Enzymatic Relay Mechanism Stimulates Cyclic GMP Synthesis in Rod Photoresponse: Biochemical and Physiological Study in Guanylyl Cyclase Activating Protein 1 Knockout Mice

Regulation of cGMP synthesis by retinal membrane guanylyl cyclase isozymes (RetGC1 and RetGC2) in rod and cone photoreceptors by calcium-sensitive guanylyl cyclase activating proteins (GCAP1 and GCAP2) is one of the key molecular mechanisms affecting the response to light and is involved in congenital retinal diseases. The objective of this study was to identify the physiological sequence of events underlying RetGC activation in vivo, by studying the electrophysiological and biochemical properties of mouse rods in a new genetic model lacking GCAP1. The GCAP1−/− retinas expressed normal levels of RetGC isozymes and other phototransduction proteins, with the exception of GCAP2, whose expression was elevated in a compensatory fashion. RetGC activity in GCAP1−/− retinas became more sensitive to Ca2+ and slightly increased. The bright flash response in electroretinogram (ERG) recordings recovered quickly in GCAP1−/−, as well as in RetGC1−/−GCAP1−/−, and RetGC2−/−GCAP1−/− hybrid rods, indicating that GCAP2 activates both RetGC isozymes in vivo. Individual GCAP1−/− rod responses varied in size and shape, likely reflecting variable endogenous GCAP2 levels between different cells, but single-photon response (SPR) amplitude and time-to-peak were typically increased, while recovery kinetics remained faster than in wild type. Recovery from bright flashes in GCAP1−/− was prominently biphasic, because rare, aberrant SPRs producing the slower tail component were magnified. These data provide strong physiological evidence that rod photoresponse recovery is shaped by the sequential recruitment of RetGC isozyme activation by GCAPs according to the different GCAP sensitivities for Ca2+ and specificities toward RetGC isozymes. GCAP1 is the ‘first-response’ sensor protein that stimulates RetGC1 early in the response and thus limits the SPR amplitude, followed by activation of GCAP2 that adds stimulation of both RetGC1 and RetGC2 to speed-up photoreceptor recovery

Ecosistema de información relacionado con el monitoreo del estilo de vida saludable de los adultos

This article discusses the problem of providing adults with reliable, relevant and timely information that allows them to organize their activities: the regime of work and rest in accordance with the goals of a healthy lifestyle and health correction. The goal is to determine the criteria and components of an information resource that will be adequate to the goals of keeping health of adults. The leading approaches to the health care mass media research are: structural-analytical, personality-oriented and cultural approaches. Research methods: analysis and synthesis of scientific and methodological literature and the information environment on the problems of the population health improving and methods of mathematical data processing. The article presents the results of determining the criteria for monitoring the information ecosystem on a healthy lifestyle, among these criteria the following were identified: the scientific validity of information, targeting, social significance and dialogue. Also, data portals that contribute to the solution of certain tasks of the adult population health improving were identified. The authors designed and implemented the informational and educational portal “3 youth” which is aimed at the integrated implementation of the basic health-improving needs of the adult population, taking into account the interconnection of health components: physical, mental, social. The results proving the effectiveness of using the authors' portal to ensure a healthy lifestyle for adults are presented and discussed. The article will be useful to adults who want to lead a healthy lifestyle with the support of the information resources, teachers and trainers working with people of mature age. This article is also useful for teachers of the Faculty of Physical Education who plan to promote a healthy lifestyle among different age categories.Este artículo analiza el problema de proporcionar a los adultos información confiable, relevante y oportuna que les permita organizar sus actividades: el régimen de trabajo y descanso de acuerdo con los objetivos de un estilo de vida saludable y la corrección de la salud. El objetivo es determinar los criterios y componentes de un recurso de información que será adecuado para los objetivos de mantener la salud de los adultos. Los enfoques principales para la investigación de los medios de comunicación de atención médica son: enfoques estructural-analíticos, orientados a la personalidad y culturales. Métodos de investigación: análisis y síntesis de la literatura científica y metodológica y el entorno de información sobre los problemas de mejora de la salud de la población y métodos de procesamiento de datos matemáticos. El artículo presenta los resultados de la determinación de los criterios para monitorear el ecosistema de información en un estilo de vida saludable, entre estos criterios se identificaron los siguientes: la validez científica de la información, la focalización, la importancia social y el diálogo. Además, se identificaron portales de datos que contribuyen a la solución de ciertas tareas de mejora de la salud de la población adulta. Los autores diseñaron e implementaron el portal informativo y educativo "3 jóvenes" que está dirigido a la implementación integrada de las necesidades básicas de mejora de la salud de la población adulta, teniendo en cuenta la interconexión de los componentes de salud: física, mental y social. Se presentan y discuten los resultados que prueban la efectividad del uso del portal de los autores para garantizar un estilo de vida saludable para los adultos. El artículo será útil para adultos que desean llevar un estilo de vida saludable con el apoyo de los recursos de información, maestros y formadores que trabajan con personas de edad madura. Este artículo también es útil para los maestros de la Facultad de Educación Física que planean promover un estilo de vida saludable entre las diferentes categorías de edad. El portal también será útil en el sistema de educación profesional adicional de instructores y entrenadores de fitness. La novedad de la investigación del autor consiste en la aplicación de enfoques metodológicos y criterios con base científica para monitorear el ecosistema de información relacionado con la organización de un estilo de vida saludable para adultos; en el desarrollo y prueba de un portal de información que resuelve un complejo de tareas para garantizar un estilo de vida saludable para los adulto

Electron traps in solid Xe

Correlated real-time measurements of thermally stimulated luminescence and exoelectron emission from solid Xe pre-irradiated with an electron beam were performed. The study enabled us to distinguish between surface and bulk traps in solid Xe and to identify a peak related to electronically induced defects. The activation energy corresponding to annihilation of these defects was estimated by the following methods: the method of different heating rates, the initial-rise method, and the curve cleaning technique with fitting of the thermally stimulated luminescence glow curve

Язык, речь, личность в зеркале психолингвистики

В издании раскрываются вопросы психологии языка, речи и личности. Исследуются проблемы переводческих универсалий. Особое внимание уделяется сравнительно новым научным понятиям и категориям: языковая личность, языковая картина мира, чувство языка, речевой опыт. Для научных работников, аспирантов, студентов и всех, кто интересуется вопросами психологических особенностей речевой деятельности.СОДЕРЖАНИЕ Предисловие 4; Часть 1. Язык и мир. Речь и личность 6; Засекина Л. В. Интеллект личности в зеркале психолингвистики 6; Засекин С. В. Язык в зеркале перевода: психолингвистическое исследование переводческих универсалий 25; Лавриненко А. Л. Когнитивно-мотивационные особенности языковой личности 53; Орап М. О. Психология речевого опыта личности 73; Савченко Е. В. Нарративный подход в исследовании индивидуального опыта на личностном уровне 94; Фомина Н. А. Соотношение различных свойств языковой личности и особенностей ее речевой деятельности 126; Часть 2. Психология языка, речи и речевой деятельности личности 148; Белык Т. Н. Психологические особености речевого имиджа личности 148; Дячук Н. В. Творческий потенциал будущего переводчика художественных текстов в его профессиональной деятельности 162; Крупыч С. О. Психологические проявления личности в речевой деятельности 176; Тарасюк И. В. Психологические основы речевой адаптации детей мигрантов 198; Шишкина К. Ю. Информационная безопасность личности в контексте психолингвистики 216; Часть 3. Психолингвистические исследования речи личности: норма-аномалия-патология 223; Василюк О. П. Психолингвистические средства реорганизации травматической памяти личности 223; Соловей О. А. Речевая деятельность детей с синдромом дефицита внимания и гиперактивности 244; Тригуб Г. В. Психологические основы овладения иностранным языком младшими школьниками с ведущей левой рукой 268; Об авторах 288

The June 2016 Optical and Gamma-Ray Outburst and Optical Micro-Variability of the Blazar 3C454.3

The quasar 3C454.3 underwent a uniquely-structured multi-frequency outburst in June 2016. The blazar was observed in the optical $R$ band by several ground-based telescopes in photometric and polarimetric modes, at $\gamma$-ray frequencies by the \emph{Fermi}\ Large Area Telescope, and at 43 GHz with the Very Long Baseline Array. The maximum flux density was observed on 2016 June 24 at both optical and $\gamma$-ray frequencies, reaching $S^\mathrm{max}_\mathrm{opt}=18.91\pm0.08$ mJy and $S_\gamma^\mathrm{max} =22.20\pm0.18\times10^{-6}$ ph cm$^{-2}$ s$^{-1}$, respectively. The June 2016 outburst possessed a precipitous decay at both $\gamma$-ray and optical frequencies, with the source decreasing in flux density by a factor of 4 over a 24-hour period in $R$ band. Intraday variability was observed throughout the outburst, with flux density changes between 1 and 5 mJy over the course of a night. The precipitous decay featured statistically significant quasi-periodic micro-variability oscillations with an amplitude of $\sim 2$-$3\%$ about the mean trend and a characteristic period of 36 minutes. The optical degree of polarization jumped from $\sim3\%$ to nearly 20\% during the outburst, while the position angle varied by \sim120\degr. A knot was ejected from the 43 GHz core on 2016 Feb 25, moving at an apparent speed $v_\mathrm{app}=20.3c\pm0.8c$. From the observed minimum timescale of variability $\tau_\mathrm{opt}^\mathrm{min}\approx2$ hr and derived Doppler factor $\delta=22.6$, we find a size of the emission region $r\lesssim2.6\times10^{15}$ cm. If the quasi-periodic micro-variability oscillations are caused by periodic variations of the Doppler factor of emission from a turbulent vortex, we derive a rotational speed of the vortex $\sim0.2c$.Comment: 19 pages, 13 figures, 3 tables, accepted to the Astrophysical Journal 2019 March

ГИПЕРТЕНЗИВНЫЕ РАССТРОЙСТВА БЕРЕМЕННОСТИ – СТРАТЕГИИ КОРРЕКЦИИ В ПОСЛЕРОДОВОМ ПЕРИОДЕ (ОБЗОР ЛИТЕРАТУРЫ)

HighlightsHypertensive disorders of pregnancy are associated with short- and long-term risks for the mother.We have identified several key points in the management strategy of this pathology in the postpartum period, which should contribute to the emergence of new directions in the prognosis and treatment modalities of this disease. AbstractThe article presents an analytical review of modern data on the treatment of hypertensive disorders of pregnancy (HDP) in the postpartum period. HDPs lead to maternal morbidity and mortality in developing and poor countries, and in regions with well-developed healthcare systems as well. HDPs can later progress into hypertension and are associated with the risk of coronary artery disease and stroke. Moreover, HDPs increase the likelihood of low-birth-weight babies and preterm births. The incidence of HDP is growing worldwide despite the implemented prevention methods: according to the Global Health Data Exchange, from 1990 to 2019 HDPs` incidence by 10.9% from 16.3 million to 18.08 million people. However, the introduction of universal approaches to prevention of complications made it possible to reduce mortality from HDP in the same period by 30.05%. The risk of hypertensive complications increases significantly in the postpartum period. Modern research confirms this – the likelihood of worsening HDP and the development of complications increases significantly in the first 24–48 hours after childbirth. About one third of cases of eclampsia occur in the postpartum period, of which almost half occur 48 hours after delivery. Stroke in women with HDP occurs in the postpartum period in half of the cases. Arterial hypertension (AH) in the postpartum period often requires an increase in doses of antihypertensive drugs, whereas after 3–6 months, many patients no longer need such therapy. During the first year after childbirth, the risk of progression of AH and the development of complications due to hypertension is increased, and remains so for many years. The feasibility of antihypertensive therapy in HDP today is beyond doubt, however, there are issues that require further study. They are related to the safety of prescribed drugs during lactation, and as a result, in many guidelines, antihypertensive therapy in the postpartum period is prescribed with reservations. Another problem is the relatively small number of RCTs directly assessing the effectiveness of antihypertensive therapy in the postpartum period.Основные положенияГипертензивные расстройства беременности ассоциированы с ближайшими и отдаленными рисками для матери.Выделено несколько ключевых позиций в стратегии коррекции данной патологии в послеродовом периоде, которые способствуют появлению новых направлений в прогнозировании и лечении заболевания. Резюме В статье представлен аналитический обзор современных источников научной литературы, посвященных вопросам коррекции гипертензивных расстройств беременности (ГРБ) в послеродовом периоде. ГРБ выступают общепризнанной причиной материнской заболеваемости и смертности, причем не только в развивающихся и бедных странах, но и регионах с хорошо развитой системой здравоохранения. ГРБ могут прогрессировать в гипертоническую болезнь и ассоциированы с риском ишемической болезни сердца и инсульта. Кроме того, ГРБ увеличивают вероятность рождения маловесных детей и преждевременных родов. Несмотря на проводимые методы профилактики, заболеваемость ГРБ в мире постоянно растет: по данным Global Health Data Exchange, в период с 1990 по 2019 г. она увеличилась на 10,9% – с 16,3 до 18,08 млн человек. В то же время внедрение единых подходов к профилактике осложнений позволило снизить смертность от ГРБ в этот же период на 30,05%. В классическом акушерстве постулируется, что риск гипертензивных осложнений значительно возрастает в послеродовом периоде. Современные исследования подтверждают этот феномен: вероятность утяжеления ГРБ и развития осложнений значительно повышается в первые 24–48 ч после родов. Около одной трети случаев эклампсии возникает в послеродовом периоде, из которых почти половина – спустя 48 ч после родов, а инсульт у женщин с ГРБ в половине случаев происходит в послеродовом периоде. Артериальная гипертензия в послеродовом периоде часто требует увеличения доз антигипертензивных препаратов, тогда как через 3–6 мес. многие пациентки перестают нуждаться в подобной терапии. В течение первого года после родов у женщин с ГРБ значительно повышается риск прогрессирования хронической артериальной гипертензии и развития обусловленных заболеванием осложнений и остается таковым долгие годы. Целесообразность антигипертензивной терапии при ГРБ сегодня не вызывает сомнений, однако остаются вопросы, требующие дальнейшего изучения. В первую очередь это безопасность назначаемых препаратов в период лактации. Вследствие этого во многих руководствах гипотензивная терапия в послеродовом периоде рекомендована с существенными оговорками. Еще одна проблема связана с относительно небольшим количеством рандомизированных клинических исследований, непосредственно включающих оценку эффективности антигипертензивной терапии в послеродовом периоде

Emission-line Variability during a Nonthermal Outburst in the Gamma-Ray Bright Quasar 1156+295

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.We present multi-epoch optical spectra of the γ-ray bright blazar 1156+295 (4C +29.45, Ton 599) obtained with the 4.3 m Lowell Discovery Telescope. During a multiwavelength outburst in late 2017, when the γ-ray flux increased to 2.5 × 10−6 phot cm−2 s−1 and the quasar was first detected at energies ≥100 GeV, the flux of the Mg ii λ2798 emission line changed, as did that of the Fe emission complex at shorter wavelengths. These emission-line fluxes increased along with the highly polarized optical continuum flux, which is presumably synchrotron radiation from the relativistic jet, with a relative time delay of ≲2 weeks. This implies that the line-emitting clouds lie near the jet, which points almost directly toward the line of sight. The emission-line radiation from such clouds, which are located outside the canonical accretion-disk related broad-line region, may be a primary source of seed photons that are up-scattered to γ-ray energies by relativistic electrons in the jet. © 2022. The Author(s). Published by the American Astronomical Society.This research was supported in part by NASA Fermi guest investigator program grants 80NSSC19K1504 and 80NSSC20K1565. We thank A. Tchekhovskoy for discussion of possible origins of the variable line-emitting clouds. These results made use of the Lowell Discovery Telescope (LDT) at Lowell Observatory. Lowell Observatory is a private, non-profit institution dedicated to astrophysical research and public appreciation of astronomy, and operates the LDT in partnership with Boston University, the University of Maryland, the University of Toledo, Northern Arizona University and Yale University. This study was based in part on observations conducted using the 1.8 m Perkins Telescope Observatory (PTO) in Arizona, which is owned and operated by Boston University. I.A. acknowledges financial support from the Spanish "Ministerio de Ciencia e Innovación" (MCINN) through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofísica de Andalucía-CSIC (SEV-2017-0709). Acquisition and reduction of the MAPCAT data were supported in part by MICINN through grants AYA2016-80889-P and PID2019-107847RB-C44. The MAPCAT observations were carried out at the German-Spanish Calar Alto Observatory, which is jointly operated by Junta de Andalucía and Consejo Superior de Investigaciones Científicas. Data from the Steward Observatory spectropolarimetric monitoring project were used; this program was supported by Fermi Guest Investigator grants NNX08AW56G, NNX09AU10G, NNX12AO93G, and NNX15AU81G. C.C. acknowledges support from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program under the grant agreement No. 771282.Peer reviewe

Multiwavelength behaviour of the blazar 3C 279: Decade-long study from γ -ray to radio

We report the results of decade-long (2008-2018) γ -ray to 1 GHz radio monitoring of the blazar 3C 279, including GASP/WEBT, Fermi and Swift data, as well as polarimetric and spectroscopic data. The X-ray and γ -ray light curves correlate well, with no delay ≳ 3 h, implying general cospatiality of the emission regions. The γ -ray-optical flux-flux relation changes with activity state, ranging from a linear to amore complex dependence. The behaviour of the Stokes parameters at optical and radio wavelengths, including 43 GHz Very Long Baseline Array images, supports either a predominantly helical magnetic field or motion of the radiating plasma along a spiral path. Apparent speeds of emission knots range from 10 to 37c, with the highest values requiring bulk Lorentz factors close to those needed to explain γ -ray variability on very short time-scales. The MgII emission line flux in the 'blue' and 'red' wings correlates with the optical synchrotron continuum flux density, possibly providing a variable source of seed photons for inverse Compton scattering. In the radio bands, we find progressive delays of the most prominent light-curve maxima with decreasing frequency, as expected from the frequency dependence of the τ= 1 surface of synchrotron self-absorption. The global maximum in the 86 GHz light curve becomes less prominent at lower frequencies, while a local maximum, appearing in 2014, strengthens toward decreasing frequencies, becoming pronounced at ∼5 GHz. These tendencies suggest different Doppler boosting of stratified radio-emitting zones in the jet. © 2020 The Author(s).We thank the referee for attentive reading and comments that helped to improve presentation of the manuscript. The data collected by the WEBT collaboration are stored in the WEBT archive at the Osservatorio Astrofisico di Torino -INAF (ht tp://www.oato.inaf.it/blazars/webt/); for questions regarding their availability, please contact the WEBT President Massimo Villata([email protected]).TheSt.Petersburg University team acknowledges support from Russian Science Foundation grant 17-12-01029. The research at BU was supported in part by National Science Foundation grant AST-1615796 and NASA Fermi Guest Investigator grants 80NSSC17K0649, 80NSSC19K1504, and 80NSSC19K1505. The PRISM camera at Lowell Observatory was developed by K. Janes et al. at BU and Lowell Observatory, with funding from the NSF, BU, and Lowell Observatory. The emission-line observations made use of the DCT at Lowell Observatory, supported by Discovery Communications, Inc., BU, the University of Maryland, the University of Toledo, and Northern Arizona University. The VLBA is an instrument of the National Radio Astronomy Observatory. The National Radio Astronomy Observatory is a facility of the US NSF, operated under cooperative agreement by Associated Universities, Inc. This research has used data from the UMRAO which was supported by the University of Michigan; research at this facility was supported by NASA under awards NNX09AU16G, NNX10AP16G, NNX11AO13G, and NNX13AP18G, and by the NSF under award AST-0607523. The Steward Observatory spectropolarimetric monitoring project was supported by NASA Fermi Guest Investigator grants NNX08AW56G, NNX09AU10G, NNX12AO93G, and NNX15AU81G. The Torino group acknowledges financial contribution from agreement ASI-INAF n.2017-14-H.0 and from contract PRIN-SKA-CTA-INAF 2016. I.A. acknowledges support by a Ramon y Cajal grant (RYC-2013-14511) of the 'Ministerio de Ciencia, Innovacion, y Universidades (MICIU)' of Spain and from MCIU through the 'Center of Excellence Severo Ochoa' award for the Instituto de Astrofisica de Andalucia-CSIC (SEV-20170709). Acquisition and reduction of the POLAMI and MAPCAT data were supported by MICIU through grant AYA2016-80889-P. The POLAMI observations were carried out at the IRAM 30-m Telescope, supported by INSU/CNRS (France), MPG (Germany) and IGN (Spain). The MAPCAT observations were carried out at theGerman-Spanish Calar Alto Observatory, jointly operated by the Max-Plank-Institut fur Astronomie and the Instituto de Astrofisica de Andalucia-CSIC. The study is based partly on data obtained with the STELLA robotic telescopes in Tenerife, an AIP facility jointly operated by AIP and IAC. The OVRO 40-m monitoring program is supported in part by NASA grants NNX08AW31G, NNX11A043G, and NNX14AQ89G, and NSF grants AST-0808050 and AST-1109911. TH was supported by the Academy of Finland projects 317383 and 320085. AZT-24 observations were made within an agreement between Pulkovo, Rome and Teramo observatories. The Submillimeter Array is a joint project between the Smithsonian Astrophysical Observatory and the Academia Sinica Institute of Astronomy and Astrophysics and is funded by the Smithsonian Institution and the Academia Sinica. The Abastumani team acknowledges financial support by the Shota Rustaveli National Science Foundation under contract FR/217950/16. r This research was partially supported by the Bulgarian National Science Fund of the Ministry of Education and Science under grants DN 081/2016, DN 18-13/2017, KP-06-H28/3 (2018), and KP-06-PN38/1 (2019), Bulgarian National Science Programme 'Young Scientists and Postdoctoral Students 2019', Bulgarian National Science Fund under grant DN18-10/2017 and National RI Roadmap Projects DO1-157/28.08.2018 and DO1-153/28.08.2018 of the Ministry of Education and Science of the Republic of Bulgaria. GD and OV gratefully acknowledge observing grant support from the Institute of Astronomy and Rozhen National Astronomical Observatory via bilateral joint research project `Study of ICRF radio-sources and fast variable astronomical objects' (head -G. Damljanovic). This work was partly supported by the National Science Fund of the Ministry of Education and Science of Bulgaria under grant DN 08-20/2016, and by project RD-08-37/2019 of the University of Shumen. This work is a part of projects nos 176011, 176004, and 176021, supported by theMinistry of Education, Science and Technological Development of the Republic of Serbia. MGM acknowledges support through the Russian Government Program of Competitive Growth of Kazan Federal University. The Astronomical Observatory of the Autonomous Region of the Aosta Valley (OAVdA) is managed by the Fondazione Clement Fillietroz-ONLUS, which is supported by the Regional Government of the Aosta Valley, the Town Municipality of Nus and the 'Unite des Communes vald 'otainesMont-Emilius'. The research at the OAVdA was partially funded by several `Research and Education' annual grants from Fondazione CRT. This article is partly based on observations made with the IAC80 and TCS telescopes operated by the Instituto de Astrofisica de Canarias in the Spanish Observatorio del Teide on the island of Tenerife. A part of the observations were carried out using theRATAN-600 scientific equipment (SAO of the Russian Academy of Sciences)

A MISSING-LINK IN THE SUPERNOVA-GRB CONNECTION: THE CASE OF SN 2012ap

Gamma Ray Bursts (GRBs) are characterized by ultra-relativistic outflows, while supernovae are generally characterized by non-relativistic ejecta. GRB afterglows decelerate rapidly usually within days, because their low-mass ejecta rapidly sweep up a comparatively larger mass of circumstellar material. However supernovae, with heavy ejecta, can be in nearly free expansion for centuries. Supernovae were thought to have non-relativistic outflows except for few relativistic ones accompanied by GRBs. This clear division was blurred by SN 2009bb, the first supernova with a relativistic outflow without an observed GRB. Yet the ejecta from SN 2009bb was baryon loaded, and in nearly-free expansion for a year, unlike GRBs. We report the first supernova discovered without a GRB, but with rapidly decelerating mildly relativistic ejecta, SN 2012ap. We discovered a bright and rapidly evolving radio counterpart driven by the circumstellar interaction of the relativistic ejecta. However, we did not find any coincident GRB with an isotropic fluence of more than a sixth of the fluence from GRB 980425. This shows for the first time that central engines in type Ic supernovae, even without an observed GRB, can produce both relativistic and rapidly decelerating outflows like GRBs.Comment: 8 pages, 5 figures, 1 table, accepted for publication in Ap

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