bluuebunny/crossref_metadata_2025_split huggingface dataset:
The domed architecture ofGiardia’s ventral disc is necessary for attachment and host pathogenesis
Authors: Hagen KD , Nosala C , Hilton NA , Müller A , Holthaus D , Laue M , Klotz C , Aebisher A , Dawson SC 
Published: July 2023

AbstractAfter ingestion of dormant cysts, the widespread protozoan parasiteGiardia lambliacolonizes the host gastrointestinal tract via direct and reversible attachment using a novel microtubule organelle, the ventral disc. Extracellular attachment to the host allows the parasite to resist peristaltic flow, facilitates colonization and is proposed to cause damage to the microvilli of host enterocytes as well as disrupt host barrier integrity. The 9 µm in diameter ventral disc is defined by a highly complex architecture of unique protein complexes scaffolded onto a spiral microtubule (MT) array of one hundred parallel, uniformly spaced MT polymers that bend approximately one and a quarter turns to form a domed structure. To investigate the role of disc-mediated attachment in causing epithelial cell damage, we used a new approach to rapidly create a stable quadruple knockout ofGiardiaof an essential ventral disc protein, MBP, using a new method of CRISPR-mediated gene disruption with multiple positive selectable markers. MBP quadruple KO mutant discs lack the characteristic domed architecture and possess a flattened “crescent” or horseshoe-shaped conformation that lacks the overlapping region, with severe defects in the microribbon-crossbridge (MR-CB) complex structure. MBP KO mutants are also unable to resist fluid flow required for attachment to inert surfaces. Importantly, MBP KO mutants have 100% penetrance off positive selection, which is essential for quantification ofin vivoimpacts of disc and attachment mutants with host cells. Using a new gastrointestinal organoid model of pathogenesis, we found that MBP KO infections had a significantly reduced ability to cause the barrier breakdown characteristic of wild-type infections. Overall, this work provides direct evidence of the role of MBP in creating the domed disc, as well as the first direct evidence that parasite attachment is necessary for host pathology, specifically epithelial barrier breakdown.
APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer
Authors: Garcia Nina Marie G. , Becerra Jessica N. , McKinney Brock J. , DiMarco Ashley V. , Wu Feinan , Fitzgibbon Matthew , Alvarez James V. 
Published: July 2023

ABSTRACTAPOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises throughde novoacquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the ΔNp63 target genes IL1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.
High prevalence of hypertension and high-normal blood pressure: findings from a large population-based survey of young adults in Zimbabwe
Authors: Sabapathy Kalpana , Mwita Fredrick Cyprian , Dauya Ethel , Bandason Tsitsi , Simms Victoria , Dziva Chikwari Chido , Doyle Aoife M , Ross David , Shah Anoop , Hayes Richard , Schutte Aletta E , Kranzer Katharina , Ferrand Rashida Abbas 
Published: July 2023

AbstractBackgroundMost cardiovascular mortality is due to hypertension and onset may be in youth. We investigated the prevalence of and risk factors for elevated blood pressure (BP) (hypertension (≥140/90mmHg) and high-normal BP (130-139/85-89mmHg)) among youth in Zimbabwe.MethodsA population-based survey of randomly sampled 18-24 year olds from 24 communities in three provinces was conducted, with standardised questionnaires to collect socio-demographic, behavioural and clinical data. Height, weight and BP were recorded. The association of potential risk factors with elevated BP was examined using multivariable logistic regression.FindingsOf 17,682 participants recruited (98% of those eligible), 17,637 had complete data. The median age was 20 (IQR: 19-22) years and 60.7% were female. After excluding pregnant women (N=754), the prevalence of hypertension and high-normal BP was 7.4% (95% CI:7.0-7.8) and 12.2% (95% CI:12.7-13.7), respectively. Prevalence of hypertension was higher in men (8.7% (95% CI:8.2-9.6) vs 6.6% (95% CI:6.0-6.9) in men and women, respectively) but with age increased to equivalent levels among women (at 18y 7.3% (95% CI:6.2-8.6) and 4.3% (95% CI:3.5-5.2); at 23-24 years 10.9% (95% CI:9.3-12.5) and 9.50% (95% CI:8.4-10.7) in men and women, respectively). After adjusting for confounders, male sex ((aOR) 1.53 (95% CI:1.36-1.74)), increasing age (19-20 years aOR:1.20 (1.00-1.44); 21-22 years aOR:1.45 (95% CI 1.20-1.75); 23-24 years aOR 1.90 (95% CI:1.57-2.30), vs 18 years) and obesity (aOR 1.94 (95% CI:1.53-2.47)) were associated with hypertension. Being underweight (aOR 0.79 (0.63-0.98)) and living with HIV (aOR 0.71 (95% CI:0.55-0.92)) were associated with lower odds of hypertension.InterpretationPrevalence of elevated BP is high among youth in SSA and rises rapidly with age. Further research is needed to understand drivers of BP elevation and the extent of target organ damage in youth in SSA, to guide implementation of prevention and management strategies.FundingWellcome Trust.
Herpesvirus infections eliminate safeguards against breast cancer and its metastasis: comparable to hereditary breast cancers
Authors: Friedenson Bernard 
Published: July 2023

AbstractBreast cancer has no simple explanation. I tested the hypothesis that Epstein-Barr (EBV) infections promote the disease because they disable breast cancer safeguards. I used bioinformatics of public information from approximately 2100 breast cancers. Results demonstrate that chromosome breakpoints in breast and ovarian cancer cluster around the same breakpoints in diverse EBV-associated cancers. Cancers unrelated to EBV do not have these clusters. Breast cancers overexpress a methylation signature caused by active EBV infection. EBV remnants interspace between MHC genes and piRNA clusters as CRISPR- like evidence of past infection. I then found breast cancer breakpoints cluster around EBV docking sites. This clustering occurs because EBV breaks chromosomes and then damages breast cancers safeguards: BRCA1/2 pathways, SMC5/6, and mitotic controls. Finally, EBV causes the same losses that drive breast cancer metastasis. Activated EBV bypasses all these safeguards without large numbers of particles or continuing presence. Immunizing against EBV proteins may prevent breast, ovarian, and other cancers.SummaryHuman papilloma virus promotes cervical cancer because it disables tumor suppressors. EBV in breast cancer resembles this model. EBV variants disable a variety of molecular and cellular safeguards that protect against breast cancer.
GroEL-proteotyping of bacterial communities by tandem mass spectrometry
Authors: Klaes Simon , Madan Shobhit , Deobald Darja , Cooper Myriel , Adrian Lorenz 
Published: July 2023

AbstractProfiling bacterial populations in mixed communities is a common task in microbiology. 16SrRNA-based sequencing is a widely accepted and functional approach but relies on amplification primers and cannot quantify isotope incorporation. Tandem mass spectrometry proteotyping is an effective alternative for taxonomically profiling microorganisms. We suggest that targeted proteotyping approaches can complement traditional population analyses. Therefore, we describe an approach to assess bacterial community compositions at the family level using the taxonomic marker protein GroEL, which is ubiquitously found in bacteria, except few obligate intracellular species. We refer to our method as GroEL-proteotyping. GroEL-proteotyping is based on high-resolution tandem mass spectrometry of GroEL peptides and identification of GroEL-derived taxa via a Galaxy workflow and a subsequent Python-based analysis script. Its advantage is that it can be performed with a curated and extendable sample-independent database and that GroEL can be pre-separated by SDS-PAGE to reduce sample complexity, improving GroEL identification while simultaneously decreasing the instrument time. GroEL-proteotyping was validated by employing it on a comprehensive raw data set obtained through a metaproteome approach from synthetic microbial communities as well as real human gut samples. Our data show that GroEL-proteotyping enables fast and straightforward profiling of highly abundant taxa in bacterial communities at reasonable taxonomic resolution.
Modulation of alpha oscillations by attention is predicted by hemispheric asymmetry of subcortical regions
Authors: Ghafari Tara , Mazzetti Cecilia , Garner Kelly , Gutteling Tjerk , Jensen Ole 
Published: July 2023

AbstractEvidence suggests that subcortical structures play a role in high-level cognitive functions such as the allocation of spatial attention. While there is abundant evidence in humans for posterior alpha band oscillations being modulated by spatial attention, little is known about how subcortical regions contribute to these oscillatory modulations, particularly under varying conditions of cognitive challenge. In this study, we combined MEG and structural MRI data to investigate the role of subcortical structures in controlling the allocation of attentional resources by employing a cued spatial attention paradigm with varying levels of perceptual load. We asked whether hemispheric lateralization of volumetric measures of the thalamus and basal ganglia predicted the hemispheric modulation of alpha-band power. Lateral asymmetry of the globus pallidus, caudate nucleus, and thalamus predicted attention-related modulations of posterior alpha oscillations. When the perceptual load was applied to the target and the distractor was salient caudate nucleus asymmetry predicted alpha-band modulations. Globus Pallidus was predictive of alpha-band modulations when either the target had a high load, or the distractor was salient, but not both. Finally, the asymmetry of the thalamus predicted alpha band modulation when neither component of the task was perceptually demanding. In addition to delivering new insight into the subcortical circuity controlling alpha oscillations with spatial attention, our finding might also have clinical applications. We provide a framework that could be followed for detecting how structural changes in subcortical regions that are associated with neurological disorders can be reflected in the modulation of oscillatory brain activity.
HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome
Authors: Lopes Filipa M. , Grenier Celine , Jarvis Benjamin W. , Mahdy Sara Al , Lène-McKay Adrian , Gurney Alison M. , Newman William G. , Waddington Simon N. , Woolf Adrian S. , Roberts Neil A. 
Published: July 2023

ABSTRACTRare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants ofHPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts ofHpse2mutant mice display impaired neurogenic relaxation. We hypothesized thatHPSE2gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach.AAV9/HPSE2,carrying humanHPSE2driven byCAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, andex vivomyography was undertaken to measure bladder function. In mice administeredAAV9/HPSE2, the viral genome was detected in pelvic ganglia. HumanHPSE2was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders whereas bladders were uniformly distended in mutant mice, a defect ameliorated byAAV9/HPSE2treatment. Therapeutically,AAV9/HPSE2significantly ameliorated impaired neurogenic relaxation ofHpse2mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.SummaryIn the first gene therapy for genetic bladder disease, we cured autonomic neurons using AAV-mediated gene delivery in a mouse model of urofacial syndrome.
Phage therapy minimally affects the water microbiota in an Atlantic salmon (Salmo salar) rearing system while still preventing infection
Authors: Fiedler Alexander W. , Gundersen Madeleine S. , Vo Toan P. , Almaas Eivind , Vadstein Olav , Bakke Ingrid 
Published: July 2023

AbstractExcessive usage of antibiotics threatens the bacterial diversity in the microbiota of animals. An alternative to antibiotics that has been suggested to not disturb the microbiota is (bacterio)phage therapy. In this study, we challenged germ-free and microbially colonized yolk sac fry of Atlantic salmon withFlavobacterium columnareand observed that the mere presence of a microbiota protected the fish against lethal infection. We then investigated the effect of phage-or oxytetracycline treatment on fish survival and rearing water bacterial community characteristics using 16S rRNA gene amplicon sequencing. Phage treatment led to an increased survival ofF. columnare-challenged fish and reduced the relative amounts of the pathogen in the water microbiota. In the absence ofF. columnare, phage treatment did not affect the composition or the α-diversity of the rearing water microbiota. In the presence of the phage’s host, phage treatment induced minor changes to the bacterial community composition, without affecting the α-diversity. Surprisingly, oxytetracycline treatment had no observable effect on the water microbiota and did not reduce the relative abundance ofF. columnarein the water. In conclusion, we showed that phage treatment prevents mortality while not negatively affecting the rearing water microbiota, thus suggesting that phage treatment may be a suitable alternative to antibiotics. We also demonstrated a protective effect of the microbiota in Atlantic salmon yolk sac fry.
A Novel Humanized Immune Stroma PDX Cancer Model for Therapeutic Studies
Authors: Yang Dongli , Beddows Ian , Tang Huijuan , Cascio Sandra , McGonigal Stacy C. , Bai Shoumei , Johnson Benjamin K. , Powers John J. , Acharya Rajesh , Bao Riyue , Bruno Tullia C. , Soong Thing R. , Conejo-Garcia Jose R. , Shen Hui , Bility Moses T. , Buckanovich Ronald J. 
Published: July 2023

AbstractStandard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, using patient-derived tumor cells, patient derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a Human Stroma-Patient Derived Xenograft (HS-PDX) tumor model. HS-PDX, compared to the standard PDX model, demonstrate greater resistance to targeted therapy and chemotherapy, and better reflect patient response to therapy. Furthermore, HS-PDX can be grown in mice with humanized bone marrow to create humanized immune stroma patient-derived xenograft (HIS-PDX) models. The HIS-PDX model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on response to CAR-T cell therapy and immune checkpoint inhibitor therapy. We show an immunosuppressive role for human tumor stroma and that this model can be used to identify immunotherapeutic combinations to overcome stromally mediated immunosuppression. Combined, our data confirm a critical role for human stoma in therapeutic response and indicate that HIS-PDX can be an important tool for preclinical drug testing.Statement of SignificanceWe developed a tumor model with human stromal, vascular, and immune cells. This model mirrors patient response to chemotherapy, targeted therapy, and immunotherapy, and can be used to study therapy resistance.
Mechanical Force Imprints Neutrophils to Orchestrate Pulmonary Homeostasis
Authors: Wang Jin , Kang Haixia , Zhao Wenying , Bai Wenjuan , Qi Xin , Yan Kepeng , Miao Naijun , Dong Dong , Wang Yuanyuan , Thanabalasuriar Ajitha , Zhang Dachuan , Ye Youqiong , Xu Tian-le , Li Bin , Wang Jing 
Published: July 2023

AbstractNeutrophils are the most abundant immune cells that constantly patrol and marginate into the vascular beds of multiple tissues to support immune homeostasis. The extent to which neutrophils undergo adaptation in response to diverse tissue microenvironments, and the resultant biological implications of such adaptation, remains unclear. Here, we performed intravital imaging, transcriptional, and functional analyses of neutrophils in different tissues. Our findings showed that the lung harbors a transcriptionally distinct neutrophil population with unique migratory behaviors. These resident-like neutrophils guarantee a rapid response upon infection and play an important role in maintaining the homeostasis of pulmonary vasculature. Notably, pulmonary neutrophils are imprinted by mechanical cues via the mechanosensitive ion channel Piezo1. Mice with conditional Piezo1 ablation lost lung-specific neutrophil signatures, and showed impaired lung capillary angiogenesis. Furthermore, these mice displayed increased susceptibility to airway infection. Collectively, these data identify mechanical sensing via Piezo1 as an important driver for tissue-specialized neutrophils that support pulmonary homeostasis.
Genome-wide transformation reveals extensive exchange across closely relatedBacillusspecies
Authors: Förster Mona , Rathmann Isabel , Yüksel Melih , Power Jeffrey J. , Maier Berenike 
Published: July 2023

AbstractBacterial transformation is an important mode of horizontal gene transfer that helps spread genetic material across species boundaries. Yet, the factors that pose barriers to genome-wide cross-species gene transfer are poorly characterized. Here, we develop a replacement accumulation assay to study the effects of genomic distance on transfer dynamics. UsingBacillus subtilisas recipient and various species of the genusBacillusas donors, we find that the rate of orthologous replacement decreases exponentially with the divergence of their core genomes. We reveal that at least 96 % of theB. subtiliscore genes are accessible to replacement by alleles fromBacillus spizizenii. For the more distantly relatedBacillus atrophaeus, gene replacement events cluster at genomic locations with high sequence identity and preferentially replace ribosomal genes. Orthologous replacement also creates mosaic patterns between donor and recipient genomes, rearranges the genome architecture, and governs gain and loss of accessory genes. We conclude that cross-species gene transfer is dominated by orthologous replacement of core genes which occurs nearly unrestricted between closely related species. At a lower rate, the interplay between the core and accessory genomes gives rise to more complex genome dynamics.
A densely sampled and richly annotated acoustic dataset from a wild bird population
Authors: Recalde Nilo Merino , Estandía Andrea , Pichot Loanne , Vansse Antoine , Cole Ella F. , Sheldon Ben C. 
Published: July 2023

AbstractWe present a high-resolution, densely-sampled dataset of wild bird songs collected over multiple years from a single population of Great Tits (Parus major) in the UK. The dataset includes over 1,100,000 individual acoustic units from 109,963 richly annotated songs, sung by more than 400 individual birds, and provides unprecedented detail on the vocal behaviour of wild birds. Here, we describe the data collection and processing procedures and provide a summary of the data. We also discuss potential research questions that can be addressed using this dataset, including behavioural repeatability and stability, links between vocal performance and reproductive success, the timing of song production, syntactic organisation of song production, and song learning in the wild. We have made the dataset and associated software tools publicly available with the aim that other researchers can benefit from this resource and use it to further our understanding of bird vocal behaviour in the wild.
Polymodal sensory perception of mechanical and chemical cues drives robust settlement and metamorphosis of a marine pre-vertebrate zooplanktonic larva
Authors: Hoyer Jorgen , Kolar Kushal , Athira Athira , Burgh Meike van den , Dondorp Daniel , Liang Zonglai , Chatzigeorgiou Marios 
Published: July 2023

AbstractThe Earth’s oceans brim with an incredible diversity of microscopic planktonic animals, many of which correspond to the transient larval stage in the life cycles of benthic marine organisms. The mechanisms by which marine larvae use their nervous system to sense and process diverse environmental cues (physical and chemical) in the water column and the benthos to settle and metamorphose is a major problem across the fields of neuroscience, development, evolution and ecology, yet they remain largely unclear.Here, we employ Ca2+imaging and behavioral assays using the larval form of the protochordateCiona intestinalisto characterise the mechanical and chemical stimuli these larvae respond to during settlement and metamorphosis. We also identify the polymodal sensory cells that detect these stimuli. Whole brain Ca2+imaging further revealed that the presentation or removal of ethological chemosensory stimuli engages the activities of different neuronal sub-populations resulting in brain state changes, which may underlie behavioral action selections and metamorphosis. Finally, chemogenetic interrogation coupled to behavioral analysis reveals that peptidergic sensory neurons including polymodal cells capable of chemotactile perception and chemosensory/neurosecretory cells of proto-placodal ectoderm origin play a pivotal role in regulating stimulus induced settlement and metamorphosis. This work suggests that marine zooplanktonic larvae utilise their streamlined nervous systems to perform multimodal integration of ethologically physical and chemical cues to explore the oceanic water column and benthos.