Miracle-dz/UniFAR-FTUs huggingface dataset:
The Pharmacology of Xenobiotics after Intracerebro Spinal Fluid Administration: Implications for the Treatment of Brain Tumors

The incidence of brain metastasis has been increasing for 10 years, with poor prognosis, unlike the improvement in survival for extracranial tumor localizations. Since recent advances in molecular biology and the development of specific molecular targets, knowledge of the brain distribution of drugs has become a pharmaceutical challenge. Most anticancer drugs fail to cross the blood–brain barrier. In order to get around this problem and penetrate the brain parenchyma, the use of intrathecal administration has been developed, but the mechanisms governing drug distribution from the cerebrospinal fluid to the brain parenchyma are poorly understood. Thus, in this review we discuss the pharmacokinetics of drugs after intrathecal administration, their penetration of the brain parenchyma and the different systems causing their efflux from the brain to the blood.
Risk of Skin Cancer among Patients with Chronic Kidney Disease Treated with Ultraviolet B Phototherapy for Uraemic Pruritus: A Nationwide Cohort Study

The safety of ultraviolet B (UVB) phototherapy with respect to cutaneous carcinogenesis has not been established for patients with chronic kidney disease. To investigate this issue, a nationwide cohort study of 10,805 patients with advanced chronic kidney disease was conducted using data from the National Health Insurance of Taiwan, the Taiwan Cancer Registry, and the national death registry. After a median follow-up of 75 months, 16 of 2,161 patients in the UVB group and 63 of 8,644 patients in the non-UVB group developed skin cancers. Compared with the non-UVB group, patients in the UVB group did not show an increased risk of skin cancer (hazard ratio 1.066; 95% confidence interval 0.584–1.944), non-melanoma skin cancer (hazard ratio 1.067; 95% confidence interval 0.571–1.996), or cutaneous melanoma (hazard ratio 1.009; 95% confidence interval 0.115–8.879). In addition, patients who received more UVB phototherapy did not show an increased risk of skin cancer. UVB phototherapy appears to be a safe treatment for uraemic pruritus in patients with chronic kidney disease.
Incorporating Drought and Submergence Tolerance QTL in Rice (Oryza sativa L.)—The Effects under Reproductive Stage Drought and Vegetative Stage Submergence Stresses

Drought and submergence have been the major constraint in rice production. The present study was conducted to develop high-yielding rice lines with tolerance to drought and submergence by introgressing Sub1 into a rice line with drought yield QTL (qDTY; QTL = quantitative trait loci) viz. qDTY3.1 and qDTY12.1 using marker-assisted breeding. We report here the effect of different combinations of Sub1 and qDTY on morpho-physiological, agronomical traits and yield under reproductive stage drought stress (RS) and non-stress (NS) conditions. Lines with outstanding performance in RS and NS trials were also evaluated in vegetative stage submergence stress (VS) trial to assess the tolerance level. The QTL class analysis revealed Sub1 + qDTY3.1 as the best QTL combination affecting the measured traits in RS trial followed by Sub1 + qDTY12.1. The effects of single Sub1, qDTY3.1 and qDTY12.1 were not as superior as when the QTLs are combined, suggesting the positive interaction of Sub1 and qDTY. Best performing lines selected from the RS and NS trials recorded yield advantage up to 4453.69 kg ha−1 and 6954 kg ha−1 over the parents, respectively. The lines were also found having great tolerance to submergence ranging from 80% to 100%, contributed by a lower percentage of shoot elongation and reduction of chlorophyll content after 14 days of VS. These lines could provide yield sustainability to farmers in regions impacted with drought and submergence while serving as important genetic materials for future breeding programs.
Evaluation of Pharmacokinetic Drug–Drug Interactions: A Review of the Mechanisms, In Vitro and In Silico Approaches

Pharmacokinetic drug–drug interactions (DDIs) occur when a drug alters the absorption, transport, distribution, metabolism or excretion of a co-administered agent. The occurrence of pharmacokinetic DDIs may result in the increase or the decrease of drug concentrations, which can significantly affect the drug efficacy and safety in patients. Enzyme-mediated DDIs are of primary concern, while the transporter-mediated DDIs are less understood but also important. In this review, we presented an overview of the different mechanisms leading to DDIs, the in vitro experimental tools for capturing the factors affecting DDIs, and in silico methods for quantitative predictions of DDIs. We also emphasized the power and strategy of physiologically based pharmacokinetic (PBPK) models for the assessment of DDIs, which can integrate relevant in vitro data to simulate potential drug interaction in vivo. Lastly, we pointed out the future directions and challenges for the evaluation of pharmacokinetic DDIs.
Quantifying sequencing error and effective sequencing depth of liquid biopsy NGS with UMI error correction.

Liquid biopsies are a minimally invasive method to diagnose and longitudinally monitor tumor mutations in patients when tissue biopsies are difficult (e.g., in lung cancer). The percentage of cell-free tumor DNA in blood plasma ranges from more than 65% to 0.1% or lower. To reliably diagnose tumor mutations at 0.1%, there are two options: unrealistically large volumes of patient blood or library preparation and sequencing depth optimized to low-input DNA. Here, we assess two library preparation methods and analysis workflows to determine feasibility and reliability based on standards with known allelic frequency (0 and 0.13% in PIK3CA). However, the implementation for patients is still costly and requires elaborate setups.
Druggable Transient Pockets in Protein Kinases

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites. ” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.
Digital Surface Regularization With Guarantees

Voxel based modeling is a very attractive way to represent complex multi-material objects. Beside artistic choices of pixel/voxel arts, representing objects as voxels allows efficient and dynamic interactions with the scene. For geometry processing purposes, many applications in material sciences, medical imaging or numerical simulation rely on a regular partitioning of the space with labeled voxels. In this article, we consider a variational approach to reconstruct interfaces in multi-labeled digital images. This approach efficiently produces piecewise smooth quadrangulated surfaces with some theoretical stability guarantee. Non-manifold parts at intersecting interfaces are handled naturally by our model. We illustrate the strength of our tool for digital surface regularization, as well as voxel art regularization by transferring colorimetric information to regularized quads and computing isotropic geodesic on digital surfaces.
Assessing the Mechanism of Fluoxetine-Mediated CYP2D6 Inhibition

Fluoxetine is still one of the most widely used antidepressants in the world. The drug is extensively metabolized by several cytochrome P450 (CYP450) enzymes and subjected to a myriad of CYP450-mediated drug interactions. In a multidrug regimen, preemptive mitigation of drug–drug interactions requires knowledge of fluoxetine actions on these CYP450 enzymes. The major metabolic pathway of fluoxetine leading to the formation of its active metabolite, norfluoxetine, is mediated by CYP2D6. Fluoxetine and norfluoxetine are strong affinity substrates of CYP2D6 and can inhibit, potentially through various mechanisms, the metabolism of other sensitive CYP2D6 substrates. Remarkably, fluoxetine-mediated CYP2D6 inhibition subsides long after fluoxetine first passes through the liver and even remains long after the discontinuation of the drug. Herein, we review pharmacokinetic and pharmacogenetic information to help us understand the mechanisms underlying the prolonged inhibition of CYP2D6 following fluoxetine administration. We propose that long-term inhibition of CYP2D6 is likely a result of competitive inhibition. This is due to strong affinity binding of fluoxetine and norfluoxetine to the enzyme and unbound fluoxetine and norfluoxetine levels circulating in the blood for a long period of time because of their long elimination half-life. Additionally, we describe that fluoxetine is a CYP2C9 substrate and a mechanism-based inhibitor of CYP2C19.
Radiation-induced cardiovascular disease: an overlooked role for DNA methylation?

ABSTRACT Radiotherapy in cancer treatment involves the use of ionizing radiation for cancer cell killing. Although radiotherapy has shown significant improvements on cancer recurrence and mortality, several radiation-induced adverse effects have been documented. Of these adverse effects, radiation-induced cardiovascular disease (CVD) is particularly prominent among patients receiving mediastinal radiotherapy, such as breast cancer and Hodgkin’s lymphoma patients. A number of mechanisms of radiation-induced CVD pathogenesis have been proposed such as endothelial inflammatory activation, premature endothelial senescence, increased ROS and mitochondrial dysfunction. However, current research seems to point to a so-far unexamined and potentially novel involvement of epigenetics in radiation-induced CVD pathogenesis. Firstly, epigenetic mechanisms have been implicated in CVD pathophysiology. In addition, several studies have shown that ionizing radiation can cause epigenetic modifications, especially DNA methylation alterations. As a result, this review aims to provide a summary of the current literature linking DNA methylation to radiation-induced CVD and thereby explore DNA methylation as a possible contributor to radiation-induced CVD pathogenesis. Graphical abstract
Insight into formation propensity of pseudocircular DNA G-hairpins

Abstract We recently showed that Saccharomyces cerevisiae telomeric DNA can fold into an unprecedented pseudocircular G-hairpin (PGH) structure. However, the formation of PGHs in the context of extended sequences, which is a prerequisite for their function in vivo and their applications in biotechnology, has not been elucidated. Here, we show that despite its ‘circular’ nature, PGHs tolerate single-stranded (ss) protrusions. High-resolution NMR structure of a novel member of PGH family reveals the atomistic details on a junction between ssDNA and PGH unit. Identification of new sequences capable of folding into one of the two forms of PGH helped in defining minimal sequence requirements for their formation. Our time-resolved NMR data indicate a possibility that PGHs fold via a complex kinetic partitioning mechanism and suggests the existence of K+ ion-dependent PGH folding intermediates. The data not only provide an explanation of cation-type-dependent formation of PGHs, but also explain the unusually large hysteresis between PGH melting and annealing noted in our previous study. Our findings have important implications for DNA biology and nanotechnology. Overrepresentation of sequences able to form PGHs in the evolutionary-conserved regions of the human genome implies their functionally important biological role(s).
MOLECULAR RECOGNITION OF THIOL-TERMINATED β-CYCLODEXTRIN DERIVATIVE BY USING QUARTZ CRYSTAL MICROBALANCE

The thiol-terminated β-cyclodextrin derivative (β-CDd) was attached to the surface of a gold electrode of quartz crystal resonator by self-assembly. The inclusion reactions of benzene derivatives and naphthalene derivatives with β-CDd were monitored in situ by using a quartz crystal microbalance (QCM). The influences of temperature, concentration, the number of substituting groups, and their positions on an aromatic ring on the inclusion constant and the rate constant were investigated. The results indicated that the stoichiometry of the inclusion complexes formed is 1:1 for the host β-CDd with various guest benzene derivatives and naphthalene derivatives, and the kinetics of their formation were fitted for the Langmuir adsorption equation. The β-CDd has good selective recognition ability as to the molecular volume, the number of substituting groups, and their positions on an aromatic ring of guest.
Recognition of industrial machine parts based on transfer learning with convolutional neural network

As the industry gradually enters the stage of unmanned and intelligent, factories in the future need to realize intelligent monitoring and diagnosis and maintenance of parts and components. In order to achieve this goal, it is first necessary to accurately identify and classify the parts in the factory. However, the existing literature rarely studies the classification and identification of parts of the entire factory. Due to the lack of existing data samples, this paper studies the identification and classification of small samples of industrial machine parts. In order to solve this problem, this paper establishes a convolutional neural network model based on the InceptionNet-V3 pretrained model through migration learning. Through experimental design, the influence of data expansion, learning rate and optimizer algorithm on the model effectiveness is studied, and the optimal model was finally determined, and the test accuracy rate reaches 99.74%. By comparing with the accuracy of other classifiers, the experimental results prove that the convolutional neural network model based on transfer learning can effectively solve the problem of recognition and classification of industrial machine parts with small samples and the idea of transfer learning can also be further promoted.
Subglottic stenosis imitating the carina – a case report of airway mimicry

We present a case of awake tracheal intubation with flexible bronchoscopy which resulted in incorrect tracheal tube placement. The presence of a stenotic subglottic lesion with an appearance similar to the carina led to the tube being positioned with only the tip within the trachea whilst the cuff was located between the vocal cords. A capnography trace was identified before induction of anaesthesia; however, visual confirmation of the carina was undertaken in a rushed manner due to the patient becoming agitated. Once the incorrect tracheal tube placement was identified, the decision was made to wake the patient. Thereafter, a more experienced operator successfully performed awake tracheal intubation with flexible bronchoscopy using a smaller tracheal tube, which easily passed through the subglottic stenosis. This report emphasises the importance of performing the ‘two‐point check’ every time awake tracheal intubation is undertaken: to confirm correct tube placement, both a capnography trace and view of the tracheal lumen including the carina and main bronchi is required. This must be properly performed before induction of anaesthesia; safety should not be compromised by a stressful environment or time pressure.
The assessment of the effect of different intraabdominal pressures used for laparoscopic cholecystectomy surgery on optic nerve sheath diameter: a prospective observational cohort study

Background/aim During laparoscopic cholecystectomy operations, increases in intraabdominal, intrathoracic, and intracranial pressures (ICP) can be seen after pneumoperitoneum created for surgical imaging. Orbital ultrasonography (USG), which has been developed in recent years, is a method that can evaluate the ICP by measuring the optic nerve sheath diameter (ONSD) from the eyeball.In our study, we aimed to evaluate whether different intraabdominal pressure values created during laparoscopic cholecystectomy operations correlate with ICP by measuring ONSD. Materials and methods The study included a total of 90 patients with American Society of Anesthesiologists (ASA) physical status classification I (ASA I) and II (ASA II) and ages from 18 to 65 years with laparoscopic cholecystectomy planned.After the patients were intubated, at the 5th min, bilateral ONSD measurements were performed. The same measurements were performed at the 15th and 30th min after CO2 insufflation and additionally 10 min after CO2 was released at the end of the operation. During intrabdominal CO2 insufflation, patients with 10 mmHg pressure applied comprised Group 1, patients with 12 mmHg pressure applied comprised Group 2, and patients with 14 mmHg pressure applied comprised Group 3. Results The study was completed with 89 patients, 51 female and 38 males. One patient was excluded from the study due to erroneous values. The variations in ONSD measured in the right-left eye before pneumoperitoneum and at the 15th and 30th min after abdominal CO2 insufflation were observed to be statistically significant (p < 0.01). In all three groups, the right and left eye ONSD values were not identified to be statistically significantly different (p > 0.01). A significant increase was observed in ONSD values in direct proportion to the increase in intraabdominal pressure in patients undergoing laparoscopic cholecystectomy surgery. Conclusion USG-guided ONSD measurements appear be a guide to ensure optimization of intraabdominal pressures and safe anesthesia administration for patients, especially those at risk of ICP increase, during laparoscopic surgery.
Comparative Analysis of the Polyphenols, Caffeine, and Antioxidant Activities of Green Tea, White Tea, and Flowers from Azorean Camellia sinensis Varieties Affected by Different Harvested and Processing Conditions

This study evaluates the polyphenol profiles as well as caffeine (dry weight basis), and antioxidant activities of green tea (GTs), white tea (WTs), and flowers (Fl) samples from Azorean Camellia sinensis varieties affected by different harvested and processing conditions. Epicatechins derivatives, determined by RP-HPLC/PDAD, presented higher values in GTs with respect to WTs, decreasing as follows: epigallocatechin-3-gallate > epicatechin-3-gallate ≫ epicatechin ≫ epigallocatechin, and higher values in summer and early autumn than in spring. This was also accompanied by an in consistent withering time pattern. Esterified catechins were higher in all samples (100.8–312.3 mg/g) with respect to non-esterified catechins (15.1–37.7 mg/g). Caffeine (6.2–27.7 mg/g) decreased as follows: WTs > GTs ≫ Fl, and inconsistent seasonal and withering patterns were observed among the WTs. Total phenolics (125.9–295.4 mg gallic acid equivalents/g dried extract) and total flavonoids (35.2–69.7 mg rutin equivalents/g dried extract), determined by Folin–Ciocalteu and colorimetric methodologies, were higher in GTs than in WTs and Fl. Concerning the antioxidant patterns, the free radical scavenging activity (FRSA) and ferric reducing antioxidant power (FRAP) presented EC50 values ranges from 3.6 to 17.3 µg/mL and 4.8 to 16.5 µg/mL, respectively, and ferrous ion-chelating (FIC) activity ranged from 47.1 to 82.8%, highlighting that FRSA was better than butylated hydroxytoluene (BHT). Tea leaves exhibited, in general, higher activities with respect to tea Fl, and the WT sample plucked in summer and withered for 23 h showed the highest FRAP and FIC activity. In conclusion, this study shows the characteristic variation of GTs, WTs, and Fl of two tea varieties and may support crop quality improvement and promote the valorization of tea Fl.
Hepatitis E Virus Occurrence in Pigs Slaughtered in Italy

Simple Summary Hepatitis E is now recognized as an emerging zoonotic disease in Europe caused by an RNA virus (HEV) and foodborne is the main route of transmission. Human cases have been linked to the consumption of contaminated pig liver sausages, raw venison, or undercooked wild boar meat. The zoonotic genotype HEV-3 is widespread in pigs at farm level but little information is available on the occurrence of HEV-positive pigs at the slaughterhouse. The aim of this study was to investigate the prevalence of HEV-positive pigs during slaughtering, to understand which biological samples (feces and organs) were more frequently HEV positive. Our results showed that pigs positive for HEV can be slaughtered and that the percentage of positive animals depends on the age of animals. The other main result is the presence of the virus in the plasma of animals, which may contribute to the contamination of meat (muscle). Nevertheless, muscles are rarely contaminated by HEV-RNA compared to liver, which is the organ of replication. Abstract In Europe, foodborne transmission has been clearly associated to sporadic cases and small clusters of hepatitis E in humans linked to the consumption of contaminated pig liver sausages, raw venison, or undercooked wild boar meat. In Europe, zoonotic HEV-genotype 3 strains are widespread in pig farms but little information is available on the prevalence of HEV positive pigs at slaughterhouse. In the present study, the prevalence of HEV-RNA positive pigs was assessed on 585 animals from 4 abattoirs located across Italy. Twenty-one pigs (3.6%) tested positive for HEV in either feces or liver by real-time RT-PCR. In these 21 pigs, eight diaphragm muscles resulted positive for HEV-RNA. Among animals collected in one abattoir, 4 out of 91 plasma tested positive for HEV-RNA. ELISA tests for the detection of total antibodies against HEV showed a high seroprevalence (76.8%), confirming the frequent exposure of pigs to the virus. The phylogenetic analyses conducted on sequences of both ORF1 and ORF2 fragments, shows the circulation of HEV-3c and of a novel unclassified subtype. This study provides information on HEV occurrence in pigs at the slaughterhouse, confirming that muscles are rarely contaminated by HEV-RNA compared to liver, which is the most frequently positive for HEV.