bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Botulinum Toxin A on the NADPH Oxidase System and Ischemia-Reperfusion Injury
Authors: Kyung Hyun Woo , Lee Seokui , Kwon Hyeokjae , Kim Sunje , Kim Joo Hak , Song Seung Han , Oh Sang-Ha , Yang Ho Jik , Ha Yooseok 
Published: August 2023

Background:
Despite the increasing popularity of various materials for ischemia-reperfusion (I/R) injury mitigation, research on botulinum toxin type A (BoNTA) remains limited. This study assesses BoNTA’s efficacy in protecting flaps from I/R injury by inhibiting the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system and reducing reactive oxygen species (ROS) production.

Methods:
Seventy-six Sprague-Dawley rats were studied. We examined the effects of BoNTA on superoxide production in four rats using a lucigenin-enhanced chemiluminescence assay (LECL). Another group of 60 rats had their superficial inferior epigastric artery (SIEA) flaps treated with either BoNTA or saline and clamped for 0, 1, and 4 hours before reperfusion. Flap survival and histological outcomes were assessed five days post-operation. ROS production in SIEA flaps and femoral vessels was analyzed in 12 additional rats, post-I/R injury.

Results:
The LECL results showed that the BoNTA group had significantly lower superoxide production compared to controls, with notable reductions at 4 hours. While no significant differences were noted at the 0 and 1-hour marks, the 4-hour mark showed significant protective effects in BoNTA-treated groups. The survival rate was 90% for BoNTA-treated rats versus 60% for controls (P = 0.028). Significant reductions in ROS were also observed in the 4-hour I/R group.

Conclusions:
BoNTA effectively protects against I/R injury by inhibiting the NADPH oxidase system and reducing ROS levels. These results support further investigation into the specific mechanisms of NADPH oxidase inhibition by BoNTA and its potential clinical applications, given its safety profile

Clinical Relevance Statement:
The findings from the present study are expected to provide a basis for clinical studies regarding this use of BoNTA.
Congenital Epulis: A Rare Head And Neck Tumor in the Newborn
Authors: De Stefano Sofia , Nadal López Emmanuela , Sabas Mariana 
Published: August 2023

Congenital epulis is a rare tumor; when voluminous and ulcerated, appearance can generate concern. Nevertheless, it is a benign lesion that is easily treated with surgery.
This is a retrospective study, with the presentation of 2 cases treated by the same team from 2016 to 2020 and a bibliographic review (PubMed and Elsiever). This surgical team is based in Buenos Aires, working in the private medical system.
Congenital epulis is an infrequent, benign tumor affecting females predominantly, appearing at birth on the alveolar median ridge of the maxilla. Its pathogenesis is uncertain. Voluminous tumors interfere with feeding, but respiratory interference is exceptional. Histologically, this tumor is similar to the granular cell tumor but has different clinical characteristics and Periodic Acid Schiff stain. Ecographic or magnetic resonance imaging prenatal diagnosis is ideal if undiagnosed prenatally. Clinical diagnosis is done based on typical features. Surgical excision is the treatment of choice.
Evolutionary genomics identifies host-directed therapeutics to treat intracellular bacterial infections
Authors: Medicielo Josette , Waltari Eric , Glascock Abigail Leigh , Dudas Gytis , DeFelice Brian , Gray Ira , Tato Cristina M. , Wong Joan , Ahyong Vida 
Published: August 2023

AbstractObligate intracellular bacteria shed essential biosynthetic pathways during their evolution towards host dependency, providing an opportunity for host-directed therapeutics. UsingRickettsiaceaeas a model, we employed a novel computational pipeline called PoMeLo to systematically compare this cytosolic family of bacteria to the relatedAnaplasmataceae, which reside in a membrane-bound vacuole in the host cell. We identified 20 metabolic pathways that have been lost since the divergence ofAnaplasmataceaeandRickettsiaceae, corresponding to the latter’s change to a cytosolic niche. We hypothesized that drug inhibition of these host metabolic pathways would reduce the levels of metabolites available to the bacteria, thereby inhibiting bacterial growth. We tested 22 commercially available inhibitors for 14 of the identified pathways and found that the majority (59%) reduced bacterial growth at concentrations that did not induce host cell cytotoxicity. Of these, 5 inhibitors with an IC50under 5 μM were tested to determine whether their mode of inhibition was bactericidal or bacteriostatic. Both mycophenolate mofetil, an inhibitor of inosine-5’-monophosphate dehydrogenase in the purine biosynthesis pathway, and roseoflavin, an analog of riboflavin, displayed bactericidal activity. A complementary unbiased mass spectrometry-based metabolomics approach identified 14 pathways impacted byRickettsiainfection based on alterations in metabolite levels. Strikingly, 11 of these (79%) overlapped with those identified by our computational predictions. Thesein vitrovalidation studies support the feasibility of a novel evolutionary genomics-guided approach for host-directed antibiotic drug development against obligate pathogens.ImportanceMany pathogens have evolved to acquire essential metabolites from their host cell, while in turn shedding their own biosynthetic capacities. This leads to an interesting dilemma: on one hand, reduced genomes allow pathogens to save energy and replicate more quickly, while on the other hand, they become more dependent on the host cell for survival. This vulnerability can be exploited by identifying and therapeutically inhibiting the host pathways that are essential for pathogen survival. The significance of our research is in predicting the precise pathways lost during a pathogen’s evolutionary adaptation to parasitism and validating these predictions through targetedin vitrogrowth assays and an unbiased metabolomic survey of the host-pathogen interface.
Chaperone Complexes From The Endoplasmic Reticulum (ER) And The Cytosol Inhibit wt-p53 By Activation The ER To Cytosol Signaling
Authors: Dabsan Salam , Zur Gali , Gilad Ayelet , Igbaria Aeid 
Published: August 2023

ABSTRACTThe Endoplasmic Reticulum (ER) is an essential sensing organelle responsible for the folding and secretion of almost one-third of eukaryotic cells’ total proteins. The ER contains numerous enzymes and chaperones which assist in oxidative protein folding and other posttranslational modifications. However, environmental, chemical, and genetic insults often lead to protein misfolding in the ER, accumulating misfolded proteins, altering homeostasis, and causing ER stress. Recently, we reported a novel ER surveillance mechanism by which proteins from the secretory pathway are refluxed to the cytosol to relieve the ER of its content during stress. In cancer cells, the refluxed proteins gain new pro-survival functions, thereby increasing cancer cell fitness. We termed this phenomenonERtoCYtosolSignaling (or “ERCY”). In yeast, ERCYS is regulated by HLJ1 (an ER-resident tail-anchored HSP40 cochaperone). Here, we found that in mammalian cells, HLJ1 has five putative orthologs possessing J-domains facing the cytosol. Among those, DNAJB12 and DNAJB14 appear to be the most significant. Mechanistically, we found that DNAJB12 and DNAJB14 bind the cytosolic HSC70 and its cochaperone – SGTA - through their cytosolically localized J-domains to facilitate ER-protein reflux to the cytosol. Moreover, we found that DNAJB12 is necessary and sufficient to drive this phenomenon to increase AGR2 reflux and inhibit wt-p53 during ER stress. Thus, we concluded that targeting the DNAJB12/14-HSC70/SGTA axis is a promising strategy to inhibit ERCYS and impair cancer cell fitness.
REPRODUCTIVE COMPATIBILITY OF TWO LINES OFDELIA PLATURA(DIPTERA: ANTHOMYIIDAE)
Authors: Bush-Beaupré Allen , Bélisle Marc , Fortier Anne-Marie , Fournier François , MacDonald Andrew , Savage Jade 
Published: August 2023

AbstractAccurate identification of agricultural pests is a major component of integrated pest management. The seedcorn maggot,Delia platura(Diptera: Anthomyiidae), is a cosmopolitan polyphagous pest species which may be found in high numbers in numerous crops. Two morphologically identical genetic lines ofD. platura(H- and N- lines) with distinct distributions were recently identified. However, no study to date has investigated the reproductive compatibility of the two lines and thus the possibility that they may actually be two unique biological entities. A previous study described the reproductive traits of the two lines and suggested that H-line females are highly selective towards the male with which they mate, pointing to a possible pre-mating isolation mechanism between the lines. Using laboratory-reared colonies originating from the Montérégie region in Québec, this study investigates the reproductive compatibility of the twoD. platuralines. We found that only one of thirty H-line females was inseminated by an N-line male, further suggesting mate choice as a pre-mating isolation mechanism between the lines. However, N-line females were readily inseminated by H-line males, suggesting a lack of pre-mating isolation in this type of cross. The eggs laid by N-line females mated with H-line males had a lower hatching rate than the ones laid by females of intra-line crosses suggesting either post-mating pre-zygotic or post-zygotic partial isolation. However, the larvae that did hatch had a comparable developmental success to those from intra-line crosses in terms of survival and developmental time from larval hatching to adult emergence, pupal weight, and adult sex ratio, suggesting a lack of post-zygotic isolation for these life stages. Considering the different biological traits of the two lines, we suggest the use of the ‘biotype’ terminology to designate the two biological entities and discuss their implications for integrated pest management.
Spatio-temporal patterns of whiting (Merlangius merlangus) in the Adriatic Sea under environmental forcing
Authors: Asciutto Emanuele , Maioli Federico , Manfredi Chiara , Anibaldi Alessandra , Cimini Jacopo , Isailović Igor , Marčeta Bojan , Casini Michele 
Published: August 2023

AbstractUnderstanding how environmental factors affect species distribution is crucial for the conservation and management of marine organisms, especially in the face of global changes. Whiting (Merlangius merlangus) is a demersal temperate fish, considered a ‘relict species’ in the Adriatic Sea. Despite its significance to commercial fisheries in the region, the specific drivers behind its spatial and temporal patterns have not been thoroughly examined. Here, we fitted a set of Generalized Linear Mixed Effects Models to data collected in the Northern and Central Adriatic from 1999 to 2019 during the Mediterranean International Trawl Survey to investigate the potential influence of depth, seafloor temperature and bottom dissolved oxygen on the annual biomass density and spatial distribution of whiting. Our results showed that depth, and to a lesser degree temperature and oxygen, are important predictors of whiting distribution in spring-summer, with preferences for depths of ∼ 45 m, temperature of ∼ 15.4 °C and dissolved oxygen > 5.5 ml L-1. We predicted a persistent core area of distribution in front of the Po River Delta, in the Northern Adriatic Sea, while the density progressively declined towards the Central and Southern Adriatic Sea along the Italian coast. Additionally, the temporal trend exhibited high fluctuations over the years, occurring in cycles of 3 to 4 years. Finally, by comparing the biomass density estimates obtained under optimum conditions with those derived from the actual values for each variable, our analysis revealed that temperature had a pronounced and general impact on biomass density in the northern survey area (prediction revealed a ratio of density reduction of approximatively a half), while oxygen displayed a minor and more localized influence. This work deepens the current knowledge about the ecology of whiting in the Adriatic Sea and provides support for the conservation and management of this species.
Discretised flux balance analysis for reaction-diffusion simulation of single-cell metabolism
Authors: Chew Yin Hoon , Spill Fabian 
Published: August 2023

AbstractMetabolites have to diffuse within the sub-cellular compartments they occupy to specific locations where enzymes are, so reactions could occur. Conventional flux balance analysis (FBA), a method based on linear programming that is commonly used to model metabolism, implicitly assumes that all enzymatic reactions are not diffusion-limited though that may not always be the case. In this work, we have developed a spatial method that implements FBA on a grid-based system, to enable the exploration of diffusion effects on metabolism. Specifically, the method discretises a living cell into a two-dimensional grid, represents the metabolic reactions in each grid element as well as the diffusion of metabolites to and from neighbouring elements, and simulates the system as a single linear programming problem. We varied the number of rows and columns in the grid to simulate different cell shapes, and the method was able to capture diffusion effects at different shapes. We then used the method to simulate heterogeneous enzyme distribution, which suggested a theoretical effect on variability at the population level. We propose the use of this method, and its future extensions, to explore how spatiotemporal organisation of sub-cellular compartments and the molecules within could affect cell behaviour.
Monorhinal and Birhinal Odor Processing in Humans: an fMRI investigation
Authors: Ekanayake Anupa , Yang Qing , Kanekar Sangam , Ahmed Biyar , McCaslin Silas , Kalra Deepak , Eslinger Paul , Karunanayaka Prasanna 
Published: August 2023

ABSTRACTThe olfactory nerve, also known as cranial nerve I, is known to have exclusive ipsilateral projections to primary olfactory cortical structures. It is still unclear whether these projections also correspond to functional pathways of odor processing. In an olfactory functional magnetic resonance imaging (fMRI) study of twenty young healthy subjects with a normal sense of smell, we tested whether nostril specific stimulation with phenyl ethyl alcohol (PEA), a pure olfactory stimulant, asymmetrically activates primary or secondary olfactory-related brain structures such as primary olfactory cortex, entorhinal cortex, and orbitofrontal cortex. The results indicated that without a challenging olfactory task, passive (no sniffing) and active (with sniffing) nostril-specific PEA stimulation did not produce asymmetrical fMRI activation in olfactory cortical structures.
PoMeLo: a systematic computational approach to predicting metabolic loss in pathogen genomes
Authors: Glascock Abigail Leigh , Waltari Eric , Dudas Gytis , Wong Joan , Ahyong Vida 
Published: August 2023

AbstractBackgroundGenome streamlining, the process by which genomes become smaller and encode fewer genes over time, is a common phenomenon among pathogenic bacteria. This reduction is driven by selection for faster replication and minimized energy expenditure in a nutrientrich environment. As pathogens evolve to become more reliant on the host, metabolic genes and resulting capabilities are lost in favor of siphoning metabolites from the host. Characterizing genome streamlining, gene loss, and pathway degradation can be useful in assessing pathogen metabolic dependency on host metabolism and identifying potential targets for host-directed therapeutics.ResultsPoMeLo (PredictorofMetabolicLoss) is a novel evolutionary genomics-guided computational approach for identifying metabolic gaps in the genomes of pathogenic bacteria. PoMeLo leverages a centralized public database of high-quality genomes and annotations and allows the user to compare an unlimited number of genomes across individual genes and pathways. PoMeLo runs locally using user-friendly prompts in a matter of minutes and generates tabular and visual outputs for users to compare predicted metabolic capacity between groups of bacteria and individual species. Each pathway is assigned a Predicted Metabolic Loss (PML) score to assess the magnitude of genome streamlining. Optionally, PoMeLo places results in an evolutionary context by including phylogenetic relationships in visual outputs. It can also initially compute phylogenetically-weighted mean genome sizes to identify genome streamlining events. Here we describe PoMeLo and demonstrate its use in identifying metabolic gaps in genomes of pathogenicTreponemaspecies.ConclusionsPoMeLo represents an advance over existing methods for identifying metabolic gaps in genomic data, allowing comparison across large numbers of genomes and placing the resulting data in a phylogenetic context. PoMeLo is freely available for academic and nonacademic use athttps://github.com/czbiohub-sf/pomelo.
SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation
Authors: Xu Huixin , Dugué Guillaume P. , Cantaut-Belarif Yasmine , Lejeune François-Xavier , Gupta Suhasini , Wyart Claire , Lehtinen Maria K. 
Published: August 2023

AbstractReissner’s fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulatingSspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated aSspoknockout mouse model using CRISPR/Cas9-mediated genome-editing.Sspoknockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably,Sspoknockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected inSspoknockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.
CDDO-Methyl Ester Inhibits BRAF Inhibitor Resistance and Remodels the Myeloid Compartment in BRAF-mutant Melanoma
Authors: Torres Gretel M. , Jarnagin Helen C. , Park Chanhyuk , Yang Heetaek , Kosarek Noelle N. , Bhandari Rajan , Wang Chen-Yu , Kolling Fred W. , Whitfield Michael L. , Turk Mary Jo , Liby Karen T. , Pioli Patricia A. 
Published: August 2023

ABSTRACTApproximately 50% of advanced melanomas harbor activating BRAFV600Emutations that are sensitive to BRAF inhibition. However, the duration of the response to BRAF inhibitors (BRAFi) has been limited due to the development of acquired resistance, which is preceded by recruitment of immunosuppressive myeloid cells and regulatory T cells (Tregs). While the addition of MAPK/ERK kinase 1 inhibitors (MEKi) prolongs therapeutic response to BRAF inhibition, most patients still develop resistance. Using a BrafV600E/+/Pten-/-graft mouse model of melanoma, we now show that the addition of the methyl ester of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (C-Me) to the BRAFi vemurafenib analog PLX4720 at resistance significantly reduces tumor burden. Dual treatment remodels the BRAFi resistant-tumor microenvironment (TME), reducing infiltration of Tregsand tumor associated macrophages (TAMs), and attenuates immunosuppressive cytokine production. For the first time, we characterize myeloid populations using scRNA-seq in BRAFi-resistant tumors and demonstrate that restoration of therapeutic response is associated with significant changes in immune-activated myeloid subset representation. Collectively, these studies suggest that C-Me inhibits acquired resistance to BRAFi. Use of C-Me in combination with other therapies may both inhibit melanoma growth and enhance therapeutic responsiveness more broadly.
Quantifying landscape-flux via single-cell transcriptomics uncovers the underlying mechanism of cell cycle
Authors: Zhu Ligang , Wang Jin 
Published: August 2023

AbstractRecent developments in single-cell sequencing technology enable the acquisition of the whole transcriptome data. However, understanding the underlying mechanism and identifying the driving force of the transcriptional regulation of the cell function directly from these data remains challenging. To address this urgent need, we reconstruct a continuous vector field of cell cycle based on the discrete single-cell RNA velocity to quantify the single-cell global non-equilibrium dynamic landscape-flux. We reveal that large fluctuations disrupt the global landscape and genetic perturbations alter landscape-flux, thus identifying key genes in maintaining cell cycle dynamics and predicting associated effects on function. Additionally, we quantify the fundamental energy cost of the cell cycle initiation and reveal that sustaining the cell cycle requires curl flux and dissipation to maintain the oscillatory phase coherence. We enable the inference of the cell cycle gene regulatory networks directly from the single-cell transcriptomic data, including the feedback mechanisms and interaction intensity. This provides a golden opportunity to experimentally verify the landscape-flux theory and also obtain its associated quantifications. Our study also offers a unique framework for combining the landscape-flux theory and single-cell high-through sequencing experiments together for understanding the underlying mechanisms of the cell cycle and can be extended to other non-equilibrium biological processes, such as differentiation-development and disease pathogenesis.
Metabolic slowdown as the proximal cause of ageing and death
Authors: Wordsworth J. , Yde Nielsen P. , Fielder E. , Chandrasegaran S. , Shanley D. 
Published: August 2023

SummaryAgeing results from the gradual loss of homeostasis, and there are currently many hypotheses for the underlying initial causes, such as molecular damage accumulation. However, few if any theories directly connect comprehensive, underlying biological mechanisms to specific age-related diseases. We recently demonstrated how a specific maintenance system impeding overactivity disorders such as cancer might undergo positive selection while still resulting in a gradual homeostatic shift toward slower metabolism. Here we connect this metabolic slowdown, via a series of unavoidable homeostatic shifts, to the hallmarks of ageing, including mitochondrial dysfunction, insulin resistance (IR), weight gain, basal inflammation, and age-related diseases such as atherosclerosis. We constructed the fuel and energy model (FEM) based on these shifts and found that ageing via metabolic slowdown could explain not only the effects of anti-ageing interventions such as rapamycin and calorie restriction, but many of the paradoxes of ageing that currently defy alternative theories.