bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells
Authors: Fischer Sabrina , Trinh Van Tuan , Simon Clara , Weber Lisa Marie , Formé Ignasi , Nist Andrea , Bange Gert , Abendroth Frank , Stiewe Thorsten , Steinchen Wieland , Liefke Robert , Vázquez Olalla 
Published: November 2022

AbstractInhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to interfere with their biological functions. The Elongin BC heterodimer (ELOB/C) is involved in transcription elongation and protein turnover by PPIs that involve the so-called BC-box. ELOB and ELOC are commonly upregulated in cancer and essential for cancer cell growth, making them attractive drug targets. However, no strategy has been established to inhibit their functions in cells, so far. Here, we report a peptide that mimics a high-affinity BC-box and tightly binds to the ELOB/C dimer (kD= 0.45 ± 0.03 nM). Our peptide blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with this peptide inhibitor show decreased cell viability, altered cell cycle and increased apoptosis. Therefore, our work proposes that blocking the BC-box binding pocket of ELOB/C is a feasible strategy to impair the function of the ELOB/C heterodimer and inhibit cancer cell growth. Our peptide inhibitor promises novel mechanistic insights into the biological function of the ELOB/C dimer and offers a starting point for therapeutics linked to ELOB/C dysfunction.
Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer
Authors: Sur Inderpreet , Zhao Wenshuo , Zhang Jilin , Pilström Margareta Kling , Rozell Björn , Webb Anna T. , Cheng Huaitao , Ristimäki Ari , Katajisto Pekka , Enge Martin , Rannikmae Helena , de la Roche Marc , Taipale Jussi 
Published: November 2022

AbstractCancer has been characterized as a wound that does not heal. Malignant cells are morphologically distinct from normal proliferating cells, but have extensive similarities to tissues undergoing wound healing and/or regeneration. The mechanistic basis of this similarity has, however, remained enigmatic. Here we show that the genomic region upstream of Myc, which is required for intestinal tumorigenesis, is also required for intestinal regeneration after radiation damage. The region is also critical for growth of adult intestinal cells in 3D organoid culture, indicating that culture conditions that recapitulate most aspects of normal tissue architecture still reprogram normal cells to proliferate using a mechanism similar to that employed by cancer cells. Our results uncover a genetic link between tissue regeneration and tumorigenesis, and establish that normal tissue renewal and regeneration of tissues after severe damage are mechanistically distinct.SummaryMyc regulatory region links regeneration and cancer
Modest transcriptomic response to polyploidization in allohexaploid wheat synthetics
Authors: Banouh Meriem , Armisen David , Bouguennec Annaig , Huneau Cecile , Sow Mamadou Dia , Pont Caroline , Salse Jerome , Civan Peter 
Published: November 2022

AbstractBread wheat is a recent allohexaploid (genomic constitution AABBDD) that emerged through a hybridization between tetraploidTriticum turgidum(AABB) and diploidAegilops tauschii(DD) <10,000 years ago. The hexaploidization can be re-created artificially, producing synthetic wheat that has been used to study immediate genomic responses to polyploidization. Here we produced several synthetic wheats from alternative parental genotypes and reciprocal crosses, and examined transcriptomes from two different tissues and successive generations. We did not detect a massive reprogramming in gene expression, with only ∼1% of expressed genes showing significant differences compared to their lower-ploidy parents. Most of the differential expression is located on the D subgenome, without consistency in the direction of the expression change. Leaves and developing endosperm show distinct patterns of homoeologous expression bias, and almost non-overlapping sets of differentially expressed genes, implying that the polyploidization-triggered reprogramming is not effectuated through permanent (epi)genetic changes. While 0-3 families of transposable elements (TEs) became upregulated in wheat synthetics, we did not detect any significant association between TEs and the expression of nearby genes. We conclude that the modest tissue-specific and partially genotype-specific transcriptomic response to polyploidization is likely caused by rare incompatibilities of parental regulomes, and we discuss the pitfalls of transcriptomic comparisons across ploidy levels that can inflate the de-regulation signal.
A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration
Authors: Weiler Simon , Rahmati Vahid , Isstas Marcel , Wutke Johann , Stark Andreas Walter , Franke Christian , Geis Christian , Witte Otto W. , Hübener Mark , Bolz Jürgen , Margrie Troy W. , Holthoff Knut , Teichert Manuel 
Published: November 2022

AbstractTactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems might combine such information. Here in mice we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a subarea of primary visual cortex (VISp) whose visual space covers the whisker search space. This is mediated by local fast spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 of the primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.
A bioorthogonal chemistry approach to detect the K1 polysialic acid capsule inEscherichia coli
Authors: Rigolot Vincent , Rossez Yannick , Biot Christophe , Lion Cédric 
Published: November 2022

AbstractMost Escherichia coli strains associated with neonatal meningitis express the K1 capsule, a sialic acid polysaccharide that is directly related to their pathogenicity. Metabolic oligosaccharide engineering (MOE) has mostly been developed in eukaryotes, but has also been successfully applied to the study of several oligosaccharides or polysaccharides constitutive of the bacterial cell wall. However, bacterial capsules are seldom targeted despite their important role as virulence factors, and the K1 polysialic acid (PSA) antigen that shields bacteria from the immune system still remains untackled. Herein, we report a fluorescence microplate assay that allows the fast and facile detection of K1 capsules with an approach that combines MOE and bioorthogonal chemistry. We exploit the incorporation of synthetic analogues of N-acetylmannosamine or N-acetylneuraminic acid, metabolic precursors of PSA, and copper-catalysed azide-alkyne cycloaddition (CuAAC) as the click chemistry reaction to specifically label the modified K1 antigen with a fluorophore. The method was optimized, validated by capsule purification and fluorescence microscopy, and applied to the detection of whole encapsulated bacteria in a miniaturized assay. We observe that analogues of ManNAc are readily incorporated into the capsule while those of Neu5Ac are less efficiently metabolized, which provides useful information regarding the capsule biosynthetic pathways and the promiscuity of the enzymes involved. Moreover, this microplate assay is transferable to screening approaches and may provide a platform to identify novel capsule-targeted antibiotics that would circumvent resistance issues.
Insights into cargo sorting by SNX32 in neuronal and non-neuronal cells: physiological implications in neurite outgrowth
Authors: Sugatha Jini , Priya Amulya , Raj Prateek , Jaimon Ebsy , Jose Anju , Datta Sunando 
Published: November 2022

ABSTRACTSorting nexins (SNX) are a family of proteins containing the Phox homology domain, which shows a preferential endo-membrane association and regulates cargo sorting processes. Even with the vast amount of information unveiled systematically, the underlying mechanism of sorting remains elusive. Here, we established that SNX32, a SNX-BAR (Bin/Amphiphysin/Rvs) sub-family member, is associated with SNX4 via its BAR domain. We identified A226, Q259, E256, R366 of SNX32, and Y258, S448 of SNX4 at the interface of these two SNX proteins that are important for maintaining the association. Via its PX domain, SNX32 interacts with the Transferrin receptor (TfR) and Cation Independent Mannose-6-Phosphate Receptor (CIMPR). We showed that the conserved F131 in its PX domain is important in stabilising the above interactions. Silencing of SNX32 led to a defect in intracellular trafficking of TfR and CIMPR, which could be rescued by overexpressing shRNA-resistant snx32. We also showed that both individual domains play an essential role in trafficking. Our results indicate that SNX4, SNX32 and Rab11 may participate in a common pathway regulating transferrin trafficking; however, the existence of an independent pathway for Rab11 and SNX32 could not be completely ruled out. Further, we established that the PX domain of SNX32 could bind to PI(3)P and PI(4)P, suggesting a possible explanation for its sub-cellular localization. Taken together, our study showed that SNX32 mediate the trafficking of specific cargo molecules along distinct pathway via its PX domain-directed binding to phosphoinositides and its BAR domain-mediated association with other SNX family members. Further, using SILAC-based differential proteomics of the wild type and the mutant SNX32, impaired in cargo binding, we identified Basigin (BSG), an immunoglobulin super family member, as a potential interactor of SNX32 in SHSY5Y cells. We then demonstrated that SNX32 binds to BSG through its PX domain and facilitates its trafficking to the cell surface. In Neuro-Glial cell lines, the silencing of SNX32 led to defects in neuronal differentiation. Moreover, abrogation in lactate transport in the SNX32 depleted cells led us to propose that the SNX may contribute to maintaining the neuro-glial coordination via its role in BSG trafficking and the associated Monocarboxylate transporter activity.
Anti-HVEM mAb therapy improves antitumoral immunity bothin vitroandin vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors
Authors: Demerle C. , Gorvel L. , Mello M. , Pastor S. , Degos C. , Zarubica A. , Angelis F. , Fiore F. , Nunes J.A. , Malissen B. , Greillier L. , Guittard G. , Luche H. , Barlesi F. , Olive D. 
Published: November 2022

AbstractBackgroundTNFRF-14/HVEM is the ligand for BTLA and CD160 negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis.MethodsWe developed C57BL/6 mouse models co-expressing human huBTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands.ResultsHere, we show that the anti-HVEM18-10 mAb increases primary human αß-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cellsin vitro(TRANS-activity). Anti-HVEM18-10 synergizes with anti-PD-L1 mAb to activate T cells in the presence of PDL-1 positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1 negative cells. In order to better understand HVEM18-10 effectin vivoand especially disentangle its CIS and TRANS effects, we developed a knock-in (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both human BTLA and human HVEM (huBTLA+/+/huHVEM+/+(DKI)).In vivopre-clinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+ tumor growth. In the DKI model, anti-HVEM 18-10 treatment induces a decrease of exhausted CD8+T cells and regulatory T cells and an increase of Effector memory CD4+T cells within the tumor. Interestingly, mice which completely rejected tumors (± 20%) did not develop tumors upon re-challenge in both settings, therefore showing a marked T cell-memory phenotype effect.ConclusionsAltogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (anti-PD1/anti-PDL-1/anti-CTLA-4).
Faecal microbiota transplantation from Alzheimer’s participants induces impairments in neurogenesis and cognitive behaviours in rats
Authors: Grabrucker Stefanie , Marizzoni Moira , Silajdžić Edina , Lopizzo Nicola , Mombelli Elisa , Nicolas Sarah , Dohm-Hansen Sebastian , Scassellati Catia , Moretti Davide Vito , Rosa Melissa , Hoffmann Karina , English Jane A , Lavelle Aonghus , O’Neill Cora , Thuret Sandrine , Cattaneo Annamaria , Nolan Yvonne M 
Published: November 2022

ABSTRACTThe gut microbiome is emerging as an important susceptibility factor in Alzheimer’s disease (AD) possibly due to the increased prevalence of pro-inflammatory genera in gut microbiota of AD participants. Microbiota-mediated changes in cognition and adult hippocampal neurogenesis (AHN), an important process for memory which is altered in AD, position the microbiota-gut-brain axis as a key regulator of AD. However, it is unknown whether gut microbiota alterations are the cause or consequence of AD symptoms. We transplanted faecal microbiota from AD participants and age-matched controls into microbiota-depleted naïve adult rats and found impairments in AHN and associated memory tasks, which correlated with clinical cognitive scores. Discrete changes in the rat caecal and hippocampal metabolome were evident. Serum from AD participants also decreased neurogenesis in vitro and correlated with cognitive scores and pro-inflammatory genera. Our results reveal that the cognitive symptoms in AD may be due to alterations in gut microbiota, and that impaired neurogenesis may be a mechanistic link between altered gut microbiota and cognitive impairment in AD.
Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments
Authors: Musawi Shaqraa , Lise-Marie-Donnio  , Zhao Zehui , Magnani Charlène , Binda Olivier , Huang Jianbo , Rassinoux Phoebe , Jacquier Arnaud , Coudert Laurent , Lomonte Patrick , Martinat Cécile , Schaeffer Laurent , Côté Jocelyn , Mari Pierre-Olivier , Giglia-Mari Giuseppina 
Published: November 2022

ABSTRACTSMA is an autosomal recessive neuromuscular disease caused by mutations in the multifunctional protein SMN. Within the nucleus, SMN localizes to Cajal bodies (CBs), which have been shown to be associated with nucleoli, nuclear organelles dedicated to the first steps of ribosome biogenesis. The highly organized structure of the nucleolus can be dynamically altered by genotoxic agents. After genotoxic stress, RNAP1, Fibrillarin (FBL) and nucleolar DNA are exported to the periphery of the nucleolus and once DNA repair is fully completed the organization of the nucleolus is restored. We found that SMN is required for the restoration of the nucleolar structure after genotoxic stress. Unexpectedly, during DNA repair, SMN shuttles from the CBs to the nucleolus. This shuttling is important for nucleolar homeostasis and relies on the presence of Coilin and the activity of PRMT1.
Development of a novel oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia
Authors: Morini Elisabetta , Chekuri Anil , Logan Emily M. , Bolduc Jessica M. , Kirchner Emily G. , Salani Monica , Krauson Aram J. , Narasimhan Jana , Gabbeta Vijayalakshmi , Grover Shivani , Dakka Amal , Mollin Anna , Jung Stephen P. , Zhao Xin , Zhang Nanjing , Zhang Sophie , Arnold Michael , Woll Matthew G. , Naryshkin Nikolai A. , Weetall Marla , Slaugenhaupt Susan A. 
Published: November 2022

AbstractFamilial Dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in the Elongator complex protein 1 gene (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1 protein, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 protein expression in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct theELP1splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in patients. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct theELP1splicing defect in the nervous system. We demonstrate that the novel compound, PTC258, efficiently restores correctELP1splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse modelTgFD9;Elp1Δ20/floxincreases full-lengthELP1transcript in a dose-dependent manner and leads to a two-fold increase in functional ELP1 protein in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.
The paradigm shift: heartbeat initiation without “the pacemaker cell”
Authors: Maltsev Victor A. , Stern Michael D. 
Published: November 2022

AbstractThe current dogma about the heartbeat origin is based on “the pacemaker cell”, a specialized cell residing in the sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated that Ca signals and APs in the SAN are heterogeneous, with many cells generating APs of different rates and rhythms or even remaining non-firing (dormant cells), i.e. generating only subthreshold signals. Here we numerically tested a hypothesis that a community of dormant cells can generate normal automaticity, i.e. “the pacemaker cell” is not required to initiate rhythmic cardiac impulses. Our model includes (i) non-excitable cells generating oscillatory local Ca releases and (ii) an excitable cell lacking automaticity. While each cell in isolation was not “the pacemaker cell”, the cell system generated rhythmic APs: the subthreshold signals of non-excitable cells were transformed into respective membrane potential oscillations via electrogenic Na/Ca exchange and further transferred and integrated (computed) by the excitable cells to reach its AP threshold, generating rhythmic pacemaking. Conclusions: Cardiac impulse is an emergent property of the SAN cellular network and can be initiated by cells lacking intrinsic automaticity. Cell heterogeneity, weak coupling, subthreshold signals, and their summation are critical properties of the new pacemaker mechanism, i.e cardiac pacemaker can operate via a signaling process basically similar to that of “temporal summation” happening in a neuron with input from multiple presynaptic cells. The new mechanism, however, does not refute the classical pacemaker cell-based mechanism: both mechanisms can co-exist and interact within SAN tissue.
Noise reduction strategies in metagenomic chromosome confirmation capture to link antibiotic resistance genes to microbial hosts
Authors: McCallum Gregory E. , Rossiter Amanda E. , Quraishi Mohammed Nabil , Iqbal Tariq H. , Kuehne Sarah A. , van Schaik Willem 
Published: November 2022

AbstractThe gut microbiota is a reservoir for antimicrobial resistance genes (ARGs). With current sequencing methods, it is difficult to assign ARGs to their microbial hosts, particularly if these ARGs are located on plasmids. Metagenomic chromosome conformation capture approaches (meta3C and Hi-C), have recently been developed to link bacterial genes to phylogenetic markers, thus potentially allowing the assignment of ARGs to their hosts on a microbiome-wide scale.Here, we generated a meta3C dataset of a human stool sample and used previously published meta3C and Hi-C datasets to investigate bacterial hosts of ARGs in the human gut microbiome. Sequence reads mapping to repetitive elements were found to cause problematic noise in, and may importantly skew interpretation of, meta3C and Hi-C data. We provide a strategy to improve the signal-to-noise ratio by discarding reads that map to repetitive elements and to the end of contigs. We also show the importance of using spike-in controls to quantify whether the cross-linking step in meta3C and Hi-C protocols has been successful.After filtering for spurious links, 87 ARGs were linked to their bacterial hosts across all datasets, including 27 ARGs in the meta3C dataset we generated. We show that commensal gut bacteria are an important reservoir for ARGs, with genes encoding for aminoglycoside and tetracycline resistance being widespread in anaerobic commensals of the human gut.
Genome assembly and annotation of the mermithid nematodeMermis nigrescens
Authors: Bhattarai Upendra R. , Poulin Robert , Gemmell Neil J. , Dowle Eddy 
Published: November 2022

AbstractGenetic studies of nematodes have been dominated byCaenorhabditis elegansas a model species. Lack of genomic resources has been a limiting factor for expansion of genetic research to other groups of nematodes. Here, we report a draft genome assembly of a mermithid nematode,Mermis nigrescens. Mermithidae are insect parasitic nematodes with hosts including a wide range of terrestrial arthropods. We sequenced, assembled, and annotated the whole genome ofM. nigrescensusing nanopore long-reads and 10X chromium link-reads. The assembly is 524 Mb in size consisting of 867 scaffolds. The N50 value is 2.42 Mb, and half of the assembly is in the 30 longest scaffolds. The assembly BUSCO score from the eukaryotic database (eukaryota_odb10) indicates that the genome is 86.7% complete and 5.1% partial. The genome has a high level of heterozygosity (6.6%) with a repeat content of 78.7%. mRNA-seq reads from different sized nematodes (≤2 cm, 3.5-7 cm, and >7 cm body length) representing different developmental stages were also generated and used for the genome annotation. Using ab initio and evidence-based gene model predictions, 12,313 protein-coding genes and 24,186 mRNAs were annotated. These genomic resources will help researchers investigate the various aspects of the biology and host-parasite interactions of mermithid nematodes.