Bimolecular sandwich aggregates of porphyrin nanorings

Extended π-systems often form supramolecular aggregates, drastically changing their optical and electronic properties. However, aggregation processes can be difficult to characterize or predict. Here, we show that butadiyne-linked 8- and 12-porphyrin nanorings form stable and well-defined bimolecular aggregates with remarkably sharp NMR spectra, despite their dynamic structures and high molecular weights (12.7 to 26.0 kDa). Pyridine breaks up the aggregates into their constituent rings, which are in slow exchange with the aggregates on the NMR time scale. All the aggregates have the same general two-layer sandwich structure, as deduced from NMR spectroscopy experiments, including 1H DOSY, 1H–1H COSY, TOCSY, NOESY, and 1H–13C HSQC. This structure was confirmed by analysis of residual dipolar couplings from 13C-coupled 1H–13C HSQC experiments on one of the 12-ring aggregates. Variable-temperature NMR spectroscopy revealed an internal ring-on-ring rotation process by which two π–π stacked conformers interconvert via a staggered conformation. A slower dynamic process, involving rotation of individual porphyrin units, was also detected by exchange spectroscopy in the 8-ring aggregates, implying partial disaggregation and reassociation. Molecular dynamics simulations indicate that the 8-ring aggregates are bowl-shaped and highly fluxional, compared to the 12-ring aggregates, which are cylindrical. This work demonstrates that large π-systems can form surprisingly well-defined aggregates and may inspire the design of other noncovalent assemblies

Rasiowa–Sikorski deduction systems in computer science applications

AbstractA Rasiowa-Sikorski system is a sequence-type formalization of logics. The system uses invertible decomposition rules which decompose a formula into sequences of simpler formulae whose validity is equivalent to validity of the original formula. There may also be expansion rules which close indecomposable sequences under certain properties of relations appearing in the formulae, like symmetry or transitivity. Proofs are finite decomposition trees with leaves having “fundamental”, valid labels. The author describes a general method of applying the R-S formalism to develop complete deduction systems for various brands of C.S and A.I. logic, including a logic for reasoning about relative similarity, a three-valued software specification logic with McCarthy's connectives and Kleene quantifiers, a logic for nondeterministic specifications, many-sorted FOL with possibly empty carriers of some sorts, and a three-valued logic for reasoning about concurrency

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The Min System and Nucleoid Occlusion Are Not Required for Identifying the Division Site in Bacillus subtilis but Ensure Its Efficient Utilization

Precise temporal and spatial control of cell division is essential for progeny survival. The current general view is that precise positioning of the division site at midcell in rod-shaped bacteria is a result of the combined action of the Min system and nucleoid (chromosome) occlusion. Both systems prevent assembly of the cytokinetic Z ring at inappropriate places in the cell, restricting Z rings to the correct site at midcell. Here we show that in the bacterium Bacillus subtilis Z rings are positioned precisely at midcell in the complete absence of both these systems, revealing the existence of a mechanism independent of Min and nucleoid occlusion that identifies midcell in this organism. We further show that Z ring assembly at midcell is delayed in the absence of Min and Noc proteins, while at the same time FtsZ accumulates at other potential division sites. This suggests that a major role for Min and Noc is to ensure efficient utilization of the midcell division site by preventing Z ring assembly at potential division sites, including the cell poles. Our data lead us to propose a model in which spatial regulation of division in B. subtilis involves identification of the division site at midcell that requires Min and nucleoid occlusion to ensure efficient Z ring assembly there and only there, at the right time in the cell cycle

Intravascular tissue reactions induced by various types of bioabsorbable polymeric materials: correlation between the degradation profiles and corresponding tissue reactions

Several different bioabsorbable polymeric coil materials are currently used with the goal of improving treatment outcomes of endovascular embolization of intracranial aneurysms. However, little is known about the correlation between polymer degradation profiles and concomitant tissue responses in a blood vessel. The authors describe in vitro degradation characteristics of nine different polymeric materials and their corresponding tissue responses induced in rabbit carotid arteries. Mass loss and molecular weight loss of nine commercially available bioabsorbable sutures were evaluated in vitro up to16 weeks. The same nine materials, as well as platinum coils, were implanted into blind-end carotid arteries (n = 44) in rabbits, and their tissue reactions were evaluated histologically 14 days after the implantation. Five of the nine polymers elicited moderate to strong tissue reactions relative to the remaining materials. While polymer mass loss did not correlate with their histologic findings, polymers that showed a faster rate of molecular weight loss had a tendency to present more active tissue reactions such as strong fibrocellular response around the implanted material with a moderate inflammatory cell infiltration. Maxon exhibited the fastest rate of molecular weight loss and poly-l-lactic acid the slowest. The rate of molecular weight loss may be an important factor that is associated with the degree of bioactivity when bioabsorbable polymers are implanted into blood vessels. For further quantitative analysis, additional experiments utilizing established aneurysm models need to be conducted

Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

To study the impact of the 79A > C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients. Patients (n = 20) received gemcitabine 1,125 mg/m(2) as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0-6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A > C genotype was determined with PCR and DNA sequencing. Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A > C polymorphism was 0.40. Diplotypes were distributed as A/A n = 8, A/C n = 8 ,and C/C n = 4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life. The 79A > C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics

Effects of the Veterinary Pharmaceutical Ivermectin in Indoor Aquatic Microcosms

The effects of the parasiticide ivermectin were assessed in plankton-dominated indoor microcosms. Ivermectin was applied once at concentrations of 30, 100, 300, 1000, 3000, and 10,000 ng/l. The half-life (dissipation time 50%; DT50) of ivermectin in the water phase ranged from 1.1 to 8.3 days. The lowest NOECcommunity that could be derived on an isolated sampling from the microcosm study by means of multivariate techniques was 100 ng/l. The most sensitive species in the microcosm study were the cladocerans Ceriodaphnia sp. (no observed effect concentration, NOEC = 30 ng/l) and Chydorus sphaericus (NOEC = 100 ng/l). The amphipod Gammarus pulex was less sensitive to ivermectin, showing consistent statistically significant reductions at the 1000-ng/l treatment level. Copepoda taxa decreased directly after application of ivermectin in the highest treatment but had already recovered at day 20 posttreatment. Indirect effects (e.g., increase of rotifers, increased primary production) were observed at the highest treatment level starting only on day 13 of the exposure phase. Cladocera showed the highest sensitivity to ivermectin in both standard laboratory toxicity tests as well as in the microcosm study. This study demonstrates that simple plankton-dominated test systems for assessing the effects of ivermectin can produce results similar to those obtained with large complex outdoor systems

Factors predicting hospital length-of-stay and readmission after colorectal resection: a population-based study of elective and emergency admissions

<p>Abstract</p> <p>Background</p> <p>The impact of developments in colorectal cancer surgery on length-of-stay (LOS) and re-admission have not been well described. In a population-based analysis, we investigated predictors of LOS and emergency readmission after the initial surgery episode.</p> <p>Methods</p> <p>Incident colorectal cancers (ICD-O2: C18-C20), diagnosed 2002-2008, were identified from the National Cancer Registry Ireland, and linked to hospital in-patient episodes. For those who underwent colorectal resection, the associated hospital episode was identified. Factors predicting longer LOS (upper-quartile, > 24 days) for elective and emergency admissions separately, and whether LOS predicted emergency readmission within 28 days of discharge, were investigated using logistic regression.</p> <p>Results</p> <p>8197 patients underwent resection, 63% (n = 5133) elective and 37% (n = 3063) emergency admissions. Median LOS was 14 days (inter-quartile range (IQR) = 11-20) for elective and 21 (15-33) for emergency admissions. For both emergency and elective admissions, likelihood of longer LOS was significantly higher in patients who were older, had co-morbidities and were unmarried; it was reduced for private patients. For emergency patients only the likelihood of longer LOS was lower for patients admitted to higher-volume hospitals. Longer LOS was associated with increased risk of emergency readmission.</p> <p>Conclusions</p> <p>One quarter of patients stay in hospital for at least 25 days following colorectal resection. Over one third of resected patients are emergency admissions and these have a significantly longer median LOS. Patient- and health service-related factors were associated with prolonged LOS. Longer LOS was associated with increased risk of emergency readmission. The cost implications of these findings are significant.</p

Inhibition of Neuroblastoma Tumor Growth by Targeted Delivery of MicroRNA-34a Using Anti-Disialoganglioside GD2 Coated Nanoparticles

Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD(2)), providing a target for tumor-specific delivery.Nanoparticles encapsulating miR-34a and conjugated to a GD(2) antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2) protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors.These novel findings highlight the potential of anti-GD(2)-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD(2)-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth

Persistent DNA Damage after High Dose In Vivo Gamma Exposure of Minipig Skin

Exposure to high doses of ionizing radiation (IR) can lead to localized radiation injury of the skin and exposed cells suffer dsDNA breaks that may elicit cell death or stochastic changes. Little is known about the DNA damage response after high-dose exposure of the skin. Here, we investigate the cellular and DNA damage response in acutely irradiated minipig skin.IR-induced DNA damage, repair and cellular survival were studied in 15 cm(2) of minipig skin exposed in vivo to ~50 Co-60 γ rays. Skin biopsies of control and 4 h up to 96 days post exposure were investigated for radiation-induced foci (RIF) formation using γ-H2AX, 53BP1, and active ATM-p immunofluorescence. High-dose IR induced massive γ-H2AX phosphorylation and high 53BP1 RIF numbers 4 h, 20 h after IR. As time progressed RIF numbers dropped to a low of <1% of keratinocytes at 28-70 days. The latter contained large RIFs that included ATM-p, indicating the accumulation of complex DNA damage. At 96 days most of the cells with RIFs had disappeared. The frequency of active-caspase-3-positive apoptotic cells was 17-fold increased 3 days after IR and remained >3-fold elevated at all subsequent time points. Replicating basal cells (Ki67+) were reduced 3 days post IR followed by increased proliferation and recovery of epidermal cellularity after 28 days.Acute high dose irradiation of minipig epidermis impaired stem cell replication and induced elevated apoptosis from 3 days onward. DNA repair cleared the high numbers of DBSs in skin cells, while RIFs that persisted in <1% cells marked complex and potentially lethal DNA damage up to several weeks after exposure. An elevated frequency of keratinocytes with persistent RIFs may thus serve as indicator of previous acute radiation exposure, which may be useful in the follow up of nuclear or radiological accident scenarios