Synthesis and biological evaluation of prodigiosene conjugates of porphyrin,estrone and 4-hydroxytamoxifen

To generate the first series of prodigiosene conjugates, the tripyrrolic skeleton was appended to estrone, tamoxifen and porphyrin frameworks by way of ester linkers and various hydrocarbon chain lengths. The ability of the conjugates to inhibit various types of cancer cells was evaluated in vitro. The porphyrin conjugates did not exhibit significant activity. The estrone conjugates exhibited modest activity, for the most part. However, significantly greater growth inhibition activity against certain breast, colon, lung, leukemia, melanoma and prostate cell lines was noted. This unusual effect for this first generation model class of compound warrants further investigation and comparison to cases where estrogens are linked to prodigiosenes via connection points that do not feature in estrogen receptor binding. The 4-hydroxytamoxifen conjugates exhibit nanomolar range activity against the MCF-7 breast cancer cell line, paving the way to expand the scope and connectivity of prodigiosene–tamoxifen conjugates.     

How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains

BackgroundMouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies.MethodsThe present work was designed in an attempt to determine guidelines in the field of salt-induced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry).ResultsIn this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges.ConclusionsTherefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites.     

The first endocast of the extinct dodo (Raphus cucullatus) and an anatomical comparison amongst close relatives (Aves,Columbiformes)

The dodo (Raphus cucullatus) became extinct only 100 years after humans first arrived on the Indian Ocean island of Mauritius. Even though it has become an example of oddity, obsolescence, stupidity, and extinction, most aspects of its biology are still unknown. We used high‐resolution X‐ray computed tomography (CT) scanning to examine the endocranial morphology of the dodo and compare this virtual endocast to eight close relatives. Enlarged olfactory bulbs are a shared characteristic of the Raphinae and posteriorly angled semicircular canals are particular to the dodo compared with the other eight species sampled here. A regression of log endocranial volume against log body size shows that the dodo has an endocranial volume on par with other pigeons. Aspects of the dodo's biology are discussed in relation to these endocranial features.     

Two data pre-processing workflows to facilitate the discovery of biomarkers by 2D NMR metabolomics

Metabolomics - Sleep is increasingly being viewed as an issue of public health concern, yet few epidemiologic studies have explored associations between sleep habits and metabolomic profile. To...     

Rapid identification and interpretation of gene–environment associations using the new R.SamBada landscape genomics pipeline

sam βada is a genome–environment association software, designed to search for signatures of local adaptation. However, pre‐ and postprocessing of data can be labour‐intensive, preventing wider uptake of the method. We have now developed R.SamBada, an r ‐package providing a pipeline for landscape genomic analysis based on sam βada , spanning from the retrieval of environmental conditions at sampling locations to gene annotation using the Ensembl genome browser. As a result, R.SamBada standardizes the landscape genomics pipeline and eases the search for candidate genes of local adaptation, enhancing reproducibility of landscape genomic studies. The efficiency and power of the pipeline is illustrated using two examples: sheep populations from Morocco with no evident population structure and Lidia cattle from Spain displaying population substructuring. In both cases, R.SamBada enabled rapid identification and interpretation of candidate genes, which are further discussed in the light of local adaptation. The package is available in the r CRAN package repository and on GitHub (github.com/SolangeD/R.SamBada).     

A new role for C/EBPbeta in acute promyelocytic leukemia

The differentiating properties of retinoic acid (RA) have been used beneficially for the treatment of Acute Promyelocytic Leukemia (APL) for more than a decade. However, the molecular mechanisms of how RA induces APL cell differentiation are still poorly understood. In our previous work, we provided a novel mechanism to explain the unique sensitivity to RA of APL cells. We proposed that C/EBPbeta is an ATRA-dependent PML/RARA target gene and that its activation is critical during ATRA-induced differentiation of APL cells. Here, I discuss how C/EBPbeta could be an important gene in APL pathogenesis.     

Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement

Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8 – two cytokines that are known to upregulate MMP-9 – both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.     

The rationale for probiotics in female urogenital healthcare

Urogenital infections are a major reason that women visit their family physician and are referred to gastroenterology, gynecology, urology, and infectious disease specialists. The association between abnormal vaginal microbiota and increased risk for sexually transmitted infections, bladder and vaginal infections per se, and a higher rate of preterm labor indicate the need to better understand and manage urogenital health. The concept of probiotics arose from the realization that humans are inhabited with microbes from birth and that these organisms play a role in preventing disease. Defined as "live microorganisms, which when administered in adequate amounts confer a health benefit on the host," probiotic strains have already been shown to effectively prevent diarrhea and to hold potential in preventing and treating tonsillitis, caries, renal calculi, and respiratory infections. This review provides a rationale for the use of probiotics in maintaining female vaginal and bladder health and as a treatment option for recurrent bacterial vaginosis, urinary tract infection, yeast vaginitis, and sexually transmitted infections. We consider only probiotic strains that fulfill the United Nations/World Health Organization Guidelines for Probiotics in being fully characterized and clinically documented through scientific investigations describing known or presumed mechanisms of action. Although medical practitioners as yet are unable to access these probiotic strains, an awareness of recent and ongoing research for probiotics is important, as results are encouraging. The concept of probiotic therapy is familiar to many consumers and although it has historically lacked credibility in the medical community, perceptions are changing.     

Mapping of a conformational epitope shared between E1 and E2 on the serum-derived human hepatitis C virus envelope

Monoclonal antibody D32.10 produced by immunizing mice with a hepatitis C virus (HCV)-enriched pellet obtained from plasmapheresis of a chronically HCV1b-infected patient binds HCV particles derived from serum of different HCV1a- and HCV1b-infected patients. Moreover, this monoclonal has been shown to recognize both HCV envelope proteins E1 and E2. In an attempt to provide novel insight into the membrane topology of HCV envelope glycoproteins E1 and E2, we localized the epitope recognized by D32.10 on the E1 and/or E2 sequence using Ph.D.-12 phage display peptide library technology. Mimotopes selected from the phage display dodecapeptide library by D32.10 shared partial similarities with 297RHWTTQGCNC306 of the HCV E1 glycoprotein and with both 613YRLWHYPCT621 and 480PDQRPYCWHYPPKPC494 of the HCV E2 glycoprotein. Immunoreactivity of D32.10 with overlapping peptides corresponding to these three HCV regions confirmed these localizations and suggested that the three regions identified are likely closely juxtaposed on the surface of serum-derived particles as predicted by the secondary model structure of HCV E2 derived from the tick-borne encephalitis virus E protein. This assertion was supported by the detection of specific antibodies directed against these three E1E2 regions in sera from HCV-infected patients.