Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolving Consciousness: Insights From Turing, and the Shaping of Experience

A number of conceptual difficulties arise when considering the evolutionary origin of consciousness from the pre-conscious condition. There are parallels here with biological pattern formation, where, according to Alan Turing’s original formulation of the problem, the statistical properties of molecular-level processes serve as a source of incipient pattern. By analogy, the evolution of consciousness can be thought of as depending in part on a competition between alternative variants in the microstructure of synaptic networks and/or the activity patterns they generate, some of which then serve as neural correlates of consciousness (NCCs). Assuming that NCCs perform this function only if reliably ordered in a particular and precise way, Turing’s formulation provides a useful conceptual framework for thinking about how this is achieved developmentally, and how changes in neural structure might correlate with change at the level of conscious experience. The analysis is largely silent concerning the nature and ultimate source of conscious experience, but shows that achieving sentience is sufficient to begin the process by which evolution elaborates and shapes that first experience. By implication, much of what evolved consciousness achieves in adaptive terms can in principle be investigated irrespective of whether or not the ultimate source of real-time experience is known or understood. This includes the important issue of how precisely NCCs must be structured to ensure that each evokes a particular experience as opposed to any other. Some terminological issues are clarified, including that of “noise,” which here refers to the statistical variations in neural structure that arise during development, not to sensory noise as experienced in real time.
The Role of Structure in the Biology of Interferon Signaling

Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an antiviral state at the cell, tissue, organ, and organismal level is performed by three distinct IFN families, designated as Type-I, Type-II, and Type-III IFNs. Overall, there are 21 human IFNs, (16 type-I, 12 IFNαs, IFNβ, IFNϵ, IFNκ, and IFNω; 1 type-II, IFNγ; and 4 type-III, IFNλ1, IFNλ2, IFNλ3, and IFNλ4), that induce pleotropic cellular activities essential for innate and adaptive immune responses against virus and other pathogens. IFN signaling is initiated by binding to distinct heterodimeric receptor complexes. The three-dimensional structures of the type-I (IFNα/IFNAR1/IFNAR2), type-II (IFNγ/IFNGR1/IFNGR2), and type-III (IFNλ3/IFNλR1/IL10R2) signaling complexes have been determined. Here, we highlight similar and unique features of the IFNs, their cell surface complexes and discuss their role in inducing downstream IFN signaling responses.
In Their Own Words: A Call for Increased Use of Organizational Narratives in Family Business Research

The role words and narratives play in understanding rich relationships critical to family business cannot be overstated. This truth was highlighted by a recent landmark case resulting in the awarding of $572 million dollars to the state of Oklahoma based on opioid marketing in a case against a firm Oklahoma Attorney General Mike Hunter often disparagingly referred to as “a family company. ” Unfortunately, however, the Attorney General was mistakenly referencing SC Johnson and their famous tagline rather than Johnson & Johnson— the corporation involved in the case. In response to this misstep CEO and chairman of SC Johnson H. Fisk Johnson threatened litigation until the Attorney General promised to refrain from this incorrect name association in the future (Kopecki, 2019). In addition to the attention to careless use of words surrounding his well-known family firm, H. Fisk Johnson provided an illuminating family business narrative when he released a full-page ad explicitly outlining the issues associated with cavalier use of their name. In part, he notes,
Cybersickness in Head-Mounted Displays Is Caused by Differences in the User's Virtual and Physical Head Pose

Sensory conflict, eye-movement, and postural instability theories each have difficulty accounting for the motion sickness experienced during head-mounted display based virtual reality (HMD VR). In this paper we review the limitations of existing theories in explaining cybersickness and propose a practical alternative approach. We start by providing a clear operational definition of provocative motion stimulation during active HMD VR. In this situation, whenever the user makes a head movement, his/her virtual head will tend to trail its true position and orientation due to the display lag (or motion to photon latency). Importantly, these differences in virtual and physical head pose (DVP) will vary over time. Based on our own research findings, we propose that cybersickness in HMD VR is triggered by large magnitude, time-varying patterns of DVP. We then show how this hypothesis can be tested by: (1) systematically manipulating display lag magnitudes and head movement speeds across HMD VR conditions; and (2) comparing the estimates of the user's DVP in each of these conditions to their own reports of cybersickness severity. We believe that this approach will allow researchers to precisely predict which situations will (and will not) be provocative for cybersickness in HMD VR.
Cellular Biology of Tau Diversity and Pathogenic Conformers

Tau accumulation is a prominent feature in a variety of neurodegenerative disorders and remarkable effort has been expended working out the biochemistry and cell biology of this cytoplasmic protein. Tau's wayward properties may derive from germline mutations in the case of frontotemporal lobar degeneration (FTLD-MAPT) but may also be prompted by less understood cues—perhaps environmental or from molecular damage as a consequence of chronological aging—in the case of idiopathic tauopathies. Tau properties are undoubtedly affected by its covalent structure and in this respect tau protein is not only subject to changes in length produced by alternative splicing and endoproteolysis, but different types of posttranslational modifications that affect different amino acid residues. Another layer of complexity concerns alternate conformations—“conformers”—of the same covalent structures; in vivo conformers can encompass soluble oligomeric species, ramified fibrillar structures evident by light and electron microscopy and other forms of the protein that have undergone liquid-liquid phase separation to make demixed liquid droplets. Biological concepts based upon conformers have been charted previously for templated replication mechanisms for prion proteins built of the PrP polypeptide; these are now providing useful explanations to feature tau pathobiology, including how this protein accumulates within cells and how it can exhibit predictable patterns of spread across different neuroanatomical regions of an affected brain. In sum, the documented, intrinsic heterogeneity of tau forms and conformers now begins to speak to a fundamental basis for diversity in clinical presentation of tauopathy sub-types. In terms of interventions, emphasis upon subclinical events may be worthwhile, noting that irrevocable cell loss and ramified protein assemblies feature at end-stage tauopathy, whereas earlier events may offer better opportunities for diverting pathogenic processes. Nonetheless, the complexity of tau sub-types, which may be present even within intermediate disease stages, likely mitigates against one-size-fits-all therapeutic strategies and may require a suite of interventions. We consider the extent to which animal models of tauopathy can be reasonably enrolled in the campaign to produce such interventions and to slow the otherwise inexorable march of disease progression.
Discovery of a Recombinant Human Monoclonal Immunoglobulin G Antibody Against α-Latrotoxin From the Mediterranean Black Widow Spider (Latrodectus tredecimguttatus)

Widow spiders are among the few spider species worldwide that can cause serious envenoming in humans. The clinical syndrome resulting from Latrodectus spp. envenoming is called latrodectism and characterized by pain (local or regional) associated with diaphoresis and nonspecific systemic effects. The syndrome is caused by α-latrotoxin, a ~130 kDa neurotoxin that induces massive neurotransmitter release. Due to this function, α-latrotoxin has played a fundamental role as a tool in the study of neuroexocytosis. Nevertheless, some questions concerning its mode of action remain unresolved today. The diagnosis of latrodectism is purely clinical, combined with the patient’s history of spider bite, as no analytical assays exist to detect widow spider venom. By utilizing antibody phage display technology, we here report the discovery of the first recombinant human monoclonal immunoglobulin G antibody (TPL0020_02_G9) that binds α-latrotoxin from the Mediterranean black widow spider (Latrodectus tredecimguttatus) and show neutralization efficacy ex vivo. Such antibody can be used as an affinity reagent for research and diagnostic purposes, providing researchers with a novel tool for more sophisticated experimentation and analysis. Moreover, it may also find therapeutic application in future.
Microbiota Transplant in the Treatment of Obesity and Diabetes: Current and Future Perspectives

A wealth of evidence has revealed the critical role of the gut microbiota in health and disease. Many chronic diseases have been associated with gut microbiota imbalance in its composition, diversity and functional capacity. Several types of interventions have been shown to correct microbiota imbalance and restore the beneficial metabolic outcomes of a normal microbiota. Among them, fecal microbiota transplantation (FMT) is an emergent, promising technology employed to improve clinical outcomes of various pathological conditions through modifications in the gut microbiota composition. FMT has been used successfully as a treatment option in recurrent Clostridium difficile infection, a condition characterized by severe gut microbiota dysbiosis. However, the potential usage of FMT in other microbiota-associated conditions different from C. difficile such as metabolic syndrome or obesity that are also marked by gut dysbiosis is still under investigation. Furthermore, the contribution of the gut microbiota as a cause or consequence in metabolic disease is still largely debated. This review provides critical information on the methodological approaches of FMT and its technological innovation in clinical applications. This review sheds light on the current findings and gaps in our understanding of how FMT can be used as a future biotherapeutic to restore microbial homeostasis in amelioration of obesity and diabetes.
Strategies to Enhance the Efficacy of T-Cell Therapy for Central Nervous System Tumors

Mortality rates in patients diagnosed with central nervous system (CNS) tumors, originating in the brain or spinal cord, continue to remain high despite the advances in multimodal treatment regimens, including surgery, radiation, and chemotherapy. Recent success of adoptive cell transfer immunotherapy treatments using chimeric antigen receptor (CAR) engineered T cells against in chemotherapy resistant CD19 expressing B-cell lymphomas, has provided the foundation for investigating efficacy of CAR T immunotherapies in the context of brain tumor. Although significant efforts have been made in developing and translating the novel CAR T therapies for CNS tumors, including glioblastoma (GBM), researchers are yet to achieve a similar level of success as with liquid malignancies. In this review, we discuss strategies and considerations essential for developing robust preclinical models for the translation of T cell-based therapies for CNS tumors. Some of the key considerations include route of delivery, increasing persistence of T cells in tumor environment, remodeling of myeloid environment, establishing the window of treatment opportunity, harnessing endogenous immune system, designing multiple antigen targeting T cells, and rational combination of immunotherapy with the current standard of care. Although this review focuses primarily on CAR T therapies for GBM, similar strategies, and considerations are applicable to all CNS tumors in general.
Maternal Separation Combined With Limited Bedding Increases Anxiety-Like Behavior and Alters Hypothalamic-Pituitary-Adrenal Axis Function of Male BALB/cJ Mice

Early life stress (ELS) is considered a risk factor for the development of psychiatric conditions, including depression and anxiety disorder. Individuals that live in adverse environments are usually exposed to multiple stressors simultaneously, such as maternal neglect, maltreatment, and limited resources. Nevertheless, most pre-clinical ELS models are designed to explore the impact of these events separately. For this reason, this study aims to investigate the effects of a combined model of ELS on anxiety-like behavior and hypothalamic-pituitary-adrenal (HPA) axis related targets. From PND 2 to PND 15 BALB/cJ mice were exposed simultaneously to maternal separation (MS; 3 h per day) and limited bedding (LB; ELS group) or left undisturbed (CT group). Maternal behavior was recorded in intercalated days, from PND 1 to PND 9. Male offspring were tested for anxiety-like behavior from PND 53 to PND 55 in the open field test (OF), elevated plus-maze (EPM), and light/dark test (LD). After behavioral testing, animals were euthanized, and glucocorticoid receptor (Nr3c1), corticotrophin-releasing hormone (Crh), and its receptor type 1 (Crhr1) gene expression in the hypothalamus were measured. Moreover, plasma corticosterone levels were analyzed. We observed that ELS dams presented altered quality of maternal care, characterized by a decrease in arched-back nursing, and an increase in passive nursing. Stressed dams also showed an increase in the number of exits from the nest when compared to CT dams. Furthermore, ELS animals showed increased anxiety-like behavior in the OF, EPM, and LD. Regarding gene expression, we identified an increase in hypothalamus Crh levels of ELS group when compared to CT animals, while no differences in Nr3c1 and Crhr1 expression were observed. Finally, stressed animals showed decreased levels of plasma corticosterone when compared to the CT group. In conclusion, we observed an alteration in maternal behavior in ELS dams. Later in life, animals exposed to the combined model of ELS showed increased levels of anxiety-like behavior. Moreover, the central and peripheral HPA measures observed could indicate a dysregulation in HPA function provoked by ELS exposure.
Évaluation de systèmes apprenant tout au long de la vie (Evaluation of lifelong learning systems )

Aujourd’hui les systèmes intelligents obtiennent d’excellentes performances dans de nombreux domaines lorsqu’ils sont entraînés par des experts en apprentissage automatique. Lorsque ces systèmes sont mis en production, leurs performances se dégradent au cours du temps du fait de l’évolution de leur environnement réel. Une adaptation de leur modèle par des experts en apprentissage automatique est possible mais très coûteuse alors que les sociétés utilisant ces systèmes disposent d’experts du domaine qui pourraient accompagner ces systèmes dans un apprentissage tout au long de la vie. Dans cet article nous proposons un cadre d’évaluation générique pour des systèmes apprenant tout au long de la vie (SATLV). Nous proposons d’évaluer l’apprentissage assisté par l’humain (actif ou interactif) et l’apprentissage au cours du temps.
Krüppel-Like Factors 9 and 13 Block Axon Growth by Transcriptional Repression of Key Components of the cAMP Signaling Pathway

Krüppel-like factors (KLFs) are zinc finger transcription factors implicated in diverse biological processes, including differentiation of neural cells. The ability of mammalian neurons to elongate axons decreases during postnatal development in parallel with a decrease in cAMP, and increase in expression of several Klf genes. The paralogous KLFs 9 and 13 inhibit neurite outgrowth, and we hypothesized that their actions are mediated through repression of cAMP signaling. To test this we used the adult mouse hippocampus-derived cell line HT22 engineered to control expression of Klf9 or Klf13 with doxycycline, or made deficient for these Klfs by CRISPR/Cas9 genome editing. We also used primary hippocampal cells isolated from wild type, Klf9–/– and Klf13–/– mice. Forced expression of Klf9 or Klf13 in HT22 changed the mRNA levels of several genes involved with cAMP signaling; the predominant action was gene repression, and KLF13 influenced ∼4 times more genes than KLF9. KLF9 and KLF13 repressed promoter activity of the protein kinase a catalytic subunit alpha gene in transfection-reporter assays; KLF13, but not KLF9 repressed the calmodulin 3 promoter. Forskolin activation of a cAMP-dependent promoter was reduced after forced expression of Klf9 or Klf13, but was enhanced in Klf gene knockout cells. Forced expression of Klf9 or Klf13 blocked cAMP-dependent neurite outgrowth in HT22 cells, and axon growth in primary hippocampal neurons, while Klf gene knockout enhanced the effect of elevated cAMP. Taken together, our findings show that KLF9 and KLF13 inhibit neurite/axon growth in hippocampal neurons, in part, by inhibiting the cAMP signaling pathway.
Implementation of Lean in a Health System: Lessons Learned From a Meta-Analysis of Rapid Improvement Events, 2013–2017

EXECUTIVE SUMMARY Recent data suggest that a majority of hospitals now engage in some form of Lean process improvement in an attempt to reduce costs and/or improve quality. The literature on Lean healthcare has evolved from describing theoretical benefits, implementation barriers, and best practices to studies describing where implementations have occurred and their outcomes. Nevertheless, previous studies are mostly limited to case studies in which Lean was implemented on a limited basis in a healthcare facility. In this article, we present lessons learned from the largest implementation of Lean in a single healthcare system composed of 16 hospitals, a health plan, and many outpatient clinics. Our analysis of 1,144 rapid improvement events (RIEs) over a 5-year period revealed that 45% were associated with some organizational benefit in several categories, including cost reductions, time savings, a reduction in clinical and nonclinical defects, and a reduction in workflow steps. As the organization became more experienced with RIEs, the benefits realized changed from mostly cost reductions to a more diverse mix of benefits, with time savings becoming the most common. RIEs implemented in certain settings and/or by certain types of employees were associated with the likelihood of realizing a benefit. Based on these analyses, we provide recommendations to hospital and health system leaders interested in optimizing their Lean implementations—especially on a large enterprise-wide scale.
Analysis of Factors Influencing Kidney Function of Recipients After Renal Transplantation in Southwestern China: A Retrospective Study

Background: Factors influencing the kidney function of patients after renal transplantation include both recipient-related factors and donor-related factors. To gain a better understanding of these factors and to improve clinical decision-making, we performed a retrospective study of southwestern Chinese people receiving kidney transplantation. Methods: In this retrospective analysis, a total of 2,462 recipients receiving allogeneic kidney transplantation in West China Hospital of Sichuan University from December 13, 2008 to January 10, 2018 were included. Data on recipient and donor characteristics were extracted from the Transplant Center Database and stratified by discrete time points after kidney transplantation. Univariate and multivariate logistic regression analyses were carried out on the study variables, and kidney function of postoperative patients was monitored using cystatin C (CysC) as the outcome indicator. Results: From the univariate analysis, several factors showed statistically significant short-term impact on kidney function based on CysC after kidney transplantation, including age, ethnicity, body mass index (BMI), and HLA A-B-DR-DQ loci mismatch. Gender of recipients and gender-consistency between donors and recipients revealed both short-term and long-term influence. Younger donors had significantly better medium-and-long-term influence on kidney function. From the multivariate logistic regression analysis, recipient gender, ethnicity, BMI, and donor age were independent factors affecting postoperative CysC recovery at discrete time points. Conclusion: Several factors of recipients related to renal function after kidney transplantation, such as gender, ethnicity, BMI and donor's age should be paid more attention to. Moreover, female and non-Han recipients decreased the risk of poor outcome during postoperative kidney function recovery while large BMI of recipients and higher donor age increased the risk. It is useful to predict the postoperative renal function earlier according to corresponding factors, and improve the patient's quality of life.
Root Adaptation via Common Genetic Factors Conditioning Tolerance to Multiple Stresses for Crops Cultivated on Acidic Tropical Soils

Crop tolerance to multiple abiotic stresses has long been pursued as a Holy Grail in plant breeding efforts that target crop adaptation to tropical soils. On tropical, acidic soils, aluminum (Al) toxicity, low phosphorus (P) availability and drought stress are the major limitations to yield stability. Molecular breeding based on a small suite of pleiotropic genes, particularly those with moderate to major phenotypic effects, could help circumvent the need for complex breeding designs and large population sizes aimed at selecting transgressive progeny accumulating favorable alleles controlling polygenic traits. The underlying question is twofold: do common tolerance mechanisms to Al toxicity, P deficiency and drought exist? And if they do, will they be useful in a plant breeding program that targets stress-prone environments. The selective environments in tropical regions are such that multiple, co-existing regulatory networks may drive the fixation of either distinctly different or a smaller number of pleiotropic abiotic stress tolerance genes. Recent studies suggest that genes contributing to crop adaptation to acidic soils, such as the major Arabidopsis Al tolerance protein, AtALMT1, which encodes an aluminum-activated root malate transporter, may influence both Al tolerance and P acquisition via changes in root system morphology and architecture. However, trans-acting elements such as transcription factors (TFs) may be the best option for pleiotropic control of multiple abiotic stress genes, due to their small and often multiple binding sequences in the genome. One such example is the C2H2-type zinc finger, AtSTOP1, which is a transcriptional regulator of a number of Arabidopsis Al tolerance genes, including AtMATE and AtALMT1, and has been shown to activate AtALMT1, not only in response to Al but also low soil P. The large WRKY family of transcription factors are also known to affect a broad spectrum of phenotypes, some of which are related to acidic soil abiotic stress responses. Hence, we focus here on signaling proteins such as TFs and protein kinases to identify, from the literature, evidence for unifying regulatory networks controlling Al tolerance, P efficiency and, also possibly drought tolerance. Particular emphasis will be given to modification of root system morphology and architecture, which could be an important physiological “hub” leading to crop adaptation to multiple soil-based abiotic stress factors.