gebhart/patrepeval huggingface dataset:
Rare transmission of commensal and pathogenic bacteria in the gut microbiome of hospitalized adults (2021)

Abstract Bacterial bloodstream infections are a major cause of morbidity and mortality among patients undergoing hematopoietic cell transplantation (HCT). Although previous research has demonstrated that pathogenic organisms may translocate from the gut microbiome into the bloodstream to cause infections, the mechanisms by which HCT patients acquire pathogens in their microbiome have not yet been described. We hypothesized that patient-patient transmission may be responsible for pathogens colonizing the microbiome of HCT patients, and that patients who share time and space in the hospital are more likely to share bacterial strains. Here, we used linked-read and short-read metagenomic sequencing to analyze 401 stool samples collected from 149 adults undergoing HCT and hospitalized in the same unit over five years. We used metagenomic assembly and strain-specific comparison methods to investigate transmission of gut microbiota between individuals. While patients who shared time and space in the hospital did not converge in overall microbiome composition, we did observe four pairs of patients who harbor identical or nearly identical E. faecium strains in their microbiome. These strains may be the result of transmission between patients who shared a room and bathroom, acquisition from a common source in the hospital or transmission from an unsampled source. We also observed identical Akkermansia muciniphila and Hungatella hathewayi strains in two pairs of patients. In both cases, the patients were roommates for at least one day, the strain was absent in the putative recipient’s microbiome prior to the period of roommate overlap and the putative recipient had a microbiome perturbed by antibiotic treatment for a bloodstream infection. Finally, we identified multiple patients who harbored identical strains of several species commonly found in commercial probiotics and dairy products, including Lactobacillus rhamnosus , Lactobacillus gasseri and Streptococcus thermophilus . Overall, our findings indicate that pathogenic organisms from a single source are not frequently colonizing the gut microbiome of multiple patients. However, the potential transmission of commensal microbes with immunomodulatory properties raises questions about the recovery of microbiome diversity after HCT, and indicates that patients in this setting may acquire new microbes by sharing space with others.
Effects of Transforming Growth Factor β 1 on Bonelike Tissue Formation in Three-Dimensional Cell Culture. II: Osteoblastic Differentiation (2004)

We supplemented rat marrow stromal cells (rMSCs) seeded on poly(L-lactic-co-glycolic acid) fiber meshes with transforming growth factor beta1 (TGF-beta1) to improve bone tissue formation for tissue engineering. Whereas our first study (Lieb, E., et al. Tissue Eng. 10, 1399-1413, 2004) investigated the effects of TGF-beta1 on matrix formation and mineralization, this second study focused on the differentiation of rMSCs to the osteoblastic phenotype in dynamic cell culture (orbital shaker). We assessed a series of bone markers to determine a dosing regimen for TGF-beta1 that enhances collagenous matrix formation and preserves or increases osteoblastic differentiation. Bone sialoprotein and osteonectin formation were investigated immunohistochemically and by RT-PCR. For alkaline phosphatase activity (ALP), we employed an enzyme assay. Osteocalcin was examined by RT-PCR as well as by an immunoassay. Whereas bone sialoprotein appeared to be dose-dependently increased in the immunochemistical stainings after supplementation with TGF-beta1, osteonectin remained unchanged. Both ALP activity and osteocalcin were suppressed by high doses of TGF-beta1, such as single doses of 10 ng/mL or four doses of 1 ng/mL added once a week. Considering the effects of TGF-beta1 both on differentiation and on matrix formation and mineralization, TGF-beta1 at 1 ng/mL, added once a week in the first 1 to 2 weeks, was selected as an effective dose to improve bonelike tissue formation in vitro.
The Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis (2008)

Histone deacetylase inhibitors (HDACI) are promising antitumor agents. Although transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanism and targets by which HDACIs achieve their antitumor effects remain poorly understood. It is not known whether any of the HDAC members support robust tumor growth. In this report, we show that HDAC6, a cytoplasmic-localized and cytoskeleton-associated deacetylase, is required for efficient oncogenic transformation and tumor formation. We found that HDAC6 expression is induced upon oncogenic Ras transformation. Fibroblasts deficient in HDAC6 are more resistant to both oncogenic Ras and ErbB2-dependent transformation, indicating a critical role for HDAC6 in oncogene-induced transformation. Supporting this hypothesis, inactivation of HDAC6 in several cancer cell lines reduces anchorage-independent growth and the ability to form tumors in mice. The loss of anchorage-independent growth is associated with increased anoikis and defects in AKT and extracellular signal-regulated kinase activation upon loss of adhesion. Lastly, HDAC6-null mice are more resistant to chemical carcinogen-induced skin tumors. Our results provide the first experimental evidence that a specific HDAC member is required for efficient oncogenic transformation and indicate that HDAC6 is an important component underlying the antitumor effects of HDACIs.
Comparison of electromagnetic solvers for the analysis of LTCC components (2004)

We present an accurate modeling of complex vertically integrated structures based on the new LTTC (low-temperature cofired ceramic) multilayer technology. The EM analysis is performed by means of different electromagnetic full-wave solvers in the time- and frequency-domains, namely: i) finite difference time-domain (FDTD); ii) transmission line matrix (TLM); iii) transmission line matrix integral equation (TLM-IE); iv) generalized transverse resonance diffraction (GTRD). We analyze a stacked patch antenna and a spiral inductor. The calculated S-parameters and Q-factors are compared to measured data showing good agreement.
Camptothecin, teniposide, or 4'-(9-acridinylamino)-3-methanesulfon-m-anisidide, but not mitoxantrone or doxorubicin, induces degradation of nuclear DNA in the S phase of HL-60 cells. (1991)

Short-term (2-6 h) exposure of human promyelocytic HL-60 cell cultures to the DNA topoisomerase I inhibitor camptothecin (0.05-0.5 microgram/ml) or to the topoisomerase II inhibitor, teniposide (VM-26; 0.3-3.0 micrograms/ml) or 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine; 0.8 microgram/ml) triggered rapid degradation of DNA specifically in S-phase cells. As a result of the selective death of S-phase cells, only G1 cells remained in these cultures. On the other hand, mitoxantrone (0.02-0.4 microgram/ml) or doxorubicin (adriamycin; 0.4-10.0 micrograms/ml) did not induce DNA degradation in S phase but arrested HL-60 cells in S and G2 phases. In contrast to HL-60 cells, human lymphocytic leukemic MOLT-4 cells responded to all of these drugs (camptothecin, teniposide, amsacrine, mitoxantrone, and adriamycin) at all concentrations tested, invariably by being arrested in G2 and S phases and also by entering a higher DNA ploidy cycle. The data illustrate the differences in the sensitivity of S-phase cells in myelogenous versus lymphocytic leukemic lines to both DNA topoisomerase I and II inhibitors and emphasize the tissue (leukemia type)-specific factors that modulate the cytostatic and cytotoxic effects of these inhibitors. The qualitatively different response of HL-60 cells to camptothecin, teniposide, or amsacrine (by rapidly triggered DNA degradation in S phase) as compared to mitoxantrone or adriamycin (by cell arrest in G2 and S) suggests that, despite the generally assumed common mode of action attributed to these drugs (i.e., via stabilization of the cleavable DNA-topoisomerase complexes), there are significant differences in the mechanisms by which they exert cytostatic/cytotoxic effects.
CaMKII inhibition in vascular smooth muscle improves angiotensin II–hypertension (2012)

The multifunctional calcium/calmodulin‐dependent kinase II (CaMKII) is expressed in vascular smooth muscle cells (VSMC) and activated by Angiotensin‐II (Ang‐II). To test the hypothesis that CaMKII in VSMC mediates Ang‐II‐hypertension, we developed transgenic mice that express the specific CaMKII peptide inhibitor CaMKIIN selectively in VSMC (Tg SM CaMKIIN). These mice have a 65 % reduced CaMKII activity in arteries (p&lt;0.01) and identical baseline blood pressure compared to littermate controls. Following Ang‐II infusion at pressor dose, the increase in mean pressure was significantly attenuated (129±4 mmHg vs, 116±3 mmHg, p&lt;0.05). Ang‐II increases Ca 2+ influx through L‐type Ca 2+ channels (LTCC). Cytosolic Ca 2+ ([Ca 2+ ]) rise leads to an increased vascular tone. Compared with littermates, freshly isolated mesenteric VSMC of Ang‐II treated Tg SM CaMKIIN mice had significantly reduced voltage gated L‐type Ca 2+ current ( I Ca ), I Ca facilitation. Moreover, the [Ca 2+ ] elevation in response to Ang‐II stimulation was reduced by 50 % in VSMC of TgSM CaMKIIN mice (0.045±0.002 vs, 0.025±0.003; ratio340/380; p&lt;0.05) whereas, level of total releasable SR calcium was decreased by 35 %. In conclusion, inhibition of CaMKII in VSMC significantly attenuates Ang‐II induced hypertension through regulation of LTCC and by restoring the calcium homeostasis. CaMKII may be a novel target in treating hypertension.
On the Convergence of Reinforcement Learning in Nonlinear Continuous State Space Problems (2021)

We consider the problem of Reinforcement Learning for nonlinear stochastic dynamical systems. We show that in the RL setting, there is an inherent "Curse of Variance" in addition to Bellman’s infamous "Curse of Dimensionality", in particular, we show that the variance in the solution grows factorial-exponentially in the order of the approximation. A fundamental consequence is that this precludes the search for anything other than "local" feedback solutions in RL, in order to control the explosive variance growth, and thus, ensure accuracy. We further show that the deterministic optimal control has a perturbation structure, in that the higher order terms do not affect the calculation of lower order terms, which can be utilized in RL to get accurate local solutions.
Association of Tumor Microenvironment with Biological and Chronological Age in Head and Neck Cancer (2023)

There is often a mismatch between the chronological and biological age of head and neck squamous cell carcinoma (HNSCC) patients. Treatment is based on chronological age, while biological age seems to be a better prognosticator for treatment toleration. This study investigated whether tumor characteristics are associated with chronological and biological age. The relation with survival was also assessed. Prospectively collected data from 164 newly diagnosed HNSCC patients enrolled in the OncoLifeS database were analyzed. Biological age was assessed by a multidomain geriatric assessment. Several immunological markers were tested by immunohistochemistry on tissue microarray sections from the tumor. Disease-free survival (DFS), adjusted for chronological- and biological age, was assessed by univariable and bivariable analyses. In biologically old patients, a lower infiltration of CD163+ macrophages (<i>p</i> = 0.036) as well as CD4+ (<i>p</i> = 0.019) and CD8+ (<i>p</i> = 0.026) lymphocytes was found in the tumor microenvironment. Chronological older patients showed significantly lower PD-L1 combined positive scores (<i>p</i> = 0.030). Advanced tumor stage and perineural growth were related to a worse DFS. None of the immunological markers showed a significant association with DFS. Biological age might have a stronger influence on tumor microenvironment than chronological age. These findings should initiate clinical studies investigating the response to specific treatment regimens (e.g., immunotherapy) according to the biological age.
Electrochemical Properties and CO2-Reduction Ability of m-Terphenyl Isocyanide Supported Manganese Tricarbonyl Complexes (2016)

To circumvent complications with redox-active ligands commonly encountered in the study of manganese electrocatalysts for CO<sub>2</sub> reduction, we have studied the electrochemistry of the manganese mixed carbonyl/isocyanide complexes XMn(CO)<sub>3</sub>(CNAr<sup>Dipp2</sup>)<sub>2</sub> (X = counteranion), to evaluate the pairing effects of the counteranion and their influence over the potential necessary for metal-based reduction. The complexes described herein have been shown to act as functional analogues to the known homoleptic carbonyl manganese complexes [Mn(CO)<sub>5</sub>]<sup>n</sup> (n = 1-, 0, 1+). The m-terphenyl isocyanide ligand CNAr<sup>Dipp2</sup> improves the kinetic stability of the resulting mixed carbonyl/isocyanide systems, such that conversion among all three oxidation states is easily effected by chemical reagents. Here, we have utilized an electrochemical study to fully understand the redox chemistry of this system and its ability to facilitate CO<sub>2</sub> reduction and to provide comparison to known manganese-based CO<sub>2</sub> electrocatalysts. Two complexes, BrMn(CO)<sub>3</sub>(CNAr<sup>Dipp2</sup>)<sub>2</sub> and [Mn(THF)(CO)<sub>3</sub>(CNAr<sup>Dipp2</sup>)<sub>2</sub>]OTf, have been studied using infrared spectroelectrochemistry (IR-SEC) to spectroscopically characterize the redox states of these complexes during the course of electrochemical reactions. A striking difference in the necessary potential leading to the first one-electron reduction has been found for the halide and triflate species, respectively. Complete selectivity for the formation of CO and CO<sub>3</sub><sup>2-</sup> is observed in the reactivity of [Mn(CO)<sub>3</sub>(CNAr<sup>Dipp2</sup>)<sub>2</sub>]<sup>-</sup> with CO<sub>2</sub>, which is deduced via the trapping and incorporation of liberated CO into the zerovalent species Mn(CO)<sub>3</sub>(CNAr<sup>Dipp2</sup>)<sub>2</sub> to form the dimers Mn<sub>2</sub>(CO)<sub>7</sub>(CNAr<sup>Dipp2</sup>)<sub>3</sub> and Mn<sub>2</sub>(CO)<sub>8</sub>(CNAr<sup>Dipp2</sup>)<sub>2</sub>.
How to design multi-target drugs (2007)

Despite improved rational drug design and a remarkable progress in genomic, proteomic and high-throughput screening methods, the number of novel, single-target drugs has fallen far behind expectations during the past decade. Multi-target drugs multiply the number of pharmacologically relevant target molecules by introducing a set of indirect, network-dependent effects. Parallel with this, the low-affinity binding of multi-target drugs eases the constraints of druggability and significantly increases the size of the druggable proteome. These effects tremendously expand the number of potential drug targets and introduce novel classes of multi-target drugs with smaller side effects and toxicity. Here, the authors review the recent progress in this field, compare possible network attack strategies and propose several methods to find target-sets for multi-target drugs.
Intracellular Accumulation of Secreted Proteoglycans Inhibits Cationic Lipid-mediated Gene Transfer (1999)

Molecules secreted by potential target cells may interfere with cationic lipid-mediated gene transfer. This has been studied using human lung fibroblasts and human epidermoid lung cancer cells. Secreted cell medium components caused a substantial decrease both in the uptake of cationic lipid-DNA complexes (2-4-fold) and in reporter gene expression (100-1000-fold). Metabolic labeling of the cell medium showed that especially [35S]sulfate-labeled macromolecules competed with DNA for binding to the cationic lipid. Release of DNA from the cationic lipid by cell medium components was demonstrated by an ethidium bromide intercalation assay. In the presence of the cationic lipid, the secreted macromolecules were internalized by the cells. By enzymatic digestions, it was shown that the competing macromolecules consist of chondroitin/dermatan sulfate and heparan sulfate proteoglycans and that the effects on transfection were mediated by the polyanionic glycosaminoglycan portion of the proteoglycan. Accordingly, pretreatment of cell medium with the polycationic peptide protamine sulfate abrogated the inhibitory effects on gene transfer. Fluorescence microscopy studies revealed that heparan sulfate, internalized as a complex with cationic lipids, accumulated in the cell nuclei. These results support the view that the lack of specificity of this type of gene transfer vehicle is a major hindrance to efficient and safe in vivo administration.
Desorption Electrospray Ionization Coupled with Ultraviolet Photodissociation for Characterization of Phospholipid Isomers in Tissue Sections (2018)

Desorption electrospray ionization (DESI) mass spectrometry imaging has become a powerful strategy for analysis of tissue sections, enabling differentiation of normal and diseased tissue based on changes in the lipid profiles. The most common DESI workflow involves collection of MS1 spectra as the DESI spray is rastered over a tissue section. Relying on MS1 spectra inherently limits the ability to differentiate isobaric and isomeric species or evaluate variations in the relative abundances of key isomeric lipids, such as double-bond positional isomers which may distinguish normal and diseased tissues. Here, 193 nm ultraviolet photodissociation (UVPD), a technique capable of differentiating double-bond positional isomers, is coupled with DESI to map differences in the double-bond isomer composition in tissue sections in a fast, high throughput manner compatible with imaging applications.
Joint optimization of detection thresholds and power allocation for opportunistic access in multicarrier cognitive radio networks (2009)

In cognitive radio (CR) networks, the radio access from opportunistic users depends on their capabilities to detect spectrum holes. Typically, the detection problem has been considered separately from the optimization of the transmission strategy. However, in a CR context, the detection phase has an impact on network efficiency as well as on the undesired interference generated towards licensed users. In this work, we consider the joint optimization of detection thresholds and power allocation across multichannel links, in order to maximize the aggregated opportunistic throughput, under a constraint on the interference generated towards the primary users.
Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA (2017)

Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy.
High Coupling Coefficient Resonance Mode in Al0.68Sc0.32N Surface Acoustic Wave Resonator with AlN Buffer Layer on a Silicon Substrate (2020)

We report on a resonance mode with high electro-mechanical coupling coefficient (k <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">t</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> ) in an Aluminum Scandium Nitride (AlScN) Surface Acoustic Wave (SAW) resonator with an Aluminum Nitride (AlN) buffer layer on a silicon substrate. We demonstrate the influence of electrode material, electrode thickness, AlScN thickness, and device orientation on the k <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">t</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> . We utilize the optimized parameters from this study to realize SAW devices in a CMOS compatible fabrication process and measured a k <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">t</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> as high as 4.78%, which is a high value for AlScN SAW devices reported on low cost single crystal silicon substrates.
Abstract 32: Cardiac Arrest: Who Goes to the Catheterization Lab? (2011)

Introduction: Therapeutic hypothermia (TH) is neuroprotective and increases survival in resuscitated cardiac arrest patients. Approximately 70% of sudden cardiac deaths are caused by coronary heart disease. For patients requiring angiography/PCI, TH can occur simultaneously. Methods: “Cool It” is a comprehensive TH protocol integrated into a regional STEMI network. From Feb 2006 to July 2010, 192 consecutive cardiac arrest patients who remained unresponsive following return of spontaneous circulation were enrolled in the Cool It protocol. Those patients with suspicion for ischemic etiology or evidence of STEMI were transferred directly to the cath lab. Results: On the 192 patients, angiogram was performed in 144 (75.0%). Patients sent for angiography had higher prevalence of initial rhythm VF/VT 116 (80.6%) vs. 19 (39.6%), cardiogenic shock 66 (45.8%) vs. 11 (22.9%), and ST elevation 54 (37.5%) vs. 1 (2.1%) than the 48 patients not undergoing angiography. PCI was performed in 73 (50.7% of patients undergoing angiogram, 38.0% all patients). Of these 73 patients, 64 (87.7%) had initial rhythm VF/VT, 38 (52.1%) were in cardiogenic shock, and 39 (53.4%) had ST elevation. Identified culprit arteries were LAD n=30 (41.1%), RCA n=24 (32.9%), CMX n=12 (16.4%), left main n=4 (5.5%), and none n=3 (4.1%). Mean pre-PCI TIMI flow was 1.36, and post-PCI TIMI flow was 2.91. BMS was used in 31 (42.5%), DES in 40 (54.8%), and one had balloon angioplasty only. Three were referred for CABG. Survival to hospital discharge was 43/73 (58.9%), and survival with favorable neurologic outcome (cerebral performance category 1 or 2) was 39/73 (53.4%). Patients who underwent angiography but did not receive PCI had the similar outcomes: survival was 46/71 (64.8%) and favorable neurologic outcome was seen in 44/71 (62.0%). Patients who did not undergo angiography had the poorest outcome: survival was 11/48 (22.9%) and with favorable neurologic outcome was seen in 9/48 (18.8%). Conclusion: The majority of unresponsive cardiac arrest survivors underwent angiography. Patients who underwent angiography with PCI had the similar outcomes to those with angiography alone. Favorable baseline patient characteristics appear to account for the improved outcomes in the angiography group.