Wind Power: An opportunity for Illinois

The U.S. Clean Power Plan will require states to reduce carbon emissions significantly by 2030. The mandate allows states to decide how to reach this target. Rather than relying on coal-fired power plants, Illinois can build natural gas plants or invest in renewable technology like solar, geothermal or wind. The state’s geography and climate give Illinois a special advantage in the use of wind power. This policy brief compares the cost of production for wind energy and other comparable sources, and predictions for future costs in the U.S. and Illinois. It also takes a look at considerations for placement of wind parks. </div

A Biological Porin Engineered into a Molecular, Nanofluidic Diode

We changed the nonrectifying biological porin OmpF into a nanofluidic diode. To that end, we engineered a pore that possesses two spatially separated selectivity filters of opposite charge where either cations or anions accumulate. The observed current inhibition under applied reverse bias voltage reflects, we believe, the creation of a zone depleted of charge carriers, in a sense very similar to what happens at the np junction of a semiconductor device

Basic principles, applications in oncology and improved selectivity of photodynamic therapy

Photodynamic therapy (PDT) is a promising approach for the treatment of superficially localized tumors. This review starts with a summary of the basic principles of PDT, in which the current practice, the photochemical mechanisms, cellular and subcellular targets, as well as the most prominent photosensitizers are discussed. Next, the clinical results obtained with PDT for the treatment of a variety of tumor types are outlined. Unfortunately, most of these studies revealed a lack of tumor selectivity of the photosensitizers, which resulted in prolonged skin photosensitivity and severe normal tissue toxicity. The last section of this review, therefore, focuses on novel strategies designed to improve the tumor selectivity of photosensitizers

Ca2+ Selectivity of a Chemically Modified OmpF with Reduced Pore Volume

We studied an E. coli OmpF mutant (LECE) containing both an EEEE-like locus, typical of Ca 2+ channels, and an accessible and reactive cysteine. After chemical modification with the cysteine-specific, negatively charged (−1 e ) reagents MTSES or glutathione, this LECE mutant was tested for Ca 2+ versus alkali metal selectivity. Selectivity was measured by conductance and zero-current potential. Conductance measurements showed that glutathione-modified LECE had reduced conductance at Ca 2+ mole fractions <10 −3 . MTSES-modified LECE did not. Apparently, the LECE protein is (somehow) a better Ca 2+ chelator after modification with the larger glutathione. Zero-current potential measurements revealed a Ca 2+ versus monovalent cation selectivity that was highest in the presence of Li + and lowest in the presence of Cs + . Our data clearly show that after the binding of Ca 2+ the LECE pore (even with the bulky glutathione present) is spacious enough to allow monovalent cations to pass. Theoretical computations based on density functional theory combined with Poisson-Nernst-Planck theory and a reduced pore model suggest a functional separation of ionic pathways in the pore, one that is specific for small and highly charged ions, and one that accepts preferentially large ions, such as Cs +

Conductance and selectivity fluctuations in D127 mutants of the bacterial porin OmpF

A recent molecular dynamics study questioned the protonation state and physiological role of aspartate 127 (D127) of E. coli porin OmpF. To address that question we isolated two OmpF mutants with D127 either neutralized (D127N) or replaced by a positively charged lysine (D127K). The charge state of the residue at position 127 has clear effects on both conductance and selectivity. The D127K but not the D127N mutant expresses resilient conductance and selectivity fluctuations. These fluctuations reflect, we think, either changes in the ionization state of K127 and/or transitions between unstable subconformations as induced by the electrostatic repulsion between two positively charged residues, K127 and the nearby R167. Our results slightly favor the view that in WT OmpF residue D127 is deprotonated. As for the role of D127 in OmpF functionality, the gating of both mutants shows very similar sensitivity toward voltage as WT OmpF. Moreover, the current fluctuations of the D127K mutant were observed also in the absence of an applied electric field. We therefore dismiss D127 as a key residue in the control mechanism of the voltage-dependent gating of OmpF

Comparison of aluminium (III) phthalocyanine tetrasulfonate- and meta-tetrahydroxyphenylchlorin-monoclonal antibody conjugates for their efficacy in photodynamic therapy in vitro

A challenge in photodynamic therapy (PDT) is to improve the tumour selectivity of the photosensitizers by using monoclonal antibodies (MAbs). With this aim, we developed MAb-conjugates with the hydrophobic photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC) and with the hydrophilic sensitizer aluminium (III) phthalocyanine tetrasulfonate (AI-PCS4). The capacity of these photoimmunoconjugates for selective targeting of squamous cell carcinoma (SCC) in vivo was demonstrated previously in SCC-bearing nude mice. Preliminary in vitro PDT studies with the vulvar SCC cell line A431 showed promising phototoxicity with both sensitizers when coupled to the internalizing MAb 42S. To rank the photosensitizers for their potential in photoimmunotherapy, we herein describe an extensive in vitro evaluation of mTHPC-MAb and AIPcS4-MAb conjugates. Both classes of conjugates were directly compared using 5 different SCC cell lines as target and 3 different MAbs (BIWA 4, E48 and 425) for tumour cell targeting. In contrast to free AIPcS4 (IC50 ≥ 700 nM), MAb-conjugated AIPcS4 was found to be highly phototoxic in PDT in all 5 cell lines. AIPcS4-BIWA 4 was most consistently effective with IC50 values ranging from 0.06-5.4 nM. mTHPC-MAb conjugates were in general hardly effective. Phototoxicity (log IC50) of the AIPcS4-MAb conjugates was found to be strongly correlated with their total cell binding capacity (internalized and surface bound) and to be less correlated with their internalization capacity. In conclusion, these data show a high potential of AIPcS4-MAb conjugates in comparison to mTHPC-MAb conjugates for use in PDT

Targeting of aluminum (III) phthalocyanine tetrasulfonate by use of internalizing monoclonal antibodies: Improved efficacy in photodynamic therapy

The use of monoclonal antibodies (MAbs) directed against tumor-associated antigens for targeting of photosensitizers is an interesting option to improve the selectivity of photodynamic therapy (PDT). Hydrophilic photosensitizers are most suitable for conjugation to MAbs because of their water solubility. The photosensitizer aluminum (III) phthalocyanine tetrasulfonate [AIPc(SO3H)4] has many ideal photochemical properties; however, because of its hydrophilicity, the free form of this sensitizer does not readily reach the critical intracellular target and, therefore, is ineffective in PDT. On the basis of our previous studies, we hypothesized that AIPc(SO3H)4 might be suitable for PDT when coupled to internalizing tumor-selective MAbs. In this study, a reproducible procedure is presented for coupling of AIPc(SO3H)4 to MAbs via the tetra-glycine derivative AIPc(SO2Ngly)4. Conjugation was performed to chimeric MAb (cMAb) U36 and murine MAbs (mMAb) E48 and 425 using a labile ester. Conjugates showed preservation of integrity and immunoreactivity and full stability in serum in vitro. At molar ratios >4, the solubility of the conjugates decreased. Data on the in vitro efficacy of PDT showed that in the chosen experimental setup the internalizing AIPc(SO2Ngly)4-mMAb 425 conjugate was about 7500 times more toxic to A431 cells than the free sensitizer (IC50s, 0.12 nM versus 900 nM). The AIPc(SO2Ngly)4-mMAb 425 conjugate was also more toxic than meta-tetrahydroxyphenylchlorin-mMAb 425 conjugates and free meta-tetrahydroxyphenylchlorin that had been tested previously (M. B. Vrouenraets et al., Cancer Res., 59: 1505-1513, 1999) in the same system (IC50s, 7.3 nM and 2.0 nM, respectively). Biodistribution analysis of AIPc(SO2Ngly)4-125I-labeled cMAb U36 conjugates with different sensitizer:MAb ratios in squamous cell carcinoma-bearing nude mice revealed selective accumulation in the tumor, although to a lesser extent than for the unconjugated 125I-labeled cMAb U36, whereas tumor:blood ratios were similar. These findings indicate that AIPc(SO3H)4 has high potential for use in PDT when coupled to internalizing tumor-selective MAbs

Development of meta-tetrahydroxyphenylchlorin-monoclonal antibody conjugates for photoimmunotherapy

A limitation of photodynamic therapy is the lack of tumor selectivity of the photosensitizer. To overcome this problem, a protocol was developed for coupling of meta-tetrahydroxyphenylchlorin (mTHPC), one of the most promising photosensitizers, to tumor-selective monoclonal antibodies (MAbs). mTHPC was radiolabeled with 131I to facilitate the assessment of the in vitro and in vivo behavior. After the modification to 131I-mTHPC(CH2COOH)4, thus increasing the water solubility and creating a functional moiety suitable for coupling, conjugation was performed using a labile ester. Insoluble aggregates were not formed when mTHPC-MAb conjugates with a molar ratio of up to 4 were prepared. These conjugates showed a minimal impairment of the integrity on SDS-PAGE, full stability in serum in vitro, and an optimal immunoreactivity. To test the in vivo behavior of the mTHPC-MAb conjugates, the head and neck squamous cell carcinoma-selective chimeric MAb U36 was used in head and neck squamous cell carcinoma-bearing nude mice. Biodistribution data showed that the tumor selectivity of cMAb U36-conjugated mTHPC was increased in comparison with free mTHPC, despite the fact that conjugates with a higher mTHPC:MAb ratio were more rapidly cleared from the blood. Preliminary results on the in vitro efficacy of photodynamic therapy with MAb-conjugated mTHPC showed that mTHPC coupled to the internalizing murine MAb 425 exhibited more phototoxicity than when coupled to the noninternalizing chimeric MAb U36

Targeting of a hydrophilic photosensitizer by use of internalizing monoclonal antibodies: A new possibility for use in photodynamic therapy

Coupling of photosensitizers to tumor-selective monoclonal antibodies (MAbs) is an attractive option for improving the selectivity of photodynamic therapy (PDT). For this purpose, hydrophilic sensitizers would be most suitable because of their solubility in water. However, such sensitizers are known to be ineffective in PDT, probably because they cannot readily pass the cell membrane and reach the critical intracellular target. We used the model compound TrisMPyP-ΦCO2H, a hydrophilic porphyrin derivative, to test the hypothesis that hydrophilic photosensitizers might become of therapeutic value when directed into the tumor cell by use of internalizing MAbs. TrisMPyP-ΦCO2H was conjugated using a labile ester. Conjugates showed no impairment of integrity on SDS-PAGE, full stability in serum in vitro, and optimal immunoreactivity when the sensitizer: MAb ratio was ≤3. At higher molar ratios, the solubility of the conjugates decreased. In vitro internalization experiments showed that TrisMPyP-ΦCONH-125I-cMAb U36 and TrisMPyPΦCONH-125I-mMAb 425 conjugates were internalized by A431 cells, in contrast to TrisMPyP-ΦCONH-125I-mMAb E48 conjugates. Data on the in vitro efficacy of PDT with MAb-conjugated TrisMPyP-ΦCO2H showed that the internalizing cMAb U36 and mMAb 425 conjugates were phototoxic to A431 cells, while the non-internalizing E48 conjugate and the unconjugated sensitizer were not. Biodistribution data of conjugates with sensitizer:125I-cMAb U36 ratios varying from 1:1 to 3:1 in tumor-bearing nude mice revealed selective accumulation in the tumor. Conjugates with higher molar ratios were cleared more rapidly from the blood than the unconjugated 125I-cMAb U36, resulting in lower tumor uptake but similar tumor-to-blood ratios. Our data suggest that hydrophilic photosensitizers might have therapeutic value when targeted to tumors by internalizing MAbs. (C) 2000 Wiley-Liss, Inc

Ca(2+) Selectivity of a Chemically Modified OmpF with Reduced Pore Volume

We studied an E. coli OmpF mutant (LECE) containing both an EEEE-like locus, typical of Ca(2+) channels, and an accessible and reactive cysteine. After chemical modification with the cysteine-specific, negatively charged (−1e) reagents MTSES or glutathione, this LECE mutant was tested for Ca(2+) versus alkali metal selectivity. Selectivity was measured by conductance and zero-current potential. Conductance measurements showed that glutathione-modified LECE had reduced conductance at Ca(2+) mole fractions <10(−3). MTSES-modified LECE did not. Apparently, the LECE protein is (somehow) a better Ca(2+) chelator after modification with the larger glutathione. Zero-current potential measurements revealed a Ca(2+) versus monovalent cation selectivity that was highest in the presence of Li(+) and lowest in the presence of Cs(+). Our data clearly show that after the binding of Ca(2+) the LECE pore (even with the bulky glutathione present) is spacious enough to allow monovalent cations to pass. Theoretical computations based on density functional theory combined with Poisson-Nernst-Planck theory and a reduced pore model suggest a functional separation of ionic pathways in the pore, one that is specific for small and highly charged ions, and one that accepts preferentially large ions, such as Cs(+)