bluuebunny/crossref_metadata_2025 huggingface dataset:
Chitinophaga pollutisoli sp. nov., isolated from contaminated sediment
Authors: Lee Dae Seung , Lee Jae Kyeong , Han Dong Min , Baek Ju Hye , Jeon Che Ok
Published: July 2024

A Gram-stain-negative, yellow-pigmented, and facultatively aerobic bacterium, designated strain GPA1T, was isolated from plastic waste landfill soil in the Republic of Korea. The cells were non-motile short rods exhibiting oxidase-negative and catalase-positive activities. Growth was observed at 15–40 °C (optimum, 30 °C), at pH 6.0–9.0 (optimum, pH 7.0–8.0) and in the presence of 0–2.5 % (w/v) NaCl (optimum, 0 %). Menaquinone-7 was the sole respiratory quinone, and iso-C15 : 0, C16 : 1
 ω5c, and iso-C17 : 0 3-OH were the major cellular fatty acids (>10 % of the total fatty acids). Phosphatidylethanolamine was identified as a major polar lipid. Phylogenetic analyses based on 16S rRNA gene sequences and 120 concatenated marker protein sequences revealed that strain GPA1T formed a distinct lineage within the genus Chitinophaga. The genome of strain GPA1T was 6078 kb in size with 53.8 mol% G+C content. Strain GPA1T exhibited the highest similarity to Chitinophaga rhizosphaerae T16R-86T, with a 98.6 % 16S rRNA gene sequence similarity, but their average nucleotide identity and digital DNA–DNA hybridization values were 82.5 and 25.9 %, respectively. Based on its phenotypic, chemotaxonomic, and phylogenetic characteristics, strain GPA1T represents a novel species of the genus Chitinophaga, for which the name Chitinophaga pollutisoli sp. nov. is proposed. The type strain is GPA1T (=KACC 23415T=JCM 36644T).
Molecular characterization of Pseudomonas aeruginosa from diabetic foot infections in Tunisia
Authors: Arfaoui Ameni , Rojo-Bezares Beatriz , Fethi Meha , López Maria , Toledano Paula , Sayem Noureddine , Ben Khelifa Melki Salma , Ouzari Hadda-Imene , Klibi Naouel , Sáenz Yolanda
Published: July 2024

Background.
Pseudomonas aeruginosa is an invasive organism that frequently causes severe tissue damage in diabetic foot ulcers.

Gap statement. The characterisation of P. aeruginosa strains isolated from diabetic foot infections has not been carried out in Tunisia.

Purpose. The aim was to determine the prevalence of P. aeruginosa isolated from patients with diabetic foot infections (DFIs) in Tunisia and to characterize their resistance, virulence and molecular typing.

Methods. Patients with DFIs admitted to the diabetes department of the International Hospital Centre of Tunisia, from September 2019 to April 2021, were included in this prospective study. P. aeruginosa were obtained from the wound swabs, aspiration and soft tissue biopsies during routine clinical care and were confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Antimicrobial susceptibility testing, serotyping, integron and OprD characterization, virulence, biofilm production, pigment quantification, elastase activity and molecular typing were analysed in all recovered P. aeruginosa isolates by phenotypic tests, specific PCRs, sequencing, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing.

Results. Sixteen P. aeruginosa isolates (16.3 %) were recovered from 98 samples of 78 diabetic patients and were classified into 6 serotypes (O:11 the most frequent), 11 different PFGE patterns and 10 sequence types (three of them new ones). The high-risk clone ST235 was found in two isolates. The highest resistance percentages were observed to netilmicin (69 %) and cefepime (43.8 %). Four multidrug-resistant (MDR) isolates (25 %) were detected, three of them being carbapenem-resistant. The ST235-MDR strain harboured the In51 class 1 integron (intI1 +aadA6+orfD+qacED1-sul1). According to the detection of 14 genes involved in virulence or quorum sensing, 5 virulotypes were observed, including 5 exoU-positive, 9 exoS-positive and 2 exoU/exoS-positive strains. The lasR gene was truncated by ISPpu21 insertion sequence in one isolate, and a deletion of 64 bp in the rhlR gene was detected in the ST235-MDR strain. Low biofilm, pyoverdine and elastase production were detected in all P. aeruginosa; however, the lasR-truncated strain showed a chronic infection phenotype characterized by loss of serotype-specific antigenicity, high production of phenazines and high biofilm formation.

Conclusions. Our study demonstrated for the first time the prevalence and the molecular characterization of P. aeruginosa strains from DFIs in Tunisia, showing a high genetic diversity, moderate antimicrobial resistance, but a high number of virulence-related traits, highlighting their pathological importance.
Dengue virus (DV) non-cross-reactive Omicron wave COVID-19 serums enhanced DV3 infectivity in vitro
Authors: Sarker Supratim , Dutta Chiroshri , Mallick Abinash , Das Sayantan , Das Chowdhury Chandrika , De Abhishek , Gorai Surajit , Biswas Subhajit
Published: July 2024

Introduction. In India, the SARS-CoV-2 Delta wave (2020–2021) faded away with the advent of the Omicron variants (2021–present). Dengue incidences were observed to be less in Southeast Asia during the active years of the pandemic (2020–2021). However, dengue virus type 3 (DV3) cases were increasingly reported in this region (including India) concurrent with the progression of the Omicron waves since 2022.

Hypothesis. What could be the reason(s) behind this unusual DV3 surge after an overall dip in dengue incidences in many parts of Southeast Asia?

Aim. We, therefore, investigated the current state of cross-reactivity of prevalent (Omicron era) SARS-CoV-2 serums with different DV serotypes and evaluated the impact of such serums on DV neutralization in cell culture.

Methodology. Fifty-five COVID-19 serum samples (January–September 2022) and three pre-pandemic archived serum samples from apparently healthy individuals were tested for DV or SARS-CoV-2 IgM/IgG using the lateral flow immunoassays. DV1–4 virus neutralization tests (VNTs) were done with the SARS-CoV-2 antibody (Ab)-positive serums in Huh7 cells. DV3 envelope (env) gene was PCR amplified and sequenced for three archived DV isolates, one from 2017 and two from 2021.

Results. SARS-CoV-2 Ab-positive samples constituted 74.5 % of the serums. Of these, 41.5 % were DV cross-reactive and 58.5 % were not. The DV cross-reactive serums neutralized all DV serotypes (DV1–4), as per previous results and this study. The DV non-cross-reactive serums (58.5 %) also cross-neutralized DV1, 2 and 4 but increased DV3 infectivity by means of antibody-dependent enhancement of infection as evident from significantly higher DV3 titres in VNT compared to control serums. The DV3 envelope was identical among the three isolates, including isolate 1 used in VNTs. Our results suggest that DV cross-reactivity of SARS-CoV-2 serums diminished with the shift from Delta to Omicron prevalence. Such COVID-19 serums (DV non-cross-reactive) might have played a major role in causing DV3 surge during the Omicron waves.

Conclusion. Patients suspected of dengue or COVID-19 should be subjected to virus/antigen tests and serological tests for both the diseases for definitive diagnosis, prognosis and disease management.
The human cortical motor map in post-stroke hemiparesis in the presence of treatment-related clinically important recovery
Authors: Kitago Tomoko , Silverstein Joshua , Gerber Michael B. , Thomas Charlene , Gerber Linda M. , Thickbroom Gary W. , Edwards Dylan J.
Published: July 2024

Objectives

To determine if intervention-related clinical improvement in post-stroke hemiparesis is associated with enlarged primary motor cortex representation.

Methods

Data were analyzed from a single site subset of the NICHE trial. Transcranial magnetic stimulation (TMS) motor mapping was performed in 23 participants (3-12 months post-stroke, 10 female, 40-88 yrs, baseline Fugl-Meyer Upper Extremity (FM-UE) range 13-58) before and after intervention. TMS motor maps were acquired for the extensor digitorum communis muscle (EDC) bilaterally, at 110% resting motor threshold (RMT).

Results

Improvement on the primary outcome measure (FM-UE) was statistically and clinically significant (mean pre= 38(±15), post= 45(±16); p <0.001; n=23). Significant improvement was also observed on secondary impairment and activity outcome measures (p<0.05). Ipsilesional hemisphere RMT and map volume (MV) remained unchanged (RMT pre = 42(±13), post = 41(±11), p=0.60; MV pre =77.98(±71.37) mV*mm2, post =109.54(±139.06) mV*mm2, p=0.36). The magnitude of clinical benefit was unrelated to difference in map characteristics from pre to post (Spearman’s rho= 0.06, p=0.79).

Conclusions

Intervention-related clinical improvement of the upper limb 3-12 months following stroke, was not associated with change in motor cortex excitability or increase in motor maps. Clinical improvements may not solely rely on consistent changes in the cortical motor representation.
The Impact of Omega-3 Fatty Acids on SM23-33 Abundance in Stool and Children with Obesity: A Mendelian Randomization Analysis
Authors: Zhang Min
Published: July 2024

Background

Children with obesity may be associated with gut microbiota and omega-3 fatty acids. However, the understanding of children with obesity, gut microbiota, and omega-3 fatty acids remains unclear.

Objectives

This study aimed to examine the relationships between omega-3 fatty acids, SM23-33 abundance in stool, and children with obesity.

Methods

We conducted LDSC to assess the genetic correlation between SM23-33 abundance in stool, Omega-3 fatty acids, and children with obesity. Subsequently, bidirectional MR analyses were performed to investigate the causal connections between SM23-33 abundance in stool and children with obesity, while a two-step MR analysis was employed to identify any potential mediation by Omega-3 fatty acids in this relationship. All statistical analyses were carried out using R software, and the STROBE-MR checklist was followed for reporting MR studies.

Results

There was no significant genetic correlation among SM23-33 abundance in stool, Omega-3 fatty acids, and children with obesity (rg_p>0.05). MR analysis identified SM23-33 abundance in stool causally associated with children with obesity (OR=0.747, 95%CI: 0.584-0.957,P=0.021). Furthermore, there was no strong evidence that genetically predicted children with obesity affected SM23-33 abundance in stool. Further, two-step MR analysis found the associations between SM23-33 abundance in stool and children with obesity were mediated by Docosahexaenoic Acid (DHA) of Omega-3 fatty acids with proportions of 3.56% (95%CI: 3.43%, 3.69.0%).

Conclusions

The present study provides evidence supporting the causal relationships between SM23-33 Abundance in Stool and Children with Obesity, with a potential effect mediated by Docosahexaenoic Acid (DHA).
Modulating the Human Gut Microbiome and Health Markers through Kombucha Consumption: A Controlled Clinical Study
Authors: Ecklu-Mensah Gertrude , Miller Rachel , Maseng Maria Gjerstad , Hawes Vienna , Hinz Denise , Kim Cheryl , Gilbert Jack
Published: July 2024

Fermented foods are surging in popularity globally due to their links to metabolic health and the gut microbiome. However, direct clinical evidence for the health claims is lacking. Here, we describe an eight-week clinical trial that explored the effects of a kombucha supplement in healthy individuals consuming a Western diet, randomized into the kombucha (n= 16) or control (n= 8) group. We collected longitudinal stool and blood samples to profile the human microbiome and inflammation markers. Paired analysis between baseline and end of intervention time points within kombucha or control groups revealed increases in fasting insulin and in HOMA-IR in the kombucha group whereas reductions in HDL cholesterol were associated with the control group. Shotgun metagenomic analysis revealed the relative abundance ofWeizmannia, a kombucha-associated probiotic to be overrepresented in consumers at the end of the intervention. Short-term kombucha intervention induced modest impacts on human gut microbiome composition and biochemical parameters.

Highlights

There is a global rise in popularity of fermented foods due to their links to metabolic health. However, empirical evidence supporting the health conferring benefits is lacking.

This eight-week randomized controlled clinical trial tested the effect of kombucha on gut microbiome and inflammation in healthy participants consuming a Western diet.

Biochemical indicators and inflammation markers were not different between the control and intervention groups at the end of the intervention.

Kombucha-associated probiotic,Weizmanniaand short chain fatty acids synthesizing microbes were enriched in consumers after 4 weeks of kombucha intervention.

Graphical abstract
Structure of a novel α-synuclein filament fold from multiple system atrophy
Authors: Yan Nicholas L. , Candido Francisco , Tse Eric , Melo Arthur A. , Prusiner Stanley B. , Mordes Daniel A. , Southworth Daniel R. , Paras Nick A. , Merz Gregory E.
Published: July 2024

Multiple system atrophy (MSA) is a synucleinopathy, a group of related diseases characterized by the accumulation of α-synuclein aggregates in the brain. In MSA, these aggregates form glial cytoplasmic inclusions, which contain abundant cross-β amyloid filaments. Structures of α-synuclein filaments isolated from MSA patient tissue were determined by cryo–electron microscopy (cryo-EM), revealing three discrete folds that are distinct from α-synuclein filaments associated with other synucleinopathies. Here, we use cryo-EM classification methods to characterize filaments from one individual with MSA and identify a novel, low-populated MSA filament fold (designated Type I2) in addition to a predominant class comprising MSA Type II2. The 3.3-Å resolution structure of the Type I2filament reveals a fold consisting of two asymmetric protofilaments. One is identical to a previously solved Type I protofilament, while the second adopts a novel fold that is chimeric between two previously reported Type I and II protofilaments. These results further define disease-specific folds of α-synuclein filaments that develop in MSA and have implications for the design of therapeutic and diagnostic molecules that target disease.
Wolbachiaincompatible insect technique program optimization over large spatial scales using a process-based model of mosquito metapopulation dynamics
Authors: Lim Preston , Cook Alex R , Bansal Somya , Chow Jo Yi , Lim Jue Tao
Published: July 2024

Background

Wolbachiaincompatible insect technique (IIT) programs have been shown in field trials to be highly effective in suppressing populations of mosquitoes that carry diseases such as dengue, chikungunya and Zika. However, the frequent and repeated release ofWolbachia-infected male mosquitoes makes such programs resource-intensive. While the need for optimization is recognized, potential strategies to optimize releases and reduce resource utilization have not been fully explored.

Methods

We developed a process-based model to study the spatial-temporal metapopulation dynamics of mosquitoes in aWolbachiaIIT program, which explicitly incorporates climatic influence in mosquito life-history traits. We then used the model to simulate various scale-down and redistribution strategies to optimize the existing program in Singapore. Specifically, the model was used to study the trade-offs between the intervention efficacy outcomes and resource requirements of various release program strategies, such as the total number of release events and the number of mosquitoes released.

Results

We found that scaling down releases in existing sites from twice a week to only once a week yielded minimal changes in suppression efficacy (from 91% to 85%), while requiring 45% fewer mosquitoes and release events. Additionally, redistributing mosquitoes from already suppressed areas and releasing them in new areas once a week led to a greater total suppressive efficacy (88% compared to 65%) while also yielding a 16% and 14% reduction in the number of mosquitoes and release events required respectively.

Conclusions

Both scale-down and redistribution strategies can be implemented to significantly reduce program resource requirements without compromising the suppressive efficacy of IIT. These findings will inform planners on ways to optimize existing and future IIT programs, potentially allowing for the wider adoption of this method for mosquito-borne disease control.
Restoration of Type 17 immune signaling is not sufficient for protection during influenza-associated pulmonary aspergillosis
Authors: AHMAD AIJAZ , Singh Ravineel Bhan , Nickolich Kara , Pilewski Matthew , Ngeow Caden , Frempong-Manso Kwame , Robinson Keven Mara
Published: July 2024

Influenza-associated pulmonary aspergillosis (IAPA) is a severe complication of influenza infection that occurs in critically ill patients and results in higher mortality compared to influenza infection alone. Interleukin-17 (IL-17) and the Type 17 immune signaling pathway cytokine family are recognized for their pivotal role in fostering protective immunity against various pathogens. In this study, we investigate the role of IL-17 and Type 17 immune signaling components during IAPA. Wild-type mice were challenged with influenza A H1N1 (Flu) and then exposed to Aspergillus fumigatus ATCC42202 resting conidia on day 6 post-influenza infection, followed by the quantification of cytokines and chemokines at 48 hours post-fungal infection. Gene and protein expression levels revealed that IL-17 and Type 17 immune cytokines and antimicrobial peptides are downregulated during IAPA compared to mice singularly infected solely with A. fumigatus. Restoration of Type 17 immunity was not sufficient to provide protection against the increased fungal burden observed during IAPA. These findings contrast those observed during post-influenza bacterial super-infection, in which restoration of Type 17 immune signaling protects against exacerbation seen during super-infection. Our study highlights the need for future studies to understand the immune mechanisms that increase susceptibility to fungal infection.
Building a small brain with a simple stochastic generative model
Authors: Richter Oren , Schneidman Elad
Published: July 2024

The architectures of biological neural networks result from developmental processes shaped by genetically encoded rules, biophysical constraints, stochasticity, and learning. Understanding these processes is crucial for comprehending neural circuits’ structure and function. The ability to reconstruct neural circuits, and even entire nervous systems, at the neuron and synapse level, facilitates the study of the design principles of neural systems and their developmental plan. Here, we investigate the developing connectome ofC. elegansusing statistical generative models based on simple biological features: neuronal cell type, neuron birth time, cell body distance, reciprocity, and synaptic pruning. Our models accurately predict synapse existence, degree profiles of individual neurons, and statistics of small network motifs. Importantly, these models require a surprisingly small number of neuronal cell types, which we infer and characterize. We further show that to replicate the experimentally-observed developmental path, multiple developmental epochs are necessary. Validation of our model’s predictions of the synaptic connections using multiple reconstructions of adult worms suggests that our model identified the fundamental “backbone” of the connectivity graph. The accuracy of the generative statistical models we use here offers a general framework for studying how connectomes develop and the underlying principles of their design.
Opto-Myomatrix: μLED integrated microelectrode arrays for optogenetic activation and electrical recording in muscle tissue
Authors: Lu Jiaao , Zia Muneeb , Baig Danish A. , Yan Geyu , Kim Jeong Jun , Nagapudi Kailash , Anschutz Philip , Oh Shane , O’Connor Daniel , Sober Samuel J. , Bakir Muhannad S.
Published: July 2024

Optogenetics is a valuable and widely-used technique that allows precise perturbations of selected groups of cells with high temporal and spatial resolution by using optical systems and genetic engineering technologies. Although numerous studies have been done to investigate optogenetic tools used in the brain and central nervous system (CNS), there has been limited progress in developing similar tools for optogenetic muscle stimulation. This paper introduces Opto-Myomatrix, a novel optogenetic tool designed for precise muscle fiber control and high-resolution recording. Based on a flexible and biocompatible polymer substrate, the device incorporates an integrated µLED that delivers light at 465 nm for optogenetic stimulation and 32 low-impedance electrodes for electromyography (EMG) recording. A reflector is also added to the device to improve optical power output by nearly 100% in the direction of interest. Compared to uncoated electrical contacts, the PEDOT:PSS-coated recording electrodes possess an average impedance that is 85% lower, ensuring high signal-to-noise EMG acquisition. To evaluate the potential risk of thermal tissue damage, we measured and simulated the heat dissipation characteristics of the µLED. This analysis aimed to ensure that the maximum temperature change remains within a safe range. The Opto-Myomatrix device was implanted in transgenetic mice and successfully stimulated targeted jaw muscles, inducing movement while simultaneously capturing EMG signals.
Metabolic Profiles of Encapsulated Chondrocytes Exposed to Short-Term Simulated Microgravity
Authors: Bergstrom Annika R. , Glimm Matthew G. , Houske Eden A. , Cooper Gwendolyn , Viles Ethan , Chapman Marrin , Bourekis Katherine , Welhaven Hope D. , Brahmachary Priyanka P. , Hahn Alyssa K. , June Ronald K.
Published: July 2024

The mechanism by which chondrocytes respond to reduced mechanical loading environments and the subsequent risk of developing osteoarthritis remains unclear. This is of particular concern for astronauts. In space the reduced joint loading forces during prolonged microgravity (10-6g) exposure could lead to osteoarthritis (OA), compromising quality of life post-spaceflight. In this study, we encapsulated human chondrocytes in an agarose gel of similar stiffness to the pericellular matrix to mimic the cartilage microenvironment. We then exposed agarose-chondrocyte constructs to simulated microgravity (SM) using a rotating wall vessel (RWV) bioreactor to better assess the cartilage health risks associated with spaceflight. Global metabolomic profiling detected a total of 1205 metabolite features across all samples, with 497 significant metabolite features identified by ANOVA (FDR-corrected p-value < 0.05). Specific metabolic shifts detected in response to SM exposure resulted in clusters of co-regulated metabolites, as well as key metabolites identified by variable importance in projection scores. Microgravity-induced metabolic shifts in gel constructs and media were indicative of protein synthesis, energy metabolism, nucleotide metabolism, and oxidative catabolism. The microgravity associated-metabolic shifts were consistent with early osteoarthritic metabolomic profiles in human synovial fluid, which suggests that even short-term exposure to microgravity (or other reduced mechanical loading environments) may lead to the development of OA.
Phenotypically wild barley shows evidence of introgression from cultivated barley
Authors: Liu Chaochih , Lei Li , Shao Mingqin , Franckowiak Jerome D. , Pacheco Jacob B. , Scott Jeness C. , Gavin Ryan T. , Roy Joy K. , Sallam Ahmad H. , Steffenson Brian J. , Morrell Peter L.
Published: July 2024

Plant conservation hinges on preserving biodiversity, which is crucial for long-term adaptation. Multiple studies have reported genetic evidence of crop-to-wild introgression in phenotypically wild accessions of wild barley (Hordeum vulgaressp.spontaneum). We examined 318 Wild Barley Diversity Collection (WBDC) accessions for evidence of introgression from cultivated barley. Using SNP genotype and exome capture data, we performed local ancestry inference between the 318 WBDC accessions and cultivated barley to identify genomic regions with evidence of introgression. Using the genomic intervals for well-characterized genes involved in domestication and improvement, we examined the evidence for introgression at genomic regions potentially important for maintaining a wild phenotype. Our analysis revealed that nearly 16% (48 of 318) of WBDC accessions showed evidence of introgression from cultivated barley, and up to 16.6% of the genome has been introgressed. All accessions identified as introgressed based on domestication-related phenotypes show clear genetic evidence of introgression. The size of runs of identity by state and local ancestry inference suggests that most introgression did not occur recently. This study suggests a long history of genetic exchange between wild and cultivated barley, highlighting the potential for introgression to influence the genetic makeup and future adaptation of wild populations, with implications for plant conservation strategies.
Epilepsy protein myoclonin1 interacts with inositol 1,4,5–trisphosphate (IP3) receptor and reduces Ca2+store in endoplasmic reticulum
Authors: Suzuki Toshimitsu , Aguan Kripamoy , Mizuno Hideaki , Nakamura Takeshi , Inoue Ikuyo , Mikoshiba Katsuhiko , Miyawaki Atsushi , Yamakawa Kazuhiro
Published: July 2024

Mutations ofEFHC1gene have been identified in patients with epilepsies including juvenile myoclonic epilepsy (JME), and mice withEfhc1deficiency exhibit epileptic phenotypes. Myoclonin1 protein encoded byEFHC1is not expressed in neurons but in cells with motile cilia including those of choroid plexus and ependymal cells which form an epithelial layer lining brain ventricles. Detailed molecular basis of epilepsies caused byEFHC1mutations, however, remain unclear. Here we report that myoclonin1 is well co–expressed with inositol 1,4,5–trisphosphate receptor type 1 (IP3R1) at choroid plexus and ependymal cells and these two proteins bind each other. Endoplasmic reticulum (ER) ofEfhc1–deficient mouse (Efhc1-/–) cells contains larger levels of calcium ions (Ca2+) than that of wild–type (WT) mice, and IP3–induced Ca2+release (IICR) from ER is higher inEfhc1-/–cells than that of WT. Furthermore, myoclonin1 revealed to interact with PRKCSH, also known as a protein kinase C substrate 80K–H which interacts with IP3R1. Myoclonin1 further binds to IP3R2 and IP3R3. Thus, our results indicate that myoclonin1 modulates ER–Ca2+homeostasis through interactions with IP3Rs and PRKCSH, and suggest that myoclonin1 dysfunctions cause impaired intracellular Ca2+mobilization. It’s relevance to the epileptic phenotypes of patients withEFHC1mutations is now of interest.
Estimates of the eligible population for Australia’s targeted National Lung Cancer Screening Program, 2025-2030
Authors: Wade Stephen , Ngo Preston , He Yue , Caruana Michael , Steinberg Julia , Luo Qingwei , David Michael , McWilliams Annette , Fong Kwun M , Canfell Karen , Weber Marianne
Published: July 2024

Australia’s National Lung Cancer Screening Program will commence in July 2025, targeted at individuals aged 50-70 years with a 30 pack-year smoking history, who either currently smoke or have quit within the last 10 years. We forecasted the number of screening-eligible individuals over the first 5 years of the program using data from the 2019 National Drug Strategy Household Survey, and the 2022 Australian Bureau of Statistics population projections. Multiple imputation integrated with predictive modelling of future or unmeasured smoking characteristics was used to address missing data and simultaneously, to project individuals’ smoking histories to 2030. In 2025, 930,500 (95% prediction interval 852,200-1,019,000) individuals were estimated to be eligible, with the number meeting the criteria declining slightly over the years 2025-2030 in all Australian jurisdictions. Overall, 26-30% of those eligible will have quit smoking, and 70-74% will currently smoke. These estimates can be used in resource planning and as an indicative denominator to track participation rates for the program over time.
Integrated analysis of high-throughput sequencing-based lncRNA-mediated ceRNA network in Hepatic Alveolar Echinococcosis
Authors: Liu Zhen , Shang Chang-zhen , Wang Jin-peng , Gai Zhi-gang , Ma Fu-cai , Xia Pan , Wang Yan , Yang Xiao , Zhu Hai-hong
Published: July 2024

Background

Numerous studies have indicated that long non-coding RNAs (lncRNAs) can modulate the expression of target gene mRNAs by adsorbing microRNAs (miRNAs). The lncRNA–miRNA–mRNA ceRNA network has been theorized to play an indispensable role in many types of tumors, and has been garnering increasing attention. However, the role of the lncRNA-associated ceRNA regulatory network in Hepatic Alveolar Echinococcosis (HAE) remains unclear and requires further exploration.

Methods

In this study, high-throughput sequencing was performed on lesion tissues and adjacent tissues from three patients with Hepatic Alveolar Echinococcosis (HAE) to identify differentially expressed RNAs. We utilized Cytoscape (version 3.10.1) to construct the lncRNA-miRNA-mRNA ceRNA network based on the interactions from the miRcode, miRTarBase, miRDB, and TargetScan databases, and identified hub lncRNAs from within the ceRNA network. Through the use of the “clusterProfiler” package in R, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations for the DEGs (Differentially Expressed Genes) within the ceRNA network. Concurrently, we utilized these DEGs to construct a protein-protein interaction network (PPI). Finally, an analysis was conducted on the PCBP1-AS1-miR-20b-5p/CAPRIN2 axis within the ceRNA network.

Results

In HAE, a total of 979 differentially expressed lncRNAs (DELncRNAs) and 870 differentially expressed mRNAs (DEmRNAs) were identified. An HAE-specific ceRNA network comprising 11 lncRNAs, 21 miRNAs, and 56 mRNAs was established, and analysis of this network led to the construction of a sub-network associated with hub lncRNAs. GO and KEGG pathway analyses indicated that the HAE-specific ceRNA network is related to molecular functions and pathways associated with cancer. Subsequent experiments using qPCR and dual-luciferase assays validated the interactions between PCBP1-AS1 and miR-20b-5p, as well as between miR-20b-5p and CAPRIN2. Analysis of the target gene in relation to clinical characteristics of HAE patients suggested that the PCBP1-AS1-miR-20b-5p/CAPRIN2 axis may influence the development of HAE.

Conclusion

In this study, we described the gene regulation within the lncRNA-miRNA-mRNA ceRNA network during the development of Hepatic Alveolar Echinococcosis (HAE), which contributes to a deeper exploration of the molecular mechanisms underlying HAE. Additionally, we discovered that PCBP1-AS1 may regulate the expression of CAPRIN2 by adsorbing miR-20b-5p, affecting the onset and progression of HAE. PCBP1-AS1 could potentially serve as a useful target for the diagnosis and treatment of HAE.
Discrepancies in readouts between Infinium MethylationEPIC v2.0 and v1.0 reflected in DNA methylation-based tools: implications and considerations for human population epigenetic studies
Authors: Zhuang Beryl C. , Jude Marcia Smiti , Konwar Chaini , Yusupov Natan , Ryan Calen P. , Engelbrecht Hannah-Ruth , Whitehead Joanne , Halberstam Alexandra A. , MacIsaac Julia L. , Dever Kristy , Tran Toan Khanh , Korinek Kim , Zimmer Zachary , Lee Nanette R. , McDade Thomas W. , Kuzawa Christopher W. , Huffman Kim M. , Belsky Daniel W. , Binder Elisabeth B. , Czamara Darina , Korthauer Keegan , Kobor Michael S.
Published: July 2024

Background

The recently launched DNA methylation profiling platform, Illumina MethylationEPIC BeadChip Infinium microarray v2.0 (EPICv2), is highly correlated with measurements obtained from its predecessor MethylationEPIC BeadChip Infinium microarray v1.0 (EPICv1). However, the concordance between the two versions in the context of DNA methylation-based tools, including cell type deconvolution algorithms, epigenetic clocks, and inflammation and lifestyle biomarkers has not yet been investigated. To address this, we profiled DNA methylation on both EPIC versions using matched venous blood samples from individuals spanning early to late adulthood across four cohorts.

Findings

Within each cohort, samples primarily clustered by the EPIC version they were measured on. High concordance between EPIC versions at the array level, but variable concordance at the individual probe level was noted. Significant differences between versions in estimates from DNA methylation-based tools were observed, irrespective of the normalization method, with some nuanced differences across cohorts and tools. Adjusting for EPIC version or calculating estimates separately for each version largely mitigated these version-specific discordances.

Conclusions

Our work illustrates the importance of accounting for EPIC version differences in research scenarios, especially in meta-analyses and longitudinal studies, when samples profiled across different versions are harmonized. Alongside DNA methylation-based tools, our observations also have implications in interpretation of epigenome-wide association studies (EWAS) findings, when results obtained from one version are compared to another, particularly for probes that are poorly concordant between versions.
Differential Aging Effects on Implicit and Explicit Sensorimotor Learning
Authors: Cisneros Elizabeth , Karny Sheer , Ivry Richard B. , Tsay Jonathan S.
Published: July 2024

Deterioration in motor control is a hallmark of aging, significantly contributing to a decline in quality of life. More controversial is the question of whether and how aging impacts sensorimotor learning. We hypothesized that the inconsistent picture observed in the current literature can be attributed to at least two factors. First, aging studies tend to be underpowered. Second, the learning assays used in these experiments tend to reflect, to varying degrees, the operation of multiple learning processes, making it difficult to make inferences across studies. We took a two-pronged approach to address these issues. We first performed a meta-analysis of the sensorimotor adaptation literature focusing on outcome measures that provide estimates of explicit and implicit components of adaptation. We then conducted two well-powered experiments to re-examine the effect of aging on sensorimotor adaptation, using behavioral tasks designed to isolate explicit and implicit processes. Convergently, both approaches revealed a striking dissociation: Older individuals exhibited a marked impairment in their ability to discover an explicit strategy to counteract a visuomotor perturbation. However, they exhibited enhanced implicit recalibration. We hypothesize that the effect of aging on explicit learning reflects an age-related decline in reasoning and problem solving, and the effect of aging on implicit learning reflects age-related changes in multisensory integration. Taken together, these findings deepen our understanding of the impact of aging on sensorimotor learning.
Large shifts in diatom and dinoflagellate biomass in the North Atlantic over six decades
Authors: Mutshinda Crispin M. , Finkel Zoe V. , Irwin Andrew J.
Published: July 2024

The North Atlantic Ocean has large seasonal blooms rich in diatoms and dinoflagellates which can contribute disproportionately relative to other primary producers to export production and transfer of resources up the food web. Here we analyze data from the Continuous Plankton Recorder to reconstruct variation in the diatom and dinoflagellate community biomass over 6 decades across the North Atlantic. We find: 1) diatom and dinoflagellate biomass has decreased up to 2% per year throughout the North Atlantic except in the eastern and western shelf regions, and 2) there has been a 1-2% per year increase in diatom biomass relative to total diatom and dinoflagellate biomass throughout the North Atlantic, except the Arctic province, from 1960-2017. Our results confirm the widely reported relationship where diatoms are displaced by dinoflagellates as waters warm on short time scales, but we did not observe a coherent effect of sea surface temperature.
Specialized signaling centers direct cell fate and spatial organization in a limb organoid model
Authors: Skoufa Evangelia , Zhong Jixing , Kahre Oliver , Hu Kelly , Tsissios Georgios , Carrau Louise , Herrera Antonio , Dominguez Mantes Albert , Castilla-Ibeas Alejandro , Jang Hwanseok , Weigert Martin , Manno Gioele La , Lutolf Matthias , Ros Marian , Aztekin Can
Published: July 2024

Specialized signaling centers orchestrate robust development and regeneration. Limb morphogenesis, for instance, requires interactions between the mesoderm and the signaling center apical-ectodermal ridge (AER), whose properties and role in cell fate decisions have remained challenging to dissect. To tackle this, we developed mouse embryonic stem cells (mESCs)-based heterogeneous cultures and a limb organoid model, termed budoids, comprising cells with AER, surface ectoderm, and mesoderm properties. mESCs were first induced into heterogeneous cultures that self-organized into domes in 2D. Aggregating these cultures resulted in formation of limb bud-like structures in 3D, exhibiting chondrogenesis-based symmetry breaking and elongation. Using our organoids and quantitative in situ expression profiling, we uncovered that AER-like cells support nearby limb mesoderm and fibroblast identities while enhancing tissue polarization that permits distant cartilage formation. Together, our findings provide a powerful model to study aspects of limb morphogenesis, and reveal the ability of signaling center AER cells to concurrently modulate cell fate and spatial organization.
An integrin centered complex coordinates ion transport and pH to regulate f-actin organization and cell migration in breast cancer
Authors: Capitani Chiara , Iorio Jessica , Lastraioli Elena , Duranti Claudia , Bagni Giacomo , Chioccioli Altadonna Ginevra , Colasurdo Rossella , Scarpellino Giorgia , Fraser Scott P. , Becchetti Andrea , Djamgoz Mustafa B. A. , Arcangeli Annarosa
Published: July 2024

Reciprocal signaling between the Tumor Microenvironment (TME) and cancer cells regulates abnormal proliferation, migration and pro-metastatic behavior. Major player in such interaction is integrin-mediated cell adhesion to the Extracellular Matrix (ECM). Integrin receptors organize signaling hubs constituted by multiprotein membrane complexes often comprising ion channels and transporters. We studied whether and how integrin-centered multiprotein complexes control cell behavior in Breast Cancer (BCa) cell populations with different molecular characteristics. BCa cells were cultured onto the ECM protein fibronectin (FN), to trigger β1 integrin activation. Through biochemical, immunofluorescence and electrophysiological experiments we provide evidence of a novel signaling pathway that involves a β1 integrin-centered plasma membrane complex formed by different transport proteins: the hERG1 K+channel, the neonatal form of the Na+channel NaV1.5 (nNaV1.5) and the Na+/H+antiporter NHE1. The NHE1/hERG1/β1/nNaV1.5 complex was found on the plasma membrane of BCa cells, and particularly of Triple Negative Breast Cancer (TNBCa). When engaged by cell adhesion to FN, such membrane complex recruited the cytoskeletal actin-binding protein a-actinin1 and stimulated NHE1-mediated cytoplasmic alkalinization. Thus, the multiprotein complex activation affected TNBCa migration and invasiveness by stimulating f-actin organization directly (through α-actinin1) and indirectly (by intracellular alkalinization). The contribution of both hERG1 and nNaV1.5 was essential, as the adhesion-dependent signaling pathway and its functional consequences were inhibited by blocking either channel with, respectively, E4031 and TTX, or by applying RNA silencing procedures. The contribution of hERG1 to the structural integrity of the membrane complex appeared to be critical, as the adhesion-dependent signals were hampered by harnessing the hERG1/β1 integrin complex with a single chain bispecific antibody (scDb-hERG1-β1) which disrupts the macromolecular complex without blocking the K+current, as well as by E4031, which impairs the complex formation by blocking the channel in the open state.

In conclusion, we revealed that integrin-centered macromolecular complexes in BCa cells recruit a battery of ion transport proteins that cooperate in modulating different aspects of the downstream signals that lead to malignant behavior. This complex could be targeted to develop novel therapeutic strategies for one of the most difficult-to-treat cancers, i.e. TNBCa.
Sedentary chromosomal integrons as biobanks of bacterial anti-phage defence systems
Authors: Darracq Baptiste , Littner Eloi , Brunie Manon , Bos Julia , Kaminski Pierre Alexandre , Depardieu Florence , Slesak Weronika , Debatisse Kevin , Touchon Marie , Bernheim Aude , Bikard David , Le Roux Frederique , Mazel Didier , Rocha Eduardo PC , Loot Celine
Published: July 2024

Integrons are genetic systems that accelerate bacterial adaptation by acquiring and shuffling gene cassettes. Mobile integrons spread antibiotic resistance genes among bacteria, while the sedentary chromosomal integrons contain up to hundreds of cassettes of unknown function. Here, we show that many of these cassettes encode anti-phage defence systems. We found numerous streamlined variants of known systems, which have presumably evolved to fit the small size constraints of integron cassettes recombination and genesis. Intrigued by the rarity of known systems in the sedentary chromosomal integron of the Vibrio cholerae 7th cholera pandemic strain, we tested the presence of anti-phage functions in all its cassettes of unknown function. We found that at least 16 of the strain cassettes have an anti-phage activity in V. cholerae or E. coli. This represents 18% of the tested cassettes and almost 10% of all the integron cassettes, providing at long last a key adaptive role for a significant fraction of the sedentary integrons. Most of the newly discovered systems have little or no similarity to previously known ones and our experiments show that several mediate defence through cell lysis or growth arrest. One of these systems encodes a 64 amino acids protein, which represents the smallest known protein providing autonomous phage resistance. Given the thousands of uncharacterized integron cassette families, integrons could represent an untapped treasure trove of streamlined anti-phage systems.
FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis
Authors: Yorek Matthew , Jiang Xingshan , Liu Shanshan , Hao Jiaqing , Yu Jianyu , Avellino Anthony , Liu Zhanxu , Curry Melissa , Keen Henry , Shao Jianqiang , Kanagasabapathy Anand , Kong Maiying , Xiong Yiqin , Sauter Edward R. , Sugg Sonia L. , Li Bing
Published: July 2024

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migrationin vitroand metastasisin vivo. Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

Graphic Abstract

Highlights

Unlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages.

Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophages

Deficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophages

FABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis
Step Forward Cross Validation for Bioactivity Prediction: Out of Distribution Validation in Drug Discovery
Authors: Saha Udit Surya , Vendruscolo Michele , Carpenter Anne E. , Singh Shantanu , Bender Andreas , Seal Srijit
Published: July 2024

Recent advances in machine learning methods for materials science have significantly enhanced accurate predictions of the properties of novel materials. Here, we explore whether these advances can be adapted to drug discovery by addressing the problem of prospective validation - the assessment of the performance of a method on out-of-distribution data. First, we tested whether k-fold n-step forward cross-validation could improve the accuracy of out-of-distribution small molecule bioactivity predictions. We found that it is more helpful than conventional random split cross-validation in describing the accuracy of a model in real-world drug discovery settings. We also analyzed discovery yield and novelty error, finding that these two metrics provide an understanding of the applicability domain of models and an assessment of their ability to predict molecules with desirable bioactivity compared to other small molecules. Based on these results, we recommend incorporating a k-fold n-step forward cross-validation and these metrics when building state-of-the-art models for bioactivity prediction in drug discovery.
Disruption of the PGE2synthesis / response pathway restrains atherogenesis in programmed cell death-1 (Pd-1) deficient hyperlipidemic mice
Authors: Ricciotti Emanuela , Tang Soon Yew , Mrčela Antonijo , Das Ujjalkumar S. , Lordan Ronan , Joshi Robin , Ghosh Soumita , Aoyama Justin , McConnell Ryan , Yang Jianing , Grant Gregory R. , FitzGerald Garret A.
Published: July 2024

Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs limits their clinical utility. Combinatorial strategies enhance their antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs.

Prostaglandin (PG) E2, formed by the sequential action of the cyclooxygenase (COX) and microsomal PGE synthase (mPGES-1) enzymes, acting via its E prostanoid (EP) receptors, EPr2 and EPr4, promotes lymphocyte exhaustion, revealing an additional target for ICIs. Thus, COX inhibitors and EPr4 antagonists are currently being combined with ICIs potentially to enhance antitumor efficacy in clinical trials. However, given the cardiovascular (CV) toxicity of COX inhibitors, such combinations may increase the risk particularly of CV AEs. Here, we compared the impact of distinct approaches to disruption of the PGE2synthesis /response pathway – global or myeloid cell specific depletion of mPges-1 or global depletion of Epr4 – on the accelerated atherogenesis in Pd-1 deficient hyperlipidemic (Ldlr-/-) mice.

All strategies restrained the atherogenesis. While depletion of mPGES-1 suppresses PGE2biosynthesis, reflected by its major urinary metabolite, PGE2biosynthesis was increased in mice lacking EPr4, consistent with enhanced expression of aortic Cox-1 and mPges-1. Deletions of mPges-1 and Epr4 differed in their effects on immune cell populations in atherosclerotic plaques; the former reduced neutrophil infiltration, while the latter restrained macrophages and increased the infiltration of T-cells. Consistent with these findings, chemotaxis by bone-marrow derived macrophages from Epr4-/-mice was impaired. Epr4 depletion also resulted in extramedullary lymphoid hematopoiesis and inhibition of lipoprotein lipase activity (LPL) with coincident spelenomegaly, leukocytosis and dyslipidemia. Targeting either mPGES-1 or EPr4 may restrain lymphocyte exhaustion while mitigating CV irAEs consequent to PD-1 blockade.