bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural variation in expression of the mitochondrial flavoprotein WAH-1 alters response to cyanide inC. elegans
Authors: Mercado Maria P. , Tan June H. , Schertzberg Michael R. , Fraser Andrew G. 
Published: March 2023

AbstractC. elegansis a free-living nematode that must adapt to a wide range of environments including both aerobic and anaerobic conditions. To survive in low oxygen,C. eleganscan use an unusual form of anaerobic respiration that relies on rhodoquinone (RQ) as an alternative electron carrier. Parasitic nematodes like hookworm and whipworm also require rhodoquinone-dependent metabolism (RQDM) to survive in the highly anaerobic conditions in the human gut. Understanding how RQDM is regulated inC. elegansmay thus identify new ways to combat these closely-related major human pathogens. We previously established a simple movement-based assay for RQDM inC. elegans. In this study, we tested a panel of wild-type isolates ofC. elegansin our RQDM assay and find substantial variation in their ability to use RQDM. We carried out a genome-wide association study (GWAS) to identify loci that affect RQDM — this identified a single major QTL on the right arm of Chromosome III. We used RNAi to test almost all genes within the QTL region for involvement in RQDM and found one gene,wah-1, that strongly modulates RQDM-dependent recovery inC. elegans. WAH-1 is a mitochondrial flavoprotein that affects the electron transport chain, consistent with a role in RQDM. We show thatwah-1expression varies between isolates due to major changes inwah-1transcript structures and this correlates tightly with variation in RQDM. Finally, we show that there is similar complexity towah-1transcription in parasitic nematodes and thatwah-1transcript structures change as parasites shift from aerobic to anaerobic, RQ- requiring metabolism. We thus conclude that reducedwah-1expression correlates with increased ability to survive in conditions where RQDM is essential.
An intracellular hydrophobic nexus is critical for slow deactivation in hERG channels
Authors: Stevens-Sostre Whitney A. , Flores-Aldama Lisandra , Bustos Daniel , Li Jin , Delemotte Lucie , Robertson Gail A. 
Published: March 2023

AbstractSlow deactivation is a critical biophysical and physiological property of voltage-gated K+channels encoded by thehuman Ether-à-go-go-Related Gene(hERG). hERG channel deactivation is modulated by interactions between intracellular N-terminal Per-Arnt-Sim (PAS) and C-terminal cyclic nucleotide-binding homology (CNBh) domains. The PAS domain is multipartite, comprising a globular domain (residues 26-136) and an N-terminal PAS-cap that is further subdivided into an initial unstructured segment (residues 1-12) and an amphipathic α-helical region (residues 13-25). Disruption of interactions within the PAS-CNBhD complex accelerates deactivation kinetics and impairs the slow repolarization of the cardiac action potential. Similarly, deletion of the PAS-cap unstructured segment, modeled as a "foot-in-the-door,” accelerates channel closing. Here, we tested the hypothesis that a three-dimensional hydrophobic nexus, comprising residues in the PAS-cap α-helix, the globular PAS, and CNBh domains, plays a crucial role in slow deactivation. Utilizing structure-directed mutagenesis, electrophysiology, and molecular dynamics simulations, we provide evidence that altering hydrophobicity at this interface accelerates deactivation kinetics and causes a rearrangement in the network of residues comprising the hydrophobic nexus. Moreover, the PAS-cap unstructured segment disengages from the gating machinery. We propose that the nexus hydrophobicity positions the PAS-cap α-helix and promotes engagement of the upstream PAS-cap unstructured segment with the gating machinery, resulting in slow channel closing. Interestingly, several long QT syndrome disease mutations lie at this interface, underscoring the importance of the hydrophobic nexus and the novel role of the PAS-cap α-helix in hERG gating.
MerTK mediates the immunologically silent uptake of alpha-synuclein fibrils by human microglia
Authors: Dorion Marie-France , Senkevich Konstantin , Yaqubi Moein , Kieran Nicholas W. , Chen Carol X.-Q. , MacDonald Adam , Luo Wen , Wallis Amber , Shlaifer Irina , Hall Jeffery A. , Dudley Roy W. R. , Glass Ian A. ,   Birth Defects Research Laboratory, Stratton Jo Anne , Fon Edward , Bartels Tim , Antel Jack P. , Gan-or Ziv , Durcan Thomas M. , Healy Luke M. 
Published: March 2023

AbstractMerTK is a receptor tyrosine kinase that mediates the immunologically silent phagocytic uptake of diverse types of cellular debris. Highly expressed on the surface of microglial cell, MerTK is of importance in brain development, homeostasis, plasticity, and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with aging and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies.Using human primary and induced pluripotent stem cell-derived microglia, the MerTK- dependence of alpha-synuclein fibril internalization was investigatedin vitro. Relevance of this pathway to synucleinopathies was assessed by analyzing MerTK expression in patient-derived cells and tissues.Pharmacological inhibition of MerTK and siRNA-mediatedMERTKknockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the immunologically silent nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization did not induce secretion of pro-inflammatory cytokines from microglia. In addition, burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleteriousMERTKvariants and Parkinson’s disease in one of the cohorts (p= 0.002). Accordingly,MERTKexpression was significantly upregulated in nigral microglia from Parkinson’s disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (p= 5.08×10-21), and MerTK protein expression positively correlated with alpha-synuclein level in human cortex lysates (p= 0.0029).Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein aggregates by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson’s disease.
Spatially-Resolved Transcriptomics Define Clinically Relevant Subsets of Macrophages in Diffuse Large B-cell Lymphoma
Authors: Liu Min , Bertolazzi Giorgio , Mulder Kevin , Sridhar Shruti , Lee Rui Xue , Jaynes Patrick , Hoppe Michal Marek , Fan Shuangyi , Peng Yanfen , Thng Jocelyn , Chua Reiya , De Mel Sanjay , Poon Limei , Chan Esther , Lee Joanne , Hue Susan Swee-Shan , Ng Siok-Bian , Chandy K George , Ginhoux Florent , Chee Yen Lin , Tripodo Claudio , Jeyasekharan Anand D. 
Published: March 2023

AbstractBackgroundMacrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Conventional immunohistochemistry-based studies with varying prognostic significance precludes a comprehensive analysis of macrophage subtypes in DLBCL. We hypothesized that whole-transcriptomic analysis (WTA) of macrophage in-situ would identify new macrophage subsets of biological and clinical significances.MethodsDigital spatial profiling with WTA of CD68+ cells was performed in 47 DLBCL and 17 reactive lymphoid tissues (RLTs), to define macrophage signatures (termed “MacroSigs”) of distinct lymphoid spatial niches and clinical scenarios. Eight independent DLBCL datasets (4,594 patients) with transcriptomic and survival information were used for validation of MacroSigs.ResultsDigital spatial profiling revealed previously unrecognized transcriptomic differences between macrophages populating distinct spatial compartments in RLTs (light zone (LZ)/ dark zone (DZ), germinal center (GC)/ interfollicular (IF) regions), and in between disease states (RLTs and DLBCL with or without relapsed disease). This transcriptomic diversity of macrophages was categorized into eight MacroSigs. Spatial-MacroSigs associate with specific cell-of-origin (COO) subtypes of DLBCL, of particular interest being the IF-MacroSig enriched in the unclassified COO (P<0.005, 6/8 datasets). MacroSigs of relapsed-DLBCL and DZ were prognostic for shorter overall survival (P<0.05 in 5/8 datasets;P<0.05 in 8/8 datasets, respectively). Projection onto a macrophage single-cell RNA-sequencing atlas reveals the Non-relapse-DLBCL MacroSig to depict HES1/FOLR2-like macrophages, while relapse-DLBCL-MacroSig represents IL1B-like monocytes, with unique therapeutic vulnerabilities for each.ConclusionsThis study first provides spatially-resolved macrophage WTA in reactive and malignant lymphoid tissues. Gene expression signatures of macrophages in the DZ and relapsed-DLBCL samples are consistently prognostic in multiple datasets and offer insights into novel therapeutic strategies for DLBCL.
KSHV uses viral IL6 to expand infected immunosuppressive macrophages
Authors: Shimoda Michiko , Inagaki Tomoki , Davis Ryan R. , Merleev Alexander , Tepper Clifford G. , Maverakis Emanual , Izumiya Yoshihiro 
Published: March 2023

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi’s sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Here we demonstrate that KSHV preferentially infects CD14+monocytes and sustains viral replication through the viral interleukin-6 (vIL6)-mediated activation of STAT1 and 3. Using vIL6-sufficient and vIL6-deficient recombinant KSHV, we demonstrated that vIL6 plays a critical role in promoting the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL6-sufficient KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL6-deficient KSHV infection or uninfected control. These results highlight a clever strategy, in which KSHV utilizes vIL6 to secure its viral pool by expanding infected dysfunctional macrophages. This mechanism also facilitates KSHV to escape from host immune surveillance and to establish a lifelong infection. 160SummaryKSHV causes multiple inflammatory diseases, however, the underlying mechanism is not clear. Shimoda et al. demonstrate that KSHV preferentially infects monocytes and utilizes virally encoded interleukin-6 to expand and deregulate infected monocytes. This helps the virus escape from host immune surveillance.
Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030
Authors: Parsons Heather A. , Blewett Timothy , Chu Xiangying , Sridhar Sainetra , Santos Katheryn , Xiong Kan , Abramson Vandana G. , Patel Ashka , Cheng Ju , Brufsky Adam , Rhoades Justin , Force Jeremy , Liu Ruolin , Traina Tiffany A. , Carey Lisa A. , Rimawi Mothaffar F. , Miller Kathy D. , Stearns Vered , Specht Jennifer , Falkson Carla , Burstein Harold J. , Wolff Antonio C. , Winer Eric P. , Tayob Nabihah , Krop Ian E. , Makrigiorgos G. Mike , Golub Todd R. , Mayer Erica L. , Adalsteinsson Viktor A. 
Published: March 2023

AbstractPurposeTo examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT).Patients and MethodsWe identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.ResultsOf 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10−4(range: 7.9 × 10−7to 4.9 × 10−1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12.ConclusionNAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.
C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter in normative aging
Authors: Alsameen Maryam H. , Gong Zhaoyuan , Qian Wenshu , Kiely Matthew , Triebswetter Curtis , Bergeron Christopher M. , Cortina Luis E. , Faulkner Mary E. , Laporte John P. , Bouhrara Mustapha 
Published: March 2023

ABSTRACTPurposeNeurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM.MethodsUsing NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration.ResultsODI derived values using both approaches were virtually identical. We confirm the previous finding that NDI estimation using NODDI is TE-dependent. In contrast, C-NODDI-NDI exhibit lower susceptibility to TE. Further, C-NODDI-NDI values were lower than NODDI-NDI. Further, our results indicate a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. ODI exhibited overall constant trends with age. Finally, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared NODDI-NDI, with lower NDI values correspond to higher levels of NfL.ConclusionsC-NODDI provides a complementary method to NODDI for determination of NDI in white matter in normative aging.
Tigerfish designs oligonucleotide-basedin situhybridization probes targeting intervals of highly repetitive DNA at the scale of genomes
Authors: Aguilar Robin , Camplisson Conor K. , Lin Qiaoyi , Miga Karen H. , Noble William S. , Beliveau Brian J. 
Published: March 2023

AbstractFluorescentin situhybridization (FISH) is a powerful method for the targeted visualization of nucleic acids in their native contexts. Recent technological advances have leveraged computationally designed oligonucleotide (oligo) probes to interrogate >100 distinct targets in the same sample, pushing the boundaries of FISH-based assays. However, even in the most highly multiplexed experiments, repetitive DNA regions are typically not included as targets, as the computational design of specific probes against such regions presents significant technical challenges. Consequently, many open questions remain about the organization and function of highly repetitive sequences. Here, we introduce Tigerfish, a software tool for the genome-scale design of oligo probes against repetitive DNA intervals. We showcase Tigerfish by designing a panel of 24 interval-specific repeat probes specific to each of the 24 human chromosomes and imaging this panel on metaphase spreads and in interphase nuclei. Tigerfish extends the powerful toolkit of oligo-based FISH to highly repetitive DNA.
ELITE: Expression deconvoLution using lInear optimizaTion in bulk transcriptomics mixturEs
Authors: Antoranz Asier , Mackintosh Carlos , Ortiz María , Pey Jon 
Published: March 2023

AbstractUnderstanding the cellular composition of tissue samples is crucial for identifying the molecular mechanisms underlying diseases and developing cellular targets for therapeutic interventions. Digital cytometry methods have been developed to predict tissue composition from bulk transcriptomic data, avoiding the high cost associated with single-cell profiling. Here, we present ELITE, a new digital cytometry method that utilizes linear programming to solve the deconvolution problem. ELITE uses as inputs a mixture matrix representing bulk measurements, and a signature matrix representing molecular fingerprints of the cell types to be identified. The signature matrix can be obtained from single-cell datasets or the literature, making ELITE more flexible than other methods that rely solely on single-cell data. We evaluated ELITE on three publicly available single-cell datasets and compared it with five other deconvolution methods, showing superior performance, particularly when there were cell types with similar expression profiles. As a case study, we evaluated the prediction of tumor cellularity using purity estimates from 20 different TCGA carcinoma datasets.
Working memory-based and -free reward prediction in a dual dopamine system in the basal ganglia
Authors: Yoshizawa Tomohiko , Miyamura Yuuto , Ochi Yuta , Hira Riichiro , Funahashi Makoto , Sakai Yutaka , Cui Yilong , Isomura Yoshikazu 
Published: March 2023

AbstractAnimals optimize their actions by predicting and verifying their outcomes (e.g., rewards). Reward prediction often requires working memory (WM)-based information. To elucidate the neural basis of WM-based reward prediction, we compared the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) in an alternate reward condition (WM-based) with that in a random (WM-free) reward condition in rats and mice. Positron emission tomography revealed greater VTA activation in the WM-based than the WM-free condition. Lateral and medial VTA neurons displayed differential electrophysiological spike activities reflecting WM-based and WM-free reward prediction error, respectively. Furthermore, phasic DA release in the dorsal and ventral striatum changed as WM-based and WM-free classical conditioning progressed. Consistent with our WM-based model, reward acquisition caused a DA dip only in the dorsal striatum. Thus a dual DA system processes WM-based and WM-free reward prediction in parallel.
optimalTAD: annotation of topologically associating domains based on chromatin marks enrichment
Authors: Smirnov Dmitrii N. , Kononkova Anna D. , Toiber Debra , Gelfand Mikhail S. , Khrameeva Ekaterina E. 
Published: March 2023

AbstractIn many eukaryotes, chromosomes are organized as strings of spatially segregated Topologically Associating Domains (TADs), characterized by a substantially increased frequency of interactions within them. Boundaries of TADs are highly enriched in histone acetylation chromatin marks and occupied binding sites of architectural proteins, highlighting the functional role of TADs in the regulation of gene expression. While many computational approaches have been developed for TAD identification, it remains challenging because of their nested structure, resulting in weakly overlapping sets of TADs at different scales. Here, we propose a novel algorithmoptimalTADfor identifying the optimal set of TADs based on epigenetic marks enrichment. Assuming that the most dramatic enrichment corresponds to the best annotation of TAD boundaries, our algorithm optimizes TAD calling parameters by maximizing the difference in chromatin mark levels between TADs and their boundaries. Using this algorithm, we annotated TADs in multiple publicly available fruit fly and mammalian Hi-C datasets and identified a set of epigenetic marks that are best suited for TAD prediction. Through the analysis of diverse organisms and cell types with distinct underlying principles of TAD organization, we have shown thatoptimalTADis a universal tool suitable for studying TAD structure, functions, and properties unique to specific cell types and organisms.optimalTADis freely available at GitHub:https://github.com/cosmoskaluga/optimalTAD.Key PointsWe assume that the most dramatic enrichment of epigenetic marks corresponds to the best annotation of TAD boundaries.Our algorithm optimizes TAD calling parameters by maximizing the difference in chromatin mark levels between TADs and their boundaries.optimalTADis a universal tool that is applicable for studying TAD characteristics in diverse organisms and cell types.optimalTADenables the identification of a specific set of epigenetic marks that are most suitable for annotating TADs.
Spontaneous Necker-Cube Reversals are not that Spontaneous
Authors: Wilson Mareike , Hecker Lukas , Joos Ellen , Aertsen Ad , Tebartz van Elst Ludger , Kornmeier Jürgen 
Published: March 2023

AbstractDuring observation of the ambiguous Necker cube, our perception suddenly reverses between two about equally possible 3D interpretations. During passive observation, perceptual reversals seem to be sudden and spontaneous. A number of theoretical approaches postulate destabilization of neural representations as a precondition for spontaneous reversals of ambiguous figures. In the current study, we focused on possible EEG correlates of perceptual destabilization, that may allow to predict an upcoming perceptual reversal.We presented ambiguous Necker cube stimuli in an onset-paradigm and investigated the neural processes underlying endogenous reversals as compared to perceptual stability across two consecutive stimulus presentations. In a separate experimental condition, disambiguated cube variants were alternated randomly, to exogenously induce perceptual reversals. We compared the EEG immediately before and during endogenous Necker cube reversals with corresponding time windows during exogenously induced perceptual reversals of disambiguated cube variants.For the ambiguous Necker cube stimuli, we found the earliest differences in the EEG between reversal trials and stability trials already one second before a reversal occurred, at bilateral parietal electrodes. The traces remained similar until approximately 1100 ms before a perceived reversal, became maximally different at around 890 ms (p=7.59*10−6, Cohen’s d=1.35) and remained different until shortly before offset of the stimulus preceding the reversal. No such patterns were found in the case of disambiguated cube variants.The identified EEG effects may reflect destabilized states of neural representations, related to destabilized perceptual states preceding a perceptual reversal. They further indicate that spontaneous Necker cube reversals are most probably not as spontaneous as generally thought. Rather, the destabilization may occur over a longer time scale, at least one second before a reversal event.