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ABSTRACT Phage-antibiotic synergy (PAS) represents a superior treatment strategy for pathogen infections with less probability of resistance development. Here, we aim to understand the molecular mechanism by which PAS suppresses resistance in terms of population evolution. A novel hypervirulent Klebsiella pneumoniae (KP) phage H5 was genetically and structurally characterized. The combination of H5 and ceftazidime (CAZ) showed a robust synergistic effect in suppressing resistance emergence. Single-cell Raman analysis showed that the phage-CAZ combination suppressed bacterial metabolic activities, contrasting with the upregulation observed with phage alone. The altered population evolutionary trajectory was found to be responsible for the contrasting metabolic activities under different selective pressures, resulting in pleiotropic effects. A pre-existing wcaJ point mutation (wcaJG949A) was exclusively selected by H5, conferring a fitness advantage and up-regulated activity of carbohydrate metabolism, but also causing a trade-off between phage resistance and collateral sensitivity to CAZ. The wcaJ point mutation was counter-selected by H5-CAZ, inducing various mutations in galU that imposed evolutionary disadvantages with higher fitness costs, and suppressed carbohydrate metabolic activity. H5 and H5-CAZ treatments resulted in opposite effects on the transcriptional activity of the phosphotransferase system and the ascorbate and aldarate metabolism pathway, suggesting potential targets for phage resistance suppression. Our study reveals a novel mechanism of resistance suppression by PAS, highlighting how the complexity of bacterial adaptation to selective pressures drives treatment outcomes.IMPORTANCEPhage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent Klebsiella pneumoniae (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.

Abstract The hippocampal neurogenesis occurs constitutively throughout adulthood in mammalian species, but declines with age. In this study, we overtly found that the neuroblast proliferation and differentiation in the subgranular zone and the maturation into fully functional and integrated neurons in the granule-cell layer in young gerbils following cerebral ischemia/reperfusion was much more than those in old gerbils. The neurological function and cognitive and memory-function rehabilitation in the young gerbils improved faster than those in the old one. These results demonstrated that, during long term after cerebral ischemia/reperfusion, the ability of neurogenesis and recovery of nerve function in young animals were significantly higher than that in the old animals. We found that, after 14- and 28-day cerebral ischemia/reperfusion, the phosphorylation of MEK1/2, ERK1/2, p90RSK, and MSK1/2 protein levels in the hippocampus of young gerbils was significantly much higher than that of old gerbils. The levels of autophagy-related proteins, including Beclin-1, Atg3, Atg5, and LC3 in the hippocampus were effectively maintained and elevated at 28 days after cerebral ischemia/reperfusion in the young gerbils compared with those in the old gerbils. These results indicated that an increase or maintenance of the phosphorylation of ERK1/2 signal pathway and autophagy-related proteins was closely associated with the neuroblast proliferation and differentiation and the process of maturation into neurons. Further, we proved that neuroblast proliferation and differentiation in the dentate gyrus and cognitive function were significantly reversed in young cerebral ischemic gerbils by administering the ERK inhibitor (U0126) and autophagy inhibitor (3MA). In brief, following experimental young ischemic stroke, the long-term promotion of the neurogenesis in the young gerbil’s hippocampal dentate gyrus by upregulating the phosphorylation of ERK signaling pathway and maintaining autophagy-related protein levels, it overtly improved the neurological function and cognitive and memory function.

Background: Both eye movement modelling examples (EMMEs) and cues guide attention and improve learning in multimedia learning environments. EMME can act as a special form of cue. However, no studies have directly examined whether EMME would be superior to visual cues. Objective: The study was to investigate whether there were advantages of EMME over cues on visual attention, learning outcomes and subjective perception in a multimedia environment. Method: In Experiment 1, 67 college students were randomly assigned to the EMME group, cue group and control group and learned from animations explaining the synaptic transmission. In Experiment 2, we replicated Experiment 1 using longer learning material. Seventy-one college students were randomly assigned to three groups (EMME, cue and control) and learned from animations explaining the process of cell division. Results and Conclusions: In Experiment 1, results indicated both EMMEs and cues guide attention and facilitate learning. Regarding learning outcomes and subjective perception, learners did not benefit more from EMMEs than cues. Eye movement indicators showed that EMMEs were better than cues. In Experiment 2, results were consistent with Experiment 1. Implications: This study is the first to compare EMMEs and cues. We found that EMMEs and cues were equivalent in producing effects on learning outcomes and subjective perception. EMMEs were superior to cues in guiding attention and conveying strategies, as indicated by eye movements. Both theoretical and practical implications could be drawn.

Steroid 5α-reductase 2 (SRD5A2), a testosterone metabolism enzyme, is implicated in human disease. Structural and biochemical analyses of PbSRD5A, a bacterial homolog, reveal SRD5A2 substrate binding pocket and provide framework for the design of new drugs targeting this enzyme.

Children are increasingly using educational apps, but little research has been conducted to determine their effectiveness. The current study compared the effect of an interactive touchscreen app to the effect of a noninteractive video about the app on young children's Chinese characters learning and executive functions (EFs). In a mixed between-within design, 50 children aged 5 to 6 years old were randomly assigned to play the app on touchscreen or to watch a noninteractive video about the app. Results showed that children in the app condition made more progress from the pretest to the posttest in Chinese characters learning, and more improvement in working memory scores and inhibitory capacity scores compared to the video condition. Results suggest that interactive literacy apps on touchscreens benefit children's learning and EFs. Future research should continue to focus on the impact of different forms of touchscreen use on children's executive functioning.

Abstract This work is motivated by the identification of the land‐atmosphere interactions as one of the key sources of uncertainty in climate change simulations. It documents new developments in related processes, namely, boundary layer/convection/clouds parameterizations and land surface parameterization in the Earth System Model of the Institut Pierre Simon Laplace (IPSL). Simulations forced by prescribed oceanic conditions are produced with different combinations of atmospheric and land surface parameterizations. They are used to explore the sensitivity to the atmospheric physics and/or soil physics of major biases in the near surface variables over continents, the energy and moisture coupling established at the soil/atmosphere interface in not too wet (energy limited) and not too dry (moisture limited) soil moisture regions also known as transition or “hot‐spot” regions, the river runoff at the outlet of major rivers. The package implemented in the IPSL‐Climate Model for the Phase 6 of the Coupled Models Intercomparison Project (CMIP6) allows us to reduce several biases in the surface albedo, the snow cover, and the continental surface air temperature in summer as well as in the temperature profile in the surface layer of the polar regions. The interactions between soil moisture and atmosphere in hotspot regions are in better agreement with the observations. Rainfall is also significantly improved in volume and seasonality in several major river basins leading to an overall improvement in river discharge. However, the lack of consideration of floodplains and human influences in the model, for example, dams and irrigation, impacts the realism of simulated discharge.

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that has emerged as a central hub linking redox equilibrium and signal transduction in living organisms. The homeostasis of NAD is required for plant growth, development, and adaption to environmental cues. In this study, we isolated a chilling hypersensitive Arabidopsis thaliana mutant named qs-2 and identified the causal mutation in the gene encoding quinolinate synthase (QS) critical for NAD biosynthesis. The qs-2 mutant is also hypersensitive to salt stress and abscisic acid (ABA) but resistant to drought stress. The qs-2 mutant accumulates a reduced level of NAD and over-accumulates reactive oxygen species (ROS). The ABA-hypersensitivity of qs-2 can be rescued by supplementation of NAD precursors and by mutations in the ABA signaling components SnRK2s or RBOHF. Furthermore, ABA-induced over-accumulation of ROS in the qs-2 mutant is dependent on the SnRK2s and RBOHF. The expression of QS gene is repressed directly by ABI4, a transcription factor in the ABA response pathway. Together, our findings reveal an unexpected interplay between NAD biosynthesis and ABA and stress signaling, which is critical for our understanding of the regulation of plant growth and stress responses.

Background: Although adding embodied instructors on the screen is considered an effective way to improve online multimedia learning, its effectiveness is still controversial. The level of realism of embodied on-screen instructors may be an influencing factor, but it is unclear how it affects multimedia learning. Aims: We explored whether and how embodied on-screen instructors rendered with different levels of realism in multimedia lessons affect learning process and learning outcomes. Samples: We recruited 125 college students as participants. Methods: Students learned about neural transmission in an online multimedia lesson that included a real human, cartoon human, cartoon animal or no instructor. Results: Students learning with cartoon human or cartoon animal instructors tended to fixate more on the relevant portions of the screen and performed better on retention and transfer tests than no instructor group. The real human group fixated more on the instructor, fixated less on the relevant portion of the screen and performed worse on a retention test in comparison to the cartoon human group. Fixation time on the instructor fully mediated the relationship between instructor realism and retention score. Conclusions: The addition of embodied on-screen instructors can promote multimedia learning, but the promotion effect would be better if the embodied instructor was a cartoon animal or cartoon human rather than a real human. This suggests an important boundary condition in which less realism of on-screen embodied instructors produces better learning processes and outcomes.

Background: Little is known about the effectiveness of instructors when presenting content in videos alone. In recent years, researchers have increasingly begun to explore the effects of instructors' social cues (e.g., eye gaze, body orientation, etc.) on learning. However, previous studies exploring the effects of eye gaze have confounded the role of body orientation, while studies exploring body orientation have confounded the role of eye gaze. Objectives: To explore the role of direct gaze and body orientation in learning with instructional videos, absent an instructional screen, in a less confounded manner. Methods: A total of 63 subjects were presented select concepts regarding schizophrenia. Eye-tracking technology combined with current theories of parasocial interaction and social agency was used to explore different social cues that affect learning performance. Students were randomly assigned to one of three experimental conditions: frontal body + direct gaze group (FD group), frontal body + no direct gaze group (FND group), and lateral body + no direct gaze group (LND group). Result and Conclusions: Direct gaze facilitated students' immediate retention and transfer scores, reduced learners' extraneous cognitive load, and guided students' attention to the instructor. However, counter to our expectations, parasocial interaction did not affect social cues. Implications: In both online and offline classes, instruction is expected to be enhanced by focusing on the camera to the extent possible, particularly when instructional screens are absent.

This study investigated the effectiveness of visual training or verbal training on how to use a text-picture processing strategy for learning from computer-based multimedia instructional material. Sixty-nine university students were randomly assigned to the verbal training group (students received text-based instruction for a text-picture processing strategy), the visual training group (students observed a video depicting an expert's eye fixations while using a text-picture processing strategy for an initial portion of a multimedia lesson) or the control group (students did not receive any instruction). During reading a multimedia lesson on biology, students' eye movements were tracked; and after the lesson, students took a posttest. Concerning learning outcomes, both visual and verbal training helped students perform better than the control group on a recall test and the verbal training group perform better on a transfer test. Concerning learning processes, both visual and verbal training caused students to attend less to on-screen text and more to on-screen pictures as compared to the control group. Mediation analysis showed that increased attention to pictures was a mediator for better learning outcomes. Practical and theoretical implications are discussed.

Cueing facilitates retention and transfer of multimedia learning. From the perspective of cognitive load theory (CLT), cueing has a positive effect on learning outcomes because of the reduction in total cognitive load and avoidance of cognitive overload. However, this has not been systematically evaluated. Moreover, what remains ambiguous is the direct relationship between the cue-related cognitive load and learning outcomes. A meta-analysis and two subsequent meta-regression analyses were conducted to explore these issues. Subjective total cognitive load (SCL) and scores on a retention test and transfer test were selected as dependent variables. Through a systematic literature search, 32 eligible articles encompassing 3,597 participants were included in the SCL-related meta-analysis. Among them, 25 articles containing 2,910 participants were included in the retention-related meta-analysis and the following retention-related meta-regression, while there were 29 articles containing 3,204 participants included in the transfer-related meta-analysis and the transfer-related meta-regression. The meta-analysis revealed a statistically significant cueing effect on subjective ratings of cognitive load (d = -0.11, 95% CI = [-0.19, -0.02], p < 0.05), retention performance (d = 0.27, 95% CI = [0.08, 0.46], p < 0.01), and transfer performance (d = 0.34, 95% CI = [0.12, 0.56], p < 0.01). The subsequent meta-regression analyses showed that dSCL for cueing significantly predicted dretention for cueing (β = -0.70, 95% CI = [-1.02, -0.38], p < 0.001), as well as dtransfer for cueing (β = -0.60, 95% CI = [-0.92, -0.28], p < 0.001). Thus in line with CLT, adding cues in multimedia materials can indeed reduce SCL and promote learning outcomes, and the more SCL is reduced by cues, the better retention and transfer of multimedia learning.

Young children are devoting increasing time to playing on handheld touchscreen devices (e.g., iPads). Though thousands of touchscreen apps are claimed to be educational, there is a lack of sufficient evidence examining the impact of touchscreens on children’s learning outcomes. In the present study, the two questions we focused on were (a) whether using a touchscreen was helpful in teaching children to tell time, and (b) to what extent young children could transfer what they had learned on the touchscreen to other media. A pre- and posttest design was adopted. After learning to read the time on the iPad touchscreen for 10 minutes, three groups of 5- to 6-year-old children (N = 65) were respectively tested with an iPad touchscreen, a toy clock or a drawing of a clock on paper. The results revealed that posttest scores in the iPad touchscreen test group were significantly higher than those at pretest, indicating that the touchscreen itself could provide support for young children’s learning. Similarly, regardless of being tested with a toy clock or paper drawing, children’s posttest performance was also better than pretest, suggesting that children could transfer what they had learned on an iPad touchscreen to other media. However, comparison among groups showed that children tested with the paper drawing underperformed those tested with the other two media. The theoretical and practical implications of the results, as well as limitations of the present study, are discussed.

Previous cross-cultural studies find that cultures can shape how we look during scene perception, but don’t mention its condition and limited to the East and West. This study recruited Chinese and African students to testify the cultural effects on two phases. In free-viewing phase: Africans fixated more on the focal objects than Chinese, while Chinese payed more attention to the backgrounds than Africans especially on the first fourth and fifth fixations. In recognition phase, there was no cultural difference on perception, but Chinese recognized more objects than Africans. Based on chosen subjects, we conclude that cultural differences exit on scene perception under conditions of no task and more clearly in its later period, but that differences may be hidden in a deeper way (e.g. memory) in task condition.

Although gesturing onscreen instructors are widely included in video lectures, it is still unclear whether, when, and how they are conducive to learning. To clarify this issue, we conducted a set of three-level meta-analyses of 662 effect sizes from 83 articles, spanning Web of Science, PsycINFO, ERIC, Education Research Complete, ProQuest Dissertations & Theses, and Google Scholar up to March 2024. We included randomized controlled trials of gesturing instructors in multimedia learning, measuring retention test score, transfer test score, fixation time, fixation count, cognitive load, and/or social perception across all languages of publication. Funnel plot and Egger sandwich test were used to assess risk of bias. Results showed that adding gesturing instructors improved retention (g = 0.28, 95% CI:[0.19,0.37]) and transfer test scores (g = 0.31, 95% CI:[0.21,0.41]), yielding an "embodiment effect." This effect was stronger when the instructor displayed deictic, metaphorical, or a mixture of multiple gestures; when the instructor in the control condition was not visible; when the lecture was learner-paced and longer. Moreover, it increased learners' social connection ratings and eye fixation time and count on core learning material (but only when deictic gestures were used). Thus, gesturing onscreen instructors may promote learning by social and cognitive paths, deepening our understanding of the role of gesturing onscreen instructors in multimedia learning and providing guidance for designing effective video lectures. More studies with clear experimental descriptions and eye-tracking studies are needed.

Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple β-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation. [ABSTRACT FROM AUTHOR]