Miracle-dz/UniFAR-FTUs huggingface dataset:
Interest in non-social novel stimuli as a function of age in rhesus monkeys

Human cognitive and affective life changes with healthy ageing; cognitive capacity declines while emotional life becomes more positive and social relationships are prioritized. This may reflect an awareness of limited lifetime unique to humans, leading to a greater interest in maintaining social relationships at the expense of the non-social world in the face of limited cognitive and physical resources. Alternately, fundamental biological processes common to other primate species may direct preferential interest in social stimuli with increasing age. Inspired by a recent study that described a sustained interest in social stimuli but diminished interest in non-social stimuli in aged Barbary macaques, we carried out a conceptual replication to test whether old rhesus monkeys lost interest in non-social stimuli. Male and female macaques (Macaca mulatta; N = 243) 4–30 years old were tested with a food puzzle outfitted with an activity monitor to evaluate their propensity to manipulate the puzzle in order to free a food reward. We found no indication that aged monkeys were less interested in the puzzle than young monkeys, nor were they less able to solve it.
Decitabine-containing G-CSF priming regimen overcomes resistance of primary mediastinal neoplasm from early T-cell precursors to conventional chemotherapy: a case report

Abstract Early T-cell precursor (ETP) leukemia represents a new subtype of T-lymphoblastic leukemia/lymphoma with unique immunophenotypes expressing T-cell and one or more of the myeloid/stem cell markers. Here, we report a young patient who had primary mediastinal mass and pleural effusion without bone marrow involvement. A CT-guided mediastinal biopsy and flow cytometry analysis of the pleural effusion revealed the blast cells to have complicated immunophenotypes: strongly expressed T-cell antigen CD7, myeloid-lineage antigens CD33 and CD13 and stem cell markers cTdT, CD34, and HLA-DR; dimly expressed myeloid-lineage specific antigen cMPO and B-cell antigen cCD79a; but did not express T-cell specific antigen cytoplasmic CD3 and B-cell specific antigen CD19. Clonal T-cell receptor rearrangement eventually determined the cell of origin from ETPs, not myeloblasts. The patient showed primary resistance to lymphoid and myeloid-directed induction therapy. Finally, low-dose decitabine combined with modified-CAG regimen induced a complete remission and allogeneic stem cell transplantation was performed as consolidation. The case indicates a primary mediastinal neoplasm from ETP with distinctive immunophenotype from leukemia type. Low-dose decitabine and modified-CAG regimen in combination with allogeneic stem cell transplantation may improve the outcome of patient.
Effects of a comprehensive, inpatient pulmonary rehabilitation programme in a cachectic patient with very severe COPD and chronic respiratory failure

Pulmonary rehabilitation (PR) is a comprehensive intervention based on a thorough patient assessment followed by personalised interventions designed to improve the physical and psychological condition of patients with chronic respiratory diseases and to promote the long-term adherence to health-enhancing behaviours [1]. While the clinical importance of physical activity is recognised across all stages of disease, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 strategy for chronic obstructive pulmonary disease (COPD) states that patients that remain highly symptomatic and/or those with a history of moderate or severe exacerbations despite optimal pharmacotherapy are indicated for PR [2]. Improvements in symptoms, increases in quality of life and gains in functional capacity after PR are independent of age, sex or the baseline degree of airflow limitation [3, 4]. However, it is known that patients with higher symptoms of dyspnoea, worse functional capacity and poor health status at baseline are more likely to be good responders to PR [5]. While PR is traditionally applied in clinically stable patients, there is increasing evidence for its beneficial effects following hospitalisations [6] and in those with frequent exacerbations [5]. In patients with very severe disease awaiting lung transplantation significant improvements in exercise capacity and health status were reported after short-term comprehensive PR [7]. Moreover, an increasing number of specific (non-)pharmacological interventions are available and can be combined with PR in the subgroup of patients with very advanced disease, including neuromuscular electrical stimulation (NMES), noninvasive ventilatory support and anabolic agents. Finally, PR may be an appropriate setting to introduce advance care planning (ACP) [8]. The role of these personalised and targeted interventions will be highlighted in this case report. A cachectic patient with very severe COPD and chronic respiratory failure may benefit from comprehensive and personalised pulmonary rehabilitation including neuromuscular electrical stimulation, noninvasive ventilation and anabolic steroids http://bit.ly/31Ss7WZ
Hub Patterns-Based Detection of Dynamic Functional Network Metastates in Resting State: A Test-Retest Analysis

The spontaneous dynamic characteristics of resting-state functional networks contain much internal brain physiological or pathological information. The metastate analysis of brain functional networks is an effective technique to quantify the essence of brain functional connectome dynamics. However, the widely used functional connectivity-based metastate analysis ignored the topological structure, which could be locally reflected by node centrality. In this study, 23 healthy young volunteers (21–26 years) were recruited and scanned twice with a 1-week interval. Based on the time sequences of node centrality, we promoted a node centrality-based clustering method to find metastates of functional connectome and conducted a test-retest experiment to assess the stability of those identified metastates using the described method. The hub regions of metastates were further compared with the structural networks’ organization to depict its potential relationship with brain structure. Results of extracted metastates showed repeatable dynamic features between repeated scans and high overlapping rate of hub regions with brain intrinsic sub-networks. These identified hub patterns from metastates further highly overlapped with the structural hub regions. These findings indicated that the proposed node centrality-based metastates detection method could reveal reliable and meaningful metastates of spontaneous dynamics and indicate the underlying nature of brain dynamics as well as the potential relationship between these dynamics and the organization of the brain connectome.
Quantitative Security Risk Assessment for Industrial Control Systems: Research Opportunities and Challenges

Due to the gradual implementation of the Industry 4.0 vision, information technology is becoming increasingly important in industrial control systems (ICSs), such as production systems. Although the digital transformation of ICSs represents the foundation for resource-efficient and flexible industrial plants, this change increases the attack surface, leading to the emergence of new threats. Moreover, ICSs constitute an attractive target for attackers who may disrupt plant operation, causing severe physical/material damages (PD/MD), such as machinery breakdowns. In further consequence, asset owners (i.e., plant operators) may suffer from business interruption (BI) and loss of profit (LOP). Thus, security risks must be managed in all phases of the ICSs’ lifecycle, starting from engineering to decommissioning. Risk assessment is an integral part of the risk management process in which risks are identified, analyzed, and evaluated. In this context, the quantitative assessment is vital, since measuring cyber risks is required to establish an effective decision-making process for security investments. This survey article reviews the state of the art concerning quantitative security risk assessments for ICSs and identifies promising opportunities for future research and associated challenges. We report that the current state of quantitatively assessing cyber risks for ICSs is characterized by the absence of adequate (dynamic) security risk assessment methods tailored to the peculiarities of ICSs. This is aggravated by the fact that the complexity of the threat landscape increases in the light of Industry 4.0, and historical data on security incidents is lacking. As a consequence, asset owners may fail to quantitatively assess their cyber risk exposure, leaving them uncertain about security decisions. Furthermore, if they purchase cyber insurance in order to transfer the risks of non-PD BI, the underlying problem remains unsolved as (re)insurers potentially take on these unassessed risks. As an initial step to guide individuals seeking to improve the quantification of cyber risks pertaining to ICSs, this article concludes by outlining several directions for further research that are worth pursuing.
MHC binding affects the dynamics of different T-cell receptors in different ways

T cells use their T-cell receptors (TCRs) to scan other cells for antigenic peptides presented by MHC molecules (pMHC). If a TCR encounters a pMHC, it can trigger a signalling pathway that could lead to the activation of the T cell and the initiation of an immune response. It is currently not clear how the binding of pMHC to the TCR initiates signalling within the T cell. One hypothesis is that conformational changes in the TCR lead to further downstream signalling. Here we investigate four different TCRs in their free state as well as in their pMHC bound state using large scale molecular simulations totalling 26 000 ns. We find that the dynamical features within TCRs differ significantly between unbound TCR and TCR/pMHC simulations. However, apart from expected results such as reduced solvent accessibility and flexibility of the interface residues, these features are not conserved among different TCR types. The presence of a pMHC alone is not sufficient to cause cross-TCR-conserved dynamical features within a TCR. Our results argue against models of TCR triggering involving conserved allosteric conformational changes.
MRGPRX4 is a bile acid receptor for human cholestatic itch

Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca2+ responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.
The long-term impact of the Communist Revolution on social stratification in contemporary China

Significance Utilizing the latest, high-quality, 3-generation data, this article reports findings from a systematic study of the long-term impact of the Communist Revolution on the social stratification order in today’s China. It is found that the revolution disrupted the cross-generational reproduction of the prevailing social stratification at the time of the revolution in promoting the social status of children of the peasant and worker classes and disadvantaging those from privileged classes. Despite a tendency for “reversion” mitigating the revolution’s effects in the third generation toward the grandparents’ generation in social status, the impact of the revolution on the educational attainment of descendants by class classification immediately following the revolution remains strong even after 6 decades have passed. The Chinese Communist Revolution that culminated in the 1949 founding of the People’s Republic of China fundamentally transformed class relations in China. With data from a nationally representative, longitudinal survey between 2010 and 2016, this study documents the long-term impact of the Communist Revolution on the social stratification order in today’s China, more than 6 decades after the revolution. True to its stated ideological missions, the revolution resulted in promoting the social status of children of the peasant, worker, and revolutionary cadre classes and disadvantaging those who were from privileged classes at the time of the revolution. Although there was a tendency toward “reversion” mitigating the revolution’s effects in the third generation toward the grandparents’ generation in social status, the overall impact of reversion was small. The revolution effects were most pronounced for the birth cohorts immediately following the revolution, attenuating for recently born cohorts.
Metadherin–PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT–β-catenin signaling pathway

Abstract Accumulating data suggest that metadherin (MTDH) may function as an oncogene. Our previous study showed that MTDH promotes hepatocellular carcinoma (HCC) metastasis via the epithelial-mesenchymal transition. In this study, we aim to further elucidate how MTDH promotes HCC metastasis. Using Co-immunoprecipitation (co-IP) and mass spectrometry, we found that MTDH can specifically bind to protein arginine methyltransferase 5 (PRMT5). Further functional assays revealed that PRMT5 overexpression promoted the proliferation and motility of HCC cells and that knockout of PRMT5 impeded the effect of MTDH. The immunohistochemistry assay/tissue microarray results showed that when MTDH was overexpressed in HCC cells, PRMT5 translocated from the nucleus to the cytoplasm, with the subsequent translocation of β-catenin from the cytoplasm to the nucleus and upregulation of the WNT–β-catenin signaling pathway. Further in vivo experiments suggested that PRMT5 and β-catenin played a pivotal role in MTDH-mediated HCC metastasis. We therefore concluded that the MTDH–PRMT5 complex promotes HCC metastasis by regulating the WNT–β-catenin signaling pathway.
Targeting ROS and cPLA2/COX2 Expressions Ameliorated Renal Damage in Obese Mice with Endotoxemia

Obesity is associated with metabolic endotoxemia, reactive oxygen species (ROS), chronic inflammation, and obese kidney fibrosis. Although the fat–intestine–kidney axis has been documented, the pathomechanism and therapeutic targets of obese kidney fibrosis remain unelucidated. To mimic obese humans with metabolic endotoxemia, high-fat-diet-fed mice (HF group) were injected with lipopolysaccharide (LPS) to yield the obese kidney fibrosis–metabolic endotoxemia mouse model (HL group). Therapeutic effects of ROS, cytosolic phospholipases A2 (cPLA2) and cyclooxygenase-2 (COX-2) inhibitors were analyzed with a quantitative comparison of immunohistochemistry stains and morphometric approach in the tubulointerstitium of different groups. Compared with basal and HF groups, the HL group exhibited the most prominent obese kidney fibrosis, tubular epithelial lipid vacuoles, and lymphocyte infiltration in the tubulointerstitium. Furthermore, inhibitors of nonspecific ROS, cPLA2 and COX-2 ameliorated the above renal damages. Notably, the ROS-inhibitor-treated group ameliorated not only oxidative injury but also the expression of cPLA2 and COX-2, indicating that ROS functions as the upstream signaling molecule in the inflammatory cascade of obese kidney fibrosis. ROS acts as a key messenger in the signaling transduction of obese kidney fibrosis, activating downstream cPLA2 and COX-2. The given antioxidant treatment ameliorates obese kidney fibrosis resulting from a combined high-fat diet and LPS—ROS could serve as a potential therapeutic target of obese kidney fibrosis with metabolic endotoxemia.
Current and Future Horizons of Patient-Derived Xenograft Models in Colorectal Cancer Translational Research

Our poor understanding of the intricate biology of cancer and the limited availability of preclinical models that faithfully recapitulate the complexity of tumors are primary contributors to the high failure rate of novel therapeutics in oncology clinical studies. To address this need, patient-derived xenograft (PDX) platforms have been widely deployed and have reached a point of development where we can critically review their utility to model and interrogate relevant clinical scenarios, including tumor heterogeneity and clonal evolution, contributions of the tumor microenvironment, identification of novel drugs and biomarkers, and mechanisms of drug resistance. Colorectal cancer (CRC) constitutes a unique case to illustrate clinical perspectives revealed by PDX studies, as they overcome limitations intrinsic to conventional ex vivo models. Furthermore, the success of molecularly annotated "Avatar" models for co-clinical trials in other diseases suggests that this approach may provide an additional opportunity to improve clinical decisions, including opportunities for precision targeted therapeutics, for patients with CRC in real time. Although critical weaknesses have been identified with regard to the ability of PDX models to predict clinical outcomes, for now, they are certainly the model of choice for preclinical studies in CRC. Ongoing multi-institutional efforts to develop and share large-scale, well-annotated PDX resources aim to maximize their translational potential. This review comprehensively surveys the current status of PDX models in translational CRC research and discusses the opportunities and considerations for future PDX development.
Analysis of Brain and Cerebrospinal Fluid from Mouse Models of the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Changes in the Lysosomal Proteome*

Neuronal ceroid lipofuscinoses are fatal neurodegenerative lysosomal diseases. Protein biomarkers that reflect ongoing disease processes could provide a valuable readout to help optimize dose and dosing regimen and determine response to treatment. A quantitative proteomic analysis of brain and cerebrospinal fluid from mouse models of three NCL diseases and controls was conducted at time points corresponding to early and late stage disease. Resulting data were cross-referenced with previous studies in mouse and humans, identifying promising biomarker candidates for further study. Graphical Abstract Highlights Proteomic analysis of brain and cerebrospinal fluid from mouse NCL models. Disease-associated changes in lysosomal proteins and markers of neuroinflammation. Biomarker candidates identified for further evaluation. Treatments are emerging for the neuronal ceroid lipofuscinoses (NCLs), a group of similar but genetically distinct lysosomal storage diseases. Clinical ratings scales measure long-term disease progression and response to treatment but clinically useful biomarkers have yet to be identified in these diseases. We have conducted proteomic analyses of brain and cerebrospinal fluid (CSF) from mouse models of the most frequently diagnosed NCL diseases: CLN1 (infantile NCL), CLN2 (classical late infantile NCL) and CLN3 (juvenile NCL). Samples were obtained at different stages of disease progression and proteins quantified using isobaric labeling. In total, 8303 and 4905 proteins were identified from brain and CSF, respectively. We also conduced label-free analyses of brain proteins that contained the mannose 6-phosphate lysosomal targeting modification. In general, we detect few changes at presymptomatic timepoints but later in disease, we detect multiple proteins whose expression is significantly altered in both brain and CSF of CLN1 and CLN2 animals. Many of these proteins are lysosomal in origin or are markers of neuroinflammation, potentially providing clues to underlying pathogenesis and providing promising candidates for further validation.
Associations of Subjective Memory Complaints and Simple Memory Task Scores With Future Dementia in the Primary Care Setting

PURPOSE Family physicians need simple yet comprehensive algorithms to discriminate between community-dwelling older persons who are at increased risk of dementia and those who are not. We aimed to investigate associations between incident dementia and responses to a single question regarding subjective memory complaints (SMC) combined with scores on 2 simple memory tests that are easy to use in the primary care setting. METHODS Analyses were based on data from 3,454 community-dwelling older persons who participated in the 6- to 8-year Prevention of Dementia by Intensive Vascular Care (preDIVA) trial, yielding 21,341 person-years of observation. Participants were considered a single cohort. We used Cox models to assess separate and combined associations of SMC, an imperfect score on the Mini-Mental State Examination delayed recall item (MMSE-5), and an imperfect score on the Visual Association Test (VAT) with future dementia. RESULTS Subjective memory complaints alone were associated with future dementia (hazard ratio [HR] = 3.01; 95% CI, 2.31-3.94; P <.001), as were the MMSE-5 (HR = 2.14; 95% CI, 1.59-2.87; P <.001) and VAT (HR = 3.19; 95% CI, 2.46-4.13; P <.001) scores. After a median follow-up of 6.7 years, the occurrence of dementia ranged from 4% to 30% among persons with SMC, depending on the MMSE-5 and VAT scores. These test scores did not substantially alter the association with future dementia for persons without SMC. CONCLUSIONS In persons with SMC, the strength of the association between future dementia and an imperfect MMSE-5 score depends substantially on the VAT score.
Get Ready for Being Chauffeured

Objective We investigated passenger’s trust and preferences using subjective, qualitative, and psychophysiological measures while being driven either by human or automation in a field study and a driving simulator experiment. Background The passenger’s perspective has largely been neglected in autonomous driving research, although the change of roles from an active driver to a passive passenger is incontrovertible. Investigations of passenger’s appraisals on self-driving vehicles often seem convoluted with active manual driving experiences instead of comparisons with being driven by humans. Method We conducted an exploratory field study using an autonomous research vehicle (N = 11) and a follow-up experimental driving simulation (N = 24). Participants were driven on the same course by a human and an autonomous agent sitting on a passenger seat. Skin conductance, trust, and qualitative characteristics of the perceived driving situation were assessed. In addition, the effect of driving style (defensive vs. sporty) was evaluated in the simulator. Results Both investigations revealed a close relation between subjective trust ratings and skin conductance, with increased trust and by trend reduced arousal for human compared with automation in control. Even though driving behavior was equivalent in the simulator when being driven by human and automation, passengers most preferred and trusted the human-defensive driver. Conclusion Individual preferences for driving style and human or autonomous vehicle control influence trust and subjective driving characterizations. Application The findings are applicable in human-automation research, reminding to not neglect subjective attributions and psychophysiological reactions as a result of ascribed control duties in relation to specific execution characteristics.