Post-translational insertion of boron in proteins to probe and modulate function

Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cβ–Bγ bond formation provides mild, direct, site-selective access to the minimally sized residue boronoalanine (Bal) in proteins. Precise anchoring of boron within complex biomolecular systems allows dative bond-mediated, site-dependent protein Lewis acid–base-pairing (LABP) by Bal. Dynamic protein-LABP creates tunable inter- and intramolecular ligand–host interactions, while reactive protein-LABP reveals reactively accessible sites through migratory boron-to-oxygen Cβ–Oγ covalent bond formation. These modes of dative bonding can also generate de novo function, such as control of thermo- and proteolytic stability in a target protein, or observation of transient structural features via chemical exchange. These results indicate that controlled insertion of boron facilitates stability modulation, structure determination, de novo binding activities and redox-responsive ‘mutation’

Post-translational insertion of boron in proteins to probe and modulate function

Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cβ–Bγ bond formation provides mild, direct, site-selective access to the minimally sized residue boronoalanine (Bal) in proteins. Precise anchoring of boron within complex biomolecular systems allows dative bond-mediated, site-dependent protein Lewis acid–base-pairing (LABP) by Bal. Dynamic protein-LABP creates tunable inter- and intramolecular ligand–host interactions, while reactive protein-LABP reveals reactively accessible sites through migratory boron-to-oxygen Cβ–Oγ covalent bond formation. These modes of dative bonding can also generate de novo function, such as control of thermo- and proteolytic stability in a target protein, or observation of transient structural features via chemical exchange. These results indicate that controlled insertion of boron facilitates stability modulation, structure determination, de novo binding activities and redox-responsive ‘mutation’

Anomalies and Fermion Content of Grand Unified Theories in Extra Dimensions

The restrictions imposed by anomaly cancellation on the chiral fermion content of nonsupersymmetric gauge theories based on various groups are studied in spacetime dimension D=6, 8, and 10. In particular, we show that the only mathematically consistent chiral SU(5) theory in D=6 contains three nonidentical generations.Comment: 15 pages, revtex. v2: references added to match published versio

Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [F-18]olaparib in mouse models of glioma

Purpose Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [F-18]olaparib and the injected mass of [F-Total]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models. Methods [F-18]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [F-Total]olaparib (varying injected mass: 0.04-8.0 mu g, and molar activity: 1-320 GBq/mu mol). Results Selective uptake of [F-18]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [F-Total]olaparib (mu g) but not the molar activity. An injected mass of 1 mu g resulted in the highest tumour uptake (up to 6.9 +/- 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [F-Total]olaparib resulted in lower relative tumour uptake (%ID/g; P 0.5 mu g). Conclusion Our findings show that the injected mass of [F-Total]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study

[Image: see text] Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon–fluorine bond formation. Herein, we disclose the asymmetric ring opening of meso aziridinium electrophiles derived from β-chloroamines with sodium azide in the presence of a chiral bisurea catalyst. The structure of novel hydrogen bonded azide complexes was analyzed computationally, in the solid state by X-ray diffraction, and in solution phase by (1)H and (14)N/(15)N NMR spectroscopy. With N-isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis

A multi-sensor network for the protection of cultural heritage

The paper presents a novel automatic early warning system to remotely monitor areas of archaeological and cultural interest from the risk of fire. Since these areas have been treasured and tended for very long periods of time, they are usually surrounded by old and valuable vegetation or situated close to forest regions, which exposes them to an increased risk of fire. The proposed system takes advantage of recent advances in multi-sensor surveillance technologies, using optical and infrared cameras, wireless sensor networks capable of monitoring different modalities (e.g. temperature and humidity) as well as local weather stations on the deployment site. The signals collected from these sensors are transmitted to a monitoring centre, which employs intelligent computer vision and pattern recognition algorithms as well as data fusion techniques to automatically analyze sensor information. The system is capable of generating automatic warning signals for local authorities whenever a dangerous situation arises, as well as estimating the propagation of the fire based on the fuel model of the area and other important parameters such as wind speed, slope, and aspect of the ground surface. © 2011 EURASIP

Maternal complications following open and fetoscopic fetal surgery: A systematic review and meta-analysis

OBJECTIVE: To establish maternal complication rates for fetoscopic or open fetal surgery. METHODS: We conducted a systematic literature review for studies of fetoscopic or open fetal surgery performed since 1990, recording maternal complications during fetal surgery, the remainder of pregnancy, delivery and after the index pregnancy. RESULTS: One hundred and sixty-six studies were included, reporting outcomes for open fetal (n=1193 patients) and fetoscopic surgery (n=9403 patients). No maternal deaths were reported. The risk of any maternal complication in the index pregnancy was 20.9% (95%CI 15.22-27.13) for open fetal and 6.2% (95%CI 4.93-7.49) for fetoscopic surgery. For severe maternal complications (Grade III to V Clavien-Dindo classification of surgical complications) the risk was 4.5% (95%CI 3.24-5.98) for open fetal and 1.7% (95%CI 1.19-2.20) for fetoscopic surgery. In subsequent pregnancies, open fetal surgery increased the risk of preterm birth but not uterine dehiscence or rupture. Nearly one quarter of reviewed studies (n=175, 23.3%) were excluded for failing to report the presence or absence of maternal complications. CONCLUSIONS: Maternal complications occur in 6.2% fetoscopic and 20.9% open fetal surgeries, with serious maternal complications in 1.7% fetoscopic and 4.5% open procedures. Reporting of maternal complications is variable. To properly quantify maternal risks, outcomes should be reported consistently across all fetal surgery studies

Heparan Sulfate Regrowth Profiles Under Laminar Shear Flow Following Enzymatic Degradation

The local hemodynamic shear stress waveforms present in an artery dictate the endothelial cell phenotype. The observed decrease of the apical glycocalyx layer on the endothelium in atheroprone regions of the circulation suggests that the glycocalyx may have a central role in determining atherosclerotic plaque formation. However, the kinetics for the cells’ ability to adapt its glycocalyx to the environment have not been quantitatively resolved. Here we report that the heparan sulfate component of the glycocalyx of HUVECs increases by 1.4-fold following the onset of high shear stress, compared to static cultured cells, with a time constant of 19 h. Cell morphology experiments show that 12 h are required for the cells to elongate, but only after 36 h have the cells reached maximal alignment to the flow vector. Our findings demonstrate that following enzymatic degradation, heparan sulfate is restored to the cell surface within 12 h under flow whereas the time required is 20 h under static conditions. We also propose a model describing the contribution of endocytosis and exocytosis to apical heparan sulfate expression. The change in HS regrowth kinetics from static to high-shear EC phenotype implies a differential in the rate of endocytic and exocytic membrane turnover.National Heart, Lung, and Blood Institute (Grant HL090856-01)Singapore-MIT Allianc

The My Active and Healthy Aging (My-AHA) ICT platform to detect and prevent frailty in older adults: Randomized control trial design and protocol

[EN] Introduction Frailty increases the risk of poor health outcomes, disability, hospitalization, and death in older adults and affects 7%¿12% of the aging population. Secondary impacts of frailty on psychological health and socialization are significant negative contributors to poor outcomes for frail older adults. Method The My Active and Healthy Aging (My-AHA) consortium has developed an information and communications technology¿based platform to support active and healthy aging through early detection of prefrailty and provision of individually tailored interventions, targeting multidomain risks for frailty across physical activity, cognitive activity, diet and nutrition, sleep, and psychosocial activities. Six hundred adults aged 60 years and older will be recruited to participate in a multinational, multisite 18-month randomized controlled trial to test the efficacy of the My-AHA platform to detect prefrailty and the efficacy of individually tailored interventions to prevent development of clinical frailty in this cohort. A total of 10 centers from Italy, Germany, Austria, Spain, United Kingdom, Belgium, Sweden, Japan, South Korea, and Australia will participate in the randomized controlled trial. Results Pilot testing (Alpha Wave) of the My-AHA platform and all ancillary systems has been completed with a small group of older adults in Europe with the full randomized controlled trial scheduled to commence in 2018. Discussion The My-AHA study will expand the understanding of antecedent risk factors for clinical frailty so as to deliver targeted interventions to adults with prefrailty. Through the use of an information and communications technology platform that can connect with multiple devices within the older adult's own home, the My-AHA platform is designed to measure an individual's risk factors for frailty across multiple domains and then deliver personalized domain-specific interventions to the individual. The My-AHA platform is technology-agnostic, enabling the integration of new devices and sensor platforms as they emerge.This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 689582 and the Australian National Health and Medical Research Council (NHRMC) European Union grant scheme (1115818). M.J.S. reports personal fees from Eli Lilly (Australia) Pty Ltd and grants from Novotech Pty Ltd, outside the submitted work. All other authors report nothing to disclose.Summers, MJ.; Rainero, I.; Vercelli, AE.; Aumayr, GA.; De Rosario Martínez, H.; Mönter, M.; Kawashima, R. (2018). 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