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N-Cadherin based adhesion and Rac1 activity regulate tension polarization in the actin cortex

Integrative bioinformatic approach reveals novel melatonin-related biomarkers for Alzheimer’s disease

Establishment and application of a zebrafish model of Werner syndrome identifies sapanisertib as a potential antiaging drug

Aging is a complex process that affects multiple organs, and the discovery of a pharmacological approach to ameliorate aging is considered the Holy Grail of medicine. Here, we performed an N-ethyl-N-nitrosourea forward genetic screening in zebrafish and identified an accelerated aging mutant named meteor ( met ), harboring a mutation in the Werner syndrome RecQ - like helicase ( wrn ) gene. Loss of wrn leads to a short lifespan and age-related characteristics in the intestine of zebrafish embryos, such as cellular senescence, genomic instability, and epigenetic alteration. Therefore, we conducted a screening of antiaging drugs using the met mutant and revealed that sapanisertib effectively ameliorated most of the aging phenotypes of the mutant. Mechanistically, the geroprotective effects of sapanisertib may be attributed to inhibition of mTORC1/2. Furthermore, sapanisertib also attenuated chronological aging in wild-type aged zebrafish and replicative-senescence in human foreskin fibroblasts. Taken together, our study introduces a unique and efficient model for large-scale antiaging drug screening in vertebrates and suggests sapanisertib as a potential therapeutic option for treating premature aging and promoting healthy aging.

PET imaging of AAV9 and AAVBR1 trafficking in normal mice

Natural variations in <i>TT8</i> and its neighboring <i>STK</i> confer yellow seed with elevated oil content in <i>Brassica juncea</i>

Seed color is a critical quality trait in numerous plant species. In oilseed Brassica crops, including rapeseed and mustard, yellow seeds are distinguished by their significantly higher oil content and faster germination rates compared to black or brown counterparts. Despite the agronomic significance of the yellow seeds being a prime breeding target, the mechanisms underlying elevated oil content remain obscure. In this study, we assembled the first telomere-to-telomere (T2T) genome of B. juncea and further investigated the genetic regulation, molecular mechanism, and the evolutionary history of yellow seeds in B. juncea. Through an analysis of allelic variation in the TRANSPARENT TESTA 8 ( TT8 ) genes across 1,002 worldwide B . juncea accessions, we traced the single origin of yellow seeds to approximately 2,300 y ago in Southwestern China. Furthermore, we discovered the MADS-box gene SEEDSTICK ( STK ) coevolved with TT8 , and they coordinately regulated seed size, oil accumulation, and seed coat proportion in B. juncea . These findings open broad avenues for targeted breeding of yellow-seeded Brassica crops with elevated oil content.

The occurrence characteristic and dissolution mechanism of lithium-rich sediments in Salt Lake Mahai of Qaidam Basin, NW China

Rational design and modular synthesis of biodegradable ionizable lipids via the Passerini reaction for mRNA delivery

The ionizable lipid component of lipid nanoparticle (LNP) formulations is essential for mRNA delivery by facilitating endosomal escape. Conventionally, these lipids are synthesized through complex, multistep chemical processes that are both time-consuming and require significant engineering. Furthermore, the development of new ionizable lipids is hindered by a limited understanding of the structure-activity relationships essential for effective mRNA delivery. In this work, we have developed a modular platform utilizing the Passerini reaction to rapidly generate large, chemically diverse libraries of biodegradable ionizable lipids. This high-throughput approach enables the systematic exploration of various lipid components–head groups, tails, and spacers–and their impacts on mRNA delivery efficiency. By investigating the hydrogen bonding potential between the lipid’s head groups and the mRNA’s ribose phosphate complex, we found that optimizing the methylene units between the lipid’s head groups and linkages could enhance endosomal escape and, consequently, mRNA delivery efficiencies. Leveraging this insight, our platform has led to the identification of the biodegradable ionizable lipid A4B4-S3, which outperforms the current clinical benchmark, SM-102, in gene editing efficacy in mouse liver following systemic administration and demonstrates the promise for repeat-dose protein replacement treatments. This work not only offers a rapid, scalable method for ionizable lipid synthesis but also deepens our understanding of their structure-activity relationships, paving the way for more effective mRNA therapeutics.

Author Correction: Sentiment analysis of the Hamas-Israel war on YouTube comments using deep learning

Impaired spatial coding of the hippocampus in a dentate gyrus hypoplasia mouse model

The hippocampal dentate gyrus (DG) is thought to orthogonalize inputs from the entorhinal cortex (pattern separation) and relay this information to the CA3 region. In turn, attractor dynamics in CA3 perform a pattern completion or error correction operation before sending its output to CA1. In a mouse model of congenital hypoplasia of the DG, a deficiency in the Wntless (Wls) gene, specifically in cells expressing Gfap-Cre , which targets neuronal progenitors, led to an almost total absence of dentate granule cells and modestly impaired performance in spatial tasks. Here, we investigated the physiological consequences of granule cell loss in these mice by conducting in vivo calcium imaging from CA1 principal cells during behavior. The spatial selectivity of these cells was preserved without the DG. On a linear track, place fields in mutant mice were more likely to be near track terminals and to encode the distance from the start point in each running direction. In an open box, CA1 cells in mutant mice exhibited reductions in the percentage of place cells, in spatial information, and in place field stability. The reduction in place field stability across repeated exposures to the same environment resulted in a reduction in the differential representations of two different contexts in mutant mice compared to wild-type mice. These results suggest that DG helps to stabilize CA1 spatial representations, especially in 2-D environments, and that the lack of stability across similar environments may play a key role in the deficits of animals with DG dysfunction in discriminating different environments.

A polysaccharide-based hydrogel platform for tumor spheroid production and anticancer drug screening

CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex

Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models. By analysis of the CBX2-regulated transcriptional program coupled with mass spectrometry screening of CBX2-interacting proteins, we found that CBX2 suppresses interferon signaling independent of its function in the canonical PRC. Mechanistically, CBX2 directly interacts with RACK1 and facilitates the recruitment of HDAC1, which attenuates the H3K27ac modification on the promoter regions of interferon-stimulated genes, thereby suppressing interferon signaling. Consequently, CBX2 reduces tumor immunogenicity and enables immune evasion. Moreover, a high expression level of CBX2 is associated with immune suppressive tumor microenvironment and reduced efficacy of immunotherapy across various human cancer types. Our study identifies a noncanonical CBX2–RACK1–HDAC1 corepressor complex in suppression of tumor immunogenicity, thereby presenting a potential target and biomarker for tumor immunotherapy.

The prevalence, clinical features, and long-term outcome of patients with primary Sjögren’s syndrome with renal involvement

Uterine organoids reveal insights into epithelial specification and plasticity in development and disease

Understanding how epithelial cells in the female reproductive tract (FRT) differentiate is crucial for reproductive health, yet the underlying mechanisms remain poorly defined. At birth, FRT epithelium is highly malleable, allowing differentiation into various epithelial types, but the regulatory pathways guiding these early cell fate decisions are unclear. Here, we use neonatal mouse endometrial organoids and assembloid coculture models to investigate how innate cellular plasticity and external mesenchymal signals influence epithelial differentiation. Our findings demonstrate that uterine epithelium undergoes marked age-dependent changes, transitioning from a highly plastic state capable of forming both monolayered and multilayered structures to a more restricted fate as development progresses. Interestingly, parallels emerge between the developmental plasticity of neonatal uterine epithelium and pathological conditions such as endometrial cancer, where similar regulatory mechanisms may reactivate, driving abnormal epithelial differentiation and tumorigenesis. These results not only deepen our understanding of early uterine development but also offer a valuable model for studying the progression of reproductive diseases and cancers.

An investigation of hydraulic fracturing initiation and location of hydraulic fracture in preforated oil shale formations

Activation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages

The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear. Here, we identify the crucial role of MST1/2 in inflammasome-triggered cell death. Macrophages proteolytically convert full-length MST1/2 into the MST1/2 N-terminal fragments (MST1/2-NT) when the NLRC4 inflammasome detects flagellin from the pathogenic bacterium, Legionella pneumophila . Activation of the NLRP3 inflammasome by the damage-associated molecular pattern, extracellular ATP, also produces MST1/2-NT. Caspase-1, the protease activated by these inflammasomes, directly cleaves MST1/2, and blockage of caspase-1 inhibits MST1/2-NT production in macrophages challenged with L. pneumophila . Importantly, MST1/2-NT production is critical for macrophages to trigger a set of death processes associated with apoptosis upon inflammasome activation and knocking out Mst1/2 causes dysregulated gasdermin protein cleavage for pyroptotic death. Furthermore, macrophages lacking MST1/2 have increased susceptibility to virulent L. pneumophila, revealing that the Hippo kinases are important restriction factors against the pathogen. These findings demonstrate that proteolytic cleavage of MST1/2 induced by inflammatory stimuli is an immune pathway to regulate programmed cell death in macrophages and uncover a unique link between the tumor-suppressive Hippo kinases and the inflammasomes in innate immunity.

Validated HPLC method for simultaneous determination of azelastine hydrochloride fluticasone propionate and oxymetazoline in nasal mucosa and nasopharyngeal swabs from real human samples

Abstract A combination of three co-administrated drugs, such as azelastine hydrochloride (AZT), fluticasone propionate (FP), and oxymetazoline (OXY), is more effective than single therapy for the treatment of seasonal allergy and COVID-19. We established an efficient methodology for the determination of those analytes in spiked nasal mucosa and nasopharyngeal swabs from real human samples. A simple and quick protein precipitation method was used for sample extraction, using acetonitrile. RP-HPLC/DAD method was performed using an Exsil 100 ODS C18 (250 × 4.6 mm, 5 μm) column with an acetonitrile: water (70:30 v/v) solvent system at a flow rate of 0.7 mL/min. A photodiode array detector was applied at 240 nm. A good separation of the three proposed analytes with a short run time of 10 min was noted. Our method was validated according to FDA guidelines for bioanalytical validation methods. Calibration curves were linear in nasal mucosa samples at concentration ranges of 8–125, 10–100, and 10–125 µg/mL, with average recoveries ± SD of 101.56%±0.39, 102.45%±0.86, and 104.61%±4.52 for AZT, FP, and OXY; respectively. The results of precision and accuracy are within acceptable limits. According to stability assays, the three analytes under investigation were stable throughout sample preparation, storage, and injection. Our method was applied to real nasopharyngeal swabs. It shows that the results of the swabs were not affected by gender or age. Good recoveries with low % RSD were observed: 99.03% ± 0.75, 100.02% ± 0.94, and 100.94% ± 1.98 for both genders, and 100.45% ± 0.96, 100.69% ± 1.08, and 100.32% ± 1.53 for different ages for AZT, FP, and OXY; respectively. Moreover, the amount of those drugs in the nasal mucosa was observed for seven hours, and a constant concentration with a low% RSD was noted for the first four hours. Therefore, this method can be applied to monitor the therapeutic dose in the nasal mucosa for the determination of those analytes.

Institutional distance, trade agreements, and intellectual property trade networks: Evidence from cross-border data

Based on the Temporal Exponential Random Graph Models (TERGM), this paper applies global intellectual property trade data between countries to investigate the impact and mechanism of institutional distance on the intellectual property trade network. The study finds that the smaller the institutional distance between countries, the more conducive it is to build an intellectual property trade network. This conclusion remains valid after controlling for geographical adjacency, use of a common language, existence of colonial relationships, and characteristics of the intellectual property trade network. Moreover, through regression by year, it is found that this impact increases year by year. Further, after regressing on sub-indicators of institutional distance, it is found that the smaller the distance in political stability, government efficiency, and regulatory quality, the greater the probability of generating an intellectual property trade relationship. Mechanism analysis reveals that economies with smaller institutional distances are more likely to sign trade agreements, thereby generating trade relationships and promoting the establishment of intellectual property trade networks. In order to deeply participate in the intellectual property trade network, countries should actively align with international institutional norms and sign bilateral or multilateral trade agreements with countries with similar institutional levels to enhance the production level and export of intellectual property.

4-Hydroxy-2-nonenal causes nuclear accumulation of p62 by inhibiting Xpo1 and promoting the proteolytic pathway in the nucleus

p62, an adapter protein involved in selective autophagy, is mainly found in the cytoplasm under normal conditions. Because p62 has nuclear localization signal (NLS) and a nuclear export signal, it has been suggested that p62 shuttles between the nucleus and cytoplasm. We studied the effect of 4-hydroxy-nonenal (4-HNE), an endogenous lipid peroxidation product, on intracellular p62 distribution in mouse embryonic fibroblasts. We found that treatment of 4-HNE causes p62 translocation from the cytoplasm to the nucleus. Further analysis revealed that 4-HNE directly binds to exportin-1 (Xpo1), essential protein for nuclear export of various proteins. Further analysis 4-HNE enhanced intranuclear EGFP-NLS-CL1 degradation in a p62-dependent manner. Our results suggest that 4-HNE changes p62 localization to the nucleus by inhibiting Xpo1 and might affect intranuclear protein quality control.

The evolution of food security in Japan—Based on an indicator evaluation system including climate change indicators

As climate change intensifies, food security has received widespread attention. This study examines the development of Japan’s food security index and its relationship with climate change. From these findings, a food security indicator system for Japan was established. The food security system has six dimensions: availability, nutrition, climate change, society, economics, and fertilizer. The factors affecting food security are complex and variable, and this paper adds the Fertilizer Security Index (FSI) to the previous studies. The overuse of fertilizers directly contributes to soil and atmospheric pollution, which can indirectly lead to issues of food quality insecurity. Including this factor within the food security system is fully justified. This enhances the precision of the food security index system to some degree. The results showed that Japan’s overall food security index exhibited a slight downward trend from 0.113 in 1980 to 0.099 in 2022. Food security reached its lowest point of about 0.067 in 1993. In addition, all five indicators, except the fertilizer index, put pressure on the food security index. Due to the uncertainty inherent in climate change, specifically its ambiguous positive and negative impacts on food security, the Climate Change Security Index provides detailed evidence in this paper supporting whether climate change contributes to or undermines food security. Finally, the study put forward recommendations to ensure food security.

Surgical informed consent practice and associated factors among adult postoperative patients in public hospitals of Mekelle, Tigray, Ethiopia 2023/2024. Cross sectional

Background Substantial weaknesses and omissions of surgical informed consent are evident and the current elements of the surgical informed consent process are largely neglected in daily practice. This study aimed to assess surgical informed consent practice and associated factors among adult postoperative patients in public hospitals of Mekelle, Tigray, Ethiopia. Methods Institution based cross-sectional study was conducted among 314 adult postoperative patients in public hospitals of Mekelle, Tigray, Ethiopia. Participants were selected using systematic random sampling. A pretested interviewer-administered questionnaire was used to collect data. Descriptive, Descriptive, bivariate and multivariable logistic regression analyses were performed using statistical package for social science version 27. Result Only 35.8% (CI 95%, 30.6, 41) of the respondents were identified to have received the recommended (6 or more) components of surgical informed consent. Educational level [AOR 5.76 (1.02, 32.6)], timing of surgical informed consent delivery [AOR 3.27 (1.5, 7.11)], qualification of counselor who took surgical informed consent them [AOR3.185 (1.21, 8.38)], hospital type [AOR 2.85 (1.26, 6.46)], and duration of counseling [AOR 6.9 (3.33, 14.3)] were statistically significant at P&lt;0.05. Conclusion Majority of participants did not receive comprehensive information during the surgical informed consent process in the study hospitals. To improve the delivery it is suggested that health professionals; create rapport with patient, spend more time during counseling.