Low temperature glass/crystal transition in ionic liquids determined by H-bond vs. coulombic strength.

Self-assembled ionic liquid crystals are anisotropic ionic conductors, with potential applications in areas as important as solar cells, battery electrolytes and catalysis. However, many of these applications are still limited by the lack of precise control over the variety of phases that can be formed (nematic, smectic, or semi/fully crystalline), determined by a complex pattern of different intermolecular interactions. Here we report the results of a systematic study of crystallization of several imidazolium salts in which the relative contribution of isotropic coulombic and directional H-bond interactions is carefully tuned. Our results demonstrate that the relative strength of directional H-bonds with respect to the isotropic Coulomb interaction determines the formation of a crystalline, semi-crystalline or glassy phase at low temperature. The possibility of pinpointing H-bonding directionality in ionic liquids make them model systems to study the crystallization of an ionic solid under a perturbed Coulomb potential.

The role of contextual signal TGF-ß1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases: an update on its pathological significance and therapeutic potential.

Lung adenocarcinoma (LA) is the most common cause of cancer-related death worldwide. Despite the advances over last decade in new targeted therapies, cancer genetics, diagnostics, staging, and surgical techniques as well as new chemotherapy and radiotherapy protocols, the death rate from LA remains high. The tumour microenvironment is composed of several cytokines, one of which is transforming growth factor ß1 (TGF-ß1), which modulates and mediates the expression of epithelial-mesenchymal transition (EMT), correlated with invasive growth in LAs, and exhibits its pleiotropic effects through binding to transmembrane receptors TßR-1 (also termed activin receptor-like kinases - ALKs) and TßR-2. Accordingly, there is an urgent need to elucidate the molecular mechanisms associated with the tumoural spreading process and therapeutic resistance of this serious pathology. In this review, we briefly discuss the current role of contextual signal TGF-ß1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases, and give an overview of our current mechanistic understanding of the TGF-ß1-related pathways in brain metastases progression, TGF-ß1 pathway inhibitors that could be used for clinical treatment, and examination of models used to study these processes. Finally, we summarise the current progress in the therapeutic approaches targeting TGF-ß1.

[(CH3)2NH2]7Pb4X15 (X = Cl- and Br-), 2D-Perovskite Related Hybrids with Dielectric Transitions and Broadband Photoluminiscent Emission.

We have prepared two new lead halides with the novel general formula of DMA7Pb4X15 (DMA = [(CH3)2NH2]+ and X = Cl- or Br-) by using an easy route under mild conditions at room temperature. These compounds exhibit an unprecedented crystal structure, are formed by layers of distorted [PbX6] octahedra, which share corners and faces, and contain intercalated DMA cations. Very interestingly, they display dielectric transitions, which are related to a partial order-disorder process of the DMA cations between 160 and 260 K. Additionally, these new layered hybrids exhibit a broadband photoluminiscent emission, which is related to the structural distortions of the [PbX6] octahedra. These findings not only open up large possibilities for future optoelectronic applications of these materials, but they also offer a novel playground for an easy modulation of electrical and optical properties of hybrid organic-inorganic materials. We anticipate that this novel A7Pb4X15 formula can be adequate to tune the family of the hybrid lead halides using other alkylammonium cations, such as methylammonium, formamidinium, or ethylammonium, to improve their photoelectronic properties.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache.

BACKGROUND: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. OBJECTIVES: We present our long-term results of analysis of the target and its structural connectivity. METHODS: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). RESULTS: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. CONCLUSIONS: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

A Covalent Organic Helical Cage with Remarkable Chiroptical Amplification.

Purely organic shape-persistent chiral cages are designed through the use of rigid chiral axes. Covalent dimerization of a tripodal fragment bearing chiral allenes forms a molecular twisted prism with loop-like lateral edges presenting 10-fold chiroptical amplification compared to its isolated building blocks. The expected geometry of covalent organic helical cage (M,M)3 -1 was confirmed by X-ray crystal structure analysis. Comparison of the chiroptical responses of this shape-persistent molecular container with more flexible analogues highlights how the control of the conformational freedom of the molecule can be used to obtain molecular cages with strong chiroptical responses. Selective inclusion-complex formation with ferrocenium ions [(P,P)3 -1@Fc(+) ] was confirmed and quantified with HR-ESI-MS and NMR spectroscopy.

Antiphospholipid Syndrome of Late Onset: A Difficult Diagnosis of a Recurrent Embolic Stroke.

A 77-year-old woman with atrial fibrillation (AF) treated with warfarin had a cortical left middle cerebral artery (MCA) stroke (October 2009, international normalized ratio [INR], 1.6) and a cortical left frontal stroke (October 2011, INR, 1.9). Anticoagulation was adjusted. In October 2011, she had a right frontal stroke (INR, 2.3). Acetylsalicylic acid (ASA) was temporally added to the treatment. In June 2013, she had a left occipital stroke (INR, 2.3). Warfarin was changed to rivaroxaban. In August 2013, she had a right occipital stroke. ASA 100 was added to the treatment. On all occasions, repeated neurovascular studies and echocardiography were normal. Diagnoses were cardioembolic stroke. In November 2013, she was admitted because of a left MCA stroke. A complete blood analysis showed the presence of anticardiolipin, anti-b2-glycoprotein antibodies, and lupus anticoagulant. Primary antiphospholipid syndrome (APS) was later confirmed. APS should be considered in young stroke patients, however is not frequent in stroke patients older than 70 years with several cerebrovascular risk factors. The existence of AF in our patient with several embolic strokes made the cardiembolic etiology likely. Uncommon causes of stroke were not considered despite the repetition of the ischemic events. Thus, a wider etiological study should be made in all patients with a recurrent stroke regardless of age, such as a complete blood analysis including immunology study in order to exclude an APS of late onset.

Sugar-based synthesis of an enantiomorphically pure zeolite.

Zeolites, well-known by their high selectivities in catalytic and separation processes due to their porous nature, play a crucial role in various applications. One significant long-term objective is the synthesis of enantiopure zeolites, potentially enabling enantioselective processes. Earlier attempts result in partial success, yielding some enantiomorphically enriched zeolites. In this study, we introduce a zeolite synthesis approach utilizing chiral organic structure directing agents (ch-OSDAs) derived from sugars, guiding the crystallization process toward achieving enantiomorphically pure S-STW zeolite. The purity of the zeolite is confirmed through extensive analyses of individual crystals using single-crystal X-ray diffraction, extracting Flack parameters and space groups. Theoretical and structural investigations confirm that the sugar-derived ch-OSDA perfectly fits the characteristic helicoidal channel of the zeolite structure, featuring its efficacy in achieving enantiopure zeolites.

Mycobacterium tuberculosis shikimate kinase inhibitors: design and simulation studies of the catalytic turnover.

Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 Å. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.

Structure of the bacteriophage T4 long tail fiber receptor-binding tip.

Bacteriophages are the most numerous organisms in the biosphere. In spite of their biological significance and the spectrum of potential applications, little high-resolution structural detail is available on their receptor-binding fibers. Here we present the crystal structure of the receptor-binding tip of the bacteriophage T4 long tail fiber, which is highly homologous to the tip of the bacteriophage lambda side tail fibers. This structure reveals an unusual elongated six-stranded antiparallel beta-strand needle domain containing seven iron ions coordinated by histidine residues arranged colinearly along the core of the biological unit. At the end of the tip, the three chains intertwine forming a broader head domain, which contains the putative receptor interaction site. The structure reveals a previously unknown beta-structured fibrous fold, provides insights into the remarkable stability of the fiber, and suggests a framework for mutations to expand or modulate receptor-binding specificity.

Rotation-locked 2,6-pyrido-allenophanes: characterization of all stereoisomers.

New 2,6-disubstituted pyrido-allenophanes with locked rotation of aromatic spacers were designed and synthesized. The synthesis was accomplished by Pd-catalyzed C(sp(2))-C(sp) Sonogashira cross-coupling reaction between 1,3-diethynylallene (DEA) and 2,6-dibromopyridine followed by an intermolecular ring closure. Because racemic DEA was employed, pyrido-allenophanes were obtained as mixtures of stereoisomers that were resolved by preparative HPLC. The conformational space of all these diastereoisomers was explored at the CAM-B3LYP/6-31+G*//AM1 level of theory. The isomers were characterized through their symmetry properties revealed in NMR, circular dichroism, and chiral stationary-phase HPLC experiments. X-ray diffraction was used to assign and to corroborate the configuration of several diastereoisomers. The unexpected encapsulation of two molecules of CHCl(3) in the crystal structures shows the potential of these conformationally hampered allenophanes as encapsulating hosts.

'Inverted' analogs of the antibiotic gramicidin S with an improved biological profile.

A series of gramicidin S derivatives 4-15 are presented that have four ornithine residues as polar protonated side chains and two central hydrophobic amino acids with unaltered turn regions. These peptides were screened against human erthrocytes and our standard panel of Gram negative- and Gram positive bacteria, including four MRSA strains. Based on the antibacterial- and hemolytic data, peptides 13 and 14 have an improved biological profile compared to the clinically applied topical antibiotic gramicidin S.

High-resolution structures of Thermus thermophilus enoyl-acyl carrier protein reductase in the apo form, in complex with NAD+ and in complex with NAD+ and triclosan.

Enoyl-acyl carrier protein reductase (ENR; the product of the fabI gene) is an important enzyme that is involved in the type II fatty-acid-synthesis pathway of bacteria, plants, apicomplexan protozoa and mitochondria. Harmful pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum use the type II fatty-acid-synthesis system, but not mammals or fungi, which contain a type I fatty-acid-synthesis pathway consisting of one or two multifunctional enzymes. For this reason, specific inhibitors of ENR are attractive antibiotic candidates. Triclosan, a broad-range antibacterial agent, binds to ENR, inhibiting fatty-acid synthesis. As humans do not have an ENR enzyme, they are not affected. Here, high-resolution structures of Thermus thermophilus (Tth) ENR in the apo form, bound to NAD(+) and bound to NAD(+) plus triclosan are reported. Differences from and similarities to other known ENR structures are reported; in general, the structures are very similar. The cofactor-binding site is also very similar to those of other ENRs and, as reported for other species, triclosan leads to greater ordering of the loop that covers the cofactor-binding site, which, together with the presence of triclosan itself, presumably provides tight binding of the dinucleotide, preventing cycling of the cofactor. Differences between the structures of Tth ENR and other ENRs are the presence of an additional ß-sheet at the N-terminus and a larger number of salt bridges and side-chain hydrogen bonds. These features may be related to the high thermal stability of Tth ENR.

Design and Application of Automated Algorithms for Diagnosis and Treatment Optimization in Neurodegenerative Diseases.

Neurodegenerative diseases represent a growing healthcare problem, mainly related to an aging population worldwide and thus their increasing prevalence. In particular, Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative diseases. To aid their diagnosis and optimize treatment, we have developed a classification algorithm for AD to manipulate magnetic resonance images (MRI) stored in a large database of patients, containing 1,200 images. The algorithm can predict whether a patient is healthy, has mild cognitive impairment, or already has AD. We then applied this classification algorithm to therapeutic outcomes in PD after treatment with deep brain stimulation (DBS), to assess which stereotactic variables were the most important to consider when performing surgery in this indication. Here, we describe the stereotactic system used for DBS procedures, and compare different planning methods with the gold standard normally used (i.e., neurophysiological coordinates recorded intraoperatively). We used information collected from database of 72 DBS electrodes implanted in PD patients, and assessed the potentially most beneficial ranges of deviation within planning and neurophysiological coordinates from the operating room, to provide neurosurgeons with additional landmarks that may help to optimize outcomes: we observed that x coordinate deviation within CT scan and gold standard intra-operative neurophysiological coordinates is a robust matric to pre-assess positive therapy outcomes- "good therapy" prediction if deviation is higher than 2.5 mm. When being less than 2.5 mm, adding directly calculated variables deviation (on Y and Z axis) would lead to specific assessment of "very good therapy".

Color LED reflection topography: validation of equivalent keratometry reading for IOL power calculation in eyes with previous corneal myopic refractive surgery.

PURPOSE: To compare the accuracy of the equivalent keratometry reading (EKR) from a color LED corneal topographer (Cassini) with that of other no-history formulas for intraocular lens (IOL) power calculation in eyes with previous myopic excimer laser surgery. SETTING: Centro de Oftalmología Barraquer, Barcelona, Spain. DESIGN: Retrospective case series. METHODS: The refractive outcomes of the Cassini EKR entered into the Haigis formula were compared with those of the Barrett True-K, Haigis-L, and Shammas-PL formulas and the Triple-S method combined with the Haigis formula. Optimized lens constants for virgin eyes were used. The mean prediction error (PE), the median absolute error (MedAE), and the percentage of eyes with a PE within ±0.25 diopter (D), ±0.50 D, ±0.75 D, and ±1.00 D were calculated. RESULTS: The study comprised 37 patients (37 eyes). The Haigis-L, Shammas-PL, and Barrett True-K no-history methods produced a myopic mean PE that was significantly different from zero (P < .001, P < .001 and P = .004, respectively), whereas the mean PEs of Cassini EKR and the Triple-S combined with the Haigis formula were not different from zero (P > .05). Repeated-measures analysis of variance disclosed a significant difference among the PE of all methods (P < .0001). The MedAE of the Cassini EKR, Barrett True-K, Haigis-L, Shammas-PL, and Triple-S was, respectively, 0.34 D, 0.34 D, 0.49 D, 0.48 D, and 0.31 D (P = .0026). CONCLUSIONS: The performance of the combination of standard Haigis formula with Cassini EKR was comparable to other no-history formulas in eyes with previous myopic excimer laser surgery.

Crystallographic structure of porcine adenovirus type 4 fiber head and galectin domains.

Adenovirus isolate NADC-1, a strain of porcine adenovirus type 4, has a fiber containing an N-terminal virus attachment region, shaft and head domains, and a C-terminal galectin domain connected to the head by an RGD-containing sequence. The crystal structure of the head domain is similar to previously solved adenovirus fiber head domains, but specific residues for binding the coxsackievirus and adenovirus receptor (CAR), CD46, or sialic acid are not conserved. The structure of the galectin domain reveals an interaction interface between its two carbohydrate recognition domains, locating both sugar binding sites face to face. Sequence evidence suggests other tandem-repeat galectins have the same arrangement. We show that the galectin domain binds carbohydrates containing lactose and N-acetyl-lactosamine units, and we present structures of the galectin domain with lactose, N-acetyl-lactosamine, 3-aminopropyl-lacto-N-neotetraose, and 2-aminoethyl-tri(N-acetyl-lactosamine), confirming the domain as a bona fide galectin domain.

Exploring the conformational and biological versatility of ß-turn-modified gramicidin S by using sugar amino acid homologues that vary in ring size.

Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the ß-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties determines the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-containing peptides is solvent dependent. The derivative containing the pyranoid SAA is slightly less hydrophobic and displays a diminished haemolytic activity, but has similar antimicrobial properties as GS.

Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives.

In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the ß-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar side chain of the additional d-amino acid residue is positioned at the same face of the molecule as the hydrophobic side chains, and we believe that because of this compound 2 is considerably less hydrophobic than extended GS derivatives in which the strand regions are exclusively composed of l-amino acids. Using this backbone structure as our benchmark we prepared a small series of ring-extended GS analogues featuring sugar amino acid dipeptide isosteres of varied hydrophobicity at the turn region. We show that via this approach hydrophobicity of extended GS analogues can be tuned without affecting the secondary structure (as observed from NMR and CD spectra). Biological evaluation reveals that hydrophobicity correlates to cell toxicity, but still bacteriolysis is induced with GS analogues that are too hydrophilic to efficiently lyse human red blood cells.

Gramicidin S derivatives containing cis- and trans-morpholine amino acids (MAAs) as turn mimetics.

The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational properties of the thus obtained GS analogues (6-9) was assessed by using NMR spectroscopy and X-ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8, containing the dipeptide isostere trans-MAA 4, has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and -negative bacterial strains is better than the derivatives 6, 7 and 9.

An adamantyl amino acid containing gramicidin S analogue with broad spectrum antibacterial activity and reduced hemolytic activity.

The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram-negative and Gram-positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic.

Dual energy CT in the management of antiplatelet therapy in patients with acute ischemic stroke for carotid obstruction.

BACKGROUND AND PURPOSE: Acute tandem occlusions often require carotid stenting. Combination of mechanical and pharmacologic therapies in addition to antiplatelet drugs administered to prevent acute stent thrombosis might increase the risk of intracerebral hemorrhage. We present a protocol of antiplatelet regimen based on early post-procedural dual-energy CT (DE-CT). MATERIAL AND METHODS: Fifty consecutive stroke patients with tandem occlusions treated with acute carotid stenting after intracranial thrombectomy and TICI 2b/3 were reviewed. All patients received intravenous lysine acetylsalicylate during the procedure. Dual (aspirin+clopidogrel with or without clopidogrel load, groups A and B, respectively) or mono (aspirin) antiplatelet regimen (group C) was administered 12-24 h later according to brain DE-CT findings. Carotid ultrasonography was performed at 24 h and before discharge. We evaluated the rate of subsequent symptomatic intracranial hemorrhage (SICH) and acute stent thrombosis in each group. RESULTS: Between June 2014 and December 2016, 50 patients were included (mean age 66 years, 76% men, baseline NIHSS 16, median time from symptom onset to recanalization 266 min). According to DE-CT, 24 patients were assigned to group A, 19 to group B and 7 to group C (4 of them had SICH at that time). One patient suffered a subsequent SICH (belonging to group B). There was only one stent thrombosis without clinical repercussions in group B. CONCLUSIONS: DE-CT may contribute to select antiplatelet regimen after acute carotid stenting in tandem occlusions.