Miracle-dz/UniFAR-FTUs huggingface dataset:
Brain Distribution of a Novel MEK Inhibitor E6201: Implications in the Treatment of Melanoma Brain Metastases

Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and mitogen-activated protein/extracellular signal–regulated kinase (MEK) has been identified to be an important target. E6201 is a potent synthetic small-molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the blood-brain barrier on the central nervous system (CNS) exposure of E6201. In vitro studies utilizing transfected Madin-Darby canine kidney II (MDCKII) cells indicate that E6201 is not a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). In vivo studies also suggest a minimal involvement of P-gp and Bcrp in E6201’s brain distribution. The total concentrations in brain were higher than in plasma, resulting in a brain-to-plasma AUC ratio (Kp) of 2.66 in wild-type mice. The brain distribution was modestly enhanced in Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− knockout mice. The nonspecific binding of E6201 was higher in brain compared with plasma. However, free-drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro half-maximal inhibitory concentration (IC50) values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The brain distribution characteristics of E6201 make it an attractive targeted agent for clinical testing in MBM, glioblastoma, and other CNS tumors that may be effectively targeted with inhibition of MEK signaling.
Detection of Water Bodies from AVHRR Data - A TIMELINE Thematic Processor

The assessment of water body dynamics is not only in itself a topic of strong demand, but the presence of water bodies is important information when it comes to the derivation of products such as land surface temperature, leaf area index, or snow/ice cover mapping from satellite data. For the TIMELINE project, which aims to derive such products for a long time series of Advanced Very High Resolution Radiometer (AVHRR) data for Europe, precise water masks are therefore not only an important stand-alone product themselves, they are also an essential interstage information layer, which has to be produced automatically after preprocessing of the raw satellite data. The respective orbit segments from AVHRR are usually more than 2000 km wide and several thousand km long, thus leading to fundamentally different observation geometries, including varying sea surface temperatures, wave patterns, and sediment and algae loads. The water detection algorithm has to be able to manage these conditions based on a limited amount of spectral channels and bandwidths. After reviewing and testing already available methods for water body detection, we concluded that they cannot fully overcome the existing challenges and limitations. Therefore an extended approach was implemented, which takes into account the variations of the reflectance properties of water surfaces on a local to regional scale; the dynamic local threshold determination will train itself automatically by extracting a coarse-scale classification threshold, which is refined successively while analyzing subsets of the orbit segment. The threshold is then interpolated by fitting a minimum curvature surface before additional steps also relying on the brightness temperature are included to reduce possible misclassifications. The classification results have been validated using Landsat and Moderate Resolution Imaging Spectroradiometer (MODIS) data and proven an overall accuracy of 93.4%, with the majority of errors being connected to flawed geolocation accuracy of the AVHRR data. The presented approach enables the derivation of long-term water body time series from AVHRR data and is the basis for applied geoscientific studies on large-scale water body dynamics.
VSMC MIMO: A spectral efficient scheme for cooperative relay in cognitive radio networks

Multiple-Input Multiple-Output (MIMO) technology has become an efficient way to improve the capacity and reliability of wireless networks. Traditional MIMO schemes are designed mainly for the scenario of contiguous spectrum ranges. However, in cognitive radio networks, the available spectrum is discontiguous, making traditional MIMO schemes inefficient for spectrum usage. This motivates the design of new MIMO schemes that apply to networks with discontiguous spectrum ranges. In this paper, we propose a scheme called VSMC MIMO, which enables MIMO nodes to transmit variable numbers of streams in multiple discontinuous spectrum ranges. This scheme can largely improve the spectrum utilization and meanwhile maintain the same spatial multiplexing and diversity gains as traditional MIMO schemes. To implement this spectral-efficient scheme on cooperative MIMO relays in cognitive radio networks, we propose a joint relay selection and spectrum allocation algorithm and a corresponding MAC protocol for the system. We also build a testbed by the Universal Software Radio Peripherals (USRPs) to evaluate the performances of the proposed scheme in practical networks. The experimental results show that VSMC MIMO can efficiently utilize the discontiguous spectrum and greatly improve the throughput of cognitive radio networks.
Human Adenovirus Core Protein V Is Targeted by the Host SUMOylation Machinery To Limit Essential Viral Functions

ABSTRACT Human adenoviruses (HAdV) are nonenveloped viruses containing a linear, double-stranded DNA genome surrounded by an icosahedral capsid. To allow proper viral replication, the genome is imported through the nuclear pore complex associated with viral core proteins. Until now, the role of these incoming virion proteins during the early phase of infection was poorly understood. The core protein V is speculated to bridge the core and the surrounding capsid. It binds the genome in a sequence-independent manner and localizes in the nucleus of infected cells, accumulating at nucleoli. Here, we show that protein V contains conserved SUMO conjugation motifs (SCMs). Mutation of these consensus motifs resulted in reduced SUMOylation of the protein; thus, protein V represents a novel target of the host SUMOylation machinery. To understand the role of protein V SUMO posttranslational modification during productive HAdV infection, we generated a replication-competent HAdV with SCM mutations within the protein V coding sequence. Phenotypic analyses revealed that these SCM mutations are beneficial for adenoviral replication. Blocking protein V SUMOylation at specific sites shifts the onset of viral DNA replication to earlier time points during infection and promotes viral gene expression. Simultaneously, the altered kinetics within the viral life cycle are accompanied by more efficient proteasomal degradation of host determinants and increased virus progeny production than that observed during wild-type infection. Taken together, our studies show that protein V SUMOylation reduces virus growth; hence, protein V SUMOylation represents an important novel aspect of the host antiviral strategy to limit virus replication and thereby points to potential intervention strategies. IMPORTANCE Many decades of research have revealed that HAdV structural proteins promote viral entry and mainly physical stability of the viral genome in the capsid. Our work over the last years showed that this concept needs expansion as the functions are more diverse. We showed that capsid protein VI regulates the antiviral response by modulation of the transcription factor Daxx during infection. Moreover, core protein VII interacts with SPOC1 restriction factor, which is beneficial for efficient viral gene expression. Here, we were able to show that core protein V also represents a novel substrate of the host SUMOylation machinery and contains several conserved SCMs; mutation of these consensus motifs reduced SUMOylation of the protein. Unexpectedly, we observed that introducing these mutations into HAdV promotes adenoviral replication. In conclusion, we offer novel insights into adenovirus core proteins and provide evidence that SUMOylation of HAdV factors regulates replication efficiency.
New method for identifying abnormal milling states of an otological drill

Surgeons are continuing to strive toward achieving higher quality minimally invasive surgery. With the growth of modern technology, intelligent medical devices are being used to improve the safety of surgery. Milling beyond the bone tissue wall is a common abnormal milling state in ear surgery, as well as entanglement of the drill bit with the cotton swab, which will do harm to the patient’s encephalic tissues. Various methods have been investigated by engineers and surgeons in an effort to avoid this type of abnormal milling state during surgery. This paper outlines a new method for identifying these two types of abnormal milling states. Five surgeons were invited to perform experiments on calvarial bones. The average recognition rate for otological drill milling through a bone tissue wall was 93%, with only 2% of normal millings being incorrectly identified as milling faults. The average recognition rate for entanglement of the drill bit with a cotton swab was 92%, with only 2% of normal millings being identified as milling faults. The method presented here can be adapted to the needs of the individual surgeon and reliably identify milling faults.
Oral Supplementation with Beta-Hydroxy-Beta-Methylbutyrate, Arginine, and Glutamine Improves Lean Body Mass in Healthy Older Adults

ABSTRACT Oral intake of beta-hydroxy-beta-methylbutyrate (HMB), arginine, and glutamine may ameliorate muscle loss by stimulating protein synthesis and decreasing protein degradation while simultaneously decreasing inflammation. Previous studies provide evidence for improvement in body composition with dietary supplementation of these ingredients among patients with muscle-wasting diseases. The objectives of this study were to examine the effects of this amino acid mixture on lean body mass, muscle volume, and physical function among healthy older adults. Thirty-one community-dwelling men and women, aged 65–89 years, were randomized to either two oral doses of the amino acid supplement (totaling 3 g HMB, 14 g arginine, 14 g glutamine) or placebo daily for six months. At baseline and month six, lean body mass was measured by air displacement plethysmography, dual-energy X-ray absorptiometry (DXA), and four-compartment model. Muscle volume of quadriceps was quantified by magnetic resonance imaging (MRI), and participants performed a battery of tests to assess physical function. As compared to the placebo group, the treatment group exhibited improvement in a timed stair climb (p =.016) as well as significant increases in lean body mass by all methods of assessment (p <.05). Regional analysis by DXA revealed increased arm lean mass in the supplement group only (p =.035). However, no change was observed in MRI-derived quadriceps volume. Dietary supplementation with HMB, arginine, and glutamine improved total body lean mass among a small sample of healthy older adults. Further research is indicated to elucidate mechanisms of action and to determine whether supplementation may benefit frail elders. Registered under ClinicalTrials.gov identifier no. NCT01057082.
Piloting a Collaborative Web-Based System for Testing ICD-11.

BACKGROUND The 11th revision of the International Classification of Diseases (ICD-11), for the first time in ICD history, deployed web-based collaboration of experts and ICT tools. To ensure that ICD-11 is working well, it needs to be systematically field tested in different settings, across the world. This will be done by means of a number of experiments. In order to support its implementation, a web-based system (ICDfit) has been designed and developed. The present paper illustrates the current prototype of the system and its technical testing. METHODS the system has been designed according to WHO requirements, and implemented using PHP and MySQL. Then, a preliminary technical test has been designed and run in January 2016, involving 8 users. They had to carry out double coding, that is, coding case summaries with both ICD-10 and ICD-11, and answering quick questions on the coding difficulty. RESULTS the 8 users coded 632 cases each, spending an average of 163 seconds per case. While we found an issue in the mechanism used to record coding times, no further issues were found. CONCLUSION the proposed system seems to be technically adequate for supporting future ICD-11 testing.
Function of the dorsal fin in bluegill sunfish: Motor patterns during four distinct locomotor behaviors

The median fins of fishes are key features of locomotor morphology which function as complex control surfaces during a variety of behaviors. However, very few studies have experimentally assessed median fin function, as most workers focus on axial structures. In particular, the dorsal fin of many teleost fishes possesses both spiny anterior and soft posterior portions which may function separately during locomotion. We analyzed the function of the soft region of the dorsal fin and of the dorsal inclinator (Di) muscles which are the primary muscles responsible for lateral flexion. We used electromyography to measure in vivo Di activity, as well as activity of the red myomeric muscles located at a similar longitudinal position. We quantified motor patterns during four locomotor behaviors: braking and three propulsive behaviors (steady swimming, kick and glide swimming, and C‐starts). During the three propulsive swimming behaviors, the timing of Di activity was more similar to that of ipsilateral red myomeric muscle rather than to contralateral myomeric activity, whereas during braking the timing of activity of the Di muscles was similar to that of the contralateral myomeric musculature. During the three propulsive behaviors, when the Di muscles had activity, it was consistent with the function of stiffening the soft dorsal fin to oppose its tendency to bend as a result of the body being swept laterally through the water. In contrast, activity of the Di muscles during braking was consistent with the function of actively flexing the soft dorsal fin towards the side of the fish that had Di activity. Activity of the Di muscles during steady speed swimming was generally sufficient to resist lateral bending of the soft dorsal fin, whereas during high speed kick and glide swimming and C‐starts, Di activity was not sufficient to resist the bending caused by resistive forces imposed by the water. Cumulative data from all four behaviors suggest that the Di muscles can be activated independently relative to the myomeric musculature rather than having a single phase relationship with the myomeric muscle common to all of the observed behaviors. © 1996 Wiley‐Liss, Inc.
Multicenter Study of 6-Month Clinical Outcomes After Descemet Membrane Endothelial Keratoplasty

Purpose: To report the 6-month clinical outcomes of a large cohort of Descemet membrane endothelial keratoplasty (DMEK) eyes operated by 55 starting or experienced surgeons. Methods: This is a retrospective, multicenter, interventional, cohort study with a total of 2485 eyes. Best-corrected visual acuity (BCVA), endothelial cell density (ECD) decrease, and intra- and post-operative complications were evaluated. Three groups based on case order were compared: group I (cases 1–24), group II (cases 25–99), and group III (cases ≥100). Forty-nine percent of the surgeons were in their learning curve (<25 cases), representing 10.4% of the surgeries. Results: Six months after DMEK, BCVA improved in 90.5% of eyes, remained unchanged in 4.6%, and deteriorated in 4.9% (n = 1936); 75.4% of eyes reached a BCVA of ≥20/40 (≥0.5), 45.4% ≥20/25 (≥0.8), and 25.8% ≥20/20 (≥1.0) (n = 1959) and ECD decreased by 40% (±19) (n = 1272, P < 0.05). BCVA and ECD outcomes did not differ between groups I and III (P > 0.05). Intraoperative complications were reported for 9.4% of eyes, whereas graft detachment was the main postoperative complication (27.4%), with lower intra- and post-operative complication rates in group III than group I (P < 0.05). Rebubbling was performed in 20.1% of eyes; 13.8% required secondary keratoplasty within 6 months. Conclusions: DMEK is applicable for surgeons in various settings with good clinical outcomes. After an arbitrary learning curve (<25 cases), virtually all transplant-related complications declined with experience. Notably, surgeons with a higher annual caseload may pass faster through their learning curve than surgeons performing their first surgeries over an extended period.
HIV and Child Mental Health: A Case-Control Study in Rwanda

BACKGROUND: The global HIV/AIDS response has advanced in addressing the health and well-being of HIV-positive children. Although attention has been paid to children orphaned by parental AIDS, children who live with HIV-positive caregivers have received less attention. This study compares mental health problems and risk and protective factors in HIV-positive, HIV-affected (due to caregiver HIV), and HIV-unaffected children in Rwanda. METHODS: A case-control design assessed mental health, risk, and protective factors among 683 children aged 10 to 17 years at different levels of HIV exposure. A stratified random sampling strategy based on electronic medical records identified all known HIV-positive children in this age range in 2 districts in Rwanda. Lists of all same-age children in villages with an HIV-positive child were then collected and split by HIV status (HIV-positive, HIV-affected, and HIV-unaffected). One child was randomly sampled from the latter 2 groups to compare with each HIV-positive child per village. RESULTS: HIV-affected and HIV-positive children demonstrated higher levels of depression, anxiety, conduct problems, and functional impairment compared with HIV-unaffected children. HIV-affected children had significantly higher odds of depression (1.68: 95% confidence interval [CI] 1.15–2.44), anxiety (1.77: 95% CI 1.14–2.75), and conduct problems (1.59: 95% CI 1.04–2.45) compared with HIV-unaffected children, and rates of these mental health conditions were similar to HIV-positive children. These results remained significant after controlling for contextual variables. CONCLUSIONS: The mental health of HIV-affected children requires policy and programmatic responses comparable to HIV-positive children.
Epidemiology of discordance between symptoms and signs of dry eye

Background/aims The frequent lack of association between dry eye (DE) symptoms and signs leads to challenges in diagnosing and assessing the disease. Methods Participants underwent ocular surface examinations to evaluate signs of disease and completed questionnaires to assess ocular symptoms, psychological status and medication use. To assess nociceptive system integrity, quantitative sensory testing (QST), including vibratory and thermal threshold measures and temporal summation of pain were obtained at the forearm and forehead. Correlations between DE discordance score (degree of discrepancy between symptom severity and DE signs) and patient characteristics were determined. Higher discordance scores indicated more symptoms than signs. Results 326 patients participated (mean age: 62 years; SD: 10 years; 92% men). Age was negatively correlated with DE discordance score (Pearson r=−0.30, p<0.0005), while mental health indices were positively correlated. Chronic pain elsewhere in the body (ie, non-ocular pain conditions) and intensity ratings of prolonged aftersensations of pain evoked by noxious hot and cold stimuli were also significantly correlated with DE discordance score. Multiple linear regression demonstrated that post-traumatic stress disorder and non-ocular pain intensity were important predictors of DE discordance score, Dry Eye Questionnaire-5 and Ocular Surface Disease Index and that DE discordance was also sensitive to QST as well. Conclusions The present study provides evidence that the degree of discordance between DE symptom report and measurable signs of ocular surface disease is associated with comorbidities related to clinical pain and to hyperalgesia as demonstrated with QST. Understanding the epidemiology of DE discordance can aid in interpreting the DE exam and individualising treatment.
The issue of HPLC determination of endogenous lipoic acid in human plasma.

Lipoic acid (LA) is used extensively as a therapeutic agent for the treatment of various diseases. Many methods have been reported for the determination of LA plasma levels and its metabolites after its supplementation, but available information concerning endogenous plasma levels is still scarce. Studies which directly focused on determining the endogenous plasma levels provided highly controversial results, <4.9 nmol/L or 143.7-197.0 nmol/L. The main aim of this study was to verify the levels of free LA in the plasma of 40 individuals (17 women, 23 men). This group was nonsupplemented with LA and met the conditions for incorporation into the blood donors register. We measured the levels of LA using an HPLC method with very sensitive coulometric detection after previous sample preparation including deproteination and solid-phase extraction with a Phenyl cartridge. Our limit of detection was 1.85 nmol/L and was better than the values reported in studies that directly focused on determining the endogenous plasma levels of LA: 2.4 and 4.9 nmol/L respectively. However, the levels of free LA in the plasma of nonsupplemented voluntary blood donors were not detectable in all cases. The presented results of our study show that endogenous concentrations of LA are <1.85 nmol/L.
Scanning force microspy study of biogenic nanoparticles for medical applications

We present a combined atomic force microscopy (AFM) and magnetic force microscopy (MFM) study of bacterial magnetosomes, consisting of membrane-covered magnetite particles. AFM imaging unambiguously demonstrates the existence of single isolated magnetosomes with a size of about 40 nm, in addition to various clusters of magnetosomes. With MFM we have particularly addressed the magnetic properties of single magnetosomes. These nanoparticles behave like single mono-domain nanomagnets, as shown by the comparison of the MFM data to simple simulations. These simulations also provide information on the size of the magnetic kernel of the magnetosomes. Moreover, the invasiveness of the MFM tip is addressed. r 2004 Elsevier B.V. All rights reserved. PACS: 07.79. Pk; 75.50. Tt; 75.60. Ej
Finding Pareto-front Membership Functions in Fuzzy Data Mining

Abstract Transactions with quantitative values are commonly seen in real-world applications. Fuzzy mining algorithms have thus been developed recently to induce linguistic knowledge from quantitative databases. In fuzzy data mining, the membership functions have a critical influence on the final mining results. How to effectively decide the membership functions in fuzzy data mining thus becomes very important. In the past, we proposed a fuzzy mining approach based on the Multi-Objective Genetic Algorithm (MOGA) to find the Pareto front of the desired membership functions. In this paper, we adopt a more sophisticated multi-objective approach, the SPEA2, to find the appropriate sets of membership functions for fuzzy data mining. Two objective functions are used to find the Pareto front. The first one is the suitability of membership functions and the second one is the total number of large 1-itemsets derived. Experimental comparisons of the proposed and the previous approaches are also made to show the effe.