bluuebunny/crossref_metadata_2025_split huggingface dataset:
New auranofin analogs with antibacterial properties against Burkholderia clinical isolates
Authors: Maydaniuk Dustin , Wu Bin , Truong Dang , Liyanage Sajani H. , Hogan Andrew M. , Yap Zhong Ling , Yan Mingdi , Cardona Silvia T. 
Published: September 2021

AbstractBacteria of the genus Burkholderia include pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show that two auranofin analogs, MS-40S and MS-40, have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for multistep resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40S and MS-40, demonstrating that these compounds have low toxicity in these model organisms. In summary, we show that MS-40 and MS-40S have the potential to be effective therapeutic options to treat Burkholderia infections.
Peroxide antimalarial drugs target redox homeostasis in Plasmodium falciparum infected red blood cells
Authors: Siddiqui Ghizal , Giannangelo Carlo , De Paoli Amanda , Schuh Anna Katharina , Heimsch Kim C. , Anderson Dovile , Brown Timothy G. , MacRaild Christopher A. , Wu Jianbo , Wang Xiaofang , Dong Yuxiang , Vennerstrom Jonathan L. , Becker Katja , Creek Darren J 
Published: September 2021

AbstractPlasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of protein targets for peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted LC-MS-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.ImportanceThe frontline treatments for malaria are combination therapies based on the peroxide antimalarial, artemisinin. Concerningly, artemisinin resistance has emerged in malaria-endemic regions, and now poses a major threat to malaria treatment and eradication efforts. New medicines are urgently required to replace the artemisinins, and some of the most advanced candidates are the fully synthetic peroxide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel). The mechanism of action of peroxide antimalarials involves the reductive activation of the peroxide bond by intra-parasitic haem, but there is no consensus regarding the specific protein targets of the resulting radical species for artemisinins and/or the ozonides. This study provides a comprehensive and unbiased chemoproteomic profile of over 400 target proteins, and confirms the specific impact of peroxide antimalarials on redox metabolism. The key role of redox targets is particularly relevant considering that the mechanism of artemisinin resistance appears to involve modulation of peroxide activation and redox homeostasis.
Acoustic frequency-dependent physical mechanism of sub-MHz ultrasound neurostimulation
Authors: Fan Haixiao , Shimba Kenta , Ishijima Ayumu , Sasaoka Kenya , Takahashi Tsuyoshi , Chang Chih-Hsiang , Jimbo Yasuhiko , Azuma Takashi , Takagi Shu 
Published: September 2021

AbstractUltrasound is an innovative physical modality allowing non-invasive and reversible modulation of neural circuit activity in the brain with high spatial resolution. Despite growing interest in clinical applications, the safe and effective use of ultrasound neuromodulation has been limited by a lack of understanding of the physical mechanisms underlying its effects. Here, we demonstrate acoustic frequency-dependent physical effects that underlie ultrasound neuromodulation, where cavitation and radiation forces are the dominant sources of low- and high-frequency stimulation, respectively. We used 39.5 kHz and 500 kHz acoustic frequencies to stimulate cultured neural and glial cells, excised from rat cortex, to study acoustic frequency-dependent neural responses. We demonstrate increased evoked responses due to increased cavitation activity at the 39.5 kHz acoustic frequency. In contrast, notable cavitation activity was not detected at 500 kHz despite detection of evoked responses. Our work highlights the dependence of ultrasound neuromodulation on acoustic frequencies, with different physical effects underlying cell responses to low and high sub-MHz acoustic frequency ranges.
Passive plasma membrane transporters play a critical role in perception of carbon availability in yeast
Authors: Jalihal Amogh Prabhav , DeGennaro Christine , Jhuang Han-Ying , Commins Nicoletta , Hamrick Spencer , Springer Michael 
Published: September 2021

AbstractRecently, our lab found that the canonical glucose/galactose regulation pathway in yeast makes the decision to metabolize galactose based on the ratio of glucose to galactose concentrations in the external medium. This led to the question of where and how the ratio-sensing is achieved. Here, we consider the possibilities of an intracellular, extracellular, or membrane bound ratio sensing mechanisms. We show that hexose transporters in the plasma membrane are mainly responsible for glucose/galactose ratio-sensing in yeast. Further, while the glucose sensors Gpr1, Snf3, and Rgt2 are not required for ratio sensing, they help modulate the ratio sensing phenotype by regulating the expression of individual transporters in different environments. Our study provides an example of an unexpected, but potentially widespread, mechanism for making essential decisions.
Quantitative analysis of the orientation of white stork nestlings’ parents from video monitoring
Authors: Gayout Ariane 
Published: September 2021

AbstractVideo-monitoring has become in the last decades common practice for animal observation and conservation purposes. In Ornithology, it is mostly used for tracking predators and nest surveillance, but, with the rapid development and spreading of webcams on nests for educational purposes, new opportunities arise for behavioral investigation, through citizen science for instance. In this article, we use video-monitoring from a public webcam on a White stork (Ciconia ciconia) nest and perform systematic image analysis to record the positioning and orientation of the guarding parent on the nest, during the nestling period over 60 days. From this data of 450 orientation samples, correlations with weather parameters are drawn. Our results suggest that the sun is responsible for most of the orientation with an hourly dependence, while the wind has prevalence during rainy days. A change in the parent behavior is also observed around the time the nestlings are known to attain their maximal weight. These preliminary findings provide new insights on weather influence on parental care behavior likely linked with the parent’s sensing. The versatility of the proposed method allows for behavioral studies on a wide variety of species.
Vegetation structure determines cyanobacterial communities during soil development across global biomes
Authors: Cano-Díaz Concha , Maestre Fernando T. , Wang Juntao , Li Jing , Singh Brajesh , Ochoa Victoria , Gozalo Beatriz , Delgado-Baquerizo Manuel 
Published: September 2021

SummarySoil cyanobacteria play essential ecological roles and are known to experience large changes in their diversity and abundance throughout early succession. However, much less is known about how and why soil cyanobacterial communities change as soil develops from centuries to millennia, and the effects of aboveground vegetation on these communities.We combined an extensive field survey including 16 global soil chronosequences across contrasting ecosystems (from deserts to tropical forests) with molecular analyses to investigate how the diversity and abundance of soil cyanobacteria under vegetation change during soil development from hundreds to thousands of years.We show that, in most chronosequences, the abundance, species richness and community composition of soil cyanobacteria were relatively stable as soil develops (from centuries to millennia). Regardless of soil age, forest chronosequences were consistently dominated by non-photosynthetic cyanobacteria (Vampirovibrionia), while grasslands and shrublands were dominated by photosynthetic cyanobacteria. Chronosequences undergoing drastic vegetation shifts during soil development (e.g. transitions from grasslands to forests) experienced significant changes in the composition of soil cyanobacteria communities.Our results advance our understanding of the ecology of cyanobacterial classes, specially the understudied non-photosynthetic ones and highlight the key role of vegetation as a major driver of their temporal dynamics as soil develops.
Adaptive convergent evolution of genome proofreading in SARS-CoV2: insights into the Eigen’s paradox
Authors: Aswin Keerthic , Ramachandran Srinivasan , Natarajan Vivek T 
Published: September 2021

AbstractEvolutionary history of coronaviruses holds the key to understand mutational behavior and prepare for possible future outbreaks. By performing comparative genome analysis of nidovirales that contain the family of coronaviruses, we traced the origin of proofreading, surprisingly to the eukaryotic antiviral component ZNFX1. This common recent ancestor contributes two zinc finger (ZnF) motifs that are unique to viral exonuclease, segregating them from DNA proof-readers. Phylogenetic analyses indicate that following acquisition, genomes of coronaviruses retained and further fine-tuned proofreading exonuclease, whereas related families harbor substitution of key residues in ZnF1 motif concomitant to a reduction in their genome sizes. Structural modelling followed by simulation suggests the role of ZnF in RNA binding. Key ZnF residues strongly coevolve with replicase, and the helicase involved in duplex RNA unwinding. Hence, fidelity of replication in coronaviruses is a result of convergent evolution, that enables maintenance of genome stability akin to cellular proofreading systems.
Activation of stably silenced genes by recruitment of a synthetic de-methylating module
Authors: Chan Wing Fuk , Keenan Christine R. , Johanson Timothy M. , Allan Rhys S. 
Published: September 2021

AbstractStably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we created an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). TETact induces transcription of heavily suppressed non-coding RNA and surface protein, and the reactivation of embryonic haemoglobin genes in non-erythroid cells.
Implications of taxonomic and numerical resolution on DNA metabarcoding-based inference of benthic macroinvertebrate responses to river restoration
Authors: Serrana Joeselle M. , Li Bin , Sumi Tetsuya , Takemon Yasuhiro , Watanabe Kozo 
Published: September 2021

AbstractExploring and clearly defining the level of taxonomic identification and quantification approaches for diversity and biomonitoring studies are essential, given its potential influence on the assessment and interpretation of ecological outcomes. In this study, we evaluated the response of benthic macroinvertebrate communities to the restoration or construction of gravel bars conducted in the dam-impacted Trinity River, with the non-dam influenced tributaries serving as the reference sites. We aim to evaluate the performance of different taxonomic and numerical (i.e., abundance vs. presence/absence data) resolutions of DNA metabarcoding with consequent comparison to morphology-based identification and how it affects assessment outcomes. DNA metabarcoding detected 93% of the morphologically identified individuals and provided finer taxonomic resolution. We also detected significant correlations between morphological sample abundance, biomass, and DNA metabarcoding read abundance. We observed a relatively high and significant congruence in macroinvertebrate community structure and composition between different taxonomic and numerical resolutions of both methods, indicating a satisfactory surrogacy between the two approaches and their varying identification levels and data transformation. Additionally, the community-environmental association were significant for all datasets but showed varying significant associations against the physicochemical parameters. Furthermore, both methods identifiedSimuliumspp. as significant indicators of the dam-impacted gravel bars. Still, only DNA metabarcoding showed significant false discovery rate proving the method’s robustness compared to morphology-based identification. Our observations imply that coarser taxonomic resolution could be highly advantageous to DNA metabarcoding-based applications in situations where the lack of taxonomic information, e.g., poor reference database, might severely affect the quality of biological assessments.
Behavioral and Neurostructural changes associated with Chronic Amygdala Hyperactivation
Authors: Misquitta Keith A. , Codeluppi Sierra A. , Knoch Jaime K. , Bansal Yashika , Tomoda Toshi , Ellegood Jacob , Lerch Jason P. , Sibille Etienne , Nikolova Yuliya S. , Banasr Mounira 
Published: September 2021

AbstractBackgroundThe amygdala (AMY) is a key brain region of the limbic system that plays a critical role in emotion processing and stress response. Functional magnetic resonance imaging (fMRI) studies identified abnormal AMY activation in psychiatric illnesses including major depressive disorder (MDD). Stress exposure is a major precipitating factor of MDD episodes which are associated with AMY hyperactivity. Preclinical studies using of pharmacologic, opto- and chemogenetic approaches to activate AMY neurons have consistently demonstrated that acute AMY hyperactivation induces anxiety-like behaviors in mice. However, it remains unknown if chronic hyperactivation of the amygdala (cHOA) is sufficient to induce chronic stress-like deficits or is a susceptibility factor for chronic stress-induced behavioral, volumetric and synaptic deficits.MethodsUsing designer receptor exclusively activated by designer drug (DREADD) approach, basolateral amygdala (BLA) neurons of Camk2a-cre mice infected with a virus driving the expression of the Gq-coupled DREADD were activated with clozapine-N-oxide (in drink water for 5 weeks). Mice were then exposed to chronic restraint stress (CRS; 1X/day for 1hr) for 2 weeks. All mice were behaviorally assessed in the Phenotyper (PT), and sucrose consumption tests (SCT) each week and in the novelty supressed feeding (NSF, once at the end of the experiment). Animals were then perfused for ex vivo-MRI and puncta density analysis.ResultsWe found that mice with cHOA displayed a progressive increase in baseline anxiety-like deficits in the PT test and slightly more marked deficits following CRS compared to controls, but not statistically different from animals subjected to CRS alone. Also, cHOA did not exacerbate CRS effect in the NSF. No significant cAH effect was found in the SCT before or after CRS. MRI analysis revealed no statistical charges between groups, while increased synaptic puncta density was found in cHOA mice subjected to CRS compared to cHOA or CRS alone.ConclusionWe demonstrate that cAH is sufficient to induce anxiety and may exacerbate CRS effects on anxiety and synaptic measures. Results also suggest that cHOA was not sufficient to induce depressive-like behavior and was not a vulnerability factor for stress-induced depressive-like behavior in mice. Altogether, our findings imply that a strong causal link between AMY hyperactivity and elevated anxiety, but not depressive-like behaviors and provide critical information to clinical research focused on using AMY activity level as a biomarker in stress-related illnesses.
Parvalbumin neurons, temporal coding, and cortical noise in complex scene analysis
Authors: Nocon Jian Carlo , Gritton Howard J. , James Nicholas M. , Mount Rebecca A. , Qu Zhili , Han Xue , Sen Kamal 
Published: September 2021

AbstractCortical representations supporting many cognitive abilities emerge from underlying circuits comprised of several different cell types. However, cell type-specific contributions to rate and timing-based cortical coding are not well-understood. Here, we investigated the role of parvalbumin (PV) neurons in cortical complex scene analysis. Many complex scenes contain sensory stimuli which are highly dynamic in time and compete with stimuli at other spatial locations. PV neurons play a fundamental role in balancing excitation and inhibition in cortex and sculpting cortical temporal dynamics; yet their specific role in encoding complex scenes via timing-based coding, and the robustness of temporal representations to spatial competition, has not been investigated. Here, we address these questions in auditory cortex using a cocktail party-like paradigm, integrating electrophysiology, optogenetic manipulations, and a family of spike-distance metrics, to dissect PV neurons’ contributions towards rate and timing-based coding. We find that suppressing PV neurons degrades cortical discrimination of dynamic sounds in a cocktail party-like setting via changes in rapid temporal modulations in rate and spike timing, over a wide range of time-scales. Our findings suggest that PV neurons play a critical role in enhancing cortical temporal coding and reducing cortical noise, thereby improving representations of dynamic stimuli in complex scenes.Significance StatementOne impressive example of sensory perception by the brain is its ability to analyze complex scenes, e.g., following what a friend is saying at a party amongst other speakers. Although some humans can solve this problem with relative ease, it remains very difficult for humans with a variety of impairments, e.g., hearing impairments, ADHD, and autism. The brain mechanisms underlying complex scene analysis remain poorly understood. Here, we recorded neural activity in auditory cortex in a complex auditory scene. When we suppressed PV neuron activity in auditory cortex, cortical performance decreased, and the timing of cortical responses was degraded. Our findings suggest that PV neurons improve the brain’s ability to analyze complex scenes by enhancing the timing of cortical responses while reducing cortical noise.
Design of T cell epitope-based vaccine candidate for SARS-CoV-2 targeting nucleocapsid and spike protein escape variants
Authors: Jabbour Gabriel , Rego Samantha , Nguyenkhoa Vincent , Dakshanamurthy Sivanesan 
Published: September 2021

AbstractThe current COVID-19 pandemic continues to spread and devastate in the absence of effective treatments, warranting global concern and action. Despite progress in vaccine development, the rise of novel, increasingly infectious SARS-CoV-2 variants makes it clear that our response to the virus must continue to evolve along with it. The use of immunoinformatics provides an opportunity to rapidly and efficiently expand the tools at our disposal to combat the current pandemic and prepare for future outbreaks through epitope-based vaccine design. In this study, we validated and compared the currently available epitope prediction tools, and then used the best tools to predict T cell epitopes from SARS-CoV-2 spike and nucleocapsid proteins for use in an epitope-based vaccine. We combined the mouse MHC affinity predictor and clinical predictors such as HLA affinity, immunogenicity, antigenicity, allergenicity, toxicity and stability to select the highest quality CD8 and CD4 T cell epitopes for the common SARS-CoV-2 variants of concern suitable for further preclinical studies. We also identified variant-specific epitopes to more precisely target the Alpha, Beta, Gamma, Delta, Cluster 5 and US variants. We then modeled the 3D structures of our top 4 N and S epitopes to investigate the molecular interaction between peptide-MHC and peptide-MHC-TCR complexes. Following in vitro and in vivo validation, the epitopes identified by this study may be used in an epitope-based vaccine to protect across all current variants, as well as in variant-specific booster shots to target variants of concern. Immunoinformatics tools allowed us to efficiently predict epitopes in silico most likely to prove effective in vivo, providing a more streamlined process for vaccine development in the context of a rapidly evolving pandemic.
Elevated levels of active Transforming Growth Factor β1 in the subchondral bone relate spatially to cartilage loss and impaired bone quality in human knee osteoarthritis
Authors: Muratovic Dzenita , Findlay David M. , Quarrington Ryan D. , Cao Xu , Solomon Lucian B. , Atkins Gerald J. , Kuliwaba Julia S. 
Published: September 2021

AbstractObjectiveOver-activity of transforming growth factor β1 (TGFβ1) in subchondral bone has a direct causal role in rodent models of knee osteoarthritis (OA), which can be blocked by TGFβ1 neutralisation. In this study, we investigated whether the spatially distributed level of active TGFβ1 in human subchondral bone associates with the characteristic structural, cellular and molecular parameters of human knee OA.DesignSubchondral bone samples (35 OA arthroplasty patients, aged 69±9 years) were obtained from regions below either macroscopically present or denuded cartilage. Bone samples were processed to determine the concentration of active TGFβ1 (ELISA) and gene-specific mRNA expression (RT-PCR). Synchrotron micro-CT imaging was utilised to assess the bone microstructure, bone mineralization, the osteocyte lacunar network and bone matrix vascularity. Finally, samples were histologically examined for cartilage OARSI grading, quantification of tartrate resistant acid phosphatase positive cells and bone marrow micro-vasculature.ResultsSubchondral bone below severely degenerated/depleted cartilage, characterised by impaired bone matrix quality due to sclerotic microarchitecture, disorganised collagen, high heterogeneity of the mineral distribution, contained increased concentrations of active TGFβ1, compared to adjacent areas with more intact cartilage. In addition, increased levels of active TGFβ1 related directly to increased bone volume while increased OARSI grade associated directly with morphometric characteristics (size, shape and orientation) of osteocyte lacunae.ConclusionThese results indicate that increased active TGFβ1 associates spatially with impaired bone quality and the disease severity of human OA. This study therefore suggests that TGFβ1 could be a therapeutic target to prevent or reduce human disease progression.