Pharmacol Res Perspect. 2024 Dec;12(6):e70045. doi: 10.1002/prp2.70045.

ABSTRACT

Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis response can result in anxiety and other neuropsychiatric disorders and effective therapeutics are needed to mitigate this maladaptive response. Here we examined the effects of Teneurin C-terminal Associated Peptide (TCAP)-1, a peptide known to inhibit corticotropin releasing factor (CRF)-mediated stress, on the physiological expression of stress, and whether the effects of TCAP-1 were dependent on the route of administration. We first examined whether subcutaneous administration of TCAP-1 influenced tube restraint stress-induced corticosterone (CORT) increases in both male mice and rats. Using a similar model, we further examined the efficacy and time course of intranasal TCAP-1. Results showed that subcutaneous TCAP-1 administration attenuated the expression of the physiological manifestation of stress in male mice and rats, and that intranasal TCAP-1 delivered prophylactically is effective at attenuating stress-induced CORT increases in male rats. These data indicate that TCAP-1 delivered though non-invasive routes of administration could have potential as a clinically relevant anxiolytic.

PMID:39651597 | DOI:10.1002/prp2.70045

bioRxiv [Preprint]. 2024 Nov 27:2024.11.27.625729. doi: 10.1101/2024.11.27.625729.

ABSTRACT

Platelets fulfill their essential physiological roles sensing the extracellular environment through their membrane proteins. The native membrane environment provides essential regulatory cues that impact the protein structure and mechanism of action. Single-particle cryogenic electron microscopy (cryo-EM) has transformed structural biology by allowing high-resolution structures of membrane proteins to be solved from homogeneous samples. Our recent breakthroughs in data processing now make it feasible to obtain atomic-level-resolution protein structures from crude preparations in their native environments by integrating cryo-EM with the "Build-and-Retrieve" (BaR) data processing methodology. We applied this iterative bottom-up methodology on resting human platelet membranes for an in-depth systems biology approach to uncover how lipids, metal binding, post-translational modifications, and co-factor associations in the native environment regulate platelet function at the molecular level. Here, we report using cryo-EM followed by the BaR method to solve the first unmodified integrin αIIbβ3 structure directly from resting human platelet membranes in its inactivated and intermediate states at 2.75Å and 2.67Å, respectively. Further, we also solved a novel dimer conformation of αIIbβ3 at 2.85Å formed by two intermediate-states of αIIbβ3. This may indicate a previously unknown self-regulatory mechanism of αIIbβ3 in its native environment. In conclusion, our data show the power of using cryo-EM with the BaR method to determine three distinct structures including a novel dimer directly from natural sources. This approach allows us to identify unrecognized regulation mechanisms for proteins without artifacts due to purification processes. These data have the potential to enrich our understanding of platelet signaling circuitry.

PMID:39651215 | PMC:PMC11623648 | DOI:10.1101/2024.11.27.625729

iScience. 2024 Nov 6;27(12):111339. doi: 10.1016/j.isci.2024.111339. eCollection 2024 Dec 20.

ABSTRACT

As the global population continues to grow, so does the demand for longer, healthier lives and environmentally responsible choices. Consumers are increasingly drawn to naturally sourced products with proven health and wellbeing benefits. The marine environment presents a promising yet underexplored resource for the cosmetics industry, offering bioactive compounds with the potential for safe and biocompatible ingredients. This manuscript provides a comprehensive overview of the potential of marine organisms for cosmetics production, highlighting marine-derived compounds and their applications in skin/hair/oral-care products, cosmeceuticals and more. It also lays down critical safety considerations and addresses the methodologies for sourcing marine compounds, including harvesting, the biorefinery concept, use of systems biology for enhanced product development, and the relevant regulatory landscape. The review is enriched by three case studies: design of macroalgal skincare products in Iceland, establishment of a microalgal cosmetics spin-off in Italy, and the utilization of marine proteins for cosmeceutical applications.

PMID:39650733 | PMC:PMC11625311 | DOI:10.1016/j.isci.2024.111339

iScience. 2024 Nov 9;27(12):111351. doi: 10.1016/j.isci.2024.111351. eCollection 2024 Dec 20.

ABSTRACT

Prostate cancer (PCa) exhibits significant intratumor heterogeneity, frequently manifesting as a multifocal disease. This study utilized Visium spatial transcriptomics (ST) to explore transcriptome patterns in PCa regions with varying Gleason scores (GSs). Principal component analysis (PCA) and Louvain clustering analysis revealed transcriptomic classifications aligned with the histology of different GSs. The increasing degree of tumor malignancy during GS progression was validated using inferred copy number variation (inferCNV) analysis. Diffusion pseudotime (DPT) and partition-based graph abstraction (PAGA) analyses predicted the developmental trajectories among distinct clusters. Differentially expressed gene (DEG) analysis through pairwise comparisons of various GSs identified genes associated with GS progression. Validation with The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset confirmed the differential expression of RBM39, a finding further supported by cytological and histological experiments. These findings enhance our understanding of GS evolution through spatial transcriptomics and highlight RBM39 as a gene associated with GS progression.

PMID:39650727 | PMC:PMC11625293 | DOI:10.1016/j.isci.2024.111351

Sovrem Tekhnologii Med. 2024;16(3):12-22. doi: 10.17691/stm2024.16.3.02. Epub 2024 Jun 28.

ABSTRACT

The aim of the study is to develop an experimental method to effectively assess the working memory in rats. The method uses a state-of-the-art controlled virtual environment with a virtual maze. The setup includes a treadmill for rodents, a fixation system, a dome for displaying virtual environment, and a control unit.

MATERIALS AND METHODS: Biological part of the investigation: In our study, young healthy Wistar rats aged 6-7 months were used. The initial stage involved habituating the experimental animals to the experimenter over a period of two weeks. The habituation process was conducted in several successive steps. First, the rats were acclimated to wearing a jacket, which is part of the apparatus that holds the animal in the experimental setup. Next, they were familiarized with the fixation system. Following this, the rats were introduced to the treadmill (a sphere), and finally, they were acclimated to the entire setup. Subsequently, the rats were gradually habituated to the virtual maze and the associated reward system through positive reinforcement. This approach helped minimize stress and facilitated their adaptation to the new conditions. The second stage involved exploring the virtual space and learning the features of the virtual maze, including walls, turns, and the end goal. During the learning phase, the animals received positive reinforcement in the form of sugared water from the automatic water dispenser for correctly performed tasks. To navigate the T-maze, the rats used visual cues such as wall color and figures on the wall. At this stage, the rats learned to use virtual space to achieve their goals. Once the rats showed evident progress in learning the virtual environment, we implemented a protocol to assess their working memory. This assessment was based on the time it took for the rats to find the maze arm that provided positive reinforcement.Engineering part of the investigation: The animal is positioned on a foam plastic sphere with a 30 cm radius, using a custom device that allows its head and paws to remain mobile. Bearing fix the sphere in place, enabling the rat to rotate freely around its vertical axis. The rat's forward and backward movements cause the sphere to rotate, simulating a treadmill. The sphere's movements are detected by two infrared sensors (adapted from optical LED mice with USB interfaces) and transmitted to a computer, which generates an image of the virtual environment - a maze with landmarks on its walls. The virtual environment, created using the Unity Real-Time 3D Development Platform, is projected onto a custom-designed dome display containing the sphere and the lab rat. The setup provided the rat with a 360° field of view.

CONCLUSION: In our study, we present a setup that includes a projector, a dome display, a sphere (treadmill), a virtual T-maze, motion capture sensors, systems for securing animals to the sphere, and positive reinforcement delivery systems. We have developed an optimal protocol for immersing laboratory animals into a virtual environment and evaluating their cognitive functions, particularly working memory. The application of virtual reality in biological experiments enables more precise control over study conditions and allows for the creation of highly accurate and realistic behavioral protocols to assess cognitive functions in animals. This approach enhances our understanding of the mechanisms underlying working memory and their relationship with behavioral processes in rats and other animals.

PMID:39650274 | PMC:PMC11618531 | DOI:10.17691/stm2024.16.3.02

Front Neurol. 2024 Nov 22;15:1476708. doi: 10.3389/fneur.2024.1476708. eCollection 2024.

ABSTRACT

BACKGROUND: Paper symptom diaries are a common tool for assessing motor fluctuations in Parkinson's disease (PD) patients, but there are concerns about inaccuracies in the assessment of motor fluctuation due to recall bias and poor compliance. We, therefore, developed an electronic diary with reminder and real-time recording functions.

OBJECTIVES AND METHODS: To evaluate the effectiveness of the electronic diary, we compared compliance and motor fluctuation assessment with a paper diary. Nineteen PD patients were recruited and recorded paper diaries every 30 min from 8 am to 8 pm for 7 days, followed by 7 days of electronic diary recording using a smartphone and smartwatch. Prior to the recording period, the Parkinson's Disease Questionnaire (PDQ)-39 and the Movement Disorders Society-sponsored Unified Parkinson's Disease Rating Scale-Revised (MDS-UPDRS) 1, 2, 3, 4 were measured. Patients completed a patient questionnaire on the usability of the diaries after the recording period.

RESULTS: Total reported time was significantly longer in paper diaries, but there was no significant difference in the number of entries (paper 115 [71-147] vs. electronic 109 [93-116], p = 0.77). There was a significant correlation between paper and electronic diaries with respect to motor status. ON time rate recorded in the electronic diary was significantly correlated with PDQ-39, MDS-UPDRS 1, 2, and 4, while MDS-UPDRS 1 was only correlated with ON time rate in the paper diary. The usability of our electronic diary was found to be satisfactory based on the results of patient questionnaire.

CONCLUSION: Electronic diaries are useful tools that more accurately reflect PD motor fluctuations.

PMID:39650241 | PMC:PMC11622251 | DOI:10.3389/fneur.2024.1476708

Oncol Lett. 2024 Nov 26;29(2):77. doi: 10.3892/ol.2024.14823. eCollection 2025 Feb.

ABSTRACT

Cervical cancer (CC) is the fourth leading cause of cancer-associated mortalities among women worldwide. The chemotherapeutical platinum-based agent cisplatin (DDP) is the standard therapy for locally advanced or recurrent CC; however, platinum resistance limits its clinical benefit. Therefore, the present study aimed to identify key genes associated with DDP resistance in patients with CC and investigate the underlying molecular mechanisms. Firstly, using the CRISPR-Cas9 dataset of CC cells derived from DepMap portal, 699 genes associated with CC cell survival were identified. Subsequently, using the gene expression profiles of normal and CC samples with a response status to DDP, derived from The Cancer Genome Atlas (TCGA), hypoxia upregulated 1 (HYOU1) was further identified as significantly upregulated in CC samples and patients that did not respond to DDP (non-responders) when compared with healthy controls and patients that did respond to DDP (responders), respectively, using unpaired student's t-tests. Additionally, the log-rank test revealed that the high expression of HYOU1 was significantly associated with the poor survival of patients receiving DDP. The association between the high HYOU1 expression levels and the poor survival of patients receiving DDP was validated in the remaining TCGA dataset of patients with CC. HYOU1 expression levels were positively associated with the half-maximal inhibitory concentration value of DDP in CC cells using data derived from the Genomics of Drug Sensitivity in Cancer database. In vitro, western blotting experiments revealed high HYOU1 protein expression levels in DDP-resistant HeLa cells compared with their parental HeLa cells. Furthermore, the knockdown of HYOU1 resulted in an increased sensitivity of HeLa cells to DDP. Finally, using the sequence-based RNA adenosine methylation site predictor program, it was found that N6-methyladenosine (m6A) was highly enriched in HYOU1. The expression levels of the m6A reader, EIF3A, was positively correlated with the expression levels of HYOU1 and was upregulated in the non-response group compared with the response group in a dataset from TCGA database. Additionally, EIF3A had the highest probability of binding to the m6A motifs of HYOU1 compared with other genes. In GSE56363 obtained from the Gene Expression Omnibus, the non-responders had significantly increased expression levels of EIF3A compared with the responders. In conclusion, high expression levels of HYOU1, which may be regulated by EIF3A due to m6A modifications, was associated with DDP resistance in patients with CC and could potentially be used as an indicator of DDP treatment resistance.

PMID:39650230 | PMC:PMC11622003 | DOI:10.3892/ol.2024.14823

Genes Dis. 2024 Jun 14;12(2):101349. doi: 10.1016/j.gendis.2024.101349. eCollection 2025 Mar.

NO ABSTRACT

PMID:39649843 | PMC:PMC11625315 | DOI:10.1016/j.gendis.2024.101349

New Phytol. 2024 Dec 8. doi: 10.1111/nph.20334. Online ahead of print.

ABSTRACT

A unique cell size-sensing mechanism is at the heart of the life cycle of diatoms. During population growth, cell size decreases until a sexual size threshold (SST) is reached, below which cells become sexually competent. In most pennate diatoms, the two mating types undergo biochemical and behavioral differentiation below the SST, although the molecular pathways underlying their size-dependent maturation remain unknown. Here, we developed a method to shorten the generation time of Cylindrotheca closterium through single-cell microsurgery, enabling the transcriptomic comparison of genetically identical large and undifferentiated cells with small, sexually competent cells for six different genotypes. We identified 21 genes upregulated in small cells regardless of their mating type, revealing how cells undergo specific transcriptional reprogramming when passing the SST. Furthermore, we revealed a size-regulated gene cluster with three mating type-specific genes susceptible to sex-inducing pheromones. In addition, comparative transcriptomics confirmed the shared mating type specificity of Mating-type Related Minus 2 homologs in three pennate diatoms, suggesting them to be part of a conserved partner recognition mechanism. This study sheds light on how diatoms acquire sexual competence in a strictly size-dependent manner, revealing a complex machinery underlying size-dependent maturation, mating behavior, and heterothally in pennate diatoms.

PMID:39648404 | DOI:10.1111/nph.20334

J Virol Methods. 2024 Dec 6:115096. doi: 10.1016/j.jviromet.2024.115096. Online ahead of print.

ABSTRACT

The surface of HIV-1 is embedded with numerous host-derived proteins. Characterizing these proteins can enhance knowledge of virus biology and potentially identify novel therapeutic targets. As many of these proteins are present in low abundance on virion surfaces, their identification can be hindered by inherent variables in the methods employed to detect them, including their varying assay sensitivities, sample processing, quantitative capacity, and experimental reproducibility. Here, we have compared the quantification of virion-incorporated proteins using conventional virus immunocapture assays and western blotting, alongside an emerging technique called flow virometry (FV). Using four different pseudovirus models that each express a human protein of interest (CD14, CD38, CD59 and CD162), we compared four experimental techniques for their ability to reliably quantify the incorporation of those four proteins onto virion surfaces. Our results shed light on the advantages and caveats of each technique for detecting virion-incorporated proteins and highlight the breadth in quantification for each technique under different experimental conditions. Protein detection with flow virometry provided distinct advantages as it enabled highly reproducible quantifications, had the lowest sample requirements and reagent costs, and minimal hands-on experimental time. We additionally highlight some important considerations in experimental design when studying virion-incorporated proteins, such as the effect of different antibody clones, assay incubation times, and contributions of extracellular vesicles. Most importantly, our data illustrate the importance of using a combination of orthogonal approaches to detect virus-associated proteins, to enable reliable and reproducible quantification that accounts for individual assay biases.

PMID:39647666 | DOI:10.1016/j.jviromet.2024.115096

J Dairy Sci. 2024 Dec 6:S0022-0302(24)01374-2. doi: 10.3168/jds.2024-25578. Online ahead of print.

ABSTRACT

Efforts to optimize the longevity of dairy cows are hindered by the increased risk of adverse health events, culling or dying on farm with increased parity. Lipidomics provides a platform to help identify important biomarkers and biological pathways associated with increased parity and associated aging. A large, multi-site (15 pasture-based, 15 TMR farms) cross-sectional study collected plasma samples from nonlactating, late pregnant, 'dry' cow (696 cows, ~27 d prepartum) and peak-milk cows (796 cows, ~58 DIM) in a disproportionate stratified (parity: 0, 1, 2, > 2 for dry cows; 1, 2, 3, > 3 for peak-milk cows) random sampling frame. A total of 185 lipid species, comprising the lipids classes of phospholipids, sphingomyelins (SM) and triacylglycerols, were quantified in a targeted, liquid chromatography-mass spectrometry (LC-MS) approach. Dry and peak-milk cohorts were analyzed separately throughout. Variation in lipid profiles was mostly attributed to farm of origin (36-41% of variation), with feeding system explaining 13-21% and parity 6-9%, according to ANOVA simultaneous component analysis (ASCA) modeling. Multiple linear regression (MLR) and orthogonal-partial least squares (O-PLS) investigated the association of the lipid profile with age (d), while discriminate analysis compared 1st parity with > 3 parity cows in O-PLS discriminate analysis (O-PLS-DA), random forest (RF) and support vector machine (SVM) models. Rankings of the most important lipid species for each model type were compared. Phospholipids with 40 carbon atoms and 6 double bond equivalents (40:6) were consistently decreased with increasing parity and age across both dry and peak-milk cohorts. These lipids most likely contained stearate (18:0) and docosahexaenoic acid (DHA, C22:6;n-3), an omega-3 fatty acid. Additionally, phospholipids with 40:5, 38:6, lysophosphatidylcholine (17:0), SM(35:1), and SM(35:2) were commonly identified lipids that decreased in concentration with parity and age. Docosahexaenoic acid has been associated with improved cattle health, reproduction, and milk production and quality. This study raises the hypothesis that reduced DHA levels in older cows may be a significant factor increasing susceptibility to adverse health events, reduced reproductive performance, and herd removal. Studies that supplement DHA or its precursors can test this hypothesis and may be important in optimizing longevity of cows.

PMID:39647623 | DOI:10.3168/jds.2024-25578

Plant J. 2024 Dec 8. doi: 10.1111/tpj.17204. Online ahead of print.

ABSTRACT

The implementation of genome editing strategies in grapevine is the easiest way to improve sustainability and resilience while preserving the original genotype. Among others, the Mildew Locus-O (MLO) genes have already been reported as good candidates to develop powdery mildew-immune plants. A never-explored grapevine target is NPR3, a negative regulator of the systemic acquired resistance. We report the exploitation of a cisgenic approach with the Cre-lox recombinase technology to generate grapevine-edited plants with the potential to be transgene-free while preserving their original genetic background. The characterization of three edited lines for each target demonstrated immunity development against Erysiphe necator in MLO6-7-edited plants. Concomitantly, a significant improvement of resilience, associated with increased leaf thickness and specific biochemical responses, was observed in defective NPR3 lines against E. necator and Plasmopara viticola. Transcriptomic analysis revealed that both MLO6-7 and NPR3 defective lines modulated their gene expression profiles, pointing to distinct though partially overlapping responses. Furthermore, targeted metabolite analysis highlighted an overaccumulation of stilbenes coupled with an improved oxidative scavenging potential in both editing targets, likely protecting the MLO6-7 mutants from detrimental pleiotropic effects. Finally, the Cre-loxP approach allowed the recovery of one MLO6-7 edited plant with the complete removal of transgene. Taken together, our achievements provide a comprehensive understanding of the molecular and biochemical adjustments occurring in double MLO-defective grape plants. In parallel, the potential of NPR3 mutants for multiple purposes has been demonstrated, raising new questions on its wide role in orchestrating biotic stress responses.

PMID:39645650 | DOI:10.1111/tpj.17204

J Cardiothorac Vasc Anesth. 2024 Nov 12:S1053-0770(24)00888-7. doi: 10.1053/j.jvca.2024.11.010. Online ahead of print.

ABSTRACT

OBJECTIVES: Optimal blood pressure goals during cardiopulmonary bypass (CPB) remain uncertain and new metrics to individualize perfusion targets are needed. Critical closing pressure (Pcrit) is a fundamental property of the arterial circulation related to vascular tone and represents the outflow pressure impacting flow across the systemic circulation. We examined Pcrit as a prognostic marker of acute kidney injury (AKI).

DESIGN: Retrospective cohort study.

SETTING: Single tertiary care hospital PARTICIPANTS: We included 1,038 adult cardiac surgery patients who underwent CPB.

INTERVENTIONS: Pcrit was calculated using arterial waveform data before initiation of CPB. Pcrit was examined in relation to incidence of stage 2 or higher postoperative AKI according to standard Kidney Disease Improving Global Outcomes definitions.

MEASUREMENTS AND MAIN RESULTS: Of the 1,038 patients included in the study, 50 (5%) experienced AKI. Patients who suffered AKI had significantly higher preoperative risk factors, including higher incidence of severe chronic kidney disease and higher Society of Thoracic Surgeons risk score (p < 0.01). They also had longer operative times and longer cross-clamp times (p < 0.01). All patients were maintained at similar mean arterial pressure while on CPB. Patients who suffered AKI had a significantly higher prebypass Pcrit than those who did not (49.0 mmHg vs 44.1 mmHg; p = 0.018). In a multivariate regression, Pcrit remained a significant predictor, representing a 16% increased risk of AKI for each 5 mmHg increase in prebypass Pcrit (p = 0.011).

CONCLUSIONS: A higher prebypass Pcrit is associated with a significantly higher incidence of postoperative AKI. Future study is warranted to investigate using intraoperative Pcrit to determine a personalized blood pressure goal during CPB.

PMID:39645444 | DOI:10.1053/j.jvca.2024.11.010

Infect Genet Evol. 2024 Dec 5:105695. doi: 10.1016/j.meegid.2024.105695. Online ahead of print.

ABSTRACT

The prevalence and evolution of foamy viruses (FVs) have become the focus of research because of the risk of new zoonotic diseases. FVs have been isolated from various mammals and exhibit long-term co-speciation with their hosts. They also appear to be mild and nonpathogenic to their hosts. However, they may increase the risk of infection by other pathogens or exacerbate the symptoms of other diseases. Based on the data obtained using next-generation sequencing (NGS), we amplified and obtained the complete genomes of the two new FVs discovered in the bottlenose dolphin (Tursiops truncatus) and the South American sea lion (Otaria byronia) at the Qingdao Polar Haichang Ocean Park. Analysis and prediction of the novel FV's genomic structure revealed that it was consistent with that of the known mammalian FVs. The polmerase (pol) genes of the novel OFVoby_1 and DFVttr_1 showed less than 61.87 % and 61.83 % amino acid identity, respectively, with other known FVs belonging to the Retroviridae family. The host was likely to carry the FV for a considerable amount of time, as evidenced by the different times DFVttr_1 was discovered. The phylogenetic analysis revealed that the pol of OFVoby_1 and DFVttr_1 closely clustered with the FVs of Simiispumavirus and Felispumavirus, respectively. However, they both displayed distinct branches. According to the international committee on taxonomy of viruses (ICTV) FV classification criteria, FVs carried by dolphins and sea lions belong to two new genera within the Spumaretrovirinae subfamily. Using Bayesian analysis to simultaneously determine divergence dates and phylogenetic relationships revealed unique FVs with a divergence date of approximately 60 million years. This study helps us understand the FVs evolution and provides a scientific basis for future investigations into animal-borne infectious diseases.

PMID:39644946 | DOI:10.1016/j.meegid.2024.105695

Cell Rep Methods. 2024 Nov 28:100913. doi: 10.1016/j.crmeth.2024.100913. Online ahead of print.

ABSTRACT

Decoding cellular state transitions is crucial for understanding complex biological processes in development and disease. While recent advancements in single-cell RNA sequencing (scRNA-seq) offer insights into cellular trajectories, existing tools primarily study expressional rather than regulatory state shifts. We present CellTran, a statistical approach utilizing paired-gene expression correlations to detect transition cells from scRNA-seq data without explicitly resolving gene regulatory networks. Applying our approach to various contexts, including tissue regeneration, embryonic development, preinvasive lesions, and humoral responses post-vaccination, reveals transition cells and their distinct gene expression profiles. Our study sheds light on the underlying molecular mechanisms driving cellular state transitions, enhancing our ability to identify therapeutic targets for disease interventions.

PMID:39644902 | DOI:10.1016/j.crmeth.2024.100913

Cell. 2024 Dec 3:S0092-8674(24)01276-5. doi: 10.1016/j.cell.2024.11.002. Online ahead of print.

ABSTRACT

Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.

PMID:39644898 | DOI:10.1016/j.cell.2024.11.002

Dev Cell. 2024 Nov 29:S1534-5807(24)00674-9. doi: 10.1016/j.devcel.2024.11.009. Online ahead of print.

ABSTRACT

How do growth hormones interact to specify female-germline cell types in flowering plants and control production of the first female-germline cell? Here, we find that gibberellin (GA) biosynthesis and signaling are restricted in ovule primordia, with overexpression of receptors and biosynthetic enzymes resulting in multiple and enlarged megaspore mother cells (MMCs) in Arabidopsis. GA signaling machinery interacts with and promotes the degradation of cytokinin (CK) type-B Arabidopsis response regulators (ARR1/10/12), which also directly interact with DELLA proteins. CK biosynthesis and signaling components are expressed in both MMCs and sporophytic cells, with signaling negatively controlled by GA in ovule primordia, and perturbations leading to the induction of multiple, enlarged MMC-like cells. The vacuolar sorting protein SHRUBBY (SHBY) interacts with GA and CK signaling components to block GA-induced degradation. CK signaling restricts multiple sub-epidermal cells in distal ovule primordia from acquiring MMC identity. By balancing degradation activity, GA and CK signaling antagonistically control female-germline cell specification.

PMID:39644895 | DOI:10.1016/j.devcel.2024.11.009

J Pharm Biomed Anal. 2024 Nov 28;255:116588. doi: 10.1016/j.jpba.2024.116588. Online ahead of print.

ABSTRACT

Artemisia species have been regarded as an important source of ethnic medicinal plants, such as A. annua and A. capillaris, both of which are widely used in clinical treatment. The clinical efficacy of A. japonica is similar to that of A. capillaris, but fewer pharmaceutical studies have been reported. Given that the extracts of A. japonica were observed to reduce the rectal temperature of febrile rats induced by LPS, this study was designed to demonstrate this regulatory effect of the extracts, with a particular focus on the lipidomic profiling of the febrile rat hypothalamus. A total of 72 differential metabolites were filtered out and the association between lipid profiling and potential mechanism was explored. Sphingolipid, glycerophospholipid, arachidonic acid and ether lipid metabolism pathways were significantly enriched. TNF-α, IL-6 and PGE2 cytokines in the hypothalamus were significantly downregulated by the intervention of the extracts of A. japonica. Enzymatic reaction enrichment analysis suggested that PEMT and COX-2 might be potential targets of the efficacy, and which were testified to be downregulated by the ELISA assay under the extracts intervention.

PMID:39644683 | DOI:10.1016/j.jpba.2024.116588

J Agric Food Chem. 2024 Dec 7. doi: 10.1021/acs.jafc.4c08110. Online ahead of print.

ABSTRACT

Triterpenoids are the major active constituents of licorice, a well-known traditional medicinal herb. Licorice triterpenoids, represented by glycyrrhizin and glycyrrhetic acid, have a high structural diversity and are excellent lead compounds for the development of potent pharmaceuticals. However, their further application can be limited by insufficient activities, low bioavailability, and the presence of side effects, as well as the inefficiency of traditional plant extraction processes for compound production. To address these issues, researchers are focusing on rare triterpenoid components in the genus Glycyrrhiza and developing derivatives to preserve or enhance the original physiological activities with improved bioavailability and reduced side effects. At the same time, synthetic biology offers opportunities to shorten the production cycle, create eco-friendly manufacturing processes, and reduce the cost of producing licorice triterpenoids. Although much progress has been achieved in this field in recent years, there is still a lack of a comprehensive review to summarize the overall characteristics of licorice triterpenoids rather than glycyrrhizin and glycyrrhetinic acid. Based on this, our review comprehensively outlines the structures, origins, and pharmacological activities of licorice triterpenoids and predicts their pharmacological activities using the drugCIPHER algorithm. Furthermore, this paper reviews the advances and strategies for the biomanufacturing of licorice triterpenoids using synthetic biology methods and outlines the perspectives and structure-activity relationships for the derivatization of licorice triterpenoids. This review provides new insights into the discovery and synthesis of pharmaceuticals derived from natural triterpenes.

PMID:39644261 | DOI:10.1021/acs.jafc.4c08110

STAR Protoc. 2024 Dec 5;5(4):103469. doi: 10.1016/j.xpro.2024.103469. Online ahead of print.

ABSTRACT

Measuring the electrophysiological responses of olfactory receptor neurons (ORNs) to odorants in spotted lanternfly (SLF) (Lycorma delicatula) is crucial for understanding how this invasive sap-feeding planthopper locates host plants, aggregates, and mates. Here, we present a protocol for single sensillum recording from SLF labial ORNs to measure their sensitivity, specificity, and response dynamics to odorants. We describe the steps for preparing odorant cartridges, mounting the labium, setting up the electrophysiology rig, recording neuronal responses to odorants, and analyzing data. For complete details on the use and execution of this protocol, please refer to Dweck and Claire.1.

PMID:39643964 | DOI:10.1016/j.xpro.2024.103469