bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin B5, a Coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects inDrosophilaand human cells
Authors: Asadi Paria , Milev Miroslav P. , Saint-Dic Djenann , Gamberi Chiara , Sacher Michael 
Published: November 2022

ABSTRACTMutations in theTransportandGolgiOrganization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model ofTANGO2-related disease in the fruit flyDrosophila melanogasterthat recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a Coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated withTANGO2deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss-of-function inDrosophilaand rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2-deficiency disease. Possible mechanisms for the rescue are discussed including restoration of lipid homeostasis.SYNOPSISUsing aDrosophilafruit fly model that recapitulates many defective phenotypes associated with TANGO2 deficiency disease (TDD), we show that treatment with vitamin B5 rescues these defects and suggest a multivitamin or B complex vitamin containing vitamin B5 may prevent the potentially lethal metabolic crises associated with TDD.
Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes
Authors: Leem Jiyeon , Kim Jae-Sung , Oh Jeong Su 
Published: November 2022

AbstractBecause DNA double-strand breaks (DSBs) greatly threaten genomic integrity, effective DNA damage sensing and repair are essential for cellular survival in all organisms. However, DSB repair mainly occurs during the interphase and is repressed during mitosis. Here, we show that, unlike mitotic cells, oocytes can repair DSBs during meiosis through microtubule-dependent chromosomal recruitment of the CIP2A-MDC1-TOPBP1 complex from spindle poles. After DSB induction, we observed spindle shrinkage and stabilization, as well as BRCA1 and 53BP1 recruitment to chromosomes and subsequent DSB repair during meiosis I. Moreover, p-MDC1 and p-TOPBP1 were recruited from spindle poles to chromosomes in a CIP2A-dependent manner. This pole-to-chromosome relocation of the CIP2A-MDC1-TOPBP1 complex was impaired not only by depolymerizing microtubules but also by depleting CENP-A or HEC1, indicating that the kinetochore/centromere serves as a structural hub for microtubule-dependent transport of the CIP2A-MDC1-TOPBP1 complex. Mechanistically, DSB-induced CIP2A-MDC1-TOPBP1 relocation is regulated by PLK1 but not by ATM activity. Our data provide new insights into the critical crosstalk between chromosomes and spindle microtubules in response to DNA damage to maintain genomic stability during oocyte meiosis.
Drivers of dispersal and diversification in bromeliads
Authors: Kessous Igor M. , Farooq Harith , Testo Weston , Jiménez María Fernanda T. , Neves Beatriz , Pinto Alessandra R. , Salgueiro Fabiano , Costa Andrea F. , Bacon Christine D. 
Published: November 2022

SummaryDispersal strategies strongly influence an array of plant traits, especially the shape and function of fruits and seeds, and can be important drivers of diversification dynamics. In this study we investigated how fruit morphology and habitat influence dispersal capacity and diversification rate in bromeliads. We hypothesize that (1) the evolution of berry fruits increased dispersal capacity and diversification rates; and (2) climatic factors contribute to increased dispersal capacity and diversification rates.To understand the influence of fruit and habitat traits on evolutionary dynamics, we generated a time-calibrated phylogeny including 1,268 species of bromeliads and integrated that evolutionary framework with distribution, habitat, and morphological trait data.We find that lineages with berry fruits have the highest rates of diversification. We also identify significant correlation between diversification rates and both elevation and forest canopy height. We demonstrate that dispersal capacity is not related to fruit morphology and covaries with forest canopy height and mean annual temperature.We show that factors influencing the dispersal capacity and diversification are heterogeneous among the subfamilies. These new insights into the rise and spread of bromeliads emphasize the importance of considering the plurality of morphological and ecological features to improve the understanding of the evolutionary dynamics.
Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck
Authors: Nigam N , Bernard B , Kim S , Burkitt K , Tsai D , Robbins Y , Sievers C , Clint A , Bennett RL , Tettey TT , Carter B , Bao R , Rinaldi L , Lingen M.W. , Sater H , Edmondson EF , Cheng H , Luo X , Brennan K , Chen C , Sevilla S , Murali M , Sakata S , Takeuchi K , Nakamura Y , Uppaluri R , Sunwoo JB , Van Waes C , Licht JD , Hager GL , Saloura V 
Published: November 2022

SUMMARYCancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)- negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss increased the sensitivity of HNSCC cancer cells to IFN-β, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain- Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC, and was associated with poor response to pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.
An immune-suppressing protein in human endogenous retroviruses
Authors: Zhang Huan , Ni Shengliang , Frith Martin C. 
Published: November 2022

ABSTRACTRetroviruses are important contributors to disease and evolution in vertebrates. Sometimes, retrovirus DNA is heritably inserted in a vertebrate genome: an endogenous retrovirus (ERV). Vertebrate genomes have many such virus-derived fragments, usually with mutations disabling their original functions.Some primate ERVs appear to encode an overlooked protein. This protein is homologous to protein MC132 from Molluscum contagiosum virus, which is a human poxvirus, not a retrovirus. MC132 suppresses the immune system by targeting NF-κB, and it had no known homologs until now. The ERV homologs of MC132 in the human genome are mostly disrupted by mutations, but there is an intact copy on chromosome 4. We found homologs of MC132 in ERVs of apes, monkeys, and bushbaby, but not tarsiers, lemurs or non-primates. This suggests that some primate retroviruses had, or have, an extra immune-suppressing protein, which underwent horizontal genetic transfer between unrelated viruses.
Shield co-opts an RmuC domain to mediate phage defence acrossPseudomonasspecies
Authors: Macdonald Elliot , Strahl Henrik , Blower Tim R. , Palmer Tracy , Mariano Giuseppina 
Published: November 2022

ABSTRACTCompetitive bacteria-bacteriophage interactions have resulted in the evolution of a plethora of bacterial defense systems preventing phage propagation. In recent years, computational and bioinformatic approaches have underpinned the discovery of numerous novel bacterial defense systems. Anti-phage systems are frequently encoded together in genomic loci termed defense islands. Here we report the identification and characterisation of a novel anti-phage system, which we have termed Shield, that forms part of thePseudomonasdefensive arsenal. The Shield system comprises a membrane-bound protein, ShdA, harboring an RmuC domain. Heterologous production of ShdA alone is sufficient to mediate bacterial immunity against a panel of phages. We show that ShdA homologues can degrade phage DNAin vitroand, when expressed in a heterologous host, can alter the organisation of chromosomal DNA to a nucleoid structure. Further analysis reveals that Shield can be divided into four subtypes, three of which contain additional components that in some cases can modulate the activity of ShdA and/or provide additional lines of phage defence. Collectively, our results identify a new player within thePseudomonasbacterial immunity arsenal that displays a novel mechanism of protection, and reveals a surprising role of RmuC domains in phage defence.SIGNIFICANCEThe evolutionary pressure exerted by bacteriophages has driven bacteria to acquire numerous defense systems. Recent studies have highlighted the extraordinary diversity of these systems, uncovering exciting links between bacterial and eukaryotic immunity. Here we describe a novel anti-phage system, named Shield, found withinPseudomonasspecies. We identify several Shield subtypes, all harboring the same core component, and describe its mode of action. The growing instance of multidrug-resistant bacterial infections urgently requires the development of alternative treatments. Phage therapy is a particularly pertinent approach to treat multi-drug resistantPseudomonas aeruginosastrains causing severe lung infection in cystic fibrosis patients. A detailed understanding of bacterial immunity and phage counter-strategies is an essential step to underpin the rational design of phage therapy to fight disease.
Autophagy protects against high-doseMycobacterium tuberculosisinfection
Authors: Feng Siwei , Nehls E. Michael , Kinsella Rachel L. , Chavez Sthefany M. , Naik Sumanta K. , McKee Samuel R. , Dubey Neha , Samuels Amanda , Swain Amanda , Cui Xiaoyan , Hendrix Skyler V. , Woodson Reilly , Kreamalmeyer Darren , Smirnov Asya , Artyomov Maxim N. , Virgin Herbert W. , Wang Ya-Ting , Stallings Christina L. 
Published: November 2022

SummaryHost autophagy had been associated with the control ofMycobacterium tuberculosis(Mtb) infection due to its ability to sequesters microorganisms through a process termed “xenophagy”1–4. Xenophagy purportedly limits Mtb replication within infected macrophages1–4. However, studies in mice using a standard low-dose infection model demonstrated that xenophagy in infected phagocytes is not required to control Mtb pathogenesis5,6. Instead, an autophagy-independent function of ATG5 in myeloid cells controls low-dose Mtb infection through limiting neutrophilic inflammation5. Hitherto, anin vivorole for autophagy during Mtb infection remained to be elucidated. We report herein that autophagy in myeloid cells mediates protection against high-dose Mtb infection, providing the first evidence for a role for autophagy in myeloid cells during Mtb infectionin vivo. With the exception of ATG5, the autophagy proteins required to control high-dose Mtb infection are dispensable for host defense against a standard low-dose Mtb infection. Specifically, autophagy is required in CD11c+cells, but is dispensable in neutrophils, to control a high-dose Mtb infection in the lung. The role for autophagy is not to directly degrade Mtb in macrophages through xenophagy, but mainly to limit myeloid-derived suppressor cell accumulation and to promote sustained protective T cell responses. Together, our data highlight a novel role for autophagy in controlling Mtb infection, distinct from that of Atg5 during low-dose Mtb infection, or any previously reported roles for autophagy. In addition, our finding that the result of a pathogen-plus-susceptibility gene interaction is dependent on pathogen burden has important implications on our understanding of how Mtb infection in humans can lead to a spectrum of outcomes, the variables that contribute to autophagy gene function during infection and inflammation, and the potential use of autophagy modulators in clinical medicine.
Different ways of evolving tool-using brains in teleosts and amniotes
Authors: Estienne Pierre , Simion Matthieu , Hagio Hanako , Yamamoto Naoyuki , Jenett Arnim , Yamamoto Kei 
Published: November 2022

AbstractIn mammals and birds, tool-using species are characterized by a high degree of encephalization with a relatively large telencephalon containing a higher proportion of total brain neurons compared to other species. Some teleost species in the wrasse family have convergently evolved tool-using abilities. In this study, we compared the brains of tool-using wrasses with various teleost species from a broad phylogenetic range. Using the isotropic fractionator, we show that in the tool-using wrasses, the telencephalon and the ventral part of the forebrain and midbrain are significantly enlarged compared to other teleost species but do not contain a larger proportion of cells. Instead, we found with tract tracing and selective neuronal fiber visualization that this size difference is due to large fiber tracts connecting the dorsal part of the telencephalon (pallium) to the inferior lobe (IL), a ventral mesencephalic structure absent in amniotes. The high degree of connectivity between the IL and the pallium in tool-using wrasses suggests that this unique teleostean structure could contribute to higher-order cognitive functions. Given remarkable differences in their overall brain organization, we conclude that, unlike in amniotes, the evolution of non-telencephalic structures might have been key in the emergence of higher-order cognitive functions in teleosts.
Loss ofMfn1but notMfn2enhances adipogenesis
Authors: Mann JP , Tabara LC , Alvarez-Guaita A , Dong L , Haider A , Lim K , Tandon P , Minchin JEN , O’Rahilly S , Patel S , Fazakerley DJ , Prudent J , Semple RK , Savage DB 
Published: November 2022

AbstractObjectiveA biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2)on adipogenesis in cultured cells.MethodsWe characterised adipocyte differentiation of wildtype (WT),Mfn1-/-andMfn2-/-mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.ResultsMfn1-/-MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile includingPpargupregulation.Mfn2-/-MEFs also had a disrupted mitochondrial morphology, but in contrast toMfn1−/-MEFs they showed reduced expression of adipocyte markers and no increase in insulin-stimulated glucose uptake.Mfn1andMfn2siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.ConclusionsLoss ofMfn1but notMfn2in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.
Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes
Authors:   Carlos Company, Jürgen Schmitt Matthias , Dramaretska Yuliia , Kertalli Sonia , Jiang Ben , Serresi Michela , Barozzi Iros , Gargiulo Gaetano 
Published: November 2022

AbstractDescriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of syntheticcis-regulatory DNA(LSD), a computational framework leveraging phenotypic biomarkers andtrans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or customcis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrated LSD with a computational classifier to rank phenotypic specificity of putativecis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters.In silico, an LSD-unsupervised mesenchymal glioblastoma reporter outperformed previously validated ones. In genome-scale CRISPRa screens, it discovered known and novelbona fidecell-state-drivers. Thus, LSD captures core principles ofcis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.
Systematic analysis and optimization of early warning signals for critical transitions
Authors: Proverbio Daniele , Skupin Alexander , Gonçalves Jorge 
Published: November 2022

AbstractAbrupt shifts between alternative regimes occur in complex systems, from cell regulation to brain functions to ecosystems. Several model-free Early Warning Signals (EWS) have been proposed to detect impending transitions, but failure or poor performance in some systems have called for better investigation of their generic applicability. In particular, there are still ongoing debates whether such signals can be successfully extracted from data. In this work, we systematically investigate properties and performance of dynamical EWS in different deteriorating conditions, and we propose an optimised combination to trigger warnings as early as possible, eventually verified on experimental data. Our results explain discrepancies observed in the literature between warning signs extracted from simulated models and from real data, provide guidance for EWS selection based on desired systems and suggest an optimised composite indicator to alert for impending critical transitions.HighlightsHow to extract early warning signals (EWS) against critical transitions from data is still poorly understoodA mathematical framework assesses and explains the performance of EWS in noisy deteriorating conditionsComposite indicators are optimised to alert for impending shiftsThe results are applicable to wide classes of systems, as shown with models and on empirical data.
V0-ATPase downregulation induces MVID-like brush border defects independently of apical trafficking in the mammalian intestine
Authors: Bidaud-Meynard Aurélien , Nicolle Ophélie , Bourdais Anne , Duclos Maela , Saleh Jad , Ruemmele Frank , Farin Henner F , Delacour Delphine , Moshous Despina , Michaux Grégoire 
Published: November 2022

SummaryIntestinal microvillus atrophy is a major cause of enteropathies such as idiopathic or congenital diarrhea that are often associated with severe morbidity. It can be caused by genetic disorders, inflammatory diseases, toxins or pathogens. In particular, Microvillus inclusion disease (MVID) is characterized by a chronic intractable diarrhea and a severe microvillus atrophy. It is triggered by mutations inMYO5B, STX3, MUNC18.2orUNC45Awhich alter epithelial polarity by affecting apical trafficking in intestinal epithelial cells. Furthermore, we recently established that the depletion of the V0sector of the V-ATPase complex induces an MVID-like phenotype inC. elegans. In this study we investigated the function of the V0-ATPase complex in mouse intestinal organoids. We found that its depletion also triggers a very severe microvillus atrophy in this model. Furthermore, we established that the polarity of intestinal cells is affected in a patient carrying mutations inTCIRG1which encodes a V0-ATPase subunit. However, V0- ATPase depletion does not recapitulate other MVID-specific phenotypes such as subapical vesicle accumulation and Rab11+ endosomes mislocalization. Finally, we found that the apical localization of the V0-ATPase is disrupted in MVID patients. Altogether these results suggest a role for the V0-ATPase in microvillus atrophy which might be independent from apical trafficking.
Size compensation in Drosophila after generalised cell death
Authors: Pinal Noelia , Azpiazu Natalia , Morata Ginés 
Published: November 2022

AbstractRegeneration is a response mechanism to restore tissues that have been damaged or lost by mechanical or physiological insults. We are studying in the wing imaginal disc ofDrosophilathe regenerative response to a high dose of Ionizing Radiation (IR), which we estimate kills at least 35% of the cells. After such treatment irradiated discs are able to restore normal size and shape, indicating there is a mechanism to replace the lost cells. We have tested the role of the Jun N-terminal Kinase (JNK), Janus Kinase (JAK/STAT) and Wingless (Wg) pathways, which have been shown to promote cell proliferation in regenerating tissues. We find that there is size compensation after IR in the absence of function of these pathways, strongly suggesting that they are not necessary for the compensation. We also find that the proliferation rate is not increased after IR. We argue that after generalized death caused by IR there is not a specific mechanism to promote cell proliferation. The irradiated discs suffer a developmental delay and then resume growth at normal rate until they reach the final stereotyped size. The delay appears to be associated with a developmental reversion, as irradiated discs undergo rejuvenation towards an earlier developmental stage. The response to generalized damage is fundamentally different from that to localized damage, which requires activity of JNK and Wg.