Exhaustive CoMFA and CoMSIA analyses around different chemical entities: a ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands

The 5-hydroxytryptamine (5-HT_1A) receptors represent an attractive target in drug discovery. In particular, 5-HT_1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT_1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT_1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT_1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target_. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT_1AR ligands.

     

Functional proteomic insights in B-cell chronic lymphocytic leukemia

Introduction: B cell chronic lymphocytic leukemia (B-CLL) is a hematological malignancy considered as the most common leukemia in the Western world. The understanding of B cell differentiation is crucial for the diagnosis, prognosis, and treatment of the disease.

Areas covered: In this review, B-cell ontogeny and its relation with the CLL development, in combination with the proteomic approaches which could provide a deep characterization of the disease through the characterization of the cellular signaling pathways involved in the pathological cells is described.

Expert commentary: Although conventional strategies (genome sequencing, morphology assays, and immunophenotyping by flow cytometry and/or immunochemistry) have allowed the establishment of the disease stage based on different parameters, it is still necessary to utilize novel approaches (e.g., proteomics) that have the potential to simultaneously analyze thousands of molecules to improve understanding of CLL.     

Genomes of Thaumarchaeota from deep sea sediments reveal specific adaptations of three independently evolved lineages

Marine sediments represent a vast habitat for complex microbiomes. Among these, ammonia oxidizing archaea (AOA) of the phylum Thaumarchaeota are one of the most common, yet little explored, inhabitants, which seem extraordinarily well adapted to the harsh conditions of the subsurface biosphere. We present 11 metagenome-assembled genomes of the most abundant AOA clades from sediment cores obtained from the Atlantic Mid-Ocean ridge flanks and Pacific abyssal plains. Their phylogenomic placement reveals three independently evolved clades within the order Nitrosopumilales, of which no cultured representative is known yet. In addition to the gene sets for ammonia oxidation and carbon fixation known from other AOA, all genomes encode an extended capacity for the conversion of fermentation products that can be channeled into the central carbon metabolism, as well as uptake of amino acids probably for protein maintenance or as an ammonia source. Two lineages encode an additional (V-type) ATPase and a large repertoire of DNA repair systems that may allow to overcome the challenges of high hydrostatic pressure. We suggest that the adaptive radiation of AOA into marine sediments occurred more than once in evolution and resulted in three distinct lineages with particular adaptations to this extremely energy-limiting and high-pressure environment.Subject terms: Phylogenetics, Metagenomics     

Acute responses of muscle oxygen saturation during different cluster training configurations in resistance-trained individuals

This study compared the perceptual responses, physiological indicators and technical parameters between different training protocols focused on upper body exercises. A randomized crossover design was performed, and 12 trained individuals (age: 27.1 ± 5.7 years; height: 173.7 ± 10.7 cm; BMI: 23.9 ± 2.3) completed three resistance training sessions under different protocols separated by at least 72 h: traditional training (TT) (4 x 6 repetitions at 85% of 1RM with 120 s of rest between sets), cluster 1 (CL1) (4 x 2+2+2 repetitions at 85% of 1RM with 15 s of intra-rep rest and 80 s between sets), and cluster 2 (CL2) (24 repetitions at 85% of 1RM with 15 s of inter-set recovery). Before training, arterial blood pressure (BP) and repetitions to failure of pull-up and push-up (FT) were collected. Muscle oxygen saturation (SmO₂) in the chest and movement velocity were evaluated in barbell bench press during the training session. After finishing, lactate, BP, rate of perceived exertion and FT were assessed. The percentage of velocity loss (TT: 19.24%; CL1: 5.02% and CL2: 7.30%) in the bench press and lactate concentration (TT: 8.90 mmol·l^-1; CL1: 6.13 mmol·l^-1 and CL2: 5.48 mmol·l^-1) were significantly higher (p < 0.05) for TT compared to both CLs. RPE values were higher (p < 0.05) in TT compared to CL1 (7.95 a.u. vs. 6.91 a.u., respectively). No differences (p > 0.05) were found between protocols for SmO₂, BP, FT, pain or heart rate between set configurations. Cluster configurations allow one to maintain higher movement velocity and lower lactate and RPE values compared to a traditional configuration, but with similar concentrations of SmO₂.     

Expression of A1 adenosine receptors in the developing avian retina: in vivo modulation by A2A receptors and endogenous adenosine

Little is known about the mechanisms that regulate the expression of adenosine receptors during CNS development. We demonstrate here that retinas from chick embryos injected in ovo with selective adenosine receptor ligands show changes in A1 receptor expression after 48 h. Exposure to A1 agonist N⁶‐cyclohexyladenosine (CHA) or antagonist 8‐Cyclopentyl‐1, 3‐dipropylxanthine (DPCPX) reduced or increased, respectively, A1 receptor protein and [³H]DPCPX binding, but together, CHA+DPCPX had no effect. Interestingly, treatment with A_2A agonist 3‐[4‐[2‐[[6‐amino‐9‐[(2R,3R,4S,5S)‐5‐(ethylcarbamoyl)‐3,4‐dihydroxy‐oxolan‐2‐yl]purin‐2‐yl]amino] ethyl]phenyl] propanoic acid (CGS21680) increased A1 receptor protein and [³H]DPCPX binding, and reduced A_2A receptors. The A_2A antagonists 7‐(2‐phenylethyl)‐5‐amino‐2‐(2‐furyl)‐pyrazolo‐[4,3‐e]‐1,2,4‐trizolo[1,5‐c] pyrimidine (SCH58261) and 4‐(2‐[7‐amino‐2‐[2‐furyl][1,2,4]triazolo[2,3‐a][1,3,5]triazo‐5‐yl‐amino]ethyl)phenol (ZM241385) had opposite effects on A1 receptor expression. Exposure to CGS21680 + CHA did not change A1 receptor levels, whereas CHA + ZM241385 or CGS21680 + DPCPX had no synergic effect. The blockade of adenosine transporter with S‐(4‐nitrobenzyl)‐6‐thioinosine (NBMPR) also reduced [³H]DPCPX binding, an effect blocked by DPCPX, but not enhanced by ZM241385. [³H]DPCPX binding kinetics showed that treatment with CHA reduced and CGS21680 increased the Bmax, but did not affect Kd values. CHA, DPCPX, CGS21680, and ZM241385 had no effect on A1 receptor mRNA. These data demonstrated an in vivo regulation of A1 receptor expression by endogenous adenosine or long‐term treatment with A1 and A_2A receptors modulators.     

Short-term effects of litter from 21 woody species on plant growth and root development

Background and aims

Plant litter has an important role in terrestrial ecosystems (Lambers et al. 2008). Our aim was to assess the short-term effect of litter from 21 woody species (deciduous and evergreens) on plant growth and root development.

Methods

We conducted a short-term experiment (10 weeks) under controlled conditions adding litter from 21 woody species to pots with Dactylis glomerata (target species). We determined plant biomass and root development and related these variables to decomposition rate and litter quality.

Results

Litter from two species enhanced plant growth whereas litter of five species inhibited it. Considering all species in the data set, plant growth was associated to litter with high decomposition rate and high litter quality: high Ca and N concentration and low polyphenols concentration. However, excluding from the analyses the two species that increased growth, litter inhibition effect on plant growth was related to the litter-polyphenols concentration. Plants growing with nutrient-richer litter had a lower proportion of fine roots which could be related to a litter mediated increase in soil nutrient.

Conclusions

Enhanced plant growth or, on the contrary, plant growth inhibition could be the result of a positive or, in turn, negative balance between nutrient and polyphenols concentration in litter.