bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of the neural sex-determination system in insects: Thedoublesexhomolog in crickets functions as an X-linked masculinizing factor to regulate morphological but not behavioral sexual dimorphism
Authors: Watanabe Takayuki 
Published: September 2024

AbstractIn animals, sex-specific social behaviors, such as courtship and aggression, are controlled by sex-specific neural circuits. To understand the neural mechanisms of sex-specific social behaviors from a comparative perspective, it is necessary to understand the sex determination mechanisms of neural circuits and their evolution across animal lineages. To address this, I have focused on the evolution of the neural sex determination system in insects. In the fruit flyDrosophila melanogaster, a model insect with powerful genetics, the molecular mechanisms underlying neuronal sex determination are well understood, and two transcription factor genes,fruitlessanddoublesex(dsx), have been identified as terminal differentiators. In contrast, those in direct-developing insects, which diverged from the holometabolous lineage, includingDrosophila, about 400 million years ago, remain unclear. My previous studies found that thefruitlesshomolog is unlikely to be integrated into the neuronal sex determination system in direct-developing insects. In this study, I investigated whether thedsxhomolog in direct-developing insects contributes to neuronal sex determination to form neural circuits that regulate adult social behaviors. I identified thedsxhomolog in the two-spotted cricketGryllus bimaculatus(Gryllus dsxgene) and revealed that it has a unique isoform configuration, and its encoded proteins contain a cryptic DNA-binding DM domain with accumulated amino acid substitutions. A knockout study revealed that theGryllus dsxgene functions as an X-linked morphological masculinizing factor but does not determine the sexual orientation or behavioral patterns of adult social behavior in crickets. These results suggest that, at least in crickets, an unknown sex determination factor(s) other thanfruitlessanddsxplays a central role in neuronal sex determination.
The effects of P2Y12 loss on microglial gene expression, dynamics, and injury response in the cerebellum and cerebral cortex
Authors: Stoessel Mark B. , Stowell Rianne D. , Lowery Rebecca L. , Le Linh , Vu Andy N. , Whitelaw Brendan S. , Majewska Ania K. 
Published: September 2024

AbstractDespite the emerging consensus that microglia are critical to physiological and pathological brain function, it is unclear how microglial roles and their underlying mechanisms differ between brain regions. Microglia throughout the brain express common markers, such as the purinergic receptor P2Y12, that delineate them from peripheral macrophages. P2Y12 is a critical sensor of injury but also contributes to the sensing of neuronal activity and remodeling of synapses, with microglial loss of P2Y12 resulting in behavioral deficits. P2Y12 has largely been studied in cortical microglia, despite the fact that a growing body of evidence suggests that microglia exhibit a high degree of regional specialization. Cerebellar microglia, in particular, exhibit transcriptional, epigenetic, and functional profiles that set them apart from their better studied cortical and hippocampal counterparts. Here, we demonstrate that P2Y12 deficiency does not alter the morphology, distribution, or dynamics of microglia in the cerebellum. In fact, loss of P2Y12 does little to disturb the distinct transcriptomic profiles of cortical and cerebellar microglia. However, unlike in cortex, P2Y12 is not required for a full microglial response to focal injury, suggesting that cerebellar and cortical microglia use different cues to respond to injury. Finally, we show that P2Y12 deficiency impairs cerebellar learning in a delay eyeblink conditioning task, a common test of cerebellar plasticity and circuit function. Our findings suggest not only region-specific roles of microglial P2Y12 signaling in the focal injury response, but also indicate a conserved role for P2Y12 in microglial modulation of plasticity across regions.
Detection of intra-tumoral microbiota from transcriptomic sequencing of Asian breast cancer
Authors: Yeo Li-Fang , Yan Lee Audrey Weng , Ern Tee Phoebe Yon , Fong Chin Joyce Seow , Lee Bernard KB , Lim Joanna , Teo Soo-Hwang , Pan Jia Wern 
Published: September 2024

AbstractThe human microbiome has garnered significant interest in recent years as an important driver of human health and disease. Likewise, it has been suggested that the intra-tumoral microbiome may be associated with specific features of cancer such as tumour progression and metastasis. However, additional research is needed to validate these findings in diverse populations. In this study, we characterized the intra-tumoral microbiota of 883 Malaysian breast cancer patients using transcriptomic data from bulk tumours and investigated their association with clinical variables and immune scores. We found that the tumour microbiome was not associated with breast cancer molecular subtype, cancer stage, tumour grade, or patient age, but was weakly associated with immune scores. We also found that the tumour microbiome was able to predict immune scores in our cohort using random forest models, suggesting the possibility of an interaction between the tumour microbiome and the tumour immune microenvironment in Asian breast cancer.
Heterotrophic diazotrophy along a river–lake continuum: lifestyle and contribution to N2fixation
Authors: Geisler Eyal , Siebner Hagar , Kolton Max , Sisma-Ventura Guy , Rahav Eyal , Arnon Shai , Bar-Zeev Edo 
Published: September 2024

AbstractHeterotrophic diazotrophs are potentially important agents in freshwater ecosystems, yet they remain poorly understood. This study elucidates the contribution of freshwater heterotrophic diazotrophs as free-living or aggregate-associated cells to total N2fixation along the continuum from the Jordan River to Lake Kinneret, Israel. Heterotrophic diazotrophs accounted for 25%–56% of the total diazotrophs and commonly found as free-living cells or attached to aggregates in the river. N2fixation by heterotrophic diazotrophs associated with aggregates varied along the river, while accounting for ~50% of N2fixation in the lake. Non-cyanobacterial diazotrophs dominated the free-living fraction in the river, and cyanobacteria were mostly identified in the lake. The diversity of free-living diazotrophs was sensitive to environmental changes, as the aggregates have likely provided a protected micro-environment. The results reveal the dynamic lifestyle of heterotrophic diazotrophs along a river–lake continuum and highlight their contribution to total N2fixation and primary production.TeaserFreshwater heterotrophic diazotrophs are more ubiquitous than previously thought, can be found as free-living cells or associated with aggregates, and significantly contribute to primary production.
Inhibition of Ribosome Biogenesisin vivoCauses p53-Dependent Death and p53-Independent Dysfunction
Authors: Cho Charles J. , Nguyen Thanh , Rougeau Amala K. , Huang Yang-Zhe , To Sarah , Lin Xiaobo , Gamage Supuni Thalalla , Meier Jordan L. , Mills Jason C. 
Published: September 2024

ABSTRACTRibosomes are critical for cell function; their synthesis (known as ribosome biogenesis; “RiBi”) is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cellsin vivoin adult tissue. Here, we generated mice with conditional deletion ofNat10, an essential gene for RiBi and translation, to investigate effects of RiBi blockadein vivo.We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis. We observed a surprising latency of several weeks betweenNat10deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death, which was associated with translocation of ribosomal proteins RPL5 and RPL11 into acinar cell nucleoplasm. Indeed, deletion ofTrp53could rescue acinar cells from apoptotic cell death; however,Nat10Δ/Δ; Trp53Δ/Δacinar cells remained morphologically and functionally abnormal. Moreover, the deletion ofTrp53did not rescue the lethality of inducible, globally deletedNat10in adult mice nor did it rescue embryonic lethality of globalNat10deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion ofNat10in acinar cells blockedKras-oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless ofTrp53mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translationin vivo.
Directed evolution of an orthogonal transcription engine for programmable gene expression in eukaryotes
Authors: Kar Shaunak , Gardner Elizabeth C. , Javanmardi Kamyab , Boutz Daniel R. , Shroff Raghav , Horton Andrew P. , Segall-Shapiro Thomas H. , Ellington Andrew D. , Gollihar Jimmy 
Published: September 2024

AbstractT7 RNA polymerase has enabled orthogonal control of gene expression and recombinant protein production across diverse prokaryotic host chassis organisms for decades. However, the absence of 5’ methyl guanosine caps on T7 RNAP derived transcripts has severely limited its utility and widespread adoption in eukaryotic systems. To address this shortcoming, we evolved a fusion enzyme combining T7 RNAP with the single subunit capping enzyme from African swine fever virus usingSaccharomyces cerevisiae. We isolated highly active variants of this fusion enzyme, which exhibited roughly two orders of magnitude higher protein expression compared to the wild-type enzyme. We demonstrate the programmable control of gene expression using T7 RNAP-based genetic circuits in yeast and validate enhanced performance of these engineered variants in mammalian cells. This study presents a robust, orthogonal gene regulatory system applicable across diverse eukaryotic hosts, enhancing the versatility and efficiency of synthetic biology applications.
Early Prediction of Ischaemic Stroke Outcomes: A Novel Computational Approach
Authors: Chen Xi , El-Bouri Wahbi , Payne Stephen , Lu Lei 
Published: September 2024

Malignant stroke can lead to a death rate as high as 80%. Although early interventions can improve patient outcomes, they also lead to side effects. Therefore, the early prediction of stroke outcomes is crucial for clinical strategies. Imaging markers such as brain swelling volume and midline shift have been critical predictors in various stroke scoring systems. However, these markers can only become visible on brain images days after stroke onset, which delays clinical decisions. A primary challenge in predicting these markers is that brain swelling is a biomechanical process that relies on anatomical features, such as lesion size and location. To tackle this problem, we propose a novel computational pipeline to predict brain swelling after stroke. We first provide a mathematical model of the brain by using a five-compartment poroelastic theory. It allows us to generate high-quality stroke cases with varied 3D brain and lesion anatomy, which are then used to train and validate a deep neural network (DNN). Our in silico experimentation with 3,000 cases shows that anatomical features of stroke brains are well-learned by the DNN, with minimal errors in brain swelling prediction found in the hold-out testing cases. In addition, we used the DNN to process clinical imaging data of 60 stroke patients. The results show that the markers generated from the DNN can predict 3-month stroke outcomes with an AUC of around 0.7. It indicates that the proposed computational pipeline can potentially advance the time point for clinical decisions.Significance StatementStroke is the second leading cause of death in the world, and malignant stroke can lead to a death rate of 80%. Early interventions can improve patient outcomes but can also cause side effects. Therefore, it is crucial to predict stroke outcomes at an early stage. Radiological markers such as brain swelling volume and midline shift have been used in various stroke scoring systems. However, these markers can only become visible after days to stroke onset, which delays clinical decisions. To tackle this issue, we propose a novel computational pipeline to predict brain swelling after stroke onset. The proposed pipeline is found to predict brain swelling accurately and can potentially assist early clinical decision-making.
Elucidation of α-glucosidase inhibitory activity and UHPLC-ESI-QTOF-MS based metabolic profiling of endophytic fungiAlternariasp. BRN05. isolated from seeds ofSwietenia macrophyllaKing
Authors: Kumar Piyush , Kannakazhi Kantari Sai Anand , Biswal Ranendra Pratap , Ghanta Prasanth , Dharanikota Malleswara 
Published: September 2024

AbstractThere is a growing demand for new diabetes drugs with fewer side effects to replace current medications known for their adverse effects. Inhibition of α-glucosidase responsible for postprandial hyperglycaemia among diabetes patients is a promising strategy for managing the disease. This study aims to explore and identify novel bioactive molecules with anti-diabetes potential fromAlternariasp. BRN05, an endophytic fungus isolated from a well-known medicinal plantSwietenia macrophyllaKing. Ethyl acetate extracts ofAlternariasp. BRN05 grown in full-strength (EFS) and quarter-strength (EQS) media respectively were evaluated for their α-glucosidase inhibitory activities. Based on IC50values, EQS exhibited significantly greater inhibitory activity (0.01482 ± 1.809 mg/mL) as compared to EFS (1.16 ± 0.173 mg/mL) as well as acarbose control (0.494 ± 0.009 mg/mL). EFS and EQS were subjected to metabolic profiling using Ultra-High-Performance Liquid Chromatography - Electrospray Ionization - Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-ESI-QTOF-MS). A total of nineteen molecules from EFS and twenty from EQS were tentatively identified based on MS/MS fragmentation. Molecular docking analysis revealed that twelve among these exhibited greater binding energies than that of acarbose (-6.6 kcal/mol). Two molecules from EQS, 3’,4’,7-trihydroxyisoflavanone (-7.5 kcal/mol) and alternariol 9-methyl ether (-7 kcal/mol), were subjected to ensemble docking studies, which further strengthened their promise as good α-glucosidase inhibitors for treating diabetes.
SbcB facilitates natural transformation inVibrio choleraein an exonuclease-independent manner
Authors: Dalia Triana N. , Dalia Ankur B. 
Published: September 2024

ABSTRACTNatural transformation (NT) is a conserved mechanism of horizontal gene transfer in bacterial species. During this process, DNA is taken up into the cytoplasm where it can be integrated into the host genome by homologous recombination. We have previously shown that some cytoplasmic exonucleases inhibit NT by degrading ingested DNA prior to its successful recombination. However, one exonuclease, SbcB, counterintuitively promotes NT inVibrio cholerae. Here, through a systematic analysis of the distinct steps of NT, we show that SbcB acts downstream of DNA uptake into the cytoplasm, but upstream of recombinational branch migration. Through mutational analysis, we show that SbcB promotes NT in a manner that does not rely on its exonuclease activity. Finally, we provide genetic evidence that SbcB directly interacts with the primary bacterial recombinase, RecA. Together, these data advance our molecular understanding of horizontal gene transfer inV. cholerae, and reveal that SbcB promotes homologous recombination during NT in a manner that does not rely on its canonical exonuclease activity.IMPORTANCEHorizontal gene transfer by natural transformation contributes to the spread of antibiotic resistance and virulence factors in bacterial species. Here, we study how one protein, SbcB, helps facilitate this process in the facultative bacterial pathogenVibrio cholerae. SbcB is a well-known for its exonuclease activity (i.e., the ability to degrade the ends of linear DNA). Through this study we uncover that while SbcB is important for natural transformation, it does not facilitate this process using its exonuclease activity. Thus, this work helps further our understanding of the molecular events required for this conserved evolutionary process, and uncovers a function for SbcB beyond its canonical exonuclease activity.
Pseudomonas aeruginosaLasR-deficient mutants have increased methylglyoxal and hydrogen peroxide sensitivity due to low intracellular glutathione
Authors: Ruzic Marina , Altamirano Hefferan Ana I. , Conaway Amy , Hogan Deborah A. 
Published: September 2024

AbstractThe electrophile methylglyoxal (MG) is produced by microorganisms and host cells through central metabolic pathways. MG is a highly reactive electrophile, so it must be rapidly detoxified to prevent damaging modifications to macromolecules.Pseudomonas aeruginosa, a pathogen of concern due to its ability develop multidrug resistance, causes many types of infections that have been associated with elevated MG levels, including cystic fibrosis (CF).P. aeruginosaisolates commonly have mutations that lead to LasR loss-of-function (LasR-) and we found thatlasRmutations confer sensitivity to MG in multiple strain backgrounds. LasR-strains have increased activity of the CbrAB two-component system which represses Crc regulation of metabolism. Here, we show that higher CbrAB activity and low Crc activity renders cells sensitive to MG. We found thatP. aeruginosaLasR-strains are more sensitive to MG and have lower intracellular reduced glutathione (GSH) compared to their LasR+ comparators. Consistent with published reports, mutants lackinggloA3, which encodes a MG-glyoxalase, and mutants lacking GSH biosynthesis enzymes (gshAorgshB) were sensitive to MG. Exogenous GSH rescued MG sensitivity in LasR-strains andgshAorgshBmutants, but not in agloA3mutant strain. We propose that low GSH levels in LasR-strains contribute to increased sensitivity to MG and H2O2.SignificanceMethylglyoxal is a highly reactive metabolite that is detected in various disease states, including those wherePseudomonas aeruginosais present and MG resistance requires the glutathione-dependent glyoxalase enzyme GloA3 enzyme. This study reveals thatP.aeruginosastrains with LasR mutations, which are commonly found in clinical isolates, are more sensitive to methylglyoxal (MG) and hydrogen peroxide due to lower intracellular glutathione levels and high activity of the CbrAB-Crc regulatory pathway. This could be significant for understanding the selective pressures that driveP. aeruginosaevolution in infection sites, as well as a better understanding of LasR-strain metabolism in infections such as those associated with cystic fibrosis.
Synthesis of NovelN-Substitutedβ-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens
Authors: Kavaliauskas Povilas , Grybaitė Birutė , Sapijanskaite-Banevič Birute , Petraitienė Rūta , Grigalevičiūtė Ramunė , Garcia Andrew , Naing Ethan , Mickevičius Vytautas , Petraitis Vidmantas 
Published: September 2024

AbstractThe increasing prevalence of antimicrobial resistance among ESKAPE group pathogens presents a significant challenge in the healthcare sector, contributing to higher morbidity and mortality rates globally. Thus, it is essential to develop novel antimicrobial agents effective against drug-resistant pathogens. In this study, we report the synthesis andin vitroantimicrobial activity characterization of novelN-substitutedβ-amino acid derivatives bearing 2-hydroxyphenyl core against multidrug-resistant bacterial pathogens. The synthesized compounds (2–26) exhibited promising antimicrobial activity specifically against Gram-positive bacteria, with minimum inhibitory concentrations (MIC) ranging from 4 to 128 µg/mL. None of the compounds demonstrated activity against Gram-negative pathogens or drug-resistant fungi. Compounds9(R = 4-nitrophenyl),17(R = 5-nitro-2-thienyl),18(R = 5-nitro-2-furyl), thiosemicarbazide16, and26exhibited the most promising activity againstStaphylococcus aureusMRSA USA300 lineage strain TCH-1516, with MIC values between 4 and 16 µg/mL. Compound26demonstrated strong antimicrobial activity against bothS. aureusTCH-1516 andE. faecalisAR-0781, with the activity comparable to control antibiotics. These findings indicate thatN-substitutedβ-amino acid derivatives with a 2-hydroxyphenyl core warrant further investigation as a potential scaffold for the further development of antimicrobial agents based on compound26targeting Gram-positive pathogens.
Decay study of
Be11
with an optical time-projection chamber
Authors: Sokołowska N. , Guadilla V. , Mazzocchi C. , Ahmed R. , Borge M. J. G. , Cardella G. , Ciemny A. A. , Cosentino L. G. , De Filippo E. , Fedosseev V. , Fijałkowska A. , Fraile L. M. , Geraci E. , Giska A. , Gnoffo B. , Granados C. , Janas Z. , Janiak Ł. , Johnston K. , Kamiński G. , Korgul A. , Kubiela A. , Maiolino C. , Marsh B. , Martorana N. S. , Miernik K. , Molkanov P. , Ovejas J. D. , Pagano E. V. , Pirrone S. , Pomorski M. , Quynh A. M. , Riisager K. , Russo A. , Russotto P. , Świercz A. , Viñals S. , Wilkins S. , Pfützner M. ,   ISOLDE Collaboration
Published: September 2024

The β decay of one-neutron halo nucleus Be11 was investigated using the Warsaw Optical Time Projection Chamber (OTPC) detector to measure β-delayed charged particles. The results of two experiments are reported. In the first one, carried out in LNS Catania, the absolute branching ratio for β-delayed α emission was measured by counting incoming Be11 ions stopped in the detector and the observed decays with the emission of α particle. The result of 3.27(46)% is in good agreement with the literature value. In the second experiment, performed at the HIE-ISOLDE facility at CERN, bunches containing several hundreds of Be11 ions were implanted into the OTPC detector followed by the detection of decays with the emission of charged particles. The energy spectrum of β-delayed α particles was determined in the full energy range. It was analyzed in the R-matrix framework and was found to be consistent with the literature. The best description of the spectrum was obtained assuming that the two 3/2+ and one 1/2+ states in B11 are involved in the transition. The search for β-delayed emission of protons was undertaken. Only the upper limit for the branching ratio for this process of (2.2±0.6stat±0.6sys)×10−6 could be determined. This value is in conflict with the result published by Ayyad [] but does agree with the limit reported by Riisager [].

Published by the American Physical Society
2024