Semin Thromb Hemost. 2024 Aug 27. doi: 10.1055/s-0044-1789183. Online ahead of print.

ABSTRACT

von Willebrand disease (VWD) is the most common well-studied genetic bleeding disorder worldwide. Much less is known about platelet-type VWD (PT-VWD), a rare platelet function defect, and a "nonidentical" twin bleeding phenotype to type 2B VWD (2B-VWD). Rather than a defect in the von Willebrand factor (VWF) gene, PT-VWD is caused by a platelet GP1BA mutation leading to a hyperaffinity of the glycoprotein Ibα (GPIbα) platelet surface receptor for VWF, and thus increased platelet clearing and high-molecular-weight VWF multimer elimination. Nine GP1BA gene mutations are known. It is historically believed that this enhanced binding was enabled by the β-switch region of GPIbα adopting an extended β-hairpin form. Recent evidence suggests the pathological conformation that destabilizes the compact triangular form of the R-loop-the GPIbα protein's region for VWF binding. PT-VWD is often misdiagnosed as 2B-VWD, even the though distinction between the two is crucial for proper treatment, as the former requires platelet transfusions, while the latter requires VWF/FVIII concentrate administration. Nevertheless, these PT-VWD treatments remain unsatisfactory, owing to their high cost, low availability, risk of alloimmunity, and the need to carefully balance platelet administration. Antibodies such as 6B4 remain undependable as an alternative therapy due to their questionable efficacy and high costs for this purpose. On the other hand, synthetic peptide therapeutics developed with In-Silico Protein Synthesizer to disrupt the association between GPIbα and VWF show preliminary promise as a therapy based on in vitro experiments. Such peptides could serve as an effective diagnostic technology for discriminating between 2B-VWD and PT-VWD, or potentially all forms of VWD, based on their high specificity. This field is rapidly growing and the current review sheds light on the complex pathology and some novel potential therapeutic and diagnostic strategies.

PMID:39191406 | DOI:10.1055/s-0044-1789183

Behav Brain Res. 2024 Aug 25:115215. doi: 10.1016/j.bbr.2024.115215. Online ahead of print.

ABSTRACT

Pain is a crucial protective mechanism for the body. It alerts us to potential tissue damage or injury and promotes the avoidance of harmful stimuli. Injury-induced inflammation and tissue damage lead to pain sensitization, which amplifies responses to subsequent noxious stimuli even after an initial primary injury has recovered. This phenomenon, commonly referred to as hyperalgesic priming, was investigated in male and female mice to determine whether it is specific to the site of previous injury. We used 10μl of 50% Freund's complete adjuvant (CFA) administered to the left hind paw as a model of peripheral injury. Both male and female mice exhibited robust site-specific mechanical hypersensitivity after CFA, which resolved within one-week post-injection. After injury resolution, only male CFA-primed mice showed enhanced and prolonged mechanical sensitivity in response to a chemical challenge or a single 0.5mA electric footshock. Among CFA-primed male mice, shock-induced mechanical hypersensitivity was expressed in both the left (previously injured) and the right (uninjured) hind paws, suggesting a pivotal role for altered centralized processes in the expression of pain sensitization. These findings indicate that pain history regulates sensory responses to subsequent mechanical and chemical pain stimuli in a sex-specific manner-foot-shock-induced hyperalgesic priming expression among male mice generalized beyond the initial injury site.

PMID:39191370 | DOI:10.1016/j.bbr.2024.115215

Dev Cell. 2024 Aug 23:S1534-5807(24)00484-2. doi: 10.1016/j.devcel.2024.08.001. Online ahead of print.

ABSTRACT

To ensure an even segregation of chromosomes during somatic cell division, eukaryotes rely on mitotic spindles. Here, we measured prime characteristics of the Arabidopsis mitotic spindle and built a three-dimensional dynamic model using Cytosim. We identified the cell-cycle regulator CYCLIN-DEPENDENT KINASE B1 (CDKB1) together with its cyclin partner CYCB3;1 as key regulators of spindle morphology in Arabidopsis. We found that the augmin component ENDOSPERM DEFECTIVE1 (EDE1) is a substrate of the CDKB1;1-CYCB3;1 complex. A non-phosphorylatable mutant rescue of ede1 resembled the spindle phenotypes of cycb3;1 and cdkb1 mutants and the protein associated less efficiently with spindle microtubules. Accordingly, reducing the level of augmin in simulations recapitulated the phenotypes observed in the mutants. Our findings emphasize the importance of cell-cycle-dependent phospho-control of the mitotic spindle in plant cells and support the validity of our model as a framework for the exploration of mechanisms controlling the organization of the eukaryotic spindle.

PMID:39191252 | DOI:10.1016/j.devcel.2024.08.001

Prev Vet Med. 2024 Aug 23;232:106328. doi: 10.1016/j.prevetmed.2024.106328. Online ahead of print.

ABSTRACT

Bluetongue virus (BT) is a vector-borne virus that causes a disease, called bluetongue, which results in significant economic loss and morbidity in sheep, cattle, goats and wild ungulates across all continents of the world except Antarctica. Despite the geographical breadth of its impact, most BT epidemiological models are informed by parameters derived from the 2006-2009 BTV-8 European outbreak. The aim of this study was to develop a highly adaptable model for BT which could be used elsewhere in the world, as well as to identify the parameters which most influence outbreak dynamics, so that policy makers can be properly informed with the most current information to aid in disease planning. To provide a framework for future outbreak modelling and an updated parameterisation that reflects natural variation in infections, a newly developed and parameterised two-host, two-vector species ordinary differential equation model was formulated and analysed. The model was designed to be adaptable to be implemented in any region of the world and able to model both epidemic and endemic scenarios. It was parameterised using a systematic literature review of host-to-vector and vector-to-host transmission rates, host latent periods, host infectious periods, and vaccine protection factors. The model was demonstrated using the updated parameters, with South Africa as a setting based on the Western Cape's known cattle and sheep populations, local environmental parameters, and Culicoides spp. presence data. The sensitivity analysis identified that the duration of the infectious period for sheep and cows had the greatest impact on the outbreak length and number of animals infected at the peak of the outbreak. Transmission rates from cows and sheep to C. imicola midges greatly influenced the day on which the peak of the outbreak occurred, along with the duration of incubation period, and infectious period for cows. Finally, the protection factor of the vaccine had the greatest influence on the total number of animals infected. This knowledge could aid in the development of control measures. Due to gradual climate and anthropological change resulting in alterations in vector habitat suitability, BT outbreaks are likely to continue to increase in range and frequency. Therefore, this research provides an updated BT modelling framework for future outbreaks around the world to explore transmission, outbreak dynamics and control measures.

PMID:39191049 | DOI:10.1016/j.prevetmed.2024.106328

Leukemia. 2024 Aug 27. doi: 10.1038/s41375-024-02392-7. Online ahead of print.

ABSTRACT

Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.

PMID:39192036 | DOI:10.1038/s41375-024-02392-7

Mamm Genome. 2024 Aug 27. doi: 10.1007/s00335-024-10066-z. Online ahead of print.

ABSTRACT

The goal of systems biology is to gain a network level understanding of how gene interactions influence biological states, and ultimately inform upon human disease. Given the scale and scope of systems biology studies, resource constraints often limit researchers when validating genome-wide phenomena and potentially lead to an incomplete understanding of the underlying mechanisms. Further, prioritization strategies are often biased towards known entities (e.g. previously studied genes/proteins with commercially available reagents), and other technical issues that limit experimental breadth. Here, heterogeneous biological information is modeled as an association graph to which a high-performance minimum dominating set solver is applied to maximize coverage across the graph, and thus increase the breadth of experimentation. First, we tested our model on retrieval of existing gene functional annotations and demonstrated that minimum dominating set returns more diverse terms when compared to other computational methods. Next, we utilized our heterogenous network and minimum dominating set solver to assist in the process of identifying understudied genes to be interrogated by the International Mouse Phenotyping Consortium. Using an unbiased algorithmic strategy, poorly studied genes are prioritized from the remaining thousands of genes yet to be characterized. This method is tunable and extensible with the potential to incorporate additional user-defined prioritizing information. The minimum dominating set approach can be applied to any biological network in order to identify a tractable subset of features to test experimentally or to assist in prioritizing candidate genes associated with human disease.

PMID:39191873 | DOI:10.1007/s00335-024-10066-z

Hepatology. 2024 Aug 27. doi: 10.1097/HEP.0000000000001065. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: TM6SF2 rs58542926 (E167K) is related to increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Conflicting mouse study results highlight the need for a human model to understand this mutation's impact. This study aims to create and characterize a reliable human in vitro model to mimic the effects of the TM6SF2-E167K mutation for future studies.

APPROACH AND RESULTS: We used gene editing on human human-induced pluripotent stem cells (iPSC) from a healthy individual to create cells with the TM6SF2-E167K mutation. After hepatocyte directed differentiation, we observed decreased TM6SF2 protein expression, increased intracellular lipid droplets and total cholesterol in addition to reduced VLDL secretion. Transcriptomics revealed upregulation of genes involved in lipid, fatty acid, and cholesterol transport, flux, and oxidation. Global lipidomics showed increased lipid classes associated with ER stress, mitochondrial dysfunction, apoptosis, and lipid metabolism. Additionally, the TM6SF2-E167K mutation conferred a pro-inflammatory phenotype with signs of mitochondria and ER stress. Importantly, by facilitating protein folding within the ER of hepatocytes carrying TM6SF2-E167K mutation, VLDL secretion and ER stress markers improved.

CONCLUSIONS: Our findings indicate that induced hepatocytes generated from iPSCs carrying the TM6SF2-E167K recapitulate the effects observed in human hepatocytes from individuals with the TM6SF2 mutation. This study characterizes an in vitro model that can be used as a platform to identify potential clinical targets and highlights the therapeutic potential of targeting protein misfolding to alleviate ER stress and mitigate the detrimental effects of the TM6SF2-E167K mutation on hepatic lipid metabolism.

PMID:39190693 | DOI:10.1097/HEP.0000000000001065

Int J Syst Evol Microbiol. 2024 Aug;74(8). doi: 10.1099/ijsem.0.006502.

ABSTRACT

Gene- and genome-based approaches were used to determine whether Vigna little leaf (ViLL) phytoplasma, which occurs in northern Australia, is a distinct 'Candidatus Phytoplasma' species. The ViLL 16S rRNA gene sequences exhibited the highest known similarity to species in the 16SrXXIX-A and 16SrIX-D subgroups, namely 'Candidatus Phytoplasma omanense' (98.03-98.10%) and 'Candidatus Phytoplasma phoenicium' (96.87-97.20%), respectively. A total of 48 single-copy orthologue genes were identified to be shared among the two draft ViLL phytoplasma genomes, 30 publicly available phytoplasma genomes, and one Acholeplasma laidlawii genome as the outgroup taxon. Phylogenomic assessments using the 48 shared single-copy orthologue genes supported that ViLL and 'Ca. Phytoplasma phoenicium' were closely related yet distinct species. The 16S rRNA gene sequence analysis and phylogenomic assessment indicate that ViLL phytoplasmas are a distinct taxon. As such, a novel species, 'Candidatus Phytoplasma vignae', is proposed. Strain BAWM-336 (genome accession number JAUZLI000000000) detected in Momordica charantia (bitter melon) serves as the reference strain of this species, with infected plant material deposited in the Victorian Plant Pathology Herbarium (VPRI) as VPRI 44369.

PMID:39190596 | DOI:10.1099/ijsem.0.006502

Proc Natl Acad Sci U S A. 2024 Sep 3;121(36):e2410598121. doi: 10.1073/pnas.2410598121. Epub 2024 Aug 27.

ABSTRACT

To counter the rising incidence of diabetes and to meet the daily protein needs, we created low glycemic index (GI) rice varieties with protein content (PC) surpassing 14%. In the development of recombinant inbred lines using Samba Mahsuri and IR36 amylose extender (IR36ae) as parental lines, we identified quantitative trait loci and genes associated with low GI, high amylose content (AC), and high PC. By integrating genetic techniques with classification models, this comprehensive approach identified candidate genes on chromosome 2 (qGI2.1/qAC2.1 spanning the region from 18.62 Mb to 19.95 Mb), exerting influence on low GI and high amylose. Notably, the phenotypic variant with high value was associated with the recessive allele of the starch branching enzyme 2b (sbeIIb). The genome-edited sbeIIb line confirmed low GI phenotype in milled rice grains. Further, combinations of alleles created by the highly significant SNPs from the targeted associations and epistatically interacting genes showed ultralow GI phenotypes with high amylose and high protein. Metabolomics analysis of rice with varying AC, PC, and GI revealed that the superior lines of high AC and PC, and low GI were preferentially enriched in glycolytic and amino acid metabolisms, whereas the inferior lines of low AC and PC and high GI were enriched with fatty acid metabolism. The high amylose high protein recombinant inbred line (HAHP_101) was enriched in essential amino acids like lysine. Such lines may be highly relevant for food product development to address diabetes and malnutrition.

PMID:39190344 | DOI:10.1073/pnas.2410598121

Biochem Cell Biol. 2024 Aug 27. doi: 10.1139/bcb-2024-0029. Online ahead of print.

ABSTRACT

After 20 years of stagnation, federal scholarships have finally been increased within the new budget of the Canadian government. Tuition fees, inflation, and costs of living kept rising, which has resulted a rising number of graduate students in the life sciences living below poverty line, despite working far more than 40 h a week on science research in Canada. This does not only negatively affect the students research projects and thus science and innovation in Canada, but also their downstream decisions on whether to continue a research career in Canada and what jobs and economic endeavors to pursue. Graduate students are not just a line item in the budgets of universities, but integral for science and innovation, as well as the future high-quality personnel of the country. This importance should be reflected in all stipends and salaries of graduate students, not just the ones with a government scholarship.

PMID:39189454 | DOI:10.1139/bcb-2024-0029

ACS Nano. 2024 Aug 27. doi: 10.1021/acsnano.4c09551. Online ahead of print.

ABSTRACT

This study focuses on the design and characterization of binary nanoparticle superlattices: Two differently sized, supercharged protein nanocages are used to create a matrix for nanoparticle arrangement. We have previously established the assembly of protein nanocages of the same size. Here, we present another approach for multicomponent biohybrid material synthesis by successfully assembling two differently sized supercharged protein nanocages with different symmetries. Typically, the ordered assembly of objects with nonmatching symmetry is challenging, but our electrostatic-based approach overcomes the symmetry mismatch by exploiting electrostatic interactions between oppositely charged cages. Moreover, our study showcases the use of nanoparticles as a contrast enhancer in an elegant way to gain insights into the structural details of crystalline biohybrid materials. The assembled materials were characterized with various methods, including transmission electron microscopy (TEM) and single-crystal small-angle X-ray diffraction (SC-SAXD). We employed cryo-plasma-focused ion beam milling (cryo-PFIB) to prepare lamellae for the investigation of nanoparticle sublattices via electron cryo-tomography. Importantly, we refined superlattice structure data obtained from single-crystal SAXD experiments, providing conclusive evidence of the final assembly type. Our findings highlight the versatility of protein nanocages for creating distinctive types of binary superlattices. Because the nanoparticles do not influence the type of assembly, protein cage matrices can combine various nanoparticles in the solid state. This study not only contributes to the expanding repertoire of nanoparticle assembly methods but also demonstrates the power of advanced characterization techniques in elucidating the structural intricacies of these biohybrid materials.

PMID:39189351 | DOI:10.1021/acsnano.4c09551

J Infect Dis. 2024 Aug 27:jiae378. doi: 10.1093/infdis/jiae378. Online ahead of print.

ABSTRACT

As investigations of low-biomass microbial communities have become more common, so too has the recognition of major challenges affecting these analyses. These challenges have been shown to compromise biological conclusions and have contributed to several controversies. Here, we review some of the most common and influential challenges in low-biomass microbiome research. We highlight key approaches to alleviate these potential pitfalls, combining experimental planning strategies and data analysis methods.

PMID:39189314 | DOI:10.1093/infdis/jiae378

Front Allergy. 2024 Aug 12;5:1469718. doi: 10.3389/falgy.2024.1469718. eCollection 2024.

NO ABSTRACT

PMID:39188990 | PMC:PMC11345248 | DOI:10.3389/falgy.2024.1469718

Nat Commun. 2024 Aug 26;15(1):7337. doi: 10.1038/s41467-024-51780-1.

ABSTRACT

There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.

PMID:39187565 | DOI:10.1038/s41467-024-51780-1

Nat Commun. 2024 Aug 27;15(1):7352. doi: 10.1038/s41467-024-51680-4.

ABSTRACT

The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.

PMID:39187492 | DOI:10.1038/s41467-024-51680-4

Nat Commun. 2024 Aug 26;15(1):7343. doi: 10.1038/s41467-024-51468-6.

ABSTRACT

Intervention efforts against falciparum malaria in high-transmission regions remain challenging, with rapid resurgence typically following their relaxation. Such resilience co-occurs with incomplete immunity and a large transmission reservoir from high asymptomatic prevalence. Incomplete immunity relates to the large antigenic variation of the parasite, with the major surface antigen of the blood stage of infection encoded by the multigene and recombinant family known as var. With a stochastic agent-based model, we investigate the existence of a sharp transition in resurgence ability with intervention intensity and identify molecular indicators informative of its proximity. Their application to survey data with deep sampling of var sequences from individual isolates in northern Ghana suggests that the transmission system was brought close to transition by intervention with indoor residual spraying. These results indicate that sustaining and intensifying intervention would have pushed malaria dynamics to a slow-rebound regime with an increased probability of local parasite extinction.

PMID:39187488 | DOI:10.1038/s41467-024-51468-6

Nat Commun. 2024 Aug 26;15(1):7061. doi: 10.1038/s41467-024-51258-0.

ABSTRACT

Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism of protein synthesis. However, the current method has substantial issues: contamination by rRNAs and the lack of appropriate methods to measure ribosome numbers in transcripts. Here, we overcome these hurdles through the development of "Ribo-FilterOut", which is based on the separation of footprints from ribosome subunits by ultrafiltration, and "Ribo-Calibration", which relies on external spike-ins of stoichiometrically defined mRNA-ribosome complexes. A combination of these approaches estimates the number of ribosomes on a transcript, the translation initiation rate, and the overall number of translation events before its decay, all in a genome-wide manner. Moreover, our method reveals the allocation of ribosomes under heat shock stress, during aging, and across cell types. Our strategy of modified ribosome profiling measures kinetic and stoichiometric parameters of cellular translation across the transcriptome.

PMID:39187487 | DOI:10.1038/s41467-024-51258-0

Int J Biol Macromol. 2024 Aug 24:135025. doi: 10.1016/j.ijbiomac.2024.135025. Online ahead of print.

ABSTRACT

Keratin is one of the major components of solid waste, and the degradation products have extensive applications in various commercial industries. Due to the complexity of the structure of keratin, especially the disulfide bonds between keratin polypeptides, keratinolytic activity is efficient with a mixture of proteins with proteases, peptidases, and oxidoreductase activity. The present work aimed to create an engineered chimeric protein with a disulfide reductase domain and a protease domain connected with a flexible linker. The structure, stability, and substrate interaction were analyzed using the protein modeling tools and codon-optimized synthetic gene cloned, expressed, and purified using Ni2+-NTA chromatography. The keratinolytic activity of the protein was at its maximum at 70 °C. The suitable pH for the enzyme activity was pH 8. While Ni2+, Mg2+, and Na+ inhibited the keratinolytic activity, Cu2+, Ca2+, and Mn2+ enhanced it significantly. Biochemical characterization of the protease domain indicated significant keratinolytic activity at 70 °C at pH 10.0 but was less efficient than the chimeric protein. Experiments using feathers as the substrate showed a clear degradation pattern in the SEM analysis. The samples collected from the degradation experiments indicated the release of proteins (2-fold) and amino acids (8.4-fold) in a time-dependent manner. Thus, the protease with an added disulfide reductase domain showed excellent keratin degradation activity and has the potential to be utilized in the commercial industries.

PMID:39187103 | DOI:10.1016/j.ijbiomac.2024.135025

Rapid Commun Mass Spectrom. 2024 Oct 30;38(20):e9898. doi: 10.1002/rcm.9898.

ABSTRACT

RATIONALE: Although Naomaitai capsule (NMC) is widely used in clinical practice and has a good curative effect for cerebral infarction, its material basis and mechanism of action remain unclear.

METHODS: In this study, ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole Orbitrap MS technology was used to analyse the in vivo and in vitro components of NMC, and the Global Natural Products Social Molecular Networking website was used to further analyse the components of NMC. Next, systems biology approaches were employed to investigate the mechanism of action of NMC. Finally, molecular docking technology was used to verify the network pharmacological results.

RESULTS: In total, 177 compounds were identified in vitro, including 65 terpenoids, 62 flavonoids, 25 organic acids and 11 quinones. 64 compounds were identified in the blood of mice, and the main active components included ginkgolide C, ginkgolide A, ligustilide, tanshinone IIB, olmelin, emodin and puerarin. The main targets in vivo included TP53, SRC, STAT3, PIK3CA and PIK3R1.

CONCLUSIONS: In conclusion, this study has revealed that NMC acts on multiple targets in the body through various active components, exerting synergistic effects in the treatment of CI. Its mechanism of action may involve inhibiting neuronal apoptosis, oxidative stress and inflammatory responses as well as reducing cerebral vascular permeability and promoting cerebral vascular regeneration.

PMID:39185580 | DOI:10.1002/rcm.9898

J Med Imaging (Bellingham). 2024 Jul;11(4):044006. doi: 10.1117/1.JMI.11.4.044006. Epub 2024 Aug 23.

ABSTRACT

PURPOSE: We address the need for effective stain domain adaptation methods in histopathology to enhance the performance of downstream computational tasks, particularly classification. Existing methods exhibit varying strengths and weaknesses, prompting the exploration of a different approach. The focus is on improving stain color consistency, expanding the stain domain scope, and minimizing the domain gap between image batches.

APPROACH: We introduce a new domain adaptation method, Stain simultaneous augmentation and normalization (SAN), designed to adjust the distribution of stain colors to align with a target distribution. Stain SAN combines the merits of established methods, such as stain normalization, stain augmentation, and stain mix-up, while mitigating their inherent limitations. Stain SAN adapts stain domains by resampling stain color matrices from a well-structured target distribution.

RESULTS: Experimental evaluations of cross-dataset clinical estrogen receptor status classification demonstrate the efficacy of Stain SAN and its superior performance compared with existing stain adaptation methods. In one case, the area under the curve (AUC) increased by 11.4%. Overall, our results clearly show the improvements made over the history of the development of these methods culminating with substantial enhancement provided by Stain SAN. Furthermore, we show that Stain SAN achieves results comparable with the state-of-the-art generative adversarial network-based approach without requiring separate training for stain adaptation or access to the target domain during training. Stain SAN's performance is on par with HistAuGAN, proving its effectiveness and computational efficiency.

CONCLUSIONS: Stain SAN emerges as a promising solution, addressing the potential shortcomings of contemporary stain adaptation methods. Its effectiveness is underscored by notable improvements in the context of clinical estrogen receptor status classification, where it achieves the best AUC performance. The findings endorse Stain SAN as a robust approach for stain domain adaptation in histopathology images, with implications for advancing computational tasks in the field.

PMID:39185474 | PMC:PMC11342968 | DOI:10.1117/1.JMI.11.4.044006