bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia is a dominant remodeler of the CD8+T cell surface proteome relative to activation and regulatory T cell-mediated suppression
Authors: Byrnes James R. , Weeks Amy M. , Shifrut Eric , Carnevale Julia , Kirkemo Lisa , Ashworth Alan , Marson Alexander , Wells James A. 
Published: June 2021

ABSTRACTImmunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the anti-tumor immune response. T cell surface receptors that influence interactions and function in the TME are already proven targets for cancer immunotherapy. However, surface proteome remodeling of primary human T cells in response to suppressive forces in the TME has never been characterized systematically. Using a reductionist cell culture approach with primary human T cells and SILAC-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8+surface proteome (surfaceome). Surprisingly, the CD8+/Treg co-culture only modestly affected the CD8+surfaceome, but did reverse several activation-induced surfaceomic changes. In contrast, hypoxia dramatically altered the CD8+surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4+T cell surfaceome similarly responded to hypoxia, revealing a novel hypoxia-induced surface receptor program. Our findings are consistent with the premise that hypoxic environments create a metabolic challenge for T cell activation, which may underlie the difficulty encountered in treating solid tumors with immunotherapies. Together, the data presented here provide insight into how suppressive TME factors remodel the T cell surfaceome and represent a valuable resource to inform future therapeutic efforts to enhance T cell function in the TME.
Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells
Authors: Yang Rui , Wang Wenzhe , Dong Meichen , Roso Kristen , Greer Paula , Bao Xuhui , Pirozzi Christopher J. , Bigner Darell D. , Yan Hai , Ashley David M. , Zhabotynsky Vasyl , Zou Fei , He Yiping 
Published: June 2021

AbstractMyc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.
Genome wide association mapping ofPyrenophora teresf.maculataandPyrenophora teresf.teresresistance loci utilizing natural Turkish wild and landrace barley populations
Authors: Clare Shaun J. , Oğuz Arzu Çelik , Effertz Karl , Poudel Roshan Sharma , See Deven , Karakaya Aziz , Brueggeman Robert S. 
Published: June 2021

ABSTRACTUnimproved landraces and wild relatives of crops are sources of genetic diversity that were lost post domestication in modern breeding programs. To tap into this rich resource, genome wide association studies in large plant genomes have enabled the rapid genetic characterization of desired traits from natural landrace and wild populations. Wild barley (Hordeum spontaneum), the progenitor of domesticated barley (H. vulgare), is dispersed across Asia and North Africa, and has co-evolved with the ascomycetous fungal pathogensPyrenophora teresf.teresandP. teresf.maculata, the casual agents of the diseases net form of net blotch and spot form of net blotch, respectively. Thus, these wild and local adapted barley landraces from the region of origin of both the host and pathogen represent a diverse gene pool to identify new sources of resistance, due to millions of years of co-evolution. The barley -P. terespathosystem is governed by complex genetic interactions with dominant, recessive, and incomplete resistances and susceptibilities, with many isolate-specific interactions. Here we provide the first genome wide association study of wild and landrace barley from the Fertile Crescent for resistance to both forms ofP. teres. A total of 14 loci, four againstP. teresf.maculataand ten againstPyrenophora teresf.teres,were identified in both wild and landrace populations, showing that both are genetic reservoirs for novel sources of resistance. We also highlight the importance of using multiple algorithms to both identify and validate additional loci.
Blocking antibodies against integrin-α3, -αM, and -αMβ2 de-differentiate myofibroblasts and reverse lung and kidney fibroses
Authors: White Michael JV , Ozkan Melis , Gomez-Medellin Jorge Emiliano , Rączy Michal M , Koss Kyle M , Solanki Ani , Zhang Zheng Jenny , Alpar Aaron T. , Naved Bilal , Wertheim Jason , Hubbell Jeffrey A 
Published: June 2021

AbstractFibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of the disease. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and reverse lung and kidney fibrosis in vivo. Decorin’s collagen-binding peptide directs blocking antibodies (against integrins-α3, -αM, -αMβ2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to reverse fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment and reversal of fibrosis.SummaryBlocking antibodies against integrins-α3, -αM, and -αMβ2 can be targeted to sites of fibrosis, reverse lung and kidney fibroses, and offer the potential to bring immunotherapy to fibrosis
Bioelectromagnetic platform for stimulation
Authors: Ashbaugh Ryan C , Udpa Lalita , Israeli Ron R. , Gilad Assaf A. , Pelled Galit 
Published: June 2021

ABSTRACTMagnetogenetics is a new field that utilizes electromagnetic fields to remotely control cellular activity. In addition to the development of the biological genetic tools, this approach requires designing hardware with a specific set of demands for the electromagnets used to provide the desired stimulation for electrophysiology and imaging experiments. Here we present a universal stimulus delivery system comprised of four magnet designs compatible with electrophysiology, fluorescence and luminescence imaging, microscopy, and freely behaving animal experiments. The overall system includes a low-cost stimulation controller which enables rapid switching between active and sham stimulation trials as well as precise control of stimulation delivery.
An extension of Wang’s protein design model using Blosum62 substitution matrix
Authors: Rahmani Amin , Mirakabad Fatemeh Zare 
Published: June 2021

AbstractHumans life depends on the functionality of molecules in the body. One of these essential molecules is the protein that plays a vital role in our life, such that its malfunction can cause severe damages. Such roles make protein structure and its functionality necessary to understand. One of the problems that help us understand the relation between protein structure is the well-known protein design problem which attempts to find an amino acid sequence that can fold into a desired tertiary structure. However, despite having an acceptable accuracy in protein design, this accuracy is an identical percentage of amino acid retrieving. At the same time, it is well-known that amino acids can replace each other in evolution while the function and structure of protein stay the same. Thus the designed sequence does not have the opportunity to be close to the target in the evolutionary aspect. This paper presents an extension to Wang’s deep learning model, which uses evolutionary information in the Blosum62 substitution matrix to take amino acid replacement probability into account while designing a sequence.
Strain-Programmable Patch for Diabetic Wound Healing
Authors: Theocharidis Georgios , Yuk Hyunwoo , Roh Heejung , Wang Liu , Mezghani Ikram , Wu Jingjing , Kafanas Antonios , Chen Lihong , Guo Chuan Fei , Jayaswal Navin , Katopodi Xanthi-Leda , Nabzdyk Christoph S. , Vlachos Ioannis S. , Veves Aristidis , Zhao Xuanhe 
Published: June 2021

ABSTRACTChronic wounds with impaired healing capability such as diabetic foot ulcers (DFU) are devastating complications in diabetic patients, inflicting rapidly growing clinical and economic burdens in aging societies. Despite recent advances in therapeutic approaches, limited benefits of the existing solutions highlight the critical need for novel therapeutic solutions for diabetic wound healing. Here we propose a strain-programmable patch capable of rapid robust adhesion on and programmable mechanical contraction of wet wounded tissues over days to offer a new therapeutic platform for diabetic wounds. The strain-programmable patch, consisting of a dried bioadhesive layer and a pre-stretched elastomer backing, implements a hydration-based shape-memory mechanism to achieve both uniaxial and biaxial contractions and stress remodeling of wet wounds in a programmable manner. We develop theoretical and numerical models to rationally guide the strain-programming and mechanical modulation of wounds. In vivo rodent and ex vivo human skin culture models validate the programmability and efficacy of the proposed platform and identify mechanisms of action for accelerated diabetic wound healing.One Sentence SummaryA strain-programmable bioadhesive patch is developed for accelerated closure and healing of wounds in diabetic mice and human skin.
Nutrient profiling reveals extracellular uridine as a fuel for pancreatic cancer through uridine phosphorylase 1
Authors: Ward Matthew H. , Nwosu Zeribe C. , Poudel Pawan , Kasperek Steven , Tolstyka Zach , Menjivar Rosa E. , Ragulan Chanthirika , Nyamundanda Gift , Zhang Li , Andren Anthony , Halbrook Christopher J. , Carpenter Eileen S. , di Magliano Marina Pasca , Sadanandam Anguraj , Lyssiotis Costas A. 
Published: June 2021

AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by high invasiveness, therapeutic resistance, and metabolic aberrations. Although altered metabolism drives PDA growth and survival, the complete spectrum of metabolites used as nutrients by PDA remains largely unknown. Here, we aimed to determine novel nutrients utilized by PDA. We assessed how >175 metabolites impacted metabolic activity in 19 PDA cell lines under nutrient-restricted conditions. This analysis identified uridine as a novel metabolite driver of PDA survival in glucose-deprived conditions. Uridine utilization strongly correlated with expression of the enzyme uridine phosphorylase 1 (UPP1). Metabolomics profiling, notably13C-stable isotope tracing, revealed that uridine-derived ribose is the relevant component supporting redox balance, survival, and proliferation in glucose-deprived PDA cells. We demonstrate that UPP1 catabolizes uridine, shunting its ribose component into central carbon metabolism to support glycolysis, the tricarboxylic acid (TCA) cycle and nucleotide biosynthesis. Compared to non-tumoral tissues, we show that PDA tumors express highUPP1, which correlated with poor overall survival in multiple patient cohorts. Further, uridine is enriched in the pancreatic tumor microenvironment, and we demonstrate that this may be provided in part by tumor associated macrophages. Finally, we found that inhibition ofUPP1restricted the ability of PDA cells to use uridine, and thatUPP1knockout impairs tumor growthin vivo. Our data identifies uridine catabolism as a critical aspect of compensatory metabolism in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.
Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals
Authors: Monday Hannah R. , Kharod Shivani C. , Yoon Young J. , Singer Robert H. , Castillo Pablo E. 
Published: June 2021

SUMMARYLearning and memory critically rely on long-lasting, synapse-specific modifications. While postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remains unclear. Here, we examined the hippocampal mossy fiber (MF)-CA3 synapse which expresses both structural and functional presynaptic plasticity. We report that MF boutons synthesize protein locally and contain ribosomes. Long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with translation-dependent enlargement of MF boutons. Moreover, increasing in vitro and in vivo MF activity enhanced protein synthesis in MFs. Remarkably, deletion of presynaptic Fragile X mental retardation protein (FMRP), an RNA-binding protein expressed in MF boutons and previously implicated in local postsynaptic protein synthesis-dependent plasticity, blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic function. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature brain.HighlightsMossy fiber boutons (MFBs) synthesize protein locally and contain ribosomesLocal presynaptic translation is increased by in vitro and in vivo GC activityMFB structural plasticity relies on de novo protein synthesis.Presynaptic FMRP is required for MF-CA3 structural and functional plasticityIn BriefMonday et al. report that FMRP and protein synthesis in hippocampal mossy fiber boutons mediate functional and structural presynaptic plasticity.
DRUG-seq Provides Unbiased Biological Activity Readouts for Drug Discovery
Authors: Li Jingyao , Ho Daniel J. , Henault Martin , Yang Chian , Neri Marilisa , Ge Robin , Renner Steffen , Mansur Leandra , Lindeman Alicia , Tumkaya Tayfun , Russ Carsten , Hild Marc , Keller Caroline Gubser , Jenkins Jeremy L. , Worringer Kathleen A. , Sigoillot Frederic D. , Ihry Robert J. 
Published: June 2021

AbstractUnbiased transcriptomic RNA-seq data has provided deep insights about biological processes. However, its impact in drug discovery has been narrow given high costs and low throughput. Proof-of-concept studies with Digital RNA with pertUrbation of Genes (DRUG)-seq demonstrated the potential to address this gap. We extended the DRUG-seq platform by subjecting it to rigorous testing and by adding an open-source analysis pipeline. The results demonstrate high reproducibility and ability to resolve the mechanism(s) of action for a diverse set of compounds. Overall, the protocol and open-source analysis pipeline are a step towards industrializing RNA-seq for high complexity transcriptomics studies performed at a saturating scale.
Cool temperature limit Zika virus genome replication
Authors: Tesla Blanka , Powers Jenna S. , Barnes Yvonne , Lakhani Shamil , Acciani Marissa D. , Murdock Courtney C. , Brindley Melinda A. 
Published: June 2021

AbstractZika virus is a mosquito-borne flavivirus known to cause severe birth defects and neuroimmunological disorders. We have previously demonstrated that mosquito transmission of Zika virus decreases with temperature. While transmission was optimized at 29°C, it was limited at cool temperatures (< 22°C) due to poor virus establishment in the mosquitoes. Temperature is one of the strongest drivers of vector-borne disease transmission due to its profound effect on ectothermic mosquito vectors, viruses, and their interaction. Although there is substantial evidence of temperature effects on arbovirus replication and dissemination inside mosquitoes, little is known about whether temperature affects virus replication directly or indirectly through mosquito physiology. In order to determine the mechanisms behind temperature-induced changes in Zika virus transmission potential, we investigated different steps of the virus replication cycle in mosquito cells (C6/36) at optimal (28°C) and cool (20°C) temperatures. We found that cool temperature did not alter Zika virus entry or translation but reduced the amount of double-stranded RNA replication intermediates. If replication complexes were first formed at 28°C and the cells were subsequently shifted to 20°C, the late steps in the virus replication cycle were efficiently completed. These data suggest that cool temperature decreases the efficiency of Zika virus genome replication in mosquito cells. This phenotype was observed in the Asian-lineage of Zika virus, while the African-lineage Zika virus was less restrictive at 20°C.ImportanceWith half of the human population at risk, arboviral diseases represent a substantial global health burden. Zika virus, previously known to cause sporadic infections in humans, emerged in the Americas in 2015 and quickly spread worldwide. There was an urgent need to better understand the disease pathogenesis, develop therapeutics and vaccines, as well as to understand, predict, and control virus transmission. In order to efficiently predict the seasonality and geography for Zika virus transmission, we need a deeper understanding of the host-pathogen interactions and how they can be altered by environmental factors such as temperature. Identifying the step in the virus replication cycle that is inhibited in cool conditions can have implications in modeling the temperature suitability for arbovirus transmission as global environmental patterns change. Understanding the link between pathogen replication and environmental conditions can potentially be exploited to develop new vector control strategies in the future.
Systematic review of Economic studies of Partner Notification and management interventions for sexually transmitted infections including HIV in men who have sex with men
Authors: Okeke Ogwulu CB , Abdali Z , Williams EV , Estcourt CS , Howarth AR , Copas A , Mapp F , Woode-Owusu M , Roberts TE 
Published: June 2021

ABSTRACTObjectivesMen who have sex with men (MSM) are disproportionately affected by sexually transmitted infections (STIs). Partner notification (PN) to identify, test and treat sex partners of MSM with bacterial STIs is challenging because MSM often report larger numbers of sex partners and a higher proportion of one-off partners who may be difficult to engage. However, one-off partners contribute disproportionately to onward transmission. Economic research on PN has typically focused on heterosexual people and evidence of effectiveness of PN in MSM is scant. We conducted a systematic review of economic studies of PN interventions in MSM to inform the development of a novel PN intervention for MSM with one-off partners.MethodSix electronic databases were searched up to June 2020. Cost studies and full economic evaluations, which focused on PN and/or testing and treatment (in the context of PN) of sex partners of MSM with STIs, and/or HIV, were included. A two-stage categorisation process was used for study selection and a narrative synthesis was reported.ResultsTwenty-six studies of a possible 1909 met the selection criteria. Sixteen focused on MSM but only three of these were on PN. Few studies reported on patients’ characteristics and settings. Most studies were cost-utility analyses with outcomes reported as quality-adjusted life years (QALYs) which were derived from studies on heterosexual people.ConclusionsNone of the identified studies specifically addressed cost-effectiveness of PN in MSM. The few studies identified as potentially relevant relied on costs and QALYs data from studies in heterosexual people, which may be inappropriate given the different patterns of sexual partnerships reported by these two groups. The lack of evidence on efficient PN approaches for MSM, a group with a high burden of infection, supports the need for new interventions tailored to the needs and preferences of MSM with parallel economic evaluation.
Bayesian mapping of the striatal microcircuit reveals robust asymmetries in the probabilities and distances of connections
Authors: Cinotti François , Humphries Mark D. 
Published: June 2021

ABSTRACTThe striatum’s complex microcircuit is made by connections within and between its D1- and D2-receptor expressing projection neurons and at least five species of interneuron. Precise knowledge of this circuit is likely essential to understanding striatum’s functional roles and its dysfunction in a wide range of movement and cognitive disorders. We introduce here a Bayesian approach to mapping neuron connectivity using intracellular recording data, which lets us simultaneously evaluate the probability of connection between neuron types, the strength of evidence for it, and its dependence on distance. Using it to synthesise a complete map of the mouse striatum, we find strong evidence for two asymmetries: a selective asymmetry of projection neuron connections, with D2 neurons connecting twice as densely to other projection neurons than do D1 neurons, but neither subtype preferentially connecting to another; and a length-scale asymmetry, with interneuron connection probabilities remaining non-negligible at more than twice the distance of projection neuron connections. We further show our Bayesian approach can evaluate evidence for wiring changes, using data from the developing striatum and a mouse model of Huntington’s disease. By quantifying the uncertainty in our knowledge of the microcircuit, our approach reveals a wide range of potential striatal wiring diagrams consistent with current data.