Miracle-dz/UniFAR-FTUs huggingface dataset:
The PPARγ agonist rosiglitazone sensitizes the BH3 mimetic (−)‐gossypol to induce apoptosis in cancer cells with high level of Bcl‐2

The BH3 mimetic (−)‐gossypol (−)‐G has shown promising efficacy to kill several kinds of cancer cells or potentiate current chemotherapeutics. But it induces limited apoptosis in cancer cells with high level of Bcl‐2. The nuclear receptor PPARγ and its agonist rosiglitazone can suppress various malignancies. More importantly, rosiglitazone is able to enhance the anti‐tumor effects of chemotherapy drugs such as carboplatin and tyrosine kinase inhibitors. In this study, we for the first time demonstrated that rosiglitazone could sensitize (−)‐G to induce apoptosis in cancer cells with high level of Bcl‐2. Furthermore, we found that (−)‐G increased the mRNA level and protein stability of Mcl‐1, which weakened the pro‐apoptotic effect of (−)‐G. Rosiglitazone attenuated the (−)‐G‐induced Mcl‐1 stability through decreasing JNK phosphorylation. Additionally, rosiglitazone upregulated dual‐specificity phosphatase 16 (DUSP16), leading to a reduction of (−)‐G‐triggered JNK phosphorylation. Animal experiments showed that rosiglitazone could sensitize (−)‐G to repress the growth of cancer cells with high level of Bcl‐2 in vivo. Taken together, our results suggest that the PPARγ agonists may enhance the therapeutic effect of BH3 mimetics in cancers with high level of Bcl‐2 through regulating the DUSP16/JNK/Mcl‐1 singling pathway. This study may provide novel insights into the cancer therapeutics based on the combination of PPARγ agonists and BH3 mimetics.
Non-equilibrium repressor binding kinetics link DNA damage dose to transcriptional timing within the SOS gene network

Biochemical pathways are often genetically encoded as simple transcription regulation networks, where one transcription factor regulates the expression of multiple genes in a pathway. The relative timing of each promoter’s activation and shut-off within the network can impact physiology. In the DNA damage repair pathway (known as the SOS response) of Escherichia coli, approximately 40 genes are regulated by the LexA repressor. After a DNA damaging event, LexA degradation triggers SOS gene transcription, which is temporally separated into subsets of ‘early’, ‘middle’, and ‘late’ genes. Although this feature plays an important role in regulating the SOS response, both the range of this separation and its underlying mechanism are not experimentally defined. Here we show that, at low doses of DNA damage, the timing of promoter activities is not separated. Instead, timing differences only emerge at higher levels of DNA damage and increase as a function of DNA damage dose. To understand mechanism, we derived a series of synthetic SOS gene promoters which vary in LexA-operator binding kinetics, but are otherwise identical, and then studied their activity over a large dose-range of DNA damage. In distinction to established models based on rapid equilibrium assumptions, the data best fit a kinetic model of repressor occupancy at promoters, where the drop in cellular LexA levels associated with higher doses of DNA damage leads to non-equilibrium binding kinetics of LexA at operators. Operators with slow LexA binding kinetics achieve their minimal occupancy state at later times than operators with fast binding kinetics, resulting in a time separation of peak promoter activity between genes. These data provide insight into this remarkable feature of the SOS pathway by demonstrating how a single transcription factor can be employed to control the relative timing of each gene’s transcription as a function of stimulus dose.
A Systematic Review of Zosteriform Rash in Breast Cancer Patients: An Objective Proof of Flap Reinnervation and a Management Algorithm

Background Zosteriform rash in cancer patients provides objective clues to the process of reinnervation of the reconstructed breast. This rash should also raise suspicion for metastasis, which can be confused with herpes zoster. Objectives The aims of this study were to explain the reconstruction flap sensory reinnervation mechanism based on the clinical findings and provide a diagnostic and management algorithm of zosteriform rash in breast cancer patients. Methods On November 15, 2017, we conducted a search of published articles in MEDLINE and Cochrane databases. All the articles describing a zosteriform rash in a patient with a history of breast cancer were included in this review. Results Eleven articles from the literature and 1 case from our practice were selected for inclusion in this systematic review. Five patients had a breast reconstruction with a flap. The flap skin was affected by the rash in 4 of these patients, providing an objective proof of the reinnervation of the reconstructed breast. In 6 patients, the presentation was typical, and the diagnosis of herpes zoster was made without additional diagnostic testing. In 4 cases, the eruption was atypical, and a biopsy was done to confirm the diagnosis of a cancer metastasis. In 2 patients, the rash was multidermatomal, and a polymerase chain reaction was done to confirm the diagnosis of disseminated herpes zoster. Conclusions Zoster reactivation in breast reconstructed patients is an objective proof of the reinnervation of the skin flap. Moreover, zosteriform rash in cancer patients should raise suspicion for metastasis, which can be confused with herpes zoster.
The Drosophila Hox gene Ultrabithorax controls appendage shape by regulating extracellular matrix dynamics

ABSTRACT Although the specific form of an organ is frequently important for its function, the mechanisms underlying organ shape are largely unknown. In Drosophila, the wings and halteres, homologous appendages of the second and third thoracic segments, respectively, bear different forms: wings are flat, whereas halteres are globular, and yet both characteristic shapes are essential for a normal flight. The Hox gene Ultrabithorax (Ubx) governs the difference between wing and haltere development, but how Ubx function in the appendages prevents or allows flat or globular shapes is unknown. Here, we show that Ubx downregulates Matrix metalloproteinase 1 (Mmp1) expression in the haltere pouch at early pupal stage, which in turn prevents the rapid clearance of Collagen IV compared with the wing disc. This difference is instrumental in determining cell shape changes, expansion of the disc and apposition of dorsal and ventral layers, all of these phenotypic traits being characteristic of wing pouch development. Our results suggest that Ubx regulates organ shape by controlling Mmp1 expression, and the extent and timing of extracellular matrix degradation. Summary: The Drosophila Hox gene Ultrabithorax, which distinguishes halteres from wings, downregulates Matrix metalloproteinase 1 expression to maintain ECM protein levels and so form the haltere globular shape instead of the flat wing.
Crystal structures of the kinase domain of PpkA, a key regulatory component of T6SS, reveal a general inhibitory mechanism.

The type VI secretion system (T6SS) is a versatile and widespread export system found in many Gram-negative bacteria that delivers effector proteins into target cells. The functions of T6SSs are tightly regulated by diverse mechanisms at multiple levels, including post-translational modification through threonine phosphorylation via the Ser/Thr protein kinase (STPK) PpkA. Here, we identified that PpkA is essential for T6SS secretion in Serratia marcescens since its deletion eliminated the secretion of haemolysin co-regulated protein, while the periplasmic and transmembrane portion of PpkA was found to be disposable for T6SS secretion. We further determined the crystal structure of the kinase domain of PpkA (PpkA-294). The structure of PpkA-294 was determined in its apo form to a 1.6 Å resolution as well as in complex with ATP to a 1.41 Å resolution and with an ATP analogue AMP-PCP to a 1.45 Å resolution. The residues in the activation loop of PpkA-294 were fully determined, and the N-terminus of the loop was folded into an unprecedented inhibitory helix, revealing that the PpkA kinase domain was in an auto-inhibitory state. The ternary MgATP-PpkA-294 complex was also inactive with nucleotide ribose and phosphates in unexpected and unproductive conformations. The αC-helix in the inactive PpkA-294 adopted a conformation towards the active site but with the conserved glutamate in the helix rotated away, which we suggest to be a general conformation for all STPK kinases in the inactive form. Structural comparison of PpkA with its eukaryotic homologues reinforced the universal regulation mechanism of protein kinases.
Evaluation of the dosimetry approaches in ablation treatment of thyroid cancer

Abstract In this study, we aimed to evaluate dosimetric approaches in ablation treatment of Differentiated Thyroid Carcinoma (DTC) without interrupting the clinical routine. Prior to therapy, 10.7 MBq 131I in average was orally given to 24 patients suffering from DTC. MIRD formalism was used for dosimetric calculations. For blood and bone marrow dosimetry, blood samples and whole‐body counts were collected at 2, 24, 72, and 120 h after I‐131 administration. For remnant tissue dosimetry, uptake measurements were performed at the same time intervals. To estimate the remnant volume, anterior and lateral planar gamma camera images were acquired with a reference source within the field of view at 24 h after I‐131 administration. Ultrasound imaging was also performed. Treatment activities determined with the fixed activity method were administered to the patients. Secondary cancer risk relative to applied therapy was evaluated for dosimetric approaches. The average dose to blood and bone marrow were determined as 0.15 ± 0.04 and 0.11 ± 0.04 Gy/GBq, respectively. The average remnant tissue dose was 0.58 ± 0.52 Gy/MBq and the corresponding required activity to ablate the remnant was approximately 1.3 GBq of 131I. A strong correlation between 24th‐hour uptake and time‐integrated activity coefficient values was obtained. Compared to fixed activity method, approximately five times higher secondary cancer risk was determined in bone marrow dosimetry, while the risk was about three times lower in lesion‐based dosimetry.
Cooperation of multi robots for disaster rescue

Nowadays, robots take more charges of human activities, especially in repeated tasks, daily homecare and emergency rescue. Instead of using a solo robot to execute specific tasks, it calls for multi robots to cooperate in more scenarios, especially doing complex and difficult tasks that a single robot could not complete. In this paper, firstly it demonstrates a simplified model of the real disaster rescue scenario where requires robots to remove rocks from the road. Then it discusses the system how multi robots communicate wirelessly and cooperate together based on this abstract scenario. Finally, it evaluates and reflects the built system.
Dental Caries Status and Caries Risk Factors in Students Ages 12–14 Years in Zhejiang, China

Background An accurate and valid caries prevention policy is absent in Zhejiang because of insufficient data. Therefore, the aim of this study was to investigate oral health status and related risk factors in 12- to 14-year-old students in Zhejiang, China. Material/Methods Using multi-stage, stratified, random sampling, we recruited a total of 4860 students aged 12 to 14 years old from 6 regions in Zhejiang in this cross-sectional study. Dental caries was measured using the Decayed, Missing and Filled Teeth (DMFT) index and the Significant Caries Index (SiC). Information concerning family background and relevant behaviors was collected in a structured questionnaire. Logistic regression analysis was used to study risk factors related to dental caries. Results The overall prevalence of dental caries was 44% and the mean DMFT and SiC scores were 1.14 and 3.11, respectively. Female students had a higher level of dental caries than male students (P<0.01). The annual increase in caries prevalence was 3% with increasing age, and the DMFT score was 0.15. The results of logistic regression analysis showed that female sex, older age, snacks consumption once or more per day, fair or poor self-assessment of dental health, toothache experience, and dental visits were the most significant risk factors for dental caries, with odds ratios ranging from 1.24 to 2.25 (P<0.01). Conclusions The prevalence of dental caries in 12- to 14-year-old students in Zhejiang was low, with a tendency to increase compared with previous oral surveys. Female sex, older age, increased sugar intake, poor oral health self-assessment, and bad dental experience were the most important factors increasing dental caries risks.
Implemetation of image classification CNN using multi thread GPU

This study implemented an image classification CNN using a multi-thread GPU. For the CNN, the CIFAR10 dataset was used, and the multi-thread GPU had 256 threads. Using the 256 threads limited to each layer, allocation and parallel processing were conducted. The image classification CNN took 807 ms for computation.
A Customizable, Low-Cost Perfusion System for Sustaining Tissue Constructs

The fabrication of engineered vascularized tissues and organs requiring sustained, controlled perfusion has been facilitated by the development of several pump systems. Currently, researchers in the field of tissue engineering require the use of pump systems that are in general large, expensive, and generically designed. Overall, these pumps often fail to meet the unique demands of perfusing clinically useful tissue constructs. Here, we describe a pumping platform that overcomes these limitations and enables scalable perfusion of large, three-dimensional hydrogels. We demonstrate the ability to perfuse multiple separate channels inside hydrogel slabs using a preprogrammed schedule that dictates pumping speed and time. The use of this pump system to perfuse channels in large-scale engineered tissue scaffolds sustained cell viability over several weeks.
Effects of Genetic Polymorphism on Susceptibility to Nephrotoxic Properties of BTEXs Compounds

Objective: The aim of this study was to ascertain whether genetic polymorphism affects susceptibility of individuals to nephrotoxic potentials of benzene, toluene, ethyl-benzene, and xylenes (BTEXs). Methods: Fifty BTEXs exposed workers with one or more abnormal parameter of kidney function and 232 referent subjects, with similar exposure history, free from any abnormal kidney parameters were investigated. Atmospheric concentrations of BTEXs were measured. In addition, genetic polymorphisms were determined by multiplex polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP). Results: The frequencies of GSTP1 Ile-Val/Val-Val, null GSTT1, and null GSTT1/GSTM1 genotypes and mean values of blood urea nitrogen and plasma creatinine were significantly higher, while average glomerular filtration rate was significantly lower in cases than in referent subjects. Conclusion: These findings indicate that individuals carrying null GSTT1 or null GSTT1/GSTM1 are more susceptible to nephrotoxic properties of BTEXs compounds.
Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1–40) Fibrils

One of the principal hallmarks of Alzheimer’s disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists of either blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-epigallocatechin-3-gallate, quercetin, and rosmarinic acid) with amyloid-β(1–40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulates the double-layered structure stability.
The Benefits of Non-Pharmacological Interventions for Individuals with Dementia: A Systematic Review

Individuals with dementia experience many symptoms as the illness progress. Some of the common symptoms of dementia are memory loss, depression, anxiety, agitation, and aggression. Non-pharmacological interventions can help alleviate the common symptoms of dementia. Some of these interventions include therapies, relaxation techniques, and creative activities. This systematic review was designed to explore the research question: What are the benefits for non-pharmacological interventions for individuals with dementia? The systematic review used peer-reviewed articles that were published in the last eight years. The databases that were used in the review were PsychINFO, PubMed, and the search terms that were used were Alzheimer’s disease, non-pharmacological treatment options, non-pharmacological, nonpharmacological, Alzheimer’s disease & music therapy, Alzheimer’s disease & Art Therapy, Dementia, and Therapies, benefits of music therapy. Out of the articles that were found, 14 articles satisfied the inclusion criteria and were used in the final review. There were three themes found in the research articles for the study; 1) therapies, 2) relaxation technique, and 3) creative activities. The research found that there were several benefits for the use of non-pharmacological interventions for individuals with dementia. BENEFITS OF NON-PHARMACOLOGICAL INTERVENTIONS FOR PEOPLE WITH DEMENTIA 3 Table of
An examination of Alternative Multidimensional Scaling Techniques

The purpose of this study is to compare alternative multidimensional scaling (MDS) methods for constraining the stimuli on the circumference of a circle and on the surface of a sphere. Specifically, the existing MDS-T method for plotting the stimuli on the circumference of a circle is applied, and its extension is proposed for constraining the stimuli on the surface of a sphere. The data analyzed come from previous research and concerns Maslach and Jackson’s burnout syndrome and Holland’s vocational personality types. The configurations for the same data on the circle and the sphere shared similarities but also had differences, that is, the general item-groupings were the same but most of the differences across the two methods resulted in more meaningful interpretations for the three-dimensional configuration. Furthermore, in most cases, items and/or scales could be better discriminated from each other on the sphere.
T-cell Responses to TP53 “Hotspot” Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers

Purpose: This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Patients and Methods: Tumor-infiltrating lymphocytes (TIL) were expanded from resected ovarian cancer metastases, which were analyzed by whole-exome and transcriptome sequencing to identify autologous somatic mutations. All mutated neoepitopes, independent of prediction algorithms, were expressed in autologous antigen-presenting cells and then cocultured with TIL fragment cultures. Secretion of IFNγ or upregulation of 41BB indicated a T-cell response. Results: Seven women with metastatic ovarian cancer were evaluated, and 5 patients had clear, dominant T-cell responses to mutated neoantigens, which were corroborated by comparison with the wild-type sequence, identification of the minimal epitope, human leukocyte antigen (HLA) restriction element(s), and neoantigen-specific T-cell receptor(s). Mutated neoantigens were restricted by HLA-B, -C, -DP, -DQ, and/or -DR alleles and appeared to principally arise from random, somatic mutations unique to each patient. We established that TP53 “hotspot” mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S) expressed by two different patients' tumors were both immunogenic in the context of HLA-DRB3*02:02. Conclusions: Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. In addition, transfer of TP53 “hotspot” mutation-reactive T-cell receptors into peripheral blood T cells could be evaluated as a gene therapy for a diverse range of tumor histologies. Clin Cancer Res; 24(22); 5562–73. ©2018 AACR. See related commentary by McNeish, p. 5493
Suppression of Bone Resorption by miR‐141 in Aged Rhesus Monkeys

Aging‐related osteoporosis (OP) is considered a serious public health concern. Approximately 30% of postmenopausal women suffer from OP; more than 40% of them risk fragility fractures. Multiple drugs have been prescribed to treat OP, but they are not ideal because of low cure rates and adverse side effects. miRNA‐based gene therapy is a rapidly developing strategy in disease treatment that presents certain advantages, such as large‐scale production capability, genetic safety, and rapid effects. miRNA drugs have been used primarily in cancer treatments; they have not yet been reported as candidates for osteoclast‐targeted‐OP treatment in primates. Their therapeutic efficacy has been limited by several shortcomings, such as low efficiency of selective delivery, insufficient expression levels in targeting cells, and unexpected side effects. Here, we identify miR‐141 as a critical suppressor of osteoclastogenesis and bone resorption. The expression levels of miR‐141 are positively correlated with BMD and negatively correlated with the aging of bones in both aged rhesus monkeys (Macaca mulatta) and osteoporotic patients. Selective delivery of miR‐141 into the osteoclasts of aged rhesus monkeys via a nucleic acid delivery system allowed for a gradual increase in bone mass without significant effects on the health and function of primary organs. Furthermore, we found that the functional mechanism of miR‐141 resides in its targeting of two osteoclast differentiation players, Calcr (calcitonin receptors) and EphA2 (ephrin type‐A receptor 2 precursor). Our study suggests that miRNAs, such as miR‐141, could play a crucial role in suppressing bone resorption in primates and provide reliable experimental evidence for the clinical application of miRNA in OP treatment. © 2018 American Society for Bone and Mineral Research.
MicroRNA-145 promotes esophageal cancer cells proliferation and metastasis by targeting SMAD5

Abstract Objective: To clarify the relative expression and molecular function of microRNA (miR)-145 in esophageal cancer and understand its mechanistic involvement in this disease. Material and methods: The relative expression of miR-145 in clinical samples was analyzed using the public GSE43732 dataset. The prognostic analysis with respect to miR-145 expression was performed with Kaplan–Meier plot. Cell viability was measured by MTT assay and the anchorage-independent growth was evaluated by soft agar assay. The migration and invasion of esophageal cancer cells were measured using transwell chamber. The regulatory effect of miR-145 on SMAD5 was determined by dual-luciferase reporter assay. The endogenous SMAD5 protein was measured by Western blot. Results: We demonstrated high expression of miR-145 associated with late stage and unfavorable prognosis of esophageal cancer. Ectopic expression of miR-145 mimic significantly stimulated cell proliferation and anchorage-independent growth. Furthermore, high level of miR-145 significantly promoted both migration and invasion in vitro. Notably, we identified SMAD5 as direct target of miR-145, the suppressed expression of which consequently led to increased cell proliferation and migration/invasion. Conclusion: Our study uncovered the crucial role of miR-145/SMAD5 in esophageal cancer and highlighted its target potential for diagnostic and therapeutic purpose.