Gene Deletion in Barley Mediated by LTR-retrotransposon BARE

A poly-row branched spike (prbs) barley mutant was obtained from soaking a two-rowed barley inflorescence in a solution of maize genomic DNA. Positional cloning and sequencing demonstrated that the prbs mutant resulted from a 28 kb deletion including the inflorescence architecture gene HvRA2. Sequence annotation revealed that the HvRA2 gene is flanked by two LTR (long terminal repeat) retrotransposons (BARE) sharing 89% sequence identity. A recombination between the integrase (IN) gene regions of the two BARE copies resulted in the formation of an intact BARE and loss of HvRA2. No maize DNA was detected in the recombination region although the flanking sequences of HvRA2 gene showed over 73% of sequence identity with repetitive sequences on 10 maize chromosomes. It is still unknown whether the interaction of retrotransposons between barley and maize has resulted in the recombination observed in the present study.Peer reviewe

Crossway Diffusion: Improving Diffusion-based Visuomotor Policy via Self-supervised Learning

Sequence modeling approaches have shown promising results in robot imitation learning. Recently, diffusion models have been adopted for behavioral cloning, benefiting from their exceptional capabilities in modeling complex data distribution. In this work, we propose Crossway Diffusion, a method to enhance diffusion-based visuomotor policy learning by using an extra self-supervised learning (SSL) objective. The standard diffusion-based policy generates action sequences from random noise conditioned on visual observations and other low-dimensional states. We further extend this by introducing a new decoder that reconstructs raw image pixels (and other state information) from the intermediate representations of the reverse diffusion process, and train the model jointly using the SSL loss. Our experiments demonstrate the effectiveness of Crossway Diffusion in various simulated and real-world robot tasks, confirming its advantages over the standard diffusion-based policy. We demonstrate that such self-supervised reconstruction enables better representation for policy learning, especially when the demonstrations have different proficiencies.Comment: 18 pages, 10 figure

Regulation of microRNA biosynthesis and expression in 2102Ep embryonal carcinoma stem cells is mirrored in ovarian serous adenocarcinoma patients

Background. Tumours with high proportions of differentiated cells are considered to be of a lower grade to those containing high proportions of undifferentiated cells. This property may be linked to the differentiation properties of stem cell-like populations within malignancies. We aim to identify molecular mechanism associated with the generation of tumours with differing grades from malignant stem cell populations with different differentiation potentials. In this study we assessed microRNA (miRNA) regulation in two populations of malignant Embryonal Carcinoma (EC) stem cell, which differentiate (NTera2) or remain undifferentiated (2102Ep) during tumourigenesis, and compared this to miRNA regulation in ovarian serous carcinoma (OSC) patient samples. Methods. miRNA expression was assessed in NTera2 and 2102Ep cells in the undifferentiated and differentiated states and compared to that of OSC samples using miRNA qPCR. Results. Our analysis reveals a substantial overlap between miRNA regulation in 2102Ep cells and OSC samples in terms of miRNA biosynthesis and expression of mature miRNAs, particularly those of the miR-17/92 family and clustering to chromosomes 14 and 19. In the undifferentiated state 2102Ep cells expressed mature miRNAs at up to 15,000 fold increased levels despite decreased expression of miRNA biosynthesis genes Drosha and Dicer. 2102Ep cells avoid differentiation, which we show is associated with consistent levels of expression of miRNA biosynthesis genes and mature miRNAs while expression of miRNAs clustering to chromosomes 14 and 19 is deemphasised. OSC patient samples displayed decreased expression of miRNA biosynthesis genes, decreased expression of mature miRNAs and prominent clustering to chromosome 14 but not 19. This indicates that miRNA biosynthesis and levels of miRNA expression, particularly from chromosome 14, are tightly regulated both in progenitor cells and in tumour samples. Conclusion. miRNA biosynthesis and expression of mature miRNAs, particularly the miR-17/92 family and those clustering to chromosomes 14 and 19, are highly regulated in both progenitor cells and tumour samples. Strikingly, 2102Ep cells are not simply malfunctioning but respond to differentiation specifically, a mechanism that is highly relevant to OSC samples. Our identification and future manipulation of these miRNAs may facilitate generation of lower grade malignancies from these high-grade cells. © 2009 Gallagher et al; licensee BioMed Central Ltd

Plasminogen deficiency causes reduced angiogenesis and behavioral recovery after stroke in mice

Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of plasmin/plasminogen in mediating angiogenesis and thereby contributing to functional recovery post-stroke. Wild-type plasminogen naive (Plg(+/+)) mice and plasminogen knockout (Plg(-/-)) mice were subjected to unilateral permanent middle cerebral artery occlusion (MCAo). Blood vessels were labeled with FITC-dextran. Functional outcomes, and cerebral vessel density were compared between Plg(+/+) and Plg(-/-) mice at different time points after stroke. We found that Plg(-/-) mice exhibited significantly reduced functional recovery, associated with significantly decreased vessel density in the peri-infarct area in the ipsilesional cortex compared with Plg(+/+) mice. In vitro, cerebral endothelial cells harvested from Plg(-/-) mice exhibited significantly reduced angiogenesis assessed using tube formation assay, and migration, as evaluated using Scratch assays, compared to endothelial cells harvested from Plg(+/+) mice. In addition, using Western blots, expression of thrombospondin (TSP)-1 and TSP-2 were increased after MCAo in the Plg(-/-) group compared to Plg(+/+) mice, especially in the ipsilesional side of brain. Taken together, our data suggest that plasmin/plasminogen down-regulates the expression level of TSP-1 and TSP-2, and thereby promotes angiogenesis in the peri-ischemic brain tissue, which contributes to functional recovery after ischemic stroke

Application of a macrocyclization strategy in kinase inhibitor development

Kinases have a pivotal role in phosphorylation and kinase dysregulation has been implicated in the occurrence and progression of various diseases. By mid-2024 the Food and Drug Administration had approved 81 small-molecule kinase inhibitors targeting greater than 30 kinases, providing substantial clinical benefits for patients with cancer and other diseases. However, many reported kinase inhibitors exhibit poor target selectivity, limited solubility, and issues with drug resistance. To address these challenges medicinal chemists have used a macrocyclization strategy to optimize these molecules and three macrocyclic kinase inhibitors (lorlatinib [ALK/ROS1], pacritinib [Flt3/JAK2], and repotrectinib [TRK/ROS1]) have received FDA approval. The macrocyclization strategy is now widely used to enhance kinase inhibitory activity, overcome drug resistance caused by point mutations, improve kinase selectivity, and optimize drug-like properties. In this review we provide a comprehensive overview of the utilization of macrocyclization in the optimization of kinase inhibitors by detailing the structural modification process from lead compounds to macrocyclic molecules that has been applied in recent years. In addition, we discuss the limitations of existing macrocyclic kinase inhibitors and propose key considerations for the development of improved macrocyclic molecules. We aim for this review to offer valuable insights for future advances in kinase inhibitor development

Cerebrospinal fluid/serum albumin ratio in patients with Lewy body disease: a systematic review and meta-analysis

BackgroundAbnormal cerebrospinal fluid (CSF)/serum albumin ratio (Qalb) levels have been observed in patients with cognitive impairment. Few studies have specifically focused on Lewy Body Disease (LBD), and the results were controversial. Thus, we conducted this systematic review and meta-analysis to investigate Qalb levels in patients with LBD by including data from different studies.MethodWe systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases for a collection of studies containing studies comparing Qalb levels in patients with LBD and healthy controls (including healthy controls and other dementia subtypes). In the initial search, 86 relevant papers were retrieved. Standardized mean differences (SMD) in Qalb levels were calculated using a random effects model.ResultsA total of 13 eligible studies were included. Mean Qalb levels were significantly higher in patients with LBD compared to healthy older adults [standardized mean difference (SMD): 2.95, 95% confidence interval (CI): 0.89–5.00, Z = 2.81, p = 0.005]; and were significantly higher in patients with LBD than in patients with Alzheimer’s disease (AD) (SMD: 1.13, 95% CI: 0.42–1.83, Z = 3.15, p = 0.002);whereas mean Qalb levels were significantly higher in patients with frontotemporal lobar degeneration (FTLD) compared to those with AD (SMD: 1.13, 95% CI,0.14–2.13, Z = 2.24, p = 0.03).ConclusionQalb levels were significantly elevated in LBD patients compared with normal older adults and were higher than those in AD patients and FTLD patients, which helped in the differential diagnosis of LBD from other neurodegenerative diseases.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024496616

5-deoxy-rutaecarpine protects against LPS-induced acute lung injury via inhibiting NLRP3 inflammasome-related inflammation

IntroductionAcute lung injury (ALI) induced by lipopolysaccharide (LPS) is a significant medical condition characterized by severe pulmonary inflammation and tissue damage. NLRP3 inflammasome-driven inflammation is essential in ALI pathogenesis, inspiring novel therapeutic strategies that focus on NLRP3 and inflammation. In this study, we investigated the therapeutic potential of 5-deoxy-rutaecarpine (5-DR), a rutaecarpine derivative, in attenuating LPS-induced ALI.MethodsIn this study, we evaluated the effects of 5-DR treatment in mice exposed to LPS, lung tissues, bronchoalveolar lavage fluid, and serum were collected for analysis. LPS-stimulated J774A.1 mouse macrophages were used to further investigate the anti-inflammatory effects of 5-DR in vitro. Various techniques including histopathology, Western blotting, and luciferase reporter assay were employed.Results5-DR treatment significantly reduced lung edema, inflammatory cell infiltration in mice with LPS burden, and reduced the levels of inflammatory mediators like interleukin-1β in the mice and in LPS-stimulated J774A.1 mouse macrophages. Further western blotting analysis showed 5-DR decreased the levels of NLRP3, cleaved caspase-1, and mature IL-1β in mice and J774A.1 cells exposed to LPS. Additionally, NF-κB pathway activation significantly diminished the inhibition of the NLRP3 inflammasome by 5-DR.DiscussionOur findings highlight the therapeutic potential of 5-DR as a promising candidate for treating LPS-induced ALI, offering insights into its underlying mechanism that targets NLRP3 inflammasome-mediated inflammation

Alzheimer's disease pathology: pathways between chronic vascular risk factors and blood-brain barrier dysfunction in a cohort of patients with different types of dementia

BackgroundBlood brain barrier (BBB) breakdown is considered a potential mechanism of dementia. The Alzheimer's disease (AD) biomarkers and vascular factors are also associated with BBB permeability.ObjectiveIn the present study, the combination effects of neuropathological biomarkers of AD and chronic vascular risk factors for BBB were investigated.MethodsThe cerebrospinal fluid (CSF)/serum albumin ratio (Qalb), an indicator of BBB permeability, was measured in a total of 95 hospitalized dementia patients. The demographics, clinical information, and laboratory tests were collected from the inpatient records. The CSF neuropathological biomarkers of AD and apolipoprotein E (APOE) genotype were also collected. The mediation analysis model was used to calculate the associations among neuropathological biomarkers of AD (mediator), the Qalb, and chronic vascular risk factors.ResultsThree types of dementia, AD (n = 52), Lewy body dementia (LBD, n = 19), and frontotemporal lobar degeneration (n = 24), were included with a mean Qalb of 7.18 (± 4.36). The Qalb was significantly higher in dementia patients with type 2 diabetes mellitus (T2DM, p = 0.004) but did not differ based on the presence of APOE ε4 allele, CMBs, or amyloid/tau/neurodegeneration (ATN) framework. The Qalb was negatively associated with the levels of Aβ1-42 (B = −20.775, p = 0.009) and Aβ1-40 (B = −305.417, p = 0.005) and positively associated with the presence of T2DM (B = 3.382, p < 0.001) and the levels of glycosylated hemoglobin (GHb, B = 1.163, p < 0.001) and fasting blood glucose (FBG, B = 1.443, p < 0.001). GHb is a direct chronic vascular risk factor for higher Qalb (total effect B = 1.135, 95% CI: 0.611–1.659, p < 0.001). Ratios of Aβ1-42/Aβ1-40 or t-tau/Aβ1-42 were mediators of the association between the Qalb and GHb; the direct effect of GHb on the Qalb was 1.178 (95% CI: 0.662–1.694, p < 0.001).ConclusionGlucose exposure can directly or indirectly affect BBB integrity through Aβ and tau, indicating glucose affects BBB breakdown and glucose stability plays an important role in dementia protection and management