bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tick Innate Immune Responses to Hematophagy andEhrlichiaInfection at Single-Cell Resolution
Authors: Adegoke Abdulsalam , Ribeiro Jose M. C. , Smith Ryan C. , Karim Shahid 
Published: October 2023

AbstractTicks rely on robust cellular and humoral immune responses to control microbial infection. However, several aspects of the tick’s innate immune system remain uncharacterized, most notably that of the immune cells (called hemocytes), which are known to play a significant role in cellular and humoral responses toward microbes. Despite the importance of hemocytes in regulating microbial infection, our understanding of their basic biology and molecular mechanisms remains limited. Therefore, we believe that a more detailed understanding of the role of hemocytes in the interactions between ticks and tick-borne microbes is crucial to illuminate their function in vector competence and to help identify novel targets for developing new strategies to block tick-borne pathogen transmission. This study examined hemocytes from the lone star tick (Amblyomma americanum) at the transcriptomic level using the 10X genomics single-cell RNA sequencing platform to analyze hemocyte populations from unfed, partially blood-fed, andEhrlichia chaffeensis-infected ticks. Our data exhibit the identification of twelve and nineteen distinct hemocyte populations, respectively, from uninfected andEhrlichia-infected ticks. Our results show a significant increase of clusters representing granulocyte and oenocytoids populations withEhrlichiainfection. This work opens a new field of tick innate immunobiology to understand the role of hemocytes, particularly in response to prolonged blood-feeding (hematophagy) and tick-microbial interactions.SignificanceThe immune response of ticks plays a crucial role in their ability to survive and transmit pathogens. Hemocytes, the primary immune cells in arthropods, are key mediators of tick’s immune defense and provide deep insights into immune responses to microbial infection. However, tick hemocytes’ cellular complexity and heterogeneity have posed challenges for comprehensive characterization. This study employed single-cell RNA sequencing (scRNA-seq) to profile tick hemocytes and elucidate their transcriptional diversity. We identified distinct subpopulations of hemocytes and characterized their unique gene expression profiles. We observed significant variation in immune-related gene expression between hemocyte subpopulations during hematophagy and in response toEhrlichiainfection, suggesting specialized functional roles. Our analysis revealed potential marker genes associated with specific hemocyte functions. Our study provides the first comprehensive single-cell atlas of tick hemocytes, shedding light on these cells’ molecular diversity and immune functions. The findings enhance our understanding of tick-host interactions and offer a step toward understanding arthropod immunobiology.
SARS-CoV-2 neurotropism-induced anxiety/depression-like behaviors require Microglia activation
Authors: Ge Qian , Zhou Shan , Porras Jose , Fu Panfeng , Wang Ting , Du Jianyang , Li Kun 
Published: October 2023

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with a wide range of “long COVID” neurological symptoms. However, the mechanisms governing SARS-CoV-2 neurotropism and its effects on long-term behavioral changes remain poorly understood. Using a highly virulent mouse-adapted SARS-CoV-2 strain, denoted as SARS2-N501YMA30, we demonstrated that intranasal inoculation of SARS2-N501YMA30results in viral dissemination to multiple brain regions, including the amygdala and hippocampus. Behavioral assays indicated a marked elevation in anxiety- and depression-like behaviors post infection. A comparative analysis of RNA expression profiles disclosed alterations in the post-infected brains. Additionally, we observed dendritic spine remodeling on neurons within the amygdala after infection. Infection with SARS2-N501YMA30was associated with microglial activation and a subsequent increase in microglia-dependent neuronal activity in the amygdala. Pharmacological inhibition of microglial activity subsequent to viral spike inoculation mitigates microglia-dependent neuronal hyperactivity. Transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating microglia-driven neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Overall, these data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.
APOLLO: A genome-scale metabolic reconstruction resource of 247,092 diverse human microbes spanning multiple continents, age groups, and body sites
Authors: Heinken Almut , Hulshof Timothy Otto , Nap Bram , Martinelli Filippo , Basile Arianna , O’Brolchain Amy , O’Sullivan Neil Francis , Gallagher Celine , Magee Eimer , McDonagh Francesca , Lalor Ian , Bergin Maeve , Evans Phoebe , Daly Rachel , Farrell Ronan , Delaney Rose Marie , Hill Saoirse , McAuliffe Saoirse Roisin , Kilgannon Trevor , Fleming Ronan M.T. , Thinnes Cyrille C. , Thiele Ines 
Published: October 2023

SummaryComputational modelling of microbiome metabolism has proved instrumental to catalyse our understanding of diet-host-microbiome-disease interactions through the interrogation of mechanistic, strain- and molecule-resolved metabolic models. We present APOLLO, a resource of 247,092 human microbial genome-scale metabolic reconstructions spanning 19 phyla and accounting for microbial genomes from 34 countries, all age groups, and five body sites. We explored the metabolic potential of the reconstructed strains and developed a machine learning classifier able to predict with high accuracy the taxonomic strain assignments. We also built 14,451 sample-specific microbial community models, which could be stratified by body site, age, and disease states. Finally, we predicted faecal metabolites enriched or depleted in gut microbiomes of people with Crohn’s disease, Parkinson disease, and undernourished children. APOLLO is compatible with the human whole-body models, and thus, provide unprecedented opportunities for systems-level modelling of personalised host-microbiome co-metabolism. APOLLO will be freely available underhttps://www.vmh.life/.
Biochemically-functionalized probes for cell type-specific targeting and recording in the brain
Authors: Zhang Anqi , Zwang Theodore J. , Lieber Charles M. 
Published: October 2023

AbstractSelective targeting and modulation of distinct cell types and neuron subtypes is central to understanding complex neural circuitry, and could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh electronic probes, which elicit minimal immune response, with antibodies or peptides to target specific cell markers. Histology studies reveal selective association of targeted neurons, astrocytes and microglia with functionalized probe surfaces without accumulating off-target cells. In vivo chronic electrophysiology further yields recordings consistent with selective targeting of these cell types. Last, probes functionalized to target dopamine 2 receptor expressing neurons show the potential for neuron subtype specific targeting and electrophysiology.
Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity
Authors: Krause Christin , Britsemmer Jan H. , Bernecker Miriam , Molenaar Anna , Taege Natalie , Lopez-Alcantara Nuria , Geißler Cathleen , Kaehler Meike , Iben Katharina , Judycka Anna , Wagner Jonas , Wolter Stefan , Mann Oliver , Pfluger Paul T. , Cascorbi Ingolf , Lehnert Hendrik , Stemmer Kerstin , Schriever Sonja C. , Kirchner Henriette 
Published: October 2023

AbstractBackgroundThe development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing.MethodsLiver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.ResultsHere we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target geneLRP6was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restoredLrp6expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.ConclusionBy mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression ofLRP6by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.Graphical Abstract
A Drug-Free Pathogen Capture and Neutralizing Nasal Spray to Prevent Emerging Respiratory Infections
Authors: Joseph John , Baby Helna Mary , Quintero Joselyn Rojas , Kenney Devin , Mebratu Yohannes A , Bhatia Eshant , Shah Purna , Swain Kabir , Kaur Shahdeep , Li Xiang-Ling , Mwangi John , Snapper Olivia , Nair Remya , Agus Eli , Ranganathan Sruthi , Kage Julian , Gao Jingjing , Luo James N , Yu Anthony , Douam Florian , Tesfaigzi Yohannes , Karp Jeffrey M , Joshi Nitin 
Published: October 2023

AbstractRespiratory infections pose a global health crisis. Vaccines are pathogen specific, and new vaccines are needed for mutants and emerging pathogens. Here, we report a “drug free” prophylactic platform - a “Pathogen Capture and Neutralizing Spray” (PCANS) that actsviaa multi-pronged approach to prevent a broad spectrum of respiratory infections. PCANS forms a protective coating in the nasal cavity that enhances the capture of large respiratory droplets. The coating acts as a physical barrier against a broad spectrum of viruses and bacteria, and rapidly neutralizes them, reducing the pathogen load by >99.99%. In mice, PCANS showed nasal retention for at least 8 h and was safe for daily administration. A single prophylactic dose of PCANS protected mice against supra-lethal dosages of a mouse-adapted H1N1 Influenza virus (PR8), reduced lung viral titer by >99.99%, improved survival, and suppressed pathological manifestations. Together, our data suggest PCANS as a promising daily-use prophylactic approach against current and emerging respiratory infections.
Automated Stimulation and Long-Term Remote Monitoring of Multi-Plex Microfluidic Organoid Chips
Authors: Sachs David M , Costa Kevin D 
Published: October 2023

AbstractDeveloping a novel microfluidic organoid system required many experiments and iterations due to lack of knowledge about the relevant developmental biology. Collecting data on the developing organoids quickly escalated into a bottleneck as high throughput and long term culture resulted in a rapidly increasing number of specimens being observed. Commercially available automated microscope systems exist, but were either too expensive or not appropriate, and could not be modified. To satisfy the increasing need for automated data collection, a custom robotic system was developed to collect data from within a standard incubator. An X-Y belt driven gantry was designed with an architecture chosen to balance high accuracy, low cost, speed, and range of motion. Focus control was implemented with dual miniature leadscrews. A linear sliding mechanism was used to switch between two microscope objectives. 3D printed chip attachments were designed to implement illuminators for bright field imaging, and electrodes for stimulating the cardiac organoids. A fluorescent filter block was designed using a 3D printed piece to hold optical components, and a multi-band filter set that allowed for three color fluorescence without moving parts. A pulley driven tilting stage gravitationally biased the organoids during development. In order to ensure accurate image collection despite the inevitable position shifting of the chips, an image processing pipeline was developed for locating organoids using geometrical microfluidic chip features. The resulting robotic system automated imaging data collection on organoids and electrical and mechanical stimulation, in addition to being modifiable for future projects.
DIRECTED GRAPH THEORY FOR THE ANALYSIS OF BIOLOGICAL REGULATORY NETWORKS
Authors: Takane Martha , Bernal-González Saúl , Mauro-Moreno Jesús , García-López Gustavo , Méndez-Ambrosio Bruno , De-Miguel Francisco F. 
Published: October 2023

ABSTRACTRegulated biological networks are commonly represented as logical diagrams, in which the exact interactions between the elements remain out of sight. Here we propose a new type of excitation-inhibition graph based on Boolean logic, which we name “logical directed graph or simply, logical digraph of the biological system”. Such logical digraph allows the representation of every possible regulatory interaction among elements, based on Boolean interactions. The logical digraph contains information about the connectivity, dynamics, limit cycles, and attractors of the network. As proof of the application, the logical digraph was applied to analyze the functioning of the well-known neural network that produces oscillatory swimming in the mollusk Tritonia. Our method permits to transit from a regulatory network to its logical digraph and vice versa. In addition, we show that the spectral properties of the so-called state matrix provide mathematical evidence about why the elements in the attractors and limit cycles contain information about the dynamics of the biological system. Open software routines are provided for the calculations of the components of the network and the attractors and limit cycles. This approach offers new possibilities to visualize and analyze regulatory networks in biology.
Investigating markers of pulmonary aspiration in bronchoalveolar lavage from children with severe neurodisability
Authors: Maher Rosemary E , Trinick Ruth E , Dalzell Mark , Beynon Robert J , McNamara Paul S 
Published: October 2023

AbstractRespiratory exacerbations are a frequent cause of hospitalisation in children with severe neurodisability (ND). Direct aspiration of food/saliva, reflux aspiration of gastric contents or a combination of both is thought to be a common cause of respiratory symptoms and disease, particularly when this occurs ‘silently’. A number of aspiration biomarkers, including bile acids and pepsin, have been proposed, however, no gold-standard diagnostic tests are currently available. In children with severe ND at high risk of both direct and reflux aspiration, we analysed lower airway samples for saliva- and/or gastric-specific proteins with biomarker potential.
BOLD: Blood-gas and Oximetry Linked Dataset – Open Source Research
Authors: Matos João , Struja Tristan , Gallifant Jack , Nakayama Luis , Charpignon Marie-Laure , Liu Xiaoli , Economou-Zavlanos Nicoleta , Cardoso Jaime S. , Johnson Kimberly S , Bhavsar Nrupen , Gichoya Judy , Celi Leo Anthony , Wong A. Ian 
Published: October 2023

AbstractPulse oximeters measure peripheral arterial oxygen saturation (SpO2) noninvasively, while the gold standard (SaO2) involves arterial blood gas measurement. There are known racial and ethnic disparities in their performance. BOLD is a new comprehensive dataset that aims to underscore the importance of addressing biases in pulse oximetry accuracy, which disproportionately affect darker-skinned patients.The dataset was created by harmonizing three Electronic Health Record databases (MIMIC-III, MIMIC-IV, eICU-CRD) comprising Intensive Care Unit stays of US patients. Paired SpO2and SaO2measurements were time-aligned and combined with various other sociodemographic and parameters to provide a detailed representation of each patient. BOLD includes 49,099 paired measurements, within a 5-minute window and with oxygen saturation levels between 70-100%. Minority racial and ethnic groups account for ∼25% of the data – a proportion seldom achieved in previous studies. The codebase is publicly available.Given the prevalent use of pulse oximeters in the hospital and at home, we hope that BOLD will be leveraged to develop debiasing algorithms that can result in more equitable healthcare solutions.
Repeat Testing of Mpox Specimens with Late CTs Improves Detection of Potential False Positive Cases
Authors: Shean Ryan C. , Hymas Weston C. , Klein Jeremy , Pyne Michael , Hillyard David R. , Bradley Benjamin T. 
Published: October 2023

AbstractThe global outbreak of mpox necessitated the rapid development of clinical assays for monkeypox virus detection. While the majority of mpox specimens have high viral loads with corresponding early CT values, reports have indicated some specimens with late CT values can represent false positive results. To mitigate this risk, the Centers for Disease Control and Prevention (CDC) published an advisory recommending repeat testing of all specimens with CT values ≥34. However, limited experimental data was available to support this specific cutoff. In this study, we examine whether a more conservative approach in which all specimens with CT values ≥29 are repeated would improve the detection of potential false positive results. Compared to the CDC algorithm, our approach identified an additional 20% (5/25) of potential false positive results. To assess the impact of this cutoff on laboratory workload, we estimated the expected increase in test volume and turnaround time (TAT) relative to the CDC method. Using a lower repeat threshold, test volume increased by 0.7% and the mean TAT for positive specimens increased by less than 15 minutes. Overall, a lower threshold than recommended by the CDC for repeating late CT mpox specimens may reduce the number of false positives reported while minimally impacting testing volume and TAT.
Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders
Authors: Xu Huifang , Sun Yitang , Francis Michael , Cheng Claire F. , Modulla Nitya T.R. , Brenna J. Thomas , Chiang Charleston W. K. , Ye Kaixiong 
Published: October 2023

AbstractThe neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2) and rs4818766 (ADARB1). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.
Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma
Authors: Labidi Soumaya , Meti Nicholas , Barua Reeta , Li Mengqi , Riromar Jamila , Jiang Di Maria , Fallah-Rad Nazanin , Sridhar Srikala S. , del Rincon Sonia V. , Pezo Rossanna C. , Ferrario Cristiano , Cheng Susanna , Sacher Adrian G. , Rose April A. N. 
Published: October 2023

AbstractBackgroundAnti-PD-1/L1 immune checkpoint inhibitors (ICI) are indicated for metastatic urothelial cancer (mUC), however, only a minority of patients will derive therapeutic benefit. Strong predictive and prognostic factors are lacking. We investigated if clinical variables were associated with ICI outcomes in mUC.MethodsWe performed a multi-center retrospective cohort study of patients with mUC who received anti-PD-1/L1 ICI for metastatic disease between 2016-2021 at 3 Canadian cancer centres. Clinical characteristics, including demographics, BMI, metastatic sites, neutrophil-to-lymphocyte ratio (NLR), objective response, and survival were abstracted from chart review. ICI treatment response was determined by investigator assessment of clinical and radiologic parameters. Fisher’s exact test was used to assess differences in response rates between groups. Log rank and Cox regression models were used to assess overall survival (OS).ResultsWe identified 135 patients with mUC who received anti-PD1/L1 ICI. A BMI ≥ 25 was significantly correlated to a higher overall response rate (ORR) to ICI (45.4% vs 16.3%, P = 0.020). After a median follow-up of 14.5 months, patients with BMI ≥ 30 experienced significant longer median OS 24.8 months vs. 14.4 months for 25 ≤ BMI < 30 and 8.5 months for BMI < 25 (P = 0.012). The ORR was significantly less in the presence of bone metastasis 16% vs 41% P = 0.006, and liver metastasis 16% vs 39% P = 0.013. Conversely, the presence of metastatic lymph nodes was significantly correlated with higher ORR 40% vs 20% P = 0.032. The median OS for patients with bone metastasis was 7.3 months vs 18 months in the absence of bone metastasis (P < 0.001). Patients with liver metastasis had a median OS of 8.6 months compared to 15 months for those without liver metastasis (P = 0.006). For lung metastasis, median OS was 8.7 months compared to 17.3 months (P = 0.004). No statistical difference was shown in OS for lymph nodes metastasis, with a median of 13.5 months vs 12.7 months (P = 0.175). Patients with NLR ≥ 4 had a significant worse OS (8.2 months vs 17.7 months P = 0.0001). In multivariate analysis, BMI ≥ 30, bone metastasis and NLR ≥ 4 were independent prognosis factor for OS.ConclusionsOur data identified BMI and bone metastasis as novel, independent, clinical biomarkers that were strongly and independently associated with ICI response and survival in mUC. External validation of these data in a larger study and investigations into the mechanisms behind these findings are warranted.