Structural Investigations of Phthalazinone Derivatives as Allosteric Inhibitors of Human DNA Methyltransferase 3A.

The development of new therapeutics targeting enzymes involved in epigenetic pathways such as histone modification and DNA methylation has received a lot of attention, particularly for targeting diverse cancers. Unfortunately, irreversible nucleoside inhibitors (azacytidine and decitabine) have proven highly cytotoxic, and competitive inhibitors are also problematic. This work describes synthetic and structural investigations of a new class of allosteric DNA methyltransferase 3A (DNMT3A) inhibitors, leading to the identification of several critical pharmacophores in the lead structure. Specifically, we find that the tetrazole and phthalazinone moieties are indispensable for the inhibitory activity of DNMT3A and elucidate other modifiable regions in the lead compound.

Dissolution Heterogeneity Observed in Anisotropic Ruthenium Dioxide Nanocrystals via Liquid-Phase Transmission Electron Microscopy.

Noble metal oxides such as ruthenium dioxide are highly active electrocatalysts for anodic reactions in acidic electrolytes, but dissolution during electrochemical operation impedes wide-scale applications in renewable energy technologies. Improving the fundamental understanding of the dissolution dynamics of application-relevant morphologies such as nanocrystals is critical for the grid-scale implementation of these materials. Herein, we report the nanoscale heterogeneity observed via liquid-phase transmission electron microscopy during ruthenium dioxide nanocrystal dissolution under oxidizing conditions. Single-crystalline ruthenium dioxide nanocrystals enabled the direct observation of dissolution along different crystallographic facets, allowing an unprecedented direct comparison of crystal facet stability. The nanoscale observations revealed substantial heterogeneity in the relative stability of crystallographic facets across different nanocrystals, attributed to the nanoscale strains present in these crystals. These findings highlight the importance of nanoscale heterogeneity in determining macroscale properties such as electrocatalyst stability and provide a characterization methodology that can be integrated into next-generation electrocatalyst discovery efforts.

American crocodiles (Crocodylus acutus: Reptilia: Crocodilidae) visiting the facilities of a freshwater aquaculture of the Northern Pacific region, Costa Rica, carry tetracycline-resistant Escherichia coli.

Apex predators are exposed to antimicrobial compounds and resistant microbes, which accumulate at different trophic levels of the related ecosystems. The study aimed to characterize the presence and the antimicrobial resistance patterns of fecal Escherichia coli isolated from cloacal swab samples obtained from wild-living American crocodiles (Crocodylus acutus) (n = 53). Sampling was conducted within the distinctive context of a freshwater-intensive aquaculture farm in Costa Rica, where incoming crocodiles are temporarily held in captivity before release. Phenotypic antimicrobial susceptibility profiles were determined in all isolates, while resistant isolates were subjected to whole-genome sequencing and bioinformatics analyses. In total, 24 samples contained tetracycline-resistant E. coli (45.3%). Isolates carried either tet(A), tet(B), or tet(C) genes. Furthermore, genes conferring resistance to ß-lactams, aminoglycosides, fosfomycin, sulfonamides, phenicol, quinolones, trimethoprim, and colistin were detected in single isolates, with seven of them carrying these genes on plasmids. Genome sequencing further revealed that sequence types, prevalence of antibiotic resistance carriage, and antibiotic resistance profiles differed between the individuals liberated within the next 24 h after their capture in the ponds and those liberated from enclosures after longer abodes. The overall presence of tetracycline-resistant E. coli, coupled with potential interactions with various anthropogenic factors before arriving at the facilities, hinders clear conclusions on the sources of antimicrobial resistance for the studied individuals. These aspects hold significant implications for both the aquaculture farm's biosecurity and the planning of environmental monitoring programs using such specimens. Considering human-crocodile conflicts from the One Health perspective, the occurrence of antimicrobial resistance underscores the importance of systematical surveillance of antibiotic resistance development in American crocodiles.

Improving Optical Flow Sensor Using a Gimbal for Quadrotor Navigation in GPS-Denied Environment.

This paper proposes a new sensor using optical flow to stabilize a quadrotor when a GPS signal is not available. Normally, optical flow varies with the attitude of the aerial vehicle. This produces positive feedback on the attitude control that destabilizes the orientation of the vehicle. To avoid this, we propose a novel sensor using an optical flow camera with a 6DoF IMU (Inertial Measurement Unit) mounted on a two-axis anti-shake stabilizer mobile aerial gimbal. We also propose a robust algorithm based on Sliding Mode Control for stabilizing the optical flow sensor downwards independently of the aerial vehicle attitude. This method improves the estimation of the position and velocity of the quadrotor. We present experimental results to show the performance of the proposed sensor and algorithms.

The leachate from the Urban Solid Waste Transfer Station produces neurotoxicity in Wistar rats.

Leachate from municipal solid waste is a mixture of xenobiotics capable of contaminating bodies of water and causing damage to the health of living beings that inhabit or consume contaminated water. A previous study revealed the presence of heavy metals in Urban Solid Waste Transfer Station (USWTS) leachate above the permissible national and international limits. In the present study, we demonstrate that subchronic oral administration (5 and 25 % v/v) of leachate to male Wistar rats caused changes in the immunoreactivity of the glial markers: GFAP and Iba-1, accompanied by an increase in the expression of caspase-3, and a decrease in the expression of the NeuN protein. Results indicate that the heavy metals present in the leachate induced neuronal loss in the prefrontal cortex, suggesting that these contaminants can cause neurological problems in mammals that consume surface water with xenobiotics, since the leachate could contaminate water bodies and underground water.

Understanding the nervous system: lessons from Frontiers in Neurophotonics.

The Frontiers in Neurophotonics Symposium is a biennial event that brings together neurobiologists and physicists/engineers who share interest in the development of leading-edge photonics-based approaches to understand and manipulate the nervous system, from its individual molecular components to complex networks in the intact brain. In this Community paper, we highlight several topics that have been featured at the symposium that took place in October 2022 in Québec City, Canada.

Teleoperator-Robot-Human Interaction in Manufacturing: Perspectives from Industry, Robot Manufacturers, and Researchers.

OCCUPATIONAL APPLICATIONSIndustrial robots have become an important aspect in modern industry. In the context of human-robot collaboration, enabling teleoperated robots to work in close proximity to local/onsite humans can provide new opportunities to improve human engagement in a distributed workplace. Interviews with industry stakeholders highlighted several potential benefits of such teleoperator-robot-human collaboration (tRHC), including the application of tRHC to tasks requiring both expertise and manual dexterity (e.g., maintenance and highly skilled tasks in sectors including construction, manufacturing, and healthcare), as well as opportunities to expand job accessibility for individuals with disabilities and older individuals. However, interviewees also indicated potential challenges of tRHC, particularly related to human perception (e.g., perceiving remote environments), safety, and trust. Given these challenges, and the current limited information on the practical value and implementation of tRHC, we propose several future research directions, with a focus on human factors and ergonomics, to help realize the potential benefits of tRHC.

Background The increasing prevalence of robots in industrial environments is attributed in part to advancements in collaborative robot technologies, enabling robots to work in close proximity to humans. Simultaneously, the rise of teleoperation, involving remote robot control, poses unique opportunities and challenges for human-robot collaboration (HRC) in diverse and distributed workspaces.Purpose There is not yet a comprehensive understanding of HRC in teleoperation, specifically focusing on collaborations involving the teleoperator, the robot, and the local or onsite workers in industrial settings, here referred to as teleoperator-robot-human collaboration (tRHC). We aimed to identify opportunities, challenges, and potential applications of tRHC through insights provided from industry stakeholders, thereby supporting effective future industrial implementations.Methods Thirteen stakeholders in robotics, specializing in different domains (i.e., safety, robot manufacturing, aerospace/automotive manufacturing, and supply chains), completed semi-structured interviews that focused on exploring diverse aspects relevant to tRHC. The interviews were then transcribed and thematic analysis was applied to group responses into broader categories, which were further compared across stakeholder industries.Results We identified three main categories and 13 themes from the interviews. These categories include Benefits, Concerns, and Technical Challenges. Interviewees highlighted accessibility, ergonomics, flexibility, safety, time & cost saving, and trust as benefits of tRHC. Concerns raised encompassed safety, standards, trust, and workplace optimization. Technical challenges consisted of critical issues such as communication time delays, the need for high dexterity in robot manipulators, the importance of establishing shared situational awareness among all agents, and the potential of augmented and virtual reality in providing immersive control interfaces.Conclusions Despite important challenges, tRHC could offer unique benefits, facilitating seamless collaboration among the teleoperator, teleoperated robot(s), and onsite workers across physical and geographic boundaries. To realize such benefits and address the challenges, we propose several research directions to further explore and develop tRHC capabilities.

Technetium-99m-ubiquicidin 29-41 SPECT-CT to detect postsurgical spinal infection: A case report.

Background: Postsurgical spinal infections are a severe complication and a challenge to the neurosurgeon due to their complex management. Revision surgeries and the removal of hardware are usually necessary. Recently, advances in nuclear medicine have made it possible to employ radiotracers to identify infections. The radiolabeled antimicrobial peptide technetium-99m-ubiquicidin (99mTc-UBI) (29-41) has been demonstrated to detect bacterial infections. UBI 29-41 is a peptide sequence with selective binding to the anionic cell membrane of bacteria, which has recently been used to differentiate between infection and inflammation. Here, we describe the clinical utility of 99mTc-UBI 29-41 single-photon emission computed tomography-computed tomography (SPECT-CT) in a patient suspected of a postoperative infection. Case description: A 54-year-old male who presented with conus medullaris syndrome secondary to T12 spondylodiscitis and multiple abscess collections was initially managed with debridement, corpectomy, and minimally invasive lateral instrumentation. The patient developed postsurgical empyema near the surgical site. The image study avoided the need for a second surgery and hardware removal. Conclusion: The use of 99mTc-UBI 29-41 SPECT-CT served as a tool to avoid a second invasive procedure; instead, conservative management with antibiotics was performed with an effective outcome after two weeks. This radiotracer has utility in cases in which infection is suspected, but the location is not entirely clear, and information is needed to guide the therapeutic approach.

VOIS: A framework for recording Voice Over Internet Surveys.

Verbal data provide researchers insight beyond that offered by text-based responses, including tone, reasoning elaboration, and experienced difficulty, among other processes. Additionally, it offers a less cognitively taxing way for participants to provide long responses. Verbal data collection methods are found in a variety of fields, mostly conducted in lab-based settings or requiring specialized hardware. Restricting verbal protocols to lab-based settings can have several drawbacks, including smaller sample sizes, biased populations, reduced adoption, and incompatibility with potential social distancing requirements. No method currently exists for researchers to collect verbal data within major online survey collection platforms. The current paper offers a user-friendly approach for collecting verbal data online, where a researcher can copy and paste JavaScript code into the desired survey platform. By providing a framework that does not require any advanced programming ability, researchers can collect verbal data in a scalable way using familiar modalities.

Comparison Between Pantoprazole Intermittent Dosing and Continuous Infusion in Suspected Upper Gastrointestinal Bleeding Prior to Endoscopy: Impact of a Pharmacist-Driven Protocol to Reduce Utilization of Pantoprazole Continuous Infusion.

BACKGROUND: Current practice for patients with suspected or confirmed upper gastrointestinal bleeding (GIB) is to utilize a proton pump inhibitor (PPI) bolus followed by a continuous infusion for 72 hours. Literature has shown similar outcomes with intermittent bolus dosing compared to continuous infusion. Substitution would lead to reduced costs and utilization of resources. METHODS: This was a retrospective case-control study conducted via chart review. Utilizing electronic healthcare record reports, patients in the control arm were screened for inclusion if they received a pantoprazole continuous infusion from December 1, 2020, to March 31, 2021. A total of 38 patients were included in the control arm. Patients in the experimental arm were screened for inclusion with pantoprazole intermittent therapy from January 1, 2022, to June 30, 2022. A total of 60 patients were included in the experimental arm. The primary outcome was a 30-day GIB recurrence. Secondary outcomes included 30-day hospital readmission, 30-day Clostridioides difficile (C. difficile), hospital length of stay (LOS), and number of pantoprazole vials utilized. RESULTS: There was a 65% reduction in the 30-day GIB recurrence in the intermittent bolus arm compared to the continuous infusion arm. Thirty-day hospital readmission was 57% lower in the intermittent bolus arm compared to the continuous infusion arm. The LOS between the two arms was almost identical with the median being five days for the intermittent bolus arm and the median being four days for the continuous infusion arm. The 30-day C. difficile infection rate had 5% of patients acquiring C. difficile in the intermittent bolus arm and 2.5% in the continuous infusion arm. The intermittent bolus arm used 55% fewer pantoprazole vials than the continuous infusion arm. CONCLUSION: In hospitalized patients, the utilization of pantoprazole intermittent bolus is not only comparably efficacious but potentially represents a safer and economically advantageous alternative compared to the current guideline recommendation of a 72-hour pantoprazole continuous infusion. Further studies could provide more robust data to support our findings and challenge the current recommendation for patients who meet the indication criteria.

Real-Time Person Detection in Wooded Areas Using Thermal Images from an Aerial Perspective.

Detecting people in images and videos captured from an aerial platform in wooded areas for search and rescue operations is a current problem. Detection is difficult due to the relatively small dimensions of the person captured by the sensor in relation to the environment. The environment can generate occlusion, complicating the timely detection of people. There are currently numerous RGB image datasets available that are used for person detection tasks in urban and wooded areas and consider the general characteristics of a person, like size, shape, and height, without considering the occlusion of the object of interest. The present research work focuses on developing a thermal image dataset, which considers the occlusion situation to develop CNN convolutional deep learning models to perform detection tasks in real-time from an aerial perspective using altitude control in a quadcopter prototype. Extended models are proposed considering the occlusion of the person, in conjunction with a thermal sensor, which allows for highlighting the desired characteristics of the occluded person.

Myelination- and migration-associated genes are downregulated after phagocytosis in cultured oligodendrocyte precursor cells.

In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such as astrocytes, are also recently recognized to show phagocytotic activity under some conditions. Oligodendrocyte precursor cells (OPCs), which belong to the same glial cell family as microglia and astrocytes, may have similar functions. However, it remains largely unknown whether OPCs exhibit phagocytic activity against foreign materials like microglia. To answer this question, we examined the phagocytosis activity of OPCs using primary rat OPC cultures. Since innate phagocytosis activity could trigger cell death pathways, we also investigated whether participating in phagocytosis activity may lead to OPC cell death. Our data shows that cultured OPCs phagocytosed myelin-debris-rich lysates prepared from rat corpus callosum, without progressing to cell death. In contrast to OPCs, mature oligodendrocytes did not show phagocytotic activity against the bait. OPCs also exhibited phagocytosis towards lysates of rat brain cortex and cell membrane debris from cultured astrocytes, but the percentage of OPCs that phagocytosed beta-amyloid was much lower than the myelin debris. We then conducted RNA-seq experiments to examine the transcriptome profile of OPC cultures and found that myelination- and migration-associated genes were downregulated 24 h after phagocytosis. On the other hand, there were a few upregulated genes in OPCs 24 h after phagocytosis. These data confirm that OPCs play a role in debris removal and suggest that OPCs may remain in a quiescent state after phagocytosis.

Antibacterial and Antibiofilm Activity of Chemically and Biologically Synthesized Silver Nanoparticles.

Bacterial biofilms are a significant problem in the food industry, as they are difficult to eradicate and represent a threat to consumer health. Currently, nanoparticles as an alternative to traditional chemical disinfectants have garnered much attention due to their broad-spectrum antibacterial activity and low toxicity. In this study, silver nanoparticles (AgNPs) were synthesized by a biological method using a Jacaranda mimosifolia flower aqueous extract and by a chemical method, and the factors affecting both syntheses were optimized. The nanoparticles were characterized by Ultraviolet-visible (UV-Vis) spectrophotometry, Fourier-transform infrared spectroscopy (FTIR), Dynamic light scattering (DLS), X-ray diffraction (XRD), and Transmission electron microscopy (TEM) with a spherical and uniform shape. The antibacterial and antibiofilm formation activity was carried out on bacterial species of Pseudomonas aeruginosa and Staphylococcus aureus with the capacity to form biofilm. The minimum inhibitory concentration was 117.5 µg/mL for the chemical and 5.3 µg/mL for the biological nanoparticles. Both types of nanoparticles showed antibiofilm activity in the qualitative Congo red test and in the quantitative microplate test. Antibiofilm activity tests on fresh lettuce showed that biological nanoparticles decreased the population of S. aureus and P. aeruginosa by 0.63 and 2.38 logarithms, respectively, while chemical nanoparticles had little microbial reduction. In conclusion, the biologically synthesized nanoparticles showed greater antibiofilm activity. Therefore, these results suggest their potential application in the formulation of sanitizing products for the food and healthcare industries.

Informality, economic complexity, and internalization of rules.

This research aimed to find out the relationship between informality and the internalization of the rules of behavior required for complexity in the economic system, as better knowledge is required for formalization policy to have a greater impact. We use the economic complexity index (ECI) for 2018 at the regional level in Colombia, which combines the country's productive structure with the amount of knowledge and know-how embodied in the goods it produces. The informality measure we use is the individual's affiliation to social security (in particular health insurance), and we use a proxy of civic rule's internalization as an inverse relation with traffic tickets. This research aimed to shed new light on public policy to improve formalization and its economic impact. First, we include a theory that includes both intrinsic and extrinsic motivation types. The self-determination theory or organismic integration theory proposes this theory. Second, we have argued that the motivation to formalize is intrinsic to greater cultural capacity. Individuals gradually internalize rules of behavior that have repercussions on social dynamics. Third, the composition and characteristics of the families in the study sample seem to show that some factors increase the propensity for informality. Our empirical analysis reveals that group of people with a lower educational level are the ones who are more likely to belong to the informal labor market. These results are consistent with the literature. Multivariate Probit regression was used to examine these factors.

Mean platelet volume and mortality in patients with alcohol use disorder.

Several recent studies have pointed out the relationship of platelet size with increased mortality or adverse clinical course. Most studies show that increased mean platelet volume (MPV) may be associated with a deleterious outcome in different settings such as sepsis or neoplasia, whereas other researchers have found the opposite. In inflammatory conditions there is an altered secretion of several cytokines, some of them exerting a marked influence on platelet biogenesis and/or on platelet activation and aggregation. Alcohol use disorder is a chronic situation characterized by a protracted low-grade inflammation. In this study we analyze the relationship between proinflammatory cytokines and MPV and their relationships with mortality in patients with alcohol abuse. We determined serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 and routine laboratory variables among 184 patients with alcohol use disorder admitted to our hospital and followed-up for a median of 42 months. We found that MPV was inversely related to TNF-α (ρ=-0.34), and directly to IL-8 (ρ=0.32, p<0.001 in both cases) and to IL-6 (ρ=0.15; p = 0.046). Reduced MPV was related both with short-term (<6 months) and long-term mortality. Conclusion: These results suggest that inflammatory cytokines are strongly related to MPV. A low MPV is associated with a poor prognosis among patients with alcohol use disorder.

Minds of Monsters: Scary Imbalances Between Cognition and Emotion.

Four studies investigate a fear of imbalanced minds hypothesis that threatening agents perceived to be relatively mismatched in capacities for cognition (e.g., self-control and reasoning) and emotion (e.g., sensations and emotions) will be rated as scarier and more dangerous by observers. In ratings of fictional monsters (e.g., zombies and vampires), agents seen as more imbalanced between capacities for cognition and emotion (high cognition-low emotion or low cognition-high emotion) were rated as scarier compared to those with equally matched levels of cognition and emotion (Studies 1 and 2). Similar effects were observed using ratings of scary animals (e.g., tigers, sharks; Studies 2 and 3), and infected humans (Study 4). Moreover, these effects are explained through diminished perceived control/predictability over the target agent. These findings highlight the role of balance between cognition and emotion in appraisal of threatening agents, in part because those agents are seen as more chaotic and uncontrollable.

EELS Studies of Cerium Electrolyte Reveal Substantial Solute Concentration Effects in Graphene Liquid Cells.

Graphene liquid cell transmission electron microscopy is a powerful technique to visualize nanoscale dynamics and transformations at atomic resolution. However, the solution in liquid cells is known to be affected by radiolysis, and the stochastic formation of graphene liquid cells raises questions about the solution chemistry in individual pockets. In this study, electron energy loss spectroscopy (EELS) was used to evaluate a model encapsulated solution, aqueous CeCl3. First, the ratio between the O K-edge and Ce M-edge was used to approximate the concentration of cerium salt in the graphene liquid cell. It was determined that the ratio between oxygen and cerium was orders of magnitude lower than what is expected for a dilute solution, indicating that the encapsulated solution is highly concentrated. To probe how this affects the chemistry within graphene liquid cells, the oxidation of Ce3+ was measured using time-resolved parallel EELS. It was determined that Ce3+ oxidizes faster under high electron fluxes, but reaches the same steady-state Ce4+ concentration regardless of flux. The time-resolved concentration profiles enabled direct comparison to radiolysis models, which indicate rate constants and g-values of certain molecular species are substantially different in the highly concentrated environment. Finally, electron flux-dependent gold nanocrystal etching trajectories showed that gold nanocrystals etch faster at higher electron fluxes, correlating well with the Ce3+ oxidation kinetics. Understanding the effects of the highly concentrated solution in graphene liquid cells will provide new insight on previous studies and may open up opportunities to systematically study systems in highly concentrated solutions at high resolution.

Tutorial: multiphoton microscopy to advance neuroscience research.

Multiphoton microscopy (MPM) employs ultrafast infrared lasers for high-resolution deep three-dimensional imaging of live biological samples. The goal of this tutorial is to provide a practical guide to MPM imaging for novice microscopy developers and life-science users. Principles of MPM, microscope setup, and labeling strategies are discussed. Use of MPM to achieve unprecedented imaging depth of whole mounted explants and intravital imaging via implantable glass windows of the mammalian nervous system is demonstrated.

Concern about experiencing downward socioeconomic mobility generates precarious types of motivation among students of color.

Students' beliefs about whether they will experience changes in their socioeconomic status influence their academic motivation. We propose that students who are concerned about downward socioeconomic mobility will focus their attention on negative academic outcomes and exhibit motivational goals oriented towards preventing negative possibilities and that this relationship will be particularly pronounced among students of color. Two studies investigated the relationship between college students' concerns about downward socioeconomic mobility and their adoption of academic achievement goals. The more that students of color expressed concerns about experiencing downward socioeconomic mobility, the more they adopted academic mastery-avoidance goals (ß = 0.76), whereas there was no significant relationship between concerns about downward socioeconomic mobility and mastery-avoidance goals among White students (ß = - 0.24; Study 1). Experimentally induced concerns about downward socioeconomic mobility increased academic mastery-avoidance goals among students of color (ß = - 0.58) but decreased mastery-avoidance goals among White students (ß = 0.46; Study 2). Together, results indicate that there is a strong relationship between concerns about downward socioeconomic mobility and mastery-avoidance goals among students of color, highlighting the importance of understating how students of color make sense of their future socioeconomic prospects in order to most effectively support their academic trajectories positively. Supplementary Information: The online version contains supplementary material available at 10.1007/s11218-023-09763-5.