Advanced crystallisation methods for small organic molecules.

Molecular materials based on small organic molecules often require advanced structural analysis, beyond the capability of spectroscopic techniques, to fully characterise them. In such cases, diffraction methods such as single crystal X-ray diffraction (SCXRD), are one of the most powerful tools available to researchers, providing molecular and structural elucidation at atomic level resolution, including absolute stereochemistry. However SCXRD, and related diffraction methods, are heavily dependent on the availability of suitable, high-quality crystals, thus crystallisation often becomes the major bottleneck in preparing samples. Following a summary of classical methods for the crystallisation of small organic molecules, this review will focus on a number of recently developed advanced methods for crystalline material sample preparation for SCXRD. This review will cover two main areas of modern small organic molecule crystallisation, namely the inclusion of molecules within host complexes (e.g., "crystalline sponge" and tetraaryladamantane based inclusion chaperones) and the use of high-throughput crystallisation, employing "under-oil" approaches (e.g., microbatch under-oil and ENaCt). Representative examples have been included for each technique, together with a discussion of their relative advantages and limitations to aid the reader in selecting the most appropriate technique to overcome a specific analytical challenge.

An outbreak of hepatitis A virus infection in a secondary school in England with no undetected asymptomatic transmission among students.

In June 2019 the Health Protection Team in Yorkshire and Humber, England, was notified of cases of hepatitis A virus (HAV) infection in staff at a secondary school. Investigation revealed that an earlier case worked as a food handler in the school kitchen. Indirect transmission through food from the canteen was considered the most likely route of transmission. Cases were described according to setting of exposure. Oral fluid was obtained from students for serological testing. Environmental investigations were undertaken at settings where food handling was considered a potential transmission risk. Thirty-three confirmed cases were linked to the outbreak. All of those tested (n = 31) shared the same sequence with a HAV IB genotype. The first three cases were a household cluster and included the index case for the school. A further 19 cases (16 students, 3 staff) were associated with the school and consistent with indirect exposure to the food handler. One late onset case could not be ruled out as a secondary case within the school and resulted in vaccination of the school population. Five cases were linked to a bakery where a case from the initial household cluster worked as a food server. No concerns about hygiene standards were noted at either the school or the bakery. Oral fluid samples taken at the time of vaccination from asymptomatic students (n = 219, 11-16 years-old) showed no evidence of recent or current infection. This outbreak included household and foodborne transmission but limited (and possibly zero) person-to-person transmission among secondary school students. Where adequate hygiene exists, secondary transmission within older students may not occur.

Reduced variance analysis of molecular dynamics simulations by linear combination of estimators.

Building upon recent developments of force-based estimators with a reduced variance for the computation of densities, radial distribution functions, or local transport properties from molecular simulations, we show that the variance can be further reduced by considering optimal linear combinations of such estimators. This control variates approach, well known in statistics and already used in other branches of computational physics, has been comparatively much less exploited in molecular simulations. We illustrate this idea on the radial distribution function and the one-dimensional density of a bulk and confined Lennard-Jones fluid, where the optimal combination of estimators is determined for each distance or position, respectively. In addition to reducing the variance everywhere at virtually no additional cost, this approach cures an artifact of the initial force-based estimators, namely, small but non-zero values of the quantities in regions where they should vanish. Beyond the examples considered here, the present work highlights, more generally, the underexplored potential of control variates to estimate observables from molecular simulations.

COVID-19: public health management of the first two confirmed cases identified in the UK.

We report key learning from the public health management of the first two confirmed cases of COVID-19 identified in the UK. The first case imported, and the second associated with probable person-to-person transmission within the UK. Contact tracing was complex and fast-moving. Potential exposures for both cases were reviewed, and 52 contacts were identified. No further confirmed COVID-19 cases have been linked epidemiologically to these two cases. As steps are made to enhance contact tracing across the UK, the lessons learned from earlier contact tracing during the country's containment phase are particularly important and timely.

Chemical and structural data of (1,2,3-triazol-4-yl)pyridine-containing coordination compounds.

The data presented in this paper are related to the research article entitled "Novel dichloro(bis{2-[1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl-κN3]pyridine-κN})metal(II) coordination compounds of seven transition metals (Mn, Fe, Co, Ni, Cu, Zn and Cd)" (Conradie et al., 2018) [1]. This paper presents characterization and structural data of the 2-(1-(4-methyl-phenyl)-1H-1,2,3-triazol-1-yl)pyridine ligand (L2) (Tawfiq et al., 2014) [2] as well as seven dichloro(bis{2-[1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl-κN3]pyridine-κN})metal(II) coordination compounds, [M(L2)2Cl2], all containing the same ligand but coordinated to different metal ions. The data illustrate the shift in IR, UV/VIS, and NMR (for diamagnetic complexes) peaks when L is coordinated to the metals, as well as the influence of the different metals on the peak positions. Solid state structural data is presented for M = Ni and Zn, while density functional theory calculated energies, structures and optimized coordinates are provided for the lowest energy cis and trans conformations for L2 as well as [M(L2)2Cl2] with M = Mn, Fe, Co, Ni, Cu, Zn and Cd.

Optimized delivery of siRNA into 3D tumor spheroid cultures in situ.

3D tissue culture provides a physiologically relevant and genetically tractable system for studying normal and malignant human tissues. Despite this, gene-silencing studies using siRNA has proved difficult. In this study, we have identified a cause for why traditional siRNA transfection techniques are ineffective in eliciting gene silencing in situ within 3D cultures and proposed a simple method for significantly enhancing siRNA entry into spheroids/organoids. In 2D cell culture, the efficiency of gene silencing is significantly reduced when siRNA complexes are prepared in the presence of serum. Surprisingly, in both 3D tumour spheroids and primary murine organoids, the presence of serum during siRNA preparation rapidly promotes entry and internalization of Cy3-labelled siRNA in under 2 hours. Conversely, siRNA prepared in traditional low-serum transfection media fails to gain matrigel or spheroid/organoid entry. Direct measurement of CTNNB1 mRNA (encoding ß-catenin) from transfected tumour spheroids confirmed a transient but significant knockdown of ß-catenin when siRNA:liposome complexes were formed with serum, but not when prepared in the presence of reduced-serum media (Opti-MEM). Our studies suggest a simple modification to standard lipid-based transfection protocols facilitates rapid siRNA entry and transient gene repression, providing a platform for researchers to improve siRNA efficiency in established 3D cultures.

[MIII2MII3] n+ trigonal bipyramidal cages based on diamagnetic and paramagnetic metalloligands.

A family of five [MIII2MII3] n+ trigonal bipyramidal cages (MIII = Fe, Cr and Al; MII = Co, Zn and Pd; n = 0 for 1-3 and n = 6 for 4-5) of formulae [Fe2Co3L6Cl6] (1), [Fe2Zn3L6Br6] (2), [Cr2Zn3L6Br6] (3), [Cr2Pd3L6(dppp)3](OTf)6 (4) and [Al2Pd3L6(dppp)3](OTf)6 (5) (where HL is 1-(4-pyridyl)butane-1,3-dione and dppp is 1,3-bis(diphenylphosphino)propane) are reported. Neutral cages 1-3 were synthesised using the tritopic [MIIIL3] metalloligand in combination with the salts CoIICl2 and ZnIIBr2, which both act as tetrahedral linkers. The assembly of the cis-protected [PdII(dppp)(OTf)2] with [MIIIL3] afforded the anionic cages 4-5 of general formula [MIII2PdII3](OTf)6. The metallic skeleton of all cages describes a trigonal bipyramid with the MIII ions occupying the two axial sites and the MII ions sitting in the three equatorial positions. Direct current (DC) magnetic susceptibility, magnetisation and heat capacity measurements on 1 reveal weak antiferromagnetic exchange between the FeIII and CoII ions. EPR spectroscopy demonstrates that the distortion imposed on the {MO6} coordination sphere of [MIIIL3] by complexation in the {MIII2MII3} supramolecules results in a small, but measurable, increase of the zero field splitting at MIII. Complete active space self-consistent field (CASSCF) calculations on the three unique CoII sites of 1 suggest DCo ≈ -14 cm-1 and E/D ≈ 0.1, consistent with the magnetothermal and spectroscopic data.

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides.

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low µM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

Oman's coral reefs: A unique ecosystem challenged by natural and man-related stresses and in need of conservation.

Oman contains diverse and abundant reef coral communities that extend along a coast that borders three environmentally distinct water bodies, with corals existing under unique and often stressful environmental conditions. In recent years Oman's reefs have undergone considerable change due to recurrent predatory starfish outbreaks, cyclone damage, harmful algal blooms, and other stressors. In this review we summarize current knowledge of the biology and status of corals in Oman, particularly in light of recent stressors and projected future threats, and examine current reef management practices. Oman's coral communities occur in marginal environmental conditions for reefs, and hence are quite vulnerable to anthropogenic effects. We recommend a focus on developing conservation-oriented coral research to guide proactive management and expansion of the number and size of designated protected areas in Oman, particularly those associated with critical coral habitat.

Isolation and structural determination of non-racemic tertiary cathinone derivatives.

The racemic tertiary cathinones N,N-dimethylcathinone (1), N,N-diethylcathinone (2) and 2-(1-pyrrolidinyl)-propiophenone (3) have been prepared in reasonable yield and characterized using NMR and mass spectroscopy. HPLC indicates that these compounds are isolated as the anticipated racemic mixture. These can then be co-crystallized with (+)-O,O'-di-p-toluoyl-D-tartaric, (+)-O,O'-dibenzoyl-D-tartaric and (−)-O,O'-dibenzoyl-L-tartaric acids giving the single enantiomers S and R respectively of 1, 2 and 3, in the presence of sodium hydroxide through a dynamic kinetic resolution. X-ray structural determination confirmed the enantioselectivity. The free amines could be obtained following basification and extraction. In methanol these are reasonably stable for the period of several hours, and their identity was confirmed by HPLC and CD spectroscopy.

Metal-organic fireworks: MOFs as integrated structural scaffolds for pyrotechnic materials.

A new approach to formulating pyrotechnic materials is presented whereby constituent ingredients are bound together in a solid-state lattice. This reduces the batch inconsistencies arising from the traditional approach of combining powders by ensuring the key ingredients are 'mixed' in appropriate quantities and are in intimate contact. Further benefits of these types of material are increased safety levels as well as simpler logistics, storage and manufacture. A systematic series of new frameworks comprising fuel and oxidiser agents (group 1 and 2 metal nodes & terephthalic acid derivatives as linkers) has been synthesised and structurally characterised. These new materials have been assessed for pyrotechnic effect by calorimetry and burn tests. Results indicate that these materials exhibit the desired pyrotechnic material properties and the effect can be correlated to the dimensionality of the structure. A new approach to formulating pyrotechnic materials is proposed whereby constituent ingredients are bound together in a solid-state lattice. A series of Metal-organic framework frameworks comprising fuel and oxidiser agents exhibits the desired properties of a pyrotechnic material and this effect is correlated to the dimensionality of the structure.

Total laparoscopic management of lesions involving liver segment 7.

BACKGROUND: Until recently, laparoscopic resection of tumors involving segment 7 (s7) of the liver was seen as a relative contraindication. We analyzed our experiences with laparoscopic resection of tumors in s7. METHODS: Retrospective analysis of prospective database on operative and postoperative characteristics and surgical outcomes of patients in whom the intention was to remove tumors located in s7 of the liver laparoscopically. We defined two groups: those with laparoscopic metastasectomy of s7 (s7 group) and those undergoing laparoscopic right posterior sectionectomy (RPS group). RESULTS: Of 400 patients undergoing laparoscopic liver resection, 20 patients (5 %) underwent total laparoscopic resections of tumors in s7 (7 metastasectomy of s7 and 13 RPS). The type of resection was decided on the basis of tumor size and location. Median age was 70 years (range 46-82), and the indication for surgery was mainly CRLM (n = 13, 65 %) and HCC (n = 4, 20 %). There was 1 (5 %) conversion. Mean operative times were 252 min (±69) for s7 and 271 min (±102) for RPS. The mean intraoperative blood loss was 400 mL (±493) for s7 and 625 mL (±363) for RPS. A Pringle maneuver was used in 86 % of patients in s7 group and 75 % of patients in RPS group. Mean total hospital stay was 4.6 days (±2.5) in s7 and 6.9 days (±7.8) for RPS. The overall R0 resection rate was 95 % (s7 100 %, RPS 92 %). CONCLUSION: Although resection of lesions in s7 is technically demanding, a laparoscopic approach can be performed safely and effectively in experienced hands.

Anabolic steroids detected in bodybuilding dietary supplements - a significant risk to public health.

Twenty-four products suspected of containing anabolic steroids and sold in fitness equipment shops in the United Kingdom (UK) were analyzed for their qualitative and semi-quantitative content using full scan gas chromatography-mass spectrometry (GC-MS), accurate mass liquid chromatography-mass spectrometry (LC-MS), high pressure liquid chromatography with diode array detection (HPLC-DAD), UV-Vis, and nuclear magnetic resonance (NMR) spectroscopy. In addition, X-ray crystallography enabled the identification of one of the compounds, where reference standard was not available. Of the 24 products tested, 23 contained steroids including known anabolic agents; 16 of these contained steroids that were different to those indicated on the packaging and one product contained no steroid at all. Overall, 13 different steroids were identified; 12 of these are controlled in the UK under the Misuse of Drugs Act 1971. Several of the products contained steroids that may be considered to have considerable pharmacological activity, based on their chemical structures and the amounts present. This could unwittingly expose users to a significant risk to their health, which is of particular concern for naïve users.

Occurrence of Cr(VI) in drinking water of Greece and relation to the geological background.

This study provides a survey on potential Cr(VI) exposure attributed to drinking water in Greece. For this reason, a wide sampling and chemical analysis of tap waters from around 600 sites, supplied by groundwater resources, was conducted focusing on areas in which the geological substrate is predominated by ultramafic minerals. Results indicate that although violations of the current chromium regulation limit in tap water are very rare, 25% of cases showed Cr(VI) concentrations above 10 µg/L, whereas Cr(VI) was detectable in 70% of the samples (>2 µg/L). Mineralogy and conditions of groundwater reservoirs were correlated to suggest a possible Cr(VI) leaching mechanism. Higher Cr(VI) values are observed in aquifers in alluvial and neogene sediments of serpentine and amphibolite, originating from the erosion of ophiolithic and metamorphic rocks. In contrast, Cr(VI) concentration in samples from ophiolithic and metamorphic rocks was always below 10 µg/L due to both low contact time and surface area, as verified by low conductivity and salt concentration values. These findings indicate that under specific conditions, pollution of water by Cr(VI) is favorable by a slow MnO2-catalyzed oxidation of soluble Cr(III) to Cr(VI) in which manganese products [Mn(III)/Mn(II)] are probably re-oxidized by oxygen.

A truncated [Mn(III)12] tetrahedron from oxime-based [Mn(III)3O] building blocks.

The use of the novel pro-ligand H4L combining the complimentary phenolic oxime and diethanolamine moieties in one organic framework, results in the formation of the first example of a [Mn(III)12] truncated tetrahedron and an extremely rare example of a Mn cage conforming to an Archimedean solid.

Pentacoordinate silicon complexes with dynamic motion resembling a pendulum on the S(N)2 reaction pathway.

A series of glutarimide derivatives which has two carbonyl coordination sites for intramolecular pentacoordination at silicon with a X(1+n)SiC(3-n)O moiety have been synthesised and characterized. The substituent (leaving group) effects on the Si-O bond exchange between the two coordination sites (resembling a pendulum) have been studied by comparison of the differently substituted (X = F, Cl, OTf, Br and I) structures. The activation parameters for the Si-O bond exchange process were measured by NMR and separately computed and are consistent with the strength of Si-O bond coordination and the nature of the leaving group, X. The temperature-dependent (29)Si NMR spectroscopy is supported by X-ray crystallography and shows that the tetrahedral reactant is converted into pentacoordinate intermediates by intramolecular O-Si association followed by reversion to a tetrahedral geometry by Si-X dissociation. The two association/dissociation patterns offer a model for nucleophilic substitution at a silicon atom. A continuum of structures on the S(N)2 reaction profile from the glutarimide derivatives correlates reasonably well with the structural data obtained from derivatives of lactams, diketopiperazines and quinolones.

Nasal dysfunction induced by chlorinate water in competitive swimmers.

AIMS: Swimmers commonly complain of nasal symptoms probably due to mucosal irritation caused by chlorinated water. The aim of the present prospective study was to investigate changes in nasal function and cytology in a cohort of 15 volunteer competitive swimmers, as compared with a control group of 15 competitive athletes practicing other sports. METHODS: Olfactory threshold for n-butanol was measured in a population of competitive swimmers. Changes in nasal function and cytology were compared between the two groups of volunteer competitive athletes. RESULTS: There were no significant differences between the two groups in terms of mean 20-Item Sino-Nasal Outcome Test scores, peak nasal inspiratory flow, pulmonary peak expiratory flow, or total nasal resistance on anterior active rhinomanometry. Nasal mucociliary transport time (MCTt) was significantly shorter for the non-swimmers than for the swimmers. The mean olfactory threshold for n-butanol in the swimmers was significantly lower than in the other group of athletes. CONCLUSIONS: Data seem to confirm the utility of MCTt in studying nasal mucosa damage caused by chlorinated water. The present results also support the hypothesis of a role for the olfactory threshold in evaluating damage to the olfactory mucosa exposed to chlorinated water.