muFlowReacT: A Library to Solve Multiphase Multicomponent Reactive Transport on Unstructured Meshes.

In this paper we present a new reactive transport code for the efficient simulation of groundwater quality problems. The new code couples the two previously existing tools OpenFoam and PhreeqcRM. The major objective of the development was to transfer and expand the capabilities of the MODFLOW/MT3DMS-family of codes, especially their outstanding ability to suppress numerical dispersion, to a versatile and computationally efficient code for unstructured grids. Owing to the numerous, previously existing transport solvers contained in OpenFoam, the newly developed code achieves this objective and provides a solid basis for future expansions of the code capabilities. The flexibility of the OpenFoam framework is illustrated by the addition of diffusional processes for gaseous compounds in the unsaturated zone and the advection of gases (multiphase transport). The code capabilities and accuracy are illustrated through several examples: (1) a simple 2D case for conservative solute transport under saturated conditions, (2) a gas diffusion case with reactions in the unsaturated zone, (3) a hydrogeologically complex 3D reactive transport problem, and finally (4) the injection of CO2 into a deep aquifer with acidification being buffered by carbonate minerals.

Quantum Monte Carlo Method in the Steady State.

We present a numerically exact steady-state inchworm Monte Carlo method for nonequilibrium quantum impurity models. Rather than propagating an initial state to long times, the method is directly formulated in the steady state. This eliminates any need to traverse the transient dynamics and grants access to a much larger range of parameter regimes at vastly reduced computational costs. We benchmark the method on equilibrium Green's functions of quantum dots in the noninteracting limit and in the unitary limit of the Kondo regime. We then consider correlated materials described with dynamical mean field theory and driven away from equilibrium by a bias voltage. We show that the response of a correlated material to a bias voltage differs qualitatively from the splitting of the Kondo resonance observed in bias-driven quantum dots.

Inter and intraspecific variability of dieldrin accumulation in Cucurbita fruits: New perspectives for food safety and phytomanagement of contaminated soils.

Due to past agricultural practices, it is common to identify arable soils contaminated with persistent and potentially toxic organochlorine pesticides (OCPs). Occurrence of OCPs, including dieldrin, in vegetables can lead to chronic exposure of the consumers. Some market vegetables, particularly the Cucurbitaceae, are known to accumulate high OCP concentrations. Dieldrin concentration in Cucurbita fruits can exceed the Maximal Residue Limit (MRL) resulting in cultivation and sale restrictions for market gardeners. To assess the intra- and interspecific variability of Cucurbitaceae species for low dieldrin concentration in fruits could be a solution. Here, 24 varieties from seven Cucurbitaceae species were cultivated outdoors in large pots, until fruiting, in soils historically contaminated with dieldrin. More than 330 fruits were harvested and analyzed for determining the inter and intraspecific variability of dieldrin accumulation. Significant interspecific differences occurred with mean fruit concentration ranging between 4.2 ± 7.0 and 85.0 ± 19.4 µg dieldrin kg-1 fresh weigh (FW) in watermelons (C. lanatus L.) and cucumbers (C. sativus L.), respectively. Intraspecific differences only occurred for Cucurbita pepo L. with mean concentration ranging between 4.9 ± 1.1 and 70.3 ± 3.6 µg dieldrin kg-1 FW for the varieties Noire maraîchère and Orélia, respectively. For this plant species, the influence of soil concentration, plant exposure time and biomass on fruit dieldrin concentration depended mainly on varieties.

Biomarcadores de enfermedad de Alzheimer en deterioro cognitivo leve: experiencia en una clínica de memoria de Latinoamérica / Biomarkers of Alzheimer's disease in mild cognitive impairment: Experience in a memory clinic from Latin America

Objetivo: El objetivo de este estudio fue investigar el rol y pronóstico de los biomarcadores de enfermedad de Alzheimer en pacientes con diagnóstico clínico de deterioro cognitivo leve (DCL) en una clínica de memoria de Latinoamérica.MétodoOchenta y nueve pacientes con DCL, 43 con demencia tipo Alzheimer y 18 controles normales apareados por edad, sexo y escolaridad fueron estudiados con un extenso protocolo demográfico, neurológico y neuropsicológico en la clínica de memoria del Instituto FLENI de Buenos Aires. Todos completaron una RM cerebral, una PET con FDG, una PET con estudios amiloideo (PIB), genotipificación de APOE y estudio de Aβ1-42, tau and f-tau de líquido cefalorraquídeo. Basado en la presencia/ausencia de patología amiloidea y neurodegeneración los pacientes fueron categorizados como A+/A− y N+/N− respectivamente.ResultadosEn el estudio de líquido cefalorraquídeo el 18% de los controles, el 64% de los DCL y el 92% de las demencia tipo Alzheimer tenían patología amiloidea; y un 11% de los controles, el 6% de los DCL y el 8% de las DTA eran sospechosos de fisiopatología no Alzheimer. En el seguimiento a los 30 meses el 45% de los DCL con amiloide positivo y el 20% de los que presentaron amiloide negativo progresaron a demencia.ConclusionesEste estudio muestra el pronóstico de los DCL basado en los biomarcadores, y respalda su importancia en la toma de decisiones en la práctica diaria. (AU)

Objective: This study aimed to investigate the role and prognosis of Alzheimer disease biomarkers in patients with mild cognitive impairment (MCI) at a memory clinic in Latin America.MethodsWe studied 89 patients with MCI, 43 with Alzheimer-type dementia, and 18 healthy controls (matched for age, sex, and educational level) at our memory clinic (Instituto FLENI) in Buenos Aires, Argentina. Patients and controls underwent an extensive demographic, neurological, and neuropsychological assessment. All subjects underwent a brain MRI scan; FDG-PET scan; amyloid PET scan; apolipoprotein E genotyping; and cerebrospinal fluid concentrations of Aβ1-42, tau, and phosphorylated tau. Patients were categorised as positive or negative for the presence of amyloid pathology and neurodegeneration.ResultsAmyloid pathology was observed in cerebrospinal fluid results in 18% of controls, 64% of patients with MCI, and 92% of patients with Alzheimer-type dementia. Suspected non–Alzheimer disease pathophysiology was found in 11% of controls, 6% of patients with MCI, and 8% of patients with Alzheimer-type dementia. At 30 months of follow-up, 45% of amyloid-positive patients with MCI and 20% of amyloid-negative patients with MCI showed progression to dementia.ConclusionsThis study demonstrates biomarker-based MCI prognosis and supports its role in clinical decision-making in daily practice. (AU)

Biomarkers of Alzheimer's disease in mild cognitive impairment: Experience in a memory clinic from Latin America. / Biomarcadores de enfermedad de Alzheimer en deterioro cognitivo leve: experiencia en una clínica de memoria de Latinoamérica.

OBJECTIVE: This study aimed to investigate the role and prognosis of Alzheimer disease biomarkers in patients with mild cognitive impairment (MCI) at a memory clinic in Latin America. METHODS: We studied 89 patients with MCI, 43 with Alzheimer-type dementia, and 18 healthy controls (matched for age, sex, and educational level) at our memory clinic (Instituto FLENI) in Buenos Aires, Argentina. Patients and controls underwent an extensive demographic, neurological, and neuropsychological assessment. All subjects underwent a brain MRI scan; FDG-PET scan; amyloid PET scan; apolipoprotein E genotyping; and cerebrospinal fluid concentrations of Aß1-42, tau, and phosphorylated tau. Patients were categorised as positive or negative for the presence of amyloid pathology and neurodegeneration. RESULTS: Amyloid pathology was observed in cerebrospinal fluid results in 18% of controls, 64% of patients with MCI, and 92% of patients with Alzheimer-type dementia. Suspected non-Alzheimer disease pathophysiology was found in 11% of controls, 6% of patients with MCI, and 8% of patients with Alzheimer-type dementia. At 30 months of follow-up, 45% of amyloid-positive patients with MCI and 20% of amyloid-negative patients with MCI showed progression to dementia. CONCLUSIONS: This study demonstrates biomarker-based MCI prognosis and supports its role in clinical decision-making in daily practice.

The impact of a nationwide hands-on workshop on the diagnostic rates and management of obstetrical anal sphincter Injuries in Israel.

AIM: The aim was to evaluate the influence of a half day, hands-on, workshop on the detection and repair of obstetric anal sphincter injuries (OASIs). METHOD: Starting in February 2011, hands-on workshops for the diagnosis and repair of OASIs were delivered by trained urogynaecologists in departments of tertiary medical centres in Israel. The structure of the hands-on workshop resembles the workshop organized at the International Urogynecological Association annual conferences. Participants included medical staff, midwives and surgical residents from each medical centre. We collected data regarding the rate of OASIs, 1 year before and 1 year following the workshop, in 11 medical centres. The study population was composed of parturients with the following inclusion criteria: singleton pregnancy, vertex presentation and vaginal delivery. Pre-viable preterm gestations (< 24 weeks), birth weight < 500 g, stillborn, and those with major congenital anomalies, multifoetal pregnancies, breech presentations and caesarean deliveries were excluded from the analysis. RESULTS: In the reviewed centres, 70 663 (49.3%) women delivered prior to the workshop (pre-workshop group) and 72 616 (50.7%) women delivered following the workshop (post-workshop group). Third- or fourth-degree perineal tears occurred in 248 women (0.35%) before the workshop, and in 328 (0.45%) following the workshop, a significant increase of 28.7% (P = 0.002). The increase in diagnosis was significant also in women with third-degree tears alone, 226 women (0.32%) before the workshop and 298 (0.41%) following the workshop, an increase of 28.3% (P = 0.005). CONCLUSION: The detection rate of OASIs has significantly increased following the hands-on workshop. The implementation of such programmes is crucial for increasing awareness and detection rates of OASI following vaginal deliveries.

Venous thrombosis during olanzapine treatment: a complex association.

Olanzapine, a second generation antipsychotic, has previously been associated with an increased risk of venous thromboembolism (VTE). In this mini-review we describe a case of a thirty-year-old schizophrenic patient who was diagnosed with a deep venous thrombosis (DVT) six months after starting olanzapine therapy, as well as seventeen other VTE cases in patients using olanzapine reported to the Netherlands Pharmacovigilance Centre Lareb. In 14 of these reports, patients had reported additional risk factors for VTE. We found disproportionate Reporting Odds Ratios (RORs) in the global database VigiBase for olanzapine and the reactions deep vein thrombosis (ROR of 1.38 with a 95% CI (Confidence Interval) of 1.22-1.57) and pulmonary embolism (ROR of 1.99 with a 95% CI of 1.81-2.19). The mechanism behind the association of olanzapine with VTE could be explained by two risk factors, substantial weight gain and lethargy, both common side effects of olanzapine. So far, a direct effect of olanzapine on platelet aggregation or coagulation has not been found. Schizophrenic patients are more likely to have diagnostic delay in the diagnosis of VTE, as symptoms such as lethargy and impaired pain perception result in diminished pain perception and pain expression, while they are at increased risk of developing VTE. Currently no validated risk score is available for detection of psychiatric patients who might benefit from pharmacologic VTE prophylaxis. In patients developing a VTE while being treated with olanzapine, discontinuation of olanzapine could be considered based on the individual risk profile, control of psychotic symptoms and antipsychotic treatment options.

Utility of the Spanish version of the Everyday Cognition scale in the diagnosis of mild cognitive impairment and mild dementia in an older cohort from the Argentina-ADNI.

INTRODUCTION: The performance of activities of daily living in elderly patients with memory disorders is directly related to living independently and to autonomy. Documenting and assessing functional capacity through detailed scales is important for both diagnostic and treatment recommendations. The Everyday Cognition (ECog) scale is a relatively new informant-rated measure of cognitive and functional abilities. In the present study, the discriminant validity of the ECog scale was evaluated in cognitively intact controls (CN) and in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) from the Argentina-ADNI cohort to establish diagnostic accuracy. In addition, we compared the sensitivity and specificity of ECog against Functional Assessment Questionnaire (FAQ) scale to discriminate among the three groups. METHODS: We evaluated 15 CN, 28 MCI, and 13 mild AD subjects. External, convergent and divergent validity and internal consistency were examined. RESULTS: The average total score on the ECog was significantly different across the three diagnostic syndromes (p < .05). The ECog was more sensitive than FAQ in discriminating between CN and MCI patients and between MCI and AD subjects. The ECog showed a strong correlation with FAQ, and moderate correlations with neuropsychological tests. Cronbach's alpha was .98. CONCLUSIONS: The ECog scale is an efficient instrument for the differentiation of individuals with mild dementia or MCI from normal older adults, with good accuracy and good correlation with other tests measuring daily and cognitive functions. Comparing against FAQ, ECog was more useful in assessing changes in functionality in MCI patients.

Removal of NAPL from columns by oxidation, sparging, surfactant and thermal treatment.

In this paper, four treatment techniques commonly applied to Volatile Organic Compounds (VOC) removal from soil are compared in column experiments with pure sand containing a residual Light Non-Aqueous Phase Liquid (L-NAPL) contamination. Oxidation is tested through the injection of Fenton reagent, with persulfate, and combined with sparging with the injection of ozone. Surfactant treatment was conducted at low flow rates with Tween®80. Sparging was conducted by air injection but at a low flow rate of 1 mL min-1. Finally several columns were thermally treated at a temperature of 80 °C. The results showed high removal (>90%) for all techniques used, although only thermal treatment on BTEX (Benzene, Toluene, Ethylbenzene and Xylenes) reached 100% efficiency. The main limiting factors of each technique were: (i) for oxidation, the solubility of the substance limited the removal; (ii) for surfactant both the solubility in the surfactant and the type of surfactant are important; (iii) for sparging, the main factors are contaminant vapor pressure and porous media grain size; (iv) for thermal treatment, the limitation arises from the contaminant vapor pressure and the medium hydraulic conductivity. A comparison with literature data shows that the results are consistent with most of the studies conducted on one technique.

Comparison of residual NAPL source removal techniques in 3D metric scale experiments.

This study compared four treatment techniques for the removal of a toluene/n-decane as NAPL (Non Aqueous Phase Liquid) phase mixture in identical 1 cubic meter tanks filled with different kind of sand. These four treatment techniques were: oxidation with persulfate, surfactant washing with Tween80®, sparging with air followed by ozone, and thermal treatment at 80°C. The sources were made with three lenses of 26×26×6.5cm, one having a hydraulic conductivity similar to the whole tank and the two others a value 10 times smaller. The four techniques were studied after conditioning the tanks with tap water during approximately 80days. The persulfate treatment tests showed average removal of the contaminants but significant flux decrease if density effects are considered. Surfactant flushing did not show a highly significant increase of the flux of toluene but allowed an increased removal rate that could lead to an almost complete removal with longer treatment time. Sparging removed a significant amount but suggests that air was passing through localized gas channels and that the removal was stagnating after removing half of the contamination. Thermal treatment reached 100% removal after the target temperature of 80°C was kept during more than 10d. The experiments emphasized the generation of a high-spatial heterogeneity in NAPL content. For all the treatments the overall removal was similar for both n-decane and toluene, suggesting that toluene was removed rapidly and n-decane more slowly in some zones, while no removal existed in other zones. The oxidation and surfactant results were also analyzed for the relation between contaminant fluxes at the outlet and mass removal. For the first time, this approach clearly allowed the differentiation of the treatments. As a conclusion, experiments showed that the most important differences between the tested treatment techniques were not the global mass removal rates but the time required to reach 99% decrease in the contaminant fluxes, which were different for each technique.

Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody-Induced Complement Activation-A Preclinical In Vitro Study.

The classic pathway (CP) of complement is believed to significantly contribute to alloantibody-mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti-C1s monoclonal antibody TNT009 and its parental mouse variant, TNT003, in preclinical in vitro models of HLA antibody-triggered CP activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLA antigen-coated flow beads or HLA-mismatched aortic endothelial cells and splenic lymphocytes. Anti-C1s antibodies profoundly inhibited C3 activation at concentrations >20 µg/mL, in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline CP activation. This study demonstrates that anti-C1s antibodies TNT009 and TNT003 are highly effective in blocking HLA antibody-triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement-mediated tissue injury in sensitized transplant recipients.

Photon-Induced Quantum Oscillations of the Terahertz Conductivity in Graphene.

In this work, we present a theory that is able to explain the nonmonotonic decreasing behavior (observed in experimental data1-12) of the graphene terahertz conductivity with the increase of the field frequency. In this connection, the displacement of the structure of topological states inside the energy band gap, which appears in graphene due to the strong photon-electron coupling, and the narrowing of this gap, as result of electron transitions from bound photon-dressed electron states to extended states outside the energy gap driven by the field frequency, lead to a periodic change of singularities near the edge of the band gap, resulting in subtle quantum oscillations of the dynamical terahertz conductivity. This quantum contribution complements the Drude response, which fits the spectral range. On the other hand, the scattering processes by impurities favor interband transitions, suppressing this way intraband terahertz absorptions, which are related to optical transitions from inside to outside the gap.

High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a predictive biomarker of disease progression in many malignancies, including imatinib-treated chronic myeloid leukemia (CML). Although high CIP2A levels correlate with disease progression in CML, the underlying molecular mechanisms remain elusive. In a screen of diagnostic chronic phase samples from patients with high and low CIP2A protein levels, high CIP2A levels correlate with an antiapoptotic phenotype, characterized by downregulation of proapoptotic BCL-2 family members, including BIM, PUMA and HRK, and upregulation of the antiapoptotic protein BCL-XL. These results suggest that the poor prognosis of patients with high CIP2A levels is due to an antiapoptotic phenotype. Disrupting this antiapoptotic phenotype by inhibition of BCL-XL via RNA interference or A-1331852, a novel, potent and BCL-XL-selective inhibitor, resulted in extensive apoptosis either alone or in combination with imatinib, dasatinib or nilotinib, both in cell lines and in primary CD34(+) cells from patients with high levels of CIP2A. These results demonstrate that BCL-XL is the major antiapoptotic survival protein and may be a novel therapeutic target in CML.

Principles of light harvesting from single photosynthetic complexes.

Photosynthetic systems harness sunlight to power most life on Earth. In the initial steps of photosynthetic light harvesting, absorbed energy is converted to chemical energy with near-unity quantum efficiency. This is achieved by an efficient, directional and regulated flow of energy through a network of proteins. Here, we discuss the following three key principles of this flow and of photosynthetic light harvesting: thermal fluctuations of the protein structure; intrinsic conformational switches with defined functional consequences; and environmentally triggered conformational switches. Through these principles, photosynthetic systems balance two types of operational costs: metabolic costs, or the cost of maintaining and running the molecular machinery, and opportunity costs, or the cost of losing any operational time. Understanding how the molecular machinery and dynamics are designed to balance these costs may provide a blueprint for improved artificial light-harvesting devices. With a multi-disciplinary approach combining knowledge of biology, this blueprint could lead to low-cost and more effective solar energy conversion. Photosynthetic systems achieve widespread light harvesting across the Earth's surface; in the face of our growing energy needs, this is functionality we need to replicate, and perhaps emulate.

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration.

The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

Benzothiazole derivatives augment glucose uptake in skeletal muscle cells and stimulate insulin secretion from pancreatic ß-cells via AMPK activation.

Adenosine monophosphate-activated protein kinase (AMPK) has been identified as one of the major targets for antidiabetic drugs. This study describes two AMPK-activating agents 2-(benzo[d]thiazol-2-ylmethylthio)-6-ethoxybenzo[d]thiazole and 2-(propylthio)benzo[d]thiazol-6-ol, that increase the rate of glucose uptake in L6 myotubes and also augment glucose-stimulated insulin secretion in INS-1E ß-cells and rat islets. We believe that such unique bi-functional compounds can be further used for the development of a new class of antidiabetic drugs.

Adverse circulatory effects of passive smoking during infancy: surprisingly strong, manifest early, easily avoided.

AIM: To compare blood pressure reactions (BPR) of infants to mild stress for evidence of adverse cardiovascular effects of passive exposure to tobacco smoke during pregnancy and early infancy. METHODS: An observational field study conducted in Crete. We compared 4- to 6-month olds of lifelong nonsmokers minimally (controls, n = 9) or frequently exposed to tobacco smoke (passive smokers; n = 10) with those born to habitual smokers (n = 6). Smoke exposure was verified biochemically (urine cotinine each trimester and at study). We recorded beat-to-beat blood pressure (BP) during brief repositioning manoeuvres performed during a daytime nap and analysed BPR (% change in BP during head-up tilt) for associations with maternal and infant cotinine. RESULTS: We observed a 20-fold difference between BPR of infants of controls versus passive smokers - exceptional given number of infants (α error/confidence level <10% i.e. power >90%). The BPR declined linearly as the infant's (but not mother's) cotinine level rose (p = 0.04), indicating abnormal BPR was caused mainly by postnatal smoke exposure. Infants of active smokers differed from those of passive smokers. CONCLUSION: Cardiovascular effects of passive smoking by a newborn infant manifest early on and are exceptionally strong. They can be largely avoided by keeping the home smoke rigorously free.

Sympathomimetic amines effectively control pain for interstitial cystitis that had not responded to other therapies.

PURPOSE: To further investigate the efficacy of treatment of interstitial cystitis that had been refractory to standard treatment with sympathomimetic amines. METHODS: Dextroamphetamine sulfate sustained release capsules up to 30 mg per day were prescribed in women with refractory painful bladder syndrome/interstitial cystitis in six new cases. The patients were carefully evaluated for relief of symptoms. RESULTS: All six women found marked relief in their painful bladder syndrome in a rather short length of time. The benefit persisted as long as the therapy was maintained. Temporary cessation resulted in prompt return of symptoms, but resumption of sympathomimetic amines again allowed good relief of bladder pain and related symptoms. CONCLUSIONS: Because of very few side-effects and no drug dependence in the dosage used, sympathomimetic amines should be considered for first-line therapy.

Evaluation and critical assessment of putative MCL-1 inhibitors.

High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-XL but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak- and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2- or BCL-XL-dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

Reconstruction of surface potential from Kelvin probe force microscopy images.

We present an algorithm for reconstructing a sample surface potential from its Kelvin probe force microscopy (KPFM) image. The measured KPFM image is a weighted average of the surface potential underneath the tip apex due to the long-range electrostatic forces. We model the KPFM measurement by a linear shift-invariant system where the impulse response is the point spread function (PSF). By calculating the PSF of the KPFM probe (tip+cantilever) and using the measured noise statistics, we deconvolve the measured KPFM image to obtain the surface potential of the sample.The reconstruction algorithm is applied to measurements of CdS-PbS nanorods measured in amplitude modulation KPFM (AM-KPFM) and to graphene layers measured in frequency modulation KPFM (FM-KPFM). We show that in the AM-KPFM measurements the averaging effect is substantial, whereas in the FM-KPFM measurements the averaging effect is negligible.