Surface of underdoped YBa2Cu3O7- δ as revealed by STM/STS

We performed scanning tunneling microscopy and spectroscopy on untwinned crystals of underdoped YBa2Cu3O7- δ at δ = 0.4. A comprehensive statistical analysis of our topographic data indicates a doping dependent cleaving behavior of this material. We find in particular that at δ = 0.4 the material primarily cleaves in multiples of one unit cell along the c-axis with a high corrugation of the topmost layer. Our data suggest that the low temperature cleaving mainly results in a disruption of the CuO chain layers involving a redistribution of the layer atoms onto the two cleaving planes. In a few instances, fractional step heights (in terms of the c-axis lattice constant) are observed as well. Scanning tunneling spectroscopy reveals that such fractional steps connect surfaces which differ significantly in their tunneling conductance

Interleukin 15 Primes Natural Killer Cells to Kill via NKG2D and cPLA2 and This Pathway Is Active in Psoriatic Arthritis

NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase.</p

Interleukin 15 Primes Natural Killer Cells to Kill via NKG2D and cPLA2 and This Pathway Is Active in Psoriatic Arthritis

NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase

Restoration of Normal NF1 Function with Antisense Morpholino Treatment of Recurrent Pathogenic Patient-Specific Variant c.1466A&gt;G; p.Y489C

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with almost 3000 different disease-causing variants within the NF1 gene identified. Up to 44% of these variants cause splicing errors to occur within pre-mRNA. A recurrent variant in exon 13, c.1466A>G; p.Y489C (Y489C) results in the creation of an intragenic cryptic splice site, aberrant splicing, a 62 base pair deletion from the mRNA, and subsequent frameshift. We investigated the ability of phosphorodiamidate morpholino oligomers (PMOs) to mask this variant on the RNA level, thus restoring normal splicing. To model this variant, we have developed a human iPS cell line homozygous for the variant using CRISPR/Cas9. PMOs were designed to be 25 base pairs long, and to cover the mutation site so it could not be read by splicing machinery. Results from our in vitro testing showed restoration of normal splicing in the RNA and restoration of full length neurofibromin protein. In addition, we observe the restoration of neurofibromin functionality through GTP-Ras and pERK/ERK testing. The results from this study demonstrate the ability of a PMO to correct splicing errors in NF1 variants at the RNA level, which could open the door for splicing corrections for other variants in this and a variety of diseases

Structural Aspect of Formation of a Nanosystem of In/In₄Se₃ (100)

Self-assembled indium deposition-induced nanostructures are obtained on the UHV cleaved (100) surface of In₄Se₃ layered semiconductor crystals. The small indium-deposition rates and short deposition times are chosen to study growth orientation and origin of nanostructures observed by scanning tunnelling microscopy (STM) on the (100) surface of In₄Se₃ after indium deposition. The shape of these nanostructures strictly depends on the overstoichiometric indium concentration level in the melt during the crystal growth varying from 3D islands for low concentration to elongated shapes, i.e., nanowires, in the case of highly-indium-doped crystals. High-resolution STM study determines the self-assembled quasi-periodical nanowires’ growth along c-axis of (100)In₄Se₃ substrate. The spatially resolved scanning tunnelling spectroscopy (STS) study revealed metallic nature of the surface of nanostructures grown on the semiconductor substrate. The growth mechanism of indium-deposited nanostructures is considered to be powered by anisotropic striated lattice structure of In₄Se₃ (100) surface with indium nucleiin concentration depending on the degree of overstoichiometric crystal-growth indium subsequently intercalated into the interlayer gap.Самоорганизованные индиевые наноструктуры получены на сверхвысоковакуумной поверхности скалывания (100) полупроводникового слоистого кристалла In₄Se₃. Небольшие скорости и длительности напыления индия использовались с целью исследования ростовой ориентации и природы наноструктур на поверхности (100)In₄Se₃, которые изучались с помощью сканирующей туннельной микроскопии (СТМ). Форма этих наноструктур непосредственно зависит от концентрации сверхстехиометрического индия в расплаве во время роста кристалла, изменяясь от трёхмерных островков при низкой концентрации до линейных форм, т.е. нанопроводов, в случае сильно легированных индием кристаллов. СТМ з высоким разрешением позволяет установить, что квазипериодические нанопровода растут вдоль оси c кристалла In₄Se₃ на поверхности (100). С помощью сканирующей туннельной спектроскопии с пространственным разрешением установлена металлическая природа поверхностных наноструктур на полупроводниковой подкладке. Установлено, что механизм роста напылённых наноструктур обусловлен бороздчатой структурой решётки на поверхности (100) кристалла In₄Se₃ с наличием в ней зародышей индия в концентрации, зависящей от количества сверхстехиометрического ростового индия, который интеркалируется в межслоевую щель.Самоорганізовані індійові наноструктури одержано на надвисоковакуумній поверхні сколювання (100) напівпровідникового шаруватого кристалу In₄Se₃. Невеликі швидкості та тривалості напорошення індію вибиралися з метою дослідження ростової орієнтації та природи наноструктур на поверхні (100)In₄Se₃, які вивчали за допомогою сканувальної тунельної мікроскопії (СТМ). Форма цих наноструктур безпосередньо залежить від концентрації надстехіометричного індію в розтопі під час вирощування кристалу, змінюючись від тривимірних острівців за низької концентрації до лінійних форм, тобто нанодротів, у випадку сильно леґованих індієм кристалів. СТМ з високим розріжненням уможливлює встановити, що квазиперіодичні нанодроти ростуть вздовж осі c кристалу In₄Se₃ на поверхні (100). За допомогою сканувальної тунельної спектроскопії з просторовим розріжненням встановлено металічну природу поверхневих наноструктур на напівпровідниковій підкладинці. Встановлено, що механізм росту напорошених наноструктур зумовлений борознистою структурою ґратниці на поверхні (100) кристалу In₄Se₃ з наявністю у ній зародків індію у концентрації, яка залежить від кількости надстехіометричного ростового індію, що інтеркалюється у міжшарову щілину

Reprogramming of CTLs into natural killer–like cells in celiac disease

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon γ–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases

From conformons to human brains: an informal overview of nonlinear dynamics and its applications in biomedicine

Methods of contemporary physics are increasingly important for biomedical research but, for a multitude of diverse reasons, most practitioners of biomedicine lack access to a comprehensive knowledge of these modern methodologies. This paper is an attempt to describe nonlinear dynamics and its methods in a way that could be read and understood by biomedical professionals who usually are not trained in advanced mathematics. After an overview of basic concepts and vocabulary of nonlinear dynamics, deterministic chaos, and fractals, application of nonlinear methods of biosignal analysis is discussed. In particular, five case studies are presented: 1. Monitoring the depth of anaesthesia and of sedation; 2. Bright Light Therapy and Seasonal Affective Disorder; 3. Analysis of posturographic signals; 4. Evoked EEG and photo-stimulation; 5. Influence of electromagnetic fields generated by cellular phones

The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF-κB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6-specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL-4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells