Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a ...phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.
We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4–10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ≤2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo.
Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.
In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187.
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Relationship of the surface physicochemical characteristics of nanoparticles with their interactions with biological entities may provide critical information for nanomedicinal application. Here, we ...report the systematic synthesis of sub-50 nm carbon nanoparticles （CNP） presenting neutral, anionic, and cationic surface functionalities. A subset of CNPs with -10, 20, and 40 nm hydrodynamic sizes were synthesized with neutral surface headgroups. For the first time, the cellular internalization of these CNPs was systematically quantified in various stages of breast cancer cells （early, late, and metastatic）, thereby providing a parametric assessment of charge and size effects. Distinct activities were observed when these systems interacted with cancer cells in various stages. Our results indicated that metastatic breast cancer could be targeted by a nanosystem presenting anionic phosphate groups. On the contrary, for patients in late stage of cancer, drugs could be delivered with sulfonate functionalized carbon nano- particles, which have higher probability of intracellular transport. This study will facilitate the better understanding of nanoparticle-biological entity interaction, and the integration of this knowledge with pathophysiology would promote the engineering of nanomedicine with superior likelihoods of crossing the endocytic ＂barrier＂ for drug delivery inside cancerous cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
One of the most promising techniques to capture large debris on orbit consists in the use of tether-nets. With this concept currently at a medium technological readiness level only, numerical studies ...on tether-net removal missions are still needed. This paper presents a versatile simulator developed with the aim of gaining insight into the dynamics of tether-net capture of space debris. Its modular architecture supports multiple modeling choices and allows simulating diverse capture scenarios with different system designs. Simulation results are shown for the capture of a realistic launcher upper stage with the representation of the main components of the system, consisting in chaser, main tether, net, and two possible configurations of a closing mechanism. It is shown that only a closing mechanism with more than one attachment to each side of the net can guarantee containment of this type of debris after capture. It is also observed that a safer capture scenario is one in which the axis of rotation of the target is parallel to the direction of ejection of the net. Additional simulation results suggest that tether-nets could be used to capture not only large debris, but also small asteroids, and that this simulator could enable future studies.
•A versatile simulator for tether-net capture of space objects is presented.•Preferred closing mechanisms to capture launcher upper stages are identified.•Safer scenarios to capture debris rotating about its major axis are identified.•Capture of a small asteroid with a tether-net is investigated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Graphene oxide and chitosan are promising materials for tissue regeneration. The present study explores a novel biomimetic mineralization route employing a graphene oxide (GO)-chitosan (CS) conjugate ...as a template material for the biomineralization of hydroxyapatite (HAP). Structural and morphological studies involving X-ray diffraction, Fourier transform infrared spectroscopy, and electron microscopy indicated that extensive mineralization occurred in the CS-GO conjugate system because of strong electrostatic interactions between the functional groups (carboxyl groups of GO and amino groups of CS) and calcium ions in the simulated body fluid (SBF). The combination of chitosan-graphene oxide conjugate and biomineralization was advantageous in favorably modulating cellular activity (osteoblast functions: cell attachment, proliferation, actin, vinculin and fibronectin expression). It is concluded that biomineralized hydroxyapatite in the HAP-CS-GO system induced homogeneous spatial osteoblastic cell growth and quantitatively (e.g.area) and qualitatively (e.g.mineral-to-matrix ratio) increased mineralization in relation to the HAP-GO system. The data underscore that covalent linkage of HAP to chitosan influences osteoblastic cell differentiation, mineralization, and cell growth. The proposed system and the revelation of fundamental insights merit consideration in tissue engineering.
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IJS, KILJ, NUK, UL, UM, UPUK
We present an in-silico-to-in-vitro approach to develop well-defined, self-assembled, rigid-cored polymeric (Polybee) nano-architecture for controlled delivery of a key component of bee venom, ...melittin. A competitive formulation with lipid-encapsulated (Lipobee) rigid cored micelle is also synthesized. In a series of sequential experiments, we show how nanoscale chemistry influences the delivery of venom toxins for cancer regression and help evade systemic disintegrity and cellular noxiousness. A relatively weaker association of melittin in the case of lipid-based nanoparticles is compared to the polymeric particles revealed by energy minimization and docking studies, which are supported by biophysical studies. For the first time, the authors' experiment results indicate that melittin can play a significant role in DNA association-dissociation processes, which may be a plausible route for their anticancer activity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This research addresses the design and testing of a debris containment system for use in a tether-net approach to space debris removal. The tether-net active debris removal involves the ejection of a ...net from a spacecraft by applying impulses to masses on the net, subsequent expansion of the net, the envelopment and capture of the debris target, and the de-orbiting of the debris via a tether to the chaser spacecraft. To ensure a debris removal mission's success, it is important that the debris be successfully captured and then, secured within the net. To this end, we present a concept for a net closing mechanism, which we believe will permit consistently successful debris capture via a simple and unobtrusive design. This net closing system functions by extending the main tether connecting the chaser spacecraft and the net vertex to the perimeter and around the perimeter of the net, allowing the tether to actuate closure of the net in a manner similar to a cinch cord. A particular embodiment of the design in a laboratory test-bed is described: the test-bed itself is comprised of a scaled-down tether-net, a supporting frame and a mock-up debris. Experiments conducted with the facility demonstrate the practicality of the net closing system. A model of the net closure concept has been integrated into the previously developed dynamics simulator of the chaser/tether-net/debris system. Simulations under tether tensioning conditions demonstrate the effectiveness of the closure concept for debris containment, in the gravity-free environment of space, for a realistic debris target. The on-ground experimental test-bed is also used to showcase its utility for validating the dynamics simulation of the net deployment, and a full-scale automated setup would make possible a range of validation studies of other aspects of a tether-net debris capture mission.
•Tether-actuated cinch-cord mechanism for closing net around debris is proposed.•Performance of the mechanism is demonstrated in laboratory experiments.•Simulated model with realistic debris confirm functionality in space conditions.•Experimental test-bed is suitable for range of studies on tether-net debris capture.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Ligand-induced stabilization of the G-quadruplex DNA structure derived from the single-stranded 3'-overhang of the telomeric DNA is an attractive strategy for the inhibition of the telomerase ...activity. The agents that can induce/stabilize a DNA sequence into a G-quadruplex structure are therefore potential anticancer drugs. Herein we present the first report of the interactions of two novel bisbenzimidazoles (TBBz1 and TBBz2) based on Tröger's base skeleton with the G-quadruplex DNA (G4DNA). These Tröger's base molecules stabilize the G4DNA derived from a human telomeric sequence. Evidence of their strong interaction with the G4DNA has been obtained from CD spectroscopy, thermal denaturation, and UV-vis titration studies. These ligands also possess significantly higher affinity toward the G4DNA over the duplex DNA. The above results obtained are in excellent agreement with the biological activity, measured in vitro using a modified TRAP assay. Furthermore, the ligands are selectively more cytotoxic toward the cancerous cells than the corresponding noncancerous cells. Computational studies suggested that the adaptive scaffold might allow these ligands to occupy not only the G-quartet planes but also the grooves of the G4DNA.
Hydroxyapatite (HAp) was successfully synthesized from egg shells, a low cost and easily available biodegradable waste, by the precipitation method and characterized by X-ray diffraction (XRD), ...scanning electron microscopy, Fourier transform infrared, and Brunauer–Emmett–Teller (BET) surface area analysis. The surface area of HAp was found to be 144 m2/g with a crystalline size of 9–99 nm from the BET and XRD data. The maximum fluoride removal efficiency within 1 h using 0.3 g of the synthesized adsorbent at pH 6 was 95%. The adsorption of fluoride followed second-order kinetics, indicating that chemisorptions are the rate-limiting step. The experimental data were well fitted with Langmuir and Freundlich isotherms, validating both monolayer and multilayer sorption during the fluoride adsorption onto the porous HAp. The positive adsorption of F– ions at the HAp interface can be attributed to ion exchange/ion pairing and H-bonding below the pHpzc of HAp (pHpzc = 8), and the negative adsorption can be attributed to the electrostatic repulsion between O– and F– ions at alkaline pH. Both physical and chemical adsorption phenomena were also evidenced from the molecular parking area data. The results of a batch experiment show that the HAp synthesized from egg shells can be used as an effective, low-cost adsorbent for fluoride removal from a contaminated aqueous solution as well as groundwater compared to other adsorbents.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
This study identifies the critical challenges for blockchain adoption in government, and more specifically in the delivery of public services in the state governments of India. A literature review ...and focus-group with stakeholders was conducted to identify critical cfhallenges. Each challenge was ranked based on the opinions of stakeholders using conjoint analysis. Regarding government adoption of Blockchain, this study points to ecological shifts as a more significant challenge than technology. This study provides theoretical implications for researchers and valuable insights for practitioners.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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