Miracle-dz/UniFAR-FTUs huggingface dataset:
Dihydroartemisinin increases gemcitabine therapeutic efficacy in ovarian cancer by inducing reactive oxygen species

Ovarian cancer is the major cause of death in women gynecological malignancy and gemcitabine (GEM) is commonly used in related chemotherapy. However, more than 90% GEM is catalyzed into an inactive metabolite 2′‐deoxy‐2′,2′‐difluorouridine by stromal and cellular cytidine deaminase (CDA). Dihydroartemisinin (DHA), which possesses an intramolecular endoperoxide bridge, could be activated by heme or ferrous iron to produce reactive oxygen species (ROS). The excess ROS generation will excite expression of heme oxygenase‐1 and suppress CDA expression. Under low CDA expression, the inactivation of GEM is decreased in turn to exert excellent therapeutic efficiency. Herein, we first studied the ROS generation by DHA in vitro with A2780 cells by means of flow cytometry and confocal laser scanning microscopy. Furthermore, cytotoxicity assay in vitro showed that DHA + GEM had synergistic effect, with molar ratio of DHA and GEM at 10. Eventually, in A2780 ovarian cancer xenograft tumor model, DHA + GEM exhibited significant antitumor efficiency with lower blood toxicity than GEM alone. Noteworthy, the combination treatment group completely eliminated the tumors on day 14.
Bacterial Noncoding RNAs Excised from within Protein-Coding Transcripts

Bacteria and archaea utilize regulatory small noncoding RNAs (ncRNAs) to control the expression of specific genetic programs. These ncRNAs are almost exclusively encoded within intergenic regions and are independently transcribed. Here, we report on a large set ncRNAs that are “carved out” from within the protein-coding regions of Escherichia coli mRNAs by cellular RNases. These protected mRNA fragments fold into energetically stable RNA structures, reminiscent of those of intergenic regulatory ncRNAs. In addition, a subset of these ncRNAs coprecipitate with the major ncRNA chaperones Hfq and ProQ and display evolutionarily conserved sequences and conserved expression patterns between different bacterial species. Our data suggest that protein-coding genes can potentially act as a reservoir of regulatory ncRNAs. ABSTRACT Prokaryotic genomes encode a plethora of small noncoding RNAs (ncRNAs) that fine-tune the expression of specific genes. The vast majority of known bacterial ncRNAs are encoded from within intergenic regions, where their expression is controlled by promoter and terminator elements, similarly to protein-coding genes. In addition, recent studies have shown that functional ncRNAs can also be derived from gene 3′ untranslated regions (3′UTRs) via an alternative biogenesis pathway, in which the ncRNA segment is separated from the mRNA via RNase cleavage. Here, we report the detection of a large set of decay-generated noncoding RNAs (decRNAs), many of which are completely embedded within protein-coding mRNA regions rather than in the UTRs. We show that these decRNAs are “carved out” of the mRNA through the action of RNase E and that they are predicted to fold into highly stable RNA structures, similar to those of known ncRNAs. A subset of these decRNAs is predicted to interact with Hfq or ProQ or both, which act as ncRNA chaperones, and some decRNAs display evolutionarily conserved sequences and conserved expression patterns between different species. These results suggest that mRNA protein-coding regions may harbor a large set of potentially functional small RNAs. IMPORTANCE Bacteria and archaea utilize regulatory small noncoding RNAs (ncRNAs) to control the expression of specific genetic programs. These ncRNAs are almost exclusively encoded within intergenic regions and are independently transcribed. Here, we report on a large set ncRNAs that are “carved out” from within the protein-coding regions of Escherichia coli mRNAs by cellular RNases. These protected mRNA fragments fold into energetically stable RNA structures, reminiscent of those of intergenic regulatory ncRNAs. In addition, a subset of these ncRNAs coprecipitate with the major ncRNA chaperones Hfq and ProQ and display evolutionarily conserved sequences and conserved expression patterns between different bacterial species. Our data suggest that protein-coding genes can potentially act as a reservoir of regulatory ncRNAs.
Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

Covalent EGFR family inhibitors bind to and induce the degradation of the pseudokinase TRIB2 to kill cancer cells. Targeting pseudokinases with kinase inhibitors Pseudokinases are structurally similar to kinases but lack catalytic activity; instead, pseudokinases typically function as scaffolds, often promoting the degradation of substrate proteins by bringing them into close proximity with ubiquitin ligases. Two studies explored the structures and protein interactions of the pseudokinases TRIB1 (Jamieson et al.) and TRIB2 (Foulkes et al.). Their findings reveal new insights into the structural regulation of TRIB proteins and show that these proteins, which are implicated in leukemia and other cancers, can bind to clinically approved kinase inhibitors. Binding by these drugs caused structural changes in the TRIB proteins that deprotected them from degradation upon interacting with ubiquitin ligases, indicating that these drugs might be repurposed or redesigned to perturb the function of TRIBs in cancer patients. A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors and blood cancers and therefore is of interest as a therapeutic target. The unusual TRIB2 pseudokinase domain contains a unique cysteine-rich C-helix and interacts with a conserved peptide motif in its own carboxyl-terminal tail, which also supports its interaction with E3 ubiquitin ligases. We found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members. Using a thermal shift assay, we discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS) and used a drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro. TRIB2 destabilizing agents, including the covalent drug afatinib, led to rapid TRIB2 degradation in human AML cancer cells, eliciting tractable effects on signaling and survival. Our data reveal new drug leads for the development of TRIB2-degrading compounds, which will also be invaluable for unraveling the cellular mechanisms of TRIB2-based signaling. Our study highlights that small molecule–induced protein down-regulation through drug “off-targets” might be relevant for other inhibitors that serendipitously target pseudokinases.
A dissimilarity Jensen–Shannon divergence measure for intuitionistic fuzzy sets

The need of suitable divergence measures arise as they play an important role in discrimination of two probability distributions. The present communication is devoted to the introduction of one such divergence measure using Jensen inequality and Shannon entropy and its validation. Also, a new dissimilarity measure based on the proposed divergence measure is introduced. Besides establishing validation, some of its major properties are also studied. Further, a new multiple attribute decision making method based on a proposed dissimilarity measure is introduced and is thoroughly explained with the help of an illustrated example. The paper is summed up with an application of the proposed dissimilarity measure in pattern recognition.
Liver Resection for Hepatic Metastases from Soft Tissue Sarcoma: A Nationwide Study

Background: This study aims to evaluate the feasibility and safety of resection of sarcoma liver metastases, and to identify possible prognostic factors for long-term survival. Methods: All patients who underwent resection of liver metastases of sarcoma in the Netherlands from 1998 to 2014 were included. Study data was retrospectively collected from patient files. Survival rates were calculated using Kaplan-Meier survival analysis. Results: Some 38 patients treated in 16 hospitals were included (15 male, 23 female). The median age was 57 years (37–80 years). The most common histological subtype was leiomyosarcoma (63%). The predominant site of primary tumour was the abdomen (59%). R0 resection was achieved in 16 patients. Mortality was 3 and 16% of included patients had 1 or more complications. The median follow-up period was 18 months (range 1–161). After liver resection, 1-, 3-, and 5-year survival were 88, 54, and 42% respectively. Median overall survival was 46 months (1–161 months). One- and three-year progression-free survival (PFS) after liver resection were 54 and 19% respectively. Median PFS was 16 months (1–61 months). Conclusions: Liver surgery for sarcoma metastases is safe and leads to a relatively good survival. The choice for surgical treatment should always be discussed in a multidisciplinary sarcoma and liver team.
In Vivo Measurement of Middle Ear Pressure Changes during Balloon Eustachian Tuboplasty

Background Balloon Eustachian tuboplasty (BET) is known as a treatment for chronic obstructive Eustachian tube dysfunction (OETD). The precise mechanism of action is not fully understood. Observations in sheep cadavers and human cadavers have shown specific middle ear pressure changes related to BET. Methods In this prospective study using a microfibre optical pressure sensor, pressure changes during BET were for the first time monitored transtympanically in five normal human middle ears in vivo. Results Middle ear pressure changes during 21 BETs consisted of five stages (insertion, inflation, deflation, withdrawal, and recovery). The highest pressure change occurred in most of the cases during the withdrawal of the balloon catheter. Withdrawal pressure yielded a mean middle ear pressure of 4.76 mmHg (61.89 daPa) with a maximum of 13.88 mmHg (179.55 daPa). Pressure amplitudes capable of causing barotrauma to ear structures were not detected. Internal carotid artery dehiscences were detected as causative of sinusidual pressure changes. Conclusion The middle ear pressure changes detected in vivo during BET can be attributed to the balloon inflation. Further human studies with patients affected by OETD are necessary to gain more insight into the mechanism of action of BET to clarify a possible pressure related second mechanism of action of BET.
Single-Machine and Parallel-Machine Parallel-Batching Scheduling Considering Deteriorating Jobs, Various Group, and Time-Dependent Setup Time

This paper studies a set of novel integrated scheduling problems by taking into account the combinatorial features of various groups, parallel-batching, deteriorating jobs, and time-dependent setup time simultaneously under the settings of both single-machine and parallel-machine, and the objective of the studied problems is to minimize the makespan. In order to solve the single-machine scheduling problem, we first investigate the structural properties on jobs sequencing, jobs batching, and batches sequencing for the optimal solution, and then develop a scheduling rule. Moreover, for solving the parallel-machine scheduling problem, we exploit the optimal structural properties and batching rule, and propose a novel hybrid AIS-VNS algorithm incorporating Artificial Immune System algorithm (AIS) and Variable Neighbourhood Search (VNS). Extensive computational experiments are conducted to evaluate the performance of the proposed AIS-VNS algorithm, and comparison results show that the proposed algorithm performs quite well in terms of both efficiency and solution quality.
Atypical Pharmacodynamic Properties and Metabolic Profile of the Abused Synthetic Cannabinoid AB-PINACA: Potential Contribution to Pronounced Adverse Effects Relative to Δ9-THC

Recreational use of marijuana is associated with few adverse effects, but abuse of synthetic cannabinoids (SCBs) can result in anxiety, psychosis, chest pain, seizures and death. To potentially explain higher toxicity associated with SCB use, we hypothesized that AB-PINACA, a common second generation SCB, exhibits atypical pharmacodynamic properties at CB1 cannabinoid receptors (CB1Rs) and/or a distinct metabolic profile when compared to Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive cannabinoid present in marijuana. Liquid chromatography tandem mass spectrometry (LC/MS) identified AB-PINACA and monohydroxy metabolite(s) as primary phase I metabolites (4OH-AB-PINACA and/or 5OH-AB-PINACA) in human urine and serum obtained from forensic samples. In vitro experiments demonstrated that when compared to Δ9-THC, AB-PINACA exhibits similar affinity for CB1Rs, but greater efficacy for G-protein activation and higher potency for adenylyl cyclase inhibition. Chronic treatment with AB-PINACA also results in greater desensitization of CB1Rs (e.g., tolerance) than Δ9-THC. Importantly, monohydroxy metabolites of AB-PINACA retain affinity and full agonist activity at CB1Rs. Incubation of 4OH-AB-PINACA and 5OH-AB-PINACA with human liver microsomes (HLMs) results in limited glucuronide formation when compared to that of JWH-018-M2, a major monohydroxylated metabolite of the first generation SCB JWH-018. Finally, AB-PINACA and 4OH-AB-PINACA are active in vivo, producing CB1R-mediated hypothermia in mice. Taken collectively, the atypical pharmacodynamic properties of AB-PINACA at CB1Rs relative to Δ9-THC (e.g., higher potency/efficacy and greater production of desensitization), coupled with an unusual metabolic profile (e.g., production of metabolically stable active phase I metabolites) may contribute to the pronounced adverse effects observed with abuse of this SCB compared to marijuana.
Usability Study of Two In-Vehicle Information Systems Using Finger Tracking and Facial Expression Recognition Technology

ABSTRACT In this study, an experiment is conducted to compare the usability of two in-vehicle information systems (IVISs), namely, the newly developed “Calink” and the commercially available “Carlife. ” The interface style of Calink is similar to that of smartphones, while that of Carlife is similar to the interface style of traditional IVISs. This study establishes a usability index system based on the International Organization for Standardization’s definition of usability, and each evaluation index has a corresponding subjective or objective measurement method. Five new indexes, namely, angular velocity, velocity, turn angle, distance of finger movements, and valence and arousal value of facial expression, are used in the usability test. Participants are asked to complete three tasks (namely, music, telephone, and navigation) to test the usability of the IVIS interface. The results show that in the case of most of the indexes Calink performs better than Carlife. Finally, the consistency of subjective experience and objective performance is discussed.
Size agnostic change point detection framework for evolving networks

Changes in the structure of observed social and complex networks can indicate a significant underlying change in an organization, or reflect the response of the network to an external event. Automatic detection of change points in evolving networks is rudimentary to the research and the understanding of the effect of such events on networks. Here we present an easy-to-implement and fast framework for change point detection in evolving temporal networks. Our method is size agnostic, and does not require either prior knowledge about the network’s size and structure, nor does it require obtaining historical information or nodal identities over time. We tested it over both synthetic data derived from dynamic models and two real datasets: Enron email exchange and AskUbuntu forum. Our framework succeeds with both precision and recall and outperforms previous solutions.
Lifecycle management in government-driven open source projects – practical framework

In many parts of the world, public sector organizations are increasingly interested in collaborating across organizational (and even national) boundaries to develop software solutions under an open licence. However, without sound lifecycle management practices, the full benefits of open collaboration are not achieved and projects fail to achieve sustained success. This paper introduces a lifecycle management model and framework for government-driven open-source projects and reports about its use in a real-life case study. Our focus is on lifecycle management activities which take place between deployment and end-of-life. The framework was developed iteratively through a series of focus group discussions with representatives of public sector organizations. After the framework had been taken into use in our real-life case project, individual qualitative interviews were conducted to collect experiences on its benefits and weaknesses. According to the initial evidence, the deployment of the framework seems to have brought concrete benefits to the project, e.g. by contributing positively to community growth, software quality and inter-organizational learning.
Effect of low glycemic index and food exchange system diets on metabolic syndrome components in Saudi medical students

Metabolic Syndrome (MetS), a condition that manifests as a set of metabolic risk factors, is considered a global epidemic. The prevalence of MetS in Saudi Arabia has grown rapidly over the past decade. The aim of the present study was to determine the effect of Low Glycemic Index (LGI) and Food Exchange System (FES) diets on MetS components in patients with MetS in the Saudi population. We selected 69 subjects and divided them into 3 groups: LGI diet, FES diet, and control. Each group consisted of 23 subjects (12 women). Both treatment groups followed diet and physical activity regimens for 5 days per week for 6 weeks. Serum samples were taken pre- and post-treatment in all 3 groups and used for biochemical analyses. The results of study found significant difference in post-treatment values of hypertension i.e. SBP (p=0.007), DBP (p=0.01), Fasting Blood Glucose (FBG) (p=0.005), Triglycerides (TG) (p=0.0006) and Total Cholesterol (TC) (p=0.0006). There were no significant differences between groups in waist circumference (p=0.23) and high density lipoprotein (p=0.12). When the data from men and women were examined separately, we found significant differences between groups in the pretreatment values of TC (p=0.01) and the post-treatment values of FBG (p=0.65) and TG (p=0.99). We conclude that the LGI and FES diets are beneficial for patients with MetS, with a more potent impact produced by the LGI diet. We recommend implementing nutritional awareness and motivational counselling programs to help to improve the health of people with MetS in the Saudi population.
Multinationals do not export jobs, and other related results

We develop a simple model of multinational firms, in which firms engage in production abroad to take advantage of cheap labour. There are gains from multinational firms beyond the standard gains from trade. The model makes two empirically testable predictions. First, firms with more foreign employment also have more domestic employment; multinationals are not net exporters of jobs. Second, the expansion of multinational activity will increase the overall size of the firm. We find that both predictions hold empirically, using a sample of the largest multinational firms. In addition, the presence of multinational firms raises welfare relative to when they are absent, although the proportional gain is not large.
Biochemical composition of some Egyptian seaweeds with potent nutritive and antioxidant properties

The present study investigated the biochemical composition of three seaweeds; Ulva fasciata (Chlorophyta), Sargassum linifolium (Phaeophyta) and Corallina officinalis (Rhodophyta). Total chlorophyll content was maximum in U. fasciata (34.06mg/g dry wt.) while carotenoid content was the highest in C. officinalis (3.8 mg/g dry wt.). The uppermost level of carbohydrates was (27.98% of dry wt.) in C. officinalis and proteins were maximum (14.89%) in S. linifolium. Aspartic, glutamic, alanine, leucine and proline were common amino acids in the three tested species. The polyunsaturated ω6 and ω3 essential fatty acids were recorded in S. linifolium (3.28%) and in U. fasciata (3.18%). The results showed that U. fasciata contained the highest amounts of lipids (2.96%), phenols (11.95mgGA/g dry wt.), flavonoid (7.04 mgCA/g dry wt.) and ascorbic acid (4.11mg/100g), respectively. β-Carotene was maximum (3940.12 IU/100 g) in C. officinalis. DPPH antioxidant activities were the highest in U. fasciata (81.3%) followed by S. linifolium (79.8%) then C. officinalis (72.6%). Among the 12 analyzed minerals, most of them were high in S. linifolium in which ion quotient ratio was the smallest (0.343). Since these algal species are common in the Egyptian coastal waters, their biochemical composition and antioxidant activities made them promising candidates for nutritional, pharmaceutical and medicinal applications.
A bottom-up view of the biological pump: Modeling source funnels above ocean sediment traps

The sinking of particles that make up the biological pump is not vertical but nearly horizontal. This means that the locations where the particles are formed may be distant from their collection in a sediment trap. This has led to the development of the concept of the statistical funnel to describe the spatial–temporal sampling characteristics of a sediment trap. Statistical funnels can be used to quantify the source region in the upper ocean where collected particles were created (source funnels) or the location of the collected particles during that deployment (collection funnels). Here, we characterize statistical funnels for neutrally buoyant, surface-tethered and deep-ocean moored trap deployments conducted just north of Hawaii in the Pacific Ocean. Three-dimensional realizations of the synoptic velocity field, created using satellite altimeter and shipboard acoustic Doppler current profiler data, are used to advect sinking particles back to their source for sinking velocities of 50–200m per day. Estimated sourceand collection-funnel characteristics for the 5-day collections made by neutrally buoyant and surface-tethered traps are similar with typical scales of several km to several 10s of km. Deep-moored traps have daily source-funnel locations that can be many 100s of km distant from the trap and have longterm containment radii that range from 140 to 340 km depending upon sinking rate. We assess the importance of particle source regions using satellite estimates of chlorophyll concentration as a surrogate for the spatial distribution of particle export. Our analysis points to the need to diagnose water-parcel trajectories and particle sinking rates in the interpretation of sinking-particle fluxes from moored or freely drifting sediment traps, especially for regions where there are significant horizontal gradients in the export flux. But whence come the little siliceous and calcareous shellsy[brought up] from the depth of over miles? Did they live in the surface waters immediately above? Or is their habitat in some remote part of the sea, whence, at their death, the currents were set forth as pallbearers, with the command to deposit the dead corpses where the plummet found them? (Maury, 1858). r 2007 Elsevier Ltd. All rights reserved.