bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large haplotypes highlight a complex age structure within the maize pan-genome
Authors: Liu Jianing , Dawe R. Kelly 
Published: February 2022

ABSTRACTThe genomes of maize and other eukaryotes contain stable haplotypes in regions of low recombination. These regions, including centromeres, long heterochromatic blocks and rDNA arrays have been difficult to analyze with respect to their diversity and origin. Greatly improved genome assemblies are now available that enable comparative genomics over these and other non-genic spaces. Using 26 complete maize genomes, we developed methods to align intergenic sequences while excluding genes and regulatory regions. The centromere haplotypes (cenhaps) extend for megabases on either side of the functional centromere regions and appear as evolutionary strata, with haplotype divergence/coalescence times dating as far back as 450 thousand years ago (kya). Application of the same methods to other low recombination regions (heterochromatic knobs and rDNA) and all intergenic spaces revealed that deep coalescence times are ubiquitous across the maize pan-genome. Divergence estimates vary over a broad time scale with peaks at ∼300 kya and 16 kya, reflecting a complex history of gene flow among diverging populations and changes in population size associated with domestication. Cenhaps and other long haplotypes provide vivid displays of this ancient diversity.
Heat Shock Factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat-shock response
Authors: Xu Meng , Lin Ling , Chuang Kun-Han , Ram Babul , Dai Siyuan , Su Kuo-Hui , Tang Zijian , Dai Chengkai 
Published: February 2022

ABSTRACTDespite its pivotal roles in biology, how the transcriptional activity of c-MYC is attuned quantitatively remain poorly defined. Here, we show that heat shock factor 1 (HSF1), the master transcriptional regulator of the heat-shock, or proteotoxic stress, response, acts as a key modifier of the c-MYC-mediated transcription. HSF1 deficiency diminishes c-MYC DNA binding and dampens its transcriptional activity genome-widely. Mechanistically, c-MYC, MAX, and HSF1 assemble into a transcription factor complex on genomic DNAs and, surprisingly, the DNA binding of HSF1 is dispensable. Instead, HSF1 physically recruits the histone acetyltransferase GCN5, thereby promoting histone acetylation and augmenting c-MYC transcriptional activity. Thus, our studies reveal that HSF1 specifically potentiates the c-MYC-mediated transcription, distinct from its role in the canonical heat-shock response. Importantly, this mechanism of action engenders two distinct c-MYC activation states, primary and advanced, which may be important to accommodate diverse physiological and pathological conditions.
Cerebral Organoids Containing an AUTS2 Missense Variant Model Microcephaly
Authors: Fair Summer R. , Schwind Wesley , Julian Dominic , Biel Alecia , Ramadesikan Swetha , Westfall Jesse , Miller Katherine E. , Kararoudi Meisam Naeimi , Hickey Scott E. , Mosher Theresa Mihalic , McBride Kim L. , Neinast Reid , Fitch James , Lee Dean , White Peter , Wilson Richard K. , Bedrosian Tracy A. , Koboldt Daniel C. , Hester Mark E. 
Published: February 2022

ABSTRACTVariants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid (CO) model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband COs exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control COs. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-Catenin signaling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of COs to uncover molecular mechanisms underlying AUTS2 syndrome.
Preliminary Evidence of a Link between COVID-19 Vaccines and Otologic Symptoms
Authors: Woodcock Ramsi A. , Bartels Loren J. 
Published: February 2022

AbstractHypothesisThis study investigates whether U.S. Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System (VAERS) data suggest an association between vertigo, tinnitus, hearing loss, Bell’s palsy and the COVID-19 vaccines administered in the United States.BackgroundPublished case reports suggest a possible association between various otologic symptoms and the COVID-19 vaccines, but the only published analysis of VAERS data, which did not account for underreporting of late-appearing adverse events, found no association between hearing loss and the vaccines.MethodsThe incidence in VAERS of vertigo, tinnitus, hearing loss, and Bell’s palsy associated with COVID-19 vaccinations administered between December 14, 2020 and June 7, 2021 was compared with published rates for the general population. To account for underreporting of late-appearing adverse events, incidences were calculated using only the initial part of the observation period, during which reported events spike above expected events.ResultsThe COVID-19 vaccines were associated with statistically significant increases in the incidence of vertigo, tinnitus, hearing loss, and Bell’s palsy of 1877, 50, 12, and 14 cases per 100,000, respectively. In relation to the mRNA-1273 or BNT162b2 vaccines, the Ad26.COV2.S vaccine was associated with a statistically significant excess incidence of vertigo, tinnitus, and hearing loss of at least 723, 57, and 55 cases per 100,000, respectively.ConclusionThese results suggest an association between the COVID-19 vaccines and vertigo, tinnitus, hearing loss, and Bell’s palsy. They also suggest that, with respect to vertigo, tinnitus, and hearing loss, the association is relatively strong for the Ad26.COV2.S vaccine.
High nucleotide similarity of three Copia lineage LTR retrotransposons among plant genomes
Authors: Orozco-Arias Simon , Dupeyron Mathilde , Gutiérrez-Duque David , Tabares-Soto Reinel , Guyot Romain 
Published: February 2022

ABSTRACTTransposable elements (TEs) are mobile genetic elements found in the majority of eukaryotic genomes. Because of their mobility in the host genome, TEs can deeply impact the structure and evolution of chromosomes and can induce mutations affecting coding genes. In response to these potential threats, host genomes use various processes to repress the TE expression, leading to an arm-race between TEs for their persistence and host genomes for their protection. In plants, the major group of TEs is the Long Terminal Repeats retrotransposons (LTR-RT). They are classified into superfamilies (Gypsy, Copia) and sub-classified into lineages according to similarities, structures and presence of coding domains. Among the different ways LTR-RTs can proliferate, horizontal transfer (HT), defined as the nonsexual transmission of nuclear and plastid genetic material between species, is a process allowing LTR-RTs to invade a new genome. Although this phenomenon was considered rare in eukaryotic organisms, recent studies demonstrate numerous potential transfers of LTR-RTs, suggesting that HT may be more frequent than initially estimated.This study aims to determine which LTR-RT lineages are shared with high similarity among 69 reference genomes that represent the major groups of green plants. We first identified and classified 88,450 LTR-RTs and determined 143 cases of high similarities between pairs of genomes. Most of them involved three Copia lineages (Oryco/Ivana, Retrofit/Ale and Tork/Tar/Ikeros) and very few of them included the Gypsy superfamily. Interestingly, a detailed analysis of three high similarities involving the Tork/Tar/Ikeros group of lineages indicates a patchy distribution of the elements and phylogenetic incongruities, indicating they originated from potential HTs. Overall, our results demonstrate that three specific lineages of Copia share outstanding similarity between very distant species and may probably be involved in horizontal transfer mechanisms.
Dynamics of allosteric regulation of the phospholipase C-γ isozymes upon recruitment to membranes
Authors: Siraliev-Perez Edhriz , Stariha Jordan T.B. , Hoffmann Reece M. , Temple Brenda R. , Zhang Qisheng , Hajicek Nicole , Jenkins Meredith L , Burke John E. , Sondek John 
Published: February 2022

AbstractNumerous receptor tyrosine kinases and immune receptors activate phospholipase C-gamma (PLC-γ) isozymes at membranes to control diverse cellular processes including phagocytosis, migration, proliferation, and differentiation. The molecular details of this process are not well understood. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that PLC-γ1 is relatively inert to lipid vesicles that contain its substrate, PIP2, unless first bound to the kinase domain of the fibroblast growth factor receptor (FGFR1). Exchange occurs throughout PLC-γ1 and is exaggerated in PLC-γ1 containing an oncogenic substitution (D1165H) that allosterically activates the lipase. These data support a model whereby initial complex formation shifts the conformational equilibrium of PLC-γ1 to favor activation. This receptor-induced priming of PLC-γ1 also explains the capacity of a kinase-inactive fragment of FGFR1 to modestly enhance the lipase activity of PLC-γ1 operating on lipid vesicles but not a soluble analog of PIP2 and highlights cooperativity between receptor engagement and membrane proximity. Priming is expected to be greatly enhanced for receptors embedded in membranes and nearly universal for the myriad of receptors and co-receptors that bind the PLC-γ isozymes.
Structural basis for RNA-duplex unwinding by the DEAD-box helicase DbpA
Authors: Wurm Jan Philip 
Published: February 2022

AbstractDEAD-box RNA helicases are implicated in most aspects of RNA biology, where these enzymes unwind short RNA duplexes in an ATP-dependent manner. During the central step of the unwinding cycle, the two domains of the helicase core form a distinct closed conformation that destabilizes the RNA duplex, which ultimately leads to duplex melting. Despite the importance of this step for the unwinding process no high resolution structures of this state are available. Here, we employ nuclear magnetic resonance spectroscopy and X-ray crystallography to determine structures of the DEAD- box helicase DbpA in the closed conformation, complexed with substrate duplexes and single- stranded unwinding product. These structures reveal that DbpA initiates duplex unwinding by interacting with up to three base-paired nucleotides and a 5’ single-stranded RNA duplex overhang. These high-resolution snapshots, together with biochemical assays, rationalize the destabilization of the RNA duplex and are integrated into a conclusive model of the unwinding process.
A novel lipase with dual localisation in Trypanosoma brucei
Authors: Monic S , Lamy A , Thonnus M , Bizarra-Rebelo T , Bringaud F , Smith TK , Figueiredo LM , Rivière L 
Published: February 2022

AbstractPhospholipases are esterases involved in lipid catabolism. In pathogenic micro-organisms (bacteria, fungi, parasites) they often play a critical role in virulence and pathogenicity. A few phospholipases (PL) have been characterised so far at the gene and protein level in unicellular parasites including African trypanosomes (AT). They could play a role in different processes such as host-pathogen interaction, antigenic variation, intermediary metabolism. By mining the genome database of AT we found putative new phospholipase candidate genes and here we provided biochemical evidence that one of these has lypolytic activity. This protein has a unique non-canonical glycosome targeting signal responsible for its dual localisation in the cytosol and the peroxysomes-related organelles named glycosomes. We also show that this new phospholipase is excreted by these pathogens and that antibodies directed against this protein are generated during an experimental infection with T. brucei gambiense, a subspecies responsible for infection in humans. This feature makes this protein a possible tool for diagnosis.
Early identification of cooperative fragments for protein-protein interaction stabilization
Authors: de Vink Pim J. , Cossar Peter J. , Somsen Bente A. , Ottmann Christian , Brunsveld Luc 
Published: February 2022

AbstractModulating protein-protein interactions (PPIs) is an effective approach to drug discovery, with several drugs in the clinic that inhibit PPIs. The orthogonal approach of PPI stabilization has developed slowly, a function of the complicated dynamics of multi-component protein complexes. In contrast to PPI inhibition, where ligand affinity is the driving parameter for efficacy, cooperativity is frequently the directing variable for PPI stabilization. Here we show how STD NMR allows for early-stage detection of cooperativity using the hub protein 14-3-3, a focused library of fragments and several 14-3-3 partner proteins. Further, we validate that the observed enhancement in STD signal is a function of cooperativity of the ternary 14-3-3 complex, using mutagenesis and X-ray crystallography. Additionally, we assess the differential cooperativity of three fragments in a panel of 14-3-3 interaction partners. Finally, we demonstrate how selective 14-3-3 complex formation is a function of cooperativity effects
Using dilution grazing assays to measure size fractionated phytoplankton mortality rates across the freshwater-to-marine continuum
Authors: Barnard Malcolm A. , Paerl Hans W. 
Published: February 2022

AbstractThere is a need for a unified grazing method that can be used across the freshwater-to-marine continuum. To accomplish this, this research utilized dilution grazing assays across the freshwater-to-marine continuum and across the oligotrophic-to-hypereutrophic gradient by measuring size fractions of dilution-based mortality. This was investigated by using 0.7 µm and 0.2 µm prefiltered water and major ion solutions (MIS) as diluent media for use in the Landry-Hassett grazing bioassays run in lake, river, estuarine (riverine and lagoonal), and oceanic shelf systems. Because MIS does not include vitamins that would be in prefiltered natural water, vitamin effects on grazing rate determination were also investigated for the MIS bioassays. Results show that the dilution grazing method can be broadly applied across the freshwater-to-marine continuum and across trophic gradients.
Detection of functional activity in brain white matter using fiber architecture informed synchrony mapping
Authors: Zhao Yu , Gao Yurui , Zu Zhongliang , Li Muwei , Schilling Kurt G. , Anderson Adam W. , Ding Zhaohua , Gore John C. 
Published: February 2022

AbstractA general linear model is widely used for analyzing fMRI data, in which the blood oxygenation-level dependent (BOLD) signals in gray matter (GM) evoked in response to neural stimulation are modeled by convolving the time course of the expected neural activity with a canonical hemodynamic response function (HRF) obtained a priori. The maps of brain activity produced reflect the magnitude of local BOLD responses. However, detecting BOLD signals in white matter (WM) is more challenging as the BOLD signals are weaker and the HRF is different, and may vary more across the brain. Here we propose a model-free approach to detect changes in BOLD signals in WM by measuring task-evoked increases of BOLD signal synchrony in WM fibers. The proposed approach relies on a simple assumption that, in response to a functional task, BOLD signals in relevant fibers are modulated by stimulus-evoked neural activity and thereby show greater synchrony than when measured in a resting state, even if their magnitudes do not change significantly. This approach is implemented in two technical stages. First, for each voxel a fiber-architecture-informed spatial window is created with orientation distribution functions constructed from diffusion imaging data. This provides the basis for defining neighborhoods in WM that share similar local fiber architectures. Second, a modified principal component analysis (PCA) is used to estimate the synchrony of BOLD signals in each spatial window. The proposed approach is validated using a 3T fMRI dataset from the Human Connectome Project (HCP) at a group level. The results demonstrate that neural activity can be reliably detected as increases in fMRI signal synchrony within WM fibers that are engaged in a task with high sensitivities and reproducibility.
Three membrane fusion pore families determine the pathway to pore dilation
Authors: Su Rui , Wang Shuyuan , McDargh Zachary , O’Shaughnessy Ben 
Published: February 2022

AbstractDuring exocytosis secretory vesicles fuse with a target membrane and release neurotransmitters, hormones or other bioactive molecules through a membrane fusion pore. The initially small pore may subsequently dilate for full contents release, as commonly observed in amperometric traces. The size, shape and evolution of the pore is critical to the course of contents release, but exact fusion pore solutions accounting for membrane tension and bending energy constraints have not been available. Here we obtained exact solutions for fusion pores between two membranes. We find three families: a narrow pore, a wide pore and an intermediate tether-like pore. For high tensions these are close to the catenoidal and tether solutions recently reported for freely hinged membrane boundaries. We suggest membrane fusion initially generates a stable narrow pore, and the dilation pathway is a transition to the stable wide pore family. The unstable intermediate pore is the transition state that sets the energy barrier for this dilation pathway. Pore dilation is mechanosensitive, as the energy barrier is lowered by increased membrane tension. Finally, we study fusion pores in nanodiscs, powerful systems for the study of individual pores. We show that nanodiscs stabilize fusion pores by locking them into the narrow pore family.SignificanceDuring neurotransmission, hormone release and other fundamental processes, secretory vesicles fuse their membranes with target membranes to release contents through an initially small membrane fusion pore that subsequently dilates. Dilation is assisted by proteins such as SNAREs and synaptotagmin. While macroscopic soap film shapes are well characterized, finding exact solutions for microscopic cellular membrane surfaces is made more complex by bending energy constraints. Here, computational analysis revealed three families of fusion pores between two membranes. Our work suggests membrane fusion generates a member of the narrow pore family, and pore dilation is a transition to the wide pore family. The energy barrier that SNAREs or synaptotagmin must surmount to achieve dilation is set by a third unstable intermediate pore family.
Cooperativity of myosin II motors in the non-regulated and regulated thin filaments investigated with high-speed AFM
Authors: Matusovsky Oleg S. , Mansson Alf , Rassier Dilson E. 
Published: February 2022

AbstractSkeletal myosins II are non-processive molecular motors, that work in ensembles to produce muscle contraction while binding to the actin filament. Although the molecular properties of myosin II are well known, there is still debate about the collective work of the motors: is there cooperativity between myosin motors while binding to the actin filaments? In this study, we used high-speed AFM to evaluate this issue. We observed that the initial binding of small arrays of myosin heads to the non-regulated actin filaments did not affect the cooperative probability of subsequent bindings to neighboring sites and did not lead to an increase in the fractional occupancy of the actin binding sites. These results suggest that myosin motors are independent force generators when connected in small arrays, and that the binding of one myosin does not alter the kinetics of other myosins. In contrast, the probability of binding of myosin heads to regulated thin filaments under activating conditions (at high Ca2+ concentration and with 2 μM ATP) was increased with the initial binding of one myosin, leading to a larger occupancy of neighboring available binding sites. The result suggests that myosin cooperativity is defined by the activation status of the thin filaments.eLife digestMuscle contraction is the result of large ensembles of the molecular motor myosin II working in coordination while attached to actin. Myosin II produces the power stroke, responsible for force generation. In this paper, we used High-Speed Atomic Force Microscopy (HS-AFM) to determine the potential cooperativity between myosin motors bound to non-regulated and regulated thin filaments. Based on the direct visualization of myosin-actin interaction, probability of myosin binding, and the myosin fractional occupancy of binding sites along non-regulated and regulated actin filaments, our results show no cooperative effects over ∼100 nm of the actin filament length. In contrast, there is myosin cooperativity within the activated thin filament, that induces a high affinity of myosin heads to the filaments. Our results support the independent behaviour of myosin heads while attached to actin filaments, but a cooperative behavior when attached to regulated thin filaments.
Postgraduate disciplinary trends in architecture: mapping master theses in Jordan
Authors: Al Khalidi Marwa , Al-Rqaibat Sana'a , Okour Yasmein 
Published: February 2022

PurposeThe purpose of this paper is to analyze the postgraduate disciplinary trends in architecture in Jordan. It highlights current research topics in master theses of architecture programs, to enhance the selection of postgraduate thesis topics that are more responsive and adaptive to the raised research demands of communities and the profession.Design/methodology/approachThe paper analyzed 254 master's theses published from 2009 to 2019 in three Jordanian universities. The paper employed a descriptive and content analysis for theses' titles and abstracts.FindingsThe principal results identify unique geographical, temporal and disciplinary trends in the mapped theses. The findings illustrate an interest in disciplines of design studies, building technology, housing and community and urban design among postgraduate students. The findings also highlight a centralization of theses' number and geographical location within Amman governorate. Many theses also focused on residential spaces as a scale of analysis.Practical implicationsThe proposed suggestions include collaborative efforts and practical mechanisms by higher education institutions, practitioners and decision-makers for advancing rigorous, diverse and relevant research topics in postgraduate theses.Originality/valueThe paper provides a comprehensive mapping of the topics of postgraduate theses in the field of architecture. It highlights how they have evolved or have been influenced by community needs. It also draws attention toward specific disciplines that have been the focus of major architectural programs in Jordan. Finally, it highlights the coexistence of interdisciplinarity within the field of architecture.