Miracle-dz/UniFAR-FTUs huggingface dataset:
Treatment Planning in Smart Medical: A Sustainable Strategy

With the rapid development of both ubiquitous computing and the mobile internet, big data technology is gradually penetrating into various applications, such as smart traffic, smart city, and smart medical. In particular, smart medical, which is one core part of a smart city, is changing the medical structure. Specifically, it is improving treatment planning for various diseases. Since multiple treatment plans generated from smart medical have their own unique treatment costs, pollution effects, side-effects for patients, and so on, determining a sustainable strategy for treatment planning is becoming very critical in smart medical. From the sustainable point of view, this paper first presents a three-dimensional evaluation model for representing the raw medical data and then proposes a sustainable strategy for treatment planning based on the representation model. Finally, a case study on treatment planning for the group of “computer autism” patients is then presented for demonstrating the feasibility and usability of the proposed strategy.
Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors

Significance Understanding of myelin diseases and development of new treatment options are at least partly hampered by the limited availability of human oligodendrocytes. Induced pluripotent stem cells (iPSC) may be an ideal tool to circumvent this problem; however, rapid and efficient protocols to generate oligodendrocytes from human iPSC are currently lacking. The induction of the transcription factors SOX10, OLIG2, and NKX6.2 in iPSC-derived neural progenitors accelerates oligodendroglial differentiation significantly resulting in up to 70% of O4+ oligodendrocytes within 28 d. These oligodendrocytes myelinate the CNS during development and after demyelination, and are suitable for pharmacological screens and disease modeling. The strategy presented herein will markedly facilitate the studying of human myelin diseases and the development of screening platforms for drug discovery. Rapid and efficient protocols to generate oligodendrocytes (OL) from human induced pluripotent stem cells (iPSC) are currently lacking, but may be a key technology to understand the biology of myelin diseases and to develop treatments for such disorders. Here, we demonstrate that the induction of three transcription factors (SOX10, OLIG2, NKX6.2) in iPSC-derived neural progenitor cells is sufficient to rapidly generate O4+ OL with an efficiency of up to 70% in 28 d and a global gene-expression profile comparable to primary human OL. We further demonstrate that iPSC-derived OL disperse and myelinate the CNS of Mbpshi/shi Rag−/− mice during development and after demyelination, are suitable for in vitro myelination assays, disease modeling, and screening of pharmacological compounds potentially promoting oligodendroglial differentiation. Thus, the strategy presented here to generate OL from iPSC may facilitate the studying of human myelin diseases and the development of high-throughput screening platforms for drug discovery.
Targeting BCL-2 and ABL/LYN in Philadelphia chromosome–positive acute lymphoblastic leukemia

The combination of venetoclax and dasatinib is synergistically effective in treating Philadelphia chromosome–positive ALL. Showing ALL that resistance is futile Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) carries the BCR-ABL translocation; however, despite the existence of drugs that target this translocation, Ph+ALL remains very difficult to treat, and single-drug treatment is usually ineffective. Leonard et al. showed that venetoclax, an apoptosis-promoting drug, is effective in treating this disease and that dasatinib, an inhibitor of BCR-ABL, blocks a common mechanism of resistance to venetoclax. As a result, these two drugs work together synergistically in vitro and in preclinical models, offering a promising approach toward the rational treatment of this disease. Treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies. We demonstrate that the combination of TKIs with venetoclax is highly synergistic in vitro, decreasing cell viability and inducing apoptosis in Ph+ALL. Furthermore, the multikinase inhibitors dasatinib and ponatinib appear to have the added advantage of inducing Lck/Yes novel tyrosine kinase (LYN)–mediated proapoptotic BCL-2–like protein 11 (BIM) expression and inhibiting up-regulation of antiapoptotic myeloid cell leukemia 1 (MCL-1), thereby potentially overcoming the development of venetoclax resistance. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph+ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy compared to either agent alone. These data suggest that the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ALL and should be further evaluated for patient care.
LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells

Significance The molecular mechanism for sealing newly formed nuclear envelopes was unclear until the recent discovery that endosomal sorting complexes required for transport III (ESCRT-III) proteins mediate this process. Cmp7p (CHMP7), in particular, was identified as an early acting factor that recruits other ESCRT-III proteins to the nuclear envelope. A fundamental aspect of the varied roles of ESCRT factors is their recruitment by site-specific adaptors, yet the central question of how the ESCRT machinery is targeted to nuclear membranes has remained outstanding. Our study identifies the inner nuclear membrane protein LEM2 as a key, conserved factor that recruits CHMP7 and downstream ESCRT-III proteins to breaches in the nuclear envelope. Endosomal sorting complexes required for transport III (ESCRT-III) proteins have been implicated in sealing the nuclear envelope in mammals, spindle pole body dynamics in fission yeast, and surveillance of defective nuclear pore complexes in budding yeast. Here, we report that Lem2p (LEM2), a member of the LEM (Lap2-Emerin-Man1) family of inner nuclear membrane proteins, and the ESCRT-II/ESCRT-III hybrid protein Cmp7p (CHMP7), work together to recruit additional ESCRT-III proteins to holes in the nuclear membrane. In Schizosaccharomyces pombe, deletion of the ATPase vps4 leads to severe defects in nuclear morphology and integrity. These phenotypes are suppressed by loss-of-function mutations that arise spontaneously in lem2 or cmp7, implying that these proteins may function upstream in the same pathway. Building on these genetic interactions, we explored the role of LEM2 during nuclear envelope reformation in human cells. We found that CHMP7 and LEM2 enrich at the same region of the chromatin disk periphery during this window of cell division and that CHMP7 can bind directly to the C-terminal domain of LEM2 in vitro. We further found that, during nuclear envelope formation, recruitment of the ESCRT factors CHMP7, CHMP2A, and IST1/CHMP8 all depend on LEM2 in human cells. We conclude that Lem2p/LEM2 is a conserved nuclear site-specific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope.
Remote ischaemic preconditioning suppresses endogenous plasma nitrite during ischaemia–reperfusion: a randomized controlled crossover pilot study

AIM The aim of this article is to test the hypothesis that remote ischaemic preconditioning (RIPC) increases circulating endogenous local and systemic plasma (nitrite) during RIPC and ischaemia-reperfusion (IR) as a potential protective mechanism against ischaemia-reperfusion injury (IRI). METHODS Six healthy male volunteers (mean age 29.5 ± 7.6 years) were randomized in a crossover study to initially receive either RIPC (4 × 5 min cycles) to the left arm, or no RIPC (control), both followed by an ischaemia-reperfusion (IR) sequence (20 min cuff inflation to 200 mmHg, 20 min reperfusion) to the right arm. The volunteers returned at least 7 days later for the alternate intervention. The primary outcome was the effect of RIPC vs. control on local and systemic plasma (nitrite). RESULTS RIPC did not significantly change plasma (nitrite) in either the left or the right arm during the RIPC sequence. However, compared to control, RIPC decreased plasma (nitrite) during the subsequent IR sequence by ~26% (from 118 ± 9 to 87 ± 5 nmol l-1 ) locally in the left arm (P = 0.008) overall, with an independent effect of -58.70 nmol l-1 (95% confidence intervals -116.1 to -1.33) at 15 min reperfusion, and by ~24% (from 109 ± 9 to 83 ± 7 nmol l-1 ) systemically in the right arm (P = 0.03). CONCLUSIONS RIPC had no effect on plasma (nitrite) during the RIPC sequence, but instead decreased plasma (nitrite) by ~25% during IR. This would likely counteract the protective mechanisms of RIPC, and contribute to RIPC's lack of efficacy, as observed in recent clinical trials. A combined approach of RIPC with nitrite administration may be required.
Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols

Mature B-cell non-Hodgkin lymphoma is the most common subtype of non-Hodgkin lymphoma in childhood and adolescence. B-cell non-Hodgkin lymphomas are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell non-Hodgkin lymphoma patients. ID3, TCF3 and CCND3 are potential drivers of Burkitt lymphomagenesis. In the study herein, frequency and clinical relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Münster group. Mutation frequency was 78% (ID3), 13% (TCF3) and 36% (CCND3) in Burkitt lymphoma (including Burkitt leukemia). ID3 and CCND3 mutations were associated with more advanced stages of the disease in MYC rearrangement positive Burkitt lymphoma. In conclusion, ID3-TCF3-CCND3 pathway genes are mutated in more than 88% of MYC-rearranged pediatric B-cell non-Hodgkin lymphoma and the pathway may represent a highly relevant second hit of Burkitt lymphoma pathogenesis, especially in children and adolescents.
The Influence of Safety, Efficacy, and Medical Condition Severity on Natural versus Synthetic Drug Preference

Research indicates that there is a preference for natural v. synthetic products, but the influence of this preference on drug choice in the medical domain is largely unknown. We present 5 studies in which participants were asked to consider a hypothetical situation in which they had a medical issue requiring pharmacological therapy. Participants ( N = 1223) were asked to select a natural, plant-derived, or synthetic drug. In studies 1a and 1b, approximately 79% of participants selected the natural v. synthetic drug, even though the safety and efficacy of the drugs were identical. Furthermore, participants rated the natural drug as safer than the synthetic drug, and as that difference increased, the odds of choosing the natural over synthetic drug increased. In studies 2 and 3, approximately 20% of participants selected the natural drug even when they were informed that it was less safe (study 2) or less effective (study 3) than the synthetic drug. Finally, in study 4, approximately 65% of participants chose a natural over synthetic drug regardless of the severity of a specific medical condition (mild v. severe hypertension), and this choice was predicted by perceived safety and efficacy differences. Overall, these data indicate that there is a bias for natural over synthetic drugs. This bias could have implications for drug choice and usage.
Mathematical modelling for hybrid and nanoparticle imaging

In this thesis we study the mathematical modelling of new experimental imaging techniques. It is divided in two parts. The first one contains work on hybrid imaging techniques based on the interactions betwenn different types of waves. The second part is devoted to the study of the behavior of metallic nanoparticles embedded in electromagnetic fields. The first part contains three chapters in which three different imaging techniques are studied : - magneto-acoustic tomography by Lorentz force, - magneto-acoustic tomography with magnetic induction, - optical coherence tomography based elastography. In the first two chapters we give a mathematical model for the experiments studied as well as explicit reconstruction formulas for the associated inverse problems. We introduce a new direct reconstruction method ("viscosity method") allowing the recovery of the electrical conductivity of the medium. In the third chapter we give an optimisation method to reconstruct the shear modulus of the medium from a displacement field. The second part contains two chapters in which are studied the diffraction of light by small metallic nanoparticles. We study: - plasmonic resonances, - second harmonic generation. The plasmonic resonances are studied within the Maxwell frame. We give an asymptotic formula for the electromagnetic fields within a small volume approximation.
Binge drinking and family history of alcoholism are associated with an altered developmental trajectory of impulsive choice across adolescence

AIMS To test whether binge drinking, the density of familial alcoholism (FHD) and their interaction are associated with an altered developmental trajectory of impulsive choice across adolescence, and whether more life-time drinks are associated with a greater change in impulsive choice across age. DESIGN Alcohol-naive adolescents, with varying degrees of FHD, were recruited as part of an ongoing longitudinal study on adolescent development, and were grouped based on whether they remained non-drinkers (n = 83) or initiated binge drinking (n = 33) during follow-up. During all visits, adolescents completed a monetary delay discounting task to measure impulsive choice. The effects of binge-drinking status, FHD and their interaction on impulsive choice across adolescence were tested. SETTING Developmental Brain Imaging Laboratory, Oregon Health & Science University, Portland, Oregon, USA. PARTICIPANTS A total of 116 healthy male and female adolescents (ages 10-17 years at baseline) completed two to four visits between July 2008 and May 2016. MEASUREMENTS Discounting rates were obtained based on adolescents' preference for immediate or delayed rewards. FHD was based on parent-reported prevalence of alcohol use disorder in the participant's first- and second-degree relatives. Binge-drinking status was determined based on the number of recent binge-drinking episodes. FINDINGS There was a significant interaction effect of binge-drinking status and FHD on impulsive choice across age (b = 1.090, P < 0.05, β = 0.298). In adolescents who remained alcohol-naive, greater FHD was associated with a steeper decrease in discounting rates across adolescence (b = -0.633, P < 0.05, β = -0.173); however, this effect was not present in binge-drinkers. Furthermore, total life-time drinks predicted escalated impulsive choice (b = 0.002, P < 0.05, β = 0.295) in binge-drinking adolescents. CONCLUSIONS A greater degree of familial alcoholism is associated with a steeper decline in impulsive choice across adolescence, but only in those who remain alcohol-naive. Meanwhile, more life-time drinks during adolescence is associated with increases in impulsive choice across age.
Dense Neuron Clustering Explains Connectivity Statistics in Cortical Microcircuits

Local cortical circuits appear highly non-random, but the underlying connectivity rule remains elusive. Here, we analyze experimental data observed in layer 5 of rat neocortex and suggest a model for connectivity from which emerge essential observed non-random features of both wiring and weighting. These features include lognormal distributions of synaptic connection strength, anatomical clustering, and strong correlations between clustering and connection strength. Our model predicts that cortical microcircuits contain large groups of densely connected neurons which we call clusters. We show that such a cluster contains about one fifth of all excitatory neurons of a circuit which are very densely connected with stronger than average synapses. We demonstrate that such clustering plays an important role in the network dynamics, namely, it creates bistable neural spiking in small cortical circuits. Furthermore, introducing local clustering in large-scale networks leads to the emergence of various patterns of persistent local activity in an ongoing network activity. Thus, our results may bridge a gap between anatomical structure and persistent activity observed during working memory and other cognitive processes.
Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site

ABSTRACT Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4+ T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell (P < 0.001) response kinetics and superior ADCC (P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier (P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.
Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition

Pathobiont-associated cachexia in a gnotobiotic model of childhood undernutrition is determined by strain-level interactions within the gut microbiota. Neighbors matter A big unanswered question is what determines the effects of enteropathogen burden in children who are undernourished or at risk for undernutrition. In a new study, Wagner and colleagues introduce collections of sequenced gut bacterial strains cultured from healthy or underweight Bangladeshi children into germfree mice fed diets resembling those consumed by the children. The gut bacterial strains were transplanted with or without nontoxigenic or enterotoxigenic Bacteroides fragilis strains. Addition of enterotoxigenic B. fragilis induced cachexia in the transplanted mice, and altered gene expression and metabolic activity of the transplanted bacterial strains. These effects were mitigated by cocolonization with nontoxigenic B. fragilis, illustrating the influence of intra- and interspecies interactions in determining the impact of an enteropathogen on its host. To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced bacterial strains cultured from the fecal microbiota of two 24-month-old Bangladeshi children: one healthy and the other underweight. The undernourished donor’s bacterial collection contained an enterotoxigenic Bacteroides fragilis strain (ETBF), whereas the healthy donor’s bacterial collection contained two nontoxigenic strains of B. fragilis (NTBF). Analyses of mice harboring either the unmanipulated culture collections or systematically manipulated versions revealed that ETBF was causally related to weight loss in the context of its native community but not when introduced into the healthy donor’s community. This phenotype was transmissible from the dams to their offspring and was associated with derangements in host energy metabolism manifested by impaired tricarboxylic acid cycle activity and decreased acyl–coenzyme A utilization. NTBF reduced ETBF’s expression of its enterotoxin and mitigated the effects of ETBF on the transcriptomes of other healthy donor community members. These results illustrate how intraspecific (ETBF-NTBF) and interspecific interactions influence the effects of harboring B. fragilis.