Salt and ionic cocrystalline forms of amides: protonation of carbamazepine in aqueous media

The products of reactions of the pharmaceutical amide carbamazepine (CBZ) with strong acids under aqueous conditions were investigated by both powder and single crystal X-ray diffraction. Despite previous claims to the contrary, it was found that salt forms with CBZ protonated at the amide O atom could be isolated from reactions with both HCl and HBr. These forms include the newly identified hydrate phase [CBZ(H)][Cl]·H O. Reactions with other mineral acids (HI and HBF ) gave ionic cocrystalline (ICC) forms (CBZ· [acridinium][I ]·2.5I and CBZ·[H O ] [BF ] ·H O) as well as the salt form CBZ·[CBZ(H)][BF ]·0.5H O. Reaction 2 4 3 2 5 2 0.25 4 0.25 2 4 2 of CBZ with a series of sulfonic acids also gave salt forms, namely, [CBZ(H)][O SC H ], [CBZ(H)][O SC H (OH)]· 3 6 5 3 6 4 0.5H O, [CBZ(H)] [O SCH CH SO ], and [CBZ(H)][O SC H (OH) (COOH)]·H O. CBZ and protonated CBZ(H) 2 2 3 2 2 3 3 6 3 2 moieties can be differentiated in the solid state both by changes to molecular geometry and by differing packing preferences

Steric sea level variability (1993-2010) in an ensemble of ocean reanalyses and objective analyses

Quantifying the effect of the seawater density changes on sea level variability is of crucial importance for climate change studies, as the sea level cumulative rise can be regarded as both an important climate change indicator and a possible danger for human activities in coastal areas. In this work, as part of the Ocean Reanalysis Intercomparison Project, the global and regional steric sea level changes are estimated and compared from an ensemble of 16 ocean reanalyses and 4 objective analyses. These estimates are initially compared with a satellite-derived (altimetry minus gravimetry) dataset for a short period (2003–2010). The ensemble mean exhibits a significant high correlation at both global and regional scale, and the ensemble of ocean reanalyses outperforms that of objective analyses, in particular in the Southern Ocean. The reanalysis ensemble mean thus represents a valuable tool for further analyses, although large uncertainties remain for the inter-annual trends. Within the extended intercomparison period that spans the altimetry era (1993–2010), we find that the ensemble of reanalyses and objective analyses are in good agreement, and both detect a trend of the global steric sea level of 1.0 and 1.1 ± 0.05 mm/year, respectively. However, the spread among the products of the halosteric component trend exceeds the mean trend itself, questioning the reliability of its estimate. This is related to the scarcity of salinity observations before the Argo era. Furthermore, the impact of deep ocean layers is non-negligible on the steric sea level variability (22 and 12 % for the layers below 700 and 1500 m of depth, respectively), although the small deep ocean trends are not significant with respect to the products spread.

Differential interaction of estrogen receptor and thyroid hormone receptor isoforms on the rat oxytocin receptor promoter leads to differences in transcriptional regulation

Both the estrogen receptor (ER) and thyroid hormone receptor (TR) are members of the nuclear receptor superfamily. Two isoforms of the ER, alpha and beta, exist. The TRalpha and beta isoforms are products of two distinct genes that are further differentially spliced to give TRalpha1 and alpha2, TRbeta1 and beta2. The TRs have been shown to interfere with ER-mediated transcription from both the consensus estrogen response element (ERE) and the rat preproenkephalin (PPE) promoter, possibly by competing with ER binding to the ERE or by squelching coactivators essential for ER-mediated transcription. The rat oxytocin receptor (OTR) gene is thought to be involved in several facets of reproductive and affiliative behaviors. 17beta-Estradiol-bound ERs upregulate the OTR gene in the ventromedial hypothalamus, a region critical for the induction of lordosis behavior in several species. We investigated the effects of the ligand-binding TR isoforms on the ER-mediated transcription from a physiological promoter of a behaviorally relevant gene such as the OTR. Only ERalpha could induce the OTR gene in two cell lines tested, the CV-1 and the SK-N-BE2C neuroblastoma cell lines. ERbeta was incapable of inducing the gene in either cell line. ERalpha is therefore not equivalent to ERbeta on this physiological promoter. Indeed, in the neural cell line, ERbeta can inhibit ERalpha-mediated induction from the OTR promoter. While the TRalpha1 isoform inhibited ERalpha-mediated induction in the neural cell line, the TRbeta1 isoform stimulated induction, thus demonstrating isoform specificity in the interaction. The use of a DNA-binding mutant, the TR P box mutant, showed that inhibition of ERalpha-mediated induction of the rat OTR gene promoter by the TRalpha1 isoform does not require DNA-binding ability. SRC-1 overexpression relieved TRalpha1-mediated inhibition in both cell lines, suggesting that squelching for coactivators is an important molecular mechanism in TRalpha-mediated inhibition. Such interactions between TR and ER isoforms on the rat OTR promoter provide a mechanism to achieve neuroendocrine integration.

Civilian casualties – do we really care? The failure of the revolution in military affairs of non-lethal weapons in the U.S., Russia and Israel

Causing civilian casualties during military operations has become a much politicised topic in international relations since the Second World War. Since the last decade of the 20th century, different scholars and political analysts have claimed that human life is valued more and more among the general international community. This argument has led many researchers to assume that democratic culture and traditions, modern ethical and moral issues have created a desire for a world without war or, at least, a demand that contemporary armed conflicts, if unavoidable, at least have to be far less lethal forcing the military to seek new technologies that can minimise civilian casualties and collateral damage. Non-Lethal Weapons (NLW) – weapons that are intended to minimise civilian casualties and collateral damage – are based on the technology that, during the 1990s, was expected to revolutionise the conduct of warfare making it significantly less deadly. The rapid rise of interest in NLW, ignited by the American military twenty five years ago, sparked off an entirely new military, as well as an academic, discourse concerning their potential contribution to military success on the 21st century battlefields. It seems, however, that except for this debate, very little has been done within the military forces themselves. This research suggests that the roots of this situation are much deeper than the simple professional misconduct of the military establishment, or the poor political behaviour of political leaders, who had sent them to fight. Following the story of NLW in the U.S., Russia and Israel this research focuses on the political and cultural aspects that have been supposed to force the military organisations of these countries to adopt new technologies and operational and organisational concepts regarding NLW in an attempt to minimise enemy civilian casualties during their military operations. This research finds that while American, Russian and Israeli national characters are, undoubtedly, products of the unique historical experience of each one of these nations, all of three pay very little regard to foreigners’ lives. Moreover, while it is generally argued that the international political pressure is a crucial factor that leads to the significant reduction of harmed civilians and destroyed civilian infrastructure, the findings of this research suggest that the American, Russian and Israeli governments are well prepared and politically equipped to fend off international criticism. As the analyses of the American, Russian and Israeli cases reveal, the political-military leaderships of these countries have very little external or domestic reasons to minimise enemy civilian casualties through fundamental-revolutionary change in their conduct of war. In other words, this research finds that employment of NLW have failed because the political leadership asks the militaries to reduce the enemy civilian casualties to a politically acceptable level, rather than to the technologically possible minimum; as in the socio-cultural-political context of each country, support for the former appears to be significantly higher than for the latter.