ABSTRACT
A precise dynamical characterization of quantum impurity models with multiple interacting orbitals is challenging. In quantum Monte Carlo methods, this is embodied by sign problems. A dynamical sign problem makes it exponentially difficult to simulate long times. A multi-orbital sign problem generally results in a prohibitive computational cost for systems with multiple impurity degrees of freedom even in static equilibrium calculations. Here, we present a numerically exact inchworm method that simultaneously alleviates both sign problems, enabling simulation of multi-orbital systems directly in the equilibrium or nonequilibrium steady-state. The method combines ideas from the recently developed steady-state inchworm Monte Carlo framework [Erpenbeck et al., Phys. Rev. Lett. 130, 186301 (2023)] with other ideas from the equilibrium multi-orbital inchworm algorithm [Eidelstein et al., Phys. Rev. Lett. 124, 206405 (2020)]. We verify our method by comparison with analytical limits and numerical results from previous methods.
ABSTRACT
PURPOSE: Fetal sex is independently associated with pregnancy complications and impacts neonatal outcomes. Evidence suggests that females have an advantage over males, with a better outcome in the perinatal period. In addition, fetal outcome in twin gestations is also related to the intrauterine position of the fetus, such as the first, the presenting or second twin. It has been demonstrated that the neonatal outcome of the second fetus is worse than that of the first fetus. This study aimed to examine the influence of fetal sex on obstetric outcomes in twin pregnancies based on the location of the fetus in the uterus. METHODS: Retrospective study. Maternal and obstetric outcomes were compared among three groups: maleâmale, femaleâfemale, and maleâfemale groups. Comparisons of neonatal outcomes were performed among the four groups: male A-male B, male A-female B, female A-male B, and female A-female B. RESULTS: A total of 1073 twin gestations were included, comprising 288 maleâmale, 288 femaleâfemale, and 497 maleâfemale gestations. A greater percentage of neonates admitted to the NICU was observed for male fetuses than for female fetuses. Adverse composite neonatal outcome was more common in the maleâmale group than in the femaleâmale group and in the femaleâfemale group. CONCLUSION: Twin gestation with a first twin male tends to have worse neonatal outcomes than does twin gestation with a first twin female. The presence of a male co-twin increases the risk of adverse outcomes.
Subject(s)
Pregnancy Outcome , Pregnancy, Twin , Humans , Female , Pregnancy , Male , Pregnancy, Twin/statistics & numerical data , Retrospective Studies , Infant, Newborn , Pregnancy Outcome/epidemiology , Adult , Sex FactorsABSTRACT
The hyoid apparatus of tetrapods is highly diverse in its morphology. It plays an important role in feeding, breathing, sound production, and various other behaviors. Among turtles, the diversity of the hyoid apparatus has been recurrently linked to their habitat. The ossification of the hyoid corpus is often the main trait used in correlations with "niche" occupancy, an ossified corpus being associated with aquatic environments and a cartilaginous corpus with terrestrial life. Most studies conducted so far have focused on species belonging to Testudinoidea, the clade that occupies the biggest diversity of habitats (i.e., terrestrial, semi-terrestrial, and aquatic animals), while other turtle lineages have been largely understudied. We assessed the adult anatomy of the hyoid apparatus of 92 turtle species from all "families", together with ossification sequences from embryological series of 11 species, some described for the first time here. Using nearly 40 different discrete anatomical characters, we discuss the evolutionary patterns and the biological significance of morphological transformations in the turtle hyoid elements. Morphological changes are strongly associated to feeding modes, with several instances of convergent evolution within and outside the Testudines clade, and are not as strongly connected to habitat as previously thought. Some of the hyoid character states we describe are diagnostic of specific turtle clades, thus providing phylogenetically relevant information.
El aparato hyoideo de los tetrápodos es muy diverso en su morfología. El mismo desempeña un papel importante en la alimentación, la respiración, la producción de sonidos y otras funciones. En las tortugas, la diversidad del aparato hyoideo se ha relacionado con el hábitat. La osificación del cuerpo hyoideo es a menudo el rasgo principal utilizado en correlaciones con la ocupación de "nichos"; un cuerpo osificado se asocia con ambientes acuáticos y un cuerpo cartilaginoso con la vida terrestre. La mayoría de los estudios realizados se han centrado en especies pertenecientes a Testudinoidea, el clado que ocupa la mayor diversidad de hábitats (terrestre, semiterrestre y acuático), mientras que otros linajes de tortugas han sido poco estudiados. Evaluamos la anatomía adulta del aparato hyoideo de 92 especies de tortugas de todas las "familias", junto con secuencias de osificación de series embriológicas de once especies, algunas descritas por primera vez aquí. Utilizando casi 40 caracteres anatómicos discretos diferentes, discutimos los patrones evolutivos y el significado biológico de lastransformaciones morfológicas en los elementos hyoideos de las tortugas. Los cambios morfológicos están asociados con los modos de alimentación, con varios casos de convergencia dentro y fuera del clado Testudines; la asociación con el hábitat no es tan robusta como se ha hipotetizado. Algunos de los estados de caracteres que describimos son diagnósticos de clados de tortugas específicos, proporcionando así información filogenéticamente relevante.
ABSTRACT
Dieldrin, an organochlorine pesticide (OCP) widely used for crop protection in the second half of the 20th century till the 70's, is worldwide still present in arable soils. It can be transferred to crops, notably cucurbits, depending on plant species and cultivars. Finding strategies to decrease OCP bioavailability in soil is therefore a main concern. Phytomanagement strategies could provide (i) ready-to-use short term solution for maintaining the production of edible plant parts with dieldrin concentrations below the Maximum Residue Limits (MRL) and (ii) long-term solution for dieldrin phytoextraction reducing progressively its bioavailability in the soil. This field study aimed at determining dieldrin accumulation capacities and allocation pattern in 17 non-Cucurbitaceae species and 10 Cucurbita pepo varieties, and assessing the dieldrin phytoextraction potential of these plant species when grown to maturity in a historically dieldrin-contaminated soil. Out of the non-Cucurbitaceae species, vetiver was the only one able to accumulate significant amounts of dieldrin, which mainly remained in its roots. All C. pepo varieties were able to uptake and translocate high dieldrin amounts into the shoots, leading to the highest phytoextraction potential. Despite the intraspecific variability in dieldrin concentration in zucchini plant parts, mainly in the reproductive organs, the phytoextraction capacity for shoots and fruits was high for all tested varieties (147 to 275 µg dieldrin plant-1, corresponding to 5.6 % of the n-heptane extractable soil dieldrin), even for the one with low fruit dieldrin concentration. Both food safety and phytoextraction could be achieved by selecting productive zucchini varieties displaying low dieldrin concentration in fruits and high one in shoots.
Subject(s)
Biodegradation, Environmental , Cucurbita , Dieldrin , Soil Pollutants , Dieldrin/metabolism , Cucurbita/metabolism , Soil Pollutants/metabolism , Soil Pollutants/analysis , Soil/chemistryABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Cucurbita , Cucurbitaceae , Soil Pollutants , Dieldrin/analysis , Cucurbita/chemistry , Fruit/chemistry , Soil Pollutants/analysis , Soil , Food Safety , VegetablesABSTRACT
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 nonAlzheimer 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)
Subject(s)
Humans , Alzheimer Disease , Biomarkers , Amyloid , Pantothenate Kinase-Associated Neurodegeneration , Cognitive DysfunctionABSTRACT
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.
Subject(s)
Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Biomarkers , Cognitive Dysfunction/diagnosis , Disease Progression , Humans , Latin America , Peptide Fragments , tau ProteinsABSTRACT
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.
Subject(s)
Lacerations , Midwifery , Obstetric Labor Complications , Anal Canal/injuries , Delivery, Obstetric , Female , Humans , Infant, Newborn , Israel/epidemiology , Lacerations/diagnosis , Lacerations/epidemiology , Lacerations/therapy , Obstetric Labor Complications/diagnosis , Obstetric Labor Complications/epidemiology , Obstetric Labor Complications/therapy , Pregnancy , Retrospective Studies , Risk FactorsABSTRACT
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.
Subject(s)
Antipsychotic Agents/adverse effects , Fibrinolytic Agents/administration & dosage , Olanzapine/adverse effects , Schizophrenia, Paranoid/drug therapy , Venous Thrombosis/chemically induced , Adult , Antipsychotic Agents/therapeutic use , Follow-Up Studies , Humans , Injections, Intramuscular , Male , Netherlands , Olanzapine/therapeutic use , Risk Assessment , Schizophrenia, Paranoid/diagnosis , Treatment Outcome , Ultrasonography, Doppler , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/drug therapyABSTRACT
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.
Subject(s)
Activities of Daily Living , Cognitive Dysfunction/diagnosis , Dementia/diagnosis , Activities of Daily Living/psychology , Aged , Aged, 80 and over , Argentina , Cohort Studies , Female , Humans , Male , Middle Aged , Neuropsychological Tests/standards , Sensitivity and Specificity , Surveys and QuestionnairesABSTRACT
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.
Subject(s)
Environmental Restoration and Remediation/methods , Hot Temperature , Hydrocarbons, Aromatic/analysis , Models, Theoretical , Soil Pollutants/analysis , Surface-Active Agents/chemistry , Volatile Organic Compounds/analysis , Hydrocarbons, Aromatic/chemistry , Oxidants/chemistry , Oxidation-Reduction , Silicon Dioxide/chemistry , Soil Pollutants/chemistry , Solubility , Vapor Pressure , Volatile Organic Compounds/chemistryABSTRACT
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.
Subject(s)
Alkanes/isolation & purification , Environmental Restoration and Remediation/methods , Toluene/isolation & purification , Alkanes/chemistry , Groundwater , Polysorbates/chemistry , Silicon Dioxide , Soil Pollutants/chemistry , Soil Pollutants/isolation & purification , Surface-Active Agents/chemistry , Toluene/chemistry , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/isolation & purificationABSTRACT
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.
Subject(s)
Antibodies, Monoclonal/pharmacology , Complement Activation/immunology , Complement C1s/immunology , Graft Rejection/drug therapy , HLA Antigens/immunology , Isoantibodies/adverse effects , Kidney Transplantation/adverse effects , Animals , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/etiology , Graft Survival , Humans , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/surgery , Kidney Function Tests , Mice , PrognosisABSTRACT
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.
ABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Autoantigens/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Membrane Proteins/blood , bcl-X Protein/antagonists & inhibitors , Adolescent , Adult , Aged , Benzothiazoles/pharmacology , Benzothiazoles/therapeutic use , Biomarkers, Tumor/blood , Cell Line, Tumor , Female , Humans , Intracellular Signaling Peptides and Proteins , Isoquinolines/pharmacology , Isoquinolines/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Prognosis , Proto-Oncogene Proteins c-bcl-2 , Tumor Cells, Cultured , Young AdultABSTRACT
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.
ABSTRACT
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.
Subject(s)
Nerve Tissue Proteins/metabolism , Neurodegenerative Diseases/metabolism , Receptors, Glucocorticoid/metabolism , Animals , Apoptosis/genetics , Apoptosis/physiology , Drosophila , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum Stress/physiology , HeLa Cells , Humans , Nerve Tissue Proteins/genetics , Neurodegenerative Diseases/genetics , Receptors, Glucocorticoid/genetics , Signal Transduction/genetics , Signal Transduction/physiology , Unfolded Protein Response/genetics , Unfolded Protein Response/physiologyABSTRACT
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.