Miracle-dz/UniFAR-FTUs huggingface dataset:
N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.
Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins

Morinidazole is a 5-nitroimidazole drug. Its sulfate conjugate M7 was a sensitive substrate of organic anion transporter 1 (OAT1) and OAT3, whereas N+-glucuronides M8-1 and M8-2 were only OAT3 substrates. In chronic renal failure (CRF) patients, plasma exposures of the three conjugates increased by 15-fold, which were also found in 5/6 nephrectomized (5/6 Nx) rats in this study. Although the transcriptions of Oat1 and Oat3 in 5/6 Nx rat kidneys decreased by 50%, no difference was observed on the three conjugate uptakes between control and 5/6 Nx rat kidney slices. Thus, the highly elevated endogenous uremic toxins in 5/6 Nx rats and humans, namely, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), hippuric acid (HA), and indoxyl sulfate (IS), were considered as influential factors. In rat kidney slices, the uptake of M7, M8-1, and M8-2 was dose dependently reduced by HA and IS, whose plasma concentrations were elevated 5 times in 5/6 Nx rats. In OAT3-overexpressed cells, the three conjugate uptakes were inhibited by CMPF, HA, and IS with IC50 values of 19.2, 87.4, and 222 μM (M7); 8.53, 39.4, and 161 μM (M8-1); and 6.75, 24.1, and 78.3 μM (M8-2), respectively. In OAT1-overexpressed cells, CMPF, HA, and IS showed weak inhibition on M7 uptake with IC50 values of 187, 162, and 200 μM, correspondingly. Results suggest that the reduced mRNA expression of renal transporters in CRF patients may not influence the activities of these transporters. However, accumulated uremic toxins may inhibit the transporters, particularly OAT3, leading to plasma exposure changes of relevant substrates.
Effects of Mn and Zr Addition in 6000 Series Aluminum Alloys on the Formation of Stabilized Substructures during Hot Deformation

Thermal stability of substructures in 6000 series aluminum alloys containing Mn and Zr elements was investigated using plane-strain compression test. In order to form thermally stabilized substructures, the deformation parameters should be selected so as to correlate with kinetic precipitation during the deformation. For substructures of the alloys containing Mn and Zr elements, the substructures were stable during the heat treatment at 540 ̊C when the alloys were deformed at a temperature above 350 ̊C. The sheets rolled above 350 ̊C at a strain rate of under 3 s-1 per pass showed the fibrous structure and well developed β-fiber textures after the heat treatment at 540 ̊C. The sheets with the fibrous structure had an average Lankford value larger than one.
Examining Programmer Practices for Locally Handling Exceptions

Many have argued that the current try/catch mechanism for handling exceptions in Java is flawed. A major complaint is that programmers often write minimal and low quality handlers. We used the Boa tool to examine a large number of Java projects on GitHub to provide empirical evidence about how programmers currently deal with exceptions. We found that programmers handle exceptions locally in catch blocks much of the time, rather than propagating by throwing an Exception. Programmers make heavy use of actions like Log, Print, Return, or Throw in catch blocks, and also frequently copy code between handlers. We found bad practices like empty catch blocks or catching Exception are indeed widespread. We discuss evidence that programmers may misjudge risk when catching Exception, and face a tension between handlers that directly address local program statement failure and handlers that consider the program-wide implications of an exception. Some of these issues might be ad-dressed by future tools which autocomplete more complete handlers.
HIVE-Hexagon: High-Performance, Parallelized Sequence Alignment for Next-Generation Sequencing Data Analysis

Due to the size of Next-Generation Sequencing data, the computational challenge of sequence alignment has been vast. Inexact alignments can take up to 90% of total CPU time in bioinformatics pipelines. High-performance Integrated Virtual Environment (HIVE), a cloud-based environment optimized for storage and analysis of extra-large data, presents an algorithmic solution: the HIVE-hexagon DNA sequence aligner. HIVE-hexagon implements novel approaches to exploit both characteristics of sequence space and CPU, RAM and Input/Output (I/O) architecture to quickly compute accurate alignments. Key components of HIVE-hexagon include non-redundification and sorting of sequences; floating diagonals of linearized dynamic programming matrices; and consideration of cross-similarity to minimize computations. Availability https://hive.biochemistry. gwu.edu/hive/
Typechecking for XML transformers

We study the typechecking problem for XML transformers: given an XML transformation program and a DTD for the input XML documents, check whether every result of the program conforms to a specified output DTD. We model XML transformers using a novel device called a k-pebble transducer, that can express most queries without data-value joins in XML-QL, XSLT, and other XML query languages. Types are modeled by regular tree languages, a nobust extension of DTDs. The main result of the paper is that typechecking for k-pebble transducers is decidable. Consequently, typechecking can be performed for a broad range of XML transformation languages, including XML-QL and a fragment of XSLT.
Water-soluble fullerenes for medical applications

Research on fullerenes occupies a unique position in the scientific arena. Synthesis and characterisation of this nanomaterial blur the line between materials science and chemistry; careful tuning of the processing methods gives birth to a whole family of molecules and their functionalised derivatives, whose unusual properties at this nanoscopic scale can be exploited in cutting-edge technological applications. This review focuses on the functionalisation of fullerenes for use in medical applications. The first half gives an introduction to the fullerenes themselves and how their fundamental properties lead to a very rich chemistry, enabling both exohedral (external) and endohedral (internal) functionalisations of the cage. Emphasis is placed on the need for safe and reproducible synthesis routes if fullerenes are ever going to make it to the pharmaceutical market. In line with this, a selection of exohedral functionalisation protocols receives particular attention. Coverage of endohedral fullerene synthesis routes is limited to the endohedral metallofullerenes. In the second half, myriad applications of fullerenes in biomedical contexts are introduced and certain synthesis routes are critically evaluated. Discussion of the need to water solubilise the hydrophobic fullerene cages precedes an overview of fullerene-based diagnostic and therapeutic technologies. A final moment is spent on toxicity studies of fullerenes. The concluding remarks emphasise the positive effects of incorporating fullerenes into biomedical technologies, while looking at how these are perceived by the general public. A case is made for fullerenes being the optimal choice as standard bearers in the advance of nanomaterials into the medical field. This is the winning review of the 2016 Materials Literature Review Prize of the Institute of Materials, Minerals and Mining, run by the Editorial Board of MST. Sponsorship of the prize by TWI Ltd is gratefully acknowledged. Video abstract Read the transcript Watch the video on Vimeo
Comprehensive analysis of Helicobacter pylori infection-associated diseases based on miRNA-mRNA interaction network

Abstract Helicobacter pylori (H. pylori) infection remains a cause of significant morbidity and mortality worldwide. Comprehensive understanding of the pathogenic mechanism of H. pylori and its interaction with host will contribute to developing novel prophylactical and therapeutical strategies. Here, we first determined microRNA (miRNA) levels in H. pylori-infected patients with gastritis, duodenal ulcer, gastric cancer or mucosa-associated lymphoid tissue lymphoma using miRNA data sets. Thirty-four differentially expressed miRNAs were identified and functional enrichment analysis of those miRNA target genes revealed that H. pylori infection were strongly associated with pathway in cancer and regulation of mRNA synthesis. Using disease connectivity analysis of 28 hub genes, we found that H. pylori may increase the risk of many extragastric diseases (e.g. cardiovascular disease, hemic and lymphatic diseases and nervous system disease). Altogether, our integrated analysis provided a new method to predict pathogen–human disease connectivity based on miRNA-mRNA interaction network and indicated anti-H. pylori therapy as an effective means of human diseases prevention.
PKC/Nedd4-2 Signaling Pathway Regulates the Cell Surface Expression of Drug Transporter hOAT1

Human organic anion transporter-1 (hOAT1) regulates the absorption, distribution, and excretion of a wide range of clinically important drugs. Our previous work demonstrated that hOAT1 is a dynamic membrane transporter, constitutively internalizing from and recycling back to the cell plasma membrane. Short-term activation (<30 minutes) of protein kinase C (PKC) promotes the attachment of a lysine 48-linked polyubiquitin chain to hOAT1, a process catalyzed by ubiquitin ligase neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2). The ubiquitination of hOAT1 then triggers an accelerated endocytosis of the transporter from plasma membrane, which results in reduced hOAT1 expression at the cell surface and decreased hOAT1 transport activity. In the present study, we investigated the long-term effect of PKC on hOAT1. We showed that long-term activation (>2 hours) of PKC significantly enhanced hOAT1 degradation, and such action was partially blocked by ubiquitin mutant Ub-K48R, which has its lysine (K) 48 mutated to arginine (R) and is incapable of forming a K48-linked polyubiquitin chain. The ubiquitin ligase Nedd4-2 was also found to augment hOAT1 degradation. These results suggest that PKC-regulated and Nedd4-2-catalyzed attachment of a lysine 48-linked polyubiquitin chain to hOAT1 is important for hOAT1 stability. We further showed through coimmunoprecipitation experiments that there was a direct association between hOAT1 and Nedd4-2, and such interaction was weakened when the WW3 and WW4 domains of the ligase were mutated. Mutating WW3 and WW4 domains of the ligase also impaired its ability to ubiquitinate hOAT1. Therefore, WW3 and WW4 domains of Nedd4-2 are critical for its association with and modulation of the transporter.
A simple integrated smart green home design

Smart home systems were introduced to autonomously control appliances, lights and other services based on the current state inside homes. Smart home systems are designed for a wide band of applications such as healthcare, power management, safety and security. In Egypt, we are suffering from an electrical power shortage because the production is not sufficient for the actual consumption. In addition, there are some isolated areas not covered by the National Grid. Because of this persisting challenge, the need for finding solutions arose. Egypt is a developing country with limited resources, consequently economic and power saving focused solutions are needed. In this paper, a simple integrated design of a smart green house is introduced as a solution for a common Egyptian home to save the consumed power from the National Grid. This design has two main pillars: First, a smart system that controls the power consumption through monitoring the activity in the home to save the power as much as possible. This system comprises of a wireless network of controllers. Each controller monitors and controls a specific area considered a separate zone. These zone controllers exchange the current data and control parameters with a master unit, which provides supervision and control of the entire system. In addition, the system can be monitored and configured locally through a wall mounted touch screen or remotely using a mobile phone or web interface. Second, a solar power supply system equipped with a two degree of freedom sun tracker to partially or fully power the loads and hence reduces the power consumption from the National Grid. The solar system is integrated with the smart supervision system through a wireless link to the master unit.
Geographic Patterns of Genetic Variation in a Broadly Distributed Marine Vertebrate: New Insights into Loggerhead Turtle Stock Structure from Expanded Mitochondrial DNA Sequences

Previous genetic studies have demonstrated that natal homing shapes the stock structure of marine turtle nesting populations. However, widespread sharing of common haplotypes based on short segments of the mitochondrial control region often limits resolution of the demographic connectivity of populations. Recent studies employing longer control region sequences to resolve haplotype sharing have focused on regional assessments of genetic structure and phylogeography. Here we synthesize available control region sequences for loggerhead turtles from the Mediterranean Sea, Atlantic, and western Indian Ocean basins. These data represent six of the nine globally significant regional management units (RMUs) for the species and include novel sequence data from Brazil, Cape Verde, South Africa and Oman. Genetic tests of differentiation among 42 rookeries represented by short sequences (380 bp haplotypes from 3,486 samples) and 40 rookeries represented by long sequences (∼800 bp haplotypes from 3,434 samples) supported the distinction of the six RMUs analyzed as well as recognition of at least 18 demographically independent management units (MUs) with respect to female natal homing. A total of 59 haplotypes were resolved. These haplotypes belonged to two highly divergent global lineages, with haplogroup I represented primarily by CC-A1, CC-A4, and CC-A11 variants and haplogroup II represented by CC-A2 and derived variants. Geographic distribution patterns of haplogroup II haplotypes and the nested position of CC-A11.6 from Oman among the Atlantic haplotypes invoke recent colonization of the Indian Ocean from the Atlantic for both global lineages. The haplotypes we confirmed for western Indian Ocean RMUs allow reinterpretation of previous mixed stock analysis and further suggest that contemporary migratory connectivity between the Indian and Atlantic Oceans occurs on a broader scale than previously hypothesized. This study represents a valuable model for conducting comprehensive international cooperative data management and research in marine ecology.
Tripterygium wilfordii mitigates hyperglycemia-induced upregulated Wnt/β-catenin expression and kidney injury in diabetic rats

Aberrant activation of the Wnt/β-catenin pathway contributes to the development of diabetic nephropathy (DN); however, treatment with Tripterygium wilfordii (TW) may be beneficial for patients with DN. The aim of the present study was to evaluate the effect of TW on Wnt/β-catenin expression in the kidneys of diabetic rats. Male Sprague-Dawley rats were randomly injected with vehicle (control) or streptozotocin to induce diabetes. Diabetic rats were then randomly treated with vehicle (sodium carboxymethyl cellulose; SCC), TW combined with SCC (8 or 16 mg/kg) or irbesartan (50 mg/kg) daily for 8 weeks. Metabolic parameter levels and renal pathological changes were examined. mRNA and protein expression of Wnt-1, glycogen synthase kinase (GSK)-3β, β-catenin, nuclear factor (NF)-κB and transforming growth factor (TGF)-β1 in the kidneys of rats from all groups were measured. Compared with the DM group, metabolic parameters and morphological parameters, apart from blood glucose levels, were significantly improved in TW-treated rats (all P<0.01). Furthermore, levels of Wnt-1, β-catenin, NF-κB-p65 and TGF-β1 mRNA and protein were significantly reduced in the kidneys of TW-treated rats compared with DM rats, whereas levels of GSK-3β mRNA and protein did not differ significantly between any of the groups; however, the expression of P-GSK-3β protein was significantly decreased in the kidneys of TW-treated rats compared with the DM group. The protective effects of TW tended to be dose-dependent and were an improvement compared with irbesartan treatment in diabetic rats. Therefore, the results of the present study indicated that treatment with TW mitigated hyperglycemia-induced upregulated Wnt-1 and β-catenin expression in kidney tissues and ameliorated diabetes-induced kidney injury in rats.
Binaere und ternaere Carbide und Nitride der Uebergangsmetalle und ihre Phasenbeziehungen

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Memes Revisited

In this paper, I argue that the adaptive fit between human cultures and their environment is persuasive evidence that some form of evolutionary mechanism has been important in driving human cultural change. I distinguish three mechanisms of cultural evolution: niche construction leading to cultural group selection; the vertical flow of cultural information from parents to their children, and the replication and spread of memes. I further argue that both cultural group selection and the vertical flow of cultural information have been important. More conjecturally, I identify a potential role for meme-based cultural evolution in the explanation of the ‘human revolution’ of the last 100 000 or so years, and defuse an important objection to that explanation. 1. Introduction2. Cultural groups3. The cultural invention of adaptive complexes4. Niche construction models5. Dual inheritance6. Memes7. Memes or minds? 8. Conclusion Introduction Cultural groups The cultural invention of adaptive complexes Niche construction models Dual inheritance Memes Memes or minds? Conclusion
Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer’s Disease: A 7-Year Follow-Up Study

Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer’s disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson’s disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional 1H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice.
Mechanisms for the enhancement of the thermal stability of organic thin films by aluminum oxide capping layers

We present a detailed study of the thermal stability of organic thin films of diindenoperylene encapsulated by sputtered aluminum oxide layers. We studied the influence of capping layer thickness, stoichiometry, and heating rate on the thermal stability of capped films and their eventual breakdown. Under optimized encapsulation conditions (thick and stoichiometric capping layer), the organic films desorb only at temperatures 200 °C above the desorption of the uncapped film. Moreover, the capped organic films retain their crystalline order at these elevated temperatures, whereas they would normally (i.e., uncapped) be in the gas phase. This study therefore also shows a way of studying organic materials under temperature conditions normally inaccessible. Considering results from complementary techniques, we discuss possible scenarios for the eventual breakdown. The results have implications for the performance and long-term stability of organic devices for which stability against elevated temperatures as well as against exposure to ambient gases is crucial.