bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extensive uORF translation from HIV-1 transcripts conditions DDX3 dependency for expression of main ORFs and elicits specific T cell immune responses in infected individuals
Authors: Labaronne Emmanuel , Décimo Didier , Bertrand Lisa , Guiguettaz Laura , Sohier Thibault J.M. , Cluet David , Vivet-Boubou Valérie , Dahoui Clara , François Pauline , Hatin Isabelle , Lambotte Olivier , Samri Assia , Autran Brigitte , Etienne Lucie , Goujon Caroline , Paillart Jean-Christophe , Namy Olivier , Ramirez Berta Cecilia , Ohlmann Théophile , Moris Arnaud , Ricci Emiliano P. 
Published: May 2022

AbstractHuman immunodeficiency virus type-1 (HIV-1) is a complex retrovirus which relies on alternative splicing, translational and post-translational mechanisms to produce more than 15 functional proteins from its single ∼10kb transcriptional unit. Here, we have applied ribosome profiling and nascent protein labeling at different time points during infection of CD4+ T lymphocytes to characterize the translational landscape of cellular and viral transcripts during the course of infection. Our results indicate a strong impact of viral infection on host cellular transcript levels but a modest impact on global translation rates. Analysis of ribosome profiling reads from viral transcripts reveals extensive and productive non-AUG translation of small peptides from multiple upstream open reading-frames (uORFs) located in the 5’ long terminal repeat. Remarkably, these uORFs derived peptides elicit specific T cell responses in HIV-infected individuals. uORFs are conserved among other retroviruses and, together with the TAR sequence, condition the dependency on DDX3 for efficient translation of the main viral open-reading frames.
CORK1, a LRR-Malectin Receptor Kinase for Cellooligomer Perception in Arabidopsis thaliana
Authors: Tseng Yu-Heng , Scholz Sandra S. , Fliegmann Judith , Krüger Thomas , Gandhi Akanksha , Kniemeyer Olaf , Brakhage Axel A. , Oelmüller Ralf 
Published: May 2022

AbstractCell wall integrity (CWI) maintenance is central for plant cells. Mechanical or chemical distortions, pH changes, or breakdown products of cell wall polysaccharides activate plasma membrane-localized receptors and induce appropriate downstream responses. Microbial interactions alter or destroy the structure of the plant cell wall, connecting CWI maintenance to immune responses. Cellulose is the major polysaccharide in the primary and secondary cell wall. Its breakdown generates short-chain cellooligomers which induce Ca2+-dependent CWI responses. We have shown here that these responses require the malectin domain-containing CELLOOLIGOMER-RECEPTOR KINASE 1 (CORK1) in Arabidopsis. CORK1 is required for cellooligomer-induced cytoplasmic Ca2+ elevation, reactive oxygen species (ROS) production, mitogen associated protein kinase (MAPK) activation, cellulose synthase phosphorylation, and the regulation of CWI-related genes including those involved in biosynthesis of cell wall material, secondary metabolites and tryptophan. Phosphoproteome analyses identified early targets involved in signaling, cellulose synthesis, the endoplasmatic reticulum/Golgi secretory pathway, cell wall repair and immune responses. Two conserved phenylalanine residues in the malectin domain are crucial for CORK1 function. We propose that cellulose breakdown products bind to the malectin domain in CORK1, indicating its role as a novel receptor kinase for CWI maintenance.
In situ structure of a dimeric hibernating ribosome from a eukaryotic intracellular pathogen
Authors: McLaren Mathew , Gil-Diez Patricia , Isupov Michail N. , Conners Rebecca , Gambelli Lavinia , Gold Vicki , Walter Andreas , Connell Sean R. , Williams Bryony , Daum Bertram 
Published: May 2022

AbstractTranslational control is an essential process for the cell to adapt to varying physiological or environmental conditions. To survive adverse conditions such as low nutrient levels, translation can be shut down almost entirely by inhibiting ribosomal function. Here we investigated eukaryotic hibernating ribosomes from the microsporidian parasite Spraguea lophii in situ by a combination of cryo-electron tomography (cryoET) and single particle cryoEM. We show that microsporidian spores contain ribosomes primed for host cell invasion and thus shed new light on the infection mechanism of this important pathogen. Prior to host infection, virtually all ribosomes are locked in the 100 S dimeric state, which appears to be formed by a unique dimerization mechanism that is distinct from its bacterial counterparts. Within the dimer, the hibernation factor MDF1 is bound within the E site, locking the L1 stalk in a closed conformation, and thus preventing the translation of mRNAs to polypeptides.
NSF/αSNAP2-mediated cis-SNARE complex disassembly precedes membrane fusion generating the cell plate during Arabidopsis cytokinesis
Authors: Park Misoon , Mayer Ulrike , Jürgens Gerd 
Published: May 2022

SummaryEukaryotic membrane fusion requires trans-SNARE complexes bridging the gap between adjacent membranes (Jahn and Scheller, 2006). Fusion between a transport vesicle and its target membrane transforms the trans-into a cis-SNARE complex. The latter interacts with the hexameric AAA+-ATPase NSF and its co-factor αSNAP, forming a 20S complex (Zhou et al., 2015; Zhao and Brunner, 2016). ATPase activity disassembles the SNARE complex into Qa-SNARE, which folds back onto itself, and its partners (Huang et al., 2019; Kim et al., 2021). Fusion of identical membranes has a different sequence of events (Baker and Hughson, 2016). The fusion partners each have cis-SNARE complexes to be broken up by NSF and αSNAP. The Qa-SNARE monomers are then stabilized by interaction with Sec1-type regulators (SM proteins) to form trans-SNARE complexes, as shown for the yeast vacuole (Baker et al., 2015). Membrane fusion in Arabidopsis cytokinesis is formally akin to vacuolar fusion (Müller and Jürgens, 2016). Membrane vesicles fuse with one another to form the partitioning membrane known as cell plate. Cis-SNARE complexes of cytokinesis-specific Qa-SNARE KNOLLE and its SNARE partners are assembled at the ER and delivered by traffic via Golgi/TGN to the cell division plane (Karnahl and Park et al., 2017). SM protein KEULE is required for the formation of trans-SNARE complexes between adjacent membrane vesicles (Park et al., 2012). Here, we identify the missing NSF-type AAA+-ATPase and its adaptor αSNAP2 required for disassembly of KNOLLE cis-SNARE complexes. In addition, we show that NSF is also required for other trafficking pathways and interacts with the respective Q-SNAREs. In conclusion, the SNARE complex disassembly machinery is conserved in plants and plays a unique essential role in cytokinesis.
The activation of mGluR4 rescues parallel fiber LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome
Authors: Martín Ricardo , Suárez-Pinilla Alberto Samuel , García-Font Nuria , Laguna-Luque M. Luisa , López-Ramos Juan C. , Oset-Gasque María Jesús , Gruart Agnes , Delgado-García José M. , Torres Magdalena , Sánchez-Prieto José 
Published: May 2022

ABSTRACTFragile X patients and mice lacking the Fragile X Mental Retardation Protein (FMRP) suffer from multiple behavioral alterations, including deficits in motor learning. We found that enhanced synaptic vesicle (SV) docking in cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only occludes further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP). A reduction in extracellular Ca2+ restored the readily releasable pool (RRP) size, rescuing β adrenergic receptor-mediated potentiation and parallel fiber LTP. Interestingly, VU 0155041, a selective positive allosteric modulator of mGluR4, also restored both the RRP size and parallel fiber LTP. Moreover, when injected into Fmr1KO mice, VU 0155041 improved motor learning in skilled reaching, classical eyeblink conditioning and vestibuloocular reflex (VOR) tests, as well as improving the social behavior of these mice. Thus, pharmacological activation of mGluRs may offer therapeutic relief for motor learning and social deficits in Fragile X Syndrome.
The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases
Authors: Chen Zhongbo , Reynolds Regina H. , Pardiñas Antonio F. , Gagliano Taliun Sarah A. , van Rheenen Wouter , Lin Kuang , Shatunov Aleksey , Gustavsson Emil K. , Fogh Isabella , Jones Ashley R. , Robberecht Wim , Corcia Philippe , Chiò Adriano , Shaw Pamela J. , Morrison Karen E. , Veldink Jan H. , van den Berg Leonard H. , Shaw Christopher E. , Powell John F. , Silani Vincenzo , Hardy John A. , Houlden Henry , Owen Michael J. , Turner Martin R. , Ryten Mina , Al-Chalabi Ammar 
Published: May 2022

AbstractHumans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s disease.We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s disease,, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.These findings provide insight into the origins of neurodegenerative disorders within the evolution ofHomo sapiensand addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.
Transcription factor binding sites are frequently under accelerated evolution in primates
Authors: Zhang Xinru , Huang Yi-Fei 
Published: May 2022

AbstractRecent comparative genomic studies have identified many human accelerated elements (HARs) with elevated substitution rates in the human lineage. However, it remains unknown to what extent transcription factor binding sites (TFBSs) are under accelerated evolution in humans and other primates. Here, we introduce two pooling-based phylogenetic methods with dramatically enhanced sensitivity to examine accelerated evolution in TFBSs. Using these new methods, we show that more than 6,000 TFBSs annotated in the human genome have experienced accelerated evolution in Hominini, apes, and Old World monkeys. Although these TFBSs individually show relatively weak signals of accelerated evolution, they collectively are more abundant than HARs. Also, we show that accelerated evolution in Pol III binding sites may be driven by lineage-specific positive selection, whereas accelerated evolution in other TFBSs might be driven by nonadaptive evolutionary forces. Finally, the accelerated TFBSs are enriched around neurodevelopmental and pluripotency genes, suggesting that accelerated evolution in TFBSs may drive the divergence of neurodevelopmental processes between primates.
The Features Underlying the Memorability of Objects
Authors: Kramer Max A. , Hebart Martin N. , Baker Chris I. , Bainbridge Wilma A. 
Published: May 2022

ABSTRACTWhat makes certain images more memorable than others? While much of memory research has focused on participant effects, recent studies employing a stimulus-centric perspective have sparked debate on the determinants of memory, including the roles of semantic and visual features and whether the most prototypical or atypical items are best remembered. Prior studies have typically relied on constrained stimulus sets, limiting a generalized view of the features underlying what we remember. Here, we collected 1+ million memory ratings for a naturalistic dataset of 26,107 object images designed to comprehensively sample concrete objects. We establish a model of object features that is predictive of image memorability and examined whether memorability could be accounted for by the typicality of the objects. We find that semantic features exert a stronger influence than perceptual features on what we remember and that the relationship between memorability and typicality is more complex than a simple positive or negative association alone.TEASERSemantic versus perceptual features more heavily influence what we remember, and memorability cannot be reduced to typicality.
HIV-1 Rev-RRE Functional Activity in Primary Isolates is Highly Dependent on Minimal Context-Dependent Changes in Rev
Authors: Dzhivhuho Godfrey , Holsey Jordan , Honeycutt Ethan , O’Farrell Heather , Rekosh David , Hammarskjold Marie-Louise , Jackson Patrick E. H. 
Published: May 2022

AbstractDuring HIV infection, intron-containing viral mRNAs have to be exported efficiently from the host cell nucleus to the cytoplasm in order to complete the replication cycle. To overcome cellular restrictions to export incompletely spliced transcripts, HIV encodes a protein, Rev, that is constitutively expressed from a completely spliced transcript. Rev is then imported into the nucleus where it binds to an RNA structure on intron-containing viral mRNAs called the Rev Response Element (RRE). Bound Rev multimerizes and recruits cellular factors that permit the nuclear export of the resulting ribonucleoprotein complex. Primary HIV isolates display substantial variation in the functional activity of the Rev-RRE axis, which may permit viral adaptation to differing immune environments. We describe two subtype G primary isolates with disparate Rev activity. Rev activity was correlated within vitrofitness of replication-competent viral constructs. Amino acid differences within the oligomerziation domain, but not within the arginine-rich motif or nuclear export signal, determined the different levels of Rev activity. Two specific amino acid substitutions were demonstrated to be able to alter the low-activity Rev to a high-activity phenotype. However, introducing the original amino acids from the the low activity Rev into high activity Rev in this position did not result in significant alterations in activity, highlighting the importance of the broader sequence context for functional activity. These results demonstrate that studies of Rev and RRE activity variation, which may have broader implications for HIV transmission and pathogenesis, should include sequences from primary isolates, as findings using only laboratory-adapted strains cannot be generalized.
Actin cytoskeleton signaling via MRTF/SRF entrains circadian clock
Authors: Xiong Xuekai , Li Weini , Nam Jin , Qu Meng , Kay Steve A. , Ma Ke 
Published: May 2022

AbstractThe circadian clock is entrained to daily environmental cues. Integrin-linked intracellular signaling via actin cytoskeleton dynamics transduces extracellular matrix interactions to Myocardin-related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated transcription. Actin cytoskeleton organization in liver displays diurnal oscillations and SRF-MRTF activity exert transcriptional control to entrain clock. By interrogating disparate upstream events involved in actin cytoskeleton-MRTF-A/SRF signaling cascade, here we show that this signaling cascade transduce cellular niche cues to modulate circadian clock function. Pharmacological inhibitions of MRTF-A/SRF, by disrupting actin polymerization or blocking ROCK kinase, induced period lengthening with augmented clock amplitude, and genetic loss-of-functions of Srf or Mrtf-a mimic that of actin-depolymerizing agents. In contrast, actin-polymerization induced by Jasplakinolide shortened period with attenuated amplitude. In addition, interfering with cell-matrix interaction through blockade of integrin, inhibition of focal adhesion kinase or attenuating matrix rigidity led to reduced period length while enhancing amplitude. Mechanistically, we identify that core clock repressors, Per2, Nr1d1, and Nfil3, are direct transcriptional targets of MRTF-A/SRF in mediating actin dynamic-induced clock response. Collectively, our findings defined an integrin-actin cytoskeleton-MRTF/SRF pathway in linking clock entrainment with extracellular microenvironment that may facilitate cellular adaptation to its physical niche.Summary statementOur study revealed the role of actin cytoskeleton-MRTF/SRF signaling in entraining circadian clock to its extracellular physical niche environment.
Characterization of the DNA binding domain of StbA, a key protein of a new type of DNA segregation system
Authors: Quèbre Valentin , del Campo Irene , Cuevas Ana , Siguier Patricia , Rech Jérôme , Le Phan Thai Nguyen , Ton-Hoang Bao , Cornet François , Bouet Jean-Yves , Moncalian Gabriel , de la Cruz Fernando , Guynet Catherine 
Published: May 2022

AbstractLow-copy-number plasmids require sophisticated genetic devices to achieve efficient segregation of plasmid copies during cell division. Plasmid R388 uses a unique segregation mechanism, based on StbA, a small multifunctional protein. StbA is the key protein in a segregation system not involving a plasmid-encoded NTPase partner, it regulates the expression of several plasmid operons, and it is the main regulator of plasmid conjugation. The mechanisms by which StbA, together with the centromere-like sequence stbS, achieves segregation, is largely uncharacterized. To better understand the molecular basis of R388 segregation, we determined the crystal structure of the conserved N-terminal domain of StbA to 1.9 Å resolution. It folds into an HTH DNA-binding motif, structurally related to that of the PadR subfamily II of transcriptional regulators. StbA is organized in two domains. Its N-terminal domain carries the specific stbS DNA binding activity. A truncated version of StbA, deleted of its C-terminal domain, displays only partial activities in vivo, indicating that the non-conserved C-terminal domain is required for efficient segregation and subcellular plasmid positioning. The structure of StbA DNA-binding domain also provides some insight into how StbA monomers cooperate to repress transcription by binding to the stbDR and to form the segregation complex with stbS.
Decreased in vitro dihydroartemisinin sensitivity in malaria parasites infecting sickle cell disease patients
Authors: Gnondjui Albert A. , Toure Offianan A. , Ako Beranger A. , Koui Tossea S. , Assohoun Stanislas E. , Gbessi Eric A. , N’guessan Landry T. , Tuo Karim , Beourou Sylvain , Assi Serge-Brice , Yapo Francis A. , Sanogo Ibrahima , Jambou Ronan 
Published: May 2022

ABSTRACTBackgroundPartial ACTs treatment failure in Plasmodium falciparum malaria has been previously reported in sickle cell patients. The main purpose of this study was to investigate the in vitro susceptibility of clinical isolates to DHA to find out hypothesis backing up the reason of this poor therapeutic response.ResultsA total of 134 clinical isolates from patients attending health centers in Abidjan with uncomplicated Plasmodium falciparum malaria were selected. Hemoglobin HbAS, HbSS, HbAC, HbSC and HbAA were identified. Parasitemia and hemoglobin level at inclusion were lower in sickle cell patients with major forms than in patients with normal phenotype. A significant number of parasites with survival rates ranging from 14.68 to 33.75% were observed in clinical isolates from the SS phenotype. At inclusion, these resistant clinical isolates showed lower parasite densities, and patients had lower red blood cell count and hematocrit levels compared to those with susceptible clinical isolates. A low rate of parasitic growth has more often occurred with AS sickle cell phenotype. However, the decrease in in vitro sensitivity to DHA was not associated with Kelch 13-Propeller gene polymorphism.ConclusionThis study highlights an in vitro decreased sensitivity to DHA, for clinical isolates collected from sickle cell SS patients living in Abidjan (Côte d’Ivoire), which is not related to the Pfkelch13 gene mutations. These clinical isolates may represent a health threat for sickle cell disease patients especially during crisis. Moreover, these results could suggest additional mechanisms of artemisinin resistance that need to be explored.
Effects of calcium-regulated autophagy on Candidatus Liberibacter solanacearum in carrot psyllid midguts
Authors: Sarkar Poulami , Jassar Ola , Ghanim Murad 
Published: May 2022

AbstractCandidatus Liberibacter solanacearum (CLso) transmitted by the carrot psyllid, Bactericera trigonica causes carrot yellows in Israel, and has recently gained much importance due to the excessive economical loss. Understanding the interactions between CLso and the psyllid at the cellular level is fundamental for the disease management. Here, we demonstrate the role of calcium ATPase, cytosolic calcium and most importantly Beclin1 in regulating autophagy and its association with Liberibacter. Presence of CLso generates reactive oxygen species and induces the expression of the detoxification enzymes in the psyllid midguts. CLso also induces the expression of both sarco/endoplasmic reticulum Ca2+ pump (SERCA) and 1,4,5-trisphosphate receptors (ITPR) in the midguts, followed by high levels of calcium in the cytosol. Silencing these proteins individually disrupted the calcium levels in the cytosol leading to direct effects on autophagy and thus on Liberibacter. On the other hand, inhibiting Beclin1-phosphorylation through different calcium induced kinases altered the expression of autophagy and CLso abundance. This study establishes a direct correlation between cytosolic calcium levels, autophagy and CLso in the carrot psyllid midgut.
A guide for membrane potential measurements in Gram-negative bacteria using voltage-sensitive dyes
Authors: Buttress Jessica A. , Halte Manuel , te Winkel J. Derk , Erhardt Marc , Popp Philipp F. , Strahl Henrik 
Published: May 2022

ABSTRACTTransmembrane potential is one of the main bioenergetic parameters of bacterial cells, and is directly involved in energising key cellular processes such as transport, ATP synthesis, and motility. The most common approach to measure membrane potential levels is through use of voltage-sensitive fluorescent dyes. Such dyes either accumulate or are excluded from the cell in a voltage-dependent manner, which can be followed by means of fluorescence microscopy, flow cytometry, or fluorometry. Since the cell’s ability to maintain transmembrane potential relies upon low membrane ion conductivity, voltage-sensitive dyes are also highly sensitive reporters for the activity of membrane-targeting antibacterials. However, the presence of an additional membrane layer in Gram-negative (diderm) bacteria significantly complicates their use. In this manuscript, we provide guidance on how membrane potential and its changes can be reliably monitored in Gram-negatives using the voltage-sensitive dye DiSC3(5). We also discuss the confounding effects caused by the presence of the outer membrane, or by measurements performed in buffers rather than growth medium. We hope that the discussed methods and protocols provide an easily accessible basis for the use of voltage-sensitive dyes in Gram-negative organisms, and raise awareness of potential experimental pitfalls associated with their use.