bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distal-less homeobox genes Dlx5/6 regulate Müllerian duct regression
Authors: Mullen Rachel D. , Bellessort Brice , Levi Giovanni , Behringer Richard R. 
Published: April 2022

AbstractDlx5 and Dlx6 encode distal-less homeodomain transcription factors that are present in the genome as a linked pair at a single locus. Dlx5 and Dlx6 have redundant roles in craniofacial, skeletal, and uterine development. Previously, we performed a transcriptome comparison for anti-Müllerian hormone (AMH)-induced genes expressed in the Müllerian duct mesenchyme of male and female mouse embryos. In that study, we found that Dlx5 transcripts were nearly seven-fold higher in males compared to females and Dlx6 transcripts were found only in males, suggesting they may be AMH-induced genes. Therefore, we investigated the role of Dlx5 and Dlx6 during AMH-induced Müllerian duct regression. We found that Dlx5 was detected in the male Müllerian duct mesenchyme from E14.5 to E16.5. In contrast, in female embryos Dlx5 was detected in the Müllerian duct epithelium. Dlx6 expression in Müllerian duct mesenchyme was restricted to males. Dlx6 expression was not detected in female Müllerian duct mesenchyme or epithelium. Genetic experiments showed that AMH signaling is necessary for Dlx5 and Dlx6 expression. Müllerian duct regression was variable in Dlx5 homozygous mutant males at E16.5, ranging from regression like controls to a block in Müllerian duct regression. In E16.5 Dlx6 homozygous mutants, Müllerian duct tissue persisted primarily in the region adjacent to the testes. In Dlx5-6 double homozygous mutant males Müllerian duct regression was also found to be incomplete but more severe than either single mutant. These studies suggest that Dlx5 and Dlx6 act redundantly to mediate AMH-induced Müllerian duct regression during male differentiation.
Machine learning improves global models of plant diversity
Authors: Cai Lirong , Kreft Holger , Taylor Amanda , Denelle Pierre , Schrader Julian , Essl Franz , van Kleunen Mark , Pergl Jan , Pyšek Petr , Stein Anke , Winter Marten , Barcelona Julie F. , Fuentes Nicol , Inderjit  , Karger Dirk Nikolaus , Kartesz John , Kuprijanov Andreij , Nishino Misako , Nickrent Daniel , Nowak Arkadiusz , Patzelt Annette , Pelser Pieter B. , Singh Paramjit , Wieringa Jan J. , Weigelt Patrick 
Published: April 2022

AbstractDespite the paramount role of plant diversity for ecosystem functioning, biogeochemical cycles, and human welfare, knowledge of its global distribution is incomplete, hampering basic research and biodiversity conservation. Here, we used machine learning (random forests, extreme gradient boosting, neural networks) and conventional statistical methods (generalised linear models, generalised additive models) to model species richness and phylogenetic richness of vascular plants worldwide based on 830 regional plant inventories including c. 300,000 species and predictors of past and present environmental conditions. Machine learning showed an outstanding performance, explaining up to 80.9% of species richness and 83.3% of phylogenetic richness. Current climate and environmental heterogeneity emerged as the primary drivers, while past environmental conditions left only small but detectable imprints on plant diversity. Finally, we combined predictions from multiple modelling techniques (ensemble predictions) to reveal global patterns and centres of plant diversity at multiple resolutions down to 7,774 km2. Our predictive maps provide the most accurate estimates of global plant diversity available to date at grain sizes relevant for conservation and macroecology.
The Neural Response at the Fundamental Frequency of Speech is Modulated by Word-level Acoustic and Linguistic Information
Authors: Kegler Mikolaj , Weissbart Hugo , Reichenbach Tobias 
Published: April 2022

ABSTRACTSpoken language comprehension requires rapid and continuous integration of information, from lower-level acoustic to higher-level linguistic features. Much of this processing occurs in the cerebral cortex. Its neural activity exhibits, for instance, correlates of predictive processing, emerging at delays of a few hundred milliseconds. However, the auditory pathways are also characterized by extensive feedback loops from higher-level cortical areas to lower-level ones as well as to subcortical structures. Early neural activity can therefore be influenced by higher-level cognitive processes, but it remains unclear whether such feedback contributes to linguistic processing. Here, we investigated early speech-evoked neural activity that emerges at the fundamental frequency. We analyzed EEG recordings obtained when subjects listened to a story read by a single speaker. We identified a response tracking the speaker’s fundamental frequency that occurred at a delay of 11 ms, while another response elicited by the high-frequency modulation of the envelope of higher harmonics exhibited a larger magnitude and longer latency of about 18 ms. Subsequently, we determined the magnitude of these early neural responses for each individual word in the story. We then quantified the context-independent frequency of each word and used a language model to compute context-dependent word surprisal and precision. The word surprisal represented how predictable a word is, given the previous context, and the word precision reflected the confidence about predicting the next word from the past context. We found that the word-level neural responses at the fundamental frequency were predominantly influenced by the acoustic features: the average fundamental frequency and its variability. Amongst the linguistic features, only context-independent word frequency showed a weak but significant modulation of the neural response to the high-frequency envelope modulation. Our results show that the early neural response at the fundamental frequency is already influenced by acoustic as well as linguistic information, suggesting top-down modulation of this neural response.
SARS-CoV-2 mutations affect proteasome processing to alter CD8+T cell responses
Authors: Wellington Dannielle , Yin Zixi , Yu Zhanru , Heilig Raphael , Davis Simon , Fischer Roman , Felce Suet Ling , Hublitz Philip , Beveridge Ryan , Dong Danning , Liu Guihai , Yao Xuan , Peng Yanchun , Kessler Benedikt M , Dong Tao 
Published: April 2022

AbstractViral CD8+epitopes are generated by the cellular turnover of viral proteins, predominantly by the proteasome. Mutations located within viral epitopes can result in escape from memory T cells but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two of the most dominant SARS-CoV-2 nucleoprotein CD8+epitopes, we identified mutations in epitope flanking regions and investigated the contribution of these mutations to antigen processing and T cell activation using SARS-CoV-2 nucleoprotein transduced B cell lines andin vitroproteasomal processing of peptides. We found that decreased NP9-17-B*27:05 CD8+T cell responses to the NP-Q7K mutation correlated with lower epitope surface expression, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-B*07:02 epitopes, respectively, increased CD8+T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on antigen processing and presentation, thereby contributing to escape from immunodominant T cell responses. Alternatively, mutations could enhance antigen processing and efficacy of T cell recognition, opening new avenues for improving future vaccine designs.One Sentence SummaryNatural mutations in the flanking regions of known immunodominant SARS-CoV-2 nucleoprotein epitopes can decrease CD8+T cell responses leading to partial escape.
Structural and biophysical properties of FopA, a major outer membrane protein of Francisella tularensis
Authors: Nagaratnam Nirupa , Martin-Garcia Jose M. , Yang Jay-How , Goode Matthew R. , Ketawala Gihan , Craciunescu Felicia M. , Zook James D. , Grant Thomas D. , Fromme Raimund , Hansen Debra T. , Fromme Petra 
Published: April 2022

AbstractFrancisella tularensis is an extremely infectious pathogen and a category A bioterrorism agent. It causes the highly contagious zoonosis, Tularemia. Currently, FDA approved vaccines against tularemia are unavailable. F. tularensis outer membrane protein A (FopA) is a well-studied virulence determinant and protective antigen against tularemia. It is a major outer membrane protein (Omp) of F. tularensis. However, FopA-based therapeutic intervention is hindered due to lack of complete structural information for membrane localized mature FopA. In our study, we established recombinant expression, monodisperse purification, crystallization and X-ray diffraction (∼6.5 Å) of membrane localized mature FopA. Further, we performed bioinformatics and biophysical experiments to unveil its structural organization in the outer membrane. FopA consists of 393 amino acids and has less than 40% sequence identity to known bacterial Omps. Using comprehensive sequence alignments and structure predictions together with existing partial structural information, we propose a two-domain organization for FopA. Circular dichroism spectroscopy and heat modifiability assay confirmed FopA has a β-barrel domain consistent with alphafold2’s prediction of an eight stranded β-barrel at the N-terminus. Small angle X-ray scattering (SAXS) and native-polyacrylamide gel electrophoresis revealed FopA purified in detergent micelles is predominantly dimeric. Molecular density derived from SAXS at 31 Å shows putative dimeric N-terminal β-barrels surrounded by detergent corona and connected to C-terminal domains via flexible linker. Disorder analysis predicts N- and C-terminal domains are interspersed by a long intrinsically disordered region and alphafold2 predicts this region to be largely unstructured. Taken together, we propose a dimeric, two-domain organization of FopA in the outer membrane: the N-terminal β-barrel is membrane embedded, provides dimerization interface and tethers to membrane extrinsic C-terminal domain via long flexible linker. Structure determination of membrane localized mature FopA is essential to understand its role in pathogenesis and develop anti-tularemia therapeutics. Our results pave the way towards it.
Molecular Architecture of the Chikungunya Virus Replication Complex
Authors: Tan Yaw Bia , Chmielewski David , Yien Law Michelle Cheok , Zhang Kuo , He Yu , Chen Muyuan , Jin Jing , Luo Dahai , Chiu Wah 
Published: April 2022

AbstractAll positive-strand (+) RNA viruses assemble membrane-associated replication complexes (RCs) for viral RNA synthesis in virus-infected cells. However, how these multi-component RCs assemble and function in synthesizing, processing, and transporting viral RNAs to the cytosol remains poorly defined. Here, we determined both the structure of the core RNA replicase of chikungunya virus (family Togaviridae) at a near-atomic level and the native RC architecture in its cellular context at the subnanometer resolution, using in vitro reconstitution and in situ electron cryotomography, respectively. Within the core RNA replicase (nsP1+2+4), the viral RNA-dependent RNA polymerase nsP4, in complex with nsP2 helicase-protease, was found to co-fold with the membrane-anchored nsP1 RNA-capping dodecameric ring and is located asymmetrically within nsP1 central pore. This complex forms the minimal core RNA replicase, while the addition of a large cytoplasmic ring next to the C-terminus of nsP1 forms the holo-RNA-RC as observed at the neck of spherules formed in virus-infected cells. These results represent a major conceptual advance in elucidating the molecular mechanisms of RNA virus replication and the principles underlying the molecular architecture of RCs, likely to be shared with many pathogenic (+) RNA viruses. At last, our study will direct the needed development of antiviral therapies targeting RCs of pathogenic viruses.SummaryCryoEM structure of the chikungunya virus replication complex reveals a multicomponent RNA synthesis nanomachine embedded in the plasma membrane of the host cell.
Development of a monoclonal antibody to a vibriophage as a proxy forVibrio choleraedetection
Authors: Sayeed Md. Abu , Paisie Taylor , Alam Meer Taifur , Ali Afsar , Camilli Andrew , Wrammert Jens , Khan Ashraful Islam , Qadri Firdausi , Salemi Marco , Morris J. Glenn , Nelson Eric J. 
Published: April 2022

ABSTRACTCholera is an acute watery diarrheal disease that causes high rates of morbidity and mortality without treatment. Early detection of the etiologic agent of toxigenicVibrio choleraeis important to mobilize treatment and mitigate outbreaks. Monoclonal antibody (mAb) based rapid diagnostic tests (RDTs) enable early detection in settings without laboratory capacity. However, the odds of an RDT testing positive are reduced by nearly 90% when the common virulent bacteriophage ICP1 is present. We hypothesize that adding a mAb for the common, and specific, virulent bacteriophage ICP1 as a proxy forV. choleraeto an RDT will increase diagnostic sensitivity when virulent ICP1 phage are present. In this study, we used anin-silicoapproach to identify immunogenic ICP1 protein targets that were conserved across disparate time periods and locations. Specificity of targets to cholera patients with known ICP1 was determined, and specific targets were used to produce mAbs in a murine model. Candidate mAbs to the head protein demonstrated specificity to ICP1 by ELISA and an ICP1 phage neutralization assay. The limit of detection of the final mAb candidate for ICP1 phage particles spiked into cholera stool matrix was 8 × 105plaque forming units by Western blot analysis. This mAb will be incorporated into a RDT prototype for evaluation in a future diagnostic study to test the guiding hypothesis behind this study.
Structure of Importin-4 bound to the H3-H4·ASF1 histone·histone chaperone complex
Authors: Bernardes Natalia Elisa , Fung Ho Yee Joyce , Li Yang , Chen Zhe , Chook Yuh Min 
Published: April 2022

AbstractImportin-4 is the primary nuclear import receptor of core histones H3 and H4. Importin-4 binds the H3-H4 dimer and histone-chaperone ASF1 prior to nuclear import, but available structures of Importin-4·histone tail complexes do not explain how Importin-4 recognizes the biologically relevant heterotrimeric H3-H4·ASF1 cargo. Our 3.5 Å Importin-4·H3-H4·ASF1 cryo-electron microscopy structure revealed interactions with H3-H4·ASF1 different those suggested by previous Importin-H3 tail peptide structures. The N-terminal half of Importin-4 clamps the globular histone domain and the H3 αN helix while its C-terminal half binds the H3 N-terminal tail weakly, with negligible tail contribution to binding energy; ASF1 binds H3-H4 without contacting Importin-4. Together, ASF1 and Importin-4 shield nucleosomal interfaces of H3-H4 to chaperone and import it into the nucleus, where Importin-4 undergoes large conformational changes as RanGTP binds to release H3-H4·ASF1. This work explains the mechanisms of nuclear import of full-length H3-H4.
Co-Component Signal Transduction Systems: fast-evolving virulence regulation cassettes discovered in enteric bacteria
Authors: Kinch Lisa N. , Cong Qian , Jaishankar Jananee , Orth Kim 
Published: April 2022

AbstractBacterial signal transduction systems sense changes in the environment and transmit these signals to control cellular responses. The simplest one-component signal transduction systems include an input sensor domain and an output response domain encoded in a single protein chain. Alternately, two-component signal transduction systems transmit signals by phosphorelay between input and output domains from separate proteins. The membrane tethered periplasmic bile acid sensor that activates the Vibrio parahaemolyticus type III secretion system adopts an obligate heterodimer of two proteins encoded by partially overlapping VtrA and VtrC genes. This co-component signal transduction system binds bile acid using a lipocalin-like domain in VtrC and transmits the signal through the membrane to a cytoplasmic DNA-binding transcription factor in VtrA. Using the domain and operon organization of VtrA/VtrC, we identify a fast-evolving superfamily of co-component systems in enteric bacteria. Accurate machine learning-based fold predictions for the candidate co-components support their homology in the twilight zone of rapidly evolving sequence and provide mechanistic hypotheses about previously unrecognized lipid-sensing functions.Significance statementUsing the domain and operon organization of VtrA/VtrC, combined with fold predictions, we identify new co-component signal transduction systems in enteric bacteria that likely regulate virulence. We observe that the heterodimeric VtrA/VtrC periplasmic bile acid receptor controlling Vibrio parahaemolyticus T3SS2 is a distant homolog of the ToxR/ToxS master regulator of virulence and has evolved beyond confident sequence recognition. Exploiting the newly developed machine learning methods for structure prediction, we observe a VtrC-like lipocalin fold for both the ToxS periplasmic domain and for other detected periplasmic sensor components. This structure prediction supports the divergent evolution of VtrA/VtrC-like co-component signal transduction systems and suggests a role for lipid sensing in regulating virulence in enteric bacteria.
NVX-CoV2373 vaccination induces functional SARS-CoV-2–specific CD4+ and CD8+ T cell responses
Authors: Moderbacher Carolyn Rydyznski , Kim Christina , Mateus Jose , Plested Joyce , Zhu Mingzhu , Cloney-Clark Shane , Weiskopf Daniela , Sette Alessandro , Fries Louis , Glenn Gregory , Crotty Shane 
Published: April 2022

ABSTRACTNVX-CoV2373 is an adjuvanted recombinant full-length SARS-CoV-2 spike trimer protein vaccine demonstrated to be protective against COVID-19 in efficacy trials. Here we demonstrate that vaccinated subjects made CD4+ T cell responses after one and two doses of NVX-CoV2373, and a subset of individuals made CD8+ T cell responses. Characterization of the vaccine-elicited CD8+T cells demonstrated IFNγ production. Characterization of the vaccine-elicited CD4+ T cells revealed both circulating T follicular helper cells (cTFH) and TH1 cells (IFNγ, TNFα, and IL-2) were detectable within 7 days of the primary immunization. Spike-specific CD4+ T cells were correlated with the magnitude of the later SARS-CoV-2 neutralizing antibody titers, indicating that robust generation of CD4+ T cells, capable of supporting humoral immune responses, may be a key characteristic of NVX-CoV2373 which utilizes Matrix-M™ adjuvant.
In Silico Improvement of Highly Protective Anti-Malarial Antibodies
Authors: Reveiz Mateo , Tripathi Prabhanshu , Da Silva Pereira Lais , Kiyuka Patience , Liu Tracy , Zhang Baoshan , Yang Yongping , Bonilla Brian G. , Dillon Marlon , Lee Myungjin , Shen Chen-Hsiang , Schön Arne , Kratochvil Sven , Batista Facundo D. , Idris Azza H. , Seder Robert A. , Kwong Peter D. , Rawi Reda 
Published: April 2022

SUMMARYAntibody CIS43 binds Plasmodium falciparum circumsporozoite protein (PfCSP) and protects against malaria, as recently demonstrated clinically. To improve the efficacy of CIS43, we developed an in silico pipeline to optimize the interaction energy of CIS43 to its junctional epitope (peptide 21: PfCSP residues 101-115). Starting from two improved CIS43 variants, recently elicited from a CIS43-germline knock-in mice, single and double amino acid substitutions in the peptide 21-proximal heavy (VH) and light (VL) variable regions were introduced. CIS43-variants, selected on the basis of improved in silico interface and stability energies, showed increased affinity to peptide 21 and superior malaria-protective efficacy. The best designed variant, antibody P3-43, was significantly more protective than its template antibody m43.151, with greater liver-burden protection than the current best-in-class (antibody iGL-CIS43.D3). Crystal structures of improved antibodies revealed atomic-level interactions explaining gains in binding affinity. The reported pipeline provides a powerful in silico approach to improve antibody functionality.
The senescence regulator S40 family members from Caragana intermedia and Arabidopsis thaliana inhibit leaf senescence via promoting cytokinins synthesis
Authors: Yang Tianrui , Zhang Minna , Yang Qi , Liu Kun , Cui Jiaming , Chen Jia , Ren Yufan , Shao Yunjie , Wang Ruigang , Li Guojing 
Published: April 2022

AbstractLeaf senescence is regulated by both endogenous hormones and environmental stimuli in a programmed and concerted way. The members of the S40 family have been reported to play roles in leaf senescence. Here we report that overexpression of an S40 family member from Caragana intermedia, CiS40-11, delayed the leaf senescence. Phylogenetic analysis revealed that the CiS40-11 protein had the highest identity with AtS40-5 and AtS40-6 of A. thaliana. CiS40-11 was highly expressed in leaves and was down-regulated after dark treatment. The subcellular localization analysis showed that CiS40-11 was a cytoplasm-nucleus dual-localized protein. Leaf senescence was delayed in CiS40-11 transgenic A. thaliana or by its transient expression in C. intermedia. Transcriptomic analysis and endogenous hormones assay revealed that CiS40-11 inhibited leaf senescence via promoting the biosynthesis of cytokinins, through blocking AtMYB2 expression in CiS40-11 overexpression lines. Furthermore, in the ats40-5a and ats40-6a mutants, AtMYB2 expression was increased and their leaves exhibited a premature senescence phenotype. Our results show that CiS40-11 (and its orthologs, AtS40-5 and AtS40-6) promoted cytokinin synthesis by inhibiting the expression of MYB2 and releasing its negative regulation on the expression of IPTs to inhabit leaf senescence.HighlightThe senescence regulator S40 family members CiS40-11, AtS40-5 and AtS40-6 are induced by light and inhibition leaf senescence by promoting cytokinin synthesis.
Behavioral biases in trade credit policy: does it matter for financial performance?
Authors: Farooq Umar , Tabash Mosab I. , Abousamak Ahmed , Habib Samar 
Published: April 2022

PurposeCorporate firms often follow their peer firms to articulate multiple financial decisions. Among the others, trade credit policy is a vital financial decision that can impart its dynamic role in achieving financial efficiency. Therefore, the current analysis aims to assess the role of herding behavior in determining the trade credit policies of corporate firms and its relevant effect on corporate financial performance.Design/methodology/approachFor this purpose, the financial data of 13089 nonfinancial sector firms from 50 countries are employed and the dynamic generalized method of moments (GMM) model to estimate the regression is applied.FindingsThe empirical findings first reveal that corporate firms actively mimic their peer firms regarding trade credit policies. However, this mimicking behavior hampers the financial performance due to noncompatibility with peers’ trade credit policies. Peer firms often develop such trade credit policies that are not applicable to corporate firms.Practical implicationsMainly, the findings of the study suggest two implications. First, it highlights the peer effect in terms of trade credit patterns. Second, it elaborates an adverse effect regarding financial performance due to herding of peers’ trade credit policies.Originality/valueThis study adds new thoughts regarding herding behavior in terms of trade credit policy and its possible consequences for corporate financial performance. No study explores such a relationship.