bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease
Authors: Tsai Andy P. , Dong Chuanpeng , Lin Peter Bor-Chian , Oblak Adrian L. , Di Prisco Gonzalo Viana , Wang Nian , Hajicek Nicole , Carr Adam J. , Lendy Emma K. , Hahn Oliver , Atkins Micaiah , Foltz Aulden G. , Patel Jheel , Xu Guixiang , Moutinho Miguel , Sondek John , Zhang Qisheng , Mesecar Andrew D. , Liu Yunlong , Atwood Brady K. , Wyss-Coray Tony , Nho Kwangsik , Bissel Stephanie J. , Lamb Bruce T. , Landreth Gary E. 
Published: December 2022

SummaryGenetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer’s disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant ofPLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. We report the identification of aPLCG2variant,PLCG2M28L, associated with loss-of-function and confers increased AD risk. PLCG2P522Rattenuates disease in an amyloidogenic murine AD model, whereasPLCG2M28Lexacerbates the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2M28Las a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.Graphical abstractHighlightsA genetic variant of PLCG2, M28L, is associated with an increased risk for Alzheimer’s disease (AD)In an amyloidogenic AD mouse model, PLCG2M28L exacerbates disease pathogenesisConversely, PLCG2P522R, a protective PLCG2 variant, attenuates AD pathogenesisThe PLCG2 variants uniquely alter the microglial transcriptome and phenotypes
Capabilities of the CCi-Mobile Cochlear Implant Research Platform for Real-Time Sound Coding
Authors: Azadpour Mahan , Saba Juliana , Hansen John H.L. , Svirsky Mario A. 
Published: December 2022

AbstractOne important obstacle to optimizing fitting and sound coding for auditory implants is lack of flexible, powerful and portable platforms that can be used in real-world listening environments by implanted patients. The clinical processors and the typically available research tools either do not have sufficient computational power and flexibility or are not portable. In response to this need, the Center for Robust Speech Systems (CRSS) at the University of Texas at Dallas has developed CCI-Mobile, in collaboration with the Laboratory for Translational Auditory Research at New York University School of Medicine and the Binaural Hearing and Speech Laboratory at the University of Wisconsin-Madison. The CCI-Mobile platform provides unique flexibility to implement a variety of real-time sound coding algorithms in real-world environments, including algorithms that require synchronized binaural stimulation. In this paper, we will describe the overall architecture of the CCI-Mobile platform and provide practical considerations for designing real-time sound coding algorithms with this platform. CCI-Mobile is under development and future generations may provide further functionality, beyond what is described in this paper.
Structural basis for translation inhibition by the glycosylated antimicrobial peptide Drosocin fromDrosophila melanogaster
Authors: Koller Timm O. , Morici Martino , Berger Max , Safdari Haaris A. , Lele Deepti S. , Beckert Bertrand , Kaur Kanwal J. , Wilson Daniel N. 
Published: December 2022

AbstractThe proline-rich antimicrobial peptide (PrAMP) drosocin is produced byDrosophilaspecies to combat bacterial infection. Unlike many PrAMPs, drosocin is O-glycosylated at threonine 11, a post-translation modification that enhances its antimicrobial activity. Here we demonstrate that the O-glycosylation influences not only cellular uptake of the peptide, but also interacts with its intracellular target, the ribosome. Cryo-electron microscopy structures of glycosylated drosocin on the ribosome at 2.1-2.8 Å resolution reveal that the peptide interferes with translation termination by binding within the polypeptide exit tunnel and trapping RF1 on the ribosome, reminiscent of that reported for the PrAMP apidaecin. The glycosylation of drosocin enables multiple interactions with U2609 of the 23S rRNA, leading to conformational changes that break the canonical base-pair with A752. Collectively, our study provides novel molecular insights into the interaction of O-glycosylated drosocin with the ribosome, which provides a structural basis for future development of this class of antimicrobials.
Neisseria gonorrhoeaeco-opts C4b-binding protein to enhance complement-independent survival from neutrophils
Authors: Werner Lacie M. , Alcott Allison , Mohlin Frida , Ray Jocelyn C. , Dufrisne Meagan Belcher , Smirnov Asya , Columbus Linda , Blom Anna M. , Criss Alison K. 
Published: December 2022

AbstractNeisseria gonorrhoeae(Gc) is a human-specific pathogen that causes the sexually transmitted infection gonorrhea. Gc survives in neutrophil-rich gonorrheal secretions, and recovered bacteria predominantly express phase-variable, surface-expressed opacity-associated (Opa) proteins (Opa+). However, expression of Opa proteins like OpaD decreases Gc survival when exposed to human neutrophilsex vivo. Here, we made the unexpected observation that incubation with normal human serum, which is found in inflamed mucosal secretions, enhances survival of Opa+ Gc from primary human neutrophils. We directly linked this phenomenon to a novel complement-independent function for C4b-binding protein (C4BP). When bound to the bacteria, C4BP was necessary and sufficient to suppress Gc-induced neutrophil reactive oxygen species production and prevent neutrophil phagocytosis of Opa+ Gc. This research identifies for the first time a complement-independent role for C4BP in enhancing the survival of a pathogenic bacterium from phagocytes, thereby revealing how Gc exploits inflammatory conditions to persist at human mucosal surfaces.Author SummaryGonorrhea is considered an urgent threat to public health with an estimated 98 million cases occurring annually worldwide, growing antimicrobial resistance, and the absence of a gonococcal vaccine. Currently, we do not understand howN. gonorrhoeaeexpressing opacity (Opa) proteins survive neutrophil defenses and are recovered viable from infected patients. Here, we investigated how soluble elements of gonorrhea infection, present in human serum, contribute toN. gonorrhoeaesurvival from neutrophils. We found that the serum component C4b-binding protein (C4BP) protectsN. gonorrhoeaefrom neutrophil killing and suppresses neutrophil activation. C4BP limited neutrophil phagocytosis ofN. gonorrhoeaethat expressed Opa proteins that bound to neutrophil receptors of the CEACAM family. This work provides novel insight into the interplay between the noncellular and cellular aspects of the innate immune response toN. gonorrhoeae.
Incidence, antifungal resistance properties, and virulence traits of candida species isolated from HIV/AIDS Patients from the hospital system in Kenya
Authors: Miruka Haron N. , Eric Omwenga O. , Musyoki Stanslaus , Awuor Silas O. 
Published: December 2022

ABSTRACTCandidiasis is the most common fungal infection in hospitalized patients with acquired immune deficiency syndrome resulting to morbidity and mortality. This study aimed at characterizing, incidence, susceptibility, resistance genes, antibiofilm activity, and virulence traits ofCandidaspecies isolated from HIV-Infected patients. One hundred and eighty-one samples were collected and cultured on Sabouraud Dextrose Agar, biochemical tests and confirmed using automated Vitek-2®Compact bioMérieux followed by susceptibility tests. were done by use of various conventional antifungals against the isolates using standard procedures. Virulence factors, biofilm formations and resistance genes of Candida strains were determined. Out of the 181 samples, 46 were identified asCandida spp., 20C. albicans(43.5%), 6C. tropicalis(13.0%), 8C. krusei(17.4%), 4C. glabrata(8.7%), 3C. famata(6.5%), 3C. parapsilosis(6.5%), and2 C. guilliermondii(4.3%). All theCandida albicansisolated were both Gram positive and Germ test tube test positive. Eighteen (90%) of the isolates were susceptible to Clotrimazole at a concentration of 5 μg/mL – 10μg/mL followed by 17 (85%) isolates to Panosoconazole at a concentration of 0.002 μg/mL – 5μg/mL. Eight (40.0 %) of theCandida albicansisolates possessed the gene (cdr1) that was observed at 286 bp. Virulence enzymes was determined in which 100% produced Haemolysin, followed by proteinase (75.0%), phospholipase (50%), coagulase at (50%) and lastly capsulase (25.0%). Fluconazole and Clotrimazole did not inhibit growth ofC. albicansat high concentrations but from our study, it was deduced that they inhibit biofilm formation at lower concentrations.C. albicansisolates were resistant to multiple antifungal including those commonly used in the management on HIV/AIDs patient. This attributed to resistant genes and produced various virulence factors that were found to be present in the isolates. Therefore, there is a need to carry out regular surveillance on antifungal drug resistance.
Endosomal egress and intercellular transmission of hepatic ApoE-containing lipoproteins and its exploitation by the hepatitis C virus
Authors: Pham Minh-Tu , Lee Ji-Young , Ritter Christian , Thielemann Roman , Haselmann Uta , Funaya Charlotta , Laketa Vibor , Rohr Karl , Bartenschlager Ralf 
Published: December 2022

AbstractLiver-generated plasma Apolipoprotein E (ApoE)-containing lipoproteins (LPs) (ApoE-LPs) play central roles in lipid transport and metabolism. Perturbations of ApoE can result in several metabolic disorders and ApoE genotypes have been associated with multiple diseases. ApoE is synthesized at the endoplasmic reticulum and transported to the Golgi apparatus for LP assembly; however, ApoE-LPs transport from there to the plasma membrane is largely unknown. Here, we established an integrative imaging approach based on a fully functional fluorescently tagged ApoE. We found that ApoE-LPs accumulate in CD63-positive endosomes of hepatocytes. In addition, we observed the co-egress of ApoE-LPs and extracellular vesicles (EVs) along the late endosomal trafficking route. Moreover, complexes of ApoE-LPs and CD63-positive EVs were found to be transmitted from cell to cell. Given the important role of ApoE in viral infections, we studied the hepatitis C virus (HCV) and found that the viral replicase protein NS5A is enriched in ApoE-containing intraluminal vesicles. Interaction between NS5A and ApoE is required for the efficient release of EVs containing viral RNA. These vesicles are transported along the endosomal ApoE egress pathway. Taken together, our data argue for endosomal egress and transmission of hepatic ApoE-LPs, a pathway that is hijacked by HCV. Given the more general role of EV-mediated cell-to-cell communication, these insights provide new starting points for research into the pathophysiology of ApoE-related metabolic and infection-related disorders.Author SummaryThe post-Golgi egress pathway of hepatocyte-derived ApoE-containing lipoproteins (ApoE-LPs) is largely unknown. By using integrative imaging analyses, we show that ApoE-LPs are enriched in CD63-positive endosomes suggesting that these endosomes might be a central hub for the storage of ApoE-LPs from which they are released into the circulation. In addition, we provide evidence for the co-egress of ApoE-LPs with extracellular vesicles (EVs) along the late endosomal route and their transfer from cell to cell. This pathway is hijacked by the hepatitis C virus that induces the production of ApoE-associated EVs containing viral RNA. Given the important role of ApoE in multiple metabolic, degenerative and infectious diseases, and the role of EVs in cell-to-cell communication, these results provide important information how perturbations of ApoE might contribute to various pathophysiologies.
ESCRT pathway-dependent MVBs contribute to the morphogenesis of the fungusArthrobotrys oligospora
Authors: Tian Mengqing , Huang Jinrong , Cui Peijie , Li Guohong , Zhang Keqin , Wang Xin 
Published: December 2022

AbstractAmmonia opens trap formation in the nematode-trapping (NT) fungusArthrobotrys oligospora, an intriguing morphological switch in NT fungi, where saprophytic mycelia are converted to pathogenic organs. Endocytosis plays a prominent role in nutrient uptake, signaling cascades, and maintenance of cellular homeostasis in higher eukaryotes. Here, we demonstrate that ammonia efficiently promotes endocytosis via the formation of 3D-adhesive mycelial nets inA. oligospora. Trap production is followed by the presence of massive multivesicular bodies (MVBs) and membrane rupture and repair. Additionally, both the ubiquitin-proteasome system and the endosomal sorting complex for transport (ESCRT) pathway are immediately linked to endocytosis regulation and MVB formation in ammonia-induced trap formation. Moreover, disruption of the ESCRT-1 complex subunit proteins AoHse and AoVps27 led to the complete loss of membrane endocytosis and trap formation. Finally, the deletion of the deubiquitinase AoSst2 caused a significant reduction in the number of trap structures produced in response to exposure to ammonia or nematodes. Overall, our results increase our knowledge of the molecular mechanisms underlying the phenotypic changes in the NT fungal group, demonstrating that the endocytosis-ESCRT-MVB pathway participates in the regulation of trapping organs.Author SummaryThe lifestyle switch of nematode-trapping (NT) fungi is a significant event that increases their pathogenicity to nematode prey, which has resulted in large losses to agricultural crops worldwide. Here, we describe the molecular mechanism underlying how this fungal group forms a NT structure in response to ammonia, a widely preferred nitrogen source in soil niches. Ammonia enhances the endocytosis process, ubiquitin-proteasome system, and endosomal sorting complex for transport (ESCRT) pathway of the model NT fungusA. oligospora, thereby generating enriched multivesicular bodies (MVBs) during trap formation. In this process, the cell membrane morphology is remarkably damaged and then repaired. We further found that disruption of the ESCRT-0 subcomplex or ubiquitinase severely blocked trap production and membrane reorganization. Our study provides a new understanding of endocytosis-ESCRT-MVB flux in the transition of fungal NT organs.
Phylogenetic inference using Generative Adversarial Networks
Authors: Smith Megan L. , Hahn Matthew W. 
Published: December 2022

AbstractMotivationThe application of machine learning approaches in phylogenetics has been impeded by the vast model space associated with inference. Supervised machine learning approaches require data from across this space to train models. Because of this, previous approaches have typically been limited to inferring relationships among unrooted quartets of taxa, where there are only three possible topologies. Here, we explore the potential of generative adversarial networks (GANs) to address this limitation. GANs consist of a generator and a discriminator: at each step, the generator aims to create data that is similar to real data, while the discriminator attempts to distinguish generated and real data. By using an evolutionary model as the generator, we use GANs to make evolutionary inferences. Since a new model can be considered at each iteration, heuristic searches of complex model spaces are possible. Thus, GANs offer a potential solution to the challenges of applying machine learning in phylogenetics.ResultsWe developed phyloGAN, a GAN that infers phylogenetic relationships among species. phy-loGAN takes as input a concatenated alignment, or a set of gene alignments, and infers a phylogenetic tree either considering or ignoring gene tree heterogeneity. We explored the performance of phyloGAN for up to fifteen taxa in the concatenation case and six taxa when considering gene tree heterogeneity. Error rates are relatively low in these simple cases. However, run times are slow and performance metrics suggest issues during training. Future work should explore novel architectures that may result in more stable and efficient GANs for phylogenetics.AvailabilityphyloGAN is available on github:https://github.com/meganlsmith/phyloGAN/.Contactmls16@indiana.edu
Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer’s disease neurons
Authors: Haukedal Henriette , Corsi Giulia I. , Gadekar Veerendra P. , Doncheva Nadezhda T. , Kedia Shekhar , de Haan Noortje , Chandrasekaran Abinaya , Jensen Pia , Schiønning Pernille , Vallin Sarah , Marlet Frederik Ravnkilde , Poon Anna , Pires Carlota , Agha Fawzi Khoder , Wandall Hans H. , Cirera Susanna , Simonsen Anja Hviid , Nielsen Troels Tolstrup , Nielsen Jørgen Erik , Hyttel Poul , Muddashetty Ravi , Aldana Blanca I. , Gorodkin Jan , Nair Deepak , Meyer Morten , Larsen Martin Røssel , Freude Kristine 
Published: December 2022

ABSTRACTAlzheimer’s disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied Amyloid beta (Aβ) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD disease phenotypes, such as increased Aβ secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in variousin vivoandin vitrocomplementary disease models, which can be exacerbated via additional risk variants inSORL1.Abstract Figure
Genetic validation ofPfFKBP35 as an antimalarial drug target
Authors: Thommen Basil T. , Dziekan Jerzy M. , Achcar Fiona , Tjia Seth , Passecker Armin , Buczak Katarzyna , Gumpp Christin , Schmidt Alexander , Rottmann Matthias , Grüring Christof , Marti Matthias , Bozdech Zbynek , Brancucci Nicolas M. B. 
Published: December 2022

AbstractPlasmodium falciparumaccounts for the majority of over 600’000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding proteinPfFKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus). Whilst there is considerable interest in targetingPfFKBP35 with small molecules, a genetic validation of this factor as a drug target is missing and its function in parasite biology remains elusive. Here, we show that limitingPfFKBP35 levels are lethal toP. falciparumand result in a delayed death-like phenotype that is characterized by defective ribosome homeostasis and stalled protein synthesis. Our data furthermore suggest that FK506, unlike the action of this drug in model organisms, exerts its anti-proliferative activity in aPfFKBP35-independent manner and, using cellular thermal shift assays, we identify putative FK506-targets beyondPfFKBP35. In addition to revealing first insights into the function ofPfFKBP35, our results show that FKBP-binding drugs can adopt non-canonical modes of action – with major implications for the development of FK506-derived molecules active againstPlasmodiumparasites and other eukaryotic pathogens.
5-HT1Aand 5-HT2Breceptor interaction and co-clustering regulates serotonergic neuron excitability
Authors: Benhadda Amina , Delhaye Célia , Moutkine Imane , Marques Xavier , Russeau Marion , Magueresse Corentin Le , Roumier Anne , Lévi Sabine , Maroteaux Luc 
Published: December 2022

AbstractMany psychiatric diseases including depression, schizophrenia and anxiety have been associated with serotonin (5-HT) neuron dysfunction. Pacemaker-like firing of raphe 5-HT neurons was proposed to be under unique 5-HT1Areceptor-mediated autoinhibition. We previously showed that 5-HT2Breceptors were expressed by 5-HT neurons together with 5-HT1Areceptors. However, functional consequences on 5-HT neurons of putative interaction between these receptors are unknown. Using co-immunoprecipitation, BRET, confocal and super-resolution microscopy in hippocampal and 5-HT neurons, we present converging evidence that 5-HT1Aand 5-HT2Breceptors can form heterodimers and co-cluster at the surface of dendrites. 5-HT2Breceptor clusters were redistributed upon 5-HT1Areceptor expression supporting functional interactions between the two receptors. Furthermore, 5-HT2Breceptor expression prevented agonist-induced internalization of 5-HT1Areceptors, whereas 5-HT1Areceptors mimicked the clustering effect of 5-HT2Breceptor stimulation on its surface expression. The functional impact of this interactionin-vivowas assessed by recording 5-HT neuron excitability from mice lacking 5-HT2Breceptors in 5-HT neurons. Upon 5-HT1Areceptor stimulation, the firing activity of 5-HT neurons was increased in the absence of 5-HT2Breceptors and decreased in their presence through regulation of SK channels, thus demonstrating functional output of this interaction in controlling 5-HT neuron firing activity.