Growth Control Research Articles

TMIC-68. DEEP LEARNING OF THE SPATIAL IMMUNE ENGAGEMENT IN GLIOBLASTOMA UNDER TEMOZOLOMIDE TREATMENT

Abstract Effective immune synapses are a prerequisite for desirable immune surveillance and control of tumour growth. Cell-to-cell interactions form the basis of immune synapses, resulting in either immunoprotected or immunosuppressed manifestations in the tumour brain that could explain glioblastoma (GBM) recurrence. Using state-of-the-art multiplex imaging, spatial statistics, and spatially aware deep learning tools in 14 patient-matching tissues from primary and recurrent GBM, we detected spatial immune networks (SINets). SINets across 105 regions of interest comprising 2.3 million cells show stronger spatial engagement between myeloid and lymphoid lineages at recurrence. SINets’ architecture in primary tumours is associated with relapse timing. Patients, where the SINets are more modular, recur sooner than patients with denser SiNets. In addition, this association presents sexual dimorphism in our cohort (N=3 females, and N=4 males). Phenotype-to-phenotype spatial coexistence also contributes to enhancing phenotype prediction. A spatial-aware deep learning model trained with single-cell data from primary tumours reaches an average balanced accuracy of 0.76 in primary tumour cellular communities unseen during training, compared to a spatial-agnostic model that reached an average balanced accuracy of 0.69. In summary, we detected a distinct spatial engagement in glioblastoma undergoing chemo-radiation treatment. The spatial patterns of coexistence represent ecological niches that contribute to defining cell occurrence and may underpin effective immune synapses. Overall, the spatiotemporal elements provide a newer approach for dissecting glioblastoma’s complexity and discovering opportunities for stratifying patients by harnessing spatial information encoded in multicellular niches.

Chemical Composition, Biological Activity, and Application of Rosa damascena Essential Oil as an Antimicrobial Agent in Minimally Processed Eggplant Inoculated with Salmonella enterica

Rosa damascena is mostly grown for its usage in the food, medical, and perfume industries, while it is also used as an attractive plant in parks, gardens, and homes. The use of R. damascena essential oil may yield new results in relation to the antimicrobial activity of essential oils and their use mainly in extending the shelf life of foods. This study investigates the chemical composition and antimicrobial properties of Rosa damascena essential oil (RDEO) using gas chromatography–mass spectrometry (GC-MS) and various bioassays to explore its potential applications in food preservation and microorganism growth control. The GC-MS analysis revealed that RDEO is predominantly composed of phenylethyl alcohol (70%), which is known for its antimicrobial and aromatic properties. Additionally, other significant constituents were identified, including nerol, citronellol, and geraniol, which may contribute to the EOs overall bioactivity. The antimicrobial activity was assessed through the minimal inhibition concentration against five Candida yeast strains, four Gram-positive, and four Gram-negative bacteria, including biofilm-forming Salmonella enterica. Determination of minimum inhibitory concentrations (MIC) revealed the strongest effects of RDEO’s on Gram-negative species, with MIC50 values as low as 0.250 mg/mL for S. enterica. Moreover, an in situ assessment utilizing fruit and vegetable models demonstrated that the vapor phase of RDEO significantly suppressed microbial growth, with the most substantial reductions observed on kiwi and banana models. As a result of our study, the antimicrobial effect of RDEO on the microbiota of sous vide processed eggplant was detected, as well as an inhibitory effect on S. enterica during storage. The insecticidal activity against Megabruchidius dorsalis Fahreus, 1839, was also studied in this work and the best insecticidal activity was found at the highest concentrations. These results suggest that RDEO has the potential to serve as a natural antimicrobial agent in food preservation and safety applications, providing an alternative to synthetic preservatives.

Macrophage-derived extracellular vesicles from Ascaris lumbricoides antigen exposure enhance Mycobacterium tuberculosis growth control, reduce IL-1β, and contain miR-342-5p, miR-516b-5p, and miR-570-3p that regulate PI3K/AKT and MAPK signaling pathways

BackgroundHelminth coinfection with tuberculosis (TB) can alter the phenotype and function of macrophages, which are the major host cells responsible for controlling Mycobacterium tuberculosis (Mtb). However, it is not known whether helminth infection stimulates the release of host-derived extracellular vesicles (EVs) to induce or maintain their regulatory network that suppresses TB immunity. We previously showed that pre-exposure of human monocyte-derived macrophages (hMDMs) with Ascaris lumbricoides protein antigens (ASC) results in reduced Mtb infection-driven proinflammation and gained bacterial control. This effect was entirely dependent on the presence of soluble components in the conditioned medium from helminth antigen-pre-exposed macrophages.MethodsOur objective was to investigate the role of EVs released from helminth antigen-exposed hMDMs on Mtb-induced proinflammation and its effect on Mtb growth in hMDMs. Conditioned medium from 48-h pre-exposure with ASC or Schistosoma mansoni antigen (SM) was used to isolate EVs by ultracentrifugation. EVs were characterized by immunoblotting, flow cytometry, nanoparticle tracking assay, transmission electron microscopy, and a total of 377 microRNA (miRNA) from EVs screened by TaqMan array. Luciferase-expressing Mtb H37Rv was used to evaluate the impact of isolated EVs on Mtb growth control in hMDMs.ResultsEV characterization confirmed double-membraned EVs, with a mean size of 140 nm, expressing the classical exosome markers CD63, CD81, CD9, and flotillin-1. Specifically, EVs from the ASC conditioned medium increased the bacterial control in treatment-naïve hMDMs and attenuated Mtb-induced IL-1β at 5 days post-infection. Four miRNAs showed unique upregulation in response to ASC exposure in five donors. Pathway enrichment analysis showed that the MAPK and PI3K-AKT signaling pathways were regulated. Among the mRNA targets, relevant for regulating inflammatory responses and cellular stress pathways, CREB1 and MAPK13 were identified. In contrast, SM exposure showed significant regulation of the TGF-β signaling pathway with SMAD4 as a common target.ConclusionOverall, our findings suggest that miRNAs in EVs released from helminth-exposed macrophages regulate important signaling pathways that influence macrophage control of Mtb and reduce inflammation. Understanding these interactions between helminth-induced EVs, miRNAs, and macrophage responses may inform novel therapeutic strategies for TB management.

Benefits of Crotalaria juncea L. as Green Manure in Fertility and Soil Microorganisms on the Peruvian Coast

The soils of the Barranca valley are among the best soils in Peru, but with so many years of application of agrochemicals and other agricultural practices, they are losing their productive capacity. Consequently, it was suggested to assess the impact of Crotalaria juncea L. as a green manure on soil fertility and the populations of bacteria and fungi present in the soil. Crotalaria was cultivated for 75 days and incorporated as green manure. After 90 days, the presence of bacteria and fungi was evaluated. Metabarcoding was employed, and the 16S rRNA and ITS2 amplicons were sequenced using the Illumina MiSeq platform. The sequences were processed using various bioinformatics tools. The results indicate that soils have a high diversity of bacteria and fungi. Likewise, in plots where the presence and action of natural biocontrol is suppressed (C0 and P0), pathogenic fungi increase their population in the fallow period (C1), while in P1, the addition of Crotalaria as a green manure promotes an increase in the population of bacteria and fungi, and at the same time it suppresses pathogenic fungi. The genera (bacterial and/or fungal) that increase due to the effect of Crotalaria are beneficial because they are involved as degraders of organic matter, promotion of plant growth and biological control of pathogens. Crotalaria is an alternative to improve soil fertility, increase the beneficial bacterial population, and reduce pathogenic fungi.

The effect of rapamycin treatment on mouse ovarian follicle development in dehydroepiandrosterone-induced polycystic ovary syndrome mouse model.

Polycystic ovary syndrome (PCOS) is a complex reproductive and endocrine disorder affecting 5-10% of women of reproductive age, but the pathophysiology of PCOS still remains unknown. Here, the aim of our study was to analyze the effects of rapamycin treatment that may regulate impaired hormonal levels and folliculogenesis in dehydroepiandrosterone (DHEA)-treated PCOS mouse. We hypothesized that rapamycin may ameliorate the negative effects of PCOS in DHEA-induced PCOS mouse model. The target of rapamycin (TOR) gene product is a serine/threonine kinase that has been implicated in the control of cell growth, proliferation and autophagy, and rapamycin is a potent inhibitor of mTORC1 pathway. In this study, for the first time, mTORC1 and activation products are presented at protein and mRNA levels after rapamycin treatment in DHEA-induced PCOS mouse ovary. We showed that rapamycin treatment may regulate follicular development, hormonal levels and provide ovulation in DHEA-induced PCOS mouse. Additionally, we assessed decreased primordial follicle reserve, increased number of primary and secondary follicles, corpus luteum structure forms again after 10 days of rapamycin treatment. This study presented here suggests rapamycin treatment regulates hormonal phenotype and folliculogenesis in the ovary and also mTOR signalling pathway in granulosa cells of DHEA-induced PCOS mouse ovary which may have potential to attenuate understanding the mechanism of dominant follicle selection and anovulatory infertility.

Retinal "sweet spot" for myopia treatment.

We studied which retinal area controls short-term axial eye shortening when human subjects were exposed to + 3.0D monocular defocus. A custom-built infrared eye tracker recorded the point of fixation while subjects watched a movie at a 2m distance. The eye tracker software accessed each individual movie frame in real-time and covered the points of fixation in the movie with a uniform grey patch. Four patches were programmed: (1) foveal patch (0-3 degrees), (2) annular patch (3-9deg), (3) foveal patch (0-3deg) combined with an annular patch (6-9deg), and (4) full-field patch where only 6-10deg were exposed to the defocus. Axial eye shortening was elicited similarly with full-field positive defocus and with the foveal patch, indicating that the fovea made only a minor contribution (-11 ± 12μm vs. -14 ± 17μm, respectively, n.s.). In contrast, patching a 3-9 degrees annular area or fovea together with an annular area of 6-9 degrees, completely suppressed the effect when compared with full-field defocus (+ 3 ± 1μm or -2 ± 13μm vs. -11 ± 12μm, respectively, p < 0.001). Finally, we found that the near-peripheral retina (6-10 degrees) is a "sweet spot" for positive defocus detection and alone can regulate eye growth control mechanism, and perhaps long-term refractive development (-9 ± 8μm vs. full-field: -11 ± 12μm, n.s.).

Zymogen granule protein 16B (ZG16B) is a druggable epigenetic target to modulate the mammary extracellular matrix.

High tissue density of the mammary gland is considered a pro-tumorigenic factor, hence suppressing the stimuli that induce matrix buildup carries the potential for cancer interception. We found that in non-malignant mammary epithelial cells the combination of the chemopreventive agents bexarotene (Bex) and carvedilol (Carv) suppresses the zymogen granule protein 16B (ZG16B, PAUF) through an interaction of ARID1A with a proximal enhancer. Bex + Carv also reduced ZG16B levels invivo in normal breast tissue and MDA-MB231 tumor xenografts. The relevance of ZG16B is underscored by ongoing clinical trials targeting ZG16B in pancreatic cancers, but its role in breast cancer development is unclear. In immortalized mammary epithelial cells, secreted recombinant ZG16B stimulated mitogenic kinase phosphorylation, detachment and mesenchymal characteristics, and promoted proliferation, motility and clonogenic growth. Highly concerted induction of specific laminin, collagen and integrin isoforms indicated a shift in matrix properties toward increased density and cell-matrix interactions. Exogenous ZG16B alone blocked Bex + Carv-mediated control of cell growth and migration, and antagonized Bex + Carv-induced gene programs regulating cell adhesion and migration. In breast cancer cells ZG16B induced colony formation and anchorage-independent growth, and stimulated migration in a PI3K/Akt-dependent manner. In contrast, Bex + Carv inhibited colony formation, reduced Ki67 levels, ZG16B expression and glucose uptake in MDA-MB231 xenografts. These data establish ZG16B as a druggable pro-tumorigenic target in breast cell transformation and suggest a key role of the matrisome network in rexinoid-dependent antitumor activity.

Diphencyprone reduces the CD8+ lymphocytes and IL-4 and enhences IgG2a/IgG1 ratio in pathogenicity of acute leishmania major infection in BALB/c mice

BackgroundThe exact role of different immune cells and cytokines in control or promotion of intracellular growth of leishmania has still remained a controversial topic. The aim of the present study was to study effects of cellular changes and relevant cytokines in cell mediated immunity by diphencyprone (DCP) in pathogenicity of acute L.major infection in BALB/c mice. Methods45 healthy female BALB/c mice were injected with L. major promastigotes under the base of tail. The mice were randomly divided to three groups of 15 mice: (1) control group without any treatment. (2) acetone group: Acetone was applied topically on the cutaneous lesions weekly and (3) DCP group: DCP was applied topically on the cutaneous lesions with increasing concentrations to induce local allergy. The mice were followed by the end of eighth week, and then macroscopic changes, histopathology, immunology studies, and organ parasite burden were determined. ResultsIn DCP group, in comparison to other groups the ulcer size and parasite burden in ulcer site and spleen increased, significantly. There was a deep lymphohistiocytic infiltration in the ulcer site. Total IgG, IgG1, and IgG2a levels as well as IgG2a/IgG1 ratio and intracellular IFN-gamma in CD8+ lymphocytes were significantly higher. IL4 and T CD8+ lymphocytes were significantly lower in DCP group. The IgG2a/IgG1 ratio was more than 1 in all groups. ConclusionOur findings demonstrated that DCP reduced the CD8+ lymphocytes and IL-4 production. In spite of increased IgG2a/IgG1 ratio, the parasite burden and inflammation severity increased in infected mice. The results can show the pivotal role of CD8+ lymphocytes in conjunction with Th1 lymphocytes in the control of acute leishmania infection in mice.

Personalized management of hepatic glycogen storage disorders: The role of continuous glucose monitoring.

Glycogen storage disorders (GSD), inherent disorders of carbohydrate metabolism, feature hypoglycemia as a hallmark. Normoglycemia and glucose monitoring are pivotal in disease management. Conventional glucometer-based monitoring may overlook hypoglycemic trends. This study assesses glycemic control in Asian Indian GSD children using continuous glucose monitoring (CGM) and its role in facilitating dietary adjustments. A pre-post study enrolled molecularly confirmed GSDI, GSDIII, GSDVI, and GSDIX patients for baseline dietary compliance and CGM-based glycemic status evaluation. Hypoglycemic patients were stratified into diet-compliant and diet-noncompliant groups. Noncompliant patients received dietary reinforcement; compliant individuals underwent dietary adjustments. Repeat CGM (rCGM) was performed 6 weeks to 6 months postadjustments. Clinical and metabolic parameters were re-evaluated at 6 months. Of the 20 patients assessed at baseline, 11 were diet compliant. Six among these exhibited hypoglycemia, prompting diet adjustments. Among nine noncompliant patients, eight experienced hypoglycemia and received diet reinforcement. rCGM in 10 patients (five GSDI, three GSDIII, and two GSDIXc) showed a significant reduction in hypoglycemia duration in all. An improvement in height and body mass index was observed in all GSDI and GSDIII patients. Triglyceride levels, raised at baseline in two GSDI and one GSDIII, showed a substantial decline in one GSDI patient. Hepatic transaminase levels decreased in both GSDIXc patients. Plasma lactate levels decreased in all GSDI patients. CGM is an efficacious adjunct in the personalized management of hepatic GSD patients, in the Asian Indian population. The study also underscores the need for long-term follow-up to determine the role of glycemic management in growth, general well-being, and metabolic control in the GSD subtypes.

Modulatory potentials of nitric oxide in obesity-induced endothelial dysfunction

Obesity is caused by a significant increase in adipose tissue due to excessive caloric intake that exceeds energy expenditure. Obesity has emerged as a significant public health issue in both poor resource and economic developed nations, owing to its increased incidence and links to chronic diseases, such osteoarthritis, hypertension, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVDs). It is believed that uncoupled eNOS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidase, lipoxygenase, cyclooxygenase, microsomal P-450 enzymes, and pro-oxidant heme molecules are responsible for the drastic decrease in NO production and the relative increase in reactive oxygen species (ROS) secretion, which are considered as the molecular mechanisms associated with obesity-induced endothelial dysfunction. Vascular endothelium defines a monolayer of cells, which lies between the vascular smooth muscle cells (VSMCs) and the vessel lumen. It performs a number of protective actions facilitated by the release of nitric oxide (NO), a soluble gas that is generated in endothelial cells by the amino acid L-arginine through the action of endothelial nitric oxide synthase (eNOS). The maintenance of vascular homeostasis is facilitated by various biological actions of NO, such as modulation of vascular dilator tone, control of local cell growth, and protection of the endothelium from the harmful effects of cellular components in blood circulation, while maintaining normal endothelial functions. Decreased peripheral arterial endothelium-dependent dilation (EDD) in response to mechanical (intravascular shear) or chemical (acetylcholine) stimuli suggests that decreased NO bioavailability has been recognised as major molecular mechanisms associated with the progress and development of obesity-induced endothelial dysfunction. In this review, the modulatory effects of NO in obesity-induced endothelial dysfunction will be discussed.

Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.

Tumor-suppressive activities for pogo transposable element derived with KRAB domain via ribosome biogenesis restriction

Transposable elements (TEs) are indispensable for human development, with critical functions in pluripotency and embryogenesis. TE sequences also contribute to human pathologies, especially cancer, with documented activities as cis/trans transcriptional regulators, as sources of non-coding RNAs, and as mutagens that disrupt tumor suppressors. Despite this knowledge, little is known regarding the involvement of TE-derived genes (TEGs) in tumor pathogenesis. Here, systematic analyses of TEG expression across human cancer reveal a prominent role for pogo TE derived with KRAB domain (POGK). We show that POGK acts as a tumor suppressor in triple-negative breast cancer (TNBC) cells and that it couples with the co-repressor TRIM28 to directly block the transcription of ribosomal genes RPS16 and RPS29, in turn causing widespread inhibition of ribosomal biogenesis. We report that POGK undergoes deactivation by isoform switching in clinical TNBC, altogether revealing its exapted activities in tumor growth control.

Understanding the Flow Field in a Highly Loaded Tandem Compressor Cascade

Abstract Large flow turning in compressor cascades with single airfoils requires an effective control of the boundary layer growth under the diffusing flow. An alternative approach consists of distributing the loading over two subsequent airfoils, using a so-called tandem blade, to, in some measure, restart the boundary layer before flow separation occurs. It is, however, not always clear whether the benefits of the two-blade setup justify the additional manufacturing complexity. The present work explores the tandem blade concept using a gradient-based optimization method to produce an efficient, highly loaded compressor cascade blade directly. A comparison between two-dimensional single and tandem configurations is first presented to clarify the benefits of one over the other. The geometry is optimized for each concept using a gradient-based optimization technique to improve the pressure loss coefficient at multiple operating points for a given flow-turning constraint. While the optimized single and tandem blade designs have similar performance, the lower solidity of the latter provides a lighter compressor stage for the considered operating range. A three-dimensional tandem compressor cascade based on the two-dimensional study is then optimized to account for secondary flows. The aerodynamic performance and the operating range are assessed and compared, along with a study of the physical phenomena surrounding the tandem configuration. The resulting geometry presents similar non-conventional features observed during the two-dimensional study that exploits the flow mechanism of two-airfoil configurations.

Arabidopsis RALF4 Rapidly Halts Pollen Tube Growth by Increasing ROS and Decreasing Calcium Cytoplasmic Tip Levels

In recent years, the rapid alkalinization factor (RALF) family of cysteine-rich peptides has been reported to be crucial for several plant signaling mechanisms, including cell growth, plant immunity and fertilization. RALF4 and RALF19 (RALF4/19) pollen peptides redundantly regulate the pollen tube integrity and growth through binding to their receptors ANXUR1/2 (ANX1/2) and Buddha’s Paper Seal 1 and 2 (BUPS1/2), members of the Catharanthus roseus RLK1-like (CrRLK1L) family, and, thus, are essential for plant fertilization. However, the signaling mechanisms at the cellular level that follow these binding events remain unclear. In this study, we show that the addition of synthetic peptide RALF4 rapidly halts pollen tube growth along with the excessive deposition of plasma membrane and cell wall material at the tip. The ratiometric imaging of genetically encoded ROS and Ca2+ sensors-expressing pollen tubes shows that RALF4 treatment modulates the cytoplasmic levels of reactive oxygen species (ROS) and calcium (Ca2+) in opposite ways at the tip. Thus, we propose that pollen RALF4/19 peptides bind ANX1/2 and BUPS1/2 to regulate ROS and calcium homeostasis to ensure proper cell wall integrity and control of pollen tube growth.

Probing the Depths of Molecular Complexity: STAT3 as a Key Architect in Colorectal Cancer Pathogenesis.

Colorectal cancer (CRC) has become a significant threat in recent decades, and its incidence is predicted to continue rising. Despite notable advancements in therapeutic strategies, managing CRC poses complex challenges, primarily due to the lack of clinically feasible therapeutic targets. Among the myriad molecules implicated in CRC, the signal transducer and activator of transcription 3 (STAT3) stands out as a promising target tightly regulated by various genes. This intracellular transcription factor, spanning 750-795 amino acids and weighing approximately 92 kDa, is crucial in key cellular activities such as growth, migration, invasion, inflammation, and angiogenesis. Aberrant activation of STAT3 signaling has been linked to various cancers, including CRC. Therefore, targeting this signaling pathway holds significance for potential CRC treatment strategies.STAT3, as a central intracellular transcription factor, is implicated in colorectal cancer development by activating aberrant signaling pathways. Numerous studies have demonstrated that the abnormal hyperactivation of STAT3 in CRC tissues enhances cell proliferation, suppresses apoptosis, promotes angiogenesis, and facilitates tumor invasion and metastasis. As a focal point in colorectal cancer research, STAT3 emerges as a promising candidate for detecting and treating CRC. This review aims to present recent data on STAT3, emphasizing the activation and functions of STAT3 inhibitors in CRC. Indeed, STAT3 inhibitors have been identified to have therapeutic potential in CRC, especially inhibitors targeting the DNA-binding domain (DBD). Indeed, STAT3 inhibitors have been identified to have a therapeutic potential in CRC, especially the inhibitors targeting the DNA binding domain (DBD). For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.

Differential frequency of persister cells in clinically derived isolates of Pseudomonas aeruginosa after exposure to cefiderocol and ceftolozane/tazobactam.

Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections. Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters. Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation. Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure.

A hierarchical host microstructure enables regulated inner Li deposition for stable Li metal electrodes

Dendritic lithium (Li) deposition is a critical issue hindering the development of next-generation high-energy-density Li metal batteries (LMBs). Confining Li deposition within a three-dimensional host is a general strategy to suppress the volume expansion of the Li electrode. However, precise control of continuous Li growth in the pore space of the host is rarely investigated, which is a crucial issue to enable a high utilization ratio of the hosted Li for practical LMBs. Herein, a novel hierarchical host structure possessing a multifunctional secondary porous structure to regulate the continuous Li growth with high uniformity and reversibility is proposed. The secondary porous structure consisting of carbon nanotubes, nickel and Li2O-enriched solid electrolyte interphase is in-situ generated via lithiation reaction of a modified nickel foam scaffold, exhibiting high lithiophilicity, fast Li+ transportation and charge transfer. The LMB utilizing Li metal electrodes hosted by this rational structure achieved a stable cycling over 300 cycles with a practical LiFePO4 positive electrode (~2.5 mAh cm-2) at 0.5C/0.5C in the voltage window of 2.5-4.4 V. This work provides a novel approach to designing the host microstructure for constructing more stable Li metal electrode in practical LMBs.

Halophilic Phosphate-Solubilizing Microbes (Priestia megaterium and Bacillus velezensis) Isolated from Arabian Sea Seamount Sediments for Plant Growth Promotion.

Arabian Sea is a highly productive Ocean owing to deep upwelling with reports on phosphorus cycling in ocean sediments. In this study, microbes from sea mounts of the Arabian Sea at varying depths (400m, 900m) were screened to isolate and characterize phosphate-solubilizing bacteria (PSB) with plant growth-promoting properties. Out of the seven morphologically different PSBs, two bacterial strains with maximum phosphate solubilization index were identified as Priestia megaterium (H1) and Bacillus velezensis (H2) based on biochemical and molecular characteristics. Different factors influencing phosphatase production were optimized, which showed maximum solubilization at temperature of 30°C (97.5μg/mL), glucose as best carbon source (70µg/mL), 1-M NaCl (114.1µg/mL), and pH 8 (134.3µg/mL) indicating their halophilic and alkaliphilic characteristics. Alkaline phosphatase enzyme was extracted and partially purified from both PSBs wherein H2 strains showed greater specific activity (24.83 U/mg). Metabolomics studies through HPLC revealed maximum production of gluconic acid (483.75mg/L) in addition to lactic, oxalic, acetic, and succinic acid during solubilization. Biopriming effect of PSBs on tomato seed germination showed high germination index (80%) in consortia of both isolates which was also validated through root colonization by SEM analysis. Further studies using pot assay experiments also showed comparable results in marine PSB consortia with positive control (Phosphobacteria) for plant growth attributes including root height and weight. These findings suggest that the halophilic PSB strains from marine sediments could be used as potential bio-inoculants to enhance plant growth and combat saline stress for sustainable Agriculture.

Decomposition and Growth Pathways for Ammonium Nitrate Clusters and Nanoparticles.

Understanding the formation and decomposition mechanisms of aerosolized ammonium nitrate species will lead to improvements in modeling the thermodynamics and kinetics of aerosol haze formation. Studying the sputtered mass spectra of cation and anion ammonium nitrate clusters can provide insights as to which growth and evaporation pathways are favored in the earliest stages of nucleation and thereby guide the development and use of accurate models for intermolecular forces for these systems. Simulated annealing Monte Carlo optimization followed by density functional theory optimizations can be used reliably to predict minimum-energy structures and interaction energies for the cation and anion clusters observed in mass spectra as well as for neutral nanoparticles. A combination of translational and rotational mag-walking and sawtooth simulated annealing methods was used to find optimum structures of the various heterogeneous clusters identifiable in the mass spectra. Following these optimizations with ωB97X-D3 density functional theory calculations made it possible to rationalize the pattern of peaks in the mass spectra through computation of the binding energies of clusters involved in various growth and dissociation pathways. Testing these calculations against CCSD(T) and MP2 predictions of the structures and binding energies for small clusters demonstrates the accuracy of the chosen model chemistry. For the first time, the peaks corresponding with all detectable species in both the positive and negative ion mass spectra of ammonium nitrate are identified with their corresponding structures. Thermodynamic control of particle growth and decomposition of ions due to loss of ammonia or nitric acid molecules is indicated. Structures and interaction energies for larger (NH4NO3)n nanoparticles are also presented, including the prediction of new particle morphologies with trigonal pyramidal character.

Goblet cell differentiation subgroups in colorectal cancer

The poor prognosis of relatively undifferentiated cancers has long been recognized, suggesting that selection against differentiation and in favor of uncontrolled growth is one of the most powerful drivers of cancer progression. Goblet cells provide the mucous surface of the gut, and when present in colorectal cancers (CRC), the cancers are called mucinous. We have used the presence of MUC2, the main mucous product of goblet cells, and an associated gene product, TFF3, to classify a large panel of nearly 80 CRC-derived cell lines into five categories based on their levels of MUC2 and TFF3 expression. We have then shown that these five patterns of expression can be easily identified in the direct analysis of tumor specimens allowing a much finer characterization of CRCs with respect to the presence of goblet cell differentiation. In particular, about 30% of all CRCs fall into the category of expressing TFF3 but not MUC2, which has not previously been acknowledged. Using the cell line data, we suggest that there are up to 12 genes (MUC2, TFF3, ATOH1, SPDEF, CDX1, CDX2, GATA6, HES1, ETS2, OLFM4, TOX3, and LGR5) that may be involved in selection against goblet cell differentiation in CRC by changes in methylation rather than mutations. Of these, LGR5, which is particularly associated with lack of goblet cell features, may function in the control of differentiation rather than direct control of cell growth, as has so far mostly been assumed. These results emphasize the importance of methylation changes in driving cancer progression.