Miracle-dz/UniFAR-FTUs huggingface dataset:
Upward-scaling tipping cascades to meet climate goals: plausible grounds for hope

ABSTRACT Limiting global warming to well below 2°C requires a dramatic acceleration of decarbonization to reduce net anthropogenic greenhouse gas emissions to zero around mid-century. In complex systems – including human societies – tipping points can occur, in which a small perturbation transforms a system. Crucially, activating one tipping point can increase the likelihood of triggering another at a larger scale, and so on. Here, we show how such upward-scaling tipping cascades could accelerate progress in tackling climate change. We focus on two sectors – light road transport and power – where tipping points have already been triggered by policy interventions at individual nation scales. We show how positive-sum cooperation, between small coalitions of jurisdictions and their policymakers, could lead to global changes in the economy and emissions. The aim of activating tipping points and tipping cascades is a particular application of systems thinking. It represents a different starting point for policy to the theory of welfare economics, one that can be useful when the priority is to achieve dynamic rather than allocative efficiency. Key policy insights Pricing policies and targeted investments that bring clean technologies below the threshold of cost-parity with fossil fuel technologies can trigger reinforcing feedbacks that cascade up scales to propel disproportionately rapid decarbonization. Traditional approaches to climate policy based on welfare economics principles of minimizing marginal abatement costs, and pricing externalities, are likely to miss these opportunities. Systems thinking can help identify ways for policy to drive effective change. Positive-sum cooperation between small groups of countries can accelerate the activation of tipping points in the global economy, facilitating decarbonization in all countries. Early opportunities for this are in the power and light road transport sectors, where clean technologies are increasingly competitive with fossil fuels. The value of decarbonization policies should be judged not just on their immediate effects on emissions within the implementing jurisdiction, but also for their potential to contribute to upward-scaling tipping cascades in the global economy.
Mastering Automation: New Airline Pilots’ Perspective

ABSTRACT Aircraft accidents over the last decade have raised questions about the most effective way to transition pilots onto new aircraft automation systems. This debate can range from the details contained within aircraft flight manuals to computer-based versus simulator-based training. While some questions are still under consideration, most fall short in the understanding of how pilots “actually” learn. The researchers conducted a longitudinal study focusing on pilot learning; through interviews, observations, and field documentation, 10 pilot trainees from two regional airlines were followed for 5 months throughout their initial airline training. Using joint cognitive systems theory, and concepts from curriculum theory to understand the utility of training programs, the study revealed gaps between the airlines’ intended learning outcomes and the trainees’ actual experiences. The findings demonstrate that automation, as opposed to other aircraft systems, may require different approaches to learning. Recommendations for possible modifications to current pilot training are discussed.
Customer satisfaction in post-socialist Spas: a case study of Budapest, City of Spas

ABSTRACT This paper examines spa developments in post-socialist countries, especially the process of adapting facilities to attract and accommodate commercial (non-state funded) guests and international tourists. This includes the development of infrastructure, the upgrading and regeneration of facilities, the improvement of service quality and the enhancement of visitor experiences and customer satisfaction. The research in this paper draws on customer satisfaction and service quality theory from the hospitality sector in order to consider how far spas are meeting international standards and to make recommendations for future improvements. Online review data was analysed from one of the most popular spas in Budapest, Hungary to highlight issues relating to tourist satisfaction and experience. Despite considerable investment in the thermal bath buildings and facilities as part of a national programme of regeneration, several issues relating to service quality still need to be addressed. This represents a common challenge for the whole post-socialist region, so the work aims to identify future directions for spas in this region in their transition from domestic, therapeutic medical baths to international, wellness spas.
Examining the effects of mood on quality and feasibility of design outcomes

ABSTRACT This study examines the correlation between quality and feasibility of generated design solutions with mood and rational vs. intuitive thinking. It was hypothesized that positive moods lead to better intuitive thinking, which will result in higher design quality and feasibility. The participants, who were junior and senior level undergraduate students with a design background, were given the 32-point Brunel Mood Scale (BRUMS) before solving nine 7-min design tasks in a manner that cultivated either analytical or intuitive thinking. Cronbach’s alpha was used to confirm the reliability and consistency of the self-reported mood data. Spearman’s correlation was used to illustrate the mood–performance relationship, revealing that high design solution quality is significantly positively correlated with vigor and energetic mood in the Creative Intuition (CI) condition, and downhearted mood in the Problem Solving Intuition condition, while significantly negatively correlated with depression, worn-out and bad-tempered moods in the CI condition. High design solution feasibility was positively correlated with an exhausted mood in the Rational Thinking condition, and negatively correlated with composed and relaxed moods in the CI condition. These findings help further the understanding of how mood impacts design outcomes in intuitive and analytical problem solving, which may have implications design practice.
Priority Intervention Targets Identified Using an In-Depth Sampling HIV Molecular Network in a Non-Subtype B Epidemics Area

Molecular network analysis based on the genetic similarity of HIV-1 is increasingly used to guide targeted interventions. Nevertheless, there is a lack of experience regarding molecular network inferences and targeted interventions in combination with epidemiological information in areas with diverse epidemic strains of HIV-1.We collected 2,173 pol sequences covering 84% of the total newly diagnosed HIV-1 infections in Shenyang city, Northeast China, between 2016 and 2018. Molecular networks were constructed using the optimized genetic distance threshold for main subtypes obtained using sensitivity analysis of plausible threshold ranges. The transmission rates (TR) of each large cluster were assessed using Bayesian analyses. Molecular clusters with the characteristics of ≥5 newly diagnosed cases in 2018, high TR, injection drug users (IDUs), and transmitted drug resistance (TDR) were defined as priority clusters. Several HIV-1 subtypes were identified, with a predominance of CRF01_AE (71.0%, 1,542/2,173), followed by CRF07_BC (18.1%, 393/2,173), subtype B (4.5%, 97/2,173), other subtypes (2.6%, 56/2,173), and unique recombinant forms (3.9%, 85/2,173). The overall optimal genetic distance thresholds for CRF01_AE and CRF07_BC were both 0.007 subs/site. For subtype B, it was 0.013 subs/site. 861 (42.4%) sequences of the top three subtypes formed 239 clusters (size: 2-77 sequences), including eight large clusters (size ≥10 sequences). All the eight large clusters had higher TR (median TR = 52.4/100 person-years) than that of the general HIV infections in Shenyang (10.9/100 person-years). A total of ten clusters including 231 individuals were determined as priority clusters for targeted intervention, including eight large clusters (five clusters with≥5 newly diagnosed cases in 2018, one cluster with IDUs, and two clusters with TDR (K103N, Q58E/V179D), one cluster with≥5 newly diagnosed cases in 2018, and one IDUs cluster. In conclusion, a comprehensive analysis combining in-depth sampling HIV-1 molecular networks construction using subtype-specific optimal genetic distance thresholds, and baseline epidemiological information can help to identify the targets of priority intervention in an area epidemic for non-subtype B.
Case Report: Transarterial Chemoembolization in Combination With Tislelizumab Downstages Unresectable Hepatocellular Carcinoma Followed by Radical Salvage Resection

Introduction Transarterial chemoembolization (TACE) is inefficient at converting unresectable hepatocellular carcinoma (uHCC) to resectable. Treatment with immune checkpoint inhibitors (ICIs) is an emerging strategy for uHCC. Combined therapy of TACE with ICIs is considered to improve the therapeutic effect. Case presentation A 45-year-old man was diagnosed with a bulky HCC under cirrhotic background without distant metastasis. Curative resection was infeasible, and TACE plus tislelizumab (an ICI targeting PD-1) was applied. The treatment course, starting from TACE and followed by tislelizumab one week later, was repeated every four weeks. After three courses, the tumor showed striking shrink in volume with complete radiological response, which permitted salvage resection. Notably, pathological examination found complete necrosis of the tumor with massive infiltration of lymphocytes in the tumor-nontumor interface and extensive granulomatous inflammation in the surrounding nontumor liver, indicating activated immune response synergistically caused by TACE with tislelizumab. The patient is now living well without tumor recurrence for 6 months after surgery. Conclusion TACE in combination with tislelizumab may represent a potent strategy for uHCC. Data from randomized clinical trials are needed to assess its safety and effect in the setting of preoperative downstaging therapy.
The Indirect Effect of Trauma via Cognitive Biases and Self-Disturbances on Psychotic-Like Experiences

Although self-disturbances (SD) are considered to be a core psychopathological feature of schizophrenia spectrum disorders, there is still insufficient empirical data on the mechanisms underlying these anomalous self-experiences. The aim of the present study was to test a hypothesized model in which cognitive biases and exposure to traumatic life events are related to the frequency of SD which, in turn, contribute to the frequency of psychotic-like experiences (PLEs). Our sample consisted of 193 Polish young adults from the general population (111 females; 18–35 years of age, M = 25.36, SD = 4.69) who experience frequent PLEs. Participants were interviewed for PLEs, SD and social functioning as well as completed self-reported questionnaires and behavioral tasks that measure cognitive biases (e.g., safety behaviors, attention to threat, external attribution, jumping to conclusion, source monitoring, overperceptualization). The model was tested using path analysis with structural equation modeling. All of the hypothesized relationships were statistically significant and our model fit the data well [χ2(23) = 31.201; p = 0.118; RMSEA = 0.043 (90% CI = 0.00–0.078), CFI = 0.985, SRMR = 0.041, TLI = 0.976]. The results revealed a significant indirect effect of traumatic life events on PLEs through SD and self-reported cognitive biases. However, performance-based cognitive biases measured with three behavioral tasks were unrelated to SD and PLEs. The frequency of SD explained a substantial part (43.1%) of the variance in PLEs. Further studies with longitudinal designs and clinical samples are required to verify the predictive value of the model.
Compliant Substrates Enhance Macrophage Cytokine Release and NLRP3 Inflammasome Formation During Their Pro-Inflammatory Response

Immune cells process a myriad of biochemical signals but their function and behavior are also determined by mechanical cues. Macrophages are no exception to this. Being present in all types of tissues, macrophages are exposed to environments of varying stiffness, which can be further altered under pathological conditions. While it is becoming increasingly clear that macrophages are mechanosensitive, it remains poorly understood how mechanical cues modulate their inflammatory response. Here we report that substrate stiffness influences the expression of pro-inflammatory genes and the formation of the NLRP3 inflammasome, leading to changes in the secreted protein levels of the cytokines IL-1β and IL-6. Using polyacrylamide hydrogels of tunable elastic moduli between 0.2 and 33.1 kPa, we found that bone marrow-derived macrophages adopted a less spread and rounder morphology on compliant compared to stiff substrates. Upon LPS priming, the expression levels of the gene encoding for TNF-α were higher on more compliant hydrogels. When additionally stimulating macrophages with the ionophore nigericin, we observed an enhanced formation of the NLRP3 inflammasome, increased levels of cell death, and higher secreted protein levels of IL-1β and IL-6 on compliant substrates. The upregulation of inflammasome formation on compliant substrates was not primarily attributed to the decreased cell spreading, since spatially confining cells on micropatterns led to a reduction of inflammasome-positive cells compared to well-spread cells. Finally, interfering with actomyosin contractility diminished the differences in inflammasome formation between compliant and stiff substrates. In summary, we show that substrate stiffness modulates the pro-inflammatory response of macrophages, that the NLRP3 inflammasome is one of the components affected by macrophage mechanosensing, and a role for actomyosin contractility in this mechanosensory response. Thus, our results contribute to a better understanding of how microenvironment stiffness affects macrophage behavior, which might be relevant in diseases where tissue stiffness is altered and might potentially provide a basis for new strategies to modulate inflammatory responses.
Mastery Imagery Ability Is Associated With Positive Anxiety and Performance During Psychological Stress

Mastery imagery (i.e., images of being in control and coping in difficult situations) is used to regulate anxiety. The ability to image this content is associated with trait confidence and anxiety, but research examining mastery imagery ability's association with confidence and anxiety in response to a stressful event is scant. The present study examined whether trait mastery imagery ability mediated the relationship between confidence and anxiety, and the subsequent associations on performance in response to an acute psychological stress. Participants (N = 130; 55% male; Mage = 19.94 years; SD = 1.07 years) completed assessments of mastery imagery ability and engaged in a standardized acute psychological stress task. Immediately prior to the task, confidence, cognitive and somatic anxiety intensity, and interpretation of anxiety symptoms regarding the task were assessed. Path analyses supported a model whereby mastery imagery ability mediated the relationship between confidence and cognitive and somatic anxiety interpretation. Greater mastery imagery ability and confidence were both directly associated with better performance on the stress task. Mastery imagery ability may help individuals experience more facilitative anxiety and perform better during stressful tasks. Improving mastery imagery ability by enhancing self-confidence may help individuals successfully cope with anxiety elicited during stressful situations.
Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance

Although some advances have been made in understanding the molecular regulation of mTEC development, the role of epigenetic regulators in the development and maturation of mTEC is poorly understood. Here, using the TEC-specific Sirt6 knockout mice, we found the deacetylase Sirtuin 6 (Sirt6) is essential for the development of functionally competent mTECs. First of all, TEC-specific Sirt6 deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of Sirt6-deficient mTECs. Secondly, Sirt6 deficiency specifically accelerates the differentiation of mTECs from CD80–Aire– immature population to CD80+Aire– intermediate mature population by promoting the expression of Spib. Finally, Sirt6 ablation in TECs markedly interferes the proper expression of tissue-restricted antigens (TRAs) and impairs the development of thymocytes and nTreg cells. In addition, TEC conditional knockout of Sirt6 results in severe autoimmune disease manifested by reduced body weight, the infiltration of lymphocytes and the presence of autoantibodies. Collectively, this study reveals that the expression of epigenetic regulator Sirt6 in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.
Full-Length Transcriptome Analyses of Genes Involved in Triterpenoid Saponin Biosynthesis of Psammosilene tunicoides Hairy Root Cultures With Exogenous Salicylic Acid

Triterpenoid saponins constitute a diverse class of bioactive compounds in medicinal plants. Salicylic acid (SA) is an efficient elicitor for secondary metabolite production, but a transcriptome-wide regulatory network of SA-promoted triterpenoid saponin biosynthesis remains little understood. In the current study, we described the establishment of the hairy root culture system for Psammosilene tunicoides, a triterpenoid saponin-producing medicinal herb in China, using genetic transformation by Agrobacterium rhizogenes. Compared to controls, we found that total saponin content was dramatically increased (up to 2.49-fold) by the addition of 5 mg/L SA in hairy roots for 1 day. A combination of single-molecule real-time (SMRT) and next-generation sequencing (Illumina RNA-seq) was generated to analyze the full-length transcriptome data for P. tunicoides, as well as the transcript profiles in treated (8 and 24 h) and non-treated (0 h) groups with 5 mg/L SA in hairy roots. A total of 430,117 circular consensus sequence (CCS) reads, 16,375 unigenes and 4,678 long non-coding RNAs (lncRNAs) were obtained. The average length of unigenes (2,776 bp) was much higher in full-length transcriptome than that derived from single RNA-seq (1,457 bp). The differentially expressed genes (DEGs) were mainly enriched in the metabolic process. SA up-regulated the unigenes encoding SA-binding proteins and antioxidant enzymes in comparison with controls. Additionally, we identified 89 full-length transcripts encoding enzymes putatively involved in saponin biosynthesis. The candidate transcription factors (WRKY, NAC) and structural genes (AACT, DXS, SE, CYP72A) might be the key regulators in SA-elicited saponin accumulation. Their expression was further validated by quantitative real-time PCR (qRT-PCR). These findings preliminarily elucidate the regulatory mechanisms of SA on triterpenoid saponin biosynthesis in the transcriptomic level, laying a foundation for SA-elicited saponin augmentation in P. tunicoides.
The Transferrin Receptor-Directed CAR for the Therapy of Hematologic Malignancies

As many patients ultimately relapse after chimeric antigen receptor (CAR) T-cell therapy, identification of alternative targets is currently being evaluated. Substantial research efforts are underway to develop new targets. The transferrin receptor (TfR) is prevalently expressed on rapidly proliferating tumor cells and holds the potential to be the alternative target. In order to investigate the efficacy and challenges of TfR-targeting on the CAR-based therapy strategy, we generated a TfR-specific CAR and established the TfR-CAR–modified T cells. To take the advantage of TfR being widely shared by multiple tumors, TfR-CAR T cells were assessed against several TfR+ hematological malignant cell lines. Data showed that TfR-CAR T cells were powerfully potent in killing all these types of cells in vitro and in killing T-ALL cells in vivo. These findings suggest that TfR could be a universal target to broaden and improve the therapeutic efficacy of CAR T cells and warrant further efforts to use these cells as an alternative CAR T cell product for the therapy of hematological malignancies.
Evaluation of Three Medetomidine-Based Anesthetic Protocols in Free-Ranging Wild Boars (Sus scrofa)

Three medetomidine-based drug protocols were compared by evaluating time courses, reliability and physiological effects in wild boars. A total of 21 cage-trapped wild boars (Sus scrofa) were immobilized using one of the following drug combinations; MTZ: medetomidine (0.2 mg/kg) + tiletamine-zolazepam (2.0 mg/kg), MK: medetomidine (0.15 mg/kg) + ketamine (5 mg/kg), and MKB: medetomidine (0.1 mg/kg) + ketamine (5.0 mg/kg) + butorphanol (0.2 mg/kg). Induction time, recovery time, and physiological variables were recorded and arterial blood gas analysis measured twice, before and after 15 min of oxygen supplementation (0.5–1.0 L/min). For reversal, 4 mg of atipamezole per mg of medetomidine was administered intramuscularly. The boars recovered in the cage and were released once ataxia resolved. The MK group had significantly longer recovery times (mean 164 min ± 79 SD) compared to the other groups. MKB elicited longer and incomplete induction compared to the other groups (mean induction time 20 min ± 10 SD), decreasing the efficiency of the capture and increasing the risk of hyperthermia. Both ketamine-based protocols required additional ketamine intramuscularly to prolong the anesthesia after 20–40 min from induction. Agreement between the pulse oximeter and the blood gas analyzer was low, with the pulse oximeter underestimating the real values of arterial oxyhemoglobin saturation, particularly at higher readings. Mild acute respiratory acidosis (PaCO2 45–60 mmHg) and mild to moderate hypoxemia (PaO2 69–80 mmHg) occurred in most boars, regardless of the treatment group but especially in the MKB group. The acid-base status improved and hypoxemia resolved in all boars during oxygen supplementation, with the PaO2 rising above the physiological reference range (81.6–107.7 mmHg) in many individuals. MK and MKB induced safe and reliable immobilization of wild boars for at least 20 min. Supplemental oxygen delivery is recommended in order to prevent hypoxemia in wild boars immobilized with the protocols used in the present study. Long and ataxic recoveries occurred in most animals, regardless of the protocol, but especially in the MKB group.