Minor and trace elemental contents of cancerous breast tissue measured by instrumental and radiochemical neutron activation analysis

Many minor and trace elements influence the permeability of cell membranes by competing for binding sites, and exert direct or indirect action on the carcinogenic process. Instrumental and radiochemical neutron activation analysis has been employed for the determination of more than 20 elements in normal and cancerous breast tissues of 6 patients. Most trace elements, viz., Zn, Cu, Mn, Co, Se, Br, As, Sb and Cd, are elevated in cancerous tissue, whereas lower levels are observed for Fe, Cs, I, and Sr. Similarly, concentrations of minor constituents, such as Na, K, P, Cl, and Mg, are enhanced compared to normal tissue. Several elements incorporate into the normal cell, change its enzymatic activity, and accelerate the growth of tumor.

     

Tuning hydrophobicity of highly cationic tetradecameric Gramicidin S analogues using adamantane amino acids

Ring extended Gramicidin S analogues containing adamantane amino acids and six cationic residues were designed and evaluated. Systematic replacement of the hydrophobic residues with adamantane amino acids resulted in a small set of compounds with varying amphipathic character. It was found that the amphipathicity of these compounds is correlated to their biological activity. Several bacterial strains including MRSA strains were shown to be killed by the novel peptides. The most potent antibacterial peptides are tetradecameric GS analogues containing six positives charges and two adamantane moieties.     

Dyadic brain modelling,mirror systems and the ontogenetic ritualization of ape gesture

The paper introduces dyadic brain modelling, offering both a framework for modelling the brains of interacting agents and a general framework for simulating and visualizing the interactions generated when the brains (and the two bodies) are each coded up in computational detail. It models selected neural mechanisms in ape brains supportive of social interactions, including putative mirror neuron systems inspired by macaque neurophysiology but augmented by increased access to proprioceptive state. Simulation results for a reduced version of the model show ritualized gesture emerging from interactions between a simulated child and mother ape.     

Effects of BRAF inhibitors on human melanoma tissue before treatment,early during treatment,and on progression

Selective BRAF inhibitors (BRAFi) are a standard of care for the treatment of BRAF^V600‐mutant metastatic melanoma. We analyzed a unique set of serial triplicate human metastatic melanoma tumor biopsies to identify biomarkers of BRAFi response and resistance. Morphologic features and immunohistochemical biomarkers were analyzed in 37 metastatic melanoma biopsies at pretreatment (PRE), early during treatment (EDT), and on progression (PROG) from 15 patients treated with a BRAFi and correlated with response and outcome. At EDT, proliferative markers decreased regardless of response, whereas markers of cell death increased in responders. High expression of nuclear p27 at baseline was the strongest predictor of a poorer OS and predicted worse response. The results show that BRAFi are universally antiproliferative, regardless of clinical response, whereas markers of cell death increased only in responders. The addition of therapies targeting the cell cycle machinery may improve the response and duration of BRAFi, and investigation of the mechanisms of apoptosis may provide additional therapeutic targets.     

Evidence for Divergence in Populations of Bonobos (Pan paniscus) in the Lomami-Lualaba and Kasai-Sankuru Regions Based on Preliminary Analysis of Craniodental Variation

Historical climatic events and riverine barriers influence the distribution of primates. The River Congo exerts the most significant influence on primate distribution in equatorial Africa, but the extent to which the inner basin of the Congo provided a refuge against Plio-Pleistocene climatic fluctuation is poorly understood. In this study we use cranial and dental morphometrics to examine how riverine barriers affect population patterns in bonobos (Pan paniscus). Bonobos and chimpanzees (Pan troglodytes) are sister species and share the distinction of being the closest evolutionary relatives of humans, yet comparatively little is known about bonobo morphological diversity. We selected 55 adult bonobo crania with well-preserved postcanine dentitions and divided them into regions separated by the rivers Lukenie, Kasai, Lomami, and Lualaba. We found good discrimination among these regions in cranial and dental metrics, but whereas the discriminant functions from cranial metrics were statistically significant, the discriminant functions from dental metrics were not. Mean classification accuracy was 89% for craniometrics, and ranged between 72% and 93% for dental metrics. On average 84–97% of phenetic variation was encountered within regions. Our results mirror molecular studies in suggesting that bonobos are characterized by a long-term stable demographic history allowing strong gene flow between regions and precluding drift and population differentiation. There are some indications that the bonobos from the Lomami-Lualaba and the Kasai-Sankuru regions are divergent, but modest sample sizes do not allow us to be conclusive. We would welcome the opportunity to work with field researchers to augment our sample sizes and reanalyze our data.     

Characterization of lactic acid bacteria-based probiotics as potential heavy metal sorbents

Aim: To isolate and characterize lactic acid bacteria (LAB) and determine whether they could potentially be used as heavy metal (cadmium and lead) absorbing probiotics. Methods and Results: The study used 53 environmental (mud and sludge) samples to isolate cadmium‐ and lead‐resistant LAB, by following spared plate technique. A total of 255 cadmium‐ and lead‐resistant LAB were isolated from these samples. The survival of 26 of the LAB was found after passing through sequential probiotic characterizations. These 26 probiotic LAB exhibited remarkable variations in their metal‐resistant and metal‐removal abilities. Of 26, seven (Cd54‐2, Cd61‐7, Cd69‐12, Cd70‐13, Pb82‐8, Pb96‐19 and Cd109‐16) and four (Pb71‐1, Pb73‐2, Pb85‐9 and Pb96‐19) strains displayed relatively elevated cadmium‐ and lead‐removal efficiencies from water, respectively, compare with that of the remaining strains. Strains Cd70‐13 and Pb71‐1 showed the highest cadmium (25%) and lead (59%) removal capacity from MRS (De Man, Rogosa and Sharpe) culture medium, respectively, amongst the selected strains and showed a good adhesive ability on fish mucus. A phylogenetic analysis of their 16S rDNA sequences revealed that the strains Cd70‐13 and Pb71‐1 belong to Lactobacillus reuteri. Conclusion: Excellent probiotic, metal sorption and adhesive characteristics of newly identified Lact. reuteri strains Cd70‐13 and Pb71‐1 were isolated, which indicated their high potential abilities to survive in the intestinal milieu and to uptake the tested metals from the environment. Significance and Impact of the Study: To our knowledge, this is the first study that has aimed to isolate, characterize and identify metal‐resistant LAB strains that have potential to be a probiotic candidate for food and in vivo challenge studies in the intestinal milieu of fish for the uptake and control of heavy metal bioaccumulation.     

Dynamic cardiorespiratory interaction during head-up tilt-mediated presyncope

In 28 healthy adults, we compared the dynamic interaction between respiration and cerebral autoregulation in 2 groups of subjects: those who did and did not develop presyncopal symptoms during 70 degrees passive head-up tilt (HUT), i.e., nonpresyncopal (23 subjects) and presyncopal (5 subjects). Airflow, CO2, cerebral blood flow velocity (CBF), ECG, and blood pressure (BP) were recorded. To determine whether influences of mean BP (MBP) and systolic SP (SBP) on CBF were altered in presyncopal subjects, coherencies and transfer functions between these variables and mean and peak CBF (CBFm and CBFp) were estimated. To determine the influence of end-tidal CO2 (ETco2) on CBF, the relative CO2 reactivity (%change in CBFm per mmHg change in ETco2) was calculated. We found that in presyncopal subjects before symptoms during HUT, coherence between SBP and CBFp was higher (P=0.02) and gains of transfer functions between BP (MBP and SBP) and CBFm were larger (MBP, P=0.01; SBP, P=0.01) in the respiratory frequency region. In the last 3 min before presyncope, presyncopals had a reduced relative CO2 reactivity (P=0.005), likely a consequence of the larger decrease in ETco2. We hypothesize that the CO2-mediated increase in resistance attenuates autoregulation such that the relationship between systemic and cerebral hemodynamics is enhanced. Our results suggest that an altered cardiorespiratory interaction involving cerebral hemodynamics may contribute in the cascade of events during tilt that culminate in unexplained syncope.     

Identification of arylamine N -acetyltransferase inhibitors as an approach towardsnovel anti-tuberculars

New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting intracellularly. Mycobacteria have a unique cell wall. Deletion of the gene for arylamine N-acetyltransferase (NAT) decreases mycobacterial cell wall lipids, particularly the distinctive mycolates, and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis BCG. The nat gene and its associated gene cluster are almost identical in sequence in M. bovis BCG and M. tuberculosis. The gene cluster is essential for intracellular survival of mycobacteria. We have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT activity. Here, we characterize one class of such molecules— triazoles—in relation to its effects on the target enzyme and on both M. bovis BCG and M. tuberculosis. The most potent triazole mimics the effects of deletion of the nat gene on growth, lipid disruption and intracellular survival. We also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth, and use ligand-protein analysis to give further insight into the structure-activity relationships. We conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved.