Novel Photosensitizers Trigger Rapid Death of Malignant Human Cells and Rodent Tumor Transplants via Lipid Photodamage and Membrane Permeabilization

BACKGROUND: Apoptotic cascades may frequently be impaired in tumor cells; therefore, the approaches to circumvent these obstacles emerge as important therapeutic modalities. METHODOLOGY/PRINCIPAL FINDINGS: Our novel derivatives of chlorin e(6), that is, its amide (compound 2) and boronated amide (compound 5) evoked no dark toxicity and demonstrated a significantly higher photosensitizing efficacy than chlorin e(6) against transplanted aggressive tumors such as B16 melanoma and M-1 sarcoma. Compound 5 showed superior therapeutic potency. Illumination with red light of mammalian tumor cells loaded with 0.1 µM of 5 caused rapid (within the initial minutes) necrosis as determined by propidium iodide staining. The laser confocal microscopy-assisted analysis of cell death revealed the following order of events: prior to illumination, 5 accumulated in Golgi cysternae, endoplasmic reticulum and in some (but not all) lysosomes. In response to light, the reactive oxygen species burst was concomitant with the drop of mitochondrial transmembrane electric potential, the dramatic changes of mitochondrial shape and the loss of integrity of mitochondria and lysosomes. Within 3-4 min post illumination, the plasma membrane became permeable for propidium iodide. Compounds 2 and 5 were one order of magnitude more potent than chlorin e(6) in photodamage of artificial liposomes monitored in a dye release assay. The latter effect depended on the content of non-saturated lipids; in liposomes consisting of saturated lipids no photodamage was detectable. The increased therapeutic efficacy of 5 compared with 2 was attributed to a striking difference in the ability of these photosensitizers to permeate through hydrophobic membrane interior as evidenced by measurements of voltage jump-induced relaxation of transmembrane current on planar lipid bilayers. CONCLUSIONS/SIGNIFICANCE: The multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with membrane permeabilization caused by lipid photodamage

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Waist-Belt Pouches (Bags) from Medieval Burial Grounds of the Vetluga-Vyatka Interfluves Area

The waist-belt pouches/bags from the 9th-11th-century burial ground sites of the Vetluga-Vyatka river interfluve refer to four basic types according to their form, technique of manufacture and decoration. Type 1 items have been found mainly in male graves, types 2 and 3 equally in male and female graves, type 4 is represented by a single instance. Judging by the location of the pouches in the graves, they were worn on the belt. The analysis of the contents of the pouches makes it possible to conclude that their destination had been more iconic than functional: the majority of the items from them seemed to be represented by amulets. Type 1 pouches, most common in the Vetluga-Vyatka interfluve, local in origin, are characteristic of the medieval Mari costume. Purses the second type had penetrated into this territory as a result of cultural and trade contacts with neighbors, especially with the Bulgars

http://archaeologie.pro/en/archive/8/141/

The article summarizes primary results of technological analysis of textile fragments (45 items) from the Mari 9th-10th-century burials located at the Rusenikha and Nizhnyaja Strelka burial ground sites in the Vetluga-Vyatka interfluve area. Six textile groups have been singled out: 1) woolen fabric of plain weave; 2) woolen fabrics of twill weave; 3) plain weave cloths from plant fibers; 4) silk fabrics; 5) cords and cord tassels from woolen yarn; 6) fragments of felt. They are remains of garments, mats and fabrics used for wrapping funerary gifts. An attempt to reconstruct the cut of individual parts of the garments has been made by the authors

Sabretache from Burial 8 of the Krasnogorsk Burial Ground. Historical Aspect

The finds of purses/sabretache with front side coating of metal sheets are of considerable interest for the study of the cultural ties of the population of the Vetluga-Vyatka interfluvial area. Purses/sabretache, decorated with sheets and plates, are well known since the 10th century in the Carpathian basin and East European region, and even found on some Scandinavian burial grounds. Items of this type in the Vetluga-Vyatka interfluve were found on the Veselovsky, Rusenikha and Anatkasy burial grounds. But, unfortunately, the finds are poorly preserved, which does not allow a complete reconstruction of the items. In 2019, another handbag was found on the Krasnogorsk burial ground of Mari culture of the 10th century. A good preservation of organic matters and a comprehensive study of the details of the sabretache made it possible to reconstruct the full view of the item. The find from burial 8 of the Krasnogorsk burial ground was examined against a background of wide analogies from the medieval sites of the Carpathian basin, East European and Eurasian regions that allowed to find the place of the item in the system of international connections and to take a closer look at the issue of the genesis and ways of spread of this type of objects

On One Type of Decoration of the Mari Costume in the 16th – 18th Centuries

The authors use materials of 12 funerary complexes from Kartukovo, Vyzhum and Vazhnanger burial grounds to study one element of the Mari costume in the 16th – 18th centuries: collars or neckline trimmings (1.5–2.5 cm wide ribbons decorated with fl ounce of golden threads). Thermal and visual methods applied to the samples established that the item was crocheted of silk threads. All studied burials are dated by 16th – 18th centuries and are the earliest complexes containing crocheted items. Artefacts of crocheting were also found in the Mordva burial grounds. The raw silk for the fabric and the fl ounce of golden thread were bought in the trade centers located in the Volga region. The materials published in this article offer new data for the study of the Finno-Ugric household (Mari and Mordovians) in the Middle Ages and the New Time, as well as history of appearance and dissemination of crocheting techniques

Burials with Beads from Anatkasy Burial Ground

The paper features the materials of burials with beads from the Anatkasy burial ground corresponding to the medieval Mari culture. The site is located on the B. Tsivil river, right tributary of the Volga river. A total of 33 burials, 2 sacrificial complexes and 2 pits with traces of ritual activities were revealed during excavations. The total number of discovered beads is 340 items, which were located in following six burials with beads: No. 2, 3, 5, 22, 24, 31. The article contains a classification of beads on the basis of Yu.L. Shchapova's work “Ancient glass. Morphology, technology, chemical composition” (Shchapova, 1989). On the basis of numerous counterparts, the authors conducted dating of the bead material representing an important chronological indicator of the site. This is the first introduction of the material from these burial complexes with beads into scientific discourse

Jewelry from the Anatkasi Burial Ground: Towards Cultural Attribution of the Site

The authors introduce into discussion and examine jewelry from the Anatkasi burial ground situated on the right bank of the Volga River. They developed typology of these jewelry items and provided a wide range of analogies. The jewelry dates the site by 10th – 11th centuries, which is confi rmed by coins. The identifi ed ethnical markers (details of headdress, temple rings, nakosnik (braid charm), and also certain types of rings and bracelets) point to a similarity of this site to the synchronous Mari burial grounds of from the Vetluga-Vyatka area. Beside the jewelry and the elements of costume typical for the Mari culture, the Anatkasi burial ground also yielded a range of foreign artefacts: Bulgarian, Old Russian, Mordovian, Kama or Cis-Uralic, which emphasizes the originality of this site. Most of the borrowed things could penetrate into this area through trade contacts encouraged by location of this burial ground on the river Tsivil, near the Volga River

Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response

It is generally thought that Mycobacterium tuberculosis (Mtb)-specific CD4+ Th1 cells producing IFN-γ are essential for protection against tuberculosis (TB). In some studies, protection has recently been associated with polyfunctional subpopulation of Mtb-specific Th1 cells, i.e., with cells able to simultaneously secrete several type 1 cytokines. However, the role for Mtb-specific Th1 cells and their polyfunctional subpopulations during established TB disease is not fully defined. Pulmonary TB is characterized by a great variability of disease manifestations. To address the role for Mtb-specific Th1 responses during TB, we investigated how Th1 and other immune cells correlated with particular TB manifestations, such as the degree of pulmonary destruction, TB extent, the level of bacteria excretion, clinical disease severity, clinical TB forms, and “Timika X-ray score,” an integrative parameter of pulmonary TB pathology. In comparison with healthy Mtb-exposed controls, TB patients (TBP) did not exhibit deficiency in Mtb-specific cytokine-producing CD4+ cells circulating in the blood and differed by a polyfunctional profile of these cells, which was biased toward the accumulation of bifunctional TNF-α+IFN-γ+IL-2− lymphocytes. Importantly, however, severity of different TB manifestations was not associated with Mtb-specific cytokine-producing cells or their polyfunctional profile. In contrast, several TB manifestations were strongly correlated with leukocyte numbers, the percent or the absolute number of lymphocytes, segmented or band neutrophils. In multiple alternative statistical analyses, band neutrophils appeared as the strongest positive correlate of pulmonary destruction, bacteria excretion, and “Timika X-ray score.” In contrast, clinical TB severity was primarily and inversely correlated with the number of lymphocytes in the blood. The results suggest that: (i) different TB manifestations may be driven by distinct mechanisms; (ii) quantitative parameters and polyfunctional profile of circulating Mtb-specific CD4+ cells play a minor role in determining TB severity; and (iii) general shifts in production/removal of granulocytic and lymphocytic lineages represent an important factor of TB pathogenesis. Mechanisms leading to these shifts and their specific role during TB are yet to be determined but are likely to involve changes in human hematopoietic system

Phthalates in Surface Waters of the Selenga River (Main Tributary of Lake Baikal) and Its Delta: Spatial-Temporal Distribution and Environmental Risk Assessment

The Selenga River provides about half of the water and chemical runoff into Lake Baikal and plays an important role in the sustainability of the ecosystem of this large natural freshwater lake. Phthalate esters (PAEs) are organic compounds that can disrupt reproductive and endocrine systems. This study focused on investigating the distribution of six priority phthalates in the Selenga River and its delta utilizing SPE-GC/MS. The study found that the highest levels of Σ6PAE were observed during the high-water years, 2021 and 2023, and were evenly distributed along the river from the sampling sites upstream of Ulan-Ude to the delta channels. In contrast, the mean annual Σ6PAE content was relatively low in the low water period of 2022. Dibutyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) are the two dominant phthalates found in the surface waters of the Selenga River and delta channels. In 2021, the average total concentration of six phthalates (Σ6PAE) ranged from 8.84 to 25.19 µg/L, while in 2022 it ranged from 0.45 to 4.01 µg/L, and in 2023 it ranged from 5.40 to 21.08 µg/L. The maximum level for the sum of phthalates was 61.64 µg/L in 2021, 13.57 µg/L in 2022, and 30.19 µg/L in 2023. The wastewater treatment facilities in Ulan-Ude were identified as a stable local source of phthalates. In some cases, PAE concentrations exceeded maximum allowable concentrations, particularly for DEHP. This could have adverse effects on aquatic organisms