bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation
Authors: Filipello Fabia , You Shih Feng , Mahali Sidhartha , Iyer Abhirami Kannan , Martinez Rita , Korvatska Olena , Raskind Wendy H , Bollman Bryan , Cantoni Claudia , De Feo Luca , Ghezzi Laura , Minaya Miguel , Cashikar Anil G , Satoh Jun-Ichi , Beatty Wandy , Cella Marina , Piccio Laura , Karch Celeste M 
Published: July 2022

ABSTRACTTREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemoral dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two siblings homozygous for the TREM2 p.Q33X mutation (termed NHD), one related non-carrier, and one unrelated non-carrier. Transcriptomic analysis and biochemical assays revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol metabolism genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation, which were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to a defect in lysosomal function. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
Knowledge, attitudes, and practices regarding COVID-19 among university students and employees in Massachusetts, USA: a qualitative study
Authors: Ravenhurst Johanna , Snyder Teah , Wallace Kate , Pennell Sheila , Goff Sarah L. , Lover Andrew A. 
Published: July 2022

AbstractBackgroundAt the time of this study, Massachusetts had recorded a total of 352,558 COVID-19 cases and 12,076 deaths. Few qualitative studies have been conducted that investigate the experiences of university students and employees during the COVID-19 pandemic. The objective of this study was to explore the knowledge, attitudes, and practices regarding COVID-19 in university affiliates to inform future COVID-19 policies.MethodsSemi-structured focus groups and interviews were conducted via Zoom between December 14, 2020 and January 15, 2021. Twenty-two focus group participants included undergraduate students, graduate students and university employees who had not experienced isolation or quarantine during the Fall 2020 semester. Fourteen participants who had experienced quarantine or isolation were interviewed individually to protect confidentiality. Data were analyzed using Dedoose software via inductive thematic analysis, with reporting as per Consolidated Criteria for Reporting Qualitative Studies (COREQ) guidelines.ResultsFive major themes emerged from these data: COVID-19 knowledge, stress and coping, trust, decision-making, and institutional feedback. Misinformation regarding COVID-19 was common, compounding high levels of stress reported by many participants. Reported direct sources of stress included physical illness, fear of infection, and lack of access to resources while in quarantine or isolation settings. Reported indirect sources of stress included social isolation and financial constraints. Levels of trust were generally high regarding mainstream news media, scientific journals, and university-related information sources. For decision-making processes, participants described altered behaviors to socialize safely during the pandemic, which included increased testing, gathering outdoors, and limiting group sizes. Conversely, some undergraduate students reported increases in socialization behaviors after testing negative for COVID-19, while most university employees did not report altered behaviors after negative test results. While some participants described negative feedback regarding university decisions, most feedback for the institution was positive, with participants reporting appreciation for the university’s asymptomatic testing program and other on-campus health response activities.ConclusionThe university’s investment in COVID-related resources, including the asymptomatic testing program and the on-campus quarantine and isolation spaces, were reported to greatly reduce stress and increase perceived safety. Key findings from this research could guide institutional communication, public health protocols, and support for university community members.
Efficacy and longevity of immune response to 3rd COVID-19 vaccine and effectiveness of a 4th dose in severely immunocompromised patients with cancer
Authors: Thakkar Astha , Pradhan Kith , Duva Benjamin , Carreño Juan Manuel , Sahu Srabani , Thiruthuvanathan Victor , Campbell Sean , Gallego Sonia , Bhagat Tushar D , Rivera Johanna , Choudhary Gaurav , Olea Raul , Sabalza Maite , Shapiro Lauren C. , Lee Matthew , Quinn Ryann , Mantzaris Ioannis , Chu Edward , Will Britta , Pirofski Liise-anne , Krammer Florian , Verma Amit , Halmos Balazs 
Published: July 2022

AbstractCancer patients show increased morbidity with COVID-19 and need effective immunization strategies. We demonstrate that a 3rd dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination. The immune response is durable as assessed by anti-S antibody titers, T-cell activity and neutralization activity against wild-type SARS-CoV2 and BA1.1.529 at 6 months of follow up. A subset of severely immunocompromised hematologic malignancy patients were unable to mount adequate immune response after the 3rd dose and were treated with a 4th dose in a prospective clinical trial which led to adequate immune-boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. These results indicate that vaccine booster-induced immunity is durable in cancer patients and additional doses can further stimulate immunity in a subset of hematologic malignancy patients.Statement of significanceWe demonstrate that a 3rd dose of vaccine leads to seroconversion in 57% of negative patients with durable immune responses at 6 months. A 4th dose of vaccine can seroconvert hematologic malignancy patients with higher baseline IgM and CD19 levels.
Vascular Encasement Image Defined Risk Factors Predict Surgical Complications in Neuroblastoma
Authors: Stokes Rachael , Bannon Aidan , Leung Bonnie , Alloo Jasmin , Davies-Payne David , Winstanley Mark , Wood Andrew , Evans Stephen , Hamill James 
Published: July 2022

AbstractBackgroundSpecific Image Defined Risk Factors (IDRF) may be of more relevance to the pediatric surgical oncologist than simply the presence of any IDRF. The aim of this study was to correlate IDRF with surgical complications with reference to vascular encasement IDRF and the grade of complication.MethodsWe searched the New Zealand Children’s Cancer Registry for all cases of neuroblastoma treated at a single pediatric oncology center between January 2007 – February 2021 and reviewed the pre-treatment axial imaging for IDRF status. Surgical complications were scored by Clavien-Dindo grade and correlated with the number of IDRF and with the subset of vascular encasement IDRF.ResultsOf 101 patients, 77 were IDRF positive. In total, 74 underwent surgical resection and 32 (43.2%) had a surgical complication. Complications were related to the number of IDRF (OR 1.33, 95% CI 1.05 – 1.73, p = 0.02) and the subgroup of vascular encasement IDRF (OR 1.78, 95% CI 1.12 – 3.04, p = 0.01) but were not significantly correlated with the subgroup of non-vascular encasement IDRF. We report three cases of chyle leak associated with tumor encasing the origin of the celiac axis and/or the superior mesenteric artery.ConclusionsThe vascular encasement IDRF subgroup is potentially a more useful prognostic indicator of surgical complications than non-vascular IDRF. More studies are needed to correlate specific IDRF with specific surgical complications to aid operative decision making.Level of evidenceLevel IIIHighlightsImage Defined Risk Factors (IDRF) in neuroblastoma correlate with survival, completeness of resection, and surgical complications.Complications correlate specifically with the subset of vascular encasement IDRF. Chylous ascites was a specific complication associated with encasement of the celiac and superior mesenteric vessels.
EvAM-Tools: tools for evolutionary accumulation and cancer progression models
Authors: Diaz-Uriarte Ramon , Herrera-Nieto Pablo 
Published: July 2022

AbstractEvAM-Tools is an R package and web application that provides a unified interface to state-of-the-art cancer progression models (CPMs) and, more generally, evolutionary models of event accumulation. The output includes, in addition to the fitted models, the transition (and transition rate) matrices between genotypes and the probabilities of evolutionary paths. Generation of random cancer progression models is also available. Using the GUI in the web application, users can easily construct models (modifying Directed Acyclic Graphs —DAGs— of restrictions, matrices of mutual hazards, or specifying genotype composition), generate data from them (with user-specified observational/genotyping error), and analyze the data.Availability and ImplementationImplemented in R and C; open source code available under the GNU Affero General Public License v3.0 athttps://github.com/rdiaz02/EvAM-Tools. Docker images freely available fromhttps://hub.docker.com/u/rdiaz02. Web app freely accessible athttps://iib.uam.es/evamtools.Contactr.diaz@uam.es
Bacterial Polyphosphates Induce CXCL4 and Synergize with Complement Anaphylatoxin C5a in Lung Injury
Authors: Roewe Julian , Walachowski Sarah , Sharma Arjun , Berthiaume Kayleigh A. , Reinhardt Christoph , Bosmann Markus 
Published: July 2022

AbstractPolyphosphates are linear polymers of inorganic phosphates that exist in all living cells and serve pleiotropic functions. Bacteria produce long-chain polyphosphates, which can interfere with host defense to infection. In contrast, short-chain polyphosphates are released from platelet dense granules and bind to the chemokine, CXCL4.Here, we report that long-chain polyphosphates induced the release of CXCL4 from mouse bone marrow-derived macrophages and peritoneal macrophages in a dose-/time-dependent fashion resulting from an induction of CXCL4 mRNA. This polyphosphate effect was lost after pre-incubation with recombinant exopolyphosphatase (PPX) Fc fusion protein, demonstrating the potency of long chains over monophosphates and ambient cations. In detail, polyphosphate chains longer than 70 inorganic phosphate residues were typically required to mediate robust CXCL4 release. Polyphosphates acted independently of the purinergic P2Y1 receptor and the MyD88 and TRIF adaptors of Toll-like receptors. On the other hand, polyphosphates augmented LPS/MyD88-induced CXCL4 release, which was explained by intracellular signaling convergence on PI3K/Akt. Polyphosphates alone induced phosphorylation of Akt at threonine-308. Pharmacologic blockade of PI3K (wortmannin, LY294002) antagonized polyphosphate-induced CXCL4 release from macrophages. Intra-tracheal polyphosphate administration to C57BL/6J mice caused histologic signs of lung injury, disruption of the endothelial-epithelial barrier, influx of Ly6G+ polymorphonuclear neutrophils, depletion of CD11c+SiglecF+ alveolar macrophages, and release of CXCL4. Long-chain polyphosphates synergized with the complement anaphylatoxin, C5a, which was partly explained by upregulation of the receptor, C5aR1, on myeloid cells. C5aR1-/- mice were protected from polyphosphate-induced lung injury. In conclusion, we demonstrate that polyphosphates govern immunomodulation in macrophages and are capable of inducing lung injury.
Optogenetic Maxwell Demon to Exploit Intrinsic Noise and Control Cell Differentiation Despite Time Delays and Extrinsic Variability
Authors: May Michael P , Munsky Brian 
Published: July 2022

AbstractThe field of synthetic biology focuses on creating modular components which can be used to generate complex and controllable synthetic biological systems. Unfortunately, the intrinsic noise of gene regulation can be large enough to break these systems. Noise is largely treated as a nuisance and much past effort has been spent to create robust components that are less influenced by noise. However, extensive analysis of noise combined with ‘smart’ microscopy tools and optognenetic actuators can create control opportunities that would be difficult or impossible to achieve in the deterministic setting. In previous work, we proposed an Optogenetic Maxwell’s Demons (OMD) control problem and found that deep understanding and manipulation of noise could create controllers that break symmetry between cells, even when those cells share the same optogenetic input and identical gene regulation circuitry. In this paper, we extend those results to analyze (in silico) the robustness of the OMD control under changes in system volume, with time observation/actuation delays, and subject to parametric model uncertainties.
A small molecule ligand for the novel pain target GPR171 produces minimal reward in mice
Authors: McDermott Max V. , Ram Akila , Mattoon Matt T. , Haderlie Emmaline E. , Raddatz Megan C. , Thomason Madi K. , Bobeck Erin N. 
Published: July 2022

AbstractProSAAS is one of the most abundant proteins in the brain and is processed into several smaller peptides. One of which, BigLEN, is an endogenous ligand for the G protein-coupled receptor, GPR171. Recent work in rodent models has shown that a small-molecule ligand for GPR171, MS15203, increases morphine antinociception and is effective in lessening chronic pain. While these studies provide evidence for GPR171 as a possible pain target, its abuse liability has not yet been assessed which we evaluate in the current study. We first mapped the distribution of GPR171 and ProSAAS throughout the reward circuit of the brain using immunohistochemistry and showed that GPR171 and ProSAAS are localized in the hippocampus, basolateral amygdala, nucleus accumbens, prefrontal cortex. In the major dopaminergic structure, the ventral tegmental area (VTA), GPR171 appeared to be primarily localized in dopamine neurons while ProSAAS is outside of dopamine neurons. Next, MS15203 was administered to mice with or without morphine, and VTA slices were stained for the immediate early gene c-Fos as a marker of neuronal activation. Quantification of c-Fos-positive cells revealed no statistical difference between MS15203 and saline, suggesting that MS15203 does not increase VTA activation and dopamine release. Similarly, the results of a conditioned place preference experiment showed that treatment with MS15203 or MS15203 + Morphine produced no place preference compared to Saline indicating a lack of reward-related behavior. Taken together this data provides evidence that the novel pain therapeutic, MS15203, has minimal reward liability. Therefore, GPR171 deserves further exploration as a pain target.Significance StatementMS15203, a drug that activates the receptor GPR171, was previously shown to increase morphine analgesia. The authors use in vivo and histological techniques to show that it fails to activate the rodent reward circuitry, providing support for the continued exploration of MS15203 as a novel pain drug, and GPR171 a novel pain target.
Integrative modeling reveals the molecular architecture of the Intraflagellar Transport A (IFT-A) complex
Authors: McCafferty Caitlyn L. , Papoulas Ophelia , Jordan Mareike A. , Hoogerbrugge Gabriel , Nichols Candice , Pigino Gaia , Taylor David W. , Wallingford John B. , Marcotte Edward M. 
Published: July 2022

AbstractIntraflagellar transport (IFT) is a conserved process of cargo transport in cilia that is essential for development and homeostasis in organisms ranging from algae to vertebrates. In humans, variants in genes encoding subunits of the cargo-adapting IFT-A and IFT-B protein complexes are a common cause of genetic diseases known as ciliopathies. While recent progress has been made in determining the atomic structure of IFT-B, little is known of the structural biology of IFT-A. Here, we combined chemical cross-linking mass spectrometry and cryo-electron tomography with AlphaFold2-based prediction of both protein structures and interaction interfaces to model the overall architecture of the monomeric six-subunit IFT-A complex, as well as its polymeric assembly within cilia. We define monomer-monomer contacts and membrane-associated regions available for association with transported cargo, and we also use this model to provide insights into the pleiotropic nature of human ciliopathy-associated genetic variants in genes encoding IFT-A subunits. Our work demonstrates the power of integration of experimental and computational strategies both for multi-protein structure determination and for understanding the etiology of human genetic disease.SummaryThe 3D structure of the six-subunit complex and its polymeric assembly gives insights into cargo transport in cilia and how specific mutations in these genes lead to ciliopathy birth defects.
Sublethal and transgenerational effects of lambda-cyhalothrin and abamectin on the development and reproduction of Cydia pomonella
Authors: Ju Di , Liu Yu-Xi , Liu Xue , Dewer Youssef , Mota-Sanchez David , Yang Xue-Qing 
Published: July 2022

AbstractThe codling moth Cydia pomonella (Lepidoptera: Tortricidae) is a major invasive pest of pome fruits and walnuts worldwide. Lambda-cyhalothrin (LCT) and abamectin (AM) have been frequently used in C. pomonella control, but control of this pest is very difficult because shortly after hatching, larvae of this insect bore tunnels and hide inside host plant fruit. In this study, a simulated field spray bioassay method was developed against neonate larvae of C. pomonella and concentration-response bioassays were conducted to evaluate the susceptibility of the neonate larvae to LCT and AM. Exposure of neonate larvae to sublethal concentrations (LC30) of LCT or AM significantly reduced the survival rate of larvae (4th and 5th instars), lowered the mean weight of larvae and pupae, and decreased the daily maximal number of eggs laid and the total number of eggs laid (fecundity) per female. The sublethal effects, including reduced body mass, mean fecundity and net reproductive rate, extended mean generation time, and shortened oviposition period, were also found in transgenerational offspring. Furthermore, the transgenerational maternal effects were more obvious for AM than LCT, in comparison to the control. Additionally, the estimated population size was decreased by exposure to LC30 of LCT and AM, and the observed reduction of fecundity and population size within and across generations was likely the result of the downregulation of the reproduction-related vitellogenin gene (CpVg) after exposure to LC30 of LCT and AM. These results provide a better understanding of the overall effects of LCT and AM on C. pomonella and the transgenerational effects which should be taken into consideration when using insecticides in order to control C. pomonella.
Flavor Classification/Categorization and Differential Toxicity of Oral Nicotine Pouches (ONPs) in Lung Epithelial Cells
Authors: Shaikh Sadiya , Tung Wai Cheung , Lucas Joseph , Yogeswaran Shaiesh , Li Dongmei , Rahman Irfan 
Published: July 2022

ABSTRACTThe prevalence of flavored tobacco product usage amongst youth in the United States is partly due to the emergence of non-combustible nicotine-containing products (NCNPs), including oral nicotine pouches (ONPs) and smokeless tobacco products. ONPs are available in various different flavors (mint, fruity, tobacco, dessert, citrus, coffee, wintergreen, and berry) and may use either Tobacco-Derived Nicotine (TDN) or Tobacco-Free Nicotine (TFN). Currently, several brands of ONPs are sold in the U.S and comprise a significant portion of NCNP sales in the U.S. There is a growing concern that flavored ONPs may not only induce oral health effects, but may also induce systemic toxic effects due to nicotine and other ONP byproducts being absorbed into systemic circulation through the oral mucosa. These byproducts can act locally on other tissues and may potentially cause redox dysregulation and heightened inflammatory responses systemically in the respiratory, cardiovascular, and/or renal systems. Hence, we determined the effects of flavored ONPs from four of the most widely sold brands in the U.S in inducing toxicological effects on the respiratory epithelium. Prior to analyzing the effects ONPs, we first classified ONPs sold in the US based on their flavor and the flavor category to which they belong to using a wheel diagram. Subsequently, using human bronchial epithelial cells (16-HBE and BEAS-2B) exposed to extracts of flavored ONPs, we assessed the levels of ONP-induced inflammatory cytokine release (IL-6 and IL-8), cellular Reactive Oxygen Species (ROS) production, and cytotoxicity in the airway epithelium. Our data showed that cells exposed to the lowest concentration treatments showed increased cytotoxicity, differential cellular ROS production, and proinflammatory cytokine release. The most striking response was observed among cells treated with the spearmint ONP, whereas ONPs containing original tobacco and fruity flavors showed varied levels of ROS release in 16-HBE cells. Our data suggest that flavored ONPs are unsafe and likely to cause systemic and local toxicological responses during chronic usage. Our study is a part of ongoing efforts to use in vitro, ex-vivo, and in vivo systems to understand how the usage of various flavored ONPs may cause both oral and pulmonary toxicity, and impact human periodontal health.
Co-opted Genes of Algal Origin Protect C. elegans against Cyanogenic Toxins
Authors: Wang Bingying , Pandey Taruna , Long Yong , Delgado-Rodriguez Sofia E. , Daugherty Matthew D. , Ma Dengke K. 
Published: July 2022

SUMMARYAmygdalin is a cyanogenic glycoside widely used by many plants in herbivore defense. Poisonous to most animals, amygdalin-derived cyanide is detoxified by potent enzymes commonly found in bacteria and plants but not most animals. Here we show that the nematode C. elegans can detoxify amygdalin by a genetic pathway comprising cysl-1, egl-9, hif-1 and cysl-2. Essential for amygdalin resistance, cysl-1 encodes a protein similar to cysteine synthetic enzymes in bacteria and plants, but functionally co-opted in C. elegans. We identify exclusively HIF-activating egl-9 mutations in a cysl-1 suppressor screen and show that cysl-1 confers amygdalin resistance by regulating HIF-1-dependent cysl-2 transcription to protect against amygdalin toxicity. Phylogenetic analysis suggests cysl-1 and cysl-2 were likely acquired from green algae through horizontal gene transfer (HGT) and functionally co-opted in protection against amygdalin. Our studies reveal that HGT-mediated evolutionary changes can facilitate host survival and adaptation to adverse environment stresses and biogenic toxins.