TRIBE: Hijacking an RNA-Editing Enzyme to Identify Cell-Specific Targets of RNA-Binding Proteins.

RNA transcripts are bound and regulated by RNA-binding proteins (RBPs). Current methods for identifying in vivo targets of an RBP are imperfect and not amenable to examining small numbers of cells. To address these issues, we developed TRIBE (targets of RNA-binding proteins identified by editing), a technique that couples an RBP to the catalytic domain of the Drosophila RNA-editing enzyme ADAR and expresses the fusion protein in vivo. RBP targets are marked with novel RNA editing events and identified by sequencing RNA. We have used TRIBE to identify the targets of three RBPs (Hrp48, dFMR1, and NonA). TRIBE compares favorably to other methods, including CLIP, and we have identified RBP targets from as little as 150 specific fly neurons. TRIBE can be performed without an antibody and in small numbers of specific cells.

Two-billion-year-old volcanism on the Moon from Chang'e-5 basalts.

The Moon has a magmatic and thermal history that is distinct from that of the terrestrial planets1. Radioisotope dating of lunar samples suggests that most lunar basaltic magmatism ceased by around 2.9-2.8 billion years ago (Ga)2,3, although younger basalts between 3 Ga and 1 Ga have been suggested by crater-counting chronology, which has large uncertainties owing to the lack of returned samples for calibration4,5. Here we report a precise lead-lead age of 2,030 ± 4 million years ago for basalt clasts returned by the Chang'e-5 mission, and a 238U/204Pb ratio (µ value)6 of about 680 for a source that evolved through two stages of differentiation. This is the youngest crystallization age reported so far for lunar basalts by radiometric dating, extending the duration of lunar volcanism by approximately 800-900 million years. The µ value of the Chang'e-5 basalt mantle source is within the range of low-titanium and high-titanium basalts from Apollo sites (µ value of about 300-1,000), but notably lower than those of potassium, rare-earth elements and phosphorus (KREEP) and high-aluminium basalts7 (µ value of about 2,600-3,700), indicating that the Chang'e-5 basalts were produced by melting of a KREEP-poor source. This age provides a pivotal calibration point for crater-counting chronology in the inner Solar System and provides insight on the volcanic and thermal history of the Moon.

Clonal barcoding of endogenous adult hematopoietic stem cells reveals a spectrum of lineage contributions.

The hierarchical model of hematopoiesis posits that self-renewing, multipotent hematopoietic stem cells (HSCs) give rise to all blood cell lineages. While this model accounts for hematopoiesis in transplant settings, its applicability to steady-state hematopoiesis remains to be clarified. Here, we used inducible clonal DNA barcoding of endogenous adult HSCs to trace their contribution to major hematopoietic cell lineages in unmanipulated animals. While the majority of barcodes were unique to a single lineage, we also observed frequent barcode sharing between multiple lineages, specifically between lymphocytes and myeloid cells. These results suggest that both single-lineage and multilineage contributions by HSCs collectively drive continuous hematopoiesis, and highlight a close relationship of myeloid and lymphoid development.

Defining unique structural features in the MAFA and MAFB transcription factors that control Insulin gene activity.

MAFA and MAFB are related basic-leucine-zipper domain-containing transcription factors which have important overlapping and distinct regulatory roles in a variety of cellular contexts, including hormone production in pancreatic islet cells. Here we first examined how mutating conserved MAF protein-DNA contact sites obtained from X-ray crystal structure analysis impacted their DNA-binding and Insulin enhancer-driven activity. While most of these interactions were essential and their disruption severely compromised activity, we identified that regions outside of these contact sites also contributed to transcriptional activity. AlphaFold 2, an artificial intelligence-based structural prediction program, was used to determine if there were also differences in the three-dimensional organization of the non-DNA binding/dimerization sequences of MAFA and MAFB. This analysis was conducted on the wildtype (WT) proteins as well as the pathogenic MAFASer64Phe and MAFBSer70Alatrans-activation domain mutants, with differences revealed between MAFAWT and MAFBWT as well as between MAFASer64Phe and MAFAWT, but not between MAFBSer70Ala and MAFBWT. Moreover, dissimilarities between these proteins were also observed in their ability to cooperatively stimulate Insulin enhancer-driven activity in the presence of other islet-enriched transcription factors. Analysis of MAFA and MAFB chimeras disclosed that these properties were influenced by their unique C-terminal region structural differences predicted by AlphaFold 2. Our findings have revealed key structural features of these closely related proteins that impact their ability to regulate gene expression.

Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

BACKGROUND: BMP9 (bone morphogenetic protein 9) is a member of the TGF-ß (transforming growth factor ß) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive. METHODS: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice. RESULTS: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in ß-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice. CONCLUSIONS: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

Nestin+ Mesenchymal Stromal Cells Fibrotic Transition Mediated by CD169+ Macrophages in Bone Marrow Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) involves multiple organs, but little is known about bone marrow (BM) alterations caused by cGVHD. In mice and humans, we found that cGVHD is associated with BM fibrosis resulting in T cell infiltration, IgG deposition, and hematopoietic dysfunction. Macrophages and Nestin+ mesenchymal stromal cells (MSCs) participated in the process of BM fibrosis during BM cGVHD development. BM macrophage numbers were significantly increased in mice and humans with BM fibrosis associated with cGVHD. Amplified macrophages produced TGF-ß1, which recruited Nestin+ MSCs forming clusters, and Nestin+ MSCs later differentiated into fibroblasts, a process mediated by increased TGF-ß/Smad signaling. TLR4/MyD88-mediated activation of endoplasmic reticulum (ER) stress in macrophages is associated with fibrosis by increasing Nestin+ MSC migration and differentiation into fibroblasts. Depletion of macrophages by clodronate-containing liposomes and inhibition of ER stress by 4-phenylbutyric acid reversed BM fibrosis by inhibiting fibroblast differentiation. These studies provide insights into the pathogenesis of BM fibrosis during cGVHD development.

The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.

The BBSome is a complex of Bardet-Biedl Syndrome (BBS) proteins that shares common structural elements with COPI, COPII, and clathrin coats. Here, we show that the BBSome constitutes a coat complex that sorts membrane proteins to primary cilia. The BBSome is the major effector of the Arf-like GTPase Arl6/BBS3, and the BBSome and GTP-bound Arl6 colocalize at ciliary punctae in an interdependent manner. Strikingly, Arl6(GTP)-mediated recruitment of the BBSome to synthetic liposomes produces distinct patches of polymerized coat apposed onto the lipid bilayer. Finally, the ciliary targeting signal of somatostatin receptor 3 needs to be directly recognized by the BBSome in order to mediate targeting of membrane proteins to cilia. Thus, we propose that trafficking of BBSome cargoes to cilia entails the coupling of BBSome coat polymerization to the recognition of sorting signals by the BBSome.

Altered resting-state brain function in endurance athletes.

Previous research has confirmed significant differences in regional brain activity and functional connectivity between endurance athletes and non-athletes. However, no studies have investigated the differences in topological efficiency of the brain functional network between endurance athletes and non-athletes. Here, we compared differences in regional activities, functional connectivity, and topological properties to explore the functional basis associated with endurance training. The results showed significant correlations between Regional Homogeneity in the motor cortex, visual cortex, cerebellum, and the training intensity parameters. Alterations in functional connectivity among the motor cortex, visual cortex, cerebellum, and the inferior frontal gyrus and cingulate gyrus were significantly correlated with training intensity parameters. In addition, the graph theoretical analysis results revealed a significant reduction in global efficiency among athletes. This decline is mainly caused by decreased nodal efficiency and nodal local efficiency of the cerebellar regions. Notably, the sensorimotor regions, such as the precentral gyrus and supplementary motor areas, still exhibit increased nodal efficiency and nodal local efficiency. This study not only confirms the improvement of regional activity in brain regions related to endurance training, but also offers novel insights into the mechanisms through which endurance athletes undergo changes in the topological efficiency of the brain functional network.

Indirect influence in social networks as an induced percolation phenomenon.

Percolation theory has been widely used to study phase transitions in network systems. It has also successfully explained various macroscopic spreading phenomena across different fields. Yet, the theoretical frameworks have been focusing on direct interactions among nodes, while recent empirical observations have shown that indirect interactions are common in many network systems like social and ecological networks, among others. By investigating the detailed mechanism of both direct and indirect influence on scientific collaboration networks, here we show that indirect influence can play the dominant role in behavioral influence. To address the lack of theoretical understanding of such indirect influence on the macroscopic behavior of the system, we propose a percolation mechanism of indirect interactions called induced percolation. Surprisingly, our model exhibits a unique anisotropy property. Specifically, directed networks show first-order abrupt transitions as opposed to the second-order continuous transition in the same network structure but with undirected links. A mix of directed and undirected links leads to rich hybrid phase transitions. Furthermore, a unique feature of the nonmonotonic pattern is observed in network connectivities near the critical point. We also present an analytical framework to characterize the proposed induced percolation, paving the way to further understanding network dynamics with indirect interactions.

Coexistence of Ferromagnetism and Superconductivity at KTaO3 Heterointerfaces.

The coexistence of superconductivity and ferromagnetism is a long-standing issue in superconductivity due to the antagonistic nature of these two ordered states. Experimentally identifying and characterizing novel heterointerface superconductors that coexist with magnetism presents significant challenges. Here, we report the observation of two-dimensional long-range ferromagnetic order in a KTaO3 heterointerface superconductor, showing the coexistence of superconductivity and ferromagnetism. Remarkably, our direct current superconducting quantum interference device measurements reveal an in-plane magnetization hysteresis loop persisting above room temperature. Moreover, first-principles calculations and X-ray magnetic circular dichroism measurements provide decisive insights into the origin of the observed robust ferromagnetism, attributing it to oxygen vacancies that localize electrons in nearby Ta 5d states. Our findings suggest KTaO3 heterointerfaces as time-reversal symmetry breaking superconductors, injecting fresh momentum into the exploration of the intricate interplay between superconductivity and magnetism enhanced by the strong spin-orbit coupling inherent to the heavy Ta in 5d orbitals.

The prognostic significance of MYC/BCL2 double expression in DLBCL in the genetic classification era.

Double expression (DE) is a World Health Organization-recognized adverse prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, the prognostic value of DE in the genetic subtyping era and potential mechanisms remain to be explored. We enrolled 246 DLBCL patients diagnosed between December 2021 and September 2023 in a Jiangsu Province Hospital cohort and included 930 DLBCL patients from three published studies in an external cohort. Double-expression DLBCL (DEL) in the external cohort was mainly distributed in the OTHER subtype (42.0%), EZB subtype (28.3%), and MCD subtype (15.0%), whereas the MCD subtype exhibited the highest ratio of DEL. DEL was significantly related to unfavorable overall survival (OS) and progression-free survival (PFS) in DLBCL, but only in EZB and OTHER subtypes that DEL retained remarkably adverse impacts on survivals compared to non-DEL. We explored the prognostic value of clinical and genetic parameters in DEL patients and found only ST2 showed better OS than A53 in DEL patients, whereas the other subtypes showed no significant difference. DEL showed similarities with the MCD subtype in mutation profiles. Furthermore, RNA-sequencing analyses exhibited upregulation in tumor proliferation-related pathways in DEL patients, but downregulation in extracellular matrix organization, T-cell activation and proliferation, type II interferon production, and pathways associated with cell death might contribute to the poor outcomes of DEL patients.

Differential Expression of KIF18B in Gastric Cancer and Its Role in Chemotherapy Sensitivity.

Gastric cancer (GC) is a main cause of cancer death in the world, and improving the chemotherapy sensitivity can enhance the chemotherapy efficacy of GC. The study objective is to explore the differential KIF18B expression in GC and its effect on GC chemotherapy sensitivity. The KIF18B expression in GC tissues and adjacent normal tissues was analyzed by real-time quantitative polymerase chain reaction. The relationship between differential KIF18B expression and different clinicopathological features was detected. It was found that KIF18B was highly expressed in GC tissues, and KIF18B expression was differential in patients with different clinicopathological features. The upregulation of KIF18B has a positive correlation with the poor therapeutic effect and high KIF18 was associated with lower 3-year overall survival and disease-free survival. The KIF18B-downregulated NCI-N87 cells were constructed and tested by cell counting kit-8 assay and colony formation. Cell migration and invasion were detected by Transwell assay. The xenograft tumor model was established to observe the effect of KIF18B on the efficacy of chemotherapy. The upregulation of KIF18B reduced the chemotherapy sensitivity of GC cells and enhanced their proliferation, migration, and invasion. Silencing KIF18B inhibited tumor growth and promoted chemotherapy efficacy in vivo. In summary, KIF18B inhibitor may have a potential function for improving the efficacy of chemotherapy in GC.

Combining transcriptome and metabolome analysis to understand the response of sorghum to Melanaphis sacchari.

BACKGROUND: The sorghum aphid Melanaphis sacchari (Zehntner) (Homoptera: Aphididae) is an important insect in the late growth phase of sorghum (Sorghum bicolor L.). However, the mechanisms of sorghum response to aphid infestation are unclear. RESULTS: In this paper, the mechanisms of aphid resistance in different types of sorghum varieties were revealed by studying the epidermal cell structure and performing a transcriptome and metabolome association analysis of aphid-resistant and aphid-susceptible varieties. The epidermal cell results showed that the resistance of sorghum to aphids was positively correlated with epidermal cell regularity and negatively correlated with the intercellular space and leaf thickness. Transcriptome and metabolomic analyses showed that differentially expressed genes in the resistant variety HN16 and susceptible variety BTX623 were mainly enriched in the flavonoid biosynthesis pathway and differentially expressed metabolites were mainly related to isoflavonoid biosynthesis and flavonoid biosynthesis. The q-PCR results of key genes were consistent with the transcriptome expression results. Meanwhile, the metabolome test results showed that after aphidinfestation, naringenin and genistein were significantly upregulated in the aphid-resistant variety HN16 and aphid-susceptible variety BTX623 while luteolin was only significantly upregulated in BTX623. These results show that naringenin, genistein, and luteolin play important roles in plant resistance to aphid infestation. The results of exogenous spraying tests showed that a 1‰ concentration of naringenin and genistein is optimal for improving sorghum resistance to aphid feeding. CONCLUSIONS: In summary, the physical properties of the sorghum leaf structure related to aphid resistance were studied to provide a reference for the breeding of aphid-resistant varieties. The flavonoid biosynthesis pathway plays an important role in the response of sorghum aphids and represents an important basis for the biological control of these pests. The results of the spraying experiment provide insights for developing anti-aphid substances in the future.

Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

A Noncentrosymmetric Metal-Free Borophosphate: Achieving a Large Birefringence and Excellent Stability by Covalent-Linkage.

Organic-inorganic hybrid linear and nonlinear optical (NLO) materials have received increasingly wide spread attention in recent years. Herein, the first hybrid noncentrosymmetric (NCS) borophosphate, (C5H6N)2B2O(HPO4)2 (4PBP), is rationally designed and synthesized by a covalent-linkage strategy. 4-pyridyl-boronic acid (4 PB) is considered as a bifunctional unit, which may effectively improve the optical properties and stability of the resultant material. On the one hand, 4 PB units are covalently linked with PO3(OH) groups via strong B-O-P connections, which significantly enhances the thermal stability of 4PBP (decomposition at 321, vs lower 200 °C of most of hybrid materials). On the other hand, the planar π-conjugated C5H6N units and their uniform layered arrangements represent large structural anisotropy and hyperpolarizability, achieving the largest birefringence (0.156 @ 546 nm) in the reported borophosphates and a second-harmonic generation response (0.7 × KDP). 4PBP also exhibits a wide transparency range (0.27-1.50 µm). This work not only provides a promising birefringent material, but also offers a practical covalent-attachment strategy for the rational design of new high-performance optical materials.

Oral colon-targeted pH-responsive polymeric nanoparticles loading naringin for enhanced ulcerative colitis therapy.

An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.

Molecular phylogeny and species diversity of the genus Dichaetophora Duda and related taxa (Diptera: Drosophilidae).

Our intensive surveys of wild drosophilids in East and Southeast Asia discovered a great species diversity (more than 100 putatively new species) of the genus Dichaetophora, which is currently comprised of 67 formally described species assigned into five species groups, i.e., agbo, tenuicauda, acutissima, sinensis and trilobita. In the present study, we delimited species from a huge amount of samples of Dichaetophora and allied taxa (the genus Mulgravea and the subgenus Dudaica of Drosophila) collected from a wide range of the Oriental and east Palearctic regions. We first sorted all specimens into morpho-species, and representative specimen(s) selected from each morpho-species were subjected to barcoding of COI (the cytochrome c oxidase subunit I gene) sequences. The applied ASAP (Assemble Species by Automatic Partitioning) analysis estimated a total of 166 to 168 MOTUs (molecular operational taxonomic units). Integrating this result with morphological evidence from re-examined, detailed structures of male terminalia, we recognized a total of 144 (109 new and 35 known) species in our sample. Out of them, 83 species representing the supraspecific taxa of Dichaetophora, Mulgravea and Dudaica were selected, along with 33 species from major genera and subgenera of Drosophila in the tribe Drosophilini, as in-group and four species from the tribe Colocasiomyini as out-group for phylogenetic reconstruction based on 12 nuclear gene markers. In the trees constructed by the maximum likelihood and Bayesian inference methods, the three focal taxa (i.e., Dichaetophora, Mulgravea and Dudaica) formed a clade provisionally called the "pan-Dichaetophora". Within this large clade, the agbo, tenuicauda, sinensis and trilobita groups of Dichaetophora, Mulgravea and Dudaica were recovered as monophyletic groups, but Dichaetophora and its acutissima group were regarded as paraphyletic. In addition, two clusters were recognized among ungrouped species of Dichaetophora. Thus, the present study has uncovered some issues concerning the taxonomy of the pan-Dichaetophora. Such issues will be addressed elsewhere in the phylogenetic reclassification of the pan-Dichaetophora, along with descriptions/redescriptions of a large number of new/known species delimited in the present study.

Predicting gestational diabetes mellitus risk at 11-13 weeks' gestation: the role of extrachromosomal circular DNA.

BACKGROUND: Gestational diabetes mellitus (GDM) significantly impacts maternal and infant health both immediately and over the long term, yet effective early diagnostic biomarkers are currently lacking. Thus, it is essential to identify early diagnostic biomarkers for GDM risk screening. Extrachromosomal circular DNA (eccDNA), being more stable than linear DNA and involved in disease pathologies, is a viable biomarker candidate for diverse conditions. In this study, eccDNA biomarkers identified for early diagnosis and assessment of GDM risk were explored. METHODS: Using Circle-seq, we identified plasma eccDNA profiles in five pregnant women who later developed GDM and five matched healthy controls at 11-13 weeks of gestation. These profiles were subsequently analyzed through bioinformatics and validated through outward PCR combined with Sanger sequencing. Furthermore, candidate eccDNA was validated by quantitative PCR (qPCR) in a larger cohort of 70 women who developed GDM and 70 normal glucose-tolerant (NGT) subjects. A ROC curve assessed the eccDNA's diagnostic potential for GDM. RESULTS: 2217 eccDNAs were differentially detected between future GDM patients and controls, with 1289 increased and 928 decreased in abundance. KEGG analysis linked eccDNA genes mainly to GDM-related pathways such as Rap1, MAPK, and PI3K-Akt, and Insulin resistance, among others. Validation confirmed a significant decrease in eccDNA PRDM16circle in the plasma of 70 women who developed GDM compared to 70 NGT women, consistent with the eccDNA-seq results. PRDM16circle showed significant diagnostic value in 11-13 weeks of gestation (AUC = 0.941, p < 0.001). CONCLUSIONS: Our study first demonstrats that eccDNAs are aberrantly produced in women who develop GDM, including PRDM16circle, which can predict GDM at an early stage of pregnancy, indicating its potential as a biomarker. TRIAL REGISTRATION: ChiCTR2300075971, http://www.chictr.org.cn . Registered 20 September 2023.

Regulation of Hippo-YAP/CTGF signaling by combining an HDAC inhibitor and 5-fluorouracil in gastric cancer cells.

Histone deacetylase (HDAC) inhibitors diminish carcinogenesis, metastasis, and cancer cell proliferation by inducing death in cancer cells. Tissue regeneration and organ development are highly dependent on the Hippo signaling pathway. Targeting the dysregulated hippo pathway is an excellent approach for cancer treatment. According to the results of this study, the combination of panobinostat, a histone deacetylase inhibitor, and 5-fluorouracil (5-FU), a chemotherapy drug, can act synergistically to induce apoptosis in gastric cancer cells. The combination of panobinostat and 5-FU was more effective in inhibiting cell viability than either treatment alone by elevating the protein levels of cleaved PARP and cleaved caspase-9. By specifically targeting E-cadherin, vimentin, and MMP-9, the combination of panobinostat and 5-FU significantly inhibited cell migration. Additionally, panobinostat significantly increased the anticancer effects of 5-FU by activating Hippo signaling (Mst 1 and 2, Sav1, and Mob1) and inhibiting the Akt signaling pathway. As a consequence, there was a decrease in the amount of Yap protein. The combination therapy of panobinostat with 5-FU dramatically slowed the spread of gastric cancer in a xenograft animal model by deactivating the Akt pathway and supporting the Hippo pathway. Since combination treatment exhibits much higher anti-tumor potential than 5-FU alone, panobinostat effectively potentiates the anti-tumor efficacy of 5-FU. As a result, it is believed that panobinostat and 5-FU combination therapy will be useful as supplemental chemotherapy in the future.

Human activity and climate change accelerate the extinction risk to non-human primates in China.

Human activity and climate change affect biodiversity and cause species range shifts, contractions, and expansions. Globally, human activities and climate change have emerged as persistent threats to biodiversity, leading to approximately 68% of the ~522 primate species being threatened with extinction. Here, we used habitat suitability models and integrated data on human population density, gross domestic product (GDP), road construction, the normalized difference vegetation index (NDVI), the location of protected areas (PAs), and climate change to predict potential changes in the distributional range and richness of 26 China's primate species. Our results indicate that both PAs and NDVI have a positive impact on primate distributions. With increasing anthropogenic pressure, species' ranges were restricted to areas of high vegetation cover and in PAs surrounded by buffer zones of 2.7-4.5 km and a core area of PAs at least 0.1-0.5 km from the closest edge of the PA. Areas with a GDP below the Chinese national average of 100,000 yuan were found to be ecologically vulnerable, and this had a negative impact on primate distributions. Changes in temperature and precipitation were also significant contributors to a reduction in the range of primate species. Under the expected influence of climate change over the next 30-50 years, we found that highly suitable habitat for primates will continue to decrease and species will be restricted to smaller and more peripheral parts of their current range. Areas of high primate diversity are expected to lose from 3 to 7 species. We recommend that immediate action be taken, including expanding China's National Park Program, the Ecological Conservation Redline Program, and the Natural Forest Protection Program, along with a stronger national policy promoting alternative/sustainable livelihoods for people in the local communities adjacent to primate ranges, to offset the detrimental effects of anthropogenic activities and climate change on primate survivorship.