Mutant p53 in cell-cell interactions.

p53 is an important tumor suppressor, and the complexities of p53 function in regulating cancer cell behaviour are well established. Many cancers lose or express mutant forms of p53, with evidence that the type of alteration affecting p53 may differentially impact cancer development and progression. It is also clear that in addition to cell-autonomous functions, p53 status also affects the way cancer cells interact with each other. In this review, we briefly examine the impact of different p53 mutations and focus on how heterogeneity of p53 status can affect relationships between cells within a tumor.

Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling.

There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell-cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.

Mutation of p53 increases the competitive ability of pluripotent stem cells.

During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality-control mechanism that contributes to this balance by eliminating viable cells that are less fit than their neighbours. The mutations that confer cells with a competitive advantage and the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are 'super-competitors' that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependent, as it does not occur when cells are pluripotent and it is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through competition for space or nutrients, but instead is mediated by short-range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.

Olfactory sniffing signals consciousness in unresponsive patients with brain injuries.

After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious1, and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions2,3. Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries4,5. Olfaction relies on brain structures that are involved in the basic mechanisms of arousal6, and we therefore hypothesized that it may serve as a biomarker for consciousness7. Here we use a non-verbal non-task-dependent measure known as the sniff response8-11 to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function10-15. We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.

Hydrogen stable isotope probing of lipids demonstrates slow rates of microbial growth in soil.

The rate at which microorganisms grow and reproduce is fundamental to our understanding of microbial physiology and ecology. While soil microbiologists routinely quantify soil microbial biomass levels and the growth rates of individual taxa in culture, there is a limited understanding of how quickly microbes actually grow in soil. For this work, we posed the simple question: what are the growth rates of soil microorganisms? In this study, we measure these rates in three distinct soil environments using hydrogen-stable isotope probing of lipids with 2H-enriched water. This technique provides a taxa-agnostic quantification of in situ microbial growth from the degree of 2H enrichment of intact polar lipid compounds ascribed to bacteria and fungi. We find that growth rates in soil are quite slow and correspond to average generation times of 14 to 45 d but are also highly variable at the compound-specific level (4 to 402 d), suggesting differential growth rates among community subsets. We observe that low-biomass microbial communities exhibit more rapid growth rates than high-biomass communities, highlighting that biomass quantity alone does not predict microbial productivity in soil. Furthermore, within a given soil, the rates at which specific lipids are being synthesized do not relate to their quantity, suggesting a general decoupling of microbial abundance and growth in soil microbiomes. More generally, we demonstrate the utility of lipid-stable isotope probing for measuring microbial growth rates in soil and highlight the importance of measuring growth rates to complement more standard analyses of soil microbial communities.

Structural evolution of an immune evasion determinant shapes pathogen host tropism.

Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi (Bb) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface protein may confer dramatic differences in host-specific, FH-binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ-human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent- and bird-associated CspZ variants alters the ability to promote rodent- and bird-specific early-onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mechanisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.

Lizards and the enzootic cycle of Borrelia burgdorferi sensu lato.

Emerging and re-emerging pathogens often stem from zoonotic origins, cycling between humans and animals, and are frequently vectored and maintained by hematophagous arthropod vectors. The efficiency by which these disease agents are successfully transmitted between vertebrate hosts is influenced by many factors, including the host on which a vector feeds. The Lyme disease bacterium Borrelia burgdorferi sensu lato has adapted to survive in complex host environments, vectored by Ixodes ticks, and maintained in multiple vertebrate hosts. The versatility of Lyme borreliae in disparate host milieus is a compelling platform to investigate mechanisms dictating pathogen transmission through complex networks of vertebrates and ticks. Squamata, one of the most diverse clade of extant reptiles, is comprised primarily of lizards, many of which are readily fed upon by Ixodes ticks. Yet, lizards are one of the least studied taxa at risk of contributing to the transmission and life cycle maintenance of Lyme borreliae. In this review, we summarize the current evidence, spanning from field surveillance to laboratory infection studies, supporting their contributions to Lyme borreliae circulation. We also summarize the current understanding of divergent lizard immune responses that may explain the underlying molecular mechanisms to confer Lyme spirochete survival in vertebrate hosts. This review offers a critical perspective on potential enzootic cycles existing between lizard-tick-Borrelia interactions and highlights the importance of an eco-immunology lens for zoonotic pathogen transmission studies.

Prospects and challenges of tissue-derived extracellular vesicles.

Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex, multicellular tissue microenvironments in biology and disease. EVs are native, lipid bilayer membraned nano-sized particles produced by all cells that are packaged with varied functional biomolecules including proteins, lipids, and nucleic acids. They are implicated in short- and long-range cellular communication and may elicit functional responses in recipient cells. To date, studies have often utilized cultured cells or biological fluids as a source for EVs that do not capture local molecular signatures of the tissue microenvironment. Recent work utilizing Ti-EVs has elucidated novel biomarkers for disease and provided insights into disease mechanisms that may lead to the development of novel therapeutic agents. Still, there are considerable challenges facing current studies. This review explores the vast potential and unique challenges for Ti-EV research and provides considerations for future studies that seek to advance this exciting field.

The dynamics of SARS-CoV-2 infectivity with changes in aerosol microenvironment.

Understanding the factors that influence the airborne survival of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets (∼5 to 10 µm equilibrated radius) over timescales spanning 5 s to 20 min using an instrument to probe survival in a small population of droplets (typically 5 to 10) containing ∼1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to ∼10% of the starting value was observable for SARS-CoV-2 over 20 min, with a large proportion of the loss occurring within the first 5 min after aerosolization. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallize at relative humidities (RHs) below 50%, leading to a near-instant loss of infectivity in 50 to 60% of the virus. However, at 90% RH, the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 min, beyond which it decays to only 10% remaining infectious after 10 min. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilization of CO2 from bicarbonate buffer within the droplet. Four different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.

Structure and function of ClpXP, a AAA+ proteolytic machine powered by probabilistic ATP hydrolysis.

ClpXP is an archetypical AAA+ protease, consisting of ClpX and ClpP. ClpX is an ATP-dependent protein unfoldase and polypeptide translocase, whereas ClpP is a self-compartmentalized peptidase. ClpXP is currently the only AAA+ protease for which high-resolution structures exist, the molecular basis of recognition for a protein substrate is understood, extensive biochemical and genetic analysis have been performed, and single-molecule optical trapping has allowed direct visualization of the kinetics of substrate unfolding and translocation. In this review, we discuss our current understanding of ClpXP structure and function, evaluate competing sequential and probabilistic mechanisms of ATP hydrolysis, and highlight open questions for future exploration.

Transdermal Hydrogen Sulfide Delivery Enabled by Open-Metal-Site Metal-Organic Frameworks.

Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter involved in many physiological processes that are integral to proper cellular functioning. Due to its profound anti-inflammatory and antioxidant properties, H2S plays important roles in preventing inflammatory skin disorders and improving wound healing. Transdermal H2S delivery is a therapeutically viable option for the management of such disorders. However, current small-molecule H2S donors are not optimally suited for transdermal delivery and typically generate electrophilic byproducts that may lead to undesired toxicity. Here, we demonstrate that H2S release from metal-organic frameworks (MOFs) bearing coordinatively unsaturated metal centers is a promising alternative for controlled transdermal delivery of H2S. Gas sorption measurements and powder X-ray diffraction (PXRD) studies of 11 MOFs support that the Mg-based framework Mg2(dobdc) (dobdc4- = 2,5-dioxidobenzene-1,4-dicarboxylate) is uniquely well-suited for transdermal H2S delivery due to its strong yet reversible binding of H2S, high capacity (14.7 mmol/g at 1 bar and 25 °C), and lack of toxicity. In addition, Rietveld refinement of synchrotron PXRD data from H2S-dosed Mg2(dobdc) supports that the high H2S capacity of this framework arises due to the presence of three distinct binding sites. Last, we demonstrate that transdermal delivery of H2S from Mg2(dobdc) is sustained over a 24 h period through porcine skin. Not only is this significantly longer than sodium sulfide but this represents the first example of controlled transdermal delivery of pure H2S gas. Overall, H2S-loaded Mg2(dobdc) is an easily accessible, solid-state source of H2S, enabling safe storage and transdermal delivery of this therapeutically relevant gas.

Phylogenetic Reconstruction and Functional Characterization of the Ancestral Nef Protein of Primate Lentiviruses.

Nef is an accessory protein unique to the primate HIV-1, HIV-2, and SIV lentiviruses. During infection, Nef functions by interacting with multiple host proteins within infected cells to evade the immune response and enhance virion infectivity. Notably, Nef can counter immune regulators such as CD4 and MHC-I, as well as the SERINC5 restriction factor in infected cells. In this study, we generated a posterior sample of time-scaled phylogenies relating SIV and HIV Nef sequences, followed by reconstruction of ancestral sequences at the root and internal nodes of the sampled trees up to the HIV-1 Group M ancestor. Upon expression of the ancestral primate lentivirus Nef protein within CD4+ HeLa cells, flow cytometry analysis revealed that the primate lentivirus Nef ancestor robustly downregulated cell-surface SERINC5, yet only partially downregulated CD4 from the cell surface. Further analysis revealed that the Nef-mediated CD4 downregulation ability evolved gradually, while Nef-mediated SERINC5 downregulation was recovered abruptly in the HIV-1/M ancestor. Overall, this study provides a framework to reconstruct ancestral viral proteins and enable the functional characterization of these proteins to delineate how functions could have changed throughout evolutionary history.

Beyond Simple vs Complex: Exploring the Nuanced and Unexpected Effects of Spatial Environmental Complexity on Mating Patterns and Female Fecundity.

The features of the physical environment set the stage upon which sexual selection operates, and consequently can have a significant impact on variation in realized individual fitness, and influence a population's evolutionary trajectory. This phenomenon has been explored empirically in several studies using fruit flies (Drosophila melanogaster) which have found that changing the spatial complexity of the mating environment influenced male-female interaction dynamics, (re)mating rates and realized female fecundities. However, these studies did not explore mating patterns, which can dramatically alter the genetic composition of the next generation, and frequently only compared a single, small "simple" environment to a single larger "complex" environment. While these studies have shown that broadly changing the characteristics of the environment can have big effects on reproductive dynamics, the plasticity of this outcome to more subtle changes has not been extensively explored. Our study set out to compare patterns of mating and courtship between large- and small-bodied males and females, and female fecundities in both a simple environment and two distinctly different spatially-complex environments. We found that realized offspring production patterns differed dramatically between all three environments, indicating that the effects of increasing spatial complexity on mating outcomes are sensitive to the specific type of environmental complexity. Furthermore, we observed female fecundities were higher for flies in both complex environments compared those in the simple environment, supporting its role as a mediator of sexual conflict. Together, these results show that the union of gametes within a population can be greatly influenced by the specific spatial features of the environment and that while some outcomes of increased environmental complexity are likely generalizable, other phenomena like mating patterns and courtship rates may vary from one complex environment to another.

Sensory Target Detection at Local and Global Timescales Reveals a Hierarchy of Supramodal Dynamics in the Human Cortex.

To ensure survival in a dynamic environment, the human neocortex monitors input streams from different sensory organs for important sensory events. Which principles govern whether different senses share common or modality-specific brain networks for sensory target detection? We examined whether complex targets evoke sustained supramodal activity while simple targets rely on modality-specific networks with short-lived supramodal contributions. In a series of hierarchical multisensory target detection studies (n = 77, of either sex) using EEG, we applied a temporal cross-decoding approach to dissociate supramodal and modality-specific cortical dynamics elicited by rule-based global and feature-based local sensory deviations within and between the visual, somatosensory, and auditory modality. Our data show that each sense implements a cortical hierarchy orchestrating supramodal target detection responses, which operate at local and global timescales in successive processing stages. Across different sensory modalities, simple feature-based sensory deviations presented in temporal vicinity to a monotonous input stream triggered a mismatch negativity-like local signal which decayed quickly and early, whereas complex rule-based targets tracked across time evoked a P3b-like global neural response which generalized across a late time window. Converging results from temporal cross-modality decoding analyses across different datasets, we reveal that global neural responses are sustained in a supramodal higher-order network, whereas local neural responses canonically thought to rely on modality-specific regions evolve into short-lived supramodal activity. Together, our findings demonstrate that cortical organization largely follows a gradient in which short-lived modality-specific as well as supramodal processes dominate local responses, whereas higher-order processes encode temporally extended abstract supramodal information fed forward from modality-specific cortices.SIGNIFICANCE STATEMENT Each sense supports a cortical hierarchy of processes tracking deviant sensory events at multiple timescales. Conflicting evidence produced a lively debate around which of these processes are supramodal. Here, we manipulated the temporal complexity of auditory, tactile, and visual targets to determine whether cortical local and global ERP responses to sensory targets share cortical dynamics between the senses. Using temporal cross-decoding, we found that temporally complex targets elicit a supramodal sustained response. Conversely, local responses to temporally confined targets typically considered modality-specific rely on early short-lived supramodal activation. Our finding provides evidence for a supramodal gradient supporting sensory target detection in the cortex, with implications for multiple fields in which these responses are studied (e.g., predictive coding, consciousness, and attention).

Decreasing Alertness Modulates Perceptual Decision-Making.

The ability to make decisions based on external information, prior knowledge, and evidence is a crucial aspect of cognition and may determine the success and survival of an organism. Despite extensive work on decision-making mechanisms/models, understanding the effects of alertness on neural and cognitive processes remain limited. Here we use EEG and behavioral modeling to characterize cognitive and neural dynamics of perceptual decision-making in awake/low alertness periods in humans (14 male, 18 female) and characterize the compensatory mechanisms as alertness decreases. Well-rested human participants, changing between full-wakefulness and low alertness, performed an auditory tone-localization task, and its behavioral dynamics were quantified with psychophysics, signal detection theory, and drift-diffusion modeling, revealing slower reaction times, inattention to the left side of space, and a lower rate of evidence accumulation in periods of low alertness. Unconstrained multivariate pattern analysis (decoding) showed a ∼280 ms delayed onset driven by low alertness of the neural signatures differentiating between left and right decision, with a spatial reconfiguration from centroparietal to lateral frontal regions 150-360 ms. To understand the neural compensatory mechanisms with decreasing alertness, we connected the evidence-accumulation behavioral parameter to the neural activity, showing in the early periods (125-325 ms) a shift in the associated patterns from right parietal regions in awake, to right frontoparietal during low alertness. This change in the neurobehavioral dynamics for central accumulation-related cognitive processes defines a clear reconfiguration of the brain networks' regions and dynamics needed for the implementation of decision-making, revealing mechanisms of resilience of cognition when challenged by decreased alertness.SIGNIFICANCE STATEMENT Most living organisms make multiple daily decisions, and these require a degree of evidence from both the environment and the internal milieu. Such decisions are usually studied under sequential sampling models and involve making a behavioral choice based on sensory encoding, central accumulation, and motor implementation processes. Since there is little research on how decreasing alertness affects such cognitive processes, this study has looked at the cognitive and neural dynamics of perceptual decision-making in people while fully awake and in drowsy periods. Using computational modeling of behavior and neural dynamics on human participants performing an auditory tone-localization task, we reveal how low alertness modulates evidence accumulation-related processes and its corresponding compensatory neural signatures.

A natural fusion of flavodiiron, rubredoxin, and rubredoxin oxidoreductase domains is a self-sufficient water-forming oxidase of Trichomonas vaginalis.

Microaerophilic pathogens such as Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis have robust oxygen consumption systems to detoxify oxygen and maintain intracellular redox balance. This oxygen consumption results from H2O-forming NADH oxidase (NOX) activity of two distinct flavin-containing systems: H2O-forming NOXes and multicomponent flavodiiron proteins (FDPs). Neither system is membrane bound, and both recycle NADH into oxidized NAD+ while simultaneously removing O2 from the local environment. However, little is known about the specific contributions of these systems in T. vaginalis. In this study, we use bioinformatics and biochemical analyses to show that T. vaginalis lacks a NOX-like enzyme and instead harbors three paralogous genes (FDPF1-3), each encoding a natural fusion product between the N-terminal FDP, central rubredoxin (Rb), and C-terminal NADH:Rb oxidoreductase domains. Unlike a "stand-alone" FDP that lacks Rb and oxidoreductase domains, this natural fusion protein with fully populated flavin redox centers directly accepts reducing equivalents of NADH to catalyze the four-electron reduction of oxygen to water within a single polypeptide with an extremely high turnover. Furthermore, using single-particle cryo-EM, we present structural insights into the spatial organization of the FDP core within this multidomain fusion protein. Together, these results contribute to our understanding of systems that allow protozoan parasites to maintain optimal redox balance and survive transient exposure to oxic conditions.

High-Concentration Self-Assembly of Zirconium- and Hafnium-Based Metal-Organic Materials.

Metal-organic frameworks (MOFs) are crystalline, porous solids constructed from organic linkers and inorganic nodes that are promising for applications in chemical separations, gas storage, and catalysis, among many others. However, a major roadblock to the widespread implementation of MOFs, including highly tunable and hydrolytically stable Zr- and Hf-based frameworks, is their benchtop-scalable synthesis, as MOFs are typically prepared under highly dilute (≤0.01 M) solvothermal conditions. This necessitates the use of liters of organic solvent to prepare only a few grams of MOF. Herein, we demonstrate that Zr- and Hf-based frameworks (eight examples) can self-assemble at much higher reaction concentrations than are typically utilized, up to 1.00 M in many cases. Combining stoichiometric amounts of Zr or Hf precursors with organic linkers at high concentrations yields highly crystalline and porous MOFs, as confirmed by powder X-ray diffraction (PXRD) and 77 K N2 surface area measurements. Furthermore, the use of well-defined pivalate-capped cluster precursors avoids the formation of ordered defects and impurities that arise from standard metal chloride salts. These clusters also introduce pivalate defects that increase the exterior hydrophobicity of several MOFs, as confirmed by water contact angle measurements. Overall, our findings challenge the standard assumption that MOFs must be prepared under highly dilute solvothermal conditions for optimal results, paving the way for their scalable and user-friendly synthesis in the laboratory.

Enhancing Dynamic Spectral Diffusion in Metal-Organic Frameworks through Defect Engineering.

The crystal packing of organic chromophores has a profound impact on their photophysical properties. Molecular crystal engineering is generally incapable of producing precisely spaced arrays of molecules for use in photovoltaics, light-emitting diodes, and sensors. A promising alternative strategy is the incorporation of chromophores into crystalline metal-organic frameworks (MOFs), leading to matrix coordination-induced emission (MCIE) upon confinement. However, it remains unclear how the precise arrangement of chromophores and defects dictates photophysical properties in these systems, limiting the rational design of well-defined photoluminescent materials. Herein, we report new, robust Zr-based MOFs constructed from the linker tetrakis(4-carboxyphenyl)ethylene (TCPE4-) that exhibit an unexpected structural transition in combination with a prominent shift from green to blue photoluminescence (PL) as a function of the amount of acid modulator (benzoic, formic, or acetic acid) used during synthesis. Time-resolved PL (TRPL) measurements provide full spectral information and reveal that the observed hypsochromic shift arises due to a higher concentration of linker substitution defects at higher modulator concentrations, leading to broader excitation transfer-induced spectral diffusion. Spectral diffusion of this type has not been reported in a MOF to date, and its observation provides structural information that is otherwise unobtainable using traditional crystallographic techniques. Our findings suggest that defects have a profound impact on the photophysical properties of MOFs and that their presence can be readily tuned to modify energy transfer processes within these materials.

The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo.

BACKGROUND: Pancreatic cancer is one of the leading causes of cancer death in Western societies. Its late diagnosis and resistance to chemotherapies result in a high mortality rate; thus, the development of more effective therapies for the treatment of pancreatic cancer is strongly warranted. Usnic acid (UA) is a secondary metabolite of lichens that shows modest antiproliferative activity toward cancer cells. Recently, we reported the synthesis of a UA pyrazole derivative, named 5, which was more active than the parent compound toward cervical cancer cells. Here, its anticancer potential has been evaluated in detail in other cancer cells, particularly pancreatic cancer cells. METHODS: The impact of UA and derivative 5 on cell viability, morphology, cell cycle, and death was assessed using the MTT test, electron microscopy, flow cytometry, and immunoblotting, respectively. The calcium ions level was detected fluorometrically. In vivo, the anticancer activity of 5 was evaluated in a murine xenograft model. RESULTS: Derivative 5 inhibited the viability of different cancer cells. Noncancerous cells were less sensitive. It induced the release of calcium ions from the endoplasmic reticulum (ER) and ER stress, which was manifested by cell vacuolization. It was accompanied by G0/G1 cell cycle arrest and cell death of pancreatic cancer cells. When applied to nude mice with xenografted pancreatic cancer cells, 5 inhibited tumor growth, with no signs of kidney or liver toxicity. CONCLUSIONS: UA derivative 5 is superior to UA inhibiting the growth and proliferation of pancreatic cancer cells. ER stress exaggeration is a mechanism underlying the activity of derivative 5.