Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulation of PKM activity affects the differentiation of TH17 cells

PKM2 activation may redirect inflammation from the spinal cord to the brain in a mouse model of multiple sclerosis. Rethinking metabolic manipulations in MS The metabolic state of TH17 cells determines whether they drive experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). Activation of the metabolic enzyme PKM2, which catalyzes a critical step in glycolysis, has been proposed as a potential treatment for MS. Seki et al. found that although PKM2 activators did limit TH17 cell differentiation by suppressing the production of IL-17, they enhanced the production of the encephalitogenic cytokine GM-CSF, which was associated with disease pathology in the brain rather than the spinal cord. PKM2 activators also blocked the generation of Tregs, an anti-inflammatory T cell subset that suppresses T cell activation. Genetic ablation of Pkm2 led to a compensatory increase in the related enzyme PKM1, which suggests that inhibiting PKM2 may lead to similar outcomes as activating PKM2. These results suggest that the therapeutic potential of PKM2 activators for MS must be reassessed. Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.
Analysis of Travel-Time Use in Crowded Trains using Discrete-Continuous Choices of Commuters in Tokyo, Japan

Travel-based multitasking and the possibility to perform activities during travel are important factors that can make a transportation mode attractive. However, serious crowding in public transportation systems might adversely affect the passengers’ free choice to participate in activities during travel. This study aims to examine how crowding in public transportation systems is related to discrete-continuous choices in different types of multitasking options using a data set of 500 commuters in the Tokyo Metropolitan Area. Employing a multiple discrete-continuous extreme value model, this study investigates the relationship between crowding levels and multitasking behavior. The results show that high crowding levels, relative to being seated, have a significantly negative association with many multitasking options, which suggests the importance of seat availability. The estimation results also show that information and communication technology (ICT)-dependent leisure activities and non-ICT active activities, such as reading and talking with other passengers, have the lowest satiation and higher baseline preference constants, which indicates that they are preferred by passengers. Meanwhile, crowding levels were observed to have a significant relationship with these multitasking activities. Finally, the key findings, contributions, and policy implications of the findings are discussed.
Integral-Proportional Derivative tuning for optimal closed loop responses to control integrating processes with inverse response

This paper provides optimum analytical tuning rules to determine tuning parameters of Integral-Proportional Derivative (I-PD) controllers for controlling integrating processes with inverse response and time delay. Integral performance criteria, such as ISTE (integral of squared time error), IST2E (integral of squared time2 error) and IST3E (integral of squared time3 error), are used to derive mentioned optimum tuning rules. The effectiveness of the proposed I-PD controller design method are shown by simulation examples. Comparisons with design methods existing in the literature, in terms of set point tracking and disturbance rejection capability, are performed to see the use of the proposed I-PD controller. Some performance measures are also given to evaluate the closed loop performances. It has been observed that the proposed I-PD controller has some important advantages over design methods used for comparison.
Synthetic Betulin Derivatives Inhibit Growth of Glioma Cells In Vitro

Background/Aim: Glioma is the most malignant tumour of the human brain still lacking effective treatment modalities. Betulin, a pentacyclic triterpene abundantly found in the birch bark, has been shown to demonstrate interesting anti-cancer activity towards many cancer cells. We determined the effects of acetylenic synthetic betulin derivatives (ASBDs) as anti-tumour agents on glioma cells in vitro. Materials and Methods: T98G and C6 glioma cell viability and proliferation were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and BrdU (bromo deoxyuridine) test, respectively. Cell-cycle progression and induction of apoptosis were investigated with flow cytometry. Results: ASBDs significantly decreased glioma cell viability/survival and inhibited proliferation in a dose-dependent manner in vitro. Moreover, ASBDs were more cytotoxic than clinically used chemotherapeutics – temozolomide and cisplatin. Conclusion: ASBDs may be considered for further study as potent anti-tumour agents in glioma treatment.
Overexpression of Pyruvate Carboxylase Is Correlated With Colorectal Cancer Progression and Supports Growth of Invasive Colon Cancer HT-29 Cell Line

Background/Aim: Pyruvate carboxylase (PC) is a major anaplerotic enzyme for generating oxaloacetate for the TCA cycle and also a key enzyme in gluconeogenesis, de novo fatty acid and amino acid synthesis in normal cells. Recent studies have identified PC overexpression in different cancers, such as breast and lung. However, the involvement of PC in colorectal cancer (CRC) is unclear. Our purpose was to investigate the PC expression levels and its correlations with potentially relevant clinical-pathological parameters in CRC. Materials and Methods: PC expression levels in tissues from 60 Thai CRC patients were investigated by immunohistochemistry while a clonogenic assay was performed for determining cell growth of HT-29 cells with PC knockdown. Results: Our results showed for the first time that high PC expression levels were significantly correlated with late stage of the cancer, perineural invasion and lymph node metastasis. The overexpression of PC was also significantly associated with poor overall and disease-free survival times of CRC patients. In addition, suppression of cancer cell growth was found in PC-deficient cell lines using CRISPR-Cas9. Conclusion: The overexpression levels of PC were correlated with CRC progression and survival times. Therefore, PC might serve as a potential clinical prognostic marker for colorectal cancer.
Cognitive Biases in Chronic Illness and Their Impact on Patients' Commitment

Cognitive biases are constructs based on erroneous or deformed perceptions which produce systematically distorted representations with respect to some aspects of the objective reality, such as prejudices (Haselton et al., 2005). Biases impact everyday life because they affect decisions and behaviors. For example, one may persist in an unhealthy behavior (e.g., smoking) because he selectively overestimates evidence that feeds up a pre-existing conviction (e.g., “smoking boosts my concentration”) (Masiero et al., 2019): this is known as confirmation bias (Hernandez and Preston, 2013). While some biases appear inherent to human cognition, others are situation–specific. Several studies have shown that there are cognitive biases typical of people who live with a chronic illness and continually attend to health management (Lichtenthal et al., 2017). These biases influence information processing about the disease and consequently decision making (DM), impacting the health and quality of life (Khatibi et al., 2014). The objectives of the present contribution are to synthetize information on biases in chronic illness and to highlight the possible effect of biases on health management. The last sections will explore how biases could influence not only the information processing, but also the motivation and agency within the patients’ healthcare journey.
Connectome-Based Model Predicts Deep Brain Stimulation Outcome in Parkinson's Disease

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective invasive treatment for advanced Parkinson's disease (PD) at present. Due to the invasiveness and cost of operations, a reliable tool is required to predict the outcome of therapy in the clinical decision-making process. This work aims to investigate whether the topological network of functional connectivity states can predict the outcome of DBS without medication. Fifty patients were recruited to extract the features of the brain related to the improvement rate of PD after STN-DBS and to train the machine learning model that can predict the therapy's effect. The functional connectivity analyses suggested that the GBRT model performed best with Pearson's correlations of r = 0.65, p = 2.58E−07 in medication-off condition. The connections between middle frontal gyrus (MFG) and inferior temporal gyrus (ITG) contribute most in the GBRT model.
The Effect of Leaders’ Coaching Behaviors on Employee Learning Orientation: A Regulatory Focus Perspective

Although scholars have recognized leaders’ importance in facilitating employee learning, the potential role that leaders’ specific behaviors play in followers’ learning outcomes remains elusive. Based on the literature, we identified two styles of leaders’ coaching behaviors that may promote followers’ learning, namely encourage-to-explore behaviors and guide-to-learn behaviors. We expect that these two styles of coaching behaviors would have different relationships with employee learning orientation, moderated by employees’ regulatory focus. To test our hypotheses, we conducted two studies: an experimental study using scenarios of leader behavior with data collected from 124 undergraduate students (study 1), and a field study with data from 334 pairs of employees and their direct supervisors (study 2). Results showed that encourage-to-explore behaviors had a positive relationship with employee learning orientation, whereas guide-to-learn behaviors had an inverted U-shaped relationship with employee learning orientation. When employees had low levels of promotion regulatory focus, encourage-to-explore behaviors showed a positive correlation with employee learning orientation. However, when they had low levels of prevention regulatory focus, employee learning orientation increased as the guide-to-learn behaviors increased; this increased up to an intermediate level and then decreased. As such, this study provides novel theoretical and empirical insights into leadership and learning literature.
Effects of Adding Zero Valent Iron on the Anaerobic Digestion of Cow Manure and Lignocellulose

Previous studies showed that adding zero valent iron (ZVI) can increase the methane production and degradation rate of organic waste by improving the performance of anaerobic digester. However, our study firstly found that ZVI (37 μm, 10 g/L) inhibited the anaerobic digestion (AD) of cow manure and lignocellulose. ZVI significantly increased the methanogenic rate of cow manure in the first 6 days, but decreased the accumulative methane yield and volatile fatty acids yield by 10.3 and 12%, respectively. The effect of ZVI on AD of liquid biomass separated from cow manure was positive, but the effect on solid biomass was negative. These results indicated that ZVI enhanced the AD of easily biodegradable organics but inhibited the biodegradation of refractory organics (lignocellulose). By analyzing the varying effects of ZVI in diverse anaerobic systems, it was found that the effects were influenced by the characteristics of substrate and inoculum-substrate ratio. This study suggested that only proper ZVI addition can improve the AD process depending on the feeding materials.
Sharing Clinical Notes in Psychotherapy: A New Tool to Strengthen Patient Autonomy

Clinical psychologists and psychotherapists have an ethical duty to respect patient autonomy (1). This means that before a patient can consent or decline to undergo psychotherapy, clinicians are obliged to present adequate and understandable information about the benefits and risks of the treatments. This conceptualization of informed consent differs from the written legal document executed before many medical procedures in the US. Before patients’ right to self-determination, providing the appropriate information may also lead to positive therapeutic benefits: demystifying the psychotherapy process can reduce anxiety, enhance patient trust, and strengthen the therapeutic alliance (2). However, informed consent to psychotherapy is “still not routine” (3) and evidence suggests that its importance is, “probably vastly underestimated by many psychologists” (4). Against the current shortcomings with disclosure practices in psychotherapy, healthcare is becoming more transparent and “open notes” —inviting patients to read their clinical notes via online portals—is a growing movement. Numerous health institutions in over a dozen countries have begun to share health records with patients (5). In the USA, fromNovember 2020, new federal rules mandate, with few exceptions, the sharing of medical notes; psychotherapy notes remain exempt from this ruling (6). Although fewer health organizations have chosen to share mental health notes (7), all patients have the right to understand their care (8). While many clinicians anticipate workflow problems from sharing notes (9, 10), studies suggest that clinicians do not experience major burdens to documentation practices (11–13). Addressing the perceived challenges with informed consent processes in psychotherapy contexts, we propose that open notes may provide an important new strategy to strengthen patient autonomy and improve clinical outcomes without sacrificing professional autonomy.
Eliminating Radiation Resistance of Non-Small Cell Lung Cancer by Dihydroartemisinin Through Abrogating Immunity Escaping and Promoting Radiation Sensitivity by Inhibiting PD-L1 Expression

Radiation resistance is linked to immune escaping and radiation sensitivity. In this study, we found that the PD-L1 expressions of non-killed tumor cells in NSCLC were enhanced after radiotherapy, and dihydroartemisinin (DHA) could synergistically enhance the antitumor effect of radiotherapy in NSCLC. A total of 48 NSCLC patients with sufficient tumor tissues for further analyses were enrolled. The PD-L1 expressions of NSCLC were evaluated by immunohistochemistry. Cell apoptosis was measured by flow cytometry, and the relationship between the PD-L1 expression and radiation resistance was investigated in patient specimens, xenograft model, and cell lines. First, the results indicate that the PD-L1 expression of NSCLC was positively related with the radiation resistance. Second, we found that DHA could eliminate the radiation resistance and synergistically enhance the antitumor effect of radiotherapy in the NSCLC cells lines and xenograft model. Finally, mechanistically, DHA could inhibit the PD-L1 expression to avoid immune escaping by inhibiting TGF-β, PI3K/Akt, and STAT3 signaling pathways. In addition, DHA could activate TRIM21 and regulate the EMT-related proteins by inhibiting the PD-L1 so as to enhance the radiation sensitivity and eliminate radiation resistance to NSCLC. Collectively, this study established a basis for the rational design of integrated radiotherapy and DHA for the treatment of NSCLC.
Triglyceride-Glucose Index Linked to Hospital Mortality in Critically Ill Stroke: An Observational Multicentre Study on eICU Database

Objective: The triglyceride-glucose (TyG) index is a reliable surrogate of insulin resistance and a marker for ischemic stroke (IS) incident. Whether the TyG index predicts stroke outcome remains uncertain. This study investigated the prognostic value of the TyG index in critically ill stroke patients. Methods: This was a retrospective observational study that included stroke patients, and all data were extracted from the eICU Collaborative Research Database. The TyG index was calculated as the ln [fasting glucose level (mg/dL) × triglyceride level (mg/dL)/2]. Outcomes included the hospital and intensive care unit (ICU) death. Multivariate logistic regression was used to determine independent risk factors. The smoothing curves and forest plots were illustrated. Results: A total of 4,570 eligible subjects were enrolled. The mean level of TyG index was 9.1 ± 0.7. The hospital and ICU mortality rate were 10.3 and 5.0%, respectively. TyG index as a continuous variable was associated hospital mortality in univariate analysis (OR 1.723, 95% CI 1.524–1.948, P < 0.001), adjusted model 1 (OR 1.861, 95% CI 1637–2.116, P < 0.001), and adjusted model 2 (OR 2.543, 95% CI 1.588–4.073, P < 0.001). TyG was also associated ICU mortality in univariate analysis (OR 2.146, 95% CI 1.826–2.523, P < 0.001), adjusted model 1 (OR 2.183, 95% CI 1.847–2.580, P < 0.001), and adjusted model 2 (OR 2.672, 95% CI 1.376–5.188, P < 0.001). The smoothing curves observed a continuous linear association after adjusting all covariates both in hospital and ICU mortality. Subgroup analysis demonstrated TyG index was associated with increased risk of hospital and ICU death in critically ill IS (P < 0.05), but not in hemorrhage stroke (P > 0.05). Conclusion: The TyG index is a potential predictor for hospital and ICU mortality in critically ill stroke patients, especially in IS patients.
Protective Intranasal Immunization Against Influenza Virus in Infant Mice Is Dependent on IL-6

Respiratory diseases adversely affect infants and are the focus of efforts to develop vaccinations and other modalities to prevent disease. The infant immune system differs from that of older children and adults in many ways that are as yet ill understood. We have used a C57BL/6 mouse model of infection with a laboratory- adapted strain of influenza (PR8) to delineate the importance of the cytokine IL-6 in the innate response to primary infection and in the development of protective immunity in adult mice. Herein, we used this same model in infant (14 days of age) mice to determine the effect of IL-6 deficiency. Infant wild type mice are more susceptible than older mice to infection, similar to the findings in humans. IL-6 is expressed in the lung in the early response to PR8 infection. While intramuscular immunization does not protect against lethal challenge, intranasal administration of heat inactivated virus is protective and correlates with expression of IL-6 in the lung, activation of lung CD8 cells, and development of an influenza-specific antibody response. In IL-6 deficient mice, this response is abrogated, and deficient mice are not protected against lethal challenge. These studies support the importance of the role of the tissue environment in infant immunity, and further suggest that IL-6 may be helpful in the generation of protective immune responses in infants.
Aging Impacts the Overall Connectivity Strength of Regions Critical for Information Transfer Among Brain Networks

Recent studies have demonstrated that connector hubs, regions considered critical for the flow of information across neural systems, are mostly involved in neurodegenerative dementia. Considering that aging can significantly affect the brain’s intrinsic connectivity, identifying aging’s impact on these regions’ overall connection strength is important to differentiate changes associated with healthy aging from neurodegenerative disorders. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of 175 healthy volunteers aging from 21 to 86 years old, we computed an intrinsic connectivity contrast (ICC) metric, which quantifies a region’s overall connectivity strength, for whole brain, short-range, and long-range connections and examined age-related changes of this metric over the adult lifespan. We have identified a limited number of hub regions with ICC values that showed significant negative relationship with age. These include the medial precentral/midcingulate gyri and insula with both their short-range and long-range (and thus whole-brain) ICC values negatively associated with age, and the angular, middle frontal, and posterior cingulate gyri with their long-range ICC values mainly involved. Seed-based connectivity analyses further confirmed that these regions are connector hubs with connectivity profile that strongly overlapped with multiple large-scale brain networks. General cognitive performance was not associated with these hubs’ ICC values. These findings suggest that even healthy aging could negatively impact the efficiency of regions critical for facilitating information transfer among different functional brain networks. The extent of the regions involved, however, was limited.
Zika Virus Inhibits IFN-α Response by Human Plasmacytoid Dendritic Cells and Induces NS1-Dependent Triggering of CD303 (BDCA-2) Signaling

Zika virus (ZIKV) dramatically emerged in French Polynesia and subsequently in the Americas where it has been associated with severe neurological complications in adults and newborns, respectively. Although plasmacytoid dendritic cells (pDCs) are a key sensor of viral infection and are critical for initiating an antiviral response, little is known about the impact of ZIKV infection on pDCs. Here, we investigated the susceptibility of human pDCs to infection with multiple strains of ZIKV and further investigated the impact of infection on pDCs functions. We observed that pDCs were refractory to cell-free ZIKV virions but were effectively infected when co-cultured with ZIKV-infected cells. However, exposure of pDCs to ZIKV-infected cells resulted in limited maturation/activation with significant down regulation of CD303 expression, a severe impairment of inflammatory cytokine production, and an inability to mount an IFN-α response. We show that ZIKV developed a strategy to inhibit the IFN-α response in primary human pDCs likely mediated through NS1-dependent CD303 signaling, thus suggesting a new mechanism of immune evasion.
Addressing the challenges of artificial intelligence in medicine

The application of artificial intelligence in medicine, particularly in relation to screening and diagnosis of disease through imaging analysis, will have a profound impact over the next decade. This communication discusses regulatory challenges that should be considered by physicians and how potential issues may be mitigated using a collaborative approach, drawing on the combined expertise of relevant stakeholders.