bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acetylcholine esterase ofDrosophila melanogaster: a laboratory model to explore applications of insecticide susceptibility gene drives
Authors: Hernandes Natalia , Qi Xiaomeng Mollyann , Bhide Soumitra , Brown Courtney , Camm Benjamin J. , Baxter Simon W. , Robin Charles 
Published: November 2023

AbstractBACKGROUNDOne of the proposed applications of gene drives has been to revert pesticide resistant mutations back to the ancestral susceptible state. Insecticides that have become ineffective because of the rise of resistance could have reinvigorated utility and be used to suppress pest populations again, perhaps at lower application doses.RESULTSWe have created a laboratory model for susceptibility gene drives that replaces field-selected resistant variants of the acetylcholine esterase (Ace) locus ofDrosophila melanogasterwith ancestral susceptible variants. We constructed a CRISPR/Cas9 homing drive and found that homing occurred in many genetic backgrounds with varying efficiencies. While the drive itself could not be homozygosed, it converted resistant alleles into susceptible ones and produced recessive lethal alleles that could suppress populations. Our studies provided evidence for two distinct classes of Gene Drive Resistance (GDR): rather than being mediated by the conventional Non-Homologous End-joining (NHEJ) pathway, one seemed to involve short homologous repair and the other was defined by genetic background.Additionally, we used simulations to explore a distinct application of susceptibility drives; the use of chemicals to prevent the spread of synthetic gene drives into protected areas.CONCLUSIONSInsecticide susceptibility gene drives could be useful tools to control pest insects however problems associated with particularities of the target loci and GDR will need to be overcome for them to be effective. Furthermore, realistic patterns of pest dispersal and high insecticide exposure rates would be required if susceptibility were to be useful as a ‘safety-switch’ to prevent the unwanted spread of gene drives.
Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes
Authors: Buchanan Hayley D. , McConville Robyn , Yeoh Lee M. , Duffy Michael F. , Boddey Justin A. , McFadden Geoffrey I. , Goodman Christopher D. 
Published: November 2023

SUMMARYAntimalarials are now used in combination with partner drugs to stem parasite drug resistance. Partners are often older, safe, cheap drugs, but resistance is already circulating for many, which raises the risk of selecting for multidrug resistance. If the partner drug(s) could be refractory to the spread of resistance, better resistance control could be implemented. We tested whether resistance to the antibiotic azithromycin, which kills malaria parasites by perturbing prokaryote-like protein synthesis in the apicoplast (relict plastid), had fitness costs to the spread of parasites via mosquitoes where parasites are not under drug pressure. Azithromycin resistance mutations in both rodent and human malaria parasites had a negative impact on the ability of resistant parasites to transmit from one vertebrate host to another via mosquitoes. Azithromycin resistance will therefore be less likely to spread geographically, making it an attractive option as a perennial partner compound to protect appropriate frontline antimalarials.
Digital Voice-Based Biomarker for Monitoring Respiratory Quality of Life: Findings from the Colive Voice Study
Authors: Despotovic Vladimir , Elbéji Abir , Fünfgeld Kevser , Pizzimenti Mégane , Ayadi Hanin , Nazarov Petr V. , Fagherazzi Guy 
Published: November 2023

AbstractRegular monitoring of respiratory quality of life (RQoL) is essential in respiratory healthcare, facilitating prompt diagnosis and tailored treatment for chronic respiratory diseases. Voice alterations resulting from respiratory conditions create unique audio signatures that can potentially be utilized for disease screening or monitoring. Analyzing data from 1908 participants from the Colive Voice study, which collects standardized voice recordings alongside comprehensive demographic, epidemiological, and patient-reported outcome data, we evaluated various strategies to estimate RQoL from voice, including handcrafted acoustic features, standard acoustic feature sets, and advanced deep audio embeddings derived from pretrained convolutional neural networks. We compared models using clinical features alone, voice features alone, and a combination of both. The multimodal model combining clinical and voice features demonstrated the best performance, achieving an accuracy of 70.34% and an area under the receiver operating characteristic curve (AUROC) of 0.77; an improvement of 5% in terms of accuracy and 7% in terms of AUROC compared to model utilizing voice features alone. Incorporating vocal biomarkers significantly enhanced the predictive capacity of clinical variables across all acoustic feature types, with a net classification improvement (NRI) of up to 0.19. Our digital voice-based biomarker is capable of accurately predicting RQoL, either as an alternative to or in conjunction with clinical measures, and could be used to facilitate rapid screening and remote monitoring of respiratory health status.
Interleaved TMS/fMRI shows that threat decreases dlPFC-mediated top-down regulation of emotion processing
Authors: Patel Milan , Teferi Marta , Casalvera Abigail , Lynch Kevin , Nitchie Frederick , Makhoul Walid , Oathes Desmond J , Sheline Yvette , Balderston Nicholas L 
Published: November 2023

AbstractBackgroundThe right dorsolateral prefrontal cortex (dlPFC) has been indicated to be a key region in the cognitive regulation of emotion by many previous neuromodulation and neuroimaging studies. However, there is little direct causal evidence supporting this top-down regulation hypothesis. Furthermore, it is unclear whether contextual threat impacts this top-down regulation. By combining TMS/fMRI, this study aimed to uncover the impact of unpredictable threat on TMS-evoked BOLD response in dlPFC-regulated emotional networks. Based on the previous findings linking the dlPFC to the downregulation of emotional network activity, we hypothesized TMS pulses would deactivate activity in anxiety expression regions, and that threat would reduce this top-down regulation.Methods44 healthy controls (no current or history of psychiatric disorders) were recruited to take part in a broader study. Subjects completed the neutral, predictable, and unpredictable (NPU) threat task while receiving TMS pulses to either the right dlPFC or a control region. dlPFC targeting was based on data from a separate targeting session, where subjects completed the Sternberg working memory (WM) task inside the MRI scanner.ResultsWhen compared to safe conditions, subjects reported significantly higher levels of anxiety under threat conditions. Additionally, TMS-evoked responses in the left insula (LI), right sensory/motor cortex (RSM), and a region encompassing the bilateral SMA regions (BSMA) differed significantly between safe and threat conditions. There was a significant TMS-evoked deactivation in safe periods that was significantly attenuated in threat periods across all 3 regions.ConclusionsThese findings suggest that threat decreases dlPFC-regulated emotional processing by attenuating the top-down control of emotion, like the left insula. Critically, these findings provide support for the use of right dlPFC stimulation as a potential intervention in anxiety disorders.
Examining the Efficacies of Different Machine Learning Algorithms on Predicting Future Potential Death from Heart Failure
Authors: Radi Osama 
Published: November 2023

Abstract1 in every 5 deaths is from heart failure. If this heart failure was able to be predicted, medical practitioners would be able to issue the proper preventative measures in order to prevent the fatal heart attack. As machine learning is gaining its place in medicine, one of the most commonly asked questions is which machine learning algorithms can be used where. This paper aims to find which machine learning algorithm is most efficacious in predicting future fatal heart disease. Two machine learning algorithms were evaluated in this study; namely linear regression models and k-nearest-neighbors models. The K-Nearest-Neighbors model was found to be most efficacious with an accuracy between 96.67% and 100% in predicting future heart failure. The reliability of this algorithm in predicting death from heart failure will surely prove useful in the future of treating at-risk patients.
Translocations spur population growth but exacerbate inbreeding in an imperiled species
Authors: Linderoth Tyler , Deaner Lauren , Chen Nancy , Bowman Reed , Boughton Raoul , Fitzpatrick Sarah W. 
Published: November 2023

AbstractLand and natural resource usage that supports human society can pose a risk to the survival of other species, spurring biodiversity loss. In extreme cases, when development threatens the existence of individuals, wildlife managers may perform mitigation translocations, relocating individuals out of harm’s way. We investigated the efficacy of mitigation translocations as a conservation strategy in Federally Threatened Florida Scrub-Jays using a dataset that provided unprecedented resolution into both the demographic and genomic outcomes of translocations. Over the course of seven years, a total of fourteen groups (51 jays) from five subpopulations that had been declining from agriculture and lack-of-fire driven habitat degradation were translocated to a larger site of more contiguous restored habitat with only four family groups, to mitigate for loss of these subpopulations from mining activity. Habitat restoration and translocations established a core population that increased 10-fold in size after only 17 years from the first translocations. Pedigree analyses of this population revealed that a small subset of mostly translocated individuals fueled the demographic expansion, with a single breeding pair responsible for ∼24% of the ancestral genetic contributions since 2008. Genomic comparisons between translocated individuals and individuals from the core population before and after translocations revealed that the high reproductive skew led to increased inbreeding and loss of genetic diversity. This study stresses the importance of demographic and genetic monitoring following translocations, and that subsequent, genetic-rescue-oriented translocations may be necessary in mitigation scenarios to counter the genetic consequences of reproductive skew in fragmented populations.Significance StatementThere is ongoing debate surrounding the effectiveness of mitigation-driven translocations for conservation, however we show that translocations to mitigate the effects of mining on Federally Threatened Florida Scrub-Jays spurred population growth; a major boon to the viability of this species. We translocated individuals from at-risk subpopulations that were demographic sinks into recently restored habitat, which quickly established a rapidly growing core population. We demonstrate that demographic and genetic recovery do not necessarily go hand-in-hand, as reproduction was highly skewed towards a small subset of mostly translocated individuals, which increased inbreeding and eroded genetic diversity. This stresses the importance of demographic and genetic monitoring for identifying reproductive skew, allowing for adaptive management that addresses inbreeding and achieves broader conservation goals.
Orientation-Independent-DIC imaging reveals that a transient rise in depletion force contributes to mitotic chromosome condensation
Authors: Iida Shiori , Ide Satoru , Tamura Sachiko , Tani Tomomi , Goto Tatsuhiko , Shribak Michael , Maeshima Kazuhiro 
Published: November 2023

AbstractGenomic information must be faithfully transmitted into two daughter cells during mitosis. To ensure the transmission process, interphase chromatin is further condensed into mitotic chromosomes. Although protein factors like condensins and topoisomerase IIα are involved in the assembly of mitotic chromosomes, the physical bases of the condensation process remain unclear. Depletion force/macromolecular crowding, an effective attractive force that arises between large structures in crowded environments around chromosomes, may contribute to the condensation process. To approach this issue, we investigated the “chromosome milieu” during mitosis of living human cells using orientation-independent-differential interference contrast (OI-DIC) module combined with a confocal laser scanning microscope, which is capable of precisely mapping optical path differences and estimating molecular densities. We found that the molecular density surrounding chromosomes increased with the progression from prometaphase to anaphase, concurring with chromosome condensation. However, the molecular density went down in telophase, when chromosome decondensation began. Changes in the molecular density around chromosomes by hypotonic or hypertonic treatment consistently altered the condensation levels of chromosomes.In vitro, native chromatin was converted into liquid droplets of chromatin in the presence of cations and a macromolecular crowder. Additional crowder made the chromatin droplets stiffer and more solid-like, with further condensation. These results suggest that a transient rise in depletion force, likely triggered by the relocation of macromolecules (proteins, RNAs and others) via nuclear envelope breakdown and also by a subsequent decrease in cell-volumes, contributes to mitotic chromosome condensation, shedding light on a new aspect of the condensation mechanism in living human cells.Significance StatementMitotic chromosome condensation is an essential process to transmit replicated chromosomes into two daughter cells during cell division. To study the underlying physical principles of this process, we focused on depletion force/macromolecular crowding, which is a force that attracts large structures in crowded cell environments. Using newly developed special light microscopy, which can image the molecular density of cellular environments, we found that crowding around chromosomes increases during cell division.In vitro, higher concentrations of macromolecules condense chromatin and make it stiffer and more solid-like. Our results suggest that the rise in depletion force renders chromosomes more rigid, ensuring accurate chromosome transmission during cell division.
eIF3 engages with 3’-UTR termini of highly translated mRNAs
Authors: Mestre-Fos Santi , Ferguson Lucas , Trinidad Marena , Ingolia Nicholas T. , Cate Jamie H. D. 
Published: November 2023

ABSTRACTStem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.
Modelling the transmission and spread of yellow fever in forest landscapes with different spatial configurations
Authors: Medeiros-Sousa Antônio Ralph , Lange Martin , Mucci Luis Filipe , Marrelli Mauro Toledo , Grimm Volker 
Published: November 2023

AbstractYellow fever (YF) is a major public health issue in tropical and subtropical areas of Africa and South America. The disease is caused by the yellow fever virus (YFV), an RNA virus transmitted to humans and other animals through the bite of infected mosquitoes (Diptera: Culicidae). In Brazil and other South American countries, YFV is restricted to the sylvatic cycle, with periodic epizootic outbreaks affecting non-human primate (NHP) populations and preceding the emergence of human infections in areas close to forests. In recent epizootic-epidemic waves, the virus has expanded its range and spread across highly fragmented landscapes of the Brazilian Atlantic coast. Empirical evidence has suggested a possible relationship between highly fragmented areas, increased risk of disease in NHP and humans, and easier permeability of YFV through the landscape. Here, we present a hybrid compartmental and network-based model to simulate the transmission and spread of YFV in forest landscapes with different spatial configurations (forest cover and edge densities) and apply the model to test the hypothesis of faster virus percolation in highly fragmented landscapes. The model was parameterized and tested using the pattern- oriented modelling approach. Two different scenarios were simulated to test variations in model outputs, a first where the landscape has no influence on model parameters (default) and a second based on the hypothesis that edge density influences mosquito and dead-end host abundance and dispersal (landscape-dependent). The model was able to reproduce empirical patterns such as the percolation speed of the virus, which presented averages close to 1 km/day, and provided insights into the short persistence time of the virus in the landscape, which was approximately three months on average. When assessing the speed of virus percolation across landscapes, it was found that in the default scenario virus percolation tended to be faster in landscapes with greater forest cover and lower edge density, which contradicts empirical observations. Conversely, in the landscape- dependent scenario, virus percolation was faster in landscapes with high edge density and intermediate forest cover, supporting empirical observations that highly fragmented landscapes favour YFV spread. The proposed model can contribute to the understanding of the dynamics of YFV spread in forested areas, with the potential to be used as an additional tool to support prevention and control measures. The potential applications of the model for YFV and other mosquito-borne diseases are discussed.
Turnover ofPPP1R15AmRNA encoding GADD34 controls the molecular memory of the cellular integrated stress response
Authors: Magg Vera , Manetto Alessandro , Kopp Katja , Wu Chia Ching , Naghizadeh Mohsen , Lindner Doris , Eke Lucy , Welsch Julia , Kallenberger Stefan M. , Schott Johanna , Haucke Volker , Locker Nicolas , Stoecklin Georg , Ruggieri Alessia 
Published: November 2023

SummaryThe integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of Growth Arrest and DNA Damage inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability ofPPP1R15AmRNA encoding GADD34. We established that the 3’ untranslated region ofPPP1R15AmRNA contains an active AU-rich element recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control ofPPP1R15AmRNA turnover as a key step in establishing the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
Bacterial aggregation triggered by low-level antibiotic-mediated lysis
Authors: Tavaddod Sharareh , Dawson Angela , Allen Rosalind J 
Published: November 2023

ABSTRACTSuspended bacterial aggregates play a central role in ocean biogeochemistry, industrial processes and probably many clinical infections – yet the factors that trigger aggregation remain poorly understood, as does the relationship between suspended aggregates and surface-attached biofilms. Here we show that very low doses of cell-wall targeting antibiotic, far below the minimal inhibitory concentration, can trigger aggregation ofEscherichia colicells. This occurs when a few cells lyse, releasing extracellular DNA – thus, cell-to-cell variability in antibiotic response leads to population-level aggregation. Although lysis-triggered aggregation echoes known trigger mechanisms for surface-attached biofilms, these aggregates appear to be of a distinct type, since they do not show typical biofilm characteristics such as protection from antibiotics, or increased biofilm-forming potential. Our work contributes to understanding the nature of bacterial aggregates and the factors that trigger their formation, and the consequences of widespread low-dose antibiotic exposure in the environment and in the body.
Deletion of sulfate transporter SUL1 extends yeast replicative lifespan via reduced PKA signaling instead of decreased sulfate uptake
Authors: Long Juan , Ma Meng , Chen Yuting , Gong Bo , Zheng Yi , Li Hao , Yang Jing 
Published: November 2023

AbstractThe regulation of cellular metabolism and growth in response to nutrient availability is essential for cell survival and can significantly impact lifespan. Central to the regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this work, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate inS. cerevisiae, as a key gene for regulating lifespan. We performed a systematic analysis to delineate the downstream mechanism underlying the lifespan extension by SUL1 deletion. Surprisingly, we found that the lifespan extending effect of SUL1 deletion is not caused by decreased sulfate transport. SUL1 deletion mutant exhibited decreased PKA signaling, resulting in a range of downstream effects, including increased stress-protective trehalose and glycogen, increased nuclear translocation of MSN2 and elevated expression of general stress response genes, enhanced autophagy, and reduced expression of amino acid biosynthetic and ribosomal genes. We show that the observed increase in lifespan is dependent on MSN2 and autophagy pathways. Our findings exemplify the influence of nutrient signaling, rather than the nutrient itself, on lifespan regulation and further substantiate the pivotal role of the PKA pathway in this process.
Expansion of human centromeric arrays in cells undergoing break-induced replication
Authors: Showman Soyeon , Talbert Paul B. , Xu Yiling , Adeyemi Richard O. , Henikoff Steven 
Published: November 2023

AbstractHuman centromeres are located within α-satellite arrays and evolve rapidly, which can lead to individual variation in array lengths. Proposed mechanisms for such alterations in lengths are unequal cross-over between sister chromatids, gene conversion, and break-induced replication. However, the underlying molecular mechanisms responsible for the massive, complex, and homogeneous organization of centromeric arrays have not been experimentally validated. Here, we use droplet digital PCR assays to demonstrate that centromeric arrays can expand and contract within ~20 somatic cell divisions of a cell line. We find that the frequency of array variation among single-cell-derived subclones ranges from a minimum of ~7% to a maximum of ~100%. Further clonal evolution revealed that centromere expansion is favored over contraction. We find that the homologous recombination protein RAD52 and the helicase PIF1 are required for extensive array change, suggesting that centromere sequence evolution can occur via break-induced replication.