence that by inhibiting further cell damage by mechanically induced oxidative stress, immediate NAC treatment can reduce proteoglycan loss by mitigating cell death (loss of proteoglycan biosynthesis) and enzymatic proteoglycan depletion. Our simulations also indicated that delayed NAC treatment may not inhibit cartilage proteoglycan loss despite reduced cell death after impact. These results enhance understanding of temporal effects of impact-related cell damage and treatment that are critical for the development of effective treatments for PTOA. In the future, our modeling framework could increase understanding of time-dependent mechanisms of oxidative stress and downstream effects in injured cartilage and aid in developing better treatments to mitigate PTOA progression.

Author summary

Post-traumatic osteoarthritis is a debilitating disease which is often initiated by trauma and characterized by cartilage degeneration. The degeneration is partly driven by trauma-induced damage, including oxidative stress, to cartilage cells. Multiple drugs have been studied to counteract the cell damage, but it remains difficult to inhibit the disease progression since temporal effects of such treatments are not fully understood. Here, we developed a computational framework to study effects of antioxidant treatment in mechanically impacted cartilage and compared our computational simulations with previously published experiments. Our results showed that the high strain induced cell damage occurring in the mechanically impacted region could be mitigated by N-acetylcysteine treatment. This mechanism could partly explain reduced cartilage proteoglycan loss compared to untreated samples. Our modeling framework could help enhance development of treatments to better inhibit osteoarthritis progression.
GelMetrics: An algorithm for analyzing the dynamics of gel-like phase separated condensates
Authors: Granik Naor , Amit Roee
Published: July 2024

Cellular compartments and organelles are essential for the spatial organization of biological matter. Recently, membraneless organelles like paraspeckles, stress granules, and Cajal bodies have garnered significant scientific interest due to their lack of membrane boundaries and crucial cellular functions. These organelles self-assemble through phase separation, a process in which a homogeneous solution separates into distinct phases. The phases most commonly encountered in cells are liquids and gels. Various microscopy techniques exist to study these phase-separated compartments. However, these are often inadequate for investigating the dynamics of gel-like condensates, where molecular motion occurs over tens of minutes rather than seconds. Here, we introduce a method to quantitatively measure the dynamics of gel-like phase-separated organelles by tracking their fluorescence signals over extended durations. We demonstrate that our algorithm can identify biological activity amidst measurement noise and estimate biophysical parameters which can provide insights into the dynamic behavior of the condensates. We validated our approach on synthetic RNA-protein granules, demonstrating its applicability both in vitro and in vivo.
Mitochondrial genomes of threeMelampusspecies (Ellobiidae; Gastropoda) and a proposed mitochondrial control region for Euthyneura
Authors: Inäbnit Thomas , Tiedemann Ralph , Dennis Alice B.
Published: July 2024

Melampus bidentatuswas recently divided into three genetically divergent cryptic species:M. bidentatus, M. jaumeiandM. gundlachi. We have assembled and annotated a mitochondrial genome for each of these species. Comparisons with other taxa showed that these three species possess a gene order that is distinct from the conserved gene order found in the six (out of nine available) Ellobiid genera. Among the species with a derived gene order, mean nucleotide divergence over all genes was on average 1.57× higher than among mitogenomes with the conserved gene order. This suggests varying evolutionary rates of mitochondrial genes in this family. We also use comparisons among 130 mitochondrial genomes within Euthyneura to support the presence of a control region preceding the Isoleucin-tRNA, including in the novel genomes presented here.
Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes
Authors: Giusti V , Park J , Giusto E , Masatti L , Ramos-Gonzalez P , Iovino L , Sandre M , Emmi A , Kaur G , Coletto E , Calura E , Petrelli F , Porzionato A , De Caro R. , Cavaliere F , Chung WS , Civiero L
Published: July 2024

Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery recruited for the recognition of synapses is not fully clarified, especially in pathological conditions. Here, we investigated the phagocytic process through individual gene silencing using a druggable gene library. Our study demonstrates that astrocyte-mediated synapse engulfment is regulated by the Atypical chemokine receptor 3 (Ackr3). Mechanistically, we have shown that Ackr3 recognizes phosphatidylethanolamine (PE)-bound Cxcl12 at synaptic terminals both in vitro and in cell culture thus serving as a novel marker of synaptic dysfunction. Notably, both the receptor and its ligand are overexpressed in post-mortem AD human brains, and downregulation of the receptor in AD mouse models (5xFAD) significantly diminishes astrocyte-mediated synaptic elimination. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in the most common neurodegenerative disease.
TheAPOEisoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer’s disease
Authors: Murphy Kitty B. , Hu Di , Wolfs Leen , Mancuso Renzo , De Strooper Bart , Marzi Sarah J.
Published: July 2024

Microglia play a key role in the response to amyloid beta in Alzheimer’s disease (AD). In this context, a major transcriptional response of microglia is the upregulation ofAPOE, the strongest late-onset AD risk gene. Of its three isoforms,APOE2is thought to be protective, whileAPOE4increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia isolated from a xenotransplantation model of AD. We identified widespread transcriptomic and epigenomic differences which are dependent onAPOEgenotype, and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD inAPOE4carriers, while increased DNA-binding of the vitamin D receptor inAPOE2microglia may contribute to the isoform’s protective role.
Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila
Authors: Dong Pengzhen , Li Yue , Wang Yuying , Zhao Qiang , Lu Tianfeng , Chen Jian , Guo Tianyu , Ma Jun , Yang Bing , Wu Honggang , Huang Hai
Published: July 2024

Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the FGF mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.
Poor Self-Reported Sleep is Associated with Prolonged White Matter T2 Relaxation in Psychotic Disorders
Authors: Yesilkaya Haluk Umit , Chen Xi , Watford Lauren , McCoy Emma , Genc Ilgin , Du Fei , Ongur Dost , Yuksel Cagri
Published: July 2024

Background

Schizophrenia (SZ) and bipolar disorder (BD) are characterized by white matter (WM) abnormalities, however, their relationship with illness presentation is not clear. Sleep disturbances are common in both disorders, and recent evidence suggests that sleep plays a critical role in WM physiology. Therefore, it is plausible that sleep disturbances are associated with impaired WM integrity in these disorders. To test this hypothesis, we examined the association of self-reported sleep disturbances with WM transverse (T2) relaxation times in patients with SZ spectrum disorders and BD with psychotic features.

Methods

28 patients with psychosis (17 BD-I, with psychotic features and 11 SZ spectrum disorders) were included. Metabolite and water T2 relaxation times were measured in the anterior corona radiata at 4T. Sleep was evaluated using the Pittsburgh Sleep Quality Index.

Results

PSQI total score showed a moderate to strong positive correlation with water T2 (r = 0.64, p<0.001). Linear regressions showed that this association was specific to sleep disturbance but was not a byproduct of exacerbation in depressive, manic, or psychotic symptoms. In our exploratory analysis, sleep disturbance was correlated with free water percentage, suggesting that increased extracellular water may be a mechanism underlying the association of disturbed sleep and prolonged water T2 relaxation.

Conclusion

Our results highlight the connection between poor sleep and WM abnormalities in psychotic disorders. Future research using objective sleep measures and neuroimaging techniques suitable to probe free water is needed to further our insight into this relationship.
HarbouringStarships: The accumulation of large Horizontal Gene Transfers in Domesticated and Pathogenic Fungi
Authors: O’Donnell Samuel , Rezende Gabriela , Vernadet Jean-Philippe , Snirc Alodie , Ropars Jeanne
Published: July 2024

Human-related environments, including food and clinical settings, present microorganisms with atypical and challenging conditions that necessitate adaptation. Several cases of novel horizontally acquired genetic material associated with adaptive traits have been recently described, contained within giant transposons namedStarships.While a handful ofStarshipshave been identified in domesticated species, their abundance has not yet been systematically explored in human-associated fungi. Here, we investigated whetherStarshipshave shaped the genomes of two major genera of fungi occurring in food and clinical environments,AspergillusandPenicillium.Using seven independent domestication events, we found in all cases that the domesticated strains or species exhibited significantly greaterStarshipcontent compared with close relatives from non-human-related environments. We found a similar pattern in clinical contexts. Our findings have clear implications for agriculture, human health and the food industry as we implicateStarshipsas a widely recurrent mechanism of gene transfer aiding the rapid adaptation of fungi to novel environments.
kcnb1loss-of-function in zebrafish causes neurodevelopmental and epileptic disorders associated with GABA dysregulation
Authors: Robichon Lauralee , Bar Claire , Marian Anca , Lehmann Lisa , Renault Solène , Kabashi Edor , Ciura Sorana , Nabbout Rima
Published: July 2024

KEY POINTS

kcnb1 is expressed in distinct cell subtypes and various regions of the central nervous system in zebrafish

Brain anatomy and neuronal circuits are not disrupted in thekcnb1loss-of-function zebrafish model

Loss ofkcnb1leads to altered behavior phenotype, light and sound-induced locomotor impairments

kcnb1knock-out zebrafish exhibit increased locomotor sensitivity to PTZ and elevated expression of epileptogenesis-related genes

kcnb1-/-larvae show spontaneous and provoked epileptiform-like electrographic activity associated with disrupted GABA regulation

Objective

KCNB1encodes an α-subunit of the delayed-rectifier voltage-dependent potassium channel Kv2.1.De novopathogenic variants ofKCNB1have been linked to developmental and epileptic encephalopathies (DEE), diagnosed in early childhood and sharing limited treatment options. Loss-of-function (LOF) ofKCNB1with dominant negative effects has been proposed as the pathogenic mechanism in these disorders. Here, we aim to characterize a knock-out (KO) zebrafish line targetingkcnb1 (kcnb1+/-andkcnb1-/-) for investigating DEEs.

Methods

This study presents the phenotypic analysis of akcnb1knock-out zebrafish model, obtained by CRISPR/Cas9 mutagenesis. Through a combination of immunohistochemistry, behavioral assays, electrophysiological recordings, and neurotransmitter quantifications, we have characterized the expression, function, and impact of thiskcnb1LOF model at early stages of development.

Results

In wild-type larval zebrafish, kcnb1 was found in various regions of the central nervous system and in diverse cell subtypes including neurons, oligodendrocytes and microglial cells. Bothkcnb1+/-andkcnb1-/-zebrafish displayed impaired swimming behavior and “epilepsy-like” features that persisted through embryonic and larval development, with variable severity. When exposed to the chemoconvulsant pentylenetetrazol (PTZ), both mutant models showed elevated locomotor activity. In addition, PTZ-exposedkcnb1-/-larvae exhibited higher bdnf mRNA expression and activated c-Fos positive neurons in the telencephalon. This same model presents spontaneous and provoked epileptiform-like electrographic activity associated with disrupted GABA regulation. In this KO model, neuronal circuit organization remained unaffected.

Significance

We conclude thatkcnb1knock-out in zebrafish leads to early-onset phenotypic features reminiscent of DEEs, affecting neuronal functions and primarily inhibitory pathways in developing embryonic and larval brains. This study highlights the relevance of this model for investigating developmental neuronal signaling pathways inKCNB1-related DEEs.
Bacterial vaginosis-driven changes in cervicovaginal immunity that expand the immunological hypothesis for increased HIV susceptibility
Authors: MacLean Finn , Tsegaye Adino Tesfahun , Graham Jessica B. , Swarts Jessica L. , Vick Sarah C. , Potchen Nicole , Talavera Irene Cruz , Warrier Lakshmi , Dubrulle Julien , Schroeder Lena K. , Saito Ayumi , Thomas Katherine K. , Mack Matthias , Sabo Michelle C. , Chohan Bhavna H. , Ngure Kenneth , Mugo Nelly , Lingappa Jairam R. , Lund Jennifer M. ,   the Kinga Study Team
Published: July 2024

Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually-acquired HIV, yet the immunological mechanisms underlying this association are not well understood. To investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples. High-parameter flow cytometry revealed an increased frequency of cervical conventional CD4+T cells (Tconv) expressing CCR5. However, we found no difference in number of CD3+CD4+CCR5+cells in the CX or VT of BV+ vs BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV have an increased frequency of dysfunctional CX and VT CD39+Tconv and CX tissue-resident CD69+CD103+Tconv, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations. Our comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV including increased HIV susceptibility.
Working smarter, not harder: silencingLAZY1inPrunus domesticacauses outward, wandering branch orientations with commercial and ornamental applications.
Authors: Kohler Andrea R , Hollender Courtney A , Raines Doug , Demuth Mark , Dardick Christopher
Published: July 2024

Controlling branch orientation is a central challenge in tree fruit production, as it impacts factors as diverse as light interception, pesticide use, fruit quality, yield, and labor costs. In an attempt to modify branch orientation, growers use many different management practices, including tying branches to wires or applying growth regulator sprays. However, these practices are often costly and ineffective. In contrast, altering the expression of genes that control branch angles and orientations would permanently optimize tree architecture with minimal management inputs. One gene implicated in branch angle control isLAZY1, which promotes upward branch growth in response to gravity. We used an antisense vector to silenceLAZY1in plum (Prunus domestica). We found that theseLAZY1-silencedlines have significantly increased branch and petiole angles. In addition, they lack apical dominance and display a wandering or weeping branch trajectory. Given these phenotypes, we assessed whether the strength or stiffness of the branches were compromised. No differences were observed in new growth. While the wood of first-yearLAZY1-silenced branches was more flexible and weaker than the control, the strength and stiffness of the branches were not decreased because branch diameter is increased. Finally, we evaluated the utility ofLAZY1-silenced trees for two planar orchard systems, training them in super slender axe and espalier.LAZY1-silenced trees had more open canopies and were easier to constrain to the trellis height. This work illustrates the power of manipulating gene expression to optimize plant architecture for horticultural applications.