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Stochastic chemical kinetics is a widely used formalism for studying stochasticity of chemical reactions inside single cells. Experimental studies of reaction networks are generally performed with cells that are part of a growing population, yet the population context is rarely taken into account when models are developed. Models that neglect the population context lose their validity whenever the studied system influences traits of cells that can be selected in the population, a property that naturally arises in the complex interplay between single-cell and population dynamics of cell fate decision systems. Here, we represent such systems as absorbing continuous-time Markov chains. We show that conditioning on non-absorption allows one to derive a modified master equation that tracks the time evolution of the expected population composition within a growing population. This allows us to derive consistent population dynamics models from a specification of the single-cell process. We use this approach to classify cell fate decision systems into two types that lead to different characteristic phases in emerging population dynamics. Subsequently, we deploy the gained insights to experimentally study a recurrent problem in biology: how to link plasmid copy number fluctuations and plasmid loss events inside single cells to growth of cell populations in dynamically changing environments. [ABSTRACT FROM AUTHOR]

This study sought to evaluate the influence of five macronutrients (acetate, calcium, sulfate, nitrogen, and phosphate) on the cell growth and heterologous mCherry protein production by Chlamydomonas reinhardtii. In the first step, three nitrogen (N) sources were tested (NH4NO3, NaNO3, and NH4Cl), and NH4NO3 was selected as N source for the following step, due to the best results for mCherry protein production. In the second step, a central composite design 25 was employed to evaluate the effect of the five macronutrients. Although all nutrients had effect on maximum biomass concentration, only acetate, nitrogen, and phosphate showed to influence mCherry protein production. By employing the experimental design with small‐scale culture in multiplates and multivariable regression, it was possible to achieve 12 % increase for recombinant protein production. [ABSTRACT FROM AUTHOR]

Plants develop along apical-basal and radial axes. In Arabidopsis thaliana , the radial axis becomes evident when the cells of the 8-cell proembryo divide periclinally, forming inner and outer cell layers. Although changes in cell polarity or morphology likely precede this oriented cell division, the initial events and the factors regulating radial axis formation remain elusive. Here, we report that three transcription factors belonging to the class IV homeodomain-leucine zipper (HD-ZIP IV) family redundantly regulate radial pattern formation: HOMEODOMAIN GLABROUS11 (HDG11), HDG12, and PROTODERMAL FACTOR2 (PDF2). The hdg11 hdg12 pdf2 triple mutant failed to undergo periclinal division at the 8-cell stage and cell differentiation along the radial axis. Live-cell imaging revealed that the mutant defect is already evident in the behavior of the embryo's initial cell (apical cell), which is generated by zygote division. In the wild type, the apical cell grows longitudinally and then radially, and its nucleus remains at the bottom of the cell, where the vertical cell plate emerges. By contrast, the mutant apical cell elongates longitudinally, and its nucleus releases from its basal position, resulting in a transverse division. Computer simulations based on the live-cell imaging data confirmed the importance of the geometric rule (the minimal plane principle and nucleus-passing principle) in determining the cell division plane. We propose that HDG11, HDG12, and PDF2 promote apical cell polarization, i.e., radial cell growth and basal nuclear retention, and set proper radial axis formation during embryogenesis. [Display omitted] • Several HD-ZIP IV genes are transcribed in the zygote and the proembryo epidermis • HDG11/12 and PDF2 redundantly regulate radial axis formation after zygote division • Apical daughter cell of the zygote selects division plane based on geometric rules • Polar cell growth and nuclear retention set the proper geometry of the apical cell Tanaka et al. show that three HD-ZIP IV transcription factors, HDG11, HDG12, and PDF2, are required for radial embryo patterning in Arabidopsis thaliana. They regulate radial cell growth and polar nuclear retention in the apical daughter cell of the zygote, suggesting that the radial polarization is already initiated just after zygote division. [ABSTRACT FROM AUTHOR]

In this article, site‐specific functionalized keratoprosthesis (KPro) was accomplished to meet epithelial on‐growth on the anterior optical surface, inhibit cell adhesion on the posterior optic surface, and promote cell ingrowth at the peripheral tissue‐haptic‐flange interface toward tissue integration. Gelatin immobilization on PC4 hydrogel surfaces was achieved through acid hydrolysis followed by EDC/NHS chemistry, and polyethylene glycol‐diacrylate (PEGDA)‐modified inter‐penetrating network (IPN) surfaces were prepared using photo‐polymerization of ethylene glycol‐diacrylate (EGDA) for enhancing and inhibiting cellular growth, respectively. The surface chemical structures of modified hydrogels were characterized using attenuated total reflectance‐infrared (ATR‐IR) spectroscopy and a bicinchoninic acid (BCA) protein adsorption assay. Further, suitable differentially functionalized surfaces were prepared and characterized using the universal testing machine (UTM), refractometer, atomic force microscopy (AFM), and contact angle measurements to understand mechanical, optical, surface morphological, and wettability properties, respectively. Finally, in vitro site‐specific cell adhesion, cell inhibition, and cell ingrowth functionalities were tested using isolated goat corneal limbal epithelial stem cells and corneal stromal fibroblast cells, respectively. Overall, the two connective articles represent a successful endeavor to develop a more esthetically pleasing, mechanically stable, tissue‐free hydrogel KPro with site‐specific surface functionality nearly mimicking the cornea's functionality. A further pre‐clinical investigation is necessary to advance this functional novel KPro to reality, especially the tissue integration aspect. [ABSTRACT FROM AUTHOR]

Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor-and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor-and nerve-derived SEMA3D indirectly reprograms macrophages through KRASMUT-dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRASMUT-dependent manner. [ABSTRACT FROM AUTHOR]

Proteasome inhibition emerges as a promising strategy for cancer prevention. PNO1, pivotal for colorectal cancer (CRC) progression, is involved in proteasome assembly in Saccharomyces cerevisiae. Hence, we aimed to explore the role of PNO1 in proteasome assembly and its up- and down-streams in CRC. Here, we demonstrated that PNO1 knockdown suppressed CRC cells growth, proteasome activities and assembly, as well as CDKN1B/p27Kip1 (p27) degradation. Moreover, p27 knockdown partially attenuated the inhibition of HCT116 cells growth by PNO1 knockdown. The up-stream studies of PNO1 identified miR-326 as a candidate miRNA directly targeting to CDS-region of PNO1 and its overexpression significantly down-regulated PNO1 protein expression, resulting in suppression of cell growth, decrease of proteasome activities and assembly, as well as increasing the stability of p27 in CRC cells. These findings indicated that miR-326 overexpression can suppress CRC cell growth, acting as an endogenous proteasome inhibitor by targeting PNO1. [ABSTRACT FROM AUTHOR]

A series of imidazothiazoles (ITZs) were conveniently accessed via an improved four‐step protocol in 55%–79% yields. The synthesized ITZs were tested in a combination of a phenotypic sea urchin embryo assay and PC‐3 human adenocarcinoma cytotoxicity studies. Both experimental approaches converged on compounds that showed microtubule targeting activity and cytotoxicity similar to the control compound, combretastatin CA‐4. Specifically, ITZs featuring electron‐donating pharmacophores in position 4, including 4‐Me‐, 4‐OMe‐, 3‐amino‐4‐Me‐, and 3,4‐ethylenedioxy‐substituted benzene ring (6, 7, 28, and 34) exhibited consistent antimitotic antitubulin effect along with the pronounced inhibition of PC‐3 cells growth. These compounds altered cleavage of the sea urchin eggs at 0.002–0.005 µM concentration and displayed cytotoxicity with IC50 values of 0.020–0.47 µM. Notably, the compound ITZ (25) featuring 3,4‐dimethoxybenzene fragment selectively inhibited growth of malignant PC‐3 cells (IC50 = 0.52 µM) while showing no effect on the sea urchin embryo development at up to 4 µM concentration. The sea urchin embryo screen also identified ITZs with systemic toxicity or solubility issues. The assay can be used to prioritize tubulin‐specific molecules for advanced evaluation. [ABSTRACT FROM AUTHOR]

Photobiomodulation (PBM) occurs when a cell is exposed to low energy intensities. A novel central venous port (CVP) with light-emitting diodes (LEDs) that emits red light with a wavelength of 680 nm via wireless energy transmission technology has been established. This comparative in vitro study examined whether PBM can reduce the growth of methicillin-resistant Staphylococcus aureus (MRSA), a common cause of central venous (CV) infections, in vitro. In this comparative in vitro study, the red light with a wavelength of 680 nm was used to irradiate an MRSA suspension in phosphate-buffered saline for 7.5, 15, 30, or 60 min in a 3.5 cm Petri dish with an area of 8.5 cm2. The total energy was 85 J at 7.5 min, 170 J at 15 min, 340 J at 30 min, and 680 J at 60 min. Six dishes for each time and 6 temperature-controlled samples were prepared. Each sample was incubated overnight at 37℃. The Shapiro-wilk test was used to determine whether the data were normally distributed. The numbers of colonies were counted and compared using one-factor ANOVA and Bonferroni's post-hoc test. The mean numbers of colonies in the control group were 60.3, where the numbers of colonies in the irradiated group were 51.4 at 7.5 min, 53.5 at 15 min, 44.6 at 30 min, 34.3 at 60 min. The mean number of colonies in the 60 min irradiated group differed significantly from that in the control, 7.5 min, and 15 min groups. The Bonferroni's post-hoc test showed significant difference in the number of colonies between control vs. 30 min control vs. 60 min, 7.5 min vs. 60 min, 15 min vs. 60 min. PBM with 680 nm LEDs on MRSA for 340 J at 30 min and 680 J at 60 min inhibited the growth of cell colonies. These findings support the use of photobiomodulation in Central venous port to prevent CV access port-Blood stream infection. [ABSTRACT FROM AUTHOR]

Toxins have been proposed as a defense mechanism for phytoplankton against zooplankton grazing. However, the associated costs are not understood. Here, we aim to reveal the costs in terms of both physiological and molecular responses in the cylindrospermopsin (CYN)‐producing cyanobacterium Raphidiopsis raciborskii. Exposure of R. raciborskii to Daphnia magna resulted in a significant increase in its CYN cell quota which was grazer cell density‐dependent, indicating an inducible effect on CYN production. A negative and significant relationship between cellular growth rate and CYN production suggested a growth‐defense trade‐off, highlighting the costly nature of toxin production. Despite strong transcriptional responses (121 differentially expressed genes) in R. raciborskii under grazing pressure, the CYN gene cluster remained largely unaffected, implying post‐transcriptional regulation of CYN biosynthesis. Significant variation was observed in transcripts for phosphorus metabolism and photosynthesis‐related genes, and evidenced that energy (ATP) metabolic processes were stimulated. This study is the first to demonstrate the high energy requirements for CYN production and provide insight into the molecular basis underlying the costs of toxin production. [ABSTRACT FROM AUTHOR]

Introduction: Bladder cancer (BCa) is a common malignancy in the urinary tract. It has high recurrence rates and often requires microscopic examination, which presents significant challenges in clinical treatment. Previous research has shown that circular TAF4B (circTAF4B) is significantly upregulated in BCa and is associated with a poor prognosis. However, the specific targets and molecular mechanisms by which circTAF4B functions in BCa are still not well - understood. Methods: In this study, an RNA pull - down assay and mass spectrometry were utilized to identify MFN2 as a binding protein of circTAF4B. Additionally, siRNA was used to silence MFN2 to observe the amplification of the inhibitory effects of circTAF4B overexpression on cell growth and migration in BCa cells. Moreover, circTAF4B shRNA lentiviral particles were employed to study their impact on BCa progression by examining the regulation of p27 and the blocking of AKT signaling. Results: It was found that MFN2 is a binding protein of circTAF4B. Silencing MFN2 with siRNA enhanced the inhibitory effects of circTAF4B overexpression on cell growth and migration in BCa cells. Also, circTAF4B shRNA lentiviral particles inhibited BCa progression by upregulating p27 and blocking AKT signaling. Discussion: In conclusion, the physical binding of circTAF4B to MFN2 is a crucial process in the tumorigenesis and progression of BCa. Targeting circTAF4B or its complexes may have potential as a therapeutic strategy for BCa diagnosis and treatment. [ABSTRACT FROM AUTHOR]

This study evaluated the in vitro effectiveness of anti-cryptosporidial agents nitazoxanide, halofuginone, the pyrazolopyridine analog KDU731, and paromomycin (PMC) in combating the significant zoonotic pathogen Cryptosporidium parvum. The study utilized HCT-8 host cells to culture C. parvum and fluorescent microscopy/quantitative PCR (qPCR) for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations (IC) against the total growth of C. parvum at 48h post-infection. The study further investigated the impact of these compounds on early parasitophorous vacuole (PV) formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102nM±2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects on C. parvum and the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, which emphasizes the importance of integrated strategies in controlling zoonotic diseases. [ABSTRACT FROM AUTHOR]

SUMMARY: The lenticel is a channel‐like structure that facilitates oxygen, carbon dioxide, and water vapor exchange on secondary growth tissue, such as a tree stem. Although the structure of lenticel has been described, there is limited understanding regarding the impact of this secondary structure on secondary growth as well as the cellular and metabolic processes underlying its formation. The study reveals the essential role of the lenticel in the process of tree secondary growth and the cellular and metabolic processes that take place during its formation. Under the stomata, lenticel development occurs when cells divide and differentiate into a structure of disconnected cells with air spaces between them. During lenticel formation, specific metabolic pathways and wax biosynthesis are activated. The SERK (somatic embryogenesis receptor kinase) gene controls lenticel density, and serk1serk3serk5 triple mutants enhance lenticel initiation. The findings shed light on the cellular and metabolic processes involved in lenticel formation, laying the groundwork for further mechanistic elucidation of their development, function, and genetic regulation in trees. Significance Statement: The lenticel is a porous, channel‐like structure that forms during plant secondary growth. Despite the description of the general structure of lenticels, their impact on plant growth and the specific cellular and molecular processes involved in their development remain incompletely understood. The study elucidates the critical role of the lenticel in tree growth and delineates the cellular process and metabolic specialization involved in its development. [ABSTRACT FROM AUTHOR]

The RAB interacting factor (RABIF) is a putative guanine nucleotide exchange factor that also functions as a RAB-stabilizing holdase chaperone. It has been implicated in pathogenesis of several cancers. However, the functional role and molecular mechanism of RABIF in hepatocellular carcinoma (HCC) are not entirely known. Here, we demonstrate an upregulation of RABIF in patients with HCC, correlating with a poor prognosis. RABIF inhibition results in decreased HCC cell growth both in vitro and in vivo. Our study reveals that depleting RABIF attenuates the STOML2-PARL-PGAM5 axis-mediated mitophagy. Consequently, this reduction in mitophagy results in diminished mitochondrial reactive oxygen species (mitoROS) production, thereby alleviating the HIF1α-mediated downregulation of glycolytic genes HK1, HKDC1, and LDHB. Additionally, we illustrate that RABIF regulates glucose uptake by controlling RAB10 expression. Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a previously unrecognized role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target. RABIF upregulation promotes HCC growth, mitophagy, and glycolysis, and enhances sorafenib resistance, suggesting it as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

The metabolic networks of microorganisms are remarkably robust to genetic and environmental perturbations. This robustness stems from redundancies such as gene duplications, isoenzymes, alternative metabolic pathways, and also from non‐enzymatic reactions. In the oxidative branch of the pentose phosphate pathway (oxPPP), 6‐phosphogluconolactone hydrolysis into 6‐phosphogluconate is catalysed by 6‐phosphogluconolactonase (Pgl) but in the absence of the latter, the oxPPP flux is thought to be maintained by spontaneous hydrolysis. However, in Δpgl Escherichia coli, an extracellular pathway can also contribute to pentose phosphate synthesis. This raises question as to whether the intracellular non‐enzymatic reaction can compensate for the absence of 6‐phosphogluconolactonase and, ultimately, on the role of 6‐phosphogluconolactonase in central metabolism. Our results validate that the bypass pathway is active in the absence of Pgl, specifically involving the extracellular spontaneous hydrolysis of gluconolactones to gluconate. Under these conditions, metabolic flux analysis reveals that this bypass pathway accounts for the entire flux into the oxPPP. This alternative metabolic route—partially extracellular—sustains the flux through the oxPPP necessary for cell growth, albeit at a reduced rate in the absence of Pgl. Importantly, these findings imply that intracellular non‐enzymatic hydrolysis of 6‐phosphogluconolactone does not compensate for the absence of Pgl. This underscores the crucial role of Pgl in ensuring the efficient functioning of the oxPPP. [ABSTRACT FROM AUTHOR]

5-Demethylnobiletin is the active ingredient in citrus polymethoxyflavones that could inhibit the proliferation of several tumor cells. However, the anti-tumor effect of 5-Demethylnobiletin on glioblastoma and the underlying molecular mechanisms are remains unknown. In our study, 5-Demethylnobiletin markedly inhibited the viability, migration and invasion of glioblastoma U87-MG, A172 and U251 cells. Further research revealed that 5-Demethylnobiletin induces cell cycle arrest at the G0/G1 phase in glioblastoma cells by downregulating Cyclin D1 and CDK6 expression levels. Furthermore, 5-Demethylnobiletin significantly induced glioblastoma cells apoptosis by upregulating the protein levels of Bax and downregulating the protein level of Bcl-2, subsequently increasing the expression of cleaved caspase-3 and cleaved caspase-9. Mechanically, 5-Demethylnobiletin trigged G0/G1 phase arrest and apoptosis by inhibiting the ERK1/2, AKT and STAT3 signaling pathway. Furthermore, 5-Demethylnobiletin inhibition of U87-MG cell growth was reproducible in vivo model. Therefore, 5-Demethylnobiletin is a promising bioactive agent that might be used as glioblastoma treatment drug. [ABSTRACT FROM AUTHOR]

SUMMARY Photosynthetic electron transport is carried out by the electron carrier, plastoquinone (PQ). Recently, another form of PQ, acylplastoquinol (APQ), was discovered in Synechocystis sp. PCC 6803 (Synechocystis), but its physiological function in photosynthesis is unclear. In the present study, we identified a lipase encoded in sll0482 gene in Synechocystis that deacylates APQ and releases a free fatty acid and a reduced PQ (plastoquinol, PQH2), which we named acylplastoquinol lipase (APL). Disruption of apl gene increased APQ content, and recovery of photodamaged PSII under low light (LL) after the exposure to very high light (vHL) at 2500 μmol photons m−2 sec−1 without aeration (vHL) for 60 min, was suppressed in the Δapl cells. Δapl cells also show the slow rate of de novo synthesis of D1, a reaction center of PSII under such condition. Under high light, the cellular growth of Δapl was inhibited; however, disruption of apl gene did not affect the photosynthetic activity or photoinhibition of PSII. In wild‐type cells, APQ content increased under vHL condition. Also, APQ was converted to PQH2 after transfer to LL with aeration by ambient air. Such striking changes in APQ were not observed in Δapl cells. The deacylation of APQ by APL may help repair PSII when PSII cannot drive photosynthetic electron transport efficiently. [ABSTRACT FROM AUTHOR]

In proliferating bacteria, growth rate is often assumed to be similar between daughter cells. However, most of our knowledge of cell growth derives from studies on symmetrically dividing bacteria. In many α-proteobacteria, asymmetric division is a normal part of the life cycle, with each division producing daughter cells with different sizes and fates. Here, we demonstrate that the functionally distinct swarmer and stalked daughter cells produced by the model α-proteobacterium Caulobacter crescentus can have different average growth rates under nutrient-replete conditions despite sharing an identical genome and environment. The discrepancy in growth rate is due to a growth slowdown associated with the cell cycle stage preceding DNA replication (the G1 phase), which initiates in the late predivisional mother cell before daughter cell separation. Both progenies experience a G1-associated growth slowdown, but the effect is more severe in swarmer cells because they have a longer G1 phase. Activity of SpoT, which produces the (p)ppGpp alarmone and extends the G1 phase, accentuates the cell cycle-dependent growth slowdown. Collectively, our data identify a coupling between cell growth, the G1 phase, and asymmetric division that C. crescentus may exploit for environmental adaptation through SpoT activity. This coupling differentially modulates the growth rate of functionally distinct daughter cells, thereby altering the relative abundance of ecologically important G1-specific traits within the population. [ABSTRACT FROM AUTHOR]

The terminal cells of the Drosophila larval tracheal system are perhaps the simplest delivery networks, providing an analogue for mammalian vascular growth and function in a system with many fewer components. These cells are a prime example of single-cell morphogenesis, branching significantly over time to adapt to the needs of the growing tissue they supply. While the genetic mechanisms governing local branching decisions have been studied extensively, an understanding of the emergence of a global network architecture is still lacking. Mapping out the full network architecture of populations of terminal cells at different developmental times of Drosophila larvae, we find that cell growth follows scaling laws relating the total edge length, supply area, and branch density. Using time-lapse imaging of individual terminal cells, we identify that the cells grow in three ways: by extending branches, by the side budding of new branches, and by internally growing existing branches. A generative model based on these modes of growth recapitulates statistical properties of the terminal cell network data. These results suggest that the scaling laws arise from the coupled contributions of branching and internal growth. This study establishes the terminal cell as a uniquely tractable model system for further studies of transportation and distribution networks. [ABSTRACT FROM AUTHOR]

Biological shape diversity is often manifested in modulation of organ symmetry and modification of the patterned elaboration of repeated shape elements. 1,2,3,4,5 Whether and how these two aspects of shape determination are coordinately regulated is unclear. 5,6,7 Plant leaves provide an attractive system to investigate this problem, because they often show asymmetries along the proximodistal (PD) axis of their blades, along which they can also produce repeated marginal outgrowths such as serrations or leaflets. 1 One aspect of leaf shape diversity is heteroblasty, where the leaf form in a single genotype is modified with progressive plant age. 8,9,10,11 In Arabidopsis thaliana, a plant with simple leaves, SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 9 (SPL9) controls heteroblasty by activating CyclinD3 expression, thereby sustaining proliferative growth and retarding differentiation in adult leaves. 12,13 However, the precise significance of SPL9 action for leaf symmetry and marginal patterning is unknown. By combining genetics, quantitative shape analyses, and time-lapse imaging, we show that PD symmetry of the leaf blade in A. thaliana decreases in response to an age-dependent SPL9 expression gradient, and that SPL9 action coordinately regulates the distribution and shape of marginal serrations and overall leaf form. Using comparative analyses, we demonstrate that heteroblastic growth reprogramming in Cardamine hirsuta, a complex-leafed relative of A. thaliana, also involves prolonging the duration of cell proliferation and delaying differentiation. We further provide evidence that SPL9 enables species-specific action of homeobox genes that promote leaf complexity. In conclusion, we identified an age-dependent layer of organ PD growth regulation that modulates leaf symmetry and has enabled leaf shape diversification. [Display omitted] • An age-dependent growth gradient underpins regulation of A. thaliana leaf symmetry • SPL9-mediated heteroblastic growth control potentiates leaf histogenic capacity • Common growth patterns underlie heteroblasty in complex and simple leaves • SPL9 enables the action of homeobox genes that promote leaf complexity Li et al. study mechanisms underlying age-dependent changes in leaf symmetry and margin shape. They show that SPL9-mediated regulation of proliferative growth and differentiation along the leaf proximodistal axis modulates organ symmetry and marginal patterning and enables the action of homeobox genes that contributed to complex leaf shape evolution. [ABSTRACT FROM AUTHOR]

Chemical screens across hundreds of cell lines have shown that the drug sensitivities of human cancers can vary by genotype or lineage. However, most drug discovery studies have relied on culture media that poorly reflect metabolite levels in human blood. Here, we perform drug screens in traditional and Human Plasma-Like Medium (HPLM). Sets of compounds that show conditional anticancer activity span different phases of global development and include non-oncology drugs. Comparisons of the synthetic and serum-derived components that comprise typical media trace sets of conditional phenotypes to nucleotide synthesis substrates. We also characterize a unique dual mechanism for brivudine, a compound approved for antiviral use. Brivudine selectively impairs cell growth in low folate conditions by targeting two enzymes involved in one-carbon metabolism. Cataloged gene essentiality data further suggest that conditional phenotypes for other compounds are linked to off-target effects. Our findings establish general strategies for identifying drug-nutrient interactions and mechanisms of action by exploiting conditional lethality in cancer cells. [ABSTRACT FROM AUTHOR]

Liver disease cases are rapidly expanding worldwide, and transplantation remains the only effective cure for end-stage disease. There is an increasing demand for developing potential drug treatments, and regenerative therapies using in-vitro culture platforms. Human decellularized extracellular matrix (dECM) is an appealing alternative to conventional animal tissues as it contains human-specific proteins and can serve as scaffolding materials. Herein we exploit this with human donor tissue from discarded liver which was not suitable for transplant using a synergistic approach to combining biological and topographical cues in electrospun materials as an in-vitro culture platform. To realise this, we developed a methodology for incorporating human liver dECM into electrospun polycaprolactone (PCL) fibres with surface nanotopographies (230–580 nm). The hybrid scaffolds were fabricated using varying concentrations of dECM; their morphology, mechanical properties, hydrophilicity and stability were analysed. The scaffolds were validated using HepG2 and primary mouse hepatocytes, with subsequent results indicating that the modified scaffolds-maintained cell growth and influenced cell attachment, proliferation and hepatic-related gene expression. This work demonstrates a novel approach to harvesting the potential from decellularized human tissues in the form of innovative in-vitro culture platforms for liver. [ABSTRACT FROM AUTHOR]

This study investigates the potential improvement of polyhemoglobin's protective properties by the addition of 3 synthetic enzymes (neo-carbonic anhydrase, neo-catalase and neo-superoxide dismutase) to polyhemoglobin after 90 and 180 min of warm in-vitro ischemia (100% Nitrogen at 37 °C). Following the warm ischemic shock, cell cultures were subjected to various treatment solutions: Controls; PolyHb; 3 neoenzymes; PolyHb + 3 neoenzymes; PolyHb + 2 neoenzymes. The cultures were then incubated (Oxygen, 5% CO2 at 37 °C) for 24 h followed by several analyses. Compared to polyhemoglobin alone, this novel solution containing polyhemoglobin + 3 neoeznymes significantly increased the viability, cell growth, albumin production, protection against oxidative stress and cellular injury of human hepatocytes. Moreover, this also protects the viability of human cardiomyocytes. These findings suggest that it could be useful as a pre-transplant cell/organ preservation solution which, in the long-term, could contribute to the development of blood substitutes. [ABSTRACT FROM AUTHOR]

The complex relationships between the structure and function of fish gills have been of interest to comparative physiologists for many years. Morphological plasticity of the gill provides a dynamic mechanism to reversibly alter its structure in response to changes in the conditions experienced by the fish. The best known example of gill remodelling is the growth or retraction of cell masses between the lamellae, a rapid process that alters the lamellar surface area that is exposed to the water (i.e. the functional lamellar surface area). Decreases in environmental O2 availability and/or increases in metabolic O2 demand stimulate uncovering of the lamellae, presumably to increase the capacity for O2 uptake. This review addresses four questions about gill remodelling: (1) what types of reversible morphological changes occur; (2) how do these changes affect physiological function from the gill to the whole animal; (3) what factors regulate reversible gill plasticity; and (4) is remodelling phylogenetically widespread among fishes? We address these questions by surveying the current state of knowledge of gill remodelling in fishes, with a focus on identifying gaps in our understanding that future research should consider. [ABSTRACT FROM AUTHOR]

Background: SUZ12 is one of the core members of the polycomb repressive complex 2 (PRC2), but its expression and role in lung adenocarcinoma (LUAD) are unclear. We aimed to explore the expression, prognosis, biological functions and roles of SUZ12 in LUAD. Methods: The expression of SUZ12 was detected by immunohistochemical staining, qRT‐PCR, and western blotting in LUAD tissues and cells. The biological functions and molecular mechanisms of SUZ12 were characterized by a range of in vitro and in vivo experiments. Results: SUZ12 was overexpressed in LUAD tissues, and high SUZ12 expression was correlated with worse clinicopathological features and a poorer prognosis. Knockdown of SUZ12 significantly inhibited cell growth, colony formation, invasion, and migration, and induced apoptosis and G1/S phase arrest, while overexpression of SUZ12 had the opposite effects. Knockdown of SUZ12 decreased the tumorigenic capacity of A549 cells in vivo. The expression of key signaling molecules related to the cell cycle, apoptosis, migration, and immunity were altered by the knockdown or overexpression of SUZ12. SUZ12 can directly bind to the Bax promoter region, EZH2 and H3K27me3 levels dependents on SUZ12. The expression levels of SUZ12 and Bax were negatively correlated in LUAD tissues. Conclusions: SUZ12 is a new oncogene related to the poor prognosis of LUAD. SUZ12 regulates LUAD progression by regulating the expression of related signaling molecules, and as a part of the PRC2 complex, it may bind to the Bax promoter to silence Bax expression. [ABSTRACT FROM AUTHOR]

Organ sizes and shapes are highly reproducible, or robust, within a species and individuals. Arabidopsis thaliana sepals, which are the leaf-like organs that enclose flower buds, have consistent size and shape, indicating robust development. Cell growth is locally heterogeneous due to intrinsic and extrinsic noise. To achieve robust organ shape, fluctuations in cell growth must average to an even growth rate, which requires that fluctuations are uncorrelated or anticorrelated in time and space. Here, we live image and quantify the development of sepals with an increased or decreased number of cell divisions (lgo mutant and LGO overexpression, respectively), a mutant with altered cell growth variability (ftsh4), and double mutants combining these. Changes in the number of cell divisions do not change the overall growth pattern. By contrast, in ftsh4 mutants, cell growth accumulates in patches of over- and undergrowth owing to correlations that impair averaging, resulting in increased organ shape variability. Thus, we demonstrate in vivo that the number of cell divisions does not affect averaging of cell growth, preserving robust organ morphogenesis, whereas correlated growth fluctuations impair averaging. [ABSTRACT FROM AUTHOR]

Objective • This work aimed to investigate the expression of acidic leucine-rich nuclear protein phosphatase 32B (ANP32B) in prostate adenocarcinoma (PRAD) and evaluate the effect of ANP32B on the proliferation of prostate adenocarcinoma cells. Methods • We evaluated the expression of ANP32B in PRAD tissues and cells compared to the controls obtained from The Cancer Genome Atlas (TCGA). siRNA targeting ANP32B was transfected into DU145 cells to knockdown the ANP32B expression and plasmids carrying ANP32B coding region were used to overexpress ANP32B in PC3 cells. We analyze the knockdown or overexpression efficiency of ANP32B with quantitative reverse- transcription PCR (RT-qPCR) and Western blot. CCK-8 assay, cell colony formation assay, transwell assay, and EdU labeling were performed to investigate the function of ANP32B on the progression of PRAD. Finally, the expression of the cell cycle marker, apoptosis marker, and epithelial-mesenchymal transition (EMT) marker were detected by Western blot. Results • ANP32B expression was upregulated in PRAD samples compared to normal samples. Exogenous ANP32B overexpression promoted cell viability, cell colony formation, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, and cell migration. Inhibition of ANP32B suppressed cell proliferation, growth, and migration. At the molecular level, the genes promoting cell growth and migration, including cyclin D1 and N-cadherin, were significantly upregulated after ANP32B overexpression, whereas those inhibiting cell growth and migration such as cleaved caspase 3 and E-cadherin were downregulated. Conclusion • The tumor-promoting function of ANP32B can be attributed to its capacity to facilitate cell progression, and it may be considered as a therapeutic marker for PRAD therapy. [ABSTRACT FROM AUTHOR]

Background: Nodular fasciitis is a benign, singularly occurring nodular fibroblastic/myofibroblastic neoplasia. Due to the rapid growth and cellular atypia, this rare differential diagnosis in the head and neck region can be mistaken for malignant sarcomas. Methods: We present a 40-year-old female patient with an unclear, rough, and poorly displaceable supraclavicular swelling on the right as part of a medical check-up. Sonographically, the lump was poorly circumscribed with little vascularization. A consecutive core needle biopsy of the lesion yielded inconclusive results showing spindle-shaped tumor cells. 68Ga-FAPI-PET/CT showed an intensive uptake of the right supraclavicular lesion in addition to postoperative changes in the right tonsil. Subsequent operative partial excision of the lesion confirmed the histopathological diagnosis of nodular fasciitis. Results: Nodular fasciitis is the most prevalent pseudosarcoma found in soft tissues. This case is the first description of 68Ga-FAPI-PET/CT in nodular fasciitis. Surgical removal is advised; nevertheless, the tumor frequently diminishes on its own, and recurrence is rare. Extensive surgical therapy is not necessary. Conlcusions: The recognition of nodular fasciitis and its benign characteristics is crucial to prevent diagnostic errors and the subsequent unnecessary operative treatment of the patient. [ABSTRACT FROM AUTHOR]

Suppressor of cytokine signaling 2 (SOCS2), an E3 ubiquitin ligase, regulates the JAK/STAT signaling pathway, essential for cytokine signaling and immune responses. Its dysregulation contributes to cardiovascular diseases (CVDs) by promoting abnormal cell growth, inflammation, and resistance to cell death. This study aimed to elucidate the molecular mechanisms underlying the interactions between Lumbricus-derived proteins and peptides and SOCS2, with a focus on identifying potential therapeutic candidates for CVDs. Utilizing a multifaceted approach, advanced computational methodologies, including 3D structure modeling, protein–protein docking, 100 ns molecular dynamics (MD) simulations, and MM/PBSA calculations, were employed to assess the binding affinities and functional implications of Lumbricus-derived proteins on SOCS2 activity. The findings revealed that certain proteins, such as Lumbricin, Chemoattractive glycoprotein ES20, and Lumbrokinase-7T1, exhibited similar activities to standard antagonists in modulating SOCS2 activity. Furthermore, MM/PBSA calculations were employed to assess the binding free energies of these proteins with SOCS2. Specifically, Lumbricin exhibited an average ΔGbinding of −59.25 kcal/mol, Chemoattractive glycoprotein ES20 showed −55.02 kcal/mol, and Lumbrokinase-7T1 displayed −69.28 kcal/mol. These values suggest strong binding affinities between these proteins and SOCS2, reinforcing their potential therapeutic efficacy in cardiovascular diseases. Further in vitro and animal studies are recommended to validate these findings and explore broader applications of Lumbricus-derived proteins. [ABSTRACT FROM AUTHOR]

This study reveals the pH-responsive behavior of collagen hydrogels prepared using ultraviolet (UV) irradiation with riboflavin as a photosensitizer. By varying the UV exposure time, we modulated the crosslinking density, thereby influencing the mechanical properties and pH responsiveness. Rheological analysis confirmed successful network formation, whereas swelling studies revealed significant pH-dependent behavior, with maximum swelling at a pH of four and minimal swelling above a pH of six, demonstrating partial reversibility over multiple pH cycles. Mechanical testing showed a pH-dependent elastic modulus, which increased 10 fold from a pH of 6 to 10. Fibroblast proliferation assays confirmed the biocompatibility of the hydrogels, with cell growth positively correlating with the UV exposure time. This research demonstrates the potential of UV-crosslinked collagen hydrogels in biomedical applications, such as tissue engineering and drug delivery, where pH responsiveness is essential. [ABSTRACT FROM AUTHOR]

Placental-derived products have been used since the early 1900s for wound applications and have shown clinical utility in supporting wound healing. A hypothermically stored amniotic membrane (HSAM) was developed using a proprietary process to allow for the retention of the extracellular matrix (ECM), viable cells, and key proteins. To evaluate its utility, we characterized the HSAM and compared it to a native unprocessed amniotic membrane (uAM) and a dehydrated amniotic membrane (dAM), as well as assessing the functionality of the HSAM as a scaffold to promote cell growth. The HSAM, uAM, and dAM were compared using scanning electron microscopy (SEM), histology, and thickness. Scaffold durability was assessed in vitro using mechanical testing and a simulated wound fluid (SWF) model. The ability of the HSAM to act as a scaffold was evaluated using an in vitro attachment model. The HSAM showed similar structural characteristics compared to the uAM; however, the dAM was significantly more compact. There were no significant differences between the HSAM and the uAM following degradation in an SWF model. ECM- and placental-related proteins were shared between the HSAM and uAM, and the HSAM enhanced the attachment and proliferation of fibroblasts in vitro. The HSAM is substantially similar to the uAM by retaining key regulatory proteins, resisting degradation in SWF, and acting as a scaffold for cellular growth and invasion. [ABSTRACT FROM AUTHOR]

Expansins comprise an ancient group of cell wall proteins ubiquitous in land plants and their algal ancestors. During cell growth, they facilitate passive yielding of the wall's cellulose networks to turgor-generated tensile stresses, without evidence of enzymatic activity. Expansins are also implicated in fruit softening and other developmental processes and in adaptive responses to environmental stresses and pathogens. The major expansin families in plants include α-expansins (EXPAs), which act on cellulose-cellulose junctions, and β-expansins, which can act on xylans. EXPAs mediate acid growth, which contributes to wall enlargement by auxin and other growth agents. The genomes of diverse microbes, including many plant pathogens, also encode expansins designated expansin-like X. Expansins are proposed to disrupt noncovalent bonding between laterally aligned polysaccharides (notably cellulose), facilitating wall loosening for a variety of biological roles. [ABSTRACT FROM AUTHOR]

Tissue engineering is a multidisciplinary field that uses biomaterials to restore tissue function and assist with drug development. Over the last decade, the fabrication of three-dimensional (3D) multifunctional scaffolds has become commonplace in tissue engineering and regenerative medicine. Thanks to the development of 3D bioprinting technologies, these scaffolds more accurately recapitulate in vivo conditions and provide the support structure necessary for microenvironments conducive to cell growth and function. The purpose of this review is to provide a background on the leading 3D bioprinting methods and bioink selections for tissue engineering applications, with a specific focus on the growing field of developing multifunctional bioinks and possible future applications. [ABSTRACT FROM AUTHOR]

Summary: During the primary fermentation of beer, the yeast simultaneously carries out a series of processes such as cell growth, pH shift, and the formation and degradation of essential flavour components. Harvested yeast from a previous fermentation can be used to inoculate the fermentation or fresh cells can be produced through aerobic propagation. This study investigated the influence of different aeration conditions during Saccharomyces pastorianus ssp. carlsbergensis propagation on the cell count development and the production of secondary metabolites during the subsequent primary beer fermentation. Propagations were conducted by applying six different dissolved oxygen concentrations, and the cells were used as inoculum for the subsequent fermentation. Cell count, pH shift, and the development of key aroma compounds were monitored throughout the primary fermentation to evaluate any difference between the conducted fermentations. The outcomes revealed significant distinctions between fermentations using yeast propagated under elevated oxygen levels and those propagated under reduced oxygen levels. Cells propagated using lower oxygen concentrations showed earlier cell growth with 40% lower final cell counts, resulting in 50% reduced biomass yields. Additionally, lower oxygen concentrations during propagation led to lower pH shifts during primary fermentation with 20% more higher alcohols and elevated formation of acetaldehyde, and esters. [ABSTRACT FROM AUTHOR]

Human cytoplasmic tRNAs contain dihydrouridine modifications at positions 16 and 17 (D16/D17). The enzyme responsible for D16/D17 formation and its cellular roles remain elusive. Here, we identify DUS1L as the human tRNA D16/D17 writer. DUS1L knockout in the glioblastoma cell lines LNZ308 and U87 causes loss of D16/D17. D formation is reconstituted in vitro using recombinant DUS1L in the presence of NADPH or NADH. DUS1L knockout/overexpression in LNZ308 cells shows that DUS1L supports cell growth. Moreover, higher DUS1L expression in glioma patients is associated with poorer prognosis. Upon vector-mediated DUS1L overexpression in LNZ308 cells, 5′ and 3′ processing of precursor tRNATyr(GUA) is inhibited, resulting in a reduced mature tRNATyr(GUA) level, reduced translation of the tyrosine codons UAC and UAU, and reduced translational readthrough of the near-cognate stop codons UAA and UAG. Moreover, DUS1L overexpression increases the amounts of several D16/D17-containing tRNAs and total cellular translation. Our study identifies a human dihydrouridine writer, providing the foundation to study its roles in health and disease. DUS1L was identified as the human tRNA dihydrouridine writer for positions 16 and 17. DUS1L overexpression changes the amount of several D16/D17-containing tRNAs and increases total cellular translation and cell growth in glioblastoma cells. [ABSTRACT FROM AUTHOR]

Thallium (Tl), a key element in high-tech industries, is recognized as a priority pollutant by the US EPA and EC. Tl accumulation threatens aquatic ecosystems. Despite its toxicity, little is known about its impact on cyanobacteria. This study explores the biochemical mechanisms of Tl(I) toxicity in cyanobacteria, focusing on physiology, metabolism, oxidative damage, and antioxidant responses. To this end, Anabaena and Nostoc were exposed to 400 µg/L, and 800 µg/L of Tl(I) over seven days. Anabaena showed superior Tl(I) accumulation with 7.8% removal at 400 µg/L and 9.5% at 800 µg/L, while Nostoc removed 2.2% and 7.4%, respectively. Tl(I) exposure significantly reduced the photosynthesis rate and function, more than in Nostoc. It also altered primary metabolism, increasing sugar levels and led to higher amino and fatty acids levels. While Tl(I) induced cellular damage in both species, Anabaena was less affected. Both species enhanced their antioxidant defense systems, with Anabaena showing a 175.6% increase in SOD levels under a high Tl(I) dose. This suggests that Anabaena's robust biosorption and antioxidant systems could be effective for Tl(I) removal. The study improves our understanding of Tl(I) toxicity, tolerance, and phycoremediation in cyanobacteria, aiding future bioremediation strategies. NOVELTY STATEMENT: This study presents novel insights into thallium (Tl) phycoremediation using Anabaena laxa and Nostoc muscorum, crucial for addressing the increasing contamination concerns stemming from high-tech industries. Elucidating the tolerance mechanisms and physiological responses of these cyanobacterial species to Tl(I) exposure. It highlights the potential of Anabaena laxa as an effective bio-remediator, offering a sustainable solution to mitigate Tl(I) environmental impact. [ABSTRACT FROM AUTHOR]

To create tissue-engineered vascular grafts (TEVGs) in vitro, vascular smooth muscle cells (VSMCs) must function effectively and produce sufficient extracellular matrix (ECM) in a three-dimensional space. In this study, we investigated whether the addition of insulin-transferrin-selenium (ITS), a medium supplement, could enhance TEVG formation. PGA fabric was used as the scaffold, and 1% ITS was added to the medium. After two weeks, the tissues were examined using electron microscopy and staining. The ITS group exhibited a denser structure and increased collagen production. VSMCs were cultured in two dimensions with ITS and assessed for collagen production, cell growth, and glucose metabolism. The results showed that ITS supplementation increased collagen production, cell growth, glucose utilization, lactate production, and ATP levels. Furthermore, reducing the amount of fetal bovine serum (FBS) in the medium did not affect the TEVGs or VSMCs when ITS was present. In conclusion, ITS improves TEVG construction by promoting VSMCs growth and reducing the need for FBS. [ABSTRACT FROM AUTHOR]

[Display omitted] The skin has a multilayered structure, and deep-seated injuries are exposed to external microbial invasion and in vivo microenvironmental destabilization. Here, a bilayer bionic skin scaffold (Bilayer SF) was developed based on methacrylated sericin protein to mimic the skin's multilayered structure and corresponding functions. The outer layer (SF@TA), which mimics the epidermal layer, was endowed with the function of resisting external bacterial and microbial invasion using a small pore structure and bio-crosslinking with tannic acid (TA). The inner layer (SF@DA@Gel), which mimics the dermal layer, was used to promote cellular growth using a large pore structure and introducing dopamine (DA) to regulate the wound microenvironment. This Bilayer SF showed good mechanical properties and structural stability, satisfactory antioxidant and promote cell proliferation and migration abilities. In vitro studies confirmed the antimicrobial properties of the outer layer and the pro-angiogenic ability of the inner layer. In vivo animal studies demonstrated that the bilayer scaffolds promoted collagen deposition, neovascularization, and marginal hair follicle formation, which might be a promising new bionic skin scaffold. [ABSTRACT FROM AUTHOR]

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Helicobacter pylori (HP) is considered a major risk factor for gastric cancer (GC) and during this process, cytotoxin‑associated gene A (CagA) plays in essence. The study mainly focused on the molecular mechanism of circular RNA 0046854 (circ_0046854) in HP‐induced GC. Clinically, 56 cases of GC and normal tissues were collected, and the GC tissues were divided into HP‐negative GC tissues (HP−) and 33 HP‐positive GC tissues (HP+). Tissue expression of circ_0046854, microRNA (miR)‐511‐3p and colony‐stimulating factor 1 (CSF1) was tested. BGC‐823/Cisplatin (DDP) resistant strain was induced and cell growth and DDP resistance were detected after HP infection. In vivo experiments were performed using a mouse xenograft model. The relationship between circ_0046854, miR‐511‐3p and CSF1 was confirmed. GC tissues especially HP+ cancer tissues expressed high circ_0046854 and CSF1 and low miR‐511‐3p. HP‐induced circ_0046854 expression in GC cells through CagA. Inhibition of circ_0046854 or miR‐511‐3p elevation inhibited the growth and DDP resistance in GC cells. Circ_0046854 acted as a sponge for miR‐511‐3p, which targeted CSF1. Restoring CSF1 could abolish the inhibitory effect of miR‐511‐3p overexpression on CagA+ HP‐induced GC progression in vitro. Circ_0046854 silencing repressed tumor growth and aggrandized the inhibiting effects of DDP on tumorigenesis in vivo. Circ_0046854/miR‐511‐3p/CSF1 axis may be involved in the development of HP‐induced GC, thus providing new ideas for studying the mechanism of HP‐related gastric diseases. [ABSTRACT FROM AUTHOR]

The molecular mechanisms driving the development of cervical adenocarcinoma (CADC) and optimal patient management strategies remain elusive. In this study, we have identified circMAN1A2_009 as an oncogenic circular RNA (circRNA) in CADC. Clinically, circMAN1A2_009 showed significant upregulation in CADC tissues, with an impressive area under the curve value of 0.8075 for detecting CADC. Functional studies, involving both gain‐of‐function and loss‐of‐function experiments, revealed that circMAN1A2_009 suppressed reactive oxygen species accumulation and apoptosis, and boosted cell viability in CADC cells. Conversely, silencing circMAN1A2_009 reversed these effects. Further mechanistic investigations indicated that circMAN1A2_009 interacted with YBX1, facilitating the phosphorylation levels of YBX1 at serine 102 (p‐YBX1S102) and facilitating YBX1 nuclear localization through sequence 245–251. This interaction subsequently increased the activity of the glyoxalase 1 (GLO1) promoter, leading to the activation of GLO1 expression. Consistently, inhibition of either YBX1 or GLO1 mirrored the biological effects of circMAN1A2_009 in CADC cells. Additionally, knockdown of YBX1 or GLO1 partially reversed the oncogenic behaviors induced by circMAN1A2_009. In conclusion, our findings propose circMAN1A2_009 as a potential oncogene and a promising indicator for diagnosing and guiding therapy in CADC patients. [ABSTRACT FROM AUTHOR]

Background: Ganoderma lucidum (G. lucidum) is a famous medicinal mushroom that has been reported to prevent and treat a variety of diseases. Different extractions from G. lucidum have been used to manage age-related diseases, including cancer. Nevertheless, the senolytic activity of G. lucidum against senescent cancer cells has not been investigated. Although cellular senescence causes tumor growth inhibition, senescent cells promote the growth of the neighboring tumor cells through paracrine effects. Therefore, the elimination of senescent cells is a new strategy for cancer treatment. Methods: In this study, senescence was triggered in HCC cells by the chemotherapeutic agent Adriamycin (ADR), and subsequently, cells were treated with TC to assess its senolytic activity. Results: We found for the first time that the triterpenoid complex (TC) from G. lucidum had senolytic effect, which could selectively eliminate adriamycin (ADR)- induced senescent cells (SCs) of hepatocellular carcinoma (HCC) cells via caspase-dependent and mitochondrial pathways-mediated apoptosis and reduce the levels of senescence markers, thereby inhibiting the progression of cancers caused by SCs. TC could block autophagy at the late stage in SCs, resulting in a significant activation of TC-induced apoptosis. Furthermore, TC inhibited the senescence-associated secretory phenotype (SASP) in SCs through the inhibition of NF-κB, TFEB, P38, ERK, and mTOR signaling pathways and reducing the number of SCs. Sequential administration of ADR and TC in vivo significantly reduced tumor growth and reversed the toxicity of ADR. Conclusion: A triterpenoid complex isolated from G. lucidum may serve as a novel senolytic agent against SCs, and its combination with chemotherapeutic agents may enhance their antitumor efficacy. [ABSTRACT FROM AUTHOR]

Context Telomerase reverse transcriptase promoter (TERT- p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT -p mutations, but such tumors show less aggressiveness and better prognosis than TERT- p mutation–positive tumors. Objective TERT has multiple splicing variants whose relationships with the TERT- p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT -p mutational status, the TERT splicing pattern, and clinicopathological features. Methods We investigated the expression of 2 major variants, α deletion (dA) and β deletion (dB), in a series of 207 PTCs operated on between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. Results The TERT -p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into 3 groups: the TERT -p mutation–negative/expression–negative group (mut−/exp−), the TERT -p mutation–negative/expression–positive group (mut−/exp+), and the TERT -p mutation–positive group (mut+/exp+). The +A+B/dB ratio in mut+/exp+ was significantly higher than that in mut−/exp+ PTCs. Analysis with clinicopathological data revealed that +A+B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor-suppressive role. Conclusion These results provide evidence that the TERT -p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Our previous study showed that pyridoxine 5'-phosphate oxidase (PNPO) is a tissue biomarker of ovarian cancer (OC) and has a prognostic implication but detailed mechanisms remain unclear. The current study focused on PNPO-regulated lysosome/autophagy-mediated cellular processes and the potential role of PNPO in chemoresistance. We found that PNPO was overexpressed in OC cells and was a prognostic factor in OC patients. PNPO significantly promoted cell proliferation via the regulation of cyclin B1 and phosphorylated CDK1 and shortened the G2M phase in a cell cycle. Overexpressed PNPO enhanced the biogenesis and perinuclear distribution of lysosomes, promoting the degradation of autophagosomes and boosting the autophagic flux. Further, an autolysosome marker LAMP2 was upregulated in OC cells. Silencing LAMP2 suppressed cell growth and induced cell apoptosis. LAMP2-siRNA blocked PNPO action in OC cells, indicating that the function of PNPO on cellular processes was mediated by LAMP2. These data suggest the existence of the PNPO-LAMP2 axis. Moreover, silencing PNPO suppressed xenographic tumor formation. Chloroquine counteracted the promotion effect of PNPO on autophagic flux and inhibited OC cell survival, facilitating the inhibitory effect of PNPO-shRNA on tumor growth in vivo. Finally, PNPO was overexpressed in paclitaxel-resistant OC cells. PNPO-siRNA enhanced paclitaxel sensitivity in vitro and in vivo. In conclusion, PNPO has a regulatory effect on lysosomal biogenesis that in turn promotes autophagic flux, leading to OC cell proliferation, and tumor formation, and is a paclitaxel-resistant factor. These data imply a potential application by targeting PNPO to suppress tumor growth and reverse PTX resistance in OC. [ABSTRACT FROM AUTHOR]

Parabens have been associated with health problems, and the inefficiency in conventional treatment systems to remove them has led to the search for alternative treatment methods, such as phytoextraction. Understanding the effect of parabens on the phytoextractor species is essential to develop an efficient alternative system. Thus, this study aims to evaluate the effect of Methylparaben and its chlorinated forms on the metabolism of Salvinia biloba and assess the possibility of its action as a phytoextractor. To do this, S. biloba was exposed to treatments with Methylparaben, Chloromethylparaben, and Dichloromethylparaben at concentrations of 100, 500, and 1000 µg/L. The phytoextract potential was assessed in the solutions after contact with the plants for phytotoxicity, genotoxicity and cytotoxicity tests with Allium cepa. The enzymatic anti-stress defense system, lipid peroxidation, and chlorophyll a and b concentrations were evaluated. The activity of the CAT and APX occurred in the chlorinated treatments. GOPX and SOD were significantly activated in response to lipid peroxidation. Chlorophyll a increased at 500 and 1,000 µg/L MPB, and chlorophyll b disappeared after 96 h in ClMPB and DiClMPB. The IM showed that MPB at the three concentrations caused reduction in the cell growth of A. cepa roots at all times of exposure. In treatments ClMPB and DiClMPB, after 72 h of treatment, root elongation was like that of the control. Thus, it is possible to affirm that S. biloba cannot absorb and transport methylparaben through its tissues but has phytoextractor potential for Chloromethylparaben and Dichloromethylparaben. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is the most common treatment for breast cancer, but its effectiveness is limited by drug resistance and dose variability. Evidence suggests that nanozymes can significantly improve drug penetration and effectiveness in breast cancer treatment, owing to their stable and targeted catalytic properties. However, their varied responses and concentration-dependent toxicities present challenges. After developing pH-sensitive Fe3O4/MnO2@DOX hybrid nanozymes (FMDHN) and evaluating their physicochemical and functional properties, their efficacy was investigated on MCF-7 cells using both two-dimensional and spheroid models. Our findings reveal that FMDHNs, sized 150–270 nm, inhibit MCF-7 cell growth through drug release triggered by acidity and photothermal therapy (PTT). The catalytic efficiency of FMHN in generating O2 and ·OH further enhances cancer cell suppression. Doubling the effective concentrations of FMHN and DOX by transitioning from two-dimensional to spheroid cell structures could adversely affect normal cells, while a synergistic approach combining the DOX and FMHN effectively inhibits MCF-7 cell growth at non-toxic dose. Combining FMDHN with PTT enhances this inhibition, lowering the effective dose to 1.08 μg/mL and effectively managing toxicity. The cytotoxicity mechanism in MCF-7 spheroids shows that PTT with FMDHN significantly elevates pro-inflammatory cytokines, including TNF-α, CASP9, CASP7 and CASP3. Optimizing the concentration of pH-sensitive nanozymes based on their synergistic effects can minimize side effects and maximize their breast cancer treatment potential. [ABSTRACT FROM AUTHOR]

The pathophysiology of amnestic Mild Cognitive Impairment (aMCI) is largely unknown, although some papers found signs of immune activation. To assess the cytokine network in aMCI after excluding patients with major depression (MDD) and to examine the immune profiles of quantitative aMCI (qMCI) and distress symptoms of old age (DSOA) scores. A case-control study was conducted on 61 Thai aMCI participants and 60 healthy old adults (both without MDD). The Bio-Plex Pro human cytokine 27-plex test kit was used to assay cytokines/chemokines/growth factors in fasting plasma samples. aMCI is characterized by a significant immunosuppression, and reductions in T helper 1 (Th)1 and T cell growth profiles, the immune-inflammatory responses system, interleukin (IL)1β, IL6, IL7, IL12p70, IL13, GM-CSF, and MCP-1. These 7 cytokines/chemokines exhibit neuroprotective effects at physiologic concentrations. In multivariate analyses, three neurotoxic chemokines, CCL11, CCL5, and CXCL8, emerged as significant predictors of aMCI. Logistic regression showed that aMCI was best predicted by combining IL7, IL1β, MCP-1, years of education (all inversely associated) and CCL5 (positively associated). We found that 38.2% of the variance in the qMCI score was explained by IL7, IL1β, MCP-1, IL13, years of education (inversely associated) and CCL5 (positively associated). The DSOA was not associated with any immune data. An imbalance between lowered levels of neuroprotective cytokines and chemokines, and relative increases in neurotoxic chemokines are key factors in aMCI. Future MCI research should always control for the confounding effects of affective symptoms. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) is typically diagnosed at advanced stages, which limits the effectiveness of therapeutic interventions. The present study aimed to explore the role of the newly identified circLIFRSA in the PTEN/AKT signaling pathway and its involvement in the malignant processes of NSCLC. Methods: CircLIFRSA expression was identified through microarray analysis, and its levels in NSCLC samples were quantified by RT-qPCR. The impact of circLIFRSA on cell growth, proliferation, apoptosis, and cell cycle were evaluated by MTT assay, colony formation assay, and flow cytometry. Additionally, Western blotting was employed to analyze the expression of PTEN and phosphorylated AKT (pAKT) in NSCLC cells. Results: The expression of circLIFRSA was found to be significantly reduced in NSCLC cells and tissues. This downregulation correlated with various clinicopathological characteristics and indicated its potential as an early diagnostic biomarker for NSCLC. Importantly, circLIFRSA was shown to inhibit cell growth and proliferation while promoting apoptosis in NSCLC cells. Mechanically, circLIFRSA was found to attenuate the malignant processes of NSCLC cells via the miR-1305/PTEN axis and the suppression of AKT phosphorylation. Conclusions: These findings indicate that circLIFRSA/miR-1305/PTEN axis attenuates malignant processes by regulating AKT phosphorylation, and provide new insights into the potential of circLIFRSA as a biomarker for early diagnosis and as a promising therapeutic target in NSCLC. [ABSTRACT FROM AUTHOR]

Machine learning-based approaches are particularly suitable for identifying essential genes as they allow the generation of predictive models trained on features from multi-source data. Gene essentiality is neither binary nor static but determined by the context. The databases for essential gene annotation do not permit the personalisation of the context, and their update can be slower than the publication of new experimental data. We propose HELP (Human Gene Essentiality Labelling & Prediction), a computational framework for labelling and predicting essential genes. Its double scope allows for identifying genes based on dependency or not on experimental data. The effectiveness of the labelling method was demonstrated by comparing it with other approaches in overlapping the reference sets of essential gene annotations, where HELP demonstrated the best compromise between false and true positive rates. The gene attributes, including multi-omics and network embedding features, lead to high-performance prediction of essential genes while confirming the existence of essentiality nuances. Author summary: Essential genes (EGs) are commonly defined as those required for an organism or cell's growth and survival. The essentiality is strictly dependent on both environmental and genetic conditions, determining a difference between those considered common EGs (cEGs), essential in most of the contexts considered, and those essential specifically to one or few contexts (context-specific EGs, csEGs). In this paper, we present a library of tools and methodologies to address the identification and prediction of cEGs and csEGs. Furthermore, we attempt to experimentally explore the statement that essentiality is not a binary property by identifying, predicting and analysing an intermediate class between the Essential (E) and Not Essential (NE) genes. Among the multi-source data used to predict the EGs, we found the best attributes combination to capture the essentiality. We demonstrated that the additional class of genes we defined as "almost Essential" shows differences in these attributes from the E and NE genes. We believe that investigating the context-specificity and the dynamism of essentiality is particularly relevant to unravelling crucial insights into biological mechanisms and suggesting new candidates for precision medicine. [ABSTRACT FROM AUTHOR]

Background: The PI3K signalling pathway regulates the metabolic activity of cells. Disruption by PI3K inhibitors causes an aerobic/anaerobic imbalance that decreases energy production and cell growth. Cancer cells adapt to PI3K inhibitors in order to reduce their effectiveness. Resistance to Apitolisib could be due to intrinsic factors or acquired adaptation. Oncologists often ask whether to discontinue Apitolisib, increase its dose, or use a drug combination. Methods: We observed the proliferation of resistant cells in (H1975R+) and out (H1975R−) of Apitolisib treatment, cell cycle pattern, energy phenotyping/reprogramming, and the effects of combining Apitolisib with Vorinostat on the acquired proliferation of H1975R− cells. Results: The Proliferation of H1975R− cells increased, while that of H1975R+ cells remained suppressed. Both conditions showed a 5 × decrease in the number of cells at the Go/G1 phase and doubled at S and G2/M phases (p < 0.0001). Both H1975R− and H1975R+ cells exhibited decreased ECAR, with a stronger effect observed in H1975R+ cells (p < 0.0001). Oxygen consumption (OCR) increased significantly in H1975R− compared with that in H1975P (p = 0.02). The resistant cells became energetically active using mitochondrial respiration in drug-free medium; H1975R+ was hypo-energetic and consumed more free fatty acids (p = 0.0001). Ketone bodies in H1975R+ were increased by 40% and 2 × in BOHB and AcAc levels, respectively, compared to that in H1975P and H1975R− (p < 0.0001). H1975R− cell survival was 80% compared with 20% in H975R+ cells treated with 7 μM Vorinostat. Vorinostat effectively controlled acquired hyperproliferation of H1975R− cells. Conclusion: If a tumour becomes unresponsive to Apitolisib, it is advisable to continue the inhibitor and consider a combination with non-tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]