Miracle-dz/UniFAR-FTUs huggingface dataset:
STAT3/NF-κB-Regulated Lentiviral TK/GCV Suicide Gene Therapy for Cisplatin-Resistant Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents approximately 20% of all breast cancers and appears resistance to conventional cytotoxic chemotherapy, demonstrating a particularly poor prognosis and a significantly worse clinical outcome than other types of cancer. Suicide gene therapy has been used for the in vivo treatment of various solid tumors in recent clinical trials. In tumor microenvironment, STAT3/NF-κB pathways are constitutively activated in stromal cells as well as in cancer stem cells (CSCs). In this study, we have cloned a novel STAT3/NF-κB-based reporter system to drive the expression of herpes simplex virus thymidine kinase (HSV-TK) against breast cancer. Lentiviral vector expressing HSV-TK under the regulation of STAT3/NF-κB fused response element was developed. In this setting, we exploited the constitutive STAT3/NF-κB activation in tumors to achieve higher transgene expression than that driven by a constitutively active CMV promotor in vivo. An orthotropic MDA-MB-231 triple negative breast cancer mouse model was used for evaluating the feasibility of STAT3-NF-κB-TK/GCV suicide gene therapy system. The basal promoter activity of Lenti-CMV-TK and Lenti-STAT3-NF-κB-TK in MDA-MB-231 cells was compared by 3H-FEAU uptake assay. The Lenti-CMV-TK showed ~5 fold higher 3H-FEAU uptake then Lenti -STAT3-NF-κB-TK. In clonogenic assay, cells expressing Lenti-CMV-TK were 2-fold more sensitive to GCV than Lenti-STAT3-NF-κB-TK transduced cells. In vitro effect of STAT3-NF-κB-induced transgene expression was determined by 10ng/mL TNF-α induction and confirmed by western blot analysis and DsRedm fluorescent microscopy. In vivo evaluation of therapeutic effect by bioluminescence and [18F]FHBG microPET imaging indicated that Lenti-STAT3-NF-κB-TK showed more tumor growth retardation than Lenti-CMV-TK when GCV (20 mg/kg) was administered. The invasiveness and expression of cancer stem cell markers were both decreased after STAT3/NF-κB-regulated HSV-TK/GCV therapy. Moreover, STAT3/NF-κB signaling targeting could further sensitize tumor cells to cisplatin. This study successfully established a theranositic approach to treat triple-negative breast cancer via STAT3-NF-κB responsive element-driven suicide gene therapy. This platform may also be an alternative strategy to handle with drug-resistant cancer cells.
A Sensory Complex Consisting of an ATP-binding Cassette Transporter and a Two-component Regulatory System Controls Bacitracin Resistance in Bacillus subtilis*

Background: BceS-like histidine kinases strictly require BceAB-like ABC transporters for sensing of peptide antibiotics. Results: BceAB of Bacillus subtilis interacted with BceS in vivo and in vitro and specifically bound the substrate peptide bacitracin. Conclusion: Complex formation with the ABC transporter affects the activity of the histidine kinase. Significance: Histidine kinase and ABC transporter form a sensory complex for the detection of peptide antibiotics. Resistance against antimicrobial peptides in many Firmicutes bacteria is mediated by detoxification systems that are composed of a two-component regulatory system (TCS) and an ATP-binding cassette (ABC) transporter. The histidine kinases of these systems depend entirely on the transporter for sensing of antimicrobial peptides, suggesting a novel mode of signal transduction where the transporter constitutes the actual sensor. The aim of this study was to investigate the molecular mechanisms of this unusual signaling pathway in more detail, using the bacitracin resistance system BceRS-BceAB of Bacillus subtilis as an example. To analyze the proposed communication between TCS and the ABC transporter, we characterized their interactions by bacterial two-hybrid analyses and could show that the permease BceB and the histidine kinase BceS interact directly. In vitro pulldown assays confirmed this interaction, which was found to be independent of bacitracin. Because it was unknown whether BceAB-type transporters could detect their substrate peptides directly or instead recognized the peptide-target complex in the cell envelope, we next analyzed substrate binding by the transport permease, BceB. Direct and specific binding of bacitracin by BceB was demonstrated by surface plasmon resonance spectroscopy. Finally, in vitro signal transduction assays indicated that complex formation with the transporter influenced the autophosphorylation activity of the histidine kinase. Taken together, our findings clearly show the existence of a sensory complex composed of TCS and ABC transporters and provide the first functional insights into the mechanisms of stimulus perception, signal transduction, and antimicrobial resistance employed by Bce-like detoxification systems.
Obesity as a Consequence of Gut Bacteria and Diet Interactions

Obesity is a major public health concern, caused by a combination of increased consumption of energy-dense foods and reduced physical activity, with contributions from host genetics, environment, and adipose tissue inflammation. In recent years, the gut microbiome has also been found to be implicated and augmented research in mice and humans have attributed to it both the manifestation and/or exacerbation of this major epidemic and vice versa. At the experimental level, analysis of fecal samples revealed a potential link between obesity and alterations in the gut flora (drop in Bacteroidetes and increase in Firmicutes), the specific gut microbiome being associated with the obese phenotype. Conventionally raised mice were found to have over 40% more total body fat compared with those raised under germ-free conditions, while conventionalization of germ-free mice resulted in a significant increase in total body fat. Similarly, the sparse data in humans supports the fact that fat storage is favoured by the presence of the gut microbiota, through a multifaceted mechanism. Efforts to identify new therapeutic strategies to modulate gut microbiota would be of high priority for public health, and to date, probiotics and/or prebiotics seem to be the most effective tools.
Establishing Human Lacrimal Gland Cultures with Secretory Function

Purpose Dry eye syndrome is a multifactorial chronic disabling disease mainly caused by the functional disruptions in the lacrimal gland. The treatment involves palliation like ocular surface lubrication and rehydration. Cell therapy involving replacement of the gland is a promising alternative for providing long-term relief to patients. This study aimed to establish functionally competent lacrimal gland cultures in–vitro and explore the presence of stem cells in the native gland and the established in-vitro cultures. Methods Fresh human lacrimal gland from patients undergoing exenteration was harvested for cultures after IRB approval. The freshly isolated cells were evaluated by flow cytometry for expression of stem cell markers ABCG2, high ALDH1 levels and c-kit. Cultures were established on Matrigel, collagen and HAM and the cultured cells evaluated for the presence of stem cell markers and differentiating markers of epithelial (E-cadherin, EpCAM), mesenchymal (Vimentin, CD90) and myofibroblastic (α-SMA, S-100) origin by flow cytometry and immunocytochemistry. The conditioned media was tested for secretory proteins (scIgA, lactoferrin, lysozyme) post carbachol (100 µM) stimulation by ELISA. Results Native human lacrimal gland expressed ABCG2 (mean±SEM: 3.1±0.61%), high ALDH1 (3.8±1.26%) and c-kit (6.7±2.0%). Lacrimal gland cultures formed a monolayer, in order of preference on Matrigel, collagen and HAM within 15–20 days, containing a heterogeneous population of stem-like and differentiated cells. The epithelial cells formed ‘spherules’ with duct like connections, suggestive of ductal origin. The levels of scIgA (47.43 to 61.56 ng/ml), lysozyme (24.36 to 144.74 ng/ml) and lactoferrin (32.45 to 40.31 ng/ml) in the conditioned media were significantly higher than the negative controls (p<0.05 for all comparisons). Conclusion The study reports the novel finding of establishing functionally competent human lacrimal gland cultures in-vitro. It also provides preliminary data on the presence of stem cells and duct-like cells in the fresh and in-vitro cultured human lacrimal gland. These significant findings could pave way for cell therapy in future.
Registro de Carcharocles megalodon en el sector oriental de la Cuenca del Guadalquivir (Mioceno superior, Sur de España)

Tortonian diatomites of the San Felix Quarry (Porcuna), in the Eastern Guadalquivir Basin, have given isolated marine vertebrate remains that include a large shark tooth (123.96 mm from apex to the baseline of the root). The large size of the crown height (92.2 mm), the triangular shape, the broad serrated crown, the convex lingual face and flat labial face, and the robust, thick angled root determine that this specimen corresponds to Carcharocles megalodon . The symmetry with low slant shows it to be an upper anterior tooth. The total length estimated from the tooth crown height is calculated by means of different methods, and comparison is made with Carcharodon carcharias . The final inferred total length of around 11 m classifies this specimen in the upper size range of the known C. megalodon specimens. The palaeogeography of the Guadalquivir Basin close to the North Betic Strait, which connected the Atlantic Ocean to the Mediterranean Sea, favoured the interaction of the cold nutrient-rich Atlantic waters with warmer Mediterranean waters. The presence of diatomites indicates potential upwelling currents in this context, as well as high productivity favouring the presence of large vertebrates such as mysticetid whales, pinnipeds and small sharks (Isurus). These large vertebrates recorded in the Eastern Guadalquivir Basin were potential prey of C. megalodon .
The Antiviral Effect of Epigallocatechin Gallate-Stearate on Enterovirus-69

1 Acknowledgments.4 List of Figures . 6 Introduction . 7 Review of Literature.8 Methodology.17 Results.22 Discussion.32 Conclusion . 35 Bibliography . 36-39 Supplemental Figures and Illustrations.40
Artificial Neural Network Model to Estimate the Viscosity of Polymer Solutions for Enhanced Oil Recovery

Polymer flooding is now considered a technically- and commercially-proven method for enhanced oil recovery (EOR). The viscosity of the injected polymer solution is the key property for successful polymer flooding. Given that the viscosity of a polymer solution has a non-linear relationship with various influential parameters (molecular weight, degree of hydrolysis, polymer concentration, cation concentration of polymer solution, shear rate, temperature) and that measurement of viscosity based on these parameters is a time-consuming process, the range of solution samples and the measurement conditions need to be limited and precise. Viscosity estimation of the polymer solution is effective for these purposes. An artificial neural network (ANN) was applied to the viscosity estimation of FlopaamTM 3330S, FlopaamTM 3630S and AN-125 solutions, three commonly-used EOR polymers. The viscosities measured and estimated by ANN and the Carreau model using Lee’s correlation, the only method for estimating the viscosity of an EOR polymer solution in unmeasured conditions, were compared. Estimation accuracy was evaluated by the average absolute relative deviation, which has been widely used for accuracy evaluation of the results of ANN models. In all conditions, the accuracy of the ANN model is higher than that of the Carreau model using Lee’s correlation.
Involvement of a Novel Class C Beta-Lactamase in the Transglutaminase Mediated Cross-Linking Cascade of Streptomyces mobaraensis DSM 40847

Streptomyces mobaraensis DSM 40847 secretes transglutaminase that cross-links proteins via γ-glutamyl-ε-lysine isopeptide bonds. Characterized substrates are inhibitory proteins acting against various serine, cysteine and metalloproteases. In the present study, the bacterial secretome was examined to uncover additional transglutaminase substrates. Fractional ethanol precipitation of the exported proteins at various times of culture growth, electrophoresis of the precipitated proteins, and sequencing of a 39 kDa protein by mass spectrometry revealed the novel beta-lactamase Sml-1. As indicated by biotinylated probes, Sml-1, produced in E. coli, exhibits glutamine and lysine residues accessible for transglutaminase. The chromogenic cephalosporin analogue, nitrocefin, was hydrolyzed by Sml-1 with low velocity. The obtained Km and kcat values of the recombinant enzyme were 94.3±1.8 μM and 0.39±0.03 s-1, respectively. Penicillin G and ampicillin proved to be weak inhibitors of nitrocefin hydrolysis (Ki of 0.1 mM and 0.18 mM). Negligible influence of metals on β-lactamase activity ruled out that Sml-1 is a Zn2+-dependent class B beta-lactamase. Rather, sequence motifs such as SITK, YSN, and HDG forming the active core in a hypothetical structure may be typical for class C beta-lactamases. Based on the results, we assume that the novel transglutaminase substrate ensures undisturbed growth of aerial hyphae in Streptomyces mobaraensis by trapping and inactivating hostile beta-lactam antibiotics.
Ventricular Electrical Delay Measured From Body Surface ECGs Is Associated With Cardiac Resynchronization Therapy Response in Left Bundle Branch Block Patients From the MADIT-CRT Trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy)

Background: Although cardiac resynchronization therapy (CRT) is beneficial in heart failure patients with left bundle branch block, 30% of these patients do not respond to the therapy. Identifying these patients before implantation of the device is one of the current challenges in clinical cardiology. Methods: We verified the diagnostic contribution and an optimized computerized approach to measuring ventricular electrical activation delay (VED) from body surface 12-lead ECGs. We applied the method to ECGs acquired before implantation (baseline) in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy). VED values were dichotomized using its quartiles, and we tested the association of VED values with the MADIT-CRT primary end point of heart failure or death. Multivariate Cox proportional models were used to estimate the risk of study end points. In addition, the association between VED values and hemodynamic changes after CRT-D implantation was examined using 1-year follow-up echocardiograms. Results: Our results showed that left bundle branch block patients with baseline VED <31.2 ms had a 35% risk of MADIT-CRT end points, whereas patients with VED ≥31.2 ms had a 14% risk (P<0.001). The hazard ratio for predicting primary end points in patients with low VED was 2.34 (95% confidence interval, 1.53–3.57; P<0.001). Higher VED values were also associated with beneficial hemodynamic changes. These strong VED associations were not found in the right bundle branch block and intraventricular conduction delay cohorts of the MADIT-CRT trial. Conclusions: Left bundle branch block patients with a high baseline VED value benefited most from CRT, whereas left bundle branch block patients with low VED did not show CRT benefits.
i>._')/:i/7_,-/)-Seismic Excitation of the Polar Motion, 1977-1993

The mass redistribution in the earth as a result of an earthquake faulting changes the earth's inertia tensor, and hence its rotation. Using the complete formulae developed by CHAO and GRoss (1987) based on the normal mode theory, we calculated the earthquake-induced polar motion excitation for the largest 11,015 earthquakes that occurred during 1977,0 1993.6. The seismic excitations in this period are found to be two orders of magnitude below the detection threshold even with today's high precision earth rotation measurements. However, it was calculated that an earthquake of only one tenth the size of the great 1960 Chile event, if happened today, could be comfortably detected in polar motion observations. Furthermore, collectively these seismic excitations have a strong statistical tendency to nudge the pole towards - 140E, away from the actually observed polar drift direction. This non-random behavior, similarly found in other earthquake-induced changes in earth rotation and low-degree gravitational field by CHAO and GROSS ( 19871, manifests some geodynamic behavior yet to be explored.
Price Dynamics and Trading Volume: A Semiparametric Approach

In this paper we investigate the relation between price impact and trading volume for a sample of stocks listed on the New York Stock Exchange. The parametric VAR-models that have been used in the literature impose strong proportionality and symmetry restrictions on the price impact of trades, although market microstructure theory provides many reasons why these restrictions would not hold. We analyze a more flexible semiparametric partially linear specification and establish significant evidence for a nonlinear, asymmetric, increasing, and concave relation between trading volume and both immediate and persistent price impact. Moreover, we compare the price-impact functions obtained in the partially linear model to the ones generated by the parametric models and show that there are considerable differences. We test the parametric specifications against the partially linear model and show that the parametric models are rejected in favor of the semiparametric model. We also test the partially linear model against a more flexible fully nonparametric specification and show that this test does not reject the partially linear model.
Parsing Epileptic Events Using a Markov Switching Process for Correlated Time Series

Patients with epilepsy can manifest short, sub-clinical epileptic “bursts” in addition to full-blown clinical seizures. We believe the relationship between these two classes of events—something not previously studied quantitatively—could yield important insights into the nature and intrinsic dynamics of seizures. A goal of our work is to parse these complex epileptic events into distinct dynamic regimes. A challenge posed by the intracranial EEG (iEEG) data we study is the fact that the number and placement of electrodes can vary between patients. We develop a Bayesian nonparametric Markov switching process that allows for (i) shared dynamic regimes between a variable numbers of channels, (ii) asynchronous regimeswitching, and (iii) an unknown dictionary of dynamic regimes. We encode a sparse and changing set of dependencies between the channels using a Markov-switching Gaussian graphical model for the innovations process driving the channel dynamics. We demonstrate the importance of this model in parsing and out-of-sample predictions of iEEG data. We show that our model produces intuitive state assignments that can help automate clinical analysis of seizures and enable the comparison of sub-clinical bursts and full clinical seizures. Proceedings of the 30 th International Conference on Machine Learning, Atlanta, Georgia, USA, 2013. JMLR: W&CP volume 28. Copyright 2013 by the author(s).
Ocular disorders in children with spastic subtype of cerebral palsy.

AIM To document common ocular abnormalities in children with spastic subtype of cerebral palsy (CP) and to find out whether any correlation exists between their occurance and etiologic factors. METHODS Totally 194 patients with the diagnosis of spastic type CP were enrolled in this retrospective study. Detailed ophthalmic examinations were performed. Demographic data and neuroradiological findings were documented. Kruskal-Wallis, Mann Whitney U, Pearson Chi-square tests and Student's t tests were used in the statistical analysis. RESULTS The mean age was 64.7±44.2 months on the first ophthalmic examination. Prevalences of diplegia (47.4%) and tetraplegia (36.1%) were found to be higher than the frequency of hemiplegia (16.5%) in our study population. Etiologic factor was asphyxia in 60.8% of the patients. Abnormal ocular findings were present in 78.9% of the patients. Statistically significant poor vision was detected in tetraplegia group among all the spastic ubtypes of CP (P=0.000). Anisometropia and significant refractive error were found in 14.4% and 70.1% of the patients, respectively. Thirty-six children (18.6%) had nystagmus and 107 children (55.2%) had strabismus. Lower gestational age and birth weight were statistically higher in patients with esotropia than exotropia (P=0.009 and P=0.024, respectively). Abnormal morphology of the optic disc was present in 152 eyes (39.2%). Severe periventricular leukomalacia (PVL) was found in 48 patients and statistically significant poor vision was detected in the presence of PVL (P=0.000). CONCLUSION Spastic diplegic or tetraplegic CP patients with positive neuroradiological symptoms, younger gestational age and lower birth weight ought to have detailed ophthalmic examinations as early as possible to provide best visual rehabilitation.
Physical Ecosystem Engineers as Agents of Biogeochemical Heterogeneity

Abstract Physical ecosystem engineers are organisms that physically modify the abiotic environment. They can affect biogeochemical processing by changing the availability of resources for microbes (e.g., carbon, nutrients) or by changing abiotic conditions affecting microbial process rates (e.g., soil moisture or temperature). Physical ecosystem engineers can therefore create biogeochemical heterogeneity in soils and sediments. They do so via general mechanisms influencing the flows of materials (i.e., modification of fluid dynamic properties, fluid pumping, and material transport) or the transfer of heat (i.e., modification of heat transfer properties, direct heat transfer, and convective forcing). The consequences of physical ecosystem engineering for biogeochemical processes can be predicted by considering the resources or abiotic conditions that limit or promote a reaction, and the effect of physical ecosystem engineering on these resources or abiotic conditions via the control they exert on material flows and heat transfer.
Clinical and Histopathological Spectrum of Vesciculobullous Lesions of skin-A Study of 40 cases

Background: Vesiculobullous lesions of skin areheterogenous group of dermatological disorders and are not uncommon. These lesions may present with common clinical presentation as blister clinically, but histopathological features differ. Aims & Objective: This study is under taken to study the clinical and histopathological features of vesciculobullous disorders. Materials and Methods: A total 40 cases of clinically diagnosed blistering disorder were included, the punch biopsy of the lesion was taken. The biopsy was studied for histopathological fetures like level of blister formation, acantholysis, spongiosis, basement membrane zone distruction, presence or absence of inflammation. Results: In the present study amongst 40 cases, Pemphigus vulgaris was diagnosed in 12 (30%) cases and detected as most common type, followed by Bullous Pemphigoid in 11 (27.5%) cases. Herpes gestationis (Bullous Pemphigoid) was diagnosed in only one case. Commonly the blisters were seen on trunk, extremeties, axilla and groin. The lesions were slightly male preponderance in the present study. Most of the cases found between 41-70 years of age. Conclusion: The distribution of vesiculobullous lesions in relation to gender, age group, presenting site and histopathological features differ in each type. Histopathological examination gives valuable clue in the diagnosis of particular type of blistering disorder.