Miracle-dz/UniFAR-FTUs huggingface dataset:
β4-Integrin/PI3K Signaling Promotes Tumor Progression through the Galectin-3–N-Glycan Complex

Malignant transformation is associated with aberrant N-glycosylation, but the role of protein N-glycosylation in cancer progression remains poorly defined. β4-integrin is a major carrier of N-glycans and is associated with poor prognosis, tumorigenesis, and metastasis. Here, N-glycosylation of β4-integrin contributes to the activation of signaling pathways that promote β4-dependent tumor development and progression. Increased expression of β1,6GlcNAc-branched N-glycans was found to be colocalized with β4-integrin in human cutaneous squamous cell carcinoma tissues, and that the β1,6GlcNAc residue was abundant on β4-integrin in transformed keratinocytes. Interruption of β1,6GlcNAc-branching formation on β4-integrin with the introduction of bisecting GlcNAc by N-acetylglucosaminyltransferase III overexpression was correlated with suppression of cancer cell migration and tumorigenesis. N-Glycan deletion on β4-integrin impaired β4-dependent cancer cell migration, invasion, and growth in vitro and diminished tumorigenesis and proliferation in vivo. The reduced abilities of β4-integrin were accompanied with decreased phosphoinositol-3 kinase (PI3K)/Akt signals and were restored by the overexpression of the constitutively active p110 PI3K subunit. Binding of galectin-3 to β4-integrin via β1,6GlcNAc-branched N-glycans promoted β4-integrin–mediated cancer cell adhesion and migration. In contrast, a neutralizing antibody against galectin-3 attenuated β4-integrin N-glycan–mediated PI3K activation and inhibited the ability of β4-integrin to promote cell motility. Furthermore, galectin-3 knockdown by shRNA suppressed β4-integrin N-glycan–mediated tumorigenesis. These findings provide a novel role for N-glycosylation of β4-integrin in tumor development and progression, and the regulatory mechanism for β4-integrin/PI3K signaling via the galectin-3–N-glycan complex. Implications: N-Glycosylation of β4-integrin plays a functional role in promoting tumor development and progression through PI3K activation via the galectin-3–N-glycan complex. Mol Cancer Res; 16(6); 1024–34. ©2018 AACR.
Secure and Robust Fragile Watermarking Scheme for Medical Images

Due to the advances in computer-based communication and health services over the past decade, the need for image security becomes urgent to address the requirements of both safety and non-safety in medical applications. This paper proposes a new fragile watermarking-based scheme for image authentication and self-recovery for medical applications. The proposed scheme locates image tampering as well as recovers the original image. A host image is broken into $4\times 4$ blocks and singular value decomposition (SVD) is applied by inserting the traces of block wise SVD into the least significant bit of the image pixels to figure out the transformation in the original image. Two authentication bits namely block authentication and self-recovery bits are used to survive the vector quantization attack. The insertion of self-recovery bits is determined with Arnold transformation, which recovers the original image even after a high tampering rate. SVD-based watermarking information improves the image authentication and provides a way to detect different attacked area of the watermarked image. The proposed scheme is tested against different types of attacks such as text removal attack, text insertion attack, and copy and paste attack. Compared with the state-of-the art methods, the proposed scheme greatly improves both tamper localization accuracy and the peak signal to noise ratio of self-recovered image.
Cell Signaling during Cold, Drought, and Salt Stress Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.000596.

Low temperature, drought, and high salinity are common stress conditions that adversely affect plant growth and crop production. The cellular and molecular responses of plants to environmental stress have been studied intensively ([Thomashow, 1999][1]; [Hasegawa et al., 2000][2]). Understanding the
Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development

SUMMARY Invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. One therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. Another challenge is the fungistatic mechanism of action of some drugs. Consequently, the identification of fungus-specific drug targets essential for fitness in vivo remains a significant goal of medical mycology research. The trehalose biosynthetic pathway is found in a wide variety of organisms, including human-pathogenic fungi, but not in humans. Genes encoding proteins involved in trehalose biosynthesis are mechanistically linked to the metabolism, cell wall homeostasis, stress responses, and virulence of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. While there are a number of pathways for trehalose production across the tree of life, the TPS/TPP (trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase) pathway is the canonical pathway found in human-pathogenic fungi. Importantly, data suggest that proteins involved in trehalose biosynthesis play other critical roles in fungal metabolism and in vivo fitness that remain to be fully elucidated. By further defining the biology and functions of trehalose and its biosynthetic pathway components in pathogenic fungi, an opportunity exists to leverage this pathway as a potent antifungal drug target. The goal of this review is to cover the known roles of this important molecule and its associated biosynthesis-encoding genes in the human-pathogenic fungi studied to date and to employ these data to critically assess the opportunities and challenges facing development of this pathway as a therapeutic target.
Targeting Foxm1 Improves Cytotoxicity of Paclitaxel and Cisplatinum in Platinum-Resistant Ovarian Cancer

Objective Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. Methods Human ovarian cancer cell lines and patients’ ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. Results Ovarian cancer cell lines and the patients’ ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients’ ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients’ ascites cells ex vivo. Conclusion Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
Mutational Analysis on Membrane Associated Transporter Protein (MATP) and Their Structural Consequences in Oculocutaeous Albinism Type 4 (OCA4)—A Molecular Dynamics Approach

Oculocutaneous albinism type IV (OCA4) is an autosomal recessive inherited disorder which is characterized by reduced biosynthesis of melanin pigmentation in skin, hair, and eyes and caused by the genetic mutations in the membrane‐associated transporter protein (MATP) encoded by SLC45A2 gene. The MATP protein consists of 530 amino acids which contains 12 putative transmembrane domains and plays an important role in pigmentation and probably functions as a membrane transporter in melanosomes. We scrutinized the most OCA4 disease‐associated mutation and their structural consequences on SLC45A2 gene. To understand the atomic arrangement in 3D space, the native and mutant structures were modeled. Further the structural behavior of native and mutant MATP protein was investigated by molecular dynamics simulation (MDS) approach in explicit lipid and water background. We found Y317C as the most deleterious and disease‐associated SNP on SLC45A2 gene. In MDS, mutations in MATP protein showed loss of stability and became more flexible, which alter its structural conformation and function. This phenomenon has indicated a significant role in inducing OCA4. Our study explored the understanding of molecular mechanism of MATP protein upon mutation at atomic level and further helps in the field of pharmacogenomics to develop a personalized medicine for OCA4 disorder. J. Cell. Biochem. 117: 2608–2619, 2016. © 2016 Wiley Periodicals, Inc.
Accelerating Lattice Quantum Chromodynamics Simulations with Value Prediction

Abstract. Communication latency problems are universal and have become a major performance bottleneck as we scale in big data infrastructure and many-core architectures. Specifically, research institutes around the world have built specialized supercomputers with powerful computation units in order to accelerate scientific computation. However, the problem often comes from the communication side instead of the computation side. In this paper we first demonstrate the severity of communication latency problems. Then we use Lattice Quantum Chromo Dynamic (LQCD) simulations as a case study to show how value prediction techniques can reduce the communication overheads, thus leading to higher performance without adding more expensive hardware. In detail, we first implement a software value predictor on LQCD simulations: our results indicate that 22.15% of the predictions result in performance gain and only 2.65% of the predictions lead to rollbacks. Next we explore the hardware value predictor design, which results in a 20-fold reduction of the prediction latency. In addition, based on the observation that the full range of floating point accuracy may not be always needed, we propose and implement an initial design of the tolerance value predictor: as the tolerance range increases, the prediction accuracy also increases dramatically.
Impact of Addition of Digital Breast Tomosynthesis to Digital Mammography in Lesion Characterization in Breast Cancer Patients

Context: Digital breast tomosynthesis (DBT) is a new development in mammography technology which reduces the effect of overlapping tissue. Aims: The aim is to interrogate whether addition of DBT to digital mammography (DM) helps in better characterization of mammographic abnormalities in breast cancer patients in general and in different breast compositions. Settings and Design: Retrospective, analytical cross-sectional study. Subjects and Methods: Mammographic findings in 164 patients with 170 pathologically proven lesions were evaluated by using first DM alone and thereafter with addition of DBT to DM. The perceived utility of adjunct DBT was scored using a rating of 0–2. A score of 0 indicating that DM plus DBT was comparable to DM alone, 1 indicating that DM plus DBT was slightly better, and 2 indicating that DM plus DBT was definitely better. Statistical Analysis: McNemar Chi-squares test, Fisher's exact test. Results: On DM, 149 lesions were characterized mass with or without calcifications, 18 asymmetries with or without calcifications, 2 as architectural distortion, and 1 as microcalcification alone. Adjunct DBT helped in better morphological characterization of 17 lesions, with revelation of underlying masses in 16 asymmetries and one architectural distortion. Adjunct DBT was perceived to be slightly better than DM alone in 44.7% lesions, and definitely better in 22.9% lesions. Lesions showing score 1 or 2 improvement were significantly higher in heterogeneously and extremely dense breasts (P < 0.001). Conclusions: Adjunct DBT improves morphological characterization of lesions in patients with breast cancer. It highlights more suspicious features of lesions that indicate the presence of cancer, particularly in dense breasts.
FGF Suppresses Poldip2 Expression in Osteoblasts

Osteoporosis is one of the most prevalent ageing‐associated diseases that are soaring in the modern world. Although various aspects of the disease have been investigated to understand the bases of osteoporosis, the pathophysiological mechanisms underlying bone loss is still incompletely understood. Poldip2 is a molecule that has been shown to be involved in cell migration of vascular cells and angiogenesis. However, expression of Poldip2 and its regulation in bone cells were not known. Therefore, we examined the Poldip2 mRNA expression and the effects of bone regulators on the Poldip2 expression in osteoblasts. We found that Poldip2 mRNA is expressed in osteoblastic MC3T3‐E1 cells. As FGF controls osteoblasts and angiogenesis, FGF regulation was investigated in these cells. FGF suppressed the expression of Poldip2 in MC3T3‐E1 cells in a time dependent manner. Protein synthesis inhibitor but not transcription inhibitor reduced the FGF effects on Poldip2 gene expression in MC3T3‐E1 cells. As for bone‐related hormones, dexamethasone was found to enhance the expression of Poldip2 in osteoblastic MC3T3‐E1 cells whereas FGF still suppressed such dexamethasone effects. With respect to function, knockdown of Poldip2 by siRNA suppressed the migration of MC3T3‐E1 cells. Poldip2 was also expressed in the primary cultures of osteoblast‐enriched cells and FGF also suppressed its expression. Finally, Poldip2 was expressed in femoral bone in vivo and its levels were increased in aged mice compared to young adult mice. These data indicate that Poldip2 is expressed in osteoblastic cells and is one of the targets of FGF. J. Cell. Biochem. 118: 1670–1677, 2017. © 2016 Wiley Periodicals, Inc.
Levorphanol use: past, present and future

Abstract Levorphanol is a potent opioid analgesic that was first approved for use in the United States in 1953. Levorphanol is approved for use in moderate to severe pain where an opioid analgesic is appropriate. Levorphanol has a wide range of activities including mu opioid agonism, delta agonism, kappa1 and kappa3 receptor agonism, N-methyl-d-aspartate receptor antagonism and reuptake inhibition of both norepinephrine and serotonin. This multimodal profile might prove effective for pain syndromes that are refractory to other opioid analgesics, such as central and neuropathic pain and opioid-induced hyperalgesia. Levorphanol is well suited as a first-line opioid and can also be used during opioid rotation. It has no known effect on the cardiac QT interval or drug–drug interactions involving hepatic cytochrome P450s enzymes. In these regards, levorphanol may offer a superior safety profile over methadone and other long-acting opioids. Despite its prospective value of multiple mechanisms of action and the potential for treating various types of pain, levorphanol use has been largely supplanted by other recently approved opioids. Its waning use over the years has caused it to be referred to as the “Forgotten Opioid” and resulted in what some consider its underutilization. In fact, levorphanol is relatively unfamiliar to most prescribers. The purpose of this review is to inform practitioners about the attributes of this opioid and reintroduce it to clinicians as an option for treating moderate to severe pain when alternative treatment options are inadequate, not indicated or contraindicated.
A Chemocentric Approach to the Identification of Cancer Targets

A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.
Lymph-Borne Chemokines and Other Low Molecular Weight Molecules Reach High Endothelial Venules via Specialized Conduits While a Functional Barrier Limits Access to the Lymphocyte Microenvironments in Lymph Node Cortex

Lymph-borne, soluble factors (e.g., chemokines and others) influence lymphocyte recirculation and endothelial phenotype at high endothelial venules (HEVs) in lymph node cortex. Yet the route lymph-borne soluble molecules travel from the subcapsular sinus to the HEVs is unclear. Therefore, we injected subcutaneously into mice and rats a wide variety of fluorophore-labeled, soluble molecules and examined their distribution in the draining lymph nodes. Rather than percolating throughout the draining lymph node, all molecules, including microbial lipopolysaccharide, were very visible in the subcapsular and medullary sinuses but were largely excluded from the cortical lymphocyte microenvironments. Exclusion prevailed even during the acute lymph node enlargement accompanying viral infection. However, low molecular mass (MW) molecules, including chemokines, did gain entry into the cortex, but in a very defined manner. Low MW, fluorophore-labeled molecules highlighted the subcapsular sinus, the reticular fibers, and the abluminal and luminal surfaces of the associated HEVs. These low MW molecules were in the fibers of the reticular network, a meshwork of collagen fibers ensheathed by fibroblastic reticular cells that connects the subcapsular sinus floor and the HEVs by intertwining with their basement membranes. Thus, low MW, lymph-borne molecules, including chemokines, traveled rapidly from the subcapsular sinus to the HEVs using the reticular network as a conduit.
Predictors of smoking initiation among college-bound high school students

Smoking rates among college students is increasing, yet little is know about the development of students' smoking. This longitudinal analysis focuses on a national sample of high school students who were college students 4 years later (n = 1,479). SUDAAN statistical analysis procedures were used to weight and adjust for sampling design and nonresponse. Approximately 37% of the college students at follow- up who were never smokers at baseline had initiated smoking within the 4 years. Among experimenters at baseline, 25% had progressed their smoking behavior over the 4 years. Multivariate logistic regression analyses showed that there were different predictors of these two transitions among college students. Students who were more likely to initiate smoking were White, did not like school as much, and were more rebellious. Students who were more likely to progress from experimentation to a higher level of smoking thought peers approved of smoking and believed experimentation with smoking was safe. Several predictors of smoking initiation and progression during the transition from high school to college were identified that could be important components of interventions targeting high school and college- bound students. Increased efforts should be employed to include college students in national smoking prevention and cessation programs.
A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug-efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug-efflux transporters in macrophages. This was evident from expression analysis of drug-efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro. We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug-efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug-efflux systems of the host.
Negative interpretation bias as a mechanism of the relationship between rejection sensitivity and depressive symptoms

ABSTRACT Rejection sensitivity and negative cognitive biases have been identified as important risk factors for depression. Rejection sensitivity is defined as the tendency to anxiously anticipate, easily perceive, and overreact to rejection. Although prior studies have found an association between one component of rejection sensitivity, the tendency to anxiously anticipate rejection, and depression, little is known about the mechanisms through which anxious anticipation of rejection might confer depression risk. One possibility is that rejection anticipation leads to negatively biased interpretations, a cognitive risk factor for depression. Results from two studies (one cross-sectional, one longitudinal) indicate that negative interpretation biases mediate the association between the anxious anticipation of rejection and depressive symptoms. These findings indicate that interpretation biases represent a mechanism through which anxious anticipation of rejection confers risk for depression, and suggest that interventions designed to challenge negative interpretations may help to decrease depression risk among individuals who anticipate rejection.
Building Cyber-Physical Energy Systems

The built environment, as hallmark of modern society, has become one of the key drivers of energy demand. This makes for meaningful application of novel paradigms, such as cyber-physical systems, with large scale impact for both primary energy consumption reduction as well as (micro-) grid stability problems. In a bottom-up approach we analyze the drivers of CPS design, deployment and adoption in smart buildings. This ranges from low-level embedded and real time system challenges, instrumentation and control issues, up to ICT security layers protecting information in a world of ubiquitous connectivity. A modeling and predictive control framework is also discussed with outlook of deployment for HVAC optimization to a new facility for research from our campus.