bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stability by gating plasticity in recurrent neural networks
Authors: Wilmes Katharina A. , Clopath Claudia 
Published: September 2020

AbstractWith Hebbian learning ‘who fires together wires together’, well-known problems arise. Hebbian plasticity can cause unstable network dynamics and overwrite stored memories. Unstable dynamics can partly be addressed with homeostatic plasticity mechanisms. Unfortunately, the time constants of homeostatic mechanisms required in network models are much shorter than those measured experimentally.We propose that homeostatic time constants can be slow if plasticity is gated. We investigate how gating plasticity influences network stability and memories in plastic balanced spiking networks of neurons with dendrites. We compare how different factors such as excitability, learning rate, and inhibition lift the requirements for homeostatic time constants. We investigate how dendritic versus perisomatic gating allows for different amounts of weight changes in stable networks. We suggest that the compartmentalisation of pyramidal cells enables dendritic synaptic changes while maintaining stability. We show that spatially restricted plasticity improves stability. Finally, we compare how different gates protect memories.Significance statementHow does the brain maintain stable neural activity in the presence of synaptic changes? This question has been studied extensively in the past, but we argue that one crucial aspect is missing in previous studies. While all theoretical work has assumed plasticity to beonall the time, plasticity is in fact heavily gated. In this light, we must reconsider the theories on stability and homeostasis of neural activity. In particular, theoretical studies show that neural networks undergoing plasticity require fast compensatory homeostatic mechanisms to be stable. However, experimentally measured homeostatic processes operate on much slower time scales. We studied how the gating of plasticity can improve network stability and thereby reduce the discrepancy in the homeostatic time constant between models and experiments.
Acute depletion of METTL3 identifies a role forN6-methyladenosine in alternative intron/exon inclusion in the nascent transcriptome
Authors: Wei Guifeng , Almeida Mafalda , Pintacuda Greta , Coker Heather , Bowness Joseph S , Ule Jernej , Brockdorff Neil 
Published: September 2020

AbstractRNAN6-methyladenosine (m6A) modification plays important roles in multiple aspects of RNA regulation. m6A is installed co-transcriptionally by the METTL3/14 complex, but its direct roles in RNA processing remain unclear. Here we investigate the presence of m6A in nascent RNA of mouse embryonic stem cells (mESCs). We find that around 10% m6A peaks are in introns, often close to 5’-splice sites. RNA m6A peaks significantly overlap with RBM15 RNA binding sites and the histone modification H3K36me3. Interestingly, acute dTAG depletion of METTL3 reveals that inclusion of m6A-bearing alternative introns/exons in the nascent transcriptome is disrupted. For terminal or variable-length exons, m6A peaks are generally located upstream of a repressed 5’-splice site, and downstream of an enhanced 5’-splice site. Intriguingly, genes with the most immediate effects on splicing include several components of the m6A pathway, suggesting an autoregulatory function. Our findings demonstrate a direct crosstalk between m6A machinery and the regulation of RNA processing.
Two Are Better Than One: Solving the Problem of Vertical Sound Source Localization via Binaural Integration of HRTFs
Authors: Oess Timo , Neumann Heiko , Ernst Marc O. 
Published: September 2020

AbstractEarly studies have shown that the localization of a sound source in the vertical plane can be accomplished with only a single ear, thus assumed the localization mechanism to be based on monaural cues. Such cues are induced by the pinna and consist of notches and peaks in the perceived spectrum which vary systematically with the elevation of sound sources. These processes pose several problems to the auditory system like identifying and extracting spectral cues on a neural level, as well as, distinguishing pinna induced peaks and notches from features already present in the source spectrum. Interestingly, at the stage of elevation estimate binaural information from both ears is already available and it seems plausible that the auditory system takes advantage of this information. Especially, since such a binaural integration can improve the localization performance dramatically as we demonstrate in the current study. For that, we first introduce a computational model architecture that takes advantage of binaural signal integration to localize sound sources in the median plane. Model performance is tested under different conditions which reveal that localization of monaural, as well as binaural inputs is best when the model is trained with binaural inputs. Furthermore, modeling results lead to the hypothesis that sound type specific prior information is taken into account to further improve localization quality. This deduced hypothesis about vertical sound source localization is confirmed in a behavioral experiment. Based on these results, we propose that elevation estimation of sound sources is facilitated by an early binaural signal integration and can incorporate sound type specific prior information for higher accuracy.
Gene exchange networks define species-like units in marine prokaryotes
Authors: Stepanauskas R. , Brown J.M. , Mai U. , Bezuidt O. , Pachiadaki M. , Brown J. , Biller S.J. , Berube P.M. , Record N.R. , Mirarab S. 
Published: September 2020

SUMMARYPost-submission note. Since the original submission of this manuscript to bioRxiv, we discovered that some of our results may be impacted by the limitations of some of the comparative genomics tools used in this study. We are working on a revised version of the manuscript.Although horizontal gene transfer is recognized as a major evolutionary process in Bacteria and Archaea, its general patterns remain elusive, due to difficulties tracking genes at relevant resolution and scale within complex microbiomes. To circumvent these challenges, we analyzed a randomized sample of >12,000 genomes of individual cells of Bacteria and Archaea in the tropical and subtropical ocean - a well-mixed, global environment. We found that marine microorganisms form gene exchange networks (GENs) within which transfers of both flexible and core genes are frequent, including the rRNA operon that is commonly used as a conservative taxonomic marker. The data revealed efficient gene exchange among genomes with <28% nucleotide difference, indicating that GENs are much broader lineages than the nominal microbial species, which are currently delineated at 4-6% nucleotide difference. The 42 largest GENs accounted for 90% of cells in the tropical ocean microbiome. Frequent gene exchange within GENs helps explain how marine microorganisms maintain millions of rare genes and adapt to a dynamic environment despite extreme genome streamlining of their individual cells. Our study suggests that sharing of pangenomes through horizontal gene transfer is a defining feature of fundamental evolutionary units in marine planktonic microorganisms and, potentially, other microbiomes.
RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities
Authors: Iqbal Waleed , Demidova Elena V. , Serrao Samantha , ValizadehAslani Taha , Rosen Gail , Arora Sanjeevani 
Published: September 2020

AbstractRRM2Bplays a crucial role in DNA replication, repair and oxidative stress. While germlineRRM2Bmutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA data, we investigatedRRM2Balterations in cancer. We found thatRRM2Bis highly amplified in multiple tumor types, particularly inMYC-amplified tumors, and is associated with increasedRRM2BmRNA expression. We also observed that the chromosomal region 8q22.3–8q24, is amplified in multiple tumors, and includesRRM2B,MYCalong with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cases that have bothRRM2B-amplified along withMYChave a distinct pattern of amplification compared to unaltered cases or cases that have amplifications inRRM2BorMYConly. These other 8q-proteins were shown to interact functionally within the RRM2B network of DNA repair, hypoxia and apoptosis regulating proteins. Notably,RRM2B-amplified tumors are characterized by mutation signatures of defective DNA repair and oxidative stress, and in some cancers also associated with poor clinical outcome. These findings suggest that some cancers may require RRM2B for cellular survival, providing novel therapeutic opportunities in these cancers.
Chronically implantable LED arrays for behavioral optogenetics in primates
Authors: Rajalingham Rishi , Sorenson Michael , Azadi Reza , Bohn Simon , DiCarlo James J , Afraz Arash 
Published: September 2020

AbstractChallenges in behavioral optogenetics in large brains demand development of a chronically implantable platform for light delivery. We have developed Opto-Array, a chronically implantable array of LEDs for high-throughput optogenetic perturbation in non-human primates. We tested the Opto-Array in the primary visual cortex of a macaque monkey, and demonstrated that optogenetic cortical silencing by the Opto-Array results in reliable retinotopic visual deficits on a luminance discrimination task.
Sphingosine Kinase 2 associates with the nsP3 of chikungunya virus and is required for replication
Authors: Oyewole Opeoluwa O. , Reid St Patrick 
Published: September 2020

AbstractSphingosine kinase 2 (SK2) is a lipid kinase that catalyzes the production of sphingosine-1-phosphate (S1P) from sphingosine. Previously, we have shown that SK2 is recruited to the viral replication complex (VRC) early during chikungunya virus (CHIKV) infection. In the present study, we demonstrate that SK2 is required for viral replication and protein production. Treatment with a SK2 inhibitor significantly impaired the function of a CHIKV replicon. Similarly, compound treatment or genetic targeting resulted in impaired viral protein production. Mechanistically, we demonstrate that CHIKV nsP3 binds to SK2. Association of nsP3 with SK2 was mediated, in part, through the FGDF motifs within the hypervariable domain (HVD) of nsP3. In a competition assay, SK2 competed with G3BP for binding to nsP3. Collectively, these results extend our previous findings and identify SK2 as a CHIKV host factor recruited by nsP3.
Augmin prevents merotelic attachments by promoting proper arrangement of bridging and kinetochore fibers
Authors: Štimac Valentina , Koprivec Isabella , Manenica Martina , Simunić Juraj , Tolić Iva M. 
Published: September 2020

ABSTRACTThe human mitotic spindle is made of microtubules nucleated at centrosomes, at kinetochores, and from pre-existing microtubules by the augmin complex. However, it is unknown how the augmin-mediated nucleation affects distinct microtubule classes and thereby mitotic fidelity. Here we use superresolution microscopy to analyze the previously indistinguishable microtubule arrangements within the crowded metaphase plate area and demonstrate that augmin is vital for the formation of uniformly arranged parallel units consisting of sister kinetochore fibers connected by a bridging fiber. This ordered geometry helps both prevent and resolve merotelic attachments. Whereas augmin-nucleated bridging fibers prevent merotelic attachments by creating a nearly parallel and highly bundled microtubule arrangement unfavorable for creating additional attachments, augmin-nucleated k-fibers produce robust force required to resolve errors during anaphase. STED microscopy revealed that bridging fibers were impaired twice as much as k-fibers following augmin depletion. The complete absence of bridging fibers from a significant portion of kinetochore pairs, especially in the inner part of the spindle, resulted in the specific reduction of the interkinetochore distance. Taken together, we propose a model where augmin promotes mitotic fidelity by generating assemblies consisting of bridging and kinetochore fibers that align sister kinetochores to face opposite poles, thereby preventing erroneous attachments.
Direct phosphorylation of HY5 by SPA1 kinase to regulate photomorphogenesis in Arabidopsis
Authors: Wang Wenli , Paik Inyup , Kim Junghyun , Hou Xilin , Sung Sibum , Huq Enamul 
Published: September 2020

SUMMARYELONGATED HYPOCOTYL5 (HY5) is a key transcription factor which promotes photomorphogenesis by regulating complex downstream growth programs. Previous studies suggest that the regulation of HY5 mainly depends on the CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) - SUPPRESSOR OF PHYTOCHROME A-105 (SPA) E3 ubiquitin ligase complex, which degrades positively acting transcription factors of light signaling to repress photomorphogenesis in the dark. SPA proteins function not only as a component of the E3 ubiquitin ligase complex but also as a kinase of PHYTOCHROME INTERACTING FACTOR1 (PIF1) through its N-terminal kinase domain. Here, we show that HY5 is a new substrate of SPA1 kinase. SPA1 can directly phosphorylate HY5in vitroandin vivo. We also demonstrate that unphosphorylated HY5 strongly interacts with both COP1 and SPA1 than phosphorylated HY5, is the preferred substrate for degradation, whereas phosphorylated HY5 is more stable in the dark. In addition, unphosphorylated HY5 actively binds to the target promoters, and is physiologically more active form. Consistently, the transgenic plants expressing unphosphorylated mutant of HY5 displays enhanced photomorphogenesis. Collectively, our study revealed that SPA1 fine-tunes the stability and the activity of HY5 to regulate photomorphogenesis.
Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome
Authors: Bonnardel François , Haslam Stuart M. , Dell Anne , Feizi Ten , Liu Yan , Tajadura-Ortega Virginia , Akune Yukie , Sykes Lynne , Bennett Phillip R. , MacIntyre David A. , Lisacek Frédérique , Imberty Anne 
Published: September 2020

AbstractBacteria use protein receptors called lectins to anchor to specific host surface sugars. The role of lectins in the vaginal microbiome, and their involvement in reproductive tract pathophysiology is poorly defined. Here we establish a classification system based on taxonomy and protein 3D structure to identify 109 lectin classes. Hidden Markov Model (HMM) profiles for each class were used to search bacterial genomes, resulting in the prediction of >100 000 bacterial lectins available at unilectin.eu/bacteria. Genome screening of 90 isolates from 21 vaginal bacterial species showed that potential pathogens produce a larger variety of lectins than commensals indicating increased glycan-binding potential. Both the number of predicted bacterial lectins, and their specificities for carbohydrates correlated with pathogenicity. This study provides new insights into potential mechanisms of commensal and pathogen colonisation of the reproductive tract that underpin health and disease states.
CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses
Authors: Zhang Meiling , Liu Zongzhi Z. , Aoshima Keisuke , Zhang Yangyi , An Yongyan , Aoshima Asako , Chan Lok Hei , Lang Sabine M. , Sun Hongyi , Tang Zhenwei , Rutter Sara J. , Booth Carmen J. , Bossuyt Veerle , Chen Xiang , Morrow Jon S. , Pusztai Lajos , Rimm David. L. , Yin Mingzhu , Yan Qin 
Published: September 2020

AbstractEpigenetic and transcriptional changes are critical for metastasis, the major cause of cancer-related deaths. Metastatic tumor cells escape immune surveillance more efficiently than tumor cells in the primary sites, but the mechanisms controlling their immune evasion are poorly understood. We found that distal metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. Acetyl-lysine reader CECR2 is an epigenetic regulator upregulated in metastases and positively associated with M2 macrophages. CECR2 specifically promotes breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, NF-κB family member RELA recruits CECR2 to activate CSF1 and CXCL1, which are critical for macrophage-mediated immunosuppression at the metastatic sites. Furthermore, pharmacological inhibition of CECR2 bromodomain impedes NF-κB-mediated immune suppression by macrophages and inhibits breast cancer metastasis. These results reveal novel therapeutic strategies to treat metastatic breast cancer.Statement of SignificanceComparison of matched primary breast tumors and distal metastases show that metastases are more immune inert with increased tumor promoting macrophages. Depletion or pharmacological inhibition of CECR2 inhibits breast cancer metastasis by suppressing macrophage inflammatory responses, nominating CECR2 as a promising therapeutic target for cancer metastasis.
A visual pathway for skylight polarization processing inDrosophila
Authors: Hardcastle Ben J. , Omoto Jaison J. , Kandimalla Pratyush , Nguyen Bao-Chau M. , Keleş Mehmet F. , Boyd Natalie K. , Hartenstein Volker , Frye Mark A. 
Published: September 2020

SUMMARYMany insects use patterns of polarized light in the sky to orient and navigate. Here we functionally characterize neural circuitry in the fruit fly,Drosophila melanogaster, that conveys polarized light signals from the eye to the central complex, a brain region essential for the fly’s sense of direction. Neurons tuned to the angle of polarization of ultraviolet light are found throughout the anterior visual pathway, connecting the optic lobes with the central complex via the anterior optic tubercle and bulb, in a homologous organization to the ‘sky compass’ pathways described in other insects. We detail how a consistent, map-like organization of neural tunings in the peripheral visual system is transformed into a reduced representation suited to flexible processing in the central brain. This study identifies computational motifs of the transformation, enabling mechanistic comparisons of multisensory integration and central processing for navigation in the brains of insects.
Does national power trigger ocean conservation?
Authors: Baldi Germán , Schauman Santiago A. , Gandini Patricia 
Published: September 2020

AbstractStates are reacting to the global crises of biodiversity and the provision of ecosystem services mainly through the expansion of their networks of protected areas. This reaction would have been boosted by the commitments made between the parties of the Convention on Biological Diversity, and facilitated by the opportunities offered by isolated territories, where economic interests are minimal. However, few studies have discussed the importance of national power as conservation conditionings, particularly in the ocean. In this regard, here we evaluate whether the relative extent of marine protected areas (MPAs) is related to different elements of national power. Following a quantitative approach and incorporating into analyses 155 countries, our models suggest that an increasing power (in terms of country size –land and ocean– and military capacity) is related to greater marine protection. Although these patterns could be initially associated with the ample human and economic resources of most powerful countries and with the opportunities provided by their overseas territories, different arguments would support national power elements as conservation drivers. Specifically, the exertion of such power through conservation could be linked to geopolitical strategies such as the (re)validation of a country’s sovereignty over its Exclusive Economic Zone (EEZ), the greater regulation of the circulation and use of this space, the greater influence in the regional context, and the assurance in the provision of future ecosystem goods and services. In this way, changes in geopolitical conditions could affect MPAs, compromising the effective conservation of biodiversity and ecosystem processes, as well as the sustainable management of assets.
Quantification of discrete gut bacterial strains following fecal transplantation for recurrentClostridioides difficileinfection demonstrates long-term stable engraftment in non-relapsing recipients
Authors: Aggarwala Varun , Mogno Ilaria , Li Zhihua , Yang Chao , Britton Graham J. , Chen-Liaw Alice , Mitcham Josephine , Bongers Gerold , Gevers Dirk , Clemente Jose C. , Colombel Jean-Frederic , Grinspan Ari , Faith Jeremiah 
Published: September 2020

AbstractFecal Microbiota Transplantation (FMT), while successful for the treatment of recurrentClostridioides difficile(rCDI) infection, lacks a quantitative identification of the discrete bacterial strains that transmit and stably engraft in recipients, and their association with clinical outcomes. Using >1,000 unique bacterial strains isolated and sequenced from a combination of 22 FMT donors and recipients, we develop a statistical approachStrainerto detect and track sequenced bacterial strains from low depth metagenomic sequencing data. On application to 14 FMT interventions, we detect stable and high engraftment of ∼71% of gut microbiota strains in recipients at even 5-years post-transplant, a remarkably durable therapeutic from a single administration. We found differential transmission and engraftment efficacy across bacterial taxonomic groups over short and long-time scales. Although ∼80% of the original pre-FMT recipient strains were eliminated by the FMT, those strains that remain persist even 5 years later, along with newer strains acquired from the environment. The precise quantification of donor bacterial strains in recipients independently explained the clinical outcomes of early and late relapse. Our framework identifies the consistently engrafting discrete bacterial strains for use in Live Biotherapeutic Products (LBP) as a safer, scalable alternative to FMT and enables systematic evaluation of different FMT and LBP study designs.
Detection of incipient pancreatic cancer with novel tumor-specific antibodies in mouse models
Authors: Oni Tobiloba E. , Bautista Carmelita , Merrill Joseph R. , Goos Jeroen A.C.M. , Rivera Keith D. , Miyabayashi Koji , Biffi Giulia , Garcia Libia , Plenker Dennis , Patel Hardik , Elyada Ela , Samaritano Maria , Yu Kenneth H. , Pappin Darryl J. , Goggins Michael G. , Hruban Ralph H. , Lewis Jason S. , Lyons Scott K. , Yeh Johannes T. , Tuveson David A. 
Published: September 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, as 90% of patients do not survive beyond five years from diagnosis. This dismal prognosis is largely due to the advanced stage of the disease at diagnosis, which precludes potentially curative surgical resection. Although early detection strategies hold significant promise for improving patient outcomes, there is still no accurate diagnostic tool to detect incipient PDAC. Here, we sought to develop antibodies for the early detection of PDAC by positron-emission tomography (PET) imaging. Accordingly, we establish a pipeline to generate novel tumor-specific monoclonal antibodies (mAbs) against cell-surface proteins of PDAC patient-derived organoids (PDOs). We identify a panel of 16 tumor organoid-binding antibodies (TOBi-bodies) that display high reactivity to human PDAC tissues but not to matched adjacent normal pancreas. We then employ biochemical, flow cytometric, mass spectrometric, and CRISPR/Cas9-mediated knockout methods to determine the cognate antigens of these TOBi-bodies. We identify two mAbs that bind to tumor-specific variants of the surface protein CEACAM6 and show minimal binding to normal tissues. PET imaging in mouse models using these TOBi-bodies enables the detection of incipient human organoid-derived PDAC tumors that are rather undetectable by palpation or high-resolution ultrasound imaging techniques. We propose that further development of these mAbs as PET radiotracers could facilitate the early detection and accurate staging of PDAC.