Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of a gas chromatography-mass spectrometry method for breast cancer diagnosis based on nucleoside metabolomes 1-methyl adenosine, 1-methylguanosine, and 8-hydroxy-2'-deoxyguanosine.

Metabolomes are small molecule metabolites (<1000 Da) produced by cellular processes. Metabolomes are close counterparts to the genome, transcriptome, and proteome. The aim of this study was to develop a method to detect and quantify candidate nucleoside metabolomes 1-methyl adenosine (1-MA), 1-methylguanosine (1-MG), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the urine of patients with breast cancer using gas chromatography-mass spectrometry (GC-MS). The method was applied to urine specimens from patients with breast cancer (n=56) and benign breast tumors (n=22), as well as from healthy females (n=20). The relative standard deviations of precision and repeatability analysis were <10%, and recoveries ranged from 88.5% to 105.6%. Limits of detection were 0.014, 0.012, and 0.018 mg/L for 1-MA, 1-MG, and 8-OHdG, respectively. The lower limits of quantitation were 0.056, 0.048, and 0.072 mg/L, respectively. There were significant differences in concentrations of candidate metabolomes between patients with cancer and the healthy individuals, especially for those in the early stages of the disease (p<0.001). No significant differences were observed between the benign and healthy groups. In conclusion, a reliable GC-MS method for detection and quantification of 1-MA, 1-MG, and 8-OHdG metabolomes in urine has been developed.
Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years

The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR‐treated patients and 78 TAC‐treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR‐treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3‐12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m2, respectively (P = 0.90) and adjusted mean change in eGFR from randomization was −8.0 versus −13.5 mL/minute/1.73 m2 (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR‐treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC‐treated patients (P = 0.05). Treated biopsy‐proven acute rejection affected 4 EVR‐treated patients and 2 TAC patients during months 6‐24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR‐treated and TAC‐treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI‐free EVR‐based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.
A comprehensive review and evaluation of computational methods for identifying protein complexes from protein-protein interaction networks

Protein complexes are the fundamental units for many cellular processes. Identifying protein complexes accurately is critical for understanding the functions and organizations of cells. With the increment of genome-scale protein-protein interaction (PPI) data for different species, various computational methods focus on identifying protein complexes from PPI networks. In this article, we give a comprehensive and updated review on the state-of-the-art computational methods in the field of protein complex identification, especially focusing on the newly developed approaches. The computational methods are organized into three categories, including cluster-quality-based methods, node-affinity-based methods and ensemble clustering methods. Furthermore, the advantages and disadvantages of different methods are discussed, and then, the performance of 17 state-of-the-art methods is evaluated on two widely used benchmark data sets. Finally, the bottleneck problems and their potential solutions in this important field are discussed.
Enhanced oral bioavailability of valsartan in rats using a supersaturable self-microemulsifying drug delivery system with P-glycoprotein inhibitors

Abstract Valsartan (VST) is a poorly water-soluble drug and a P-glycoprotein (P-gp) substrate. To enhance the dissolution and oral absorption of VST, a novel supersaturable self-microemulsifying drug delivery system (Su-SMEDDS) was formulated. Based on the previously reported Su-SMEDDS composed of Capmul® MCM (oil), Tween® 20 (T20; surfactant), Transcutol® P (cosurfactant), and Poloxamer 407 (supersaturating agent), P-gp inhibitory surfactants including Tween® 80 (T80) and Cremophor® EL (CR) were newly introduced to replace T20. All Su-SMEDDS formulations had a droplet size of <200 nm and showed rapid (>90% within 5 min) and pH-independent dissolution characteristics. The effective permeability coefficient (Peff) in rat jejunum was obtained using an in situ single-pass intestinal perfusion study: Peff values of Su-SMEDDS-T20, Su-SMEDDS-T80, and Su-SMEDDS-CR were 2.3, 4.1, and 3.4 times greater, respectively, than that of the VST solution. After oral administration of various formulations to rats (equivalent dose of VST 10 mg/kg), plasma drug levels were measured by liquid chromatography-tandem mass spectrometry. The relative bioavailabilities of Su-SMEDDS-T20, Su-SMEDDS-T80, and Su-SMEDDS-CR were 262%, 470%, and 458%, respectively, compared with the VST suspension. Thus, we propose that the Su-SMEDDS-T80 formulation is a good candidate for improving the oral absorption of poorly water-soluble and P-gp substrate drugs such as VST. Graphical Abstract
Benchmarking DFT-D Dispersion Corrections for Anharmonic Vibrational Frequencies and Harmonic Scaling Factors.

Improvements in the form of the DFT-D empirical dispersion corrections to hybrid density functional theory are shown to have made corrections sufficiently accurate to improve the calculation of both anharmonic frequencies and scaled harmonic vibrational frequencies across a wide range of commonly tested molecules. The Becke-Johnson damping function is noted as being particularly versatile across the molecules tested and the B3LYP-D3M(BJ) and B3LYP-D3(CSO) methods are found to be the most widely applicable. Dispersion corrections are shown to be important for accurately describing carbon-hydrogen bond stretching vibrations, and standard triple-dipole based three-body terms are found to cause large errors in these anharmonic frequencies. Preliminary results also indicate that there is a cancellation of error at this level of theory when using smaller finite difference step sizes to calculate anharmonic derivatives of the nuclear potential energy surface.
Ischemia-induced reperfusion injury in muscle flaps: pathogenesis and major source of free radicals.

Abstract Experimental evidence available currently indicates that injury to the muscle during reperfusion is most likely mediated by oxygen-derived free radicals (oxyradicals). The major oxyradical generating system in the skeletal muscle has yet to be identified so that an appropriate oxyradical-generating inhibitor and/or scavenger can be selected for the prevention of ischemia-induced reperfusion injury to the skeletal muscle. In addition, apart from generating oxyradicals, the activated leukocytes, platelets, and vascular endothelial cells are also known to synthesize and release vasoconstrictive substances and/or chemoattractants for leukocytes. The role of these locally released chemical substances in the pathogenesis of ischemia-induced reperfusion injury in muscle flaps has yet to be elucidated. The pathophysiology of ischemia-induced reperfusion injury to the skeletal muscle in muscle flaps is reviewed.
A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor.

AIMS Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR). METHODS AND RESULTS Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10-6 to 8.0 × 10-9), with lower risk of MI (P-trend 0.04-0.002) and lower risk of cardiovascular mortality (P-trend 0.005-0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane. CONCLUSION This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.
Sub-minimum inhibitory concentration ceftazidime inhibits Escherichia coli biofilm formation by influencing the levels of the ibpA gene and extracellular indole

Escherichia coli is a common pathogen of bacterial biofilm infections. Sub-minimum inhibitory concentration ceftazidime (sub-MIC CAZ) could inhibit the biofilm formation of E. coli. Deletion of the ibpAB genes could increase the extracellular indole concentration of E. coli and then inhibit biofilm formation. Therefore, we speculated that sub-MIC CAZ might inhibit biofilm formation via ibpAB. In this study, the results showed that sub-MIC CAZ could significantly inhibit biofilm formation, swimming motility and the expression of the ibpA gene, while it could increase the expression of tnaA gene and extracellular indole concentration. Knockout of the ibpA gene resulted in a decrease in biofilm formation and swimming motility and an increase in the indole concentration. When treated with sub-MIC CAZ, the tnaA gene expression, indole concentration, biofilm formation and swimming motility of MG1655 ΔibpA were similar to those of the control group. The results indicated that sub-MIC CAZ might inhibit the biofilm formation of E. coli by increasing the extracellular indole concentration and downregulating the ibpA gene.
On-Demand Visible-Light Sensing with Optical Memory Capability based on an Electrical Breakdown Triggered Negative Photoconductivity Effect in the Ubiquitous Transparent Hafnia.

A transparent visible light sensor may sound like an oxymoron. Indeed, this scenario is often deemed challenging in conventional photosensitive semiconducting materials due to the complementary relationship between absorbance (which determines photosensitivity) and transmittance (which determines transparency). Past studies have relied on photo-induced ionization of vacancy defect states within a wide bandgap oxide to modulate the flow of current or charge storage in specific device structures such as nanorods, hetero oxide junctions or thin film transistors. Here, we demonstrate visible-light sensing and optical memory functions in a thin, optically transparent wide-bandgap oxide such as the ubiquitous hafnium dioxide, following a soft electrical breakdown. The physical mechanism is distinguished by a persistent current decrease that spans several orders of magnitude, indicating that the breakdown oxide is restored by the visible light. Physical characterization by x-ray photoelectron spectroscopy and first-principles simulation study based on the DFT provide a strong support for the proposed light-assisted recombination of electrically induced Frenkel-pair defects as the underlying mechanism for the observed negative photoconductance response and optical memory effect. By harnessing this alternative mechanism, this work demonstrates a different approach of overcoming the traditional barrier in realizing both transparency and on-demand visible-light sensing with optical memory function all in a single device.
Biotechnology and Bioengineering

Funding information European Union (European Regional Development Fund), Grant/Award Number: 005‐1010‐0009; German Federal Ministry of Education and Research, Grant/Award Number: 031A616M; German Federal State North Rhine‐Westphalia, Grant/Award Number: 005‐1010‐0009 Abstract The continuous production of monoclonal antibodies (mAbs) with the help of disposable equipment poses one of the future major changes in the pharmaceutical industry. Consequently, continuous viral clearance needs to be developed as well. The coiled flow inverter (CFI) was successfully implemented in the continuous downstream as a residence time module for low pH viral inactivation. As the elution profile of the upstream continuously operated protein A chromatography results in fluctuating pH values, the pH level distribution inside the CFI is highly relevant. This study presents a detailed investigation of pH level distribution inside the CFI at varying inlet conditions with the help of computational fluid dynamics simulation. The simulation model was validated first with the help of experimental data. Afterwards, the model was used for further investigations. It was determined that with a pH sine curve as input, the duration until steady state at the outlet requires two times the minimum residence time of the apparatus. Moreover, it could be observed that the CFI itself offers a progressive dampening effect on the pH level distribution. Afterwards, different forms of the sine curve representing different operation modes of the continuous protein A chromatograph were tested to evaluate this dampening capability. It became clear that the switch time has the highest influence on the resulting pH of the outlet stream and should be considered for process development. Finally, the radial pH profiles at different positions inside the CFI were determined. This once again revealed the high radial mixing capability of the CFI and its influence on the resulting product stream.
The use of high flow nasal cannulae in neonatal intensive care units: Is clinical practice consistent with the evidence?

Background: In the recent years, a new treatment modality, high-flow nasa l cannulae (HFNC) has become widely used despite limited systematic evaluation. Objective: To survey the attitudes and practices in academic neonatal units in the United States regarding the use of HFNC and to review the current literature on HFNC. Methods: A questionnaire regarding HFNC use was distributed to all (n = 97) Neonatal-Perinatal Medicine Fellowship Training Program Directors in the United States. Results: Fifty eight (60%) program directors responded to the questionnaire. Of these 40 (69%) reported using heated humidified HFNC (HHHFNC) and 18 (31%) not using this modality. Reported starting flows ranged from 1 to 6 L/min and maximal flows from 2 to 8 L/min. The indication for use of HHHFNC varied between units. Conclusions: The findings of our survey and our review of the literature sug gest that the use of HHHFNC is widespread despite lack of evidence of efficacy from large clinical trials. The i ndications for HHHFNC and the initial, minimal and maximal fl ows varied widely among the centers. This report supports the need for well designed randomized controlled clinical trials to evaluate the efficacy and safety of HHHFNC for a variety of clinical ind ications.
Wallerian degeneration as a therapeutic target in traumatic brain injury.

PURPOSE OF REVIEW Diffuse or traumatic axonal injury is one of the principal pathologies encountered in traumatic brain injury (TBI) and the resulting axonal loss, disconnection, and brain atrophy contribute significantly to clinical morbidity and disability. The seminal discovery of the slow Wallerian degeneration mice (Wld) in which transected axons do not degenerate but survive and function independently for weeks has transformed concepts on axonal biology and raised hopes that axonopathies may be amenable to specific therapeutic interventions. Here we review mechanisms of axonal degeneration and also describe how these mechanisms may inform biological therapies of traumatic axonopathy in the context of TBI. RECENT FINDINGS In the last decade, SARM1 and the DLK/LZK MAPK (Dual leucine zipper bearing kinase/leucine zipper kinase (DLK/LZK) mitogen-activated protein kinases (MAPK)) cascade have been established as the key drivers of Wallerian degeneration, a complex program of axonal self-destruction which is activated by a wide range of injurious insults, including insults that otherwise leave axons structurally robust and potentially salvageable. Detailed studies on animal models and postmortem human brains indicate that this type of partial disruption is the main initial disease in traumatic axonopathy. At the same time, the molecular dissection of Wallerian degeneration has revealed that the decision that commits axons to degeneration is temporally separated from the time of injury, a window that allows potentially effective pharmacological interventions. SUMMARY Molecular signals initiating and triggering Wallerian degeneration appear to be playing an important role in traumatic axonopathy and recent advances in understanding their nature and significance is opening up new therapeutic opportunities for TBI.
Bacteremia and urogenital infection with Actinomyces urogenitalis following prolonged urinary retention

A case of bacteremia with the fastidious bacteria Actinomyces urogenitalis following lengthy urinary retention is reported in a sixty‐year‐old man. In 2013, the first case of bacteremia due to A. urogenitalis was presented, secondary to a tubo‐ovarian abscess following transvaginal oocyte retrieval. To the best of our knowledge, this is the first male bacteremic episode involving A. urogenitalis related to a urinary tract focus. The patient had no prior urogenital medical history. Extensive susceptibility testing was done on isolates from urinary and blood cultures. The organism exhibited fluoroquinolone resistance but was susceptible to most other antibiotics used in the treatment of urinary infections. Due to its unusual growth requirements infections with A. urogenitalis are most likely an underdiagnosed entity.
Depletion of CTCF induces craniofacial malformations in mouse embryos.

Increasing evidence implicates chromatin structure and epigenetic regulation in various human developmental disorders, including facial abnormalities and intellectual disability. Mutations in CCCTC-binding factor (CTCF) demonstrate its role in craniofacial development, but early lethality precludes the use of Ctcf mutant mice for phenotypic investigations. In this study, we deleted Ctcf specifically in neural crest cells, the multipotent cells that give rise to many structures of the skeleton and connective tissues in the developing head. Although the pharyngeal arches were initially morphologically normal, many of the neural crest cell-derived skeletal and non-skeletal components were truncated in the Wnt1-Cre; Ctcffl/fl mutant mice. The expression level of chondrogenic and osteogenic-related genes were significantly decreased. Our results implicate CTCF in two distinct events in craniofacial development; first, in the regulation of outgrowth and morphogenesis by cell survival and proliferation, and second, in the differentiation of the facial skeleton. Our findings highlight the important contribution of CTCF to craniofacial pathologies.
Processed EEG monitoring for anesthesia and intensive care practice.

Individual response to sedatives and hypnotics is characterized by high variability and the identification of a personalized dose during anesthesia in the operating room and during sedation in the intensive care unit may have beneficial effects. Although the brain is the main target of general intravenous and inhaled anesthetic agents, electroencephalography (EEG) is not routinely utilized to explore cerebral response to sedation and anesthesia probably because EEG trace reading is complex and requires encephalographers' skills. Automated processing algorithms (processed EEG, pEEG) of raw EEG traces provide easy-to-use indices that can be utilized to optimize anaesthetic management. A large number of high-quality studies and the recommendations of international scientific societies have confirmed the deleterious consequences of inadequate or excessively deep anesthesia (and sedation) level. In this context, anesthesia in the operating rooms and moderate/deep sedation in intensive care units driven by pEEG monitors could become a standard practice in the near future. The aim of the present review is to provide an overview of current knowledge and debate on available technologies for pEEG monitoring and their role in clinical practice for anesthesia and sedation.
Comparison of murine steatohepatitis models identifies a dietary intervention with robust fibrosis, ductular reaction, and rapid progression to cirrhosis and cancer

Progressive fibrosis, liver failure and cancer are central liver-related outcomes of nonalcoholic steatohepatitis (NASH), but notoriously difficult to achieve in mouse models. We performed a direct, quantitative comparison of hepatic fibrosis progression in well-defined methionine- and choline-deficient (MCD) and choline-deficient, amino-acid defined (CDAA) diets with increasing fat content (10-60% by calories) in C57Bl/6J and BALB/cAnNCrl mice.In C57Bl/6J mice, MCD feeding resulted in moderate fibrosis at week 8 (2-fold increase in hepatic collagen content) and progressive weight loss, irrespective of fat content. In contrast, CDAA-fed mice did not lose weight and developed progressive fibrosis starting from week 4. High dietary fat in the CDAA diet model dose-dependently induced the lipid metabolism genes SREBP and SCD2, and increased the ductular reaction and fibrosis. Longitudinal analysis of CDAA with 60% fat (HF-CDAA) feeding revealed pronounced ductular reaction and perisinusoidal bridging fibrosis, with a 7-fold increase of hepatic collagen at week 12, that showed limited spontaneous reversibility. At 24 weeks, HF-CDAA mice developed signs of cirrhosis with 10-fold HYP increase, regenerative nodules, portal hypertension and elevated serum bilirubin and ammonia; 80% of mice (8/10) developed multiple hepatocellular carcinomas (HCC). High fat supplementation of MCD in C57Bl/6J, or feeding HF-CDAA diet to fibrosis-prone BALB/cAnNCrl strain failed to result in increased fibrosis.In conclusion, HF-CDAA feeding in C57Bl/6J mice was identified as an optimal model of steatohepatitis with robust fibrosis and ductular proliferations that progress to cirrhosis and HCC within 24 weeks. This model will aid the testing of interventions and drugs for severe NASH.