Exciton Dissociation in a Model Organic Interface: Excitonic State-Based Surface Hopping versus Multiconfigurational Time-Dependent Hartree

Quantum dynamical simulations are essential for a molecular-level understanding of light-induced processes in optoelectronic materials, but they tend to be computationally demanding. We introduce an efficient mixed quantum-classical nonadiabatic molecular dynamics method termed eXcitonic state-based Surface Hopping (X-SH), which propagates the electronic Schrödinger equation in the space of local excitonic and charge-transfer electronic states, coupled to the thermal motion of the nuclear degrees of freedom. The method is applied to exciton decay in a 1D model of a fullerene-oligothiophene junction, and the results are compared to the ones from a fully quantum dynamical treatment at the level of the Multilayer Multiconfigurational Time-Dependent Hartree (ML-MCTDH) approach. Both methods predict that charge-separated states are formed on the 10-100 fs time scale via multiple "hot-exciton dissociation" pathways. The results demonstrate that X-SH is a promising tool advancing the simulation of photoexcited processes from the molecular to the true nanomaterials scale

The reaction mechanism of metallo-beta-lactamases is tuned by the conformation of an active site mobile loop

Carbapenems are "last resort" β-lactam antibiotics used to treat serious and life-threatening health care-associated infections caused by multidrug-resistant Gram-negative bacteria. Unfortunately, the worldwide spread of genes coding for carbapenemases among these bacteria is threatening these life-saving drugs. Metallo-β-lactamases (MβLs) are the largest family of carbapenemases. These are Zn(II)-dependent hydrolases that are active against almost all β-lactam antibiotics. Their catalytic mechanism and the features driving substrate specificity have been matter of intense debate. The active sites of MβLs are flanked by two loops, one of which, loop L3, was shown to adopt different conformations upon substrate or inhibitor binding, and thus are expected to play a role in substrate recognition. However, the sequence heterogeneity observed in this loop in different MβLs has limited the generalizations about its role. Here, we report the engineering of different loops within the scaffold of the clinically relevant carbapenemase NDM-1. We found that the loop sequence dictates its conformation in the unbound form of the enzyme, eliciting different degrees of active-site exposure. However, these structural changes have a minor impact on the substrate profile. Instead, we report that the loop conformation determines the protonation rate of key reaction intermediates accumulated during the hydrolysis of different β-lactams in all MβLs. This study demonstrates the existence of a direct link between the conformation of this loop and the mechanistic features of the enzyme, bringing to light an unexplored function of active-site loops on MβLs.Fil: Palacios, Antonela Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Mojica, María F.. Case Western Reserve University; Estados UnidosFil: Giannini, Estefanía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Taracila, Magdalena A.. Case Western Reserve University; Estados Unidos. Louis Stokes Veterans Affairs Medical Center; Estados UnidosFil: Bethel, Christopher R.. Louis Stokes Veterans Affairs Medical Center; Estados UnidosFil: Alzari, Pedro M.. Institut Pasteur de Paris; FranciaFil: Otero, Lisandro Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Klinke, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Llarrull, Leticia Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Bonomo, Robert A.. Case Western Reserve University; Estados UnidosFil: Vila, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentin

An experiment-informed signal transduction model for the role of the Staphylococcus aureus MecR1 protein in β-lactam resistance

The treatment of hospital- and community-associated infections by methicillin-resistant Staphylococcus aureus (MRSA) is a perpetual challenge. This Gram-positive bacterium is resistant specifically to β-lactam antibiotics, and generally to many other antibacterial agents. Its resistance mechanisms to β-lactam antibiotics are activated only when the bacterium encounters a β-lactam. This activation is regulated by the transmembrane sensor/signal transducer proteins BlaR1 and MecR1. Neither the transmembrane/metalloprotease domain, nor the complete MecR1 and BlaR1 proteins, are isolatable for mechanistic study. Here we propose a model for full-length MecR1 based on homology modeling, residue coevolution data, a new extensive experimental mapping of transmembrane topology, partial structures, molecular simulations, and available NMR data. Our model defines the metalloprotease domain as a hydrophilic transmembrane chamber effectively sealed by the apo-sensor domain. It proposes that the amphipathic helices inserted into the gluzincin domain constitute the route for transmission of the β-lactam-binding event in the extracellular sensor domain, to the intracellular and membrane-embedded zinc-containing active site. From here, we discuss possible routes for subsequent activation of proteolytic action. This study provides the first coherent model of the structure of MecR1, opening routes for future functional investigations on how β-lactam binding culminates in the proteolytic degradation of MecI.Fil: Belluzo, Bruno Salvador. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Abriata, Luciano Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. École Polytechnique Fédérale de Lausanne; SuizaFil: Giannini, Estefanía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Mihovilcevic, Damila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Dal Peraro, Matteo. École Polytechnique Fédérale de Lausanne; SuizaFil: Llarrull, Leticia Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentin

Optimal management of constipation associated with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common chronic functional disorder of the gastrointestinal tract, meanly characterized by recurrent abdominal pain or discomfort and altered bowel habit. It is a complex disorder involving biological, environmental, and psychosocial factors. The diagnosis is achieved according to the Rome III criteria provided that organic causes have been excluded. Although IBS does not constitute a life-threatening condition, it has a remarkable prevalence and profoundly reduces the quality of life with burdening socioeconomic costs. One of the principal concerns about IBS is the lack of effective therapeutic options. Up to 40% of patients are not satisfied with any available medications, especially those suffering from chronic constipation. A correct management of IBS with constipation should evolve through a global approach focused on the patient, starting with careful history taking in order to assess the presence of organic diseases that might trigger the disorder. Therefore, the second step is to examine lifestyle, dietary habits, and psychological status. On these bases, a step-up management of disease is recommended: from fiber and bulking agents, to osmotic laxative drugs, to new molecules like lubiprostone and linaclotide. Although new promising tools for relief of bowel-movement-related symptoms are being discovered, a dedicated doctor-patient relationship still seems to be the key for success

Propuesta metodológica para el mapeo de vida media de atrazina en suelos a escala regional

Ponencia presentada en el IV Jornada Nacional de Suelos de Ambientes Semiáridos, Córdoba, Argentina, 25 al 26 de septiembre del 2019.Fil: Giannini Kurina, Franca. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Cátedra de Estadística y Biometría; Argentina.Fil: Giannini Kurina, Franca. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Centro Científico Tecnológico (CCT Córdoba); Argentina.Fil: Borello, Julieta. Gobierno de la Provincia de Córdoba. Ministerio de Ciencia y Tecnología (MINCyT). Centro de Excelencia en Productos y Procesos (CEPROCOR); Argentina.Fil: Cañas, Irene. Gobierno de la Provincia de Córdoba. Ministerio de Ciencia y Tecnología (MINCyT). Centro de Excelencia en Productos y Procesos (CEPROCOR); Argentina.Fil: Balzarini, Mónica Graciela. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Cátedra de Estadística y Biometría; Argentina.Fil: Balzarini, Mónica Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Centro Científico Tecnológico (CCT Córdoba); Argentina.Fil: Hang, Susana Beatriz. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias; Argentina.En la dinámica de un fitosanitario en el suelo, el parámetro de vida media (t1/2) representa el tiempo que transcurre hasta alcanzar la mitad de la concentración inicial suministrada. Adquiere especial relevancia porque caracteriza su persistencia en dicha matriz. En este trabajo se desarrollo un protocolo para mapear el parámetro de vida media de atrazina en suelos a escala de la provincia de Córdoba. La secuencia metodológica propuesta implicó los siguientes pasos: 1) se seleccionó una muestra n=61 de sitios según cLHS basado en propiedades edáficas con el objetivo de maximizar la eficiencia de muestreo asegurando que la variabilidad en la región se encuentre completamente caracterizada. 2) Los suelos seleccionados se fortificaron y se llevaron a cámara de incubación por 21 días, se cuantificó la concentración de atrazina a los días 0,3,7,14 y 21 por cromatografía líquida acoplada a espectrometría de masas tándem (LC-MS/MS) empleando procedimiento QuEChERs. 3) Se modeló el decaimiento de la concentración de atrazina en función del tiempo y propiedades edáficas suponiendo un comportamiento exponencial a partir de modelos no lineales mixtos. 4) A partir de los modelos construidos se obtuvo el parámetro t1/2 para diversos suelos. 5) Finalmente se modelo la variabilidad espacial de el parámetro t1/2 para el territorio de la provincia de Córdoba a partir de regresiones espaciales bayesianas estimadas con R-INLA. La vida media de atrazina estimada para los suelos de la provincia de Córdoba registró una media de 12 días con un IC95 entre 1,4 y 41,5 días.Fil: Giannini Kurina, Franca. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Cátedra de Estadística y Biometría; Argentina.Fil: Giannini Kurina, Franca. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Centro Científico Tecnológico (CCT Córdoba); Argentina.Fil: Borello, Julieta. Gobierno de la Provincia de Córdoba. Ministerio de Ciencia y Tecnología (MINCyT). Centro de Excelencia en Productos y Procesos (CEPROCOR); Argentina.Fil: Cañas, Irene. Gobierno de la Provincia de Córdoba. Ministerio de Ciencia y Tecnología (MINCyT). Centro de Excelencia en Productos y Procesos (CEPROCOR); Argentina.Fil: Balzarini, Mónica Graciela. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Cátedra de Estadística y Biometría; Argentina.Fil: Balzarini, Mónica Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Centro Científico Tecnológico (CCT Córdoba); Argentina.Fil: Hang, Susana Beatriz. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias; Argentina

New Cingulata (Mammalia, Xenarthra) from the Upper Lumbrera Formation (Bartonian, middle Eocene), Salta Province, Argentina

Nós descrevemos restos isolados de cingulado do Paleógeno da localidade de El Simbolar, Formação Lumbrera Superior (Bartoniano), sul da Província de Salta, noroeste da Argentina. O material consiste em numerosos osteodermos das bandas fixas, móveis e caudais. Os osteodermos têm tamanho grande, com uma figura principal de aspecto lageniforme, como em Utaetus buccatus, U. laxus, U. argos, ?U. deustus, Punatherium catamarcensis, e o eufractino basal Archaeutatus. A combinação de caracteres morfológicos, em adição ao seu grande tamanho, nos permite reconhecer uma nova espécie de “Utaetini” para o Paleógeno do noroeste da Argentina. Esta nova espécie de ?Utaetus representa o registro mais antigo para Euphractinae nesta região e fortalece a condição endêmica das faunas paleógenas no noroeste da Argentina.We describe isolated remains of a Paleogene cingulate from El Simbolar locality, Upper Lumbrera Formation (Bartonian), southern Salta Province, northwestern Argentina. The material consists of numerous fixed, movable, and caudal sheath osteoderms. The specimen has large-sized osteoderms, with a lageniform main figure, as in Utaetus buccatus, U. laxus, U. argos, ?U. deustus, Punatherium catamarcensis, and the basal euphractin Archaeutatus. The combination of morphological characters, in addition to its large size, allows us to recognize a new species of “Utaetini” for the Paleogene of northwestern Argentina. This new species of ?Utaetus represents the oldest record of Euphractinae in this region, and strengthens the endemic condition of its Paleogene faunas.Fil: Herrera, Claudia Marcela Reina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; ArgentinaFil: Esteban, Graciela Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; ArgentinaFil: Garcia Lopez, Daniel Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Deraco, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; ArgentinaFil: Babot, María Judith. Universidad Nacional de Tucuman. Facultad de Cs.naturales E Instituto Miguel Lillo. Centro de Investigaciones En Ecología Historica.; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina. Fundación Miguel Lillo; ArgentinaFil: del Papa, Cecilia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Bertelli, Sara Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Giannini, Norberto Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; Argentin

Current management of pelvic organ prolapse in aging women : EMAS clinical guide

Management of pelvic organ prolapse (POP) is a common and challenging task. Nowadays older women are more active than they were in the past, and the development of POP disrupts quality of life and impairs social and personal activities. The menopausal transition is a time of vulnerability, during which many women start experiencing symptoms and signs of POP. The role of hormonal changes or of hormonal therapies in influencing the development or progression of POP has been explored extensively. The management of POP requires considerable clinical skills. Correct diagnosis and characterization of the prolapse and an identification of the individual woman's most bothersome symptoms are the hallmark of appropriate initial management. Therapy is multimodal and often multidisciplinary, and requires a competence in pelvic medicine and surgery. The integration of hormonal, non-hormonal and surgical strategies is important and needs to be adjusted to changing circumstances on an individualized basis. When surgery is required, optimal management requires clinicians who are familiar with the advantages and disadvantages of all the available strategies and who are able to use these strategies in a tailored manner. Complex cases should be sent to specialist referral centers. Management of POP should be integrated into the practice of healthcare professionals dealing in menopause.Peer reviewe

SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma

The Sonic Hedgehog (SHH) pathway is crucial regulator of embryonic development and stemness. Its alteration leads to medulloblastoma (MB), the most common malignant pediatric brain tumor. The SHH-MB subgroup is the best genetically characterized, however the molecular mechanisms responsible for its pathogenesis are not fully understood and therapeutic benefits are still limited. Here, we show that the pro-oncogenic stemness regulator Spalt-like transcriptional factor 4 (SALL4) is re-expressed in mouse SHH-MB models, and its high levels correlate with worse overall survival in SHH-MB patients. Proteomic analysis revealed that SALL4 interacts with REN/KCTD11 (here REN), a substrate receptor subunit of the Cullin3-RING ubiquitin ligase complex (CRL3REN) and a tumor suppressor lost in ~30% of human SHH-MBs. We demonstrate that CRL3REN induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (ΔZFC1). Interestingly, SALL4 binds GLI1 and cooperates with HDAC1 to potentiate GLI1 deacetylation and transcriptional activity. Notably, inhibition of SALL4 suppresses SHH-MB growth both in murine and patient-derived xenograft models. Our findings identify SALL4 as a CRL3REN substrate and a promising therapeutic target in SHH-dependent cancers

Impact of intra-aortic balloon counterpulsation on all-cause mortality among patients with Takotsubo syndrome complicated by cardiogenic shock: results from the German-Italian-Spanish (GEIST) registry

Aims: Takotsubo syndrome (TTS) is an acute and reversible left ventricular dysfunction and can be complicated by cardiogenic shock (CS). However, few data are available on optimal care in TTS complicated by CS. Aim of this study was to evaluate short- and long-term impact of intra-aortic balloon pumping (IABP) on mortality in this setting. Methods and results: In a multi-centre, international registry on TTS, 2248 consecutive patients were enrolled from 38 centres from Germany, Italy, and Spain. Of the 2248 patients, 212 (9.4%) experienced CS. Patients with CS had a higher prevalence of diabetes (27% vs. 19%), male sex (25% vs. 10%), and right ventricular involvement (10% vs. 5%) (P < 0.01 in all cases). Forty-three patients with CS (20% of 212) received IABP within 8 h (interquartile range 4-18) after admission. No differences in terms of age, gender, cardiovascular risk factors, and admission left ventricular ejection fraction were found among patients with and without IABP. There were no significant differences in terms of 30-day mortality (16% vs. 17%, P = 0.98), length of hospitalization (18.9 vs. 16.7 days, P = 0.51), and need of invasive ventilation (35% vs. 41%, P = 0.60) among two groups: 30-day survival was not significantly different even after propensity score adjustment (log-rank P = 0.73). At 42-month follow-up, overall mortality in patients with CS and TTS was 35%, not significantly different between patients receiving IABP and not (37% vs. 35%, P = 0.72). Conclusions: In a large multi-centre observational registry, the use of IABP was not associated with lower mortality rates at short- and long-term follow-up in patients with TTS and CS