Miracle-dz/UniFAR-FTUs huggingface dataset:
A Glycoengineered Interferon-β Mutein (R27T) Generates Prolonged Signaling by an Altered Receptor-Binding Kinetics

The glycoengineering approach is used to improve biophysical properties of protein-based drugs, but its direct impact on binding affinity and kinetic properties for the glycoengineered protein and its binding partner interaction is unclear. Type I interferon (IFN) receptors, composed of IFNAR1 and IFNAR2, have different binding strengths, and sequentially bind to IFN in the dominant direction, leading to activation of signals and induces a variety of biological effects. Here, we evaluated receptor-binding kinetics for each state of binary and ternary complex formation between recombinant human IFN-β-1a and the glycoengineered IFN-β mutein (R27T) using the heterodimeric Fc-fusion technology, and compared biological responses between them. Our results have provided evidence that the additional glycan of R27T, located at the binding interface of IFNAR2, destabilizes the interaction with IFNAR2 via steric hindrance, and simultaneously enhances the interaction with IFNAR1 by restricting the conformational freedom of R27T. Consequentially, altered receptor-binding kinetics of R27T in the ternary complex formation led to a substantial increase in strength and duration of biological responses such as prolonged signal activation and gene expression, contributing to enhanced anti-proliferative activity. In conclusion, our findings reveal N-glycan at residue 25 of R27T is a crucial regulator of receptor-binding kinetics that changes biological activities such as long-lasting activation. Thus, we believe that R27T may be clinically beneficial for patients with multiple sclerosis.
Transduction of Adeno-Associated Virus Vectors Targeting Hair Cells and Supporting Cells in the Neonatal Mouse Cochlea

Adeno-associated virus (AAV) is the preferred vector for gene therapy of hereditary deafness, and different viral serotypes, promoters and transduction pathways can influence the targeting of AAV to different types of cells and the expression levels of numerous exogenous genes. To determine the transduction and expression patterns of AAV with different serotypes or promoters in hair cells and supporting cells in the neonatal mouse cochlea, we examined the expression of enhanced green fluorescent protein (eGFP) for five different types of AAV vectors [serotypes 2, 9, and Anc80L65 with promoter cytomegalovirus (CMV)-beta-Globin and serotypes 2 and 9 with promoter chicken beta-actin (CBA)] in in vitro cochlear explant cultures and we tested the transduction of AAV2/2-CBA, AAV2/9-CBA, and AAV2/Anc80L65-CMV by in vivo microinjection into the scala media of the cochlea. We found that each AAV vector had its own transduction and expression characteristics in hair cells and supporting cells in different regions of the cochlea. There was a tonotopic gradient for the in vitro transduction of AAV2/2-CBA, AAV2/9-CBA, AAV2/2-CMV, and AAV2/9-CMV in outer hair cells (OHCs), with more OHCs expressing eGFP at the base of the cochlea than at the apex. AAV2/2-CBA in vitro and AAV2/Anc80L65-CMV in vivo induced more supporting cells expressing eGFP at the apex than in the base. We found that AAV vectors with different promoters had different expression efficacies in hair cells and supporting cells of the auditory epithelium. The CMV-beta-Globin promoter could drive the expression of the delivered construct more efficiently in hair cells, while the CBA promoter was more efficient in supporting cells. The in vitro and in vivo experiments both demonstrated that AAV2/Anc80L65-CMV was a very promising vector for gene therapy of deafness because of its high transduction rates in hair cells. These results might be useful for selecting the appropriate vectors for gene delivery into different types of inner ear cells and thus improving the effectiveness of gene therapy.
Gut Microbiota and Energy Homeostasis in Fish

The microorganisms within the intestinal tract (termed gut microbiota) have been shown to interact with the gut-brain axis, a bidirectional communication system between the gut and the brain mediated by hormonal, immune, and neural signals. Through these interactions, the microbiota might affect behaviors, including feeding behavior, digestive/absorptive processes (e.g., by modulating intestinal motility and the intestinal barrier), metabolism, as well as the immune response, with repercussions on the energy homeostasis and health of the host. To date, research in this field has mostly focused on mammals. Studies on non-mammalian models such as fish may provide novel insights into the specific mechanisms involved in the microbiota-brain-gut axis. This review describes our current knowledge on the possible effects of microbiota on feeding, digestive processes, growth, and energy homeostasis in fish, with emphasis on the influence of brain and gut hormones, environmental factors, and inter-specific differences.
The Extracellular Protein, Transthyretin Is an Oxidative Stress Biomarker

The extracellular protein, transthyretin is responsible for the transport of thyroxin and retinol binding protein complex to the various parts of the body. In addition to this transport function, transthyretin has also been involved in cardiovascular malfunctions, polyneuropathy, psychological disorders, obesity and diabetes, etc. Recent developments have evidenced that transthyretin has been associated with many other biological functions that are directly or indirectly associated with the oxidative stress, the common hallmark for many human diseases. In this review, we have attempted to address that transthyretin is associated with oxidative stress and could be an important biomarker. Potential future perspectives have also been discussed.
Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol–Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03 μm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.
Inhibitory Effect of 20(S)-Ginsenoside Rg3 on Human Platelet Aggregation and Intracellular Ca2+ Levels via Cyclic Adenosine Monophosphate Dependent Manner

Intracellular Ca2+ ([Ca2+]i) induces platelet aggregation, and influences the activation of aggregation associated-molecules. The increased [Ca2+]i activates both the Ca2+/calmodulin-dependent phosphorylation of the myosin light chain and the diacylglycerol-dependent phosphorylation of pleckstrin to trigger granule secretion (i.e., dense body and α-granule) and platelet aggregation. This study was carried out to elucidate the antagonistic effect of 20(S)-ginsenoside Rg3 (G-Rg3) present in Panax ginseng Mayer on Ca2+. G-Rg3 inhibited thrombin-induced human platelet aggregation in a dose-dependent manner and suppressed thrombin-induced elevation of [Ca2+]i mobilization. G-Rg3 increased the levels of cAMP, and subsequently, elevated the phosphorylation of inositol 1,4,5-triphosphate receptor I (Ser1756) during thrombin-induced human platelet aggregation. Moreover, G-Rg3 inhibited thapsigargin-induced Ca2+ influx and the thrombin-induced elevation of extracellular signal-regulated kinase 2 phosphorylation. G-Rg3 exhibited an inhibitory effect on [Ca2+]i levels leading to granule release and thus a therapeutic potential against platelet-mediated thrombotic disease is suggested.
Antidiarrheal Efficacy of Probiotic Bacteria in Castor Oil Induced Diarrheal Mice

Probiotics may offer a safe intervention for diarrheal diseases. The aim of the present study was the assessment of the antidiarrheal property of probiotic bacteria. For their antidiarrheal efficacy assessment, yogurt was prepared using the isolated bacteria from selective regional yogurt of Bangladesh, and mice model trails were conducted using castor oil induced diarrheal mice. The probiotic treatment was applied on three mice groups, each having 6 mice and their respective doses were 50 mL/kg body weight in treatment group (TG) 1, 100 mL/kg body weight in TG2, and 150 mL/kg body weight in TG3. A four week treatment of probiotic significantly (P<0.001) reduced the percentage (67.37%) of diarrhea in TG3 (150 mL yogurt/kg body weight). All the treatment groups showed a significant (P<0.001) increase in the latent periods, reduced the total fecal output, and frequency and fecal water content compared to the negative control group. Serum electrolytes (Na+ and K+) and total protein levels were higher in the TG3 compared to the negative control group. Further research regarding molecular characterization and identification of specific genes and proteins of interest may help to develop the next generation bacteriocins and antidiarrheal drugs.
Let-7b acts as a tumor suppressor in osteosarcoma via targeting IGF1R

MicroRNAs serve crucial functions in cancer progression by inhibiting the translation of target genes and causing mRNA degradation. However, the underlying regulatory mechanism of Let-7b in osteosarcoma (OS) has not, to the best of our knowledge, been comprehensively elucidated. The aim of the present study was to investigate the function of Let-7b in OS and clarify the regulation of insulin-like growth factor 1 receptor (IGF1R) by Let-7b. It was observed that Let-7b was significantly downregulated in OS tissues and cell lines compared with the matched adjacent non-tumorous tissues and human normal osteoblastic cell line hFOB 1.19. Overexpression of Let-7b significantly inhibited the proliferation and invasion of U2OS and SAOS-2 cells. A luciferase reporter assay validated that IGF1R was a downstream and functional target of Let-7b. Let-7b was also able to decrease the expression levels of IGF1R protein. Functional studies revealed that the antitumor effect of Let-7b was probably due to targeting and suppressing IGF1R expression. Furthermore, in OS tissues, IGF1R was identified to be significantly upregulated and negatively correlated with Let-7b levels. In conclusion, the results of the present study indicated that Let-7b suppresses OS cellular proliferation and invasion via targeting IGF1R. A novel candidate prognostic factor was identified and it is suggested that the Let-7b/IGF1R axis may represent a novel anti-metastasis therapeutic target in OS.
Expression and selective activation of somatostatin receptor subtypes induces cell cycle arrest in cancer cells

Somatostatin receptors (SSTRs) are G-protein-coupled plasma membrane receptors that have been determined to be expressed in normal and cancer tissues. Activation of SSTRs frequently results in inhibition of cell proliferation and therefore somatostatin analogues (SSAs) have been used in cancer treatment. However, the variable outcomes of SSA treatment were considered to be the consequences of loss-of-expression of SSTRs and/or subtype-specific effects. In the present study, the patterns of SSTR expression in 160 breast cancer tissues were investigated, and the mechanisms of SSTR activation and the influence on cell proliferation were further characterized. The expression levels of SSTR1-5 were determined using immunohistology. Hemagglutinin-SSTR1 and MYC-SSTR4 were transiently overexpressed in MDA-MB-435S cells, and the potential receptor dimerization was determined using immunofluorescence and co-immunoprecipitation. The influence of SSTR1 and SSTR4 expression/activation on cell proliferation was monitored using flow cytometry. The results demonstrated that all five SSTR subtypes were expressed at variable levels in tumor tissues, with the highest positive expression instance being determined for SSTR1 and SSTR4, with positive expression levels in 90.0 and 71.3% of tumor tissues, respectively. Immunofluorescence and co-immunoprecipitation revealed SSTR1/SSTR4 heterodimerization, which was increased in response to receptor activation using the subtype-specific SSA L-803087. The translocation of SSTR1/SSTR4 dimers into the cytoplasm upon receptor activation was also observed. Additionally, it was identified using flow cytometry that co-expression and activation of SSTR1 and SSTR4 in MDA-MB-435S cells resulted in a decreased proportion of S-phase cells. The results of the present study revealed that SSTR1 and SSTR4 are the most frequently expressed SSTR subtypes in breast cancer, and that the cell cycle arrest was mediated by SSTR1/SSTR4 dimerization/activation.
Circulating tumor DNA detection: A potential tool for colorectal cancer management

Colorectal cancer (CRC) is frequently diagnosed at an advanced stage of the disease, the pathogenesis of which is influenced by genetic and epigenetic events. Circulating tumor DNA (ctDNA) is extracellular DNA that is present in a number of bodily fluids, including blood, synovial fluid and cerebrospinal fluid. Compared with performing a tissue biopsy, ctDNA examination presents the advantages of minimal invasion and greater convenience. ctDNA is commonly used to identify actionable genomic alterations, monitor treatment responses, unravel therapeutic resistance and potentially detect disease progression prior to clinical and radiological confirmation. The technique can potentially serve as a non-invasive diagnostic tool in personalized medicine, as it demonstrates prognostic value in the management of patients with CRC. ctDNA detection continues to demonstrate inherent advantages compared with other methods, thus serving an increasingly important role in tumor monitoring and oncotherapy. The aim of the current review was to explore the clinical applications of ctDNA in patients with CRC, including early detection and screening, medication guidance, resistance prediction, and residual lesion and recurrence monitoring. Furthermore, several technical methods for ctDNA detection and analysis are explored, as well as other potential biomarkers.
Correlation analysis of IL-4, IL-10 and APN levels with postoperative infection of colorectal cancer

Changes in expression levels of serum interleukin-4 (IL-4), IL-10 and adiponectin (APN) in patients with postoperative infection of colorectal cancer were studied. The clinical data of 159 patients receiving radical surgery for colorectal cancer in Xiangyang No. 1 People's Hospital, Hubei University of Medicine from January 2014 to December 2017, were retrospectively analyzed. A total of 67 patients with postoperative infection were enrolled into the infection group, while the remaining 92 patients without infection were enrolled into the non-infection group. The expression levels of serum IL-4, IL-10 and APN of patients were detected via enzyme-linked immunosorbent assay. The correlation of IL-4, IL-10 and APN levels with stage of colorectal cancer were explored by the Spearmans correlation analysis. The expression levels of IL-4 and IL-10 in the infection group were significantly higher than those in the non-infection group at day 3 after surgery (P<0.05). The expression level of APN in the infection group was lower than that in the non-infection group at day 3 after surgery (P<0.05). The serum IL-4 and IL-10 levels in pulmonary infection was higher and the serum IL-10 level in pulmonary infection was higher than those in incision infection and abdominal infection (P<0.05). The IL-4 and IL-10 levels in patients with colorectal cancer in the infection group at day 3 after surgery had a significant positive correlation with the stage of colorectal cancer (r=0.9357, P<0.001; r=0.9717, P<0.001), and the APN level in patients with colorectal cancer in the infection group at day 3 after surgery had a significant negative correlation with the stage of colorectal cancer (r=−0.9736, P<0.001). The serum IL-4 and IL-10 levels in patients with postoperative infection of colorectal cancer are positively correlated with the stage of cancer, while the serum APN level was negatively correlated with the stage of cancer.
Efficacy and safety of consolidation chemotherapy during the resting period in patients with local advanced rectal cancer

It remains controversial as to whether a long interval between neoadjuvant chemoradiotherapy (NCRT) and surgery may provide clinical benefits for patients with local advanced rectal cancer (LARC). The addition of consolidation chemotherapy during the resting period was recently considered as a treatment option. The present study aimed to verify the efficacy and safety of consolidation chemotherapy during the resting period in patients with LARC. A total of 156 patients with local advanced stage T3-4N0-2 rectal cancer were enrolled between January 2010 and July 2016. Patients were divided into two groups, those who received consolidation chemotherapy prior to surgery (n=76) and the control group who did not (n=80). Multivariate logistic regression and the Kaplan-Meier method were used to explore the predictors of pathological complete response (pCR) and survival. The demographic and tumor characteristics were comparable between the two groups. The consolidation group yielded significantly higher pCR and near pCR rates compared with the control group (P=0.015). Patients in the consolidation group who also underwent standard adjuvant chemotherapy displayed improved 3-year disease-free survival (DFS) compared with the control group (P=0.036). Notably, the addition of consolidation chemotherapy between NCRT and surgery did not significantly increase the incidence of surgical complications and grade 3 or 4 toxicities when compared with the control group. Consolidation chemotherapy was associated with increased pCR/near pCR rates and improved 3-year DFS, and displayed a manageable safety profile. The present study provided primary evidence for the efficacy and safety of consolidation chemotherapy in LARC. Further prospective studies are warranted in the future to verify these results.
SUN2: A potential therapeutic target in cancer

The incidence of cancer is increasing at an alarming rate despite recent advances in prevention strategies, diagnostics and therapeutics for various types of cancer. The identification of novel biomarkers to aid in prognosis and treatment for cancer is urgently required. Uncontrolled proliferation and dysregulated apoptosis are characteristics exhibited by cancer cells in the initiation of various types of cancer. Notably, aberrant expression of crucial oncogenes or cancer suppressors is a defining event in cancer occurrence. Research has demonstrated that SAD1/UNC84 domain protein-2 (SUN2) serves a suppressive role in breast cancer, atypical teratoid/rhabdoid tumors and lung cancer progression. Furthermore, SUN2 inhibits cancer cell proliferation, migration and promotes apoptosis. Recent reports have also shown that SUN2 serves prominent roles in resistance to the excessive DNA damage that destabilizes the genome and promotes cancer development, and these functions of SUN2 are critical for evading initiation of cancer. Additionally, increasing evidence has demonstrated that SUN2 is involved in maintaining cell nuclear structure and appears to be a central component for organizing the natural nuclear architecture in cancer cells. The focus of the present review is to provide an overview on the pharmacological functions of SUN2 in cancers. These findings suggest that SUN2 may serve as a promising therapeutic target and novel predictive marker in various types of cancer.
Highly Qualified Women in the ‘New Europe’: Territorial Sex Segregation

The proportion of women in highly qualified scientific employment in central and eastern Europe and the Baltic States (CEEC-10) is higher than in western Europe. However, this relatively high representation is counteracted by unequal access to resources. This is illustrated by a new measure, the ‘honeypot indicator’. The focus of the EU ‘Lisbon strategy’ summit on increasing overall numbers of scientists does little to address the key issues of retention and advancement. Although social closure mechanisms may undermine the employment prospects of highly qualified women, the conclusion is that the accession of the CEEC-10 to the ‘mainstreaming’ of equal opportunities proclaimed by the European Union provides the best hope of improvement for their employment prospects.
Pricing of Passport Option

Passport options are derivatives on actively managed funds. There is no known explicit formula for the price of passport options in general. We estimate and analyze the value function, and give the condition that the optimal strategy becomes trivial. We also show an approximation theorem which enables us to compute the value function numerically. Finally we give the explicit formula for the value function in the case that the interest rate is zero by using stochastic analytic approach. This is somehow done in symmetric case by Hyer, Lipton-Lifschitz, and Pugachevsky using partial differential equation approach. Many traded securities are managed in the trading account. The value of the trading account is the wealth accumulated by trading the securities following to some trading strategies. The derivative security called "Pass- port option" is the contract that an option holder has the right to gain the positive part of trading account at maturity. The option holder executes a trading strategy (fictitiously) which is chosen by himself in the class of strategies specified in the contract, and whenever the option holder changes the position, he has to report the amount of security to the option writer. In this paper we suppose that there is one traded security whose value process St follows Black & Scholes model (1), i.e. under the risk neutral measure P , St satisfies dSt = St(rdt + σdBt),