Specific Growth Research Articles

Differential DNA methylation in the benign and cancerous prostate tissue of African American and European American men.

African American (AA) men are at increased risk of prostate cancer (PCa) compared to men of European ancestry (EA). Biological mechanisms, including epigenetics, likely contribute to this disparity, but prior studies have been limited by sample size, candidate gene approaches, or lack of epigenome-wide DNA methylation (DNAm) data. To improve our understanding of these mechanisms, we compared DNAm features distinguishing tumor and paired histologically benign tissue from 76 AA and 75 EA PCa patients. We measured genome-wide array-based DNAm data and conducted differential methylation analyses comparing tumor and benign tissue in each ancestry group. We then examined the predictive ability of our identified sites and differential methylation by ancestry group in each tissue. We identified 90,747 and 98,929 differentially methylated CpGs (dmCpGs) in AA and EA respectively with 76,400 common to both groups. We identified 6,267 genes with differentially methylated promoters common to both ancestries and 639 and 1,301 genes unique to AA and EA respectively as well as differentially methylated pathways. Only 10 CpGs were needed to distinguish tumor from benign based on a receiver operating characteristic curve (area under the curve, AUC>0.9), with dmCpGs in one ancestry predicting tumor vs benign in the other group. We also identified ancestry-associated CpGs (89 in tumor, 423 in benign). Methylation features distinguishing tumor and benign were similar for EA and AA men; however, subtle differences were identified. Differences in tumor and ancestry-associated CpGs may reveal differential tumor growth strategies, an important area for future disparities research.

Proanthocyanidin-Imbued Cellulosic 3-Dimentional Intrinsic Aligned Nanostructures: A Novel Approach for Dental and Bone Regeneration using Dental Pulp Derived Stem Cells

Developing effective scaffolds to address significant bone and dental defects is crucial in regenerative osteal and dental medicine. Traditional methods utilizing synthetic micropatterned scaffolds have effectively stimulated osteogenic and odontogenic differentiation of stem cells through parallel, 3D topographic, hexagonal, and elongated architectural features. However, these approaches face significant cost, scalability, and biocompatibility challenges. Recent advancements have highlighted the potential of decellularized plant scaffolds, such as those derived from Beaucarnea recurvata leaves (BLDS), which offer intrinsic microstructural advantages with solving reproducibility, scalability, incurred cost, and biocompatibility challenges. This study explores the enhancement of BLDS using grape seed proanthocyanidin extract (GSPE), a natural polyphenol known for its beneficial effects on bone and dental stem cell differentiation. By functionalizing BLDS with GSPE, we investigated its impact on osteogenic and odontogenic differentiation of human dental pulp-derived mesenchymal stem cells (DPDMSCs). The modified scaffolds exhibited improved physicochemical properties, including enhanced cell proliferation, protein absorption, scaffold interactions, and upregulated osteogenic and dental marker gene expression. SEM imaging revealed significant cellular growth and morphological changes indicative of successful differentiation. Furthermore, BLDS-GSPE demonstrated increased ALP activity and mineral deposition, suggesting its potential as a cost-effective, reproducible and biocompatible alternative for bone and dental repair compared to conventional synthetic biomaterials.

Protein Phosphatase PP2C19 Controls Hypocotyl Phototropism Through the Phosphorylation Modification of NPH3 in Arabidopsis.

Plants exhibit shoot growth in the direction of the light source to facilitate photosynthesis, known as positive phototropism. In Arabidopsis hypocotyl phototropism, it is thought that a gradient of the signal intensity of the blue light photoreceptor phototropin1 (phot1) between the light-irradiated and shaded sides leads to the differential growth of hypocotyls. The intensity of phot1 signal is regulated not only by the protein kinase activity of phot1 but also by the phosphorylation status of the NONPHOTOTROPIC HYPOCOTYL3 (NPH3) protein, which has a dark form and a blue light form of the phosphorylation modification. Previous studies have shown that phot1 drives the forward reaction from the dark form to the blue light form of NPH3. However, the molecular mechanism underlying the reverse reaction remains unknown. Here, we show that protein phosphatase PP2C19 controls the reverse reaction that converts the blue light form of NPH3 to the dark form of NPH3. The PP2C19 protein possesses the PP2C domain, two cNMP-binding domains, and the protein kinase domain. Similar to phot1 and NPH3, PP2C19 localizes to the plasma membrane, and its PP2C domain is necessary and sufficient for PP2C19 function in hypocotyl phototropism. The pp2c19 mutants show abnormalities in second positive hypocotyl phototropism with a delay in the reverse reaction of NPH3 phosphorylation modification. The present study suggests that continuous blue light irradiation induces an equilibrium state of the reversible reaction of NPH3 phosphorylation, which acts as a phot1 signaling gradient with phot1 kinase activity to induce the second positive phototropism.

What Science in the tropics should not be about

International scientific journals periodically publish articles about research which often takes place in the “global South”, nevertheless, the results of this research are frequently authored and conducted mainly by principal investigators from the “global North”. This reality reflects economic and structural disparities resulting from centuries of differential economic growth, extraction, and exploitation. Although scientists from the global North of this generation do not work for empires which are in the process of active colonization, they still have a responsibility to behave in an intellectual non-imperialistic manner. The authors of this paper, both from the global South (one practicing science in the global North), discuss examples in which the practice of field science or its reporting have failed to be inclusive or even respectful of the local investigators or communities. We also discuss examples of inclusive and respectful papers and point to how the authors of these projects behaved differently. We understand that some linguistic or reporting practices might seem benign to those who use or promote them. However, to those of us who are mis-represented by those reports, these words matter and offend. We are taking this opportunity to discuss these issues with our peers and hope for an inclusive and respectful global practice of field science, as well as a better science communication.

Concentration in contemporary society: Towards a theory of crisis based on Marx and Luhmann

When examining the current form that modern society has acquired, it is hard to overlook the emergence of a systemic dimension that has become far removed from its social-symbolic roots. This systemic dimension is the result of a process of functional differentiation and simultaneous growth that has led to the gradual formation of social systems that, alongside their coordinating effect, give rise to multiple conflicts or crises. But how are the crises of modern societies to be understood in light of this logic of functional differentiation and internal growth? The purpose of this article is to postulate one particular form of crisis, which will be understood as the result of a consubstantial tendency towards systemic growth. The trend takes the form of a concentration of the performances of social systems that recreates modern schemes of stratification, homogenizes the diversity of options and selections of these systems and, by becoming caught up in thoughtless patterns of growth, produces critical scenarios.

The wnt/pyruvate kinase, muscle axis plays an essential role in the differentiation of mouse neuroblastoma cells

Neuronal differentiation and neurite growth are essential processes in nervous system development and are regulated by several factors. Although all-trans retinoic acid (ATRA) has been shown to mediate the differentiation of mouse neuroblastoma cells via the activation of several pathways, including Wnt/β-catenin signaling, the mechanism remains unclear. The pyruvate kinase, muscle (PKM) plays an important role in the glycolysis of neuroblastoma cells and regulates the Wnt signaling pathway in various cancer cells. In this study, we hypothesized that the Wnt/PKM axis regulates the differentiation of neuroblastoma cells (Neuro-2a and N1E-115). To test this hypothesis, we used inhibitors and activators of the Wnt/β-catenin and glycolytic pathways in ATRA-induced differentiated Neuro-2a and N1E-115 cells and established cell lines with silenced or a mutant replacement of Pkm. Western blot and qPCR showed that ATRA treatment activated the Wnt signaling pathway and inhibited PKM-mediated glycolysis. The oxygen consumption rate (indicating oxidative phosphorylation) significantly increased, whereas the extracellular acidification rate (indicating glycolysis) significantly decreased during differentiation; these effects were reversed upon PKM inhibition. The Wnt inhibitor ICG-001 and PKM activator ML-265 inhibited ATRA-induced Neuro-2a and N1E-115 differentiation, whereas RNA interference-mediated Pkm silencing promoted Neuro-2a and N1E-115 differentiation, which was reversed by PKM overexpression. Treatment with the Wnt activator kenpaullone promoted Neuro-2a and N1E-115 differentiation, which was reversed by ML-265 administration. These results indicate that Wnt/β-catenin signaling promotes Neuro-2a and N1E-115 differentiation by inhibiting PKM-mediated glycolysis during ATRA-induced differentiation. These findings may provide a new theoretical basis for the role of glycolysis in nerve differentiation.

CNSC-43. NEUROTRANSMITTER DEPENDENCY UNDERLIES TUMOR GROWTH IN HUMANIZED PEDIATRIC LOW-GRADE GLIOMA MODELS

Abstract Brain tumors arise in close association with neurons, suggesting that these non-neoplastic cells may be critical stromal drivers of brain tumor initiation and growth. Previously, we have shown that murine low-grade optic glioma formation and progression in the setting of Neurofibromatosis type 1 (NF1) is dictated by neurons and neuronal activity. In these studies, these neuronal dependencies reflected neuronal activity-driven enzymatic cleavage of a growth factor (neuroligin-3) from oligodendrocyte precursors cells (tumor initiation) or neuronal production of a paracrine factor to stimulate T cell support of optic glioma growth (tumor progression). Since neurons typically communicate with other neurons through neurotransmitters, we sought to explore the possibility that neurotransmitters operate to modulate low-grade glioma growth using humanized mouse models of pilocytic astrocytoma (PA). Leveraging single cell RNA sequencing of three independent sets of pediatric PAs, we identified neurotransmitter pathway enrichment in the tumor cells. This neurotransmitter pathway enrichment reflected aberrant expression of specific neurotransmitter receptors, which we confirmed in three independently generated PA tissue microarrays and in five distinct primary PA cell lines grown in vitro. Moreover, this aberrant neurotransmitter receptor expression established differential neurotransmitter PA growth dependencies in vitro. Importantly, interruption of neurotransmitter signaling in human PA xenografts attenuated tumor growth and ERK activation in Rag1-/- mice in vivo. Finally, we discovered crosstalk between neurotransmitter receptor and receptor tyrosine kinase signaling that revealed another target for therapeutic inhibition. Taken together, these findings elucidate a previously unknown neurotransmitter PA growth dependency amenable to therapeutic targeting.

Kinetic modelling and salinity tolerance in Chlorella vulgaris and Desmodesmus communis (Chlorophyta): insights into differential growth responses

Kinetic modelling and salinity tolerance in Chlorella vulgaris and Desmodesmus communis (Chlorophyta): insights into differential growth responses

KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation.

Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription. Second, ARF targets the RUNX family transcription factor 1 (RUNX1) to selectively tune gene transcription. Consistently, ARF loss triggers RUNX1- and PAF1c-dependent transcriptional activation of pro-growth ligands (growth differentiation factor/bone morphogenetic protein [GDF/BMP]), promoting a cell-intrinsic GDF/BMP-Smad1/5 axis that aberrantly induce cell growth. Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.

Precommercial Thinning but Not Commercial Thinning Increases the Merchantable and Large Sawlog Volume Production of Lodgepole Pine on Fair Sites

Abstract The effect of thinning on stand structure and volume production is well studied. However, the effect of combinations of precommercial (PCT) and commercial thinning (CT) on the production of different log grades and differential growth responses is less understood, although it is crucial for forest managers to choose an optimal management regime. Starting with actual operational field data from a lodgepole pine (Pinus contorta var.latifolia) PCT trial on fair quality sites (site index: 16–18 m at 50 years), we used an individual tree growth model to forecast development over the entire rotation. We found thinning changed the structure (density, quadratic mean diameter) of the stands but not the total volume production. However, in terms of merchantable volume and large sawlog volume, stands with only PCT provided the largest volume, more than either CT or a combination of PCT and CT, or the unthinned control. Moreover, our study findings also showed that, by doing only PCT, stands reached maximum merchantable or large sawlog mean annual increment earlier than other thinned or unthinned stands. This indicates that PCT might shorten the rotation length and contribute to an enhanced supply of timber. Study Implications: The effect of commercial thinning (CT) on stand structure and volume production is well studied. However, the effect of combinations of precommercial (PCT) and commercial thinning (CT) on the production of different log grades and differential growth responses is less studied, although it is crucial for forest managers to choose a management option. Starting with actual operational field data from a lodgepole pine (Pinus contorta var.latifolia) PCT trial in a fair-quality site (site index [SI]: 16–18), we used an individual tree growth model to develop the stands over the entire rotation. We found thinning changed the structure (density, quadratic mean diameter) of the stands but not the total volume production. However, in terms of merchantable volume and large sawlog volume, stands with only PCT provided the largest volume, more than either CT or a combination of PCT and CT, or the unthinned control. Moreover, our study findings also showed that, by doing only PCT, stands reached maximum merchantable or large sawlog MAI earlier than other thinned or unthinned stands. This indicates that PCT might shorten the rotation length and contribute to the continuous supply of timber production.

Commercial inpatient hospital price growth driven by system affiliation and nonprofit-status hospitals.

As policymakers continue to grapple with rising health care costs and prices, understanding trends and variations in inpatient prices among hospital characteristics is an important benchmark to allow policymakers to craft targeted policies. In this study, we provide descriptive trends on variation in inpatient prices paid by commercial health plans stratified by hospital characteristics using data from Health Care Cost Institute's employer-sponsored insured claims data. Our analyses found evidence of considerable variation among inpatient price levels and growth among system affiliation and profitability. Prices among system-affiliated hospitals grew from $14 281.74 in 2012 to $20 731.95 in 2021, corresponding to a 45.2% increase during this period. On the other hand, prices among independent hospitals grew more slowly, from $13 460.50 in 2012 to $18 196.90 in 2021, corresponding to a 35.2% increase. We did not observe a similar trend in growth rates among case mix index by hospital characteristics, implying that differential inpatient price growth is not driven by changes in case mix by hospital characteristics. Heterogeneity in hospital prices and price growth by type of hospital suggests that public and private policymakers aiming to rein in health spending should consider policies that address this variation.

Mapping and evaluating spatiotemporal patterns of urban expansion in global earthquake-affected areas: a nighttime light remote sensing perspective

ABSTRACT Amidst the backdrop of frequent global earthquakes, assessing the spatiotemporal dynamics of urban expansion in earthquake-affected areas is imperative for sustainable development insights. The current analyses, however, are primarily focused on administrative units or some specific natural units. Here, we quantified spatiotemporal patterns of urban expansion from 2000 to 2020 in global earthquake-affected areas globally. Specifically, we delineated such areas using data from earthquakes of magnitude 5.5 and above since 1965. Then, employing nighttime light remote sensing data, we extracted urban entities and systematically evaluated the spatiotemporal patterns of urban expansion in earthquake-affected areas. The findings indicate a phase-based differential growth in urban expansion in earthquake-affected areas from 2000 to 2020. The average deceleration factor for urban areas in earthquake-affected areas over the past 20 years is 128.67%. Urban expansion in earthquake-affected areas is growing at a rapid pace, except for Europe and North America. In addition, 66.7% of urban expansion in global earthquake-affected areas presents low-density sprawl and solitary edge expansion trends, potentially affecting population density and land use efficiency. This study offers the most exhaustive analysis of urban expansion in earthquake-affected areas in recent decades and calls for administration beyond administrative boundaries to some extent.

Growth performances of Clarias gariepinus juveniles fed with Jatropha curcas seed meal

Jatropha curcas is an oil producing seed with high nutritional qualities for consumption. However, due to inherent anti-nutritional factors, appropriate processing is necessary to improve its nutrients utilization. This study was aimed at processing J. curcas using solvent-extraction method and evaluating its inclusion effects in the diet for Clarias gariepinus on its growth status. J. curcas meal was extracted using 80 % methanol to remove phorbol esters and other anti-nutrients. Thereafter, five iso-nitrogenous diets (40 % crude protein) were formulated containing J. curcas meal replacements of soybeans meal at 0 % (TRT0), 25 % (TRT25), 50 % (TRT50), 75 % (TRT75) and 100 % (TRT100) and fed to C. gariepinus for 70 days. Results showed that TRT25 fish had the highest mean weight gain and specific growth. The serum alkaline phosphate, alanine aminotransferase, and aspartate aminotransferase levels began to rise significantly (p ≤ 0.05) at 50 % replacement. Likewise, the assessment of gut ecology and morphology indicated that TRT25 had significantly (p ≤ 0.05) the highest gut bacteria colony forming unit (2.60 ×104±0.02cfu/g) and most favorable area of absorption (0.16±0.01 cm2). The histopathological observation of the fish intestine, liver and gills indicated no visible deformity in TRT0 and TRT25 fish. However, various degrees of degenerations were observed in the fish fed with 50 % and higher inclusion of J. curcas. This study showed that methanol-extracted J. curcas meal can be effectively utilized for C. gariepinus at 25 % of replacement.

The Modulation of Growth and Metabolism in Solanum lycopersicum Contrast With the Leaf-Specific Regulation of Wild Tomato Species.

Plant organs harbour diverse components that connect their physiology to the whole organism. The turnover of metabolites may be higher in some organs than in others, triggering differential growth patterns throughout the organism. We revealed that Solanum lycopersicum exhibits more coordinated growth and physiology across the entire plant compared to wild tomato species. Specifically, young leaves of S. lycopersicum develop more slowly than mature leaves, whereas wild species do not exhibit this pattern. Wild tomato Solanum pennellii displays young leaves with higher photosynthetic rates than mature leaves. Consequently, sucrose metabolism in S. pennellii is quite similar between young and mature leaves, while expression patterns of circadian clock genes differ significantly between leaves of different ages. Additionally, we demonstrated that introducing alleles related to tomato domestication into the wild tomato Solanum pimpinellifolium promotes coordinated growth between young and mature leaves, resulting in similar patterns to those observed in S. lycopersicum. Collectively, S. lycopersicum appears to exhibit more coordinated regulation of growth and metabolism, and understanding this process is likely fundamental to explaining its elevated harvest index.

Chemical Characteristics of Zirconium Chloride and Zirconium Oxide Nanoparticles Driving Toxicity on Lemna minor

The increasing global production and utilization of zirconium (Zr) compounds, including zirconium chloride (ZrCl4) and zirconium oxide nanoparticles (NPs-ZrO2), raises concerns about their potential environmental impact. This study investigated the toxicity mechanisms of ZrCl4 and NPs-ZrO2 on the aquatic plant Lemna minor. The physicochemical properties of NPs-ZrO2 in the test medium were characterized, revealing concentration-dependent changes in the hydrodynamic diameter, zeta potential, and solubility over time. The analysis of Zr speciation showed the predominance of Zr(OH)4(aq) species from ZrCl4. Plants of L. minor exposed to ZrCl4 and NPs-ZrO2 exhibited differential Zr bioaccumulation, growth inhibition, oxidative stress, and antioxidant responses. ZrCl4 induced a higher toxicity than NPs-ZrO2, with bioaccumulation strongly correlating with adverse effects. The differential toxicity impact between these two Zr-compounds was also determined by the lowest observed-effect doses for growth and biochemical parameters. The scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy confirmed internalization of NPs-ZrO2 and Zr uptake in the L. minor plant. Therefore, these findings highlighted the importance of chemical speciation, environmental transformations, and biological responses in assessing the ecological impact of Zr-compounds for effective risk assessment and management strategies for protecting aquatic ecosystems.

Distribution of genotypes by the growth diferential factor 9 (GDF-9) gene locus in the romanov breed sheep population

The FecG gene, also known as GDF-9 (growth factor differentiation factor 9), plays an important role in regulating reproductive function in mammals. This paper presents the results of a study of a point mutation in the differential growth factor gene in Romanov breed sheep. Mutations in exon 1 of the GDF-9 gene can lead to disturbances in ovarian development and ovulation, resulting in infertility or reduced reproductive capacity in animals. The object of the study was Romanov breed sheep in a sample of 30 individuals. For DNA extraction, venous blood samples were taken from the jugular vein. In Romanov breed sheep for the GDF-9 gene, it was found that at the G1 locus of this gene there are two alleles – G and A. Three genotypes were also identified: GG (254 bp/117 bp), AG (410bp/254/117 bp) and AA (410 bp/410 bp). The observed χ2 criterion was less than expected, therefore, the empirical and theoretical frequencies do not differ significantly, and deviations from the distribution according to the Hardy-Weinberg law are not observed. The observed heterozygosity index (Ho) was 0.27. Allele frequencies were 0,8 for G and 0,2 for A. For genotypes the following were obtained: GG – 0,66, GA – 0,27 and AA – 0,07.It can be noted that the data on the frequencies of alleles and genotypes in the population of Romanov breed sheep differ from the results for the Kulunda fine-wool, Dagestan mountain, Salsk, Lacaune and Merino breeds. The research results can be used to monitor changes in allele frequencies and genotypes in sheep during the selection process.

Laser powder bed fusion printed poly-ether-ether-ketone/bioactive glass composite scaffolds with dual-scale pores for enhanced osseointegration and bone ingrowth

Although poly-ether-ether-ketone (PEEK) implants hold significant medical promise, their bioinert nature presents challenges in osseointegration and bone ingrowth within clinical contexts. To mitigate these challenges, the present study introduces Diamond PEEK/bioactive glass (BG) composite scaffolds, characterized by macro/micro dual-porous structures, precisely fabricated via laser powder bed fusion (LPBF) technology. The findings indicate that an increase in BG content within these scaffolds significantly augments their hydrophilicity and hydroxyapatite formation capacities. Stress-strain curve analysis demonstrates reliable load-bearing stability across all scaffold types. In vitro assessments confirmed the non-cytotoxicity of PEEK/BG samples and demonstrated improved osteogenic differentiation and mineralization with increased BG incorporation. Further, in vivo experiments illustrated that the Diamond porous structure of these scaffolds facilitated bone growth, an effect notably amplified with higher BG content. Particularly in groups with 15 wt.% and 25 wt.% BG scaffolds, new bone formation was observed not only within the macropores of the Diamond structure but also within the micropores inside the scaffold rod, suggesting an almost seamless fusion with the new bone. This demonstrates the scaffolds’ effective osteointegration and bone ingrowth properties. This study conclusively established the effectiveness of Diamond-structured PEEK/BG composite scaffolds, fabricated via LPBF, in bone repair. It highlights the crucial role of BG in enhancing osteogenic potential through interaction with the macro/micro pores of the scaffold. Statement of significanceThis study addresses the bioinert nature of PEEK implants by developing Diamond-structured PEEK/bioactive glass (BG) composite scaffolds by laser powder bed fusion. The dual-porous macro/microstructure enhances hydrophilicity and hydroxyapatite formation, vital for bone regeneration. By adjusting the BG content, we controlled the melt viscosity and sintering rate, leading to the formation of beneficial microscale pores. These pores resolve the issue of ineffective bioactive fillers in previous LPBF-fabricated scaffolds, enhancing the osteogenic potential of BG and inducing superior bone ingrowth and osseointegration. In vitro and in vivo analyses show enhanced osteogenic differentiation, mineralization, and bone growth, underscoring the clinical potential of these scaffolds for bone repair.

Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3ʹ untranslated region (3ʹUTR) of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.

Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer.

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3' untranslated region (3'UTR) of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.