bluuebunny/crossref_metadata_2025_split huggingface dataset:
The catabolic nature of fermentative substrates influence proteomic rewiring inEscherichia coliunder anoxic growth
Authors: Momin Huda , Appukuttan Deepti , Venkatesh K.V 
Published: September 2024

AbstractDuring anaerobic batch fermentation byEscherichia coli, there is a decline in cell proliferation rates and a huge demand is placed on cellular proteome to cater its catabolic and anabolic needs under anoxic growth. Previous studies have established a direct relationship betweenE. coligrowth rate and cellular ribosomal content for fast proliferating cells. In this study, we integrated experimental findings with a systemic coarse-grained model of proteome allocation, to characterize the physiological outcomes at slow growth rate during anaerobic fermentative catabolism of different glycolytic and non-glycolytic substrates. The anaerobic catabolism of substrates favored high ribosomal abundances at lower growth rates. Interestingly, a modification of previously discussed “growth law”, the ratio of active to inactive ribosomal proteome was found to be linearly related to growth rate for cells proliferating in slow to moderate regime (growth rate < 0.8 h-1). Also, under nutrient- and oxygen-limited growth conditions, the proteome proportion allocated for ribosomal activity was reduced, and resources were channelized towards catabolic and metabolic activities to overcome the limitations imposed while uptake and metabolizing substrate. The energy intensive uptake mechanism or lower substrate affinity, expended more catabolic proteome, which reduced its availability to other cellular functions. Conclusively, the nature of catabolic substrates imposed either uptake limitation or metabolic limitation coupled with ribosomal limitation (arising due to anoxic and nutritional stress), which resulted in higher proteome expenditure leading to sub-optimal phenotype.
Insights into the triggering factors and determination mechanisms of host alternation in aphids
Authors: Etier Aurelie , Ghosh Rituparna , Vericel Théo , Cloteau Romuald , Denis Gaëtan , Le Floch Maïwenn , Outreman Yannick , Le Trionnaire Gaël , Simon Jean-Christophe 
Published: September 2024

AbstractThe bird cherry-oat aphidRhopalosiphum padi, is one of the ten percent of aphids that are host alternating. The annual life cycle ofR. padientails an obligatory migration between a primary woody host,Prunus padus(Rosaceae), where sexual reproduction occurs, and many secondary hosts of the Poaceae family, where successive generations reproduce parthenogenetically. Migration between the two types of host plants is achieved by specialized migrant morphs. Very little is known about the cues that trigger migrant development, host alternation establishment and the underlying mechanisms. In this study, we aimed to elucidate the key steps involved in migrant induction and determination of host alternation, and to shed light on these intricate processes. We showed that a specific stage of leaf maturity triggers the development into a migrant morph when presented toR. padiat the first or second larval instar stages. We also demonstrated the gradual establishment of acclimation to the secondary hosts that precedes the migration step. Finally, we showed that the switch to feeding on the alternative hosts is irreversible once emigrants have reached adulthood. These results not only allowed us to define the critical periods of the leaf stage associated with morph induction and determination, but also to pinpoint the emigrants’ developmental stages when acclimation to secondary hosts begins. These novel insights of these critical periods will facilitate the investigation of molecular changes associated with host alternation in aphids.
Evaluation of tick salivary and midgut extracellular vesicles as anti-tick vaccines in White-tailed deer (Odocoileus virginianus)
Authors: Gonzalez Julia , Harvey Cristina , de Souza Ribeiro-Silva Cárita , Leal-Galvan Brenda , Persinger Kelly A. , Olafson Pia U. , Johnson Tammi L. , Chavez Adela Oliva 
Published: September 2024

AbstractCurrent tick control measures are focused on the use of synthetic acaricides and personal protective measures. However, the emergence of acaricide resistance and the maintenance of tick populations in wildlife has precluded the efficient management of ticks. Thus, host-targeted, non-chemical control measures are needed to reliably reduce ticks parasitizing sylvatic reservoirs. This project aimed to evaluate extracellular vesicles (EVs) fromAmblyomma americanumas vaccine candidates for white-tailed deer (Odocoileus virginianus; WTD). Salivary gland (SG) and midgut (MG) EVs were isolated by ultracentrifugation. Three deer were vaccinated with SG and MG EVs and received two boosters at days 28 and 50. Two control deer were injected with adjuvant and PBS only. On day 58, WTD were infested with 100A. americanumnymphs, 50 females, and 50 males that were allowed to feed to repletion. On-host and off-host mortality, tick engorgement weight, nymph molting, time to oviposition, and egg hatchability were evaluated. Serum samples were recovered every seven days until the last day of tick drop off, and then at one year (Y1) and 1-year and 1-month (Y1M1). Vaccination resulted in seroconversion and significant increases in total IgG levels that remained significantly higher than controls and pre-vaccination levels at Y1 and Y1M1. No negative effects were observed in nymphs, but on-host mortality of femaleA. americanumwas significantly higher in vaccinated animals. No effects were observed on reproductive parameters. These results indicate that proteins within female tick SG and MG vesicles are not good candidates for vaccine design against nymphs; however, the on-host adult mortality suggests that tick EVs harbor protective antigens againstA. americanumfemales.
Prodrug BMP-7 attenuates pulmonary fibrosis through downregulation of bone marrow derived ApoE+ alveolar macrophage
Authors: Kim Nam Eun , Cho Sue Bean , Shin Mi Hwa , Shim Hyo Sup , Suh Young Joo , Ha Eun Kim , Lee Jin Gu , Han Dawool , Choi Hyun Kyu , Jang Si Hwan , Hwang Sung-Joo , Kim Nam Hee , Yook Jong In , Kim Hyun Sil , Park Moo Suk 
Published: September 2024

AbstractBackgroundBone morphogenetic protein-7 (BMP-7) antagonises transforming growth factor-β (TGF-β). This study investigated the ability of a prodrug BMP-7, designed as micelle nanoparticles for nasal inhalation, to ameliorate pulmonary fibrosis in a bleomycin (BLM)-induced murine model.Materials and MethodsFluorescently labelled BMP-7 was delivered to murine lungs via nasal inhalation. Thirty-eight C57BL/6J mice were divided into three groups: control, BLM and BLM with prodrug BMP-7. We then administered the prodrug BMP-7 and vehicle nasally every 72 hours for 21 days. Single-cell RNA sequencing was performed on bronchoalveolar lavage fluid (BALF) from 18 mice, divided into four groups: control, prodrug BMP-7 alone, BLM and BLM with prodrug BMP-7, to assess effects on alveolar macrophages (AM). The expression of ApoE+ AM was compared between normal and idiopathic pulmonary fibrosis (IPF) patients.ResultsThe prodrug BMP-7 group showed reduced BALF inflammatory cells and significant fibrosis reduction compared to the BLM group. Western blot showed decreased levels of collagen I, α-SMA and fibronectin in the prodrug BMP-7 group, along with downregulation of TGF-β/SMAD signalling. ELISA indicated decreased levels of chemokines CXCL10 and CXCL2 in tissue and BALF. Single-cell RNA sequencing revealed a significant increase in bone marrow-derived ApoE+ AM in the BLM group, which was reduced with prodrug BMP-7. Additionally, ApoE+ expression was higher in IPF patients compared to controls.ConclusionsProdrug BMP-7 shows potential as a therapeutic agent for pulmonary fibrosis by modulating ApoE+ AM.
Characterization and implication of the Orai3 channel and ABC type transporters in the phenomenon of chemoresistance to cisplatin and pemetrexed in lung cancer
Authors: Redoane Daoudi 
Published: September 2024

ABSTRACTOrai3 channels have been associated with cell proliferation, survival and metastasis in several cancers. Previous studies have shown that Orai3 seems to be involved in the development of acquired chemo-resistance of cisplatin in non-small cell lung cancer via ABC transporters that transport certain chemotherapeutic agents, such as cisplatin, out of the cells. Based on these studies, we hypothesize that Orai3 may be involved in the development of acquired chemo-resistance of pemetrexed. By using MTT assay, we show that pemetrexed is efficient (IC50 =0,4µM)and significantly decreases cell viability in a dose dependent manner. Furthermore, we demonstrate using siRNA-mediated Orai3 knockdown that Orai3 silencing has no effect on the chemoresistance against pemetrexed. Then, calcium imaging reveals that pemetrexed doesn’t affect the activity of calcium channels like Orai3. As transcription factors are central to the regulation of gene expression, we wonder if pemetrexed could impact on Orai3 expression. To address the issue,Mn2+-quench assays are performed in siOrai3 transfected A549 cells incubated with1µMpemetrexed for 72h. Finally, RT-PCR is used in order to determine the mRNA expression profile for Orai3 and ABC transporters in A549 cells. We demonstrate that pemetrexed increases Orai3 expression. Taken together, these results suggest that Orai3 is not involved in the development of acquired chemo-resistance of pemetrexed in non- small cell lung cancer. Pemetrexed upregulates Orai3 expression but doesn’t affect the activity of Orai3 channels. As Orai3 channels are known to be involved in the development of acquired chemo-resistance of cisplatin in non-small cell lung cancer, pemetrexed could reduce the therapeutic efficacy of cisplatin if Orai3 protein levels are linked to Orai3 mRNA levels. Moreover, cisplatin has been shown to both increase expression and function of Orai3, resulting in increased chemoresistance. Therefore, our results show that Orai3 could constitute a robust therapeutic target in non-small cells lung cancer.
Heterogeneous Kinetics of Nanobubble Ultrasound Contrast Agent and Angiogenic Signaling in Head and Neck Cancer
Authors: Van Court Benjamin , Ciccaglione Mark , Neupert Brooke , Knitz Michael W. , Maroney Sean P. , Nguyen Diemmy , Abdelazeem Khalid N.M. , Exner Agata A. , Saviola Anthony J. , Benninger Richard K.P. , Karam Sana D. 
Published: September 2024

AbstractRecently developednanobubbleultrasound contrast agents are a promising tool for imaging and drug delivery in tumors. To better understand their unusual kinetics, we implemented a novel pixel clustering analysis, which provides unique information by accounting for spatial heterogeneity. By combining ultrasound results with proteomics of the imaged tumors, we show that this analysis is highly predictive of protein expression and that specific types of nanobubble time-intensity curve are associated with upregulation of different metabolic pathways. We applied this method to study the effects of two proteins, EphB4 and ephrinB2, which control tumor angiogenesis through bidirectional juxtacrine signaling, in mouse models of head and neck cancer. We show that ephrinB2 expression by endothelial cells and EphB4 expression by cancer cells have similar effects on tumor vasculature, despite sometimes opposite effects on tumor growth. This implicates a cancer-cell-intrinsic effect of EphB4 forward signaling and not angiogenesis in EphB4’s action as a tumor suppressor.
In planta transposon sequencing for virulence gene identification inXylella fastidiosa
Authors: Burbank Lindsey , Deyett Elizabeth , Her Nancy , Rodriguez Sydney Helm , Magdeleno Mayra , Rolshausen Philippe E. , Roper Caroline 
Published: September 2024

AbstractIn bacterial genetics, large-scale screening approaches such as sequencing transposon mutant pools can be highly effective for identifying and characterizing genes with unknown functions. In the plant pathogen,Xylella fastidiosa, this approach is challenging due to the fastidious nature of this bacterial species and its niche-specific growth in the plant xylem tissue. The purpose of this study was to explore the feasibility of transposon sequencing (Tnseq) for identification of virulence genes inX. fastidiosa, with the hypothesis that this would uncover genes or pathways not previously associated with plant infection. Predicted essential genes were compared afterX. fastidiosastrain M23 was grownin vitroandin plantausing two known susceptible host species (grapevine and almond). After growthin planta, several gene categories were predicted as essential including hemagglutinins, tRNAs, toxin-antitoxin systems, and prophage genes. Three predicted essential genes (XfasM23_0359, XfasM23_0360, XfasM23_0972) were chosen for further validation by making targeted deletion mutants. Deletion mutants exhibited reduced disease in grapevines, but normal growth and aggregation phenotypesin vitro. Overall, the Tnseq approach has some practical limitations due to the nature of theX. fastidiosapathosystem, and significant bottleneck effects of inoculation, but was still able to identify genes contributing to disease in plants. Recommendations for future Tnseq studies inX. fastidiosaare discussed based on the challenges and results of this work.ImportanceXylella fastidiosais a plant pathogenic bacterial species that causes significant economic damage in multiple agricultural industries. Globally, disease epidemics in citrus, grapes, almonds, and olives launched widespread efforts in pathogen surveillance, and quarantine restrictions on plant commodities. Research efforts onX. fastidiosabiology and pathogenesis have still not yielded many new and effective disease control measures, and management in most areas relies primarily on insect vector control. Expansion of available genetic research tools to include high-throughput mutant screening protocols forin plantaexperiments will facilitate identification of novel disease control targets for this pathogen.
Repetition suppression for mirror images of objects and not Braille letters in the ventral visual stream of congenitally blind individuals
Authors: Korczyk Maksymilian , Rączy Katarzyna , Szwed Marcin 
Published: September 2024

AbstractMirror-invariance effect describes the cognitive tendency to perceive mirror-image objects as identical. Mirrored letters, however, are distinct orthographic units and must be identified as different. Mirror-invariance must be ‘broken’ to enable efficient reading. Consistent with this phenomenon, a small, localized region in the ventral visual stream, the Visual Word Form Area (VWFA), exhibits repetition suppression to identical and mirror pairs of objects but only to identical pairs of letters. The ability of congenitally blind individuals to ‘break’ mirror invariance for pairs of mirrored Braille letters has been demonstrated behaviorally. However, its neural underpinnings have not yet been investigated. Here, in an fMRI repetition suppression paradigm, congenially blind individuals (both sexes) recognized pairs of everyday objects and Braille letters in identical (’p’ & ’p’), mirror (’p’ & ’q’), and different (’p’ & ’z’) orientations. We found repetition suppression for identical and mirror pairs of everyday objects in the parietal and ventral-lateral occipital cortex, indicating that mirror-invariant object recognition engages the ventral visual stream in tactile modality as well. However, repetition suppression for identical but not mirrored pairs of Braille letters was found in the left parietal cortex and the lateral occipital cortex but not in the VWFA. These results suggest notable differences in reading-related orthographic processes between sighted and blind individuals, with the LOC region in the latter being a potential hub for letter-shape processing.Significance StatementMirror invariance is a tendency to recognize rotated objects as identical. Letters are unique shapes as people learn to recognize mirrored letters (e.g., ‘b’ and ‘d’) as distinct objects. In our study, we investigated the neural underpinnings of tactile mirror invariance in congenitally blind individuals. We demonstrated engagement of the parietal, occipital, and ventral visual regions in mirror-invariant tactile object recognition, indicating that this perceptual bias extends beyond the visual modality. Moreover, we found that unlike in the sighted, it was the parietal and lateral occipital cortex that showed neural signatures of breaking mirror invariance for Braille letters in congenitally blind individuals, suggesting substantial differences between visual and tactile reading.
GABAergic neuron dysregulation in a human neurodevelopmental model for major psychiatric disorders
Authors: Guo Ziyuan , Su Yijing , Huang Wei-kai , Yao Xiang Sean , Hong Yan , Gordin Alice , Nguyen Ha Nam , Wen Zhexing , Ringeling Francisca Rojas , Chen Gong , Li Shiying , Lu Lu , Xia Menghang , Zheng Wei , Sawa Akira , Chen Guang , Christian Kimberley M. , Song Hongjun , Ming Guo-li 
Published: September 2024

Abstract“GABA dysfunction” is a major hypothesis for the biological basis of schizophrenia with indirect supporting evidence from human post-mortem brain and genetic studies. Patient-derived induced pluripotent stem cells (iPSCs) have emerged as a valuable platform for modeling psychiatric disorders, and previous modeling has revealed glutamatergic synapse deficits. Whether GABAergic synapse properties are affected in patient-derived human neurons and how this impacts neuronal network activity remain poorly understood. Here we optimized a protocol to differentiate iPSCs into highly enriched ganglionic eminence-like neural progenitors and GABAergic neurons. Using a collection of iPSCs derived from patients of psychiatric disorders carrying aDisrupted-in-Schizophrenia 1(DISC1) mutation and their unaffected family member, together with respective isogenic lines, we identified mutation-dependent deficits in GABAergic synapse formation and function, a phenotype similar to that of mutant glutamatergic neurons. However, mutant glutamatergic and GABAergic neurons contribute differentially to neuronal network excitability and synchrony deficits. Finally, we showed that GABAergic synaptic transmission is also defective in neurons derived from several idiopathic schizophrenia patient iPSCs. Transcriptome analysis further showed some shared gene expression dysregulation, which is more prominent inDISC1mutant neurons. Together, our study supports a functional GABAergic synaptic deficit in major psychiatric disorders.
BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences
Authors: El-Khatib Sanad M. , Vagadia Arya R. , Le Anh C. D. , Ng Ding Quan , Baulch Janet E. , Du Mingyu , Tan Zhiqun , Xu Xiangmin , Chan Alexandre , Acharya Munjal M. 
Published: September 2024

ABSTRACTCranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNFin vivoin the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNFin vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT+Veh with the RT+RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.
Leveraging the Genetics of Psychiatric Disorders to Prioritize Potential Drug Targets and Compounds
Authors: Parker Nadine , Koch Elise , Shadrin Alexey A. , Fuhrer Julian , Hindley Guy F. L. , Stinson Sara , Jaholkowski Piotr , Tesfaye Markos , Dale Anders M. , Wingo Thomas S. , Wingo Aliza P. , Frei Oleksandr , O’Connell Kevin S. , Smeland Olav B. , Andreassen Ole A. 
Published: September 2024

SummaryBackgroundGenetics has the potential to inform biologically relevant drug treatment and repurposing which may ultimately improve patient care. In this study, we combine methods which leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds.MethodsWe used the largest available genome-wide association studies, in European ancestry, of four psychiatric disorders [i.e., attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] along with genes encoding drug targets. With this data, we conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We then conducted a series of molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder.FindingsWe reveal candidate drug targets shared across multiple disorders as well as disorder-specific targets. Drug prioritization indicated genetic support for several currently used psychotropic medications including the antipsychotic paliperidone as the top ranked drug for schizophrenia. We also observed genetic support for other commonly used psychotropics (e.g., clozapine, risperidone, duloxetine, lithium, and valproic acid). Opportunities for drug repurposing were revealed such as cholinergic drugs for ADHD, estrogens for depression, and gabapentin enacarbil for schizophrenia. Our findings also indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression ofCYP2D6,a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission.InterpretationHere we present a series of complimentary and comprehensive analyses that highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders. Our findings present novel opportunities for refining psychiatric treatment.