bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel triple-action inhibitor targeting B-cell receptor signaling and BRD4 demonstrates preclinical activity in chronic lymphocytic leukemia
Authors: Smith Audrey L. , Eiken Alexandria P. , Moore Dalia Y. , Umeta Lelisse T. , Smith Lynette M. , Lyden Elizabeth R. , D’Angelo Christopher R. , Kallam Avyakta , Vose Julie M. , Kutateladze Tatiana G. , El-Gamal Dalia 
Published: May 2022

AbstractB-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival-signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL still remains an incurable disease due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination therapy-related toxicities. Using SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, we demonstrate that SRX3305 attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits activation-induced proliferation of primary CLL cells in vitro, and effectively blocks microenvironment-mediated survival signals including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL providing significant rationale for its development as a therapeutic agent for CLL and related disorders.
IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function
Authors: Kotas Maya E. , Moore Camille M. , Gurrola Jose G. , Pletcher Steven D. , Goldberg Andrew N. , Alvarez Raquel , Yamato Sheyla , Bratcher Preston E. , Shaughnessy Ciaran A. , Zeitlin Pamela L. , Zhang Irene , Li Yingchun , Montgomery Michael T. , Lee Keehoon , Cope Emily K. , Locksley Richard M. , Seibold Max A. , Gordon Erin D. 
Published: May 2022

AbstractChronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single cell RNA sequencing of airway epithelium and mouse modeling, we find that IL-13 expands and programs airway tuft cells towards eicosanoid metabolism, and that tuft cell deficiency leads to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bear a signature of prostaglandin E2 activation, and PGE2 activation leads to CFTR-dependent ion and fluid secretion and accelerated mucociliary transport. Together these data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.
Parasites, infections and inoculation in synthetic minimal cells
Authors: Cash Brock , Gaut Nathaniel J. , Deich Christopher , Johnson Laura L. , Engelhart Aaron E. , Adamala Katarzyna P. 
Published: May 2022

AbstractSynthetic minimal cells provide a controllable and engineerable model for an increasing amount of biological processes. While much simpler than any live natural cell, synthetic cells offer a chassis for investigating the foundations of key biological processes. Here we show a synthetic cell system describing host cells interacting with parasites and infections of varying severity. We demonstrate how the host can be engineered to resist infection, we investigate the metabolic cost of carrying resistance, and we show a simple inoculation system that immunizes the host against pathogens. Our work expands the synthetic cell engineering toolbox by demonstrating host pathogen interactions and mechanisms for acquiring immunity. This brings synthetic cell systems one step closer to providing a comprehensive model of complex, natural life.
Improving peptide-level mass spectrometry analysis via double competition
Authors: Lin Andy , Short Temana , Noble William Stafford , Keich Uri 
Published: May 2022

AbstractThe analysis of shotgun proteomics data often involves generating lists of inferred peptide-spectrum matches (PSMs) and/or of peptides. The canonical approach for generating these discovery lists is by controlling the false discovery rate (FDR), most commonly through target-decoy competition (TDC). At the PSM level, TDC is implemented by competing each spectrum’s best-scoring target (real) peptide match with its best match against a decoy database. This PSM-level procedure can be adapted to the peptide level by selecting the top-scoring PSM per peptide prior to FDR estimation. Here we first highlight and empirically augment a little-known previous work by He et al., which showed that TDC-based PSM-level FDR estimates can be liberally biased. We thus propose that researchers instead focus on peptide-level analysis. We then investigate three ways to carry out peptide-level TDC and show that the most common method (“PSM-only”) offers the lowest statistical power in practice. An alternative approach that carries out a double competition, first at the PSM and then at the peptide level (“PSM-and-peptide”), is the most powerful method, yielding an average increase of 17% more discovered peptides at a 1% FDR threshold relative to the PSM-only method.
Optogenetic rejuvenation of mitochondrial membrane potential extendsC. eleganslifespan
Authors: Berry Brandon J. , Vodičková Anežka , Müller-Eigner Annika , Meng Chen , Ludwig Christina , Kaeberlein Matt , Peleg Shahaf , Wojtovich Andrew P. 
Published: May 2022

AbstractDespite longstanding scientific interest in the centrality of mitochondria to biological aging, directly controlling mitochondrial function to test causality has eluded researchers. We show that specifically boosting mitochondrial membrane potential through a light-activated proton pump reversed age-associated phenotypes and extendedC. eleganslifespan. We show that harnessing the energy of light to experimentally increase mitochondrial membrane potential during adulthood alone is sufficient to slow the rate of aging.
Hippocampus Modulates Natural Sound Processing at Early Auditory Centers
Authors: Wong Eddie C. , Wang Xunda , Wu Ed X. , Leong Alex T. L. 
Published: May 2022

AbstractDespite its prominence in learning and memory, hippocampal influence in early auditory processing centers remains unknown. Here, we examined how hippocampal activity modulates sound-evoked responses in the auditory midbrain and thalamus using optogenetics and functional MRI (fMRI) in rodents. Ventral hippocampus (vHP) excitatory neuron stimulation at 5 Hz evoked robust hippocampal activity that propagates to the primary auditory cortex. We then tested 5Hz vHP stimulation paired with either natural vocalizations or artificial/noise acoustic stimuli. vHP stimulation enhanced auditory responses to vocalizations (with a negative or positive valence) in the inferior colliculus, medial geniculate body, and auditory cortex, but not to their temporally reversed counterparts (artificial sounds) or broadband noise. Meanwhile, pharmacological vHP inactivation diminished response selectivity to vocalizations. These results directly reveal the large-scale hippocampal participation in natural sound processing at early centers of the ascending auditory pathway. They expand our present understanding of hippocampus in global auditory networks.
Genome-wide analysis of dendritic cell differentiation
Authors: Tiniakou Ioanna , Hsu Pei-Feng , Lopez-Zepeda Lorena S. , Lau Colleen M. , Soni Chetna , Esteva Eduardo , Adams Nicholas M. , Liu Fan , Khodadadi-Jamayran Alireza , Rodrick Tori C. , Jones Drew , Tsirigos Aristotelis , Ohler Uwe , Bedford Mark T. , Nimer Stephen D. , Reizis Boris 
Published: May 2022

SummaryDendritic cells (DCs) are immune sentinel cells that comprise antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs). Cytokine Flt3 ligand (Flt3L) supports the proliferation of hematopoietic progenitors, and is also necessary and sufficient for DC differentiation. Here we characterized the spontaneous differentiation of a Flt3L-dependent murine progenitor cell line into pDCs and “myeloid” cDCs (cDC2s), and interrogated it using a genome-wide CRISPR/Cas9 dropout screen. The screen revealed multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex, the Nieman-Pick type C cholesterol transporter and arginine methyltransferase Carm1; the role of Carm1 in pDC and cDC2 differentiation was confirmed by conditional targeting in vivo. We also found that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation. The results provide a comprehensive forward genetic analysis of DC differentiation, and help explain how the opposing processes of proliferation and differentiation could be driven by the same cytokine.
Simplified fecal community transplant restores Clostridioides difficile colonization resistance to antibiotic perturbed murine communities
Authors: Lesniak Nicholas A. , Tomkovich Sarah , Henry Andrew , Taylor Ana , Colovas Joanna , Bishop Lucas , McBride Kathryn , Schloss Patrick D. 
Published: May 2022

AbstractFecal communities transplanted into individuals can eliminate recurrent Clostridioides difficile infection (CDI) with high efficacy. However, this treatment is only used once CDI becomes resistant to antibiotics or has recurred multiple times. We sought to investigate whether a fecal community transplant (FCT) pre-treatment could be used to prevent CDI altogether. We treated male C57BL/6 mice with either clindamycin, cefoperazone, or streptomycin, and then inoculated them with the microbial community from untreated mice before challenging with C. difficile. We measured colonization and sequenced the V4 region of the 16S rRNA gene to understand the dynamics of the murine fecal community in response to the FCT and C. difficile challenge. Clindamycin-treated mice became colonized with C. difficile but cleared it naturally and did not benefit from the FCT. Cefoperazone-treated mice became colonized by C. difficile, but the FCT enabled clearance of C. difficile. In streptomycin-treated mice, the FCT was able to prevent C. difficile from colonizing. Then we diluted the FCT and repeated the experiments. Cefoperazone-treated mice no longer cleared C. difficile. However, streptomycin-treated mice colonized with 1:102 dilutions resisted C. difficile colonization. Streptomycin-treated mice that received a FCT diluted 1:103, C. difficile colonized but later was cleared. In streptomycin-treated mice, inhibition of C. difficile was associated with increased relative abundance of a group of bacteria related to Porphyromonadaceae and Lachnospiraceae. These data demonstrate that C. difficile colonization resistance can be restored to a susceptible community with a FCT as long as it complements the missing populations.ImportanceAntibiotic use, ubiquitous with the healthcare environment, is a major risk factor for Clostridioides difficile infection (CDI), the most common nosocomial infection. When C. difficile becomes resistant to antibiotics, a fecal microbiota transplant from a healthy individual can effectively restore the gut bacterial community and eliminate the infection. While this relationship between the gut bacteria and CDI is well established, there are no therapies to treat a perturbed gut community to prevent CDI. This study explored the potential of restoring colonization resistance to antibiotic-induced susceptible gut communities. We described the effect gut bacteria community variation has on the effectiveness of a fecal community transplant for inhibiting CDI. These data demonstrated that communities susceptible to CDI can be supplemented with fecal communities but the effectiveness depended on the structure of the community following the perturbation. Thus, a simplified bacterial community may be able to recover colonization resistance to patients treated with antibiotics.
Structure and mechanism of LARGE1 matriglycan polymerase
Authors: Joseph Soumya , Schnicker Nicholas J. , Xu Zhen , Yang Tiandi , Hopkins Jesse , Watkins Maxwell , Chakravarthy Srinivas , Davulcu Omar , Anderson Mary E. , Venzke David , Campbell Kevin P. 
Published: May 2022

AbstractMatriglycan is a linear polysaccharide of alternating xylose and glucuronate that binds extracellular matrix proteins and acts as a receptor for Lassa fever virus. LARGE1 synthesizes matriglycan on dystroglycan and mutations in LARGE1 cause muscular dystrophy with abnormal brain development. However, the mechanism of matriglycan polymerization by LARGE1 is unknown. Here, we report the cryo-EM structure of LARGE1. We show that LARGE1 functions as a dimer to polymerize matriglycan by alternating activities between the xylose transferase domain on one protomer and the glucuronate transferase domain on the other protomer. Biochemical analyses using a recombinant Golgi form of dystroglycan reveal that LARGE1 polymerizes matriglycan processively. Our results provide mechanistic insights into LARGE1 function and may facilitate novel therapeutic strategies for treating neuromuscular disorders or arenaviral infections.One-Sentence SummaryDimeric LARGE1 processively polymerizes matriglycan on dystroglycan using orthogonal active sites on alternate protomers.
Neuro-immune Crosstalk in the Enteric Nervous System from Early Postnatal Development to Adulthood
Authors: Francesca Viola Maria , Marta Chavero-Pieres , Elodie Modave , Nathalie Stakenborg , Marcello Delfini , Fabre Naomi , Appeltans Iris , Martens Tobie , Vandereyken Katy , Van Herck Jens , Petry Philippe , Verheijden Simon , De Schepper Sebastiaan , Sifrim Alejandro , Kierdorf Katrin , Prinz Marco , Berghe Pieter Vanden , Voet Thierry , Boeckxstaens Guy 
Published: May 2022

SummaryCorrect development and maturation of the enteric nervous system (ENS) is critical for survival. Early in life, the ENS requires significant refinement in order to adapt to the evolving needs of the tissue, changing from milk to solid food at the time of weaning. Here, we demonstrate that resident macrophages of the muscularis externa, MMϕ, refine the ENS early in life by pruning synapses and phagocytosing abundant enteric neurons. After weaning, MMϕ continue to closely interact with the ENS, acquire a microglia-like phenotype and are crucial for the survival of enteric neurons. Of note, this microglia-like phenotype is instructed by TGFβ produced by the ENS, introducing a novel reciprocal cell-cell communication responsible for the maintenance of the neuron-associated MMФ niche in the gut. These findings elucidate a novel role of intestinal macrophages in ENS refinement early in life, and open new opportunities to treat intestinal neurodegenerative disorders by manipulating the ENS-macrophage niche.
A Multimodal Neuroimaging Dataset to Study Spatiotemporal Dynamics of Visual Processing in Humans
Authors: Ebrahiminia Fatemeh , Mahdiani Morteza , Khaligh-Razavi Seyed-Mahdi 
Published: May 2022

AbstractWe describe structural and multimodal functional neuroimaging data collected from 21 healthy volunteers. Functional magnetic resonance images (fMRI) and electroencephalography (EEG) signals were acquired in separate sessions from the same individuals while they were performing a visual one-back repetition task. During functional sessions, participants were presented with images from five categories, including animals, chairs, faces, fruits, and vehicles. The stimulus set and experimental parameters were chosen to be similar to that of an available electrocorticography (ECoG) dataset, therefore creating a unique opportunity to study vision in humans with multiple complementary neuroimaging modalities. Individual-specific head models can be constructed for each participant using T1-weighted MPRAGE images and the recorded positions of the EEG electrodes. By combining the three functional modalities and the structural data, this dataset provides a unique setting to explore spatiotemporal dynamics of invariant object recognition in humans. This multimodal data can also be used to develop new methods for combining fMRI and electrophysiological modalities to come up with more accurate spatiotemporally resolved maps of brain function, which is inaccessible by any of the modalities alone.
Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition
Authors: Kimchi Ofer , King Ella M. , Brenner Michael P. 
Published: May 2022

AbstractRepeat expanded RNA molecules aggregate under certain conditions bothin vitroandin vivo. Understanding the mechanism for aggregation—including how aggregation properties change with sequence and environmental conditions—would explain and predict the behavior of RNA-based biomolecular condensates, and enable the rational design of RNA-based materials. Here, we introduce an analytical framework to predict aggregation for any repeat RNA sequence, accounting for both intra- and inter-molecular bonding. By enumerating the equilibrium landscape of multimers, we reveal the driving force for aggregation: the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, and enables the design of programmable RNA condensates.
Complexities of recapitulating polygenic effects in natural populations: replication of genetic effects on wing shape in artificially selected and wild caught populations ofDrosophila melanogaster
Authors: Pelletier Katie , Pitchers William R. , Mammel Anna , Northrop-Albrecht Emmalee , Márquez Eladio J. , Moscarella Rosa A. , Houle David , Dworkin Ian 
Published: May 2022

AbstractIdentifying the genetic architecture of complex traits is important to many geneticists, including those interested in human disease, plant and animal breeding, and evolutionary genetics. Advances in sequencing technology and statistical methods for genome-wide association studies (GWAS) have allowed for the identification of more variants with smaller effect sizes, however, many of these identified polymorphisms fail to be replicated in subsequent studies. In addition to sampling variation, this failure to replicate reflects the complexities introduced by factors including environmental variation, genetic background, and differences in allele frequencies among populations. UsingDrosophila melanogasterwing shape, we ask if we can replicate allelic effects of polymorphisms first identified in a GWAS (Pitchers et al. 2019) in three genes:dachsous (ds),extra-macrochaete (emc)andneuralized (neur),using artificial selection in the lab, and bulk segregant mapping in natural populations. We demonstrate that multivariate wing shape changes associated with these genes are aligned with major axes of phenotypic and genetic variation in natural populations. Following seven generations of artificial selection along thedsshape change vector, we observe genetic differentiation of variants indsand genomic regions containing other genes in the hippo signaling pathway. This suggests a shared direction of effects within a developmental network. We also performed artificial selection with theemcshape change vector, which is not a part of the hippo signaling network, but showed a largely shared direction of effects. The response to selection along theemcvector was similar to that ofds, suggesting that the available genetic diversity of a population, summarized by the genetic (co)variance matrix (G), influenced alleles captured by selection. Despite the success with artificial selection, bulk segregant analysis using natural populations did not detect these same variants, likely due to the contribution of environmental variation and low minor allele frequencies, coupled with small effect sizes of the contributing variants.
Astrocytic Gi-GPCR activation enhances stimulus-evoked extracellular glutamate
Authors: Vaidyanathan Trisha V. , Tse Vincent , Lim Esther M. , Poskanzer Kira E. 
Published: May 2022

AbstractAstrocytes perform critical functions in the nervous system, many of which are dependent on neurotransmitter-sensing through G protein-coupled receptors (GPCRs). However, whether specific astrocytic outputs follow specific GPCR activity remains unclear, and exploring this question is critical for understanding how astrocytes ultimately influence brain function and behavior. We previously showed that astrocytic Gi-GPCR activation is sufficient to increase slow-wave neural activity (SWA) during sleep when activated in cortical astrocytes1. Here, we investigate the outputs of astrocytic Gi-GPCRs, focusing on the regulation of extracellular glutamate and GABA, by combining in vivo fiber photometry recordings of the extracellular indicators iGluSnFR and iGABASnFR with astrocyte-specific chemogenetic Gi-GPCR activation. We find that Gi-GPCR activation does not change spontaneous dynamics of extracellular glutamate or GABA. However, Gi-GPCR activation does specifically increase visual stimulus-evoked extracellular glutamate. Together, these data point towards a complex relationship between astrocytic inputs and outputs in vivo that may depend on behavioral context. Further, they suggest an extracellular glutamate-specific mechanism underlying some astrocytic Gi-GPCR-dependent behaviors, including the regulation of sleep SWA.
Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells
Authors: Shapiro Melanie R. , Peters Leeana D. , Brown Matthew E. , Cabello-Kindelan Cecilia , Posgai Amanda L. , Bayer Allison L. , Brusko Todd M. 
Published: May 2022

ABSTRACTIL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes (T1D) progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1R was elevated on murine memory and human naïve Treg subsets. IL-2 and IGF1 promoted murine PI3K/Akt and human STAT5 signaling in Tregs. IL-2 and IGF1 treatment expanded Tregs beyond either agent alone in NOD mice. Incubation of naïve human CD4+T cells with IL-2 and IGF1 enhanced Treg proliferationin vitro, without the need for T cell receptor ligation. This synergism was attributed to increased high-affinity IL-2Rα expression on naïve Tregs, in contrast to intermediate-affinity IL-2Rβ and IL-2Rγ subunit enhancement on naïve conventional T cells (Tconv). We then demonstrated that IGF1 and IL-2 or the IL2Rγ-chain-dependent cytokine, IL-7, can be used to induce proliferation of genetically-engineered naïve Treg or Tconv cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive T cell expansions bothin vitroandin vivofor cellular therapeutics and genetic modifications.