Miracle-dz/UniFAR-FTUs huggingface dataset:
The nutrient transceptor/PKA pathway functions independently of TOR and responds to leucine and Gcn2 in a TOR-independent manner

Abstract Two nutrient‐controlled signalling pathways, the PKA and TOR pathway, play a major role in nutrient regulation of growth as well as growth‐correlated properties in yeast. The relationship between the two pathways is not well understood. We have used Gap1 and Pho84 transceptor‐mediated activation of trehalase and phosphorylation of fragmented Sch9 as a read‐out for rapid nutrient activation of PKA or TORC1, respectively. We have identified conditions in which L‐citrulline‐induced activation of Sch9 phosphorylation is compromised, but not activation of trehalase: addition of the TORC1 inhibitor, rapamycin and low levels of L‐citrulline. The same disconnection was observed for phosphate activation in phosphate‐starved cells. The leu2 auxotrophic mutation reduces amino acid activation of trehalase, which is counteracted by deletion of GCN2. Both effects were also independent of TORC1. Our results show that rapid activation of the TOR pathway by amino acids is not involved in rapid activation of the PKA pathway and that effects of Gcn2 inactivation as well as leu2 auxotrophy all act independently of the TOR pathway. Hence, rapid nutrient signalling to PKA and TOR in cells arrested by nutrient starvation acts through parallel pathways.
Optimizing pipe-like mashup execution for improving resource utilization

Mashup is usually created by end-users to provide new services by combining data or functionality from multiple sources on the Web. Given that a mashup may have millions of concurrent user access, it is essential to work out a framework to optimize the runtime engine hosting the running of a myriad of pipe-like mashups. According to our analysis, memory is the primary resource to run mashups and we work out a metric named PMT to measure the memory consumption. A scheduling framework is then put forward consisting of mashup decomposition and a PMT-aware scheduling policy, which is named “lazy-start” designed to improve memory utilization. A set of experiments are performed to show the effectiveness and efficiency of this framework.
Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia

Background Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis. Materials and methods Six different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO2 ≈1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately. Results The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin-dependent endocytosis. Conclusion The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO2) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient.
Spatial shaping of motion-data based on motion-copying system using variable temporal scaling

In the field of industrial processing, there are still many parts performed manually. For this problem, a motion-copying system was proposed to put into practical use to create the labor force instead of human. Moreover, motion data that can be processing and reproducing are needed to extend the viability of motion-copying system. In this paper, a temporal compensation method is proposed in order to maintain the reproducibility of saved human motion. Reaction force of loaded motion data is different from saved one when the data is processed by a spatial scaling. Here, a temporal compensation that is based on the variable temporal scaling is introduced in order to make equal reaction force of saved human motion data and that of loaded human motion data. The temporal processing of motion data is based on the first-order hold interpolation. It can process the motion data and solve the resample problem that occurs when discrete motion data is treated at the same time. Validity was confirmed by the experiments.
Stem cell dynamics in muscle regeneration: Insights from live imaging in different animal models

In recent years, live imaging has been adopted to study stem cells in their native environment at cellular resolution. In the skeletal muscle field, this has led to visualising the initial events of muscle repair in mouse, and the entire regenerative response in zebrafish. Here, we review recent discoveries in this field obtained from live imaging studies. Tracking of tissue resident stem cells, the satellite cells, following injury has captured the morphogenetic dynamics of stem/progenitor cells as they facilitate repair. Asymmetric satellite cell division generated a clonogenic progenitor pool, providing in vivo validation for this mechanism. Furthermore, there is an emerging role of stem/progenitor cell guidance at the injury site by cellular protrusions. This review concludes that live imaging is a critical tool for discovering the distinct processes that occur during regeneration, emphasising the importance of imaging in diverse animal models to capture the entire scope of stem cell functions.
Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells

The cytoplasmic tyrosine kinase ABL exerts positive or negative effects in solid tumours according to the cellular context, thus functioning as a “switch modulator”. The therapeutic effects of drugs targeting a set of signals encompassing ABL have been explored in several solid tumours. However, the net contribution of ABL inhibition by these agents remains elusive as these drugs also act on other signalling components. Here, using glioblastoma (GBM) as a cellular paradigm, we report that ABL inhibition exacerbates mesenchymal features as highlighted by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Cells with permanent ABL inhibition exhibit enhanced motility and invasive capabilities, while proliferation and tumorigenic properties are reduced. Intriguingly, permanent ABL inhibition also interferes with GBM neurosphere formation and with expression of stemness markers in sphere-cultured GBM cells. Furthermore, we show that the molecular and biological characteristics of GBM cells with impaired ABL are reversible by restoring ABL levels, thus uncovering a remarkable plasticity of GBM cells to ABL threshold. A phospho-signalling screen revealed that loss of tumorigenic and self-renewal properties in GBM cells under permanent ABL inhibition coincide with drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Our findings identify ABL as a crucial player for migration, invasion, proliferation, tumorigenic, and stem-cell like properties of GBM cells. Taken together, this work supports the notion that the oncogenic role of ABL in GBM cells is associated with its capability to coordinate a signalling setting that determines tumorigenic and stem-cell like properties.
Alternative Splicing in Neurogenesis and Brain Development

Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.
miR-424-5p promotes proliferation of gastric cancer by targeting Smad3 through TGF-β signaling pathway

MiRNAs have been reported to regulate gene expression and be associated with cancer progression. Recently, miR-424-5p was reported to play important role in a variety of tumors. However, the role and molecular mechanisms of miR-424-5p in GC (gastric cancer) remains largely unknown. In this study, we aimed to explore the role of miR-424-5p in GC. QRT-PCR was used to determine the expression levels of miR-424-5p and Smad3. CCK8 assay, plate clone assay and cell cycle assay were used to measure the effects of miR-424-5p on GC cell proliferation. Luciferase reporter assay and western blotting were used to prove that Smad3 was one of the direct targets of miR-424-5p. Tumorigenesis assay was used to investigate the role of miR-424-5p in tumor growth of GC cells in vivo. We found that miR-424-5p was up-regulated in GC tissues and cells. Over-expression of miR-424-5p could promote the proliferation of GC cells. In addition, luciferase reporter assay and western blotting assay revealed that Smad3 was a direct target of miR-424-5p. Over-expression of Smad3 could partially reverse the effects of miR-424-5p on GC cell proliferation. Our study further revealed that miR-424-5p could inhibit TGF-β signaling pathway by Smad3.
Ki-67 evaluation in breast cancer: The daily diagnostic practice

Context: Breast cancer is the most common malignancy in females. It is routinely classified according to the WHO histological typing. However, there is also a molecular classification of breast cancer which is routinely substituted with surrogate subtypes based on expression of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors and proliferation index (PI). PI is defined as the percentage of Ki-67-positive cells among overall cell population. The method commonly applied by pathologists to determine PI is visual scoring of the sample. Strict recommendations for PI assessment do not exist. Thus, the mode of PI evaluation differs significantly between pathologists. Aims: The aim of our study was to evaluate the daily approach to defining the PI. Settings and Design: Four practicing nonscholar pathologists were asked to evaluate PI in cases of invasive breast carcinoma. Subjects and Methods: The study was performed on a group of 98 patients diagnosed with invasive breast carcinoma. Immunohistochemical reaction was performed with monoclonal antibody against human Ki-67 antigen using Ventana BenchMark XT. Statistical Analysis Used: Results were compared using Pearson's and Spearman's rank correlation coefficients and Fleiss and Cohen's kappa values. Results: Statistical analysis showed pairwise Pearson's coefficients ranging between 0.77 and 0.84 (P < 0.001) and Spearman's rank correlation coefficients ranging between 0.68 and 0.83 (P < 0.001). The Fleiss kappa value for the 14% cutoff point was 0.58 whereas for the 20% cutoff point was 0.60. The pairwise Cohen's kappa values ranged from 0.45 to 0.69 for the 14% cutoff point and 0.53 to 0.67 for the 20% cutoff point. Friedman's rank ANOVA test showed significant differences among the four pathologists (P < 0.001). Conclusions: Our study shows a significant difference in results and methods of evaluation of PI between pathologists.
ADAPTIVE CONTROL WITH ACTUATOR DYNAMICS

Although model reference adaptive control has been used in numerous applications to achieve system performance without excessive reliance on dynamical system models, the presence of actuator dynamics can seriously limit the stability and the achievable performance of adaptive controllers. In this paper, an linear matrix inequalities-based hedging approach is developed and evaluated for model reference adaptive control of uncertain dynamical systems in the presence of actuator dynamics. The hedging method modifies the ideal reference model dynamics in order to allow correct adaptation that does not get affected due to the presence of actuator dynamics. Specifically, we first generalize the hedging approach to cover cases in which actuator output and is known and unknown. We next show the stability of the closed-loop dynamical system using tools from Lyapunov stability and linear matrix inequalities. Finally, an illustrative numerical example is provided to demonstrate the efficacy of the proposed linear matrix-inequalities-based hedging approach to model reference adaptive control.
The recollective qualities of adolescents’ and adults’ narratives about a long-ago tornado

ABSTRACT The recollective qualities of autobiographical memory are thought to develop over the course of the first two decades of life. We used a 9-year follow-up test of recall of a devastating tornado and of non-tornado-related events from before and after the storm, to compare the recollective qualities of adolescents’ (n = 20, ages 11 years, 11 months to 20 years, 8 months) and adults’ (n = 14) autobiographical memories. At the time of the tornado, half of the adolescents had been younger than age 6. Nine years after the event, all participants provided evidence that they recall the event of the tornado. Adults also had high levels of recall of the non-tornado-related events. Adolescents recalled proportionally fewer non-tornado-related events; adolescents younger than 6 at the time of the events recalled the fewest non-tornado-related events. Relative to adolescents, adults produced longer narratives. With narrative length controlled, there were few differences in the recollective qualities of adolescents’ and adults’ narrative reports, especially in the case of the tornado; the recollective qualities were stronger among adolescents older at the time of the events. Overall, participants in both age groups provided evidence of the qualities of recollection that are characteristic of autobiographical memory.
Compiled Communication for All-Optical TDM Networks

While all-optical networks offer large bandwidth for transferring data, the control mechanisms to dynamically establish all-optical paths incur large overhead. In this paper, we consider adapting all-optical multiplexed networks in multiprocessor or multicomputer environment by using compiled communication as an alternative to dynamic network control. Compiled communication eliminates the runtime overhead by managing network resources statically. Thus, it can employ complex off-line algorithms to improve resource utilization. We studied several off-line connection scheduling algorithms for minimizing the multiplexing degree required to satisfy communication requests. The performance of compiled communication is evaluated and compared with that of dynmaically controlled communication for static communications in a number of application programs. Our results show that compiled communication out-performs dynamic communication to a large degree. Since most of the communication patterns in scientific applications are static, we conclude that compiled communication is an effective mechanism for all-optical networks in multiprocessor environments.
Relationship between Oral Glucose Tolerance Test Characteristics and Adverse Pregnancy Outcomes among Women with Gestational Diabetes Mellitus

Background: Hyperglycemia is associated with adverse pregnancy outcomes. However, the relationships between them remain ambiguous. This study aimed to analyze the effect of different oral glucose tolerance test (OGTT) results on adverse perinatal outcomes. Methods: This retrospective cohort study included data from 15 hospitals in Beijing from June 20, 2013 to November 30, 2013. Women with gestational diabetes mellitus (GDM) were categorized according to the number and distribution of abnormal OGTT values, and the characteristics of adverse pregnancy outcomes were evaluated. Chi-square test and logistic regression analysis were used to determine the associations. Results: In total, 14,741 pregnant women were included in the study population, 2927 (19.86%) of whom had GDM. As the number of hyperglycemic values in the OGTT increased, the risk of cesarean delivery, preterm births, large-for-gestational age (LGA), macrosomia, and neonatal complications significantly increased. Fasting hyperglycemia had clear associations with macrosomia (odds ratios [ORs]:1.84, 95% confidence intervals [CIs]: 1.39–2.42, P < 0.001), LGA (OR: 1.70, 95% CI: 1.29–2.25, P < 0.001), and cesarean delivery (OR: 1.33, 95% CI: 1.15–1.55, P < 0.001). The associations were stronger as fasting glucose increased. GDM diagnosed by hyperglycemia at OGTT-2 h was more likely to lead to preterm birth (OR: 1.50, 95% CI: 1.11–2.03, P < 0.01). Conclusions: Various characteristics of OGTTs are associated with different adverse outcomes. A careful reconsideration of GDM with hierarchical and individualized management according to OGTT characteristics is needed.
Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial

Importance In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)–reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown. Objective To assess the safety and clinical efficacy of achieving a very low (<30 mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial. Design, Setting, and Participants This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years’ median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017. Main Outcomes and Measures Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial. Results Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater. Conclusions and Relevance Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels. Trial Registration clinicaltrials.gov Identifier: NCT00202878
Molecular characterization of the recombinant protein RmLTI-BmCG-LTB: Protective immunity against Rhipicephalus (Boophilus) microplus

The bovine tick Rhipicephalus (Boophilus) microplus is found in several tropical and subtropical regions of the world. This parasite transmits pathogens that cause disease, such as babesiosis (Babesia bovis and B. bigemina) and anaplasmosis (Anaplasma marginale). Tick infestations cause enormous livestock losses, and controlling tick infestations and the transmission of tick-borne diseases remains a challenge for the livestock industry. Because the currently available commercial vaccines offer only partial protection against R. (B.) microplus, there is a need for more efficient vaccines. Several recombinant antigens have been evaluated using different immunization strategies, and they show great promise. This work describes the construction and immunological characterization of a multi-antigen chimera composed of two R. (B.) microplus antigens (RmLTI and BmCG) and one Escherichia coli antigen (B subunit, LTB). The immunogenic regions of each antigen were selected and combined to encode a single polypeptide. The gene was cloned and expressed in E. coli. For all of the experiments, two groups (treated and control) of four Angus heifers (3–6 months old) were used. The inoculation was performed via intramuscular injection with 200 μg of purified recombinant chimeric protein and adjuvated. The chimeric protein was recognized by specific antibodies against each subunit and by sera from cattle inoculated with the chimera. Immunization of RmLTI-BmCG-LTB cattle reduced the number of adult female ticks by 6.29% and vaccination of cattle with the chimeric antigen provided 55.6% efficacy against R. (B.) microplus infestation. The results of this study indicate that the novel chimeric protein is a potential candidate for the future development of a more effective vaccine against R. (B.) microplus.