bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering Ghost Introgression Through Genomic Analysis of a Distinct East Asian Hickory Species
Authors: Zhang Wei-Ping , Ding Ya-Mei , Cao Yu , Li Pan , Yang Yang , Pang Xiao-Xu , Bai Wei-Ning , Zhang Da-Yong 
Published: June 2023

ABSTRACTAlthough the possibility of introgression from ghost lineages (all unsampled extant and extinct taxa) is now widely recognized, detecting and characterizing ghost introgression remains a challenge. Here, we propose a combined use of the popularD-statistic method, which tests for the presence of introgression, and the full-likelihood method BPP, which determines which of the possible gene-flow scenarios, including ghost introgression, is truly responsible. We illustrate the utility of this approach by investigating the reticulation and bifurcation history of the genusCarya(Juglandaceae), including the beaked hickoryCarya sinensis. To achieve this goal, we generated two chromosome-level reference genomes respectively forC. sinensisandC. cathayensis. Furthermore, we re-sequenced the whole genomes of 43 individuals fromC. sinensisand one individual from each of the 11 diploid species ofCarya. The latter dataset with one individual per species is used to reconstruct the phylogenetic networks and estimate the divergence time ofCarya. Our results unambiguously demonstrate the presence of ghost introgression from an extinct lineage into the beaked hickory, dispelling certain misconceptions about the phylogenetic history ofC. sinensis. We also discuss the profound implications of ghost introgression intoC. sinensisfor the historical biogeography of hickory species. [BPP;Carya;D-statistic; gene flow; ghost introgression]
Implicit model to capture electrostatic features of membrane environment
Authors: Samanta Rituparna , Gray Jeffrey J 
Published: June 2023

AbstractMembrane protein structure prediction and design are challenging due to the complexity of capturing the interactions in the lipid layer, such as those arising from electrostatics. Accurately capturing electrostatic energies in the low-dielectric membrane often requires expensive Poisson-Boltzmann calculations that are not scalable for membrane protein structure prediction and design. In this work, we have developed a fast-to-compute implicit energy function that considers the realistic characteristics of different lipid bilayers, making design calculations tractable. This method captures the impact of the lipid head group using a mean-field-based approach and uses a depth-dependent dielectric constant to characterize the membrane environment. This energy function Franklin2023 (F23) is built upon Franklin2019 (F19), which is based on experimentally derived hydrophobicity scales in the membrane bilayer. We evaluated the performance of F23 on five different tests probing (1) protein orientation in the bilayer, (2) stability, and (3) sequence recovery. Relative to F19, F23 has improved the calculation of the tilt angle of membrane proteins for 90% of WALP peptides, 15% of TM-peptides, and 25% of the adsorbed peptides. The performances for stability and design tests were equivalent for F19 and F23. The speed and calibration of the implicit model will help F23 access biophysical phenomena at long time and length scales and accelerate the membrane protein design pipeline.Author summaryMembrane proteins participate in many life processes. They constitute 30% of the human proteome and are targets for over 60% pharmaceuticals. Accurate and accessible computational tools to design membrane proteins will transform the platform to engineer membrane proteins for therapeutic, sensor, and separation processes. While soluble protein design has advanced, membrane protein design remains challenging due to the difficulties in modeling the lipid bilayer. Electrostatics plays an intimate role in the physics of membrane protein structure and function. However, accurately capturing electrostatic energies in the low-dielectric membrane often requires expensive calculations that are not scalable. In this work, we contribute a fast-to-compute electrostatic model that considers different lipid bilayers and their features, making design calculations tractable. We demonstrate that the updated energy function improves the calculation of the tilt angle of membrane proteins, stability, and confidence in designing charged residues.
SHARK enables homology assessment in unalignable and disordered sequences
Authors: Chow Chi Fung Willis , Ghosh Soumyadeep , Hadarovich Anna , Toth-Petroczy Agnes 
Published: June 2023

AbstractIntrinsically disordered regions (IDRs) are structurally flexible protein segments with regulatory functions in multiple contexts, such as in the assembly of biomolecular condensates.Since IDRs undergo more rapid evolution than ordered regions, identifying homology of such poorly conserved regions remains challenging for state-of-the-art alignment-based methods that rely on position-specific conservation of residues. Thus, systematic functional annotation and evolutionary analysis of IDRs have been limited, despite comprising ∼21% of proteins.To accurately assess homology between unalignable sequences, we developed an alignment-free sequence comparison algorithm, SHARK (Similarity/Homology Assessment by Relating K-mers). We trained SHARK-dive, a machine learning homology classifier, which achieved superior performance to standard alignment in assessing homology in unalignable sequences, and correctly identified dissimilar IDRs capable of functional rescue in IDR-replacement experiments reported in the literature.SHARK-dive not only predicts functionally similar IDRs, but also identifies cryptic sequence properties and motifs that drive remote homology, thereby facilitating systematic analysis and functional annotation of the unalignable protein universe.
Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2
Authors: Wang Weini , Zhou Yanchi , Wang Ji , Zhang Shu , Ozes Ali , Gao Hongyu , Fang Fang , Wang Yue , Chu Xiaona , Liu Yunlong , Wan Jun , Mitra Anirban , O’Hagan Heather M. , Nephew Kenneth P. 
Published: June 2023

AbstractPersistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer (OC), the fifth leading cause of cancer- related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long noncoding RNA (lncRNA) overexpressed in high-grade serous OC (HGSOC) and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in OCSC and how this oncogenic lncRNA contributes to drug resistant disease are incompletely understood. Here we generated HOTAIR knock-out (KO) HGSOC cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show that loss of HOTAIR function re-sensitized OC cells to platinum treatment and decreased the population of OCSC. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability, as well as expression of key stemness-associated genes ALDH1A1, Notch3, Sox9, and PROM1. HOTAIR KO altered both the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste 2 (EZH2) to catalyze H3K27 tri-methylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in OCSC and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate OC progression and resistance to platinum-based chemotherapy.
Optogenetics reveals roles for supporting cells in force transmission to and from outer hair cells in the mouse cochlea
Authors: Lukashkina Victoria A. , Levic Snezana , Simões Patricio , Xu Zhenhang , Li Yuju , Haugen Trevor , Zuo Jian , Lukashin Andrei N. , Russell Ian J. 
Published: June 2023

ABSTRACTCochlear outer hair cells (OHCs), acting as bidirectional cellular mechanoelectrical-transducers, generate, receive, and exchange forces with other major elements of the cochlear partition, including inner hair cells (IHCs). Force exchange is mediated via a supporting cell scaffold, including Deiters’ (DC) and outer pillar cells (OPC), to enable the sensitivity and exquisite frequency selectivity of the mammalian cochlea. We conditionally expressed a hyperpolarizing halorhodopsin (HOP), a light-gated inward chloride ion pump in DCs and OPCs. We measured extracellular receptor potentials (ERPs) and their DC component (ERPDC) from the Cortilymph (CL) of HOP expressing mice and compared the responses with similar potentials from littermates without HOP expression. Compound action potentials (CAP) were measured as an indication of IHC activity. HOP laser activation suppressed cochlear amplification through changing timing of its feedback, altered basilar membrane (BM) responses to tones at all measured levels and frequencies, and reduced IHC excitation. Our HOP activation results here complement previous channelrhodopsin activation studies in exploiting optogenetics to measure and understand the roles of DCs and OPCsin vivoin controlling the mechanical and electrical responses of OHCs to sound and their contribution to timed and directed electromechanical feedback to the mammalian cochlea.SIGNIFICANCE STATEMENTOuter hair cells provide electromechanical feedback to the organ of Corti, mediated via a cellular scaffold of Deiters’ and outer pillar cells, that enables the sensitivity and fine frequency tuning of the cochlea. The role of this scaffold was explored by expressing the halorhodopsin HOP in Deiters’ and pillar cells which, when illuminated, hyperpolarized them. HOP activation suppressed cochlear amplification through altering the timing of outer hair cell forces to the Organ of Corti, altered basilar membrane responses to tones, including those at levels and frequencies not subject to amplification, and reduced neural excitation. The findings implicated roles for supporting cells in mediating force transmission to and from outer hair cells along all axes of the organ of Corti.
Cracked actin filaments as mechanosensitive receptors
Authors: Zsolnay Vilmos , Gardel Margaret L. , Kovar David R. , Voth Gregory A. 
Published: June 2023

ABSTRACTActin filament networks are exposed to mechanical stimuli, but the effect of strain on actin filament structure has not been well-established in molecular detail. This is a critical gap in understanding because the activity of a variety of actin-binding proteins have recently been determined to be altered by actin filament strain. We therefore used all-atom molecular dynamics simulations to apply tensile strains to actin filaments and find that changes in actin subunit organization are minimal in mechanically strained, but intact, actin filaments. However, a conformational change disrupts the critical D-loop to W-loop connection between longitudinal neighboring subunits, which leads to a metastable cracked conformation of the actin filament, whereby one protofilament is broken prior to filament severing. We propose that the metastable crack presents a force-activated binding site for actin regulatory factors that specifically associate with strained actin filaments. Through protein-protein docking simulations, we find that 43 evolutionarily-diverse members of the dual zinc finger containing LIM domain family, which localize to mechanically strained actin filaments, recognize two binding sites exposed at the cracked interface. Furthermore, through its interactions with the crack, LIM domains increase the length of time damaged filaments remain stable. Our findings propose a new molecular model for mechanosensitive binding to actin filaments.SIGNIFICANCE STATEMENTCells continually experience mechanical strain, which has been observed to alter the interactions between actin filaments and mechanosensitive actin-binding proteins in recent experimental studies. However, the structural basis of this mechanosensitivity is not well understood. We used molecular dynamics and protein-protein docking simulations to investigate how tension alters the actin filament binding surface and interactions with associated proteins. We identified a novel metastable cracked conformation of the actin filament, whereby one protofilament breaks before the other, presenting a unique strain-induced binding surface. Mechanosensitive LIM domain actin-binding proteins can then preferentially bind the cracked interface, and this association stabilizes damaged actin filaments.
A screen of alkaline and oxidative formulations for their inactivation efficacy of metal surface adsorbed prions using a steel-bead seed amplification assay
Authors: Heinzer Daniel , Avar Merve , Pfammatter Manuela , Moos Rita , Schwarz Petra , Buhmann Matthias T. , Kuhn Benjamin , Mauerhofer Stefan , Rosenberg Urs , Aguzzi Adriano , Hornemann Simone 
Published: June 2023

AbstractIatrogenic transmission of prions, the infectious agents of fatal Creutzfeldt-Jakob disease, through inefficiently decontaminated medical instruments remains a critical issue. Harsh chemical treatments are effective, but not suited for routine reprocessing of reusable surgical instruments in medical cleaning and disinfection processes due to material incompatibilities. The identification of mild detergents with activity against prions is therefore of high interest but laborious due to the low throughput of traditional assays measuring prion infectivity. Here, we report the development of TESSA (sTainlESs steel-beadSeedAmplification assay), a prion seed amplification assay that explores the propagation activity of prions with stainless steel beads. TESSA was applied for the screening of about 70 different commercially available and novel formulations and conditions for their prion inactivation efficacy. One hypochlorite-based formulation, two commercially available alkaline formulations and a manual alkaline pre-cleaner were found to be highly effective in inactivating prions under conditions simulating automated washer-disinfector cleaning processes. The efficacy of these formulations was confirmedin vivoin a murine prion infectivity bioassay, yielding a reduction of the prion titer for the bead surface adsorbed prions below detectability. Our data suggest that TESSA represents an effective method for a rapid screening of prion-inactivating detergents, and that alkaline and oxidative formulations are promising in reducing the risk of potential iatrogenic prion transmission through insufficiently decontaminated instrument surfaces.
Vertical transmission ofBorrelia turicatae(Spirochaetales:Borreliaceae) by autogenously reproducingOrnithodoros turicata(Ixodida: Argasidae) female naturally infected with the spirochetes
Authors: Filatov Serhii , Krishnavajhala Aparna , Lopez Job E. 
Published: June 2023

AbstractOrnithodoros turicatais a vector of relapsing fever (RF) spirochetes in North America and transmitsBorrelia turicataeto a variety of vertebrate hosts. The remarkably long lifespan ofO. turicataand its ability to maintain spirochetes horizontally (between life stages) and vertically to progeny promotes the perpetuation ofB. turicataein nature. Nevertheless, the reproductive biology ofO. turicatais poorly understood. In this report, we collected ticks from a park within a neighborhood of Austin, Texas. They were reared to adulthood and male ticks were individually housed with females. We observed autogenous reproduction by the ticks and further investigated vertical transmission ofB. turicataeby quantifying filial infection rates in a cohort of progeny ticks. These results indicate thatO. turicatatransovarially transmitsB. turicataeduring autogenous reproduction and further signify the tick as a natural reservoir of the spirochetes.ImportancePrevious research has implicatedOrnithodorosticks, includingOrnithodoros turicata, as long-term reservoirs of relapsing fever (RF) spirochetes. Considering the tick’s long lifespan and their efficiency in maintaining and transferring spirochetes within the population, the infection could persist in a given enzootic focus for decades. However, little is known about the relative importance of horizontal and vertical transmission routes in the persistence and evolution of RFBorrelia. Our observations on the reproductive biology ofO. turicatain the absence of vertebrate hosts indicate an additional mechanism by whichB. turicatacan be maintained in the environment. This work establishes the foundation for studyingO. turicatareproduction and spirochete-vector interactions, which will aid in devising control measures forOrnithodorosticks and RF spirochetes.
Recombinant outer membrane vesicles coupled with cytokines act as high-performance adjuvants againstHelicobacter pyloriinfection in mice
Authors: Liu Qiong , Li Biaoxian , Lu Jiahui , Zhang Yejia , Shang Yinpan , Li Yi , Gong Tian , Zhang Chengsheng 
Published: June 2023

AbstractThe widespread prevalence ofHelicobacter pylori(H. pylori) infection remains a great challenge to the human health. The existing vaccines are not ideal for preventingH. pyloriinfection; thus, exploring highly effective adjuvants may improve the immunoprotective efficacy ofH. pylorivaccines. In a previous study, we found that outer membrane vesicles (OMVs), a type of nanoscale particle spontaneously produced by Gram-negative bacteria, could act as adjuvants to boost the immune response to vaccine antigens. In the present study, we explored the potential application of OMVs as delivery vectors for adjuvant development. We constructed recombinant OMVs containing cytokines interleukin 17A or interferon-γ and evaluated their function as adjuvants in combination with inactivated whole-cell vaccine (WCV) or UreB as vaccine antigens. Our results showed that recombinant OMVs as adjuvants could induce stronger humoral and mucosal immune responses in mice than wild-typeH. pyloriOMVs and the cholera toxin (CT) adjuvant. Additionally, the recombinant OMVs significantly promoted Th1/Th2/Th17-type immune responses. Furthermore, the recombinant OMV adjuvant induced more potent clearance ofH. pylorithan CT and wild-type OMVs. Our data suggest that the recombinant OMVs coupled with cytokines may become potent adjuvants for development of novel and effective vaccines againstH. pyloriinfection.ImportanceHelicobacter pylori(H. pylori) is one of the important risk factors for gastric cancer, and its vaccine is crucial for its prevention and control. However, to date, no effective vaccine has been approved. Exploring novel and effective vaccine adjuvants may provide new perspectives and ideas for the development ofH. pylorivaccines. Outer membrane vesicles (OMVs) deserve more attention as a novel form of vaccine and adjuvant. We have long focused on OMVs as vaccine adjuvants to enhance efficacy by delivering eukaryotic plasmid expressing immune promoting cytokines in wild-type OMVs. Our results are expected to provide a new adjuvant form for the development ofH. pylorivaccine, and this adjuvant design strategy can also be used in the development of vaccines for other types of pathogens, including bacteria and even viruses.
Cooperative control of a DNA origami force sensor
Authors: Robbins Ariel , Hildebolt Hazen , Neuhoff Michael , Beshay Peter , Winter Jessica O. , Castro Carlos E. , Bundschuh Ralf , Poirier Michael G. 
Published: June 2023

ABSTRACTMost biomolecular systems are dependent on a complex interplay of forces. Modern force spectroscopy techniques provide means of interrogating these forces. These techniques, however, are not optimized for studies in constrained or crowded environments as they typically require micron-scale beads in the case of magnetic or optical tweezers, or direct attachment to a cantilever in the case of atomic force microscopy. We implement a nanoscale force-sensing device using a DNA origami which is highly customizable in geometry, functionalization, and mechanical properties. The device, referred to as the NanoDyn, functions as a binary (open or closed) force sensor that undergoes a structural transition under an external force. The transition force is tuned with minor alterations of 1 to 3 DNA oligonucleotides and spans tens of picoNewtons (pN). This actuation of the NanoDyn is reversible and the design parameters strongly influence the efficiency of resetting the initial state, with higher stability devices (≳10 pN) resetting more reliably during repeated force-loading cycles. Finally, we show that the opening force can be adjusted in real time by the addition of a single DNA oligonucleotide. These results establish the NanoDyn as a versatile force sensor and provide fundamental insights into how design parameters modulate mechanical and dynamic properties.
Text dialogue analysis Based ChatGPT for Primary Screening of Mild Cognitive Impairment
Authors: Wang Changyu , Liu Siru , Li Aiqing , Liu Jialin 
Published: June 2023

AbstractBackgroundAI models tailored to diagnose cognitive impairment have shown excellent results. However, it is unclear whether large linguistic models can rival specialized models by text alone.ObjectivesWe would explore the effectiveness of ChatGPT for primary screening of mild cognitive impairment (MCI) and standardize the design steps and components of the prompt.MethodsWe obtained 174 participants from the DementiaBank screening and classified 70% of them into the training set and 30% into the test set. Three dimensions of variables were incorporated, including: vocabulary, syntax and grammar, and semantics. These variables were generated from published studies and statistical analyses. We used R 4.3.0. for the analysis of variables and diagnostic indicators.ResultsThe final variables included by published studies included: word frequency and word ratio, phrase frequency and phrase ratio, lexical complexity, syntactic complexity, grammatical components, semantic density, and semantic coherence; variables included in the analysis included: tip-of-the-tongue phenomenon (P < 0.001), difficulty with complex ideas (P < 0.001), and memory issues (P < 0.001). The final GPT4 model achieved the sensitivity (SEN) of 0.8636, specificity (SPE) of 0.9487 and area under the curve (AUC) of 0.9062 on the training set; on the test set, the SEN, SPE and AUC reached 0.7727, 0.8333 and 0.8030, respectively. The prompt consisted of five main parts, including character setting, scoring system setting, indicator setting, output setting, and explanatory information setting.ConclusionChatGPT was effective in primary screening of participants with possible MCI. Improved standardization of prompts by professional clinicians would also improve the performance of the model. It is important to note that ChatGPT is not a substitute for a clinician making a diagnosis.