Laser cooling with intermediate state of spin-orbit coupling of LuF molecule.

This work presents a theoretical study of the laser cooling feasibility of the molecule LuF, in the fine structure level of approximation. An ab-initio complete active space self-consistent field (CASSCF)/MRCI with Davidson correction calculation has been done in the Λ(±) and Ω(±) representations. The corresponding adiabatic potential energy curves and spectroscopic parameters have been investigated for the low-lying electronic states. The calculated values of the internuclear distances of the X3Σ0+ and (1)3Π0+ states show the candidacy of the molecule LuF for direct laser cooling. Since the existence of the intermediate (1)3Δ1 state cannot be ignored, the investigation has been done by taking into consideration the two transitions (1)3Π0+-(1)3Δ1 and (1)3Π0+ -X3Σ0+. The calculation of the Franck-Condon factors, the radiative lifetimes, the total branching ratio, the slowing distance, and the laser cooling scheme study prove that the molecule LuF is a good candidate for Doppler laser cooling.

A review of the microtremor horizontal-to-vertical spectral ratio (MHVSR) method.

The single-station microtremor horizontal-to-vertical spectral ratio (MHVSR) method was initially proposed to retrieve the site amplification function and its resonance frequencies produced by unconsolidated sediments overlying high-velocity bedrock. Presently, MHVSR measurements are predominantly conducted to obtain an estimate of the fundamental site frequency at sites where a strong subsurface impedance contrast exists. Of the earthquake site characterization methods presented in this special issue, the MHVSR method is the furthest behind in terms of consensus towards standardized guidelines and commercial use. The greatest challenges to an international standardization of MHVSR acquisition and analysis are (1) the what - the underlying composition of the microtremor wavefield is site-dependent, and thus, the appropriate theoretical (forward) model for inversion is still debated; and (2) the how - many factors and options are involved in the data acquisition, processing, and interpretation stages. This paper reviews briefly a historical development of the MHVSR technique and the physical basis of an MHVSR (the what). We then summarize recommendations for MHVSR acquisition and analysis (the how). Specific sections address MHVSR interpretation and uncertainty assessment.

Biomarkers in renal cell carcinoma: Towards a more selective immune checkpoint inhibition.

Immune checkpoint inhibitors such as programmed death protein 1/programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein 4 inhibitors are already playing a central role in the treatment of metastatic renal cell carcinoma. However, they seem to be only effective in a subset of patients, with a high risk of innate and adaptive tumor resistance. Consequently, biomarkers capable of predicting immune treatment efficacy in advanced renal cancer are needed both in the clinical and the experimental setting. We hereby present a brief summary of evidence on the most studied biomarkers in metastatic renal cell carcinoma with a focus on the possible future place of T cell immunoglobulin and mucin domain-3 (TIM-3).

Re: Updates in the management and future landscape of urothelial carcinoma.

Immunotherapy is gradually revolutionizing bladder cancer treatment. In this extensive review published by Hanna et al. in your journal, the authors presented recent studies that are trying to challenge the standard platinum-based chemotherapy as first-line treatment of metastatic bladder cancer by chemoimmunotherapy. However, upfront pembrolizumab, atezolizumab and durvalumab association with standard of care chemotherapy did not improve overall survival when compared to chemotherapy alone.We hereby highlight a study that was not included in this review, the INDUCOMAIN trial, by discussing its results and its future implications on immunotherapy for metastatic bladder cancer.

Reversible Dimerization of Polymeric Amphiphiles Acts as a Molecular Switch of Enzymatic Degradability.

Enzyme-responsive polymeric micelles have great potential as drug delivery systems due to the high selectivity and overexpression of disease-associated enzymes, which could be utilized to trigger the release of active drugs only at the target site. We previously demonstrated that enzymatic degradation rates of amphiphilic PEG-dendron hybrids could be precisely tuned by gradually increasing the hydrophobic to hydrophilic ratio. However, with the increase in hydrophobicity, the micelles rapidly became too stable and could not be degraded, as often encountered for many other amphiphilic assemblies. Here we address the challenge to balance between stability and reactivity of enzymatically degradable assemblies by utilizing reversible dimerization of diblock polymeric amphiphiles to yield jemini amphiphiles. This molecular transformation serves as a tool to control the critical micelle concentration of the amphiphiles in order to tune their micellar stability and enzymatic degradability. To demonstrate this approach, we show that simple dimerization of two polymeric amphiphiles through a single reversible disulfide bond significantly increased the stability of their micellar assemblies toward enzymatic degradation, although the hydrophilic to hydrophobic ratio was not changed. Reduction of the disulfide bond led to dedimerization of the polymeric hybrids and allowed their degradation by the activating enzyme. The generality of the approach is demonstrated by designing both esterase- and amidase-responsive micellar systems. This new molecular design can serve as a simple tool to increase the stability of polymeric micelles without impairing their enzymatic degradability.

Modular Synthetic Approach for Adjusting the Disassembly Rates of Enzyme-Responsive Polymeric Micelles.

Self-assembled nanostructures and their stimuli-responsive degradation have been recently explored to meet the increasing need for advanced biocompatible and biodegradable materials for various biomedical applications. Incorporation of enzymes as triggers that can stimulate the degradation and disassembly of polymeric assemblies may be highly advantageous owing to their high selectivity and natural abundance in all living organisms. One of the key factors to consider when designing enzyme-responsive polymers is the ability to fine-tune the sensitivity of the platform toward its target enzyme in order to control the disassembly rate. In this work, a series of enzyme-responsive amphiphilic PEG-dendron hybrids with increasing number of hydrophobic cleavable end-groups was synthesized, characterized, and compared. These hybrids were shown to self-assemble in aqueous media into nanosized polymeric micelles, which could encapsulate small hydrophobic guests in their cores and release them upon enzymatic stimulus. Utilization of dendritic scaffolds as the responsive blocks granted ultimate control over the number of enzymatically cleavable end-groups. Remarkably, as we increased the number of end-groups, the micellar stability increased significantly and the range of enzymatic sensitivity spanned from highly responsive micelles to practically nondegradable ones. The reported results highlight the remarkable role of hydrophobicity in determining the micellar stability toward enzymatic degradation and its great sensitivity to small structural changes of the hydrophobic block, which govern the accessibility of the cleavable hydrophobic groups to the activating enzyme.

Molecular Precision and Enzymatic Degradation: From Readily to Undegradable Polymeric Micelles by Minor Structural Changes.

Studying the enzymatic degradation of synthetic polymers is crucial for the design of suitable materials for biomedical applications ranging from advanced drug delivery systems to tissue engineering. One of the key parameters that governs enzymatic activity is the limited accessibility of the enzyme to its substrates that may be collapsed inside hydrophobic domains. PEG-dendron amphiphiles can serve as powerful tools for the study of enzymatic hydrolysis of polymeric amphiphiles due to the monodispersity and symmetry of the hydrophobic dendritic block, which significantly simplifies kinetic analyses. Using these hybrids, we demonstrate how precise, minor changes in the hydrophobic block are manifested into tremendous changes in the stability of the assembled micelles toward enzymatic degradation. The obtained results emphasize the extreme sensitivity of self-assembly and its great importance in regulating the accessibility of enzymes to their substrates. Furthermore, the demonstration that the structural differences between readily degradable and undegradable micelles are rather minor, points to the critical roles that self-assembly and polydispersity play in designing biodegradable materials.

The effect of photoisomerization on the enzymatic hydrolysis of polymeric micelles bearing photo-responsive azobenzene groups at their cores.

The design of stable polymeric micelles that can respond to specific stimuli is crucial for the development of smart micellar nanocarriers that can release their active cargo selectively at the target site, thus diminishing the therapeutic limitations due to non-selective damage to healthy tissues. Here we report the design and synthesis of photo- and enzyme-responsive amphiphilic PEG-dendron hybrids bearing one, two or four enzymatically cleavable azobenzene end-groups. These dual-responsive hybrids can respond to light through the reversible isomerization of the azobenzene end-groups from the non-polar trans isomer to the highly polar cis isomer and vice versa, upon UV and visible irradiation, respectively. The high structural precision of these hybrids, which emerges from the dendritic architecture, enabled a detailed study of the photoisomerization of the azobenzene end-groups with high molecular resolution. Remarkably, although the transition from trans-to-cis led to a significant increase in the polarity of the micellar cores, the micelles remained stable. Our kinetic studies show that although the trans isomer is a better substrate for the activating enzyme, the UV induced formation of the cis azobenzene end-groups led to significant acceleration of the enzymatic hydrolysis of the end-groups. These results provide strong indication that the enzyme cannot reach the core of the micelles and instead the end-groups have to leave the hydrophobic core in order to be exposed on the micelle's surface or even leave the micelle in order to allow their cleavage by the activating enzymes.

Supramolecular Translation of Enzymatically Triggered Disassembly of Micelles into Tunable Fluorescent Responses.

The need for advanced fluorescent imaging and delivery platforms has motivated the development of smart probes that change their fluorescence in response to external stimuli. Here a new molecular design of fluorescently labeled PEG-dendron hybrids that self-assemble into enzyme-responsive micelles with tunable fluorescent responses is reported. In the assembled state, the fluorescence of the dyes is quenched or shifted due to intermolecular interactions. Upon enzymatic cleavage of the hydrophobic end-groups, the labeled polymeric hybrids become hydrophilic, and the micelles disassemble. This supramolecular change is translated into a spectral response as the dye-dye interactions are eliminated and the intrinsic fluorescence is regained. We demonstrate the utilization of this molecular design to generate both Turn-On and spectral shift responses by adjusting the type of the labeling dye. This approach enables transformation of non-responsive labeling dyes into smart fluorescent probes.

Encapsulation and covalent binding of molecular payload in enzymatically activated micellar nanocarriers.

The high selectivity and often-observed overexpression of specific disease-associated enzymes make them extremely attractive for triggering the release of hydrophobic drug or probe molecules from stimuli-responsive micellar nanocarriers. Here we utilized highly modular amphiphilic polymeric hybrids, composed of a linear hydrophilic polyethylene glycol (PEG) and an esterase-responsive hydrophobic dendron, to prepare and study two diverse strategies for loading of enzyme-responsive micelles. In the first type of micelles, hydrophobic coumarin-derived dyes were encapsulated noncovalently inside the hydrophobic core of the micelle, which was composed of lipophilic enzyme-responsive dendrons. In the second type of micellar nanocarrier the hydrophobic molecular cargo was covalently linked to the end-groups of the dendron through enzyme-cleavable bonds. These amphiphilic hybrids self-assembled into micellar nanocarriers with their cargo covalently encapsulated within the hydrophobic core. Both types of micelles were highly responsive toward the activating enzyme and released their molecular cargo upon enzymatic stimulus. Importantly, while faster release was observed with noncovalent encapsulation, higher loading capacity and slower release rate were achieved with covalent encapsulation. Our results clearly indicate the great potential of enzyme-responsive micellar delivery platforms due to the ability to tune their payload capacities and release rates by adjusting the loading strategy.

Enzyme-responsive amphiphilic PEG-dendron hybrids and their assembly into smart micellar nanocarriers.

Enzyme-responsive micelles have great potential as drug delivery platforms due to the high selectivity of the activating enzymes. Here we report a highly modular design for the efficient and simple synthesis of amphiphilic block copolymers based on a linear hydrophilic polyethyleneglycol (PEG) and an enzyme-responsive hydrophobic dendron. These amphiphilic hybrids self-assemble in water into micellar nanocontainers that can disassemble and release encapsulated molecular cargo upon enzymatic activation. The utilization of monodisperse dendrons as the stimuli-responsive block enabled a detailed kinetic study of the molecular mechanism of the enzymatically triggered disassembly. The modularity of these PEG-dendron hybrids allows control over the disassembly rate of the formed micelles by simply tuning the PEG length. Such smart amphiphilic hybrids could potentially be applied for the fabrication of nanocarriers with adjustable release rates for delivery applications.

Theoretical investigation of the lowest-lying electronic structure of LuI molecules.

CASSCF/MRCI calculations using Effective Core Potential (ECP) basis sets for both Lu and I atoms, have been performed for the first 22 electronic states in the representation (2s+1)Λ((±)) for the LuI molecule. This investigation included the corresponding 43 molecular states in the representation Ω((±)) when taking the spin-orbit coupling (SOC) in consideration. Calculated potential energy curves (PECs) have been displayed. Spectroscopic constants T(e), ω(e), ω(e)χ(e), B(e) and the internuclear distance R(e) have been calculated for the ground state and for the low-lying electronic states situated below 40,410 cm(-1) and for their corresponding components with SOC. The transition dipolar moments between states have been given at the minimum position R(e)=2.75 Å of the ground state X(1)Σ(+). The calculated set of singlet and triplet states provides a theoretical prediction for more than 19 yet unobserved electronic states.

Transient lymphopenia and neutropenia: pediatric influenza A/H1N1 infection in a primary hospital in Israel.

BACKGROUND: Pandemic influenza A/H1N1 carries a relatively high morbidity, particularly in young people. Early identification would enable prompt initiation of therapy, thereby improving outcomes. OBJECTIVE: To describe the epidemiological, clinical and laboratory characteristics of children admitted to hospital with the clinical diagnosis of influenza with reference to pandemic influenza A/H1N1. METHODS: We conducted a prospective study of all children aged 16 years or less admitted to the pediatric department with the clinical diagnosis of influenza-like illness from July to October 2009. The presence of A/H1N1 virus was confirmed using real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis of nasopharyngeal secretions. Positive cases were compared with negative cases concerning epidemiological data, risk factors, clinical presentation and laboratory parameters, with emphasis on changes in the differential blood count. RESULTS: Of the 106 study patients, 53 were positive to influenza A/H1N1 and 53 were negative. In both groups nearly all patients had fever at presentation and approximately two-thirds had both fever and cough. All patients had a mild clinical course, no patient needed to be admitted to the intensive care unit and no mortalities were recorded. Hyperactive airway disease was more common in the A/H1N1-positive group. Pneumonia occurred in 30% of children in both groups. Laboratory findings included early lymphopenia and later neutropenia in theA/H1N1-infected patients. CONCLUSIONS: Leukopenia consisting of lymphopenia and later neutropenia was common in patients with A/H1N1 infection but was not correlated with disease severity or clinical course, which were similar in both groups. However, reduced leukocyte count can be used as an additional criterion for diagnosing A/H1N1 infection until RT-PCR results are available.

Structural characterization of W-Ni-Al2O3 catalysts.

A series of W/Ni/Al2O3 catalysts was prepared by coprecipitation of nickel and aluminum and impregnation of tungsten. The samples were characterized by XRD, XPS and XAS techniques. XRD measurements detected two phases: NiO as the main phase and NiAl2O4 in lower amount; no phase containing tungsten was detected. XPS measurements indicated the presence of Al2O3, NiAl2O4, and Al2(WO4)3 phases on the catalyst surfaces. The XANES spectra of catalysts were rather similar for all of the samples. According to the EXAFS results, at the short range level, tungsten does not form any bound with Ni atoms. The nickel first coordination shell in the catalysts containing tungsten is similar to that encountered in COP 1 catalyst without tungsten. The lower Ni-Ni coordination number observed for all catalysts, when compared to the NiO phase, can be attributed to the nickel-aluminum interaction.

Fatal subarachnoid hemorrhage after endoscopic third ventriculostomy. Case report.

In recent years, endoscopic third ventriculostomy has become a well-established procedure for the treatment of various forms of noncommunicating hydrocephalus. Endoscopic third ventriculostomy is considered to be an easy and safe procedure. Complications have rarely been reported in the literature. The authors present a case in which the patient suffered a fatal subarachnoid hemorrhage (SAH) after endoscopic third ventriculostomy. This 63-year-old man presented with confusion and drowsiness and was admitted in to the hospital in poor general condition. Computerized tomography scanning revealed an obstructive hydrocephalus caused by a tumor located in the cerebellopontine angle. An endoscopic third ventriculostomy was performed with the aid of a Fogarty balloon catheter. Some hours postoperatively, the patient became comatose. Computerized tomography scanning revealed a severe perimesencephalic-peripontine SAH and progressive hydrocephalus. Despite emergency external ventricular drainage, the patient died a few hours later. Although endoscopic third ventriculostomy is considered to be a simple and safe procedure, one should be aware that severe and sometimes fatal complications may occur. To avoid vascular injury, perforation of the floor of the third ventricle should be performed in the midline, halfway between the infundibular recess and the mammillary bodies, just behind the dorsum sellae.

Fatal subarachnoid hemorrhage after endoscopic third ventriculostomy. Case report.

In recent years, endoscopic third ventriculostomy has become a well-established procedure for the treatment of various forms of noncommunicating hydrocephalus. Endoscopic third ventriculostomy is considered to be an easy and safe procedure. Complications have rarely been reported in the literature. The authors present a case in which the patient suffered a fatal subarachnoid hemorrhage (SAH) after endoscopic third ventriculostomy. This 63-year-old man presented with confusion and drowsiness and was admitted in to the hospital in poor general condition. Computerized tomography scanning revealed an obstructive hydrocephalus caused by a tumor located in the cerebellopontine angle. An endoscopic third ventriculostomy was performed with the aid of a Fogarty balloon catheter. Some hours postoperatively, the patient became comatose. Computerized tomography scanning revealed a severe perimesencephalic-peripontine SAH and progressive hydrocephalus. Despite emergency external ventricular drainage, the patient died a few hours later. Although endoscopic third ventriculostomy is considered to be a simple and safe procedure, one should be aware that severe and sometimes fatal complications may occur. To avoid vascular injury, perforation of the floor of the third ventricle should be performed in the midline, halfway between the infundibular recess and the mamillary bodies, just behind the dorsum sellae.

Maffucci's syndrome as cause of chronic liquorrhea.

We present the case of a 14-year-old girl suffering from Maffucci's syndrome, a rare ailment belonging to the group of osteochondrodysplasias. At the age of 6 months, a diffuse swelling first appeared in the girl's right cheekbone region and the periauricular area. Because of recurrent meningitis with massive otoliquorrhea, several surgical revisions were performed, beginning at the age of 4 years. The histological and immunohistochemical diagnosis showed hemangioma and lymphangioma with enchondroma. As a peculiarity of our patient's diagnosis, we found multiple bone defects apparently caused by venous and lymphomatous angiomatosis. There was also enchondromatosis of the skull base and the upper cervical vertebrae, which caused the recurrent otoliquorrhea and rhinoliquorrhea. A fistula closure was undertaken through a retromastoidal, suboccipital approach and fascial graft of the posterior cranial fossa.

Neurovascular compression at the left ventrolateral medulla as an etiological factor for arterial hypertension.

Clinical studies by Jannetta and others implicated that arterial compression of the root entry zone (REZ) of cranial nerves IX and X at the left ventrolateral medulla may represent an etiological factor for arterial hypertension. Positive therapeutic outcomes with reduction of hypertension in 42 of Jannetta's patients by microsurgical decompression initiated further studies. Experience of our group points in the same direction. Four patients treated by microvascular decompression showed lasting reduction of severe hypertension postoperatively. In our previous comparing postmortem explorations and angiographic studies essential hypertensive patients displayed signs of left sided neurovascular compression in opposition to normotone controls or renal hypertensive patients. By using MR-imaging we are currently developing a method of detecting neurovascular compression syndromes in hypertensive patients suitable for surgical management.

Density Estimation Through Convex Combinations of Densities: Approximation and Estimation Bounds.

We consider the problem of estimating a density function from a sequence identically distributed observations x(i) taking value in X subset R(d). The estimation procedure constructs a convex mixture of "basis" densities and estimates the parameters using the maximum likelihood method. Viewing the error as a combination of two terms, the approximation error measuring the adequacy of the model, and the estimation error resulting from the finiteness of the sample size, we derive upper bounds to the expected total error, thus obtaining bounds for the rate of convergence. These results then allow us to derive explicit expressions relating the sample complexity and model complexity. Copyright 1996 Elsevier Science Ltd.