Dopamine D3 receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization

The lead optimization process to identify new selective dopamine D₃ receptor antagonists is reported. DMPK parameters and binding data suggest that selective D₃ receptor antagonists as potential PET ligands might have been identified.     

Synthesis and biological evaluation of new enantiomerically pure azole derivatives as inhibitors of Mycobacterium tuberculosis

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.     

The upper Shemshak Formation (Toarcian–Aalenian) of the Eastern Alborz (Iran): Biota and palaeoenvironments during a transgressive–regressive cycle

The siliciclastic, up to 4,000 m thick Upper Triassic–Bajocian Shemshak Formation is widespread across the Iran Plate, especially in the Alborz Mountains of northern Iran. In contrast to its lower, generally non-marine part, the upper part is marine. Based on the Tazareh section of the eastern Alborz, an integrated analysis of this marine interval is presented. The 1,700 m thick marine sedimentary succession records a gradual deepening from inner to mid and outer shelf environments from the Middle Toarcian to early Late Aalenian. During the Late Aalenian–Early Bajocian, the trend was reversed and infilling of the basin by a large delta system occurred. This general facies development reflects a nearly symmetrical transgressive–regressive (T–R) megacycle, terminated by the inter-regional mid-Cimmerian tectonic event. A renewed transgression in the early Late Bajocian initiated a subsequent sedimentary megacycle. The bioturbated mid and outer shelf sediments contain a low to moderately diverse benthic fauna dominated by deep burrowing bivalves, often preserved in the growth position. A hierarchy of four orders of sedimentary cycles can be recognized (parasequences, parasequence sets, unconformity-bounded third-order depositional sequences, and the 13 ma long second-order T–R megacycle). A regional correlation with the Jajarm area (200 km to the east) shows a very similar temporal facies pattern of the upper Shemshak Formation. The eastern Alborz T–R cycle is completely out-of-phase with other (eustatic) sea-level curves, suggesting regional tectonic control. Rough estimates of subsidence rates give an average value of 126 m/ma. However, much higher values for the Aalenian (230 m/ma), particularly the Late Aalenian (700 m/ma), indicate a distinct increase in subsidence rate towards the Early Bajocian mid-Cimmerian tectonic event. These high subsidence rates suggest that the sediments of the Shemshak Formation of the eastern Alborz formed in a (young) rift basin.     

Synthesis and carbonic anhydrase I,II, VII,and IX inhibition studies with a series of benzo[d]thiazole-5- and 6-sulfonamides

A series of benzo[d]thiazole-5- and 6-sulfonamides has been synthesized and investigated for the inhibition of several human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, using ethoxzolamide (EZA) as lead molecule. 2-Amino-substituted, 2-acylamino- and halogenated (bromo-and iodo-derivatives at the heterocyclic ring) compounds led to several interesting inhibitors against the cytosolic hCA I, II and VII, as well as the transmembrane, tumor-associated hCA IX isoforms. Several subnanomolar/low nanomolar, isoform-selective sulfonamide inhibitors targeting hCA II, VII and IX were detected. The sharp structure–activity relationship for CA inhibition with this small series of derivatives, with important changes of activity observed even after minor changes in the scaffold or at the 2-amino moiety, make this class of scarcely investigated sulfonamides of particular interest for further investigations.     

Graphene-based dental adhesive with anti-biofilm activity

Background

Secondary caries are considered the main cause of dental restoration failure. In this context, anti-biofilm and bactericidal properties are desired in dental materials against pathogens such as Streptococcus mutans. To this purpose, graphene based materials can be used as fillers of polymer dental adhesives. In this work, we investigated the possibility to use as filler of dental adhesives, graphene nanoplatelets (GNP), a non toxic hydrophobic nanomaterial with antimicrobial and anti-biofilm properties.

Results

Graphene nanoplatelets have been produced starting from graphite intercalated compounds through a process consisting of thermal expansion and liquid exfoliation. Then, a dental adhesive filled with GNPs at different volume fractions has been produced through a solvent evaporation method. The rheological properties of the new experimental adhesives have been assessed experimentally. The adhesive properties have been tested using microtensile bond strength measurements (µ-TBS). Biocidal activity has been studied using the colony forming units count (CFU) method. The anti-biofilm properties have been demonstrated through FE-SEM imaging of the biofilm development after 3 and 24 h of growth.

Conclusions

A significantly lower vitality of S. mutans cells has been demonstrated when in contact with the GNP filled dental adhesives. Biofilm growth on adhesive-covered dentine tissues demonstrated anti-adhesion properties of the produced materials. µ-TBS results demonstrated no significant difference in µ-TBS between the experimental and the control adhesive. The rheology tests highlighted the necessity to avoid low shear rate regimes during adhesive processing and application in clinical protocol, and confirmed that the adhesive containing the 0.2%wt of GNPs possess mechanical properties comparable with the ones of the control adhesive.

     

Tolerated drugs in subjects with severe cutaneous adverse reactions (SCARs) induced by anticonvulsants and review of the literature

Background

Anticonvulsant hypersensitivity syndrome represents a rare but potentially fatal kind of adverse drug reaction. This clinical picture often hampers the flexibility with which alternative anticonvulsants or even other classes of drugs are prescribed in these patients, negatively affecting the efficacy of treatment and the course of the disease. The aim of this study was to analyse a group of six patients with severe cutaneous drug reactions induced by anticonvulsants and to report which alternative antiepileptic drugs and which drugs of other classes were tolerated.

Case presentation

A total of six patients (2 males and 4 females, age 11–73 years) are described in this study. In all the patients the onset of the severe cutaneous drug reactions was 2–4 weeks after initiating the anticonvulsant therapy: 2 out of 6 patients presented with a drug reaction with eosinophilia and systemic symptoms under therapy with phenytoin; 2 out of 6 presented with Stevens–Johnson syndrome under therapy with lamotrigine; and 2 out of 6 presented with a toxic epidermal necrolysis, one of them under therapy with valproic acid, and the other one under therapy with lamotrigine. Alternative anticonvulsants tolerated after the reaction were: clonazepam, levetiracetam, diazepam, delorazepam and lormetazepam.

Conclusions

In our cases we observed that non aromatic anticonvulsants and benzodiazepines were well tolerated as alternative treatments in six patients with reactions to aromatic anticonvulsivants and that the risk of hypersensitivity reactions to other drug classes was not increased as compared to general population.

     

The thumb domain is not essential for the catalytic action of HoLaMa DNA polymerase

A structural and kinetic characterization of a fragment of the HoLaMa DNA polymerase is presented here. In particular, a truncated form of HoLaMa, devoid of a consistent portion of the thumb domain, was isolated and purified. This HoLaMa fragment, denoted as ΔNter-HoLaMa, is surprisingly competent in catalyzing DNA extension, albeit featuring a k_cat one order of magnitude lower than the corresponding kinetic constant of its full-length counterpart. The conformational rearrangements, if any, of enzyme tryptophanes triggered by DNA binding or extension were assayed under pre-steady-state conditions. The fluorescence of HoLaMa tryptophanes was found to significantly change upon DNA binding and extension. On the contrary, no fluorescence changes of ΔNter-HoLaMa tryptophanes were detected under the same conditions, suggesting that major conformational transitions are not required for DNA binding or extension by this truncated DNA polymerase.     

Feeding ecology of the Sicilian pond turtle <Emphasis Type="Italic">Emys trinacris</Emphasis> (Testudines,Emydidae) influenced by seasons and invasive aliens species

Feeding ecology of a species is the result of its evolutionary history, biology, physiology and local constraints, such as prey availability, intra- and inter-specific interactions and environmental characteristics. In this study we investigated the still unknown diet of the Sicilian pond turtle, with special emphasis to the relationships with recently introduced alien species in the “Lake Preola and Gorghi Tondi” Nature Reserve (Sicily, Italy). A total of 83 faecal samples were collected in three different periods. Emys trinacris seems an opportunistic and generalist species. The main prey taxa were aquatic invertebrates, including the invasive Procambarus clarkii, while non-aquatic preys are found sporadically. Plant matter, mainly leaves and roots of aquatic forms, was also found in high frequency with a high occurrence of fruits and seeds in spring. We did not find a significant difference in diet composition within sex and age, while an evident divergence was found between periods and sites. In particular, we noticed a decrease in prey abundance and in food-niche breadth from pre-reproductive period to post-reproductive period. Moreover a very clear difference was found between a site with allochthonous fishes and a site fish-free, with a more abundant and wide diet spectrum in the last one, as a result of the increased availability of prey. We highlighted the importance to take any possible actions to avoid the spread of fishes in other basins and to study the indirect impact of Procambarus clarkii, as possible vector of harmful trace element.     

The phylogeny of Hildoceratidae (Cephalopoda,Ammonitida) resolved by an integrated coding scheme of the conch

Ammonite phylogeny has mainly been established based on a stratigraphic approach, with cladistics underconsidered. The main arguments against the use of cladistics are the supposed large amount of homoplasy and the small number of characters. Resolving the phylogeny of the Hildoceratidae (Early Jurassic) is especially challenging because of its large diversity and disparity. Many forms that have not been determined as closely related in previous studies exhibit very similar shapes. Moreover, some groups are morphologically very different, adding difficulties to building a unique coding scheme at a low taxonomic resolution (i.e. species). Here we propose an integrated coding scheme of the peristome shape and the ornamentation, allowing an increased level of comparison. The shape of the peristome is used as a new reference to locate ornamental features and propose new homology hypotheses. In total, 105 taxa have been analysed for 47 characters. We code continuous characters by their means and ranges ± one standard deviation. We test two weighting schemes: equal weights standardized by unit range and implied weighting with several concavity constants. This work has led to redefinition of the phylogenetic inclusivenesses of all the hildoceratid subfamilies. The new coding scheme based on peristome shapes provides the fewest homoplastic characters. The schemes appear promising to improve phylogenetic analyses in ammonoids as well as molluscs as a whole by creating a general coding framework.