Probing Amphotericin B Single Channel Activity by Membrane Dipole Modifiers

The effects of dipole modifiers and their structural analogs on the single channel activity of amphotericin B in sterol-containing planar phosphocholine membranes are studied. It is shown that the addition of phloretin in solutions bathing membranes containing cholesterol or ergosterol decreases the conductance of single amphotericin B channels. Quercetin decreases the channel conductance in cholesterol-containing bilayers while it does not affect the channel conductance in ergosterol-containing membranes. It is demonstrated that the insertion of styryl dyes, such as RH 421, RH 237 or RH 160, in bilayers with either cholesterol or ergosterol leads to the increase of the current amplitude of amphotericin B pores. Introduction of 5α-androstan-3β-ol into a membrane-forming solution increases the amphotericin B channel conductance in a concentration-dependent manner. All the effects are likely to be attributed to the influence of the membrane dipole potential on the conductance of single amphotericin B channels. However, specific interactions of some dipole modifiers with polyene-sterol complexes might also contribute to the activity of single amphotericin B pores. It has been shown that the channel dwell time increases with increasing sterol concentration, and it is higher for cholesterol-containing membranes than for bilayers including ergosterol, 6-ketocholestanol, 7-ketocholestanol or 5α-androstan-3β-ol. These findings suggest that the processes of association/dissociation of channel forming molecules depend on the membrane fluidity

The frequency of obesity in patients with acute pancreatitis, chronic pancreatitis and pancreatic cancer

BACKGROUND: In the XXI century, the frequency of pancreas diseases increased 2–3 times. The expectation that causes a pandemic lead to the development of a number of diseases. The results of studies on the relationship of overweight, obesity with the risk of developing pancreas diseases (acute pancreatitis (AP), chronic pancreatitis (CP) and pancreas cancer (PC)) are very heterogeneous (for AP and PC) and not numerous (for CP). AIMS: to identify the frequency of obesity in AP patients (APр), CP patients (СPр) and PC patients (PCр) and compare these parameters. MATERIALS AND METHODS: at the observational multicenter clinical cross-sectional uncontrolled case-study 44 APp, 97 CPp and 45 PCp were examined; the groups were comparable by sex/age. Informed consent form for participate in the study was obtained from all patients. The main outcome of the study: the frequency of obesity in APp, CPp; PCp. RESULTS: The frequency of obesity in APp (13,6%), CPp (24,7%) and PCp (20,0%) did not differ significantly. Among the examined patients, the lowest average BMI (24,2±0,7 kg/m2) was observed in APp (p=0,049). BMI ≥22,5 kg/m2 was found to be associated with AP (OR=0,398; 95%CI 0,195–0,812; p=0,011). An inverse relationship was shown between the BMI and “definite” CP (Exp (B)=0,772; 95%CI 0,632–0,942; p=0,011). In men with CP and in CPp alcoholic etiology, weight deficit was observed significantly more often than in women with CP and in CPp biliary etiology, respectively. Earlier (a year before the present survey), obesity was more common in PCp (55,6%) than in APp (13,6%, χ2=3,3; p=0,000) and CPp (25,8%, χ2=12,0; p=0,001). A history of obesity (in our study one year before PC detection) and PC (OR=4,435; 95% CI 2,180–9,025; p=0,000) direct relationship was shown. CONCLUSIONS: the frequency of obesity in APp, CPp and PCp was similar. The average BMI was higher in APp, than in CPp and PCp. BMI≥22,5 kg/m2 was a protective factor for AP. BMI was inversely associated with “defined” CP. A history of obesity was directly associated with PC

New insights into the human brain’s cognitive organization : Views from the top, from the bottom, from the left and, particularly, from the right

The view that the left cerebral hemisphere in humans “dominates” over the “subdominant” right hemisphere has been so deeply entrenched in neuropsychology that no amount of evidence seems able to overcome it. In this article, we examine inhibitory cause-and-effect connectivity among human brain structures related to different parts of the triune evolutionary stratification —archicortex, paleocortex and neocortex— in relation to early and late phases of a prolonged resting-state functional magnetic resonance imaging (fMRI) experiment. With respect to the evolutionarily youngest parts of the human cortex, the left and right frontopolar regions, we also provide data on the asymmetries in underlying molecular mechanisms, namely on the differential expression of the protein-coding genes and regulatory microRNA sequences. In both domains of research, our results contradict the established view by demonstrating a pronounced right-to-left vector of causation in the hemispheric interaction at multiple levels of brain organization. There may be several not mutually exclusive explanations for the evolutionary significance of this pattern of lateralization. One of the explanations emphasizes the computational advantage of separating the neural substrates for processing novel information ("exploration") mediated predominantly by the right hemisphere, and processing with reliance on established cognitive routines and representations ("exploitation") mediated predominantly by the left hemisphere.publishedVersio

On the Complexity of Mechanisms and Consequences of Chromothripsis: An Update

In the present review, we focus on the phenomenon of chromothripsis, a new type of complex chromosomal rearrangements. We discuss the challenges of chromothripsis detection and its distinction from other chromoanagenesis events. Along with already known causes and mechanisms, we introduce aberrant epigenetic regulation as a possible pathway to chromothripsis. We address the issue of chromothripsis characteristics in cancers and benign tumours, as well as chromothripsis inheritance in cases of its occurrence in germ cells, zygotes and early embryos. Summarising the presented data on different phenotypic effect of chromothripsis, we assume that its consequences are most likely determined not by the chromosome shattering and reassembly themselves, but by the genome regions involved in the rearrangement

Cytogenomic Profile of Uterine Leiomyoma: In Vivo vs. In Vitro Comparison

We performed a comparative cytogenomic analysis of cultured and uncultured uterine leiomyoma (UL) samples. The experimental approach included karyotyping, aCGH, verification of the detected chromosomal abnormalities by metaphase and interphase FISH, MED12 mutation analysis and telomere measurement by Q-FISH. An abnormal karyotype was detected in 12 out of 32 cultured UL samples. In five karyotypically abnormal ULs, MED12 mutations were found. The chromosomal abnormalities in ULs were present mostly by complex rearrangements, including chromothripsis. In both karyotypically normal and abnormal ULs, telomeres were ~40% shorter than in the corresponding myometrium, being possibly prerequisite to chromosomal rearrangements. The uncultured samples of six karyotypically abnormal ULs were checked for the detected chromosomal abnormalities through interphase FISH with individually designed DNA probe sets. All chromosomal abnormalities detected in cultured ULs were found in corresponding uncultured samples. In all tumors, clonal spectra were present by the karyotypically abnormal cell clone/clones which coexisted with karyotypically normal ones, suggesting that chromosomal abnormalities acted as drivers, rather than triggers, of the neoplastic process. In vitro propagation did not cause any changes in the spectrum of the cell clones, but altered their ratio compared to uncultured sample. The alterations were unique for every UL. Compared to its uncultured counterpart, the frequency of chromosomally abnormal cells in the cultured sample was higher in some ULs and lower in others. To summarize, ULs are characterized by both inter- and intratumor genetic heterogeneity. Regardless of its MED12 status, a tumor may be comprised of clones with and without chromosomal abnormalities. In contrast to the clonal spectrum, which is unique and constant for each UL, the clonal frequency demonstrates up or down shifts under in vitro conditions, most probably determined by the unequal ability of cells with different genetic aberrations to exist outside the body

Extracellular Vesicles Derived from Acholeplasma laidlawii

Extracellular vesicle production is believed to be a ubiquitous process in bacteria, but the data on such a process in Mollicutes are absent. We report the isolation of ultramicroforms – extracellular vesicles from supernatants of Acholeplasma laidlawii PG8 (ubiquitous mycoplasma; the main contaminant of cell culture). Considering sizes, morphology, and ultrastructural organization, the ultramicroforms of A. laidlawii PG8 are similar to membrane vesicles of Gram-positive and Gram-negative bacteria. We demonstrate that A. laidlawii PG8 vesicles contain genetic material and proteins, and are mutagenic to lymphocytes of human peripheral blood. We show that Mycoplasma gallisepticum S6, the other mycoplasma, also produce similar structures, which suggests that shedding of the vesicles might be the common phenomenon in Mollicutes. We found that the action of stress conditions results in the intensive formation of ultramicroforms in mycoplasmas. The role of vesicular formation in mycoplasmas remains to be studied

Dysregulation of Long Intergenic Non-Coding RNA Expression in the Schizophrenia Brain

BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions. AIM: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions. METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold. RESULTS: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways. CONCLUSION: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research

Soluble Cyanobacterial Carotenoprotein as a Robust Antioxidant Nanocarrier and Delivery Module

To counteract oxidative stress, antioxidants including carotenoids are highly promising, yet their exploitation is drastically limited by the poor bioavailability and fast photodestruction, whereas current delivery systems are far from being efficient. Here we demonstrate that the recently discovered nanometer-sized water-soluble carotenoprotein from Anabaena sp. PCC 7120 (termed AnaCTDH) transiently interacts with liposomes to efficiently extract carotenoids via carotenoid-mediated homodimerization, yielding violet–purple protein samples. We characterize the spectroscopic properties of the obtained pigment–protein complexes and the thermodynamics of liposome–protein carotenoid transfer and demonstrate the delivery of carotenoid echinenone from AnaCTDH into liposomes with an efficiency of up to 70 ± 3%. Most importantly, we show efficient carotenoid delivery to membranes of mammalian cells, which provides protection from reactive oxygen species (ROS). Incubation of neuroblastoma cell line Tet21N in the presence of 1 μM AnaCTDH binding echinenone decreased antimycin A ROS production by 25% (p < 0.05). The described carotenoprotein may be considered as part of modular systems for the targeted antioxidant delivery.BMBF, 01DJ15007, Carotenoidbindende photoschaltbare Proteine: Lichtinduzierte Dynamik und Anwendungen in modernen mikroskopischen Verfahre

Genetic landscape in Russian patients with familial left ventricular noncompaction

BackgroundLeft ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214).MethodsAll index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines.ResultsA total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants −8 of 54 (14.8%) −have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 −7.37; p &lt;0.001) per variant after adjustment for sex, age, and family.ConclusionOverall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients