Repeated toxic injuries of murine liver are tolerated through microsteatosis and mild inflammation

The liver has a remarkable capacity to regenerate and thus compensates for repeated injuries through toxic chemicals, drugs, alcohol or malnutrition for decades. However, largely unknown is how and when alterations in the liver occur due to tolerable damaging insults. To that end, we induced repeated liver injuries over ten weeks in a mouse model injecting carbon tetrachloride (CCl4) twice a week. We lost 10% of the study animals within the first six weeks, which was accompanied by a steady deposition of extracellular matrix (ECM) regardless of metabolic activity of the liver. From week six onwards, all mice survived, and in these mice ECM deposition was rather reduced, suggesting ECM remodeling as a liver response contributing to better coping with repeated injuries. The data of time-resolved paired transcriptome and proteome profiling of 18 mice was subjected to multi-level network inference, using Knowledge guided Multi-Omics Network inference (KiMONo), identified multi-level key markers exclusively associated with the injury-tolerant liver response. Interestingly, pathways of cancer and inflammation were lighting up and were validated using independent data sets compiled of 1034 samples from publicly available human cohorts. A yet undescribed link to lipid metabolism in this damage-tolerant phase was identified. Immunostaining revealed an unexpected accumulation of small lipid droplets (microvesicular steatosis) in parallel to a recovery of catabolic processes of the liver to pre-injury levels. Further, mild inflammation was experimentally validated. Taken together, we identified week six as a critical time point to switch the liver response program from an acute response that fosters ECM accumulation to a tolerant 'survival' phase with pronounced deposition of small lipid droplets in hepatocytes potentially protecting against the repetitive injury with toxic chemicals. Our data suggest that microsteatosis formation plus a mild inflammatory state represent biomarkers and probably functional liver requirements to resist chronic damage.

Closed-loop recruitment of striatal parvalbumin interneurons prevents the onset of compulsive behaviors

A prominent electrophysiological feature of compulsive behaviours is striatal hyperactivity; but its underlying dysfunctional cellular mechanisms still need to be characterized. Within the striatum, parvalbumin-positive interneurons (PVI) exert a powerful feedforward inhibition essential for the regulation of striatal activity. To investigate the potential implication of striatal PVI in aberrant repetitive behaviors, we used the Sapap3 mutant mice which exhibit compulsive-like behaviours characterized by excessive self-grooming. When striatal PVI in the centromedial striatum of Sapap3 mice were we optogenetically activated, we first showed that the number of compulsive-like events were greatly reduced. To investigate further the critical time-window when striatal PVI needed to be recruited for the behavioural regulation of compulsive-like grooming, we then designed a novel closed-loop stimulation pipeline. We identified a transient 1-4 Hz oscillations in the orbitofrontal cortex that temporally predicted grooming onsets. Exploiting this delta band signal as a biomarker, we were able to provide on-demand stimulation of striatal PVI shortly before predicted grooming events. This targeted closed-loop optogenetics approach greatly reduced grooming events and demonstrated that the recruitment of striatal PVI regulated the initiations of compulsive-like behaviours.

Gut microbiome development in early childhood is affected by day care attendance

The human gut microbiome develops during the first years of life, followed by a relatively stable adult microbiome. Day care attendance is a drastic change that exposes children to a large group of peers in a diverse environment for prolonged periods, at this critical time of microbial development, and therefore has the potential to affect microbial composition. We characterize the effect of day care on the gut microbial development throughout a single school year in 61 children from 4 different day care facilities, and in additional 24 age-matched home care children (n = 268 samples, median age of entering the study was 12 months). We show that day care attendance is a significant and impactful factor in shaping the microbial composition of the growing child, the specific daycare facility and class influence the gut microbiome, and each child becomes more similar to others in their day care. Furthermore, in comparison to home care children, day care children have a different gut microbial composition, with enrichment of taxa more frequently observed in older populations. Our results provide evidence that daycare may be an external factor that contributes to gut microbiome maturation and make-up in early childhood.

Immunogenicity and waning immunity from the oral cholera vaccine (Shanchol™) in adults residing in Lukanga Swamps of Zambia

Introduction In cholera endemic areas, the periodicity of cholera outbreaks remains unpredictable, making it difficult to organize preventive efforts. Lack of data on duration of protection conferred by oral cholera vaccines further makes it difficult to determine when to deploy preemptive vaccination. We report on the immunogenicity and waning of immunity to Shanchol™ in Lukanga Swamps. Methods We enrolled a cohort of 223 participants aged between 18 and 65 years old from whom serum samples were collected at baseline, day 28 before administration of the second dose, and consecutively at 6, 12, 24, 30, 36, and 48 months. Vibriocidal antibody titres were measured and expressed as geometric mean titres. Box plots and 95% CI were computed at each visit for both Inaba and Ogawa. Seroconversion was defined as a four fold or greater increase in antibody titres compared to baseline titres. Results Overall, seroconversion against V. cholerae Inaba and Ogawa after 1st dose was 35/134 (26%) and 34/134 (25%) respectively. We observed a statistical difference in seroconversion between the two subgroups of baseline titres (low <80 and high ≥80) for both Inaba (p = 0.02) and Ogawa (p<0.0001). From a baseline of 13.58, anti-Ogawa GMT increased to 21.95 after the first dose, but rapidly waned to 14.52, 13.13, and 12.78 at months 6, 12 and 24 respectively, and then increased to 13.21, 18.67 and 23.65 at months 30, 36 and 48 respectively. A similar trend was observed for anti-Inaba GMT across the same time points. Conclusion We found that Shanchol™ was immunogenic in our study population and that vibriocidal antibodies may not be a good marker for long-term immunity. The observed rise in titres after 36 months suggests natural exposure, and this may be a critical time window opening for natural transmission in an endemic areas. We recommend re-vaccination at this time point in high risk areas.

Intelligent early warning method based on drone inspection

Commonly used UAV emergency inspection methods are executed by the instructions of the ground command center. The response rate depends on the stability of the communication network and the rapid response ability of the commander. The critical time window is fleeting, which is likely to cause unnecessary loss. Crisis rapid response capability has become the key to measuring system capabilities. In order to improve the system’s rapid response capability, a method of deploying decision-making agents on airborne computers and ground early warning systems is proposed. This early warning method uses key technologies such as multi-network integration, situation assessment, neural network architecture, deep learning, reinforcement learning, and intelligent cognitive reasoning to effectively ensure the effectiveness of crisis warning. The early warning method of the early warning system is as follows: the mission computer uniformly collects the flight control status parameters, the load status parameters and the load real-time data form a composite information flow. The task computer adopts the methods of protocol conversion, data classification, and danger recognition to the compound information flow to identify the crisis information and make a preliminary analysis and judgment of the crisis state. If it is determined that it is necessary to track the target in real time, the initial task assignment and parameter adjustment of the load are carried out, and the continuous tracking of the task target is carried out to realize the rapid response to the crisis on the edge side. At the same time, the composite data are downloaded to the command center. The command center performs the secondary crisis analysis and risk level determination and outputs the crisis plan deduced by the agent to realize the strategy assistance. The accuser refers to the plan strategy and issues instructions to the task computer, and the task computer receives it. Instruction and secondary adjustment and optimization of the load parameters. If there is a flight route adjustment instruction, the adjustment route will be sent to the flight controller, which greatly improves the flexibility and efficiency of handling the crisis in the UAV inspection process. By adopting this set of early warning methods, it can provide users with an updated, faster and more efficient way to realize the early warning requirements in drone inspections, which is a new breakthrough in the field of drone command methods.

Identifying the critical time window for the association of the early-life gut microbiome and metabolome with childhood neurodevelopment

It has been widely recognized that a critical time window for neurodevelopment occurs in early life, and that the host's gut microbiome plays an important role in neurodevelopment. While murine models have demonstrated that the maternal gut microbiome also influences offspring brain development, for humans it is still unclear if the critical time window for the association between the gut microbiome and neurodevelopment is prenatal, postnatal or both. Here we leverage a large-scale human study and compare the associations between the gut microbiota and metabolites from mothers and their children with the children's neurodevelopment. We show, for the first time, that the maternal gut microbiome is more relevant than the children's gut microbiome to the children's neurodevelopment in the first year of life. Interestingly, the roles of the same taxa with respect to neurodevelopment can be opposite at the two stages of fetal neurodevelopment. These findings shed light on potential therapeutic interventions to prevent neurodevelopmental disorders.

ENGLISH - MAJORING STUDENT TEACHERS’ RESPONSE TO EMPLOYABILITY IN LIGHT OF A TRANSITION TO ONLINE LEARNING

This study discussed English student teachers’ growth in employability as a driving consequence of the transition to emergency remote learning in light of COVID-19 pandemic. The authors focused on senior students reaching graduation during this critical time. The learning mode change was believed to have a significant impact on graduates’ employability capital, thus influencing their post-study career plans. This quantitative research followed Tomlinson’s (2017) graduate employability framework, covering five forms of capital explores their perceptions of employability capital and measures how perceptions vary between groups of backgrounds. Specifically, they sought to develop a comprehensive understanding of how the transition to remote learning has challenged students’ employability capital, which then affected their career-related decision-making following graduation. The findings suggested, besides implications and limitation, five clustered forms of capital and explain why they perceived differently.

Bounds on the critical times for the Fisher-KPP equation

The Fisher–Kolmogorov–Petrovsky–Piskunov (Fisher–KPP) equation is one of the prototypical reaction–diffusion equations and is encountered in many areas, primarily in population dynamics. An important consideration for the phenomena modelled by diffusion equations is the length of the diffusive process. In this paper, three definitions of the critical time are given, and bounds are obtained by a careful construction of the upper and lower solutions. The comparison functions satisfy the nonlinear, but linearizable, partial differential equations of Fisher–KPP type. Results of the numerical simulations are displayed. Extensions to some classes of reaction–diffusion systems and an application to a spatially heterogeneous harvesting model are also presented. doi:10.1017/S1446181121000365