bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern
Authors: Aggarwal Anupriya , Stella Alberto Ospina , Walker Gregory , Akerman Anouschka , Milogiannakis Vanessa , Brilot Fabienne , Amatayakul-Chantler Supavadee , Roth Nathan , Coppola Germano , Schofield Peter , Jackson Jennifer , Henry Jake Y. , Mazigi Ohan , Langley David , Lu Yonghui , Forster Charles , McAllery Samantha , Mathivanan Vennila , Fichter Christina , Hoppe Alexandra Carey , Munier Mee Ling , Jack Hans-Martin , Cromer Deborah , Darley David , Matthews Gail , Christ Daniel , Khoury David , Davenport Miles , Rawlinson William , Kelleher Anthony D. , Turville Stuart 
Published: December 2021

AbstractGenetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, the Omicron (B.1.1.529) virus variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. We assessed the impact of Omicron infection on the ability of: serum from vaccinated and / or previously infected individuals; concentrated human IgG from plasma donors, and licensed monoclonal antibody therapies to neutralise virus in vitro. There was a 17 to 22-fold reduction in neutralisation titres across all donors who had a detectable neutralising antibody titre to the Omicron variant. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 16-fold. Of all therapeutic antibodies tested, significant neutralisation of the Omicron variant was only observed for Sotrovimab, with other monoclonal antibodies unable to neutralise Omicron in vitro. These results have implications for ongoing therapy of individuals infected with the Omicron variant.
Rehydration of freeze substituted brain tissue for pre-embedding immunoelectron microscopy
Authors: Pérez-Garza Janeth , Parrish-Mulliken Emily , Deane Zachary , Ostroff Linnaea E. 
Published: December 2021

AbstractElectron microscopy (EM) volume reconstruction is a powerful tool for investigating the fundamental structure of brain circuits, but the full potential of this technique is limited by the difficulty of integrating molecular information. High quality ultrastructural preservation is necessary for EM reconstruction, and intact, highly contrasted cell membranes are essential for following small neuronal processes through serial sections. Unfortunately, the antibody labeling methods used to identify most endogenous molecules result in compromised morphology, especially of membranes. Cryofixation can produce superior morphological preservation and has the additional advantage of allowing indefinite storage of valuable samples. We have developed a method based on cryofixation that allows sensitive immunolabeling of endogenous molecules, preserves excellent ultrastructure, and is compatible with high-contrast staining for serial EM reconstruction.
Innate heuristics and fast learning support escape route selection in mice
Authors: Claudi Federico , Campagner Dario , Branco Tiago 
Published: December 2021

SummaryWhen faced with imminent danger, animals must rapidly take defensive actions to reach safety. Mice can react to innately threatening stimuli in less than 250 milliseconds [1] and, in simple environments, use spatial memory to quickly escape to shelter [2,3]. Natural habitats, however, often offer multiple routes to safety which animals must rapidly identify and choose from to maximize the chances of survival [4]. This is challenging because while rodents can learn to navigate complex mazes to obtain rewards [5,6], learning the value of different routes through trial-and-error during escape from threat would likely be deadly. Here we have investigated how mice learn to choose between different escape routes to shelter. By using environments with paths to shelter of varying length and geometry we find that mice prefer options that minimize both path distance and path angle relative to the shelter. This choice strategy is already present during the first threat encounter and after only ~10 minutes of exploration in a novel environment, indicating that route selection does not require experience of escaping. Instead, an innate heuristic is used to assign threat survival value to alternative paths after rapidly learning the spatial environment. This route selection process is flexible and allows quick adaptation to arenas with dynamic geometries. Computational modelling of different classes of reinforcement learning agents shows that the observed behavior can be replicated by model-based agents acting in an environment where the shelter location is rewarding during exploration. These results show that mice combine fast spatial learning with innate heuristics to choose escape routes with the highest survival value. They further suggest that integrating priors acquired through evolution with knowledge learned from experience supports adaptation to changing environments while minimizing the need for trial-and-error when the errors are very costly.
Structural dissection of the first events following membrane binding of the islet amyloid polypeptide
Authors: Khemtemourian Lucie , Fatafta Hebah , Davion Benoit , Lecomte Sophie , Castano Sabine , Strodel Birgit 
Published: December 2021

ABSTRACTAmyloid forming proteins are involved in many pathologies and often belong to the class of intrinsically disordered proteins. One of these proteins is the islet amyloid polypeptide (IAPP), which is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The molecular mechanism of IAPP-induced cell death is not yet understood, however it is known that cell membrane plays a dual role, being a catalyst of IAPP aggregation and the target of IAPP toxicity. Using FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Both our experiments and simulations reveal distinct IAPP-membrane interaction modes for the various IAPP variants. Membrane binding causes IAPP to fold into an amphipathic helix, which in the case of H18K- and H18R-IAPP can easily insert into the membrane. For all IAPP variants but H18E-IAPP, the membrane-bound α-helical structure is an intermediate on the way to IAPP amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel β-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel β-sheets as well as amorphous aggregates. In summary, our results emphasize the importance of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good target for destabilizing amyloid fibrils of IAPP and inhibit its toxic actions by possible therapeutic molecules.
1H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives
Authors: Dubini Romeo C. A. , Korytiaková Eva , Schinkel Thea , Heinrichs Pia , Carell Thomas , Rovó Petra 
Published: December 2021

Abstract5-carboxycytosine (5caC) is a rare epigenetic modification found in nucleic acids of all domains of life. Despite its sparse genomic abundance, 5caC is presumed to play essential regulatory roles in transcription, maintenance and baseexcision processes in DNA. In this work, we utilize nuclear magnetic resonance (NMR) spectroscopy to address the effects of 5caC incorporation into canonical DNA strands at multiple pH and temperature conditions. Our results demonstrate that 5caC has a pH-dependent global destabilizing and a base-pair mobility enhancing local impact on dsDNA, albeit without any detectable influence on the ground-state B-DNA structure. Measurement of hybridization thermodynamics and kinetics of 5caC-bearing DNA duplexes highlighted how acidic environment (pH 5.8 and 4.7) destabilizes the double-stranded structure by ~10-20 kJ mol−1 at 37 °C when compared to the same sample at neutral pH. Protonation of 5caC results in a lower activation energy for the dissociation process and a higher barrier for annealing. Studies on conformational exchange on the μs time scale regime revealed a sharply localized base-pair motion involving exclusively the modified site and its immediate surroundings. By direct comparison with canonical and 5-formylcytosine (5fC)-edited strands, we were able to address the impact of the two most oxidized naturally occurring cytosine derivatives in the genome. These insights on 5caC’s subtle sensitivity to acidic pH contribute to the long standing questions of its capacity as a substrate in base excision repair processes and its purpose as an independent, stable epigenetic mark.
A calibrated cell-based functional assay to aide classification of MLH1 DNA mismatch repair gene variants
Authors: Rath Abhijit , Radecki Alexander A. , Rahman Kaussar , Gilmore Rachel B. , Hudson Jonathan R. , Cenci Matthew , Tavtigian Sean V. , Grady James P. , Heinen Christopher D. 
Published: December 2021

ABSTRACTPURPOSEFunctional assays provide important evidence for classifying the disease significance of germline variants in the DNA mismatch repair genes. We sought to develop a cell-based approach for testing the function of variants of uncertain significance (VUS) in the MLH1 gene.METHODSUsing CRISPR gene editing, we knocked-in MLH1 VUS into the endogenous MLH1 loci in human embryonic stem cells. We examined their impact at the RNA and protein level, including their ability to maintain stability of microsatellite sequences and instigate a DNA damage response. We calibrated these assays by testing well-established pathogenic and benign control variants.RESULTSFive VUS resulted in functionally abnormal protein, 15 VUS resulted in functionally normal protein, and one VUS showed mixed results. Furthermore, we converted the functional outputs into a single odds in favor of pathogenicity score for each VUS.CONCLUSIONOur CRISPR-based functional assay successfully models phenotypes observed in patients in a cellular context. Using this approach, we generated evidence for or against pathogenicity for utilization by variant classification expert panels. Ultimately, this information will assist in proper diagnosis and disease management for suspected Lynch syndrome patients.
Preterm birth alters the maturation of the GABAergic system in the human prefrontal cortex
Authors: Lacaille Helene , Vacher Claire-Marie , Penn Anna A. 
Published: December 2021

AbstractDevelopmental changes in GABAergic and glutamatergic systems during frontal lobe development have been hypothesized to play a key role in neurodevelopmental disorders seen in children born very preterm or low birth weight, but the associated cellular changes have not yet been identified. Here we studied the molecular development of the GABAergic system specifically in the dorsolateral prefrontal cortex, a region that that has been implicated in neurodevelopmental and psychiatric disorders. The maturation state of the GABAergic system in this region was assessed in human post-mortem brain samples, from term infants ranging in age from 0 to 8 months (n=17 male, 9 female). Gene expression was measured for 47 GABAergic genes and used to calculate a maturation index. This maturation index was significantly more dynamic in male than female infants. To evaluate the impact of premature birth on the GABAergic system development, samples from one-month-old term (n=9 male, 4 female) and one-month corrected-age (n=8 male, 6 female) very preterm infants, were compared using the same gene list and methodology. The maturation index for the GABAergic system was significantly lower (–50% p<0.05) in male preterm infants, with major alterations in genes linked to GABAergic function in astrocytes, suggesting astrocytic GABAergic developmental changes as a new cellular mechanism underlying preterm brain injury.
Evidence for a mouse origin of the SARS-CoV-2 Omicron variant
Authors: Wei Changshuo , Shan Ke-Jia , Wang Weiguang , Zhang Shuya , Huan Qing , Qian Wenfeng 
Published: December 2021

ABSTRACTThe rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting the possibility of host-jumping. The molecular spectrum (i.e., the relative frequency of the twelve types of base substitutions) of mutations acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but was highly consistent with spectra associated with evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.
Cdc42 GTPase activating proteins Rga4 and Rga6 coordinate septum synthesis and membrane trafficking at the division plane during cytokinesis
Authors: Campbell Bethany F. , Hercyk Brian S. , Williams Ashlei R. , Miguel Ema San , Young Haylee G. , Das Maitreyi E. 
Published: December 2021

AbstractFission yeast cytokinesis is driven by simultaneous septum synthesis, membrane furrowing and actomyosin ring constriction. The septum consists of a primary septum flanked by secondary septa. First, delivery of the glucan synthase Bgs1 and membrane vesicles initiate primary septum synthesis and furrowing. Next, Bgs4 is delivered for secondary septum formation. It is unclear how septum synthesis is coordinated with membrane furrowing. Cdc42 promotes delivery of Bgs1 but not Bgs4. We find that after primary septum initiation, Cdc42 inactivators Rga4 and Rga6 localize to the division site. In rga4Δrga6Δ mutants Cdc42 activity is enhanced during late cytokinesis and cells take longer to separate. Electron micrographs of the division site in these mutants exhibit malformed septum with irregular membrane structures. These mutants have a larger division plane with enhanced Bgs1 delivery but fail to enhance accumulation of Bgs4 and several exocytic proteins. Additionally, these mutants show endocytic defects at the division site. This suggests that Cdc42 regulates only specific membrane trafficking events. Our data indicate that while active Cdc42 promotes primary septum synthesis, as cytokinesis progresses Rga4 and Rga6 localize to the division site to decrease Cdc42 activity. This couples specific membrane trafficking events with septum formation to allow proper septum morphology.Abstract FigureSynopsisThe GTPase Cdc42 regulates cytokinesis in cell-walled fission yeast. Active Cdc42 promotes the initiation of septum (new cell wall) synthesis to physically divide daughter cells. Here we show that Cdc42 activity must be decreased at the later stages of cytokinesis to enable proper septum formation. Mutants lacking Cdc42 inactivators, Rga4 and Rga6, lead to membrane trafficking defects and malformed septa consequently delaying cell separation.
pop-1/TCF, ref-2/ZIC and T-box factors regulate the development of anterior cells in the C. elegans embryo
Authors: Rumley Jonathan D. , Preston Elicia A. , Cook Dylan , Peng Felicia L. , Zacharias Amanda L. , Wu Lucy , Jileaeva Ilona , Murray John Isaac 
Published: December 2021

ABSTRACTPatterning of the anterior-posterior axis is fundamental to animal development. The Wnt pathway plays a major role in this process by activating the expression of posterior genes in animals from worms to humans. This observation raises the question of whether the Wnt pathway or other regulators control the expression of the many anterior-expressed genes. We found that the expression of five anterior-specific genes in Caenorhabditis elegans embryos depends on the Wnt pathway effectors pop-1/TCF and sys-1/β-catenin. We focused further on one of these anterior genes, ref-2/ZIC, a conserved transcription factor expressed in multiple anterior lineages. Live imaging of ref-2 mutant embryos identified defects in cell division timing and position in anterior lineages. Cis-regulatory dissection identified three ref-2 transcriptional enhancers, one of which is necessary and sufficient for anterior-specific expression. This enhancer is activated by the T-box transcription factors TBX-37 and TBX-38, and surprisingly, concatemerized TBX-37/38 binding sites are sufficient to drive anterior-biased expression alone, despite the broad expression of TBX-37 and TBX-38. Taken together, our results highlight the diverse mechanisms used to regulate anterior expression patterns in the embryo.
Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization
Authors: Doria-Rose Nicole A. , Shen Xiaoying , Schmidt Stephen D , O’Dell Sijy , McDanal Charlene , Feng Wenhong , Tong Jin , Eaton Amanda , Maglinao Maha , Tang Haili , Manning Kelly E. , Edara Venkata-Viswanadh , Lai Lilin , Ellis Madison , Moore Kathryn , Floyd Katharine , Foster Stephanie L. , Atmar Robert L. , Lyke Kirsten E. , Zhou Tongqing , Wang Lingshu , Zhang Yi , Gaudinski Martin R , Black Walker P , Gordon Ingelise , Guech Mercy , Ledgerwood Julie E , Misasi John N , Widge Alicia , Roberts Paul C. , Beigel John , Korber Bette , Pajon Rolando , Mascola John R. , Suthar Mehul S. , Montefiori David C. 
Published: December 2021

AbstractThe Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in live virus and pseudovirus assays. Omicron was 41-84-fold less sensitive to neutralization than D614G and 5.3-7.4-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 µg mRNA-1273. A 50 µg boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.
Acute decrease in plasma membrane tension induces macropinocytosis via
PLD2 activation
Authors: Loh Julie , Joseph Jophin , Chuang Mei-Chun , Lin Shan-Shan , Chang Yu-Chen , Su You-An , Liu Allen P. , Liu Ya-Wen 
Published: December 2021

Abstract
Internalization of macromolecules and membrane into cells through
endocytosis is critical for cellular growth, signaling, and membrane tension
homeostasis. Although endocytosis is responsive to both biochemical and physical
stimuli, how physical cues modulate endocytic pathways is less understood. In
contrary to the accumulating discoveries on effects of increased membrane
tension on endocytosis, little is known about how a drop of tension impacts
membrane trafficking. Here we reveal that acute reduction of plasma membrane
tension results in phosphatidic acid, F-actin and dynamin 2-enriched dorsal
membrane ruffling and subsequent macropinocytosis in myoblast. The membrane
flaccidity-induced local phosphatidic acid production depends on phospholipase
D2 (PLD2) that is activated via lipid raft
disruption. Furthermore, the “membrane flaccidity-PLD2-macropinocytosis” pathway
is dominant in myotube, reflecting a potential mechanism of membrane tension
homeostasis upon intensive muscle stretching and relaxation. Together, we
identify a new mechanotransduction pathway which converts acute tension drop
into PA production and subsequently initiates macropinocytosis
via actin and dynamin activities.

Summary
We reveal a mechanical induction of macropinocytosis that is elicited by
acute decrease of plasma membrane tension, followed by lipid raft
destabilization, PLD2 activation and PA production.
A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury
Authors: Ferrer Ivana R. , West Heather C. , Henderson Stephen , Ushakov Dmitry S. , Santos e Sousa Pedro , Strid Jessica , Chakraverty Ronjon , Yates Andrew J. , Bennett Clare L. 
Published: December 2021

AbstractEmbryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.HighlightsImmune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC).DC lineage cells cannot become long-term replacement LC.The size of the re-emerging network is controlled by density-dependent division of mature LC.Immune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.