Theory of traveling filaments in bistable semiconductor structures

We present a generic nonlinear model for current filamentation in semiconductor structures with S-shaped current-voltage characteristics. The model accounts for Joule self-heating of a current density filament. It is shown that the self-heating leads to a bifurcation from static to traveling filament. Filaments start to travel when increase of the lattice temperature has negative impact on the cathode-anode transport. Since the impact ionization rate decreases with temperature, this occurs for a wide class of semiconductor systems whose bistability is due to the avalanche impact ionization. We develop an analytical theory of traveling filaments which reveals the mechanism of filament motion, find the condition for bifurcation to traveling filament, and determine the filament velocity.Comment: 13 pages, 5 figure

Breathing Current Domains in Globally Coupled Electrochemical Systems: A Comparison with a Semiconductor Model

Spatio-temporal bifurcations and complex dynamics in globally coupled intrinsically bistable electrochemical systems with an S-shaped current-voltage characteristic under galvanostatic control are studied theoretically on a one-dimensional domain. The results are compared with the dynamics and the bifurcation scenarios occurring in a closely related model which describes pattern formation in semiconductors. Under galvanostatic control both systems are unstable with respect to the formation of stationary large amplitude current domains. The current domains as well as the homogeneous steady state exhibit oscillatory instabilities for slow dynamics of the potential drop across the double layer, or across the semiconductor device, respectively. The interplay of the different instabilities leads to complex spatio-temporal behavior. We find breathing current domains and chaotic spatio-temporal dynamics in the electrochemical system. Comparing these findings with the results obtained earlier for the semiconductor system, we outline bifurcation scenarios leading to complex dynamics in globally coupled bistable systems with subcritical spatial bifurcations.Comment: 13 pages, 11 figures, 70 references, RevTex4 accepted by PRE http://pre.aps.or

Исследование противовирусной активности рекомбинантного интерлейкина-7 человека на разных моделях экспериментальной вирусной инфекции гепатита С

Проблематика. Інтерлейкін-7 (ІЛ-7) є одним із найважливіших регуляторних цитокінів імунної системи. З урахуванням здатності ІЛ-7 до модуляції Т- і В-клітинної відповіді і Т-клітинного гомеостазу можливо припустити, що препарати ІЛ-7 мають властивість не лише впливати на формування специфічного імунітету та імунодефіцитного стану, а й інгібувати репродукцію вірусів, зокрема вірусу гепатиту С (ВГС). Мета дослідження. Вивчення антивірусної дії рекомбінантного ІЛ-7 людини (рІЛ-7) на моделях експериментальної вірусної інфекції гепатиту С in vitro на чутливих до вірусу епітеліальних і лімфоїдних клітинах. Методика реалізації. У роботі використовували перещеплювані культури клітин: Jurkat, невриноми вузла Гассера щура та нирки бика. Як сурогатний ВГС використовували вірус бичачої вірусної діареї. Для вивчення антивірусної активності рІЛ-7 у різних концентраціях вводили в культуру клітин, яка продукує ВГС, та визначали вірусне навантаження. Проводили також цитологічний аналіз впливу рІЛ-7 на клітини та визначення їх проліферативної активності. Результати дослідження. Було показано, що рІЛ-7 інгібує репродукцію сурогатного ВГС в умовах in vitro (СС₅₀ – 3 мкг/мл, ED₅₀ – 4,7 нг/мл, IS – 640). Найвища проліферація інтактних Т-клітин визначається при дозах рІЛ-7 0,3 і 0,025 мкг/мл. рІЛ-7 по-різному впливав на інфіковані ВГС культури: в перші 3 доби кількість клітин зменшувалася або не змінювалася, а через 2–3 тижні – збільшувалася майже в 2 рази. При введенні рІЛ-7 в дозі 6 мкг/мл упродовж 3 діб на 3-тю добу інгібування вірусного навантаження становило 89 %, а на 4-ту добу – 100 %; при використанні дози рІЛ-7 0,3 мкг/мл інгібіція на 4-ту добу становила 100 %; при використанні дози рІЛ-7 1,5 мкг/мл – на 55 % на 4-ту добу. Висновки. У результаті проведених досліджень з визначення впливу рІЛ-7 на репродукцію сурогатного ВГС показано, що рІЛ-7 ефективно інгібує репродукцію вірусу.Background. Interleukin-7 (IL-7) is one of the most important regulatory cytokine of immune system. Given the ability of IL-7 to the modulation of T- and B-cell responses and T-cell homeostasis we may assume that IL-7 not only has the ability to influence the formation of specific immunity and immunodeficiency state, but also inhibit the reproduction of viruses, including hepatitis C virus (HCV). Objective. Study of antiviral activity of recombinant human IL-7 (rIL-7) with experimental models of viral hepatitis C infection in vitro on sensitive virus epithelial and lymphoid cells. Methods. We have used the following inoculated cell cultures: Jurkat, rat neurinoma of gasserian ganglion and bovine kidney. As used surrogate HCV we used virus of bovine diarrhea. To study the antiviral activity different concentrations of rIL-7 were injected into the cell culture, producing HCV, and determined virus load. Also we have performed cytological analysis of cells and determined its proliferative activity under influence of rIL-7.Results. It has been shown that rIL-7 inhibits surrogate HCV reproduction in in vitro conditions (SS₅₀ – 3 mg/ml, ED₅₀ – 4.7 ng/ml, IS – 640). Highest proliferation of intact T-cells is determined at rIL-7 doses 0.3 mg/m and 0.025 mg/ml. rIL-7 affected HCV infected cells differently: during the first 3 days the number of cells decreased or did not change, and after 2–3 weeks the number of cells increased almost 2 times. When we injected rIL-7 with dose of 6 mg/ml within3 days we obtained 89% viral inhibition at the 3rdday and 100 % at the 4th day; using the dose of rIL-7 0.3 mg/ml the inhibition on the 4thday was 100 %; using dose of rIL-7 1.5 mg/ml the inhibition settled at 55 % for 4 days. Conclusions. As a result of the studies directed towards determining the effect of rIL-7 on surrogate HCV reproduction, HCV cDNA producing transfected human T-cells Jurkat, it was showed that rIL-7 effectively inhibits virus reproduction.Проблематика. Интерлейкин-7 (ИЛ-7) является одним из важнейших регуляторных цитокинов иммунной системы. C учетом способности ИЛ-7 к модуляции Т- и В-клеточного ответа и Т-клеточного гомеостаза возможно предположить, что препараты ИЛ-7 имеют свойство не только влиять на формирование специфического иммунитета и иммунодефицита, но и ингибировать репродукцию вирусов, в частности вируса гепатита С (ВГС).Цель исследования. Изучение антивирусного действия рекомбинантного ИЛ-7 человека (рИЛ-7) на моделях экспериментальной вирусной инфекции гепатита С in vitro на чувствительных к вирусу эпителиальных и лимфоидных клетках. Методика реализации. В работе использовали перевиваемые культуры клеток: Jurkat, невриномы узла Гассера крысы и почки быка. В качестве суррогатного ВГС использовали вирус бычьей вирусной диареи. Для изучения антивирусной активности рИЛ-7 в различных концентрациях вводили в культуру клеток, продуцирующих ВГС, и определяли вирусную нагрузку. Проводили также цитологический анализ влияния рИЛ-7 на клетки и определяли их пролиферативную активность. Результаты исследования. Было показано, что рИЛ-7 ингибирует репродукцию суррогатного ВГС в условиях in vitro (СС₅₀ – 3 мкг/мл, ED₅₀ – 4,7 нг/мл, IS – 640). Самая высокая пролиферация интактных Т-клеток определялась при дозах рИЛ-7 0,3 мкг/мг и 0,025 мкг/мл. рИЛ-7 по-разному влиял на инфицированные ВГС культуры: в первые 3 суток количество клеток уменьшалось или не менялось, а через 2–3 недели количество клеток увеличивалось почти в 2 раза. При введении рИЛ-7 в дозе 6 мкг/мл в течение 3 суток на 3-е сутки ингибирование вирусной нагрузки составляло 89 %, а на 4-е сутки – 100 %; при использовании дозы рИЛ-7 0,3 мкг/мл ингибирование на 4 сутки составило 100 %; при использовании дозы рИЛ-7 1,5 мкг/мл – на 55 % на 4-е сутки. Выводы. В результате проведенных исследований по определению влияния рИЛ-7 на репродукцию суррогатного ВГС показано, что рИЛ-7 эффективно ингибирует репродукцию вируса

Protein inactivation in mycobacteria by controlled proteolysis and its application to deplete the beta subunit of RNA polymerase

Using a component of the Escherichia coli protein degradation machinery, we have established a system to regulate protein stability in mycobacteria. A protein tag derived from the E. coli SsrA degradation signal did not affect several reporter proteins in wild-type Mycobacterium smegmatis or Mycobacterium tuberculosis. Expression of the adaptor protein SspB, which recognizes this modified tag and helps deliver tagged proteins to the protease ClpXP, strongly decreased the activities and protein levels of different reporters. This inactivation did not occur when the function of ClpX was inhibited. Using this system, we constructed a conditional M. smegmatis knockdown mutant in which addition of anhydrotetracycline (atc) caused depletion of the beta subunit of RNA polymerase, RpoB. The impact of atc on this mutant was dose-dependent. Very low amounts of atc did not prevent growth but increased sensitivity to an antibiotic that inactivates RpoB. Intermediate amounts of RpoB knockdown resulted in bacteriostasis and a more substantial depletion led to a decrease in viability by up to 99%. These studies identify SspB-mediated proteolysis as an efficient approach to conditionally inactivate essential proteins in mycobacteria. They further demonstrate that depletion of RpoB by ∼93% is sufficient to cause death of M. smegmatis

Rescue of Photoreceptor Degeneration by Curcumin in Transgenic Rats with P23H Rhodopsin Mutation

The P23H mutation in the rhodopsin gene causes rhodopsin misfolding, altered trafficking and formation of insoluble aggregates leading to photoreceptor degeneration and autosomal dominant retinitis pigmentosa (RP). There are no effective therapies to treat this condition. Compounds that enhance dissociation of protein aggregates may be of value in developing new treatments for such diseases. Anti-protein aggregating activity of curcumin has been reported earlier. In this study we present that treatment of COS-7 cells expressing mutant rhodopsin with curcumin results in dissociation of mutant protein aggregates and decreases endoplasmic reticulum stress. Furthermore we demonstrate that administration of curcumin to P23H-rhodopsin transgenic rats improves retinal morphology, physiology, gene expression and localization of rhodopsin. Our findings indicate that supplementation of curcumin improves retinal structure and function in P23H-rhodopsin transgenic rats. This data also suggest that curcumin may serve as a potential therapeutic agent in treating RP due to the P23H rhodopsin mutation and perhaps other degenerative diseases caused by protein trafficking defects

Progressive Neurodegeneration or Endogenous Compensation in an Animal Model of Parkinson's Disease Produced by Decreasing Doses of Alpha-Synuclein

The pathological hallmarks of Parkinson's disease (PD) are degeneration of dopamine (DA) neurons of the substantia nigra (SN) and the presence of alpha-synuclein (α-syn)-rich Lewy bodies in DA cells that remain. To model these aspects of the disease, we previously showed that high titer (5.1×10exp12 gp/ml) AAV1/2 driven expression of A53T α-syn in the SN of rats caused nigrostriatal pathology including a loss of DA neurons, but also with toxicity in the GFP control group. In the current study, we evaluate the effects of two lower titers by dilution of the vector (1∶3 [1.7×10exp12] and 1∶10 [5.1×10exp11]) to define a concentration that produced pathology specific for α-syn. In GFP and empty vector groups there were no behavioural or post-mortem changes at 3 or 6 weeks post-administration at either vector dose. Dilution of the AAV1/2 A53T α-syn (1∶3) produced significant paw use asymmetry, reductions in striatal tyrosine hydroxylase (TH), and increases in DA turnover at 3 weeks in the absence of overt pathology. By 6 weeks greater evidence of pathology was observed and included, reductions in SN DA neurons, striatal DA, TH and DA-transporter, along with a sustained behavioural deficit. In contrast, the 1∶10 AAV1/2 A53T α-syn treated animals showed normalization between 3 and 6 weeks in paw use asymmetry, reductions in striatal TH, and increased DA turnover. Progression of dopaminergic deficits using the 1∶3 titer of AAV1/2 A53Tα-syn provides a platform for evaluating treatments directed at preventing and/or reversing synucleinopathy. Use of the 1∶10 titer of AAV1/2 A53T α-syn provides an opportunity to study mechanisms of endogenous compensation. Furthermore, these data highlight the need to characterize the titer of vector being utilized, when using AAV to express pathogenic proteins and model disease process, to avoid producing non-specific effects

Identification of Allele-Specific RNAi Effectors Targeting Genetic Forms of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurological disorder affecting an estimated 5–10 million people worldwide. Recent evidence has implicated several genes that directly cause or increase susceptibility to PD. As well as advancing understanding of the genetic aetiology of PD these findings suggest new ways to modify the disease course, in some cases through genetic manipulation. Here we generated a ‘walk-through’ series of RNA Pol III-expressed shRNAs targeting both the α-synuclein A30P and LRRK2 G2019S PD-associated mutations. Allele-specific discrimination of the α-synuclein A30P mutation was achieved with alignments at position 10, 13 and 14 in two model systems, including a heterozygous model mimicking the disease setting, whilst 5′RACE was used to confirm stated alignments. Discrimination of the most common PD-linked LRRK2 G2019S mutation was assessed in hemizygous dual-luciferase assays and showed that alignment of the mutation opposite position 4 of the antisense species produced robust discrimination of alleles at all time points studied. Discrimination at this position was subsequently confirmed using siRNAs, where up to 10-fold discrimination was seen. The results suggest that RNAi-mediated silencing of PD-associated autosomal dominant genes could be a novel therapeutic approach for the treatment of the relevant clinical cases of PD in future