bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytoplasmic folding, mis-folding, and early stages of aggregation
Authors: Samuel Russell Premila P. , Rickard Meredith M. , Boob Mayank , Gruebele Martin , Pogorelov Taras V. 
Published: October 2022

AbstractWe examine how cellular interactions in an all-atom model of theHomo sapienscytoplasm influence the early folding events of Protein B (PB), a three-helix bundle protein. While PB is known to fold duringin vitrosimulations in three microseconds, all three initially unfolded PB copies in our cytoplasm model never completely reached their native topology across our 31 microsecond simulation. We were able to capture initial formation of all three helices and a compact topology similar to the native state. Sticking interactions between PB and surrounding macromolecules, as well as other unfolded PBs, became competitive with PB folding. Interaction between PB copies seeded beta-strand formation, modeling initial events of protein aggregation. Finally, the fold-switching potential of PB related GA domains has been explored in previous studies, and the sticking and crowding in our model thus initiates sampling of helix/sheet structural plasticity of PB.
Integrated SARS-CoV-2 serological and virological screening across an acute fever surveillance platform to monitor temporal changes in anti-spike antibody levels and risk of infection during sequential waves of variant transmission — Dominican Republic, March 2021 to August 2022
Authors: Nilles Eric J. , de St. Aubin Michael , Dumas Devan , Duke William , Etienne Marie Caroline , Abdalla Gabriela , Jarolim Petr , Oasan Timothy , Garnier Salome , Iihoshi Naomi , Lopez Beatriz , de la Cruz Lucia , Puello Yosanly Cornelio , Baldwin Margaret , Roberts Kathryn W. , Peña Farah , Durski Kara , Sanchez Isaac Miguel , Gunter Sarah M. , Kneubehl Alexander R. , Murray Kristy O. , Lino Allison , Strobel Sarah , Baez Amado Alejandro , Lau Colleen L. , Kucharski Adam , Gutiérrez Emily Zielinski , Skewes-Ramm Ronald , Vasquez Marietta , Paulino Cecilia Then 
Published: October 2022

AbstractThe global SARS-CoV-2 immune landscape and population protection against emerging variants is largely unknown. We assessed SARS-CoV-2 antibody changes in the Dominican Republic and implications for immunological protection against variants of concern. Between March 2021 and August 2022, 2,300 patients with undifferentiated febrile illnesses were prospectively enrolled. Sera was tested for total anti-spike antibodies and simultaneously collected nasopharyngeal samples for acute SARS-CoV-2 infection with RT-PCR. Geometric mean anti-spike titers increased from 6.6 BAU/ml (95% CI 5.1–8.7) to 1,332 BAU/ml (1055–1,682). Multivariable binomial odds ratios for acute SARS-CoV-2 infection were 0.55 (0.40–0.74), 0.38 (0.27–0.55), and 0.27 (0.18–0.40) for the second, third, and fourth versus the first anti-S quartile, with similar findings by viral strain. Integrated serological and virological screening can leverage existing acute fever surveillance platforms to monitor population-level immunological markers and concurrently characterize implications for emergent variant transmission in near real-time.
The nematode effector Mj-NEROSs interacts with ISP influencing plastid ROS production to suppress plant immunity
Authors: Stojilković Boris , Xiang Hui , Chen Yujin , Bauters Lander , Van de Put Hans , Steppe Kathy , Liao Jinling , de Almeida Engler Janice , Gheysen Godelieve 
Published: October 2022

AbstractRoot-knot nematodes are an important group of plant pathogens that mainly infect plant roots. They establish a feeding site in the host upon infection while secreting hundreds of effectors. These effector proteins are crucial for successful pathogen propagation. Although many effectors have been described, their targets and molecular mode of action are still unknown. Here we report the analysis of the RKN effector, Mj-NEROSs (MeloidogynejavanicanematodeeffectorROS suppressor), which emerges to have an essential role in suppressing host immunity by inhibiting INF1-induced cell death and reducing callose deposition. Secreted from the subventral esophageal glands to giant cells, Mj-NEROSs localizes in plastids where it interacts withISP, interfering with the electron transport rate and ROS production. Moreover, our transcriptome analysis shows the downregulation of ROS-related genes upon Mj-NEROSs expression. We propose that Mj-NEROSs manipulates root plastids leading to transcriptional changes, lowering ROS production, and suppressing host immunity.
Vaccine- and BTI-elicited pre-Omicron immunity more effectively neutralizes Omicron sublineages BA.1, BA.2, BA.4 and BA.5 than pre-Omicron infection alone
Authors: da Silva Eveline Santos , Servais Jean-Yves , Kohnen Michel , Arendt Victor , Gilson Georges , Staub Therese , Seguin-Devaux Carole , Perez-Bercoff Danielle 
Published: October 2022

AbstractSince the emergence of SARS-CoV-2 Omicron BA.1 and BA.2, several Omicron sublineages have emerged, supplanting their predecessors. BA.5 is the current dominant sublineage. Here we compared the neutralization of Omicron sublineages BA.1, BA.2, BA.4 and BA.5 by human sera collected from individuals who were infected with the ancestral B.1 (D614G) strain, vaccinated (3 doses), or with hybrid immunity from vaccination (2 doses) followed by pre-Omicron breakthrough infection (BTI) with Gamma or Delta. All Omicron sublineages exhibited extensive escape from all sera compared to the ancestral B.1 strain and to Delta, albeit to different levels depending on the origin of the sera. Convalescent sera were unable to neutralize BA.1, and partly neutralized BA.2, BA.4 and BA.5. Vaccinee sera partly neutralized BA.2, but BA.1, BA.4 and BA.5 evaded neutralizing antibodies. BTI sera were either non-neutralizing or partially neutralizing. In this case, they had similar neutralizing ability against all Omicron sublineages. Despite similar levels of anti-Spike and anti-Receptor Binding Domain (RBD) antibody in all groups, BTI sera had the highest cross-neutralizing ability against all Omicron sublineages and convalescent sera were the least neutralizing. The NT50:antibody titer ratio, which reflects antibody avidity, was significantly higher in sera from BTI patients compared to convalescent sera, underscoring qualitative differences in antibodies elicited by infection alone and by vaccination. Together these findings highlight the importance of vaccination to trigger highly cross-reactive antibodies that neutralize phylogenetically and antigenically distant strains, and suggest that immune imprinting by first generation vaccines may restrict, but not abolish cross-neutralization.
Amyloid-β1–42oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling
Authors: Ng Ai Na , Salter Eric W. , Georgiou John , Bortolotto Zuner A. , Collingridge Graham L. 
Published: October 2022

AbstractSynaptic dysfunction, weakening, and loss of synapses are well-correlated with the pathology of Alzheimer’s disease (AD). Oligomeric amyloid beta (oAβ) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oAβ. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluR) which is disrupted in rodent models of AD. Exogenous application of oAβ (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu5R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both NMDARs and complement C3aR/C5aR signaling. Our findings reveal a mechanistic interaction between mGlu5R, NMDARs, and the complement cascade in synaptic weakening induced by oAβ, which could represent an early trigger of synaptic loss and degeneration in AD.
Identifying brain areas for tactile perception through natural touch with MR-compatible tactile stimulus delivery system
Authors: Hwang Seong-Hwan , Park Doyoung , Paeng Somang , Lee Sue-Hyun , Kim Hyoung F. 
Published: October 2022

AbstractPrimates actively touch objects with their hands to collect information. In investigations of the tactile information processes, participants should experience tactile stimuli through active touch while brain activities are monitored. Here, we developed a pneumatic tactile stimulus delivery system (pTDS) that delivers various tactile stimuli on a programmed schedule and allows tactile perception through voluntary finger touches during MRI scanning. A pneumatic actuator moved tactile blocks and placed one in a finger hole. The time when an index finger touched a tactile stimulus was detected with a photosensor, allowing analysis of the touch-elicited brain responses. The brain responses were examined while the participants actively touched braille objects presented by the pTDS. BOLD responses during tactile perception were significantly stronger in a finger touch area of the contralateral somatosensory cortex compared with that of visual perception. This pTDS enables MR study of brain mechanisms for tactile processes through natural finger touch.
Complete functional analysis of type IV pilus components of a reemergent plant pathogen reveals neofunctionalization of paralog genes
Authors: Merfa Marcus V , Zhu Xinyu , Shantharaj Deepak , Gomez Laura M. , Naranjo Eber , Potnis Neha , Cobine Paul A. , De La Fuente Leonardo 
Published: October 2022

AbstractType IV pilus (TFP) is a multifunctional bacterial structure involved in twitching motility, adhesion, biofilm formation, as well as natural competence. Here, by mutagenesis and functional analysis, we dissected the roles of all genes required for TFP biosynthesis and regulation in the reemergent plant pathogenic fastidious prokaryoteXylella fastidiosa. This xylem-limited, insect-transmitted pathogen lives constantly under flow conditions and therefore is highly dependent on TFP for host colonization. In addition, TFP-mediated natural transformation is a process that impacts genomic diversity and environmental fitness. Ten out of the thirty-eight genes analyzed were essential for movement and natural competence. Interestingly, seven sets of paralogs exist, and mutations showed opposing phenotypes, indicating evolutionary neofunctionalization of subunits within TFP. The minor pilin FimT3 was the only protein exclusively required for natural competence. We determined that FimT3 (but not the other two FimT paralogs) is a DNA receptor that is conserved amongX. fastidiosastrains and binds DNA non-specifically via an electropositive surface. Among plant pathogens, this gene was also found in the genome of strains of the plant associated Xanthomonadaceae family. Overall, we highlight here the complex regulation of TFP inX. fastidiosa, providing a blueprint to understand TFP in other bacteria living under flow conditions.
Spt5 C-terminal repeat domain phosphorylation and length negatively regulate heterochromatin through distinct mechanisms
Authors: MacKinnon Sarah , Pagé Viviane , Martin Ryan D. , Hébert Terence E. , Tanny Jason C. 
Published: October 2022

AbstractHeterochromatin is a condensed chromatin structure that represses transcription of repetitive DNA elements and developmental genes, and is required for genome stability. Paradoxically, transcription of heterochromatic sequences is required for establishment of heterochromatin in diverse eukaryotic species. As such, components of the transcriptional machinery can play important roles in establishing heterochromatin. How these factors coordinate with heterochromatin proteins at nascent heterochromatic transcripts remains poorly understood. In the model eukaryoteSchizosaccharomcyes pombe (S. pombe), heterochromatin nucleation can be coupled to processing of nascent transcripts by the RNA interference (RNAi) pathway, or to other post-transcriptional mechanisms that are RNAi-independent. Here we show that the RNA polymerase II processivity factor Spt5 negatively regulates heterochromatin inS. pombethrough its C-terminal domain (CTD). The Spt5 CTD is analogous to the CTD of the RNA polymerase II large subunit, and is comprised of multiple repeats of an amino acid motif that is phosphorylated by Cdk9. We provide evidence that genetic ablation of Spt5 CTD phosphorylation results in aberrant RNAi-dependent nucleation of heterochromatin at an ectopic location, as well as inappropriate spread of heterochromatin proximal to centromeres. In contrast, truncation of Spt5 CTD repeat number enhanced RNAi-independent heterochromatin formation and bypassed the requirement for RNAi. We relate these phenotypes to the known Spt5 CTD-binding factor Rtf1. This separation of function argues that Spt5 CTD phosphorylation and CTD length restrict heterochromatin through unique mechanisms. More broadly, our findings argue that Spt5 CTD repeat length and phosphorylation have distinct regulatory effects on transcription.
E2 ubiquitin conjugase Bendless is essential for PINK1-Park activity to regulate Mitofusin under mitochondrial stress
Authors: Cheramangalam Rajit Narayanan , Anand Tarana , Pandey Priyanka , Balasubramanian Deepa , Varghese Reshmi , Singhal Neha , Jaiswal Sonal Nagarkar , Jaiswal Manish 
Published: October 2022

AbstractCells under mitochondrial stress often co-opt mechanisms to maintain energy homeostasis, mitochondrial quality control and cell survival. A mechanistic understanding of such responses is crucial for further insight into mitochondrial biology and diseases. Through an unbiased genetic screen inDrosophila, we identify that mutations inlrpprc2, a homolog of the humanLRPPRCgene that is linked to the French-Canadian Leigh syndrome, results in PINK1-Park activation. While the PINK1-Park pathway is well known to induce mitophagy, we show that in the case oflrpprc2mutants, PINK1-Park regulates mitochondrial dynamics by inducing degradation of the mitochondrial fusion protein Mitofusin/Marf. We also discover that Bendless, a K63-linked E2 conjugase, is a regulator of Marf, as loss ofbendlessresults in increased Marf levels. We show that Bendless is required for PINK1 stability, and subsequently for PINK1-Park mediated Marf degradation under physiological conditions, and in response to mitochondrial stress as seen inlrpprc2. Additionally, we show that loss of Bendless inlrpprc2mutant eye results in photoreceptor degeneration, indicating a neuroprotective role for Bendless-PINK1-Park mediated Marf degradation. Based on our observations, we propose that certain forms of mitochondrial stress activate Bendless-PINK1-Park to limit mitochondrial fusion, which is a cell-protective response.
Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response
Authors: Patel Anamika , Kumar Sanjeev , Lai Lilin , Chakravarthy Chennareddy , Valanparambil Rajesh , Reddy Elluri Seetharami , Gottimukkala Kamalvishnu , Bajpai Prashant , Raju Dinesh Ravindra , Edara Venkata Viswanadh , Davis-Gardner Meredith E. , Linderman Susanne , Dixit Kritika , Sharma Pragati , Mantus Grace , Cheedarla Narayanaiah , Verkerke Hans P. , Frank Filipp , Neish Andrew S. , Roback John D. , Davis Carl W. , Wrammert Jens , Ahmed Rafi , Suthar Mehul S. , Sharma Amit , Murali-Krishna Kaja , Chandele Anmol , Ortlund Eric A. 
Published: October 2022

AbstractA detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.
SORORIN is an evolutionary conserved antagonist of WAPL
Authors: Mota Ignacio Prusén , Galova Marta , Schleiffer Alexander , Nguyen Tan-Trung , Kovacikova Ines , Nishiyama Tomoko , Gregan Juraj , Peters Jan-Michael , Schlögelhofer Peter 
Published: October 2022

AbstractCohesin mediates sister chromatid cohesion to enable chromosome segregation and DNA damage repair. To perform these functions, cohesin needs to be protected from WAPL, which otherwise releases cohesin from DNA. It has been proposed that cohesin is protected from WAPL by SORORIN. However,in vivoevidence for this antagonism is missing and SORORIN is only known to exist in vertebrates and insects. It is therefore unknown how important and widespread SORORIN’s functions are. Here we report the identification of SORORIN orthologs inSchizosaccharomyces pombe(Sor1) andArabidopsis thaliana(AtSORORIN).sor1Δmutants display cohesion defects, which are partially alleviated bywpl1Δ. Atsororinmutant plants display dwarfism, tissue specific cohesion defects and chromosome mis-segregation. Furthermore,Atsororinmutant plants are sterile and separate sister chromatids prematurely at anaphase I. The somatic, but not the meiotic deficiencies can be alleviated by loss of WAPL. These results providein vivoevidence for SORORIN antagonizing WAPL, reveal that SORORIN is present in organisms beyond the animal kingdom and indicate that it has acquired tissue specific functions in plants.
A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation
Authors: Altea-Manzano Patricia , Doglioni Ginevra , Cuadros Alejandro M. , Nolan Emma , Fernandez-Garcia Juan , Wu Qi , Cidre-Aranaz Florencia , Montagne Aurelie , Planque Mélanie , Marin-Bejar Oskar , Van Elsen Joke , Vermeire Ines , Broekaert Dorien , Riera-Domingo Carla , Richard François , Geukens Tatjana , De Schepper Maxim , Leduc Sophia , Hatse Sigrid , Lambrechts Yentl , Kay Emily Jane , Lilla Sergio , Demeyer Sofie , Geldhof Vincent , Boeckx Bram , Alekseenko Alisa , de la Calle Arregui Celia , Floris Giuseppe , Marine Jean-Christophe , Lambrechts Diether , Pelechano Vicent , Mazzone Massimiliano , Zanivan Sara , Cools Jan , Wildiers Hans , Baud Véronique , Grünewald Thomas G.P. , Desmedt Christine , Malanchi Ilaria , Fendt Sarah-Maria 
Published: October 2022

AbstractCancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growthin vitroand metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-κB subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencingin vitroas well asin vivoand patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-κB signaling.
UBAP2L-dependent coupling of PLK1 localization and stability during mitosis
Authors: Guerber Lucile , Vuidel Aurore , Liao Yongrong , Kleiss Charlotte , Grandgirard Erwan , Sumara Izabela , Pangou Evanthia 
Published: October 2022

AbstractPLK1 is an important regulator of mitosis whose protein levels and activity fluctuate during the cell cycle. PLK1 dynamically localizes to various mitotic structures to regulate chromosome segregation. However, the signaling pathways linking localized PLK1 activity to its protein stability remain elusive. Here, we identify the Ubiquitin-Binding Protein 2-Like (UBAP2L) that controls both, the localization and the protein stability of PLK1.We demonstrate that UBAP2L is a spindle-associated protein whose depletion leads to severe mitotic defects. UBAP2L depleted cells are characterized by increased PLK1 protein levels and abnormal PLK1 accumulation in several mitotic structures such as kinetochores, centrosomes and mitotic spindle. UBAP2L deficient cells exit mitosis and enter the next interphase in the presence of aberrant PLK1 kinase activity. The C-terminal domain of UBAP2L mediates its function on PLK1 independently of its role in stress response signaling. Importantly, the mitotic defects of UBAP2L depleted cells are largely rescued upon chemical inhibition of PLK1. Overall, our data suggest that UBAP2L is required to finetune the ubiquitin-mediated PLK1 turnover during mitosis as a means to maintain genome fidelity.
Loss of function in the autism and schizophrenia-associated geneCYFIP1in human microglia supports a role in synaptic pruning
Authors: Sheridan Steven D. , Horng Joy E. , Yeh Hana , McCrea Liam , Fu Ting , Perlis Roy H. 
Published: October 2022

AbstractBackgroundTheCYFIP1gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood.MethodsWe generated multiple CRISPR knockoutsof CYFIP1in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human iPSC-derived neuronal cultures as anin vitromodel of synaptic pruning. We repeated these analyses in human iPSC-derived microglia, and characterized microglial development and function through morphology and motility.ResultsCYFIP1knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with statistically significant decrease in synaptic vesicle phagocytosis in microglia models derived from both PBMCs and iPSCs (p<0.0001). Morphology was also shifted toward a more ramified profile (p<0.0001), and motility was significantly reduced (p<0.0001). However, iPSC-CYFIP1knockout lines retained the ability to differentiate to functional microglia.Conclusion: The changes in microglial phenotype and function from loss ofCYFIP1may contribute to pruning abnormalities observed inCYFIP1-associated neurodevelopmental disorders. Investigating risk genes in a range of CNS cell types may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders.