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In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.
Transition point prediction in a multicomponent lattice Boltzmann model: Forcing scheme dependencies
(2018)
Companies investing in the occupied Palestinian territories are faced with a dilemma. Undoubtedly, the creation of jobs helps to put young Palestinians to work. Experience shows that especially young males are less likely to radicalise and commit crimes when having an occupation. However, negative press coverage due to the disputed status of the territory can force companies to withdraw. CSR activities can help to demonstrate that a company has a genuine interest in its employees and community at large. Our article looks into one particular case of an Israeli company that had to withdraw their operation due to public pressure, mainly Western media. We give recommendations how such failure could have been avoided by using the right kind of CSR activities that address the needs of the Palestinians.
One of the main aims of current social robotic research is to improve the robots’ abilities to interact with humans. In order to achieve an interaction similar to that among humans, robots should be able to communicate in an intuitive and natural way and appropriately interpret human affects during social interactions. Similarly to how humans are able to recognize emotions in other humans, machines are capable of extracting information from the various ways humans convey emotions-including facial expression, speech, gesture or text-and using this information for improved human computer interaction. This can be described as Affective Computing, an interdisciplinary field that expands into otherwise unrelated fields like psychology and cognitive science and involves the research and development of systems that can recognize and interpret human affects. To leverage these emotional capabilities by embedding them in humanoid robots is the foundation of the concept Affective Robots, which has the objective of making robots capable of sensing the user’s current mood and personality traits and adapt their behavior in the most appropriate manner based on that. In this paper, the emotion recognition capabilities of the humanoid robot Pepper are experimentally explored, based on the facial expressions for the so-called basic emotions, as well as how it performs in contrast to other state-of-the-art approaches with both expression databases compiled in academic environments and real subjects showing posed expressions as well as spontaneous emotional reactions. The experiments’ results show that the detection accuracy amongst the evaluated approaches differs substantially. The introduced experiments offer a general structure and approach for conducting such experimental evaluations. The paper further suggests that the most meaningful results are obtained by conducting experiments with real subjects expressing the emotions as spontaneous reactions.
Here, we present a miR mechanism which is active in the nucleus and is essential for the production of intron included, C-terminal truncated and biologically active proteins, like e.g. Vim3. We exemplified this mechanism by miRs, miR-15a and miR-498, which are overexpressed in clear cell renal carcinoma or oncocytoma. Both miRs directly interact with DNA in an intronic region, leading to transcriptional stop, and therefore repress the full length version of the pre-mRNA, resulting in intron included truncated proteins (Mxi-2 and Vim3). A computational survey shows that this miR:DNA interactions mechanism may be generally involved in regulating the human transcriptome, with putative interaction sites in intronic regions for over 1000 genes. In this work, an entirely new mechanism is revealed how miRs can repress full length protein translation, resulting in C-terminal truncated proteins.
Bei Thymian (Thymus vulgaris) handelt es sich um eine sehr varietätenreiche Art, die aufgrund ihres Gehaltes an therapeutisch wirksamen Inhaltsstoffen als Arzneipflanze monographiert ist. Insbesondere das ätherische Öl mit dem Hauptbestandteil Thymol (ca. 50%) hat eine hohe antioxidative Wirkung. Ziel ist es, dieses Potential als nachhaltig produzierte Additive zu nutzen. Hierfür eignen sich antioxidativ bzw. antimikrobiell wirksame sowie UV-absorbierende Substanzen, die das Produkt bei Zusatz vor oxidativem Stress, mikrobiellem Abbau und Qualitätsverlust schützen.
Hierzu werden zunächst sechs Varianten auf verschiedene Parameter analysiert, um die potenteste Variante auszuwählen. Auf diese Variante wird sich die weitere Forschung konzentrieren.
Daher wird das ätherische Öl durch azeotrope Destillation extrahiert und mittels GCMS analysiert. In Extrakten werden zudem das AP und Absorptionsverhalten bestimmt. Auch die chemische Zusammensetzung des Extrakts sowie die flüchtigen Stoffe des Thymians werden untersucht. Generell gibt es wenig qualitative, teilweise jedoch quantitative Unterschiede: Eine Variante weist u.a. einen deutlich höheren Thymolgehalt im Öl (ca. 65 %) und ein hohes hydrophiles AP auf. Somit ist eine vielversprechende Variante für die weitere Entwicklung und Optimierung bioaktiver Additive gefunden.
Through the “Act to Strengthen the Non-financial Reporting by Corporations in their Management and Group Management Reports” (Gesetz zur Stärkung der nichtfinanziellen Berichterstattung der Unternehmen in ihren Lage- und Konzernlageberichten) (CSR Directive Transposition Act, „CSR-RUG“) of 11 April 2017[1], the German Bundestag implemented Directive 2014/95/EU (“CSR Directive”)[2] into German law. Following the European impetus, the CSR-RUG enriches the traditional repertoire of forms of action under environmental law by a further instrument. Already the regulatory context gives an idea of its atypical nature: The centrepiece of the CSR-RUG is the amendment of and addition to the Third Book of the German Commercial Code (Handelsgesetzbuch, “HGB”), which deals with the “trading books” of undertakings, i.e., accounting and reporting requirements. Since the reporting year 2017, large capital market-oriented corporations must report extensively within the framework of their annual management reports on their activities and effects in certain areas of “Corporate Social Responsibility”. This also includes environmental matters. The transparency and publicity this entails is intended to generate positive stimuli for more responsible, sustained and not least of all environmentally friendly entrepreneurial action.
Following a brief presentation of the European legal bases and their implementation in Germany (I.), we will classify the provisions within the underlying concept of Corporate Social Responsibility (II.) and analyse and systemise the governance effects of non-financial reporting (III.). A few remarks on selected aspects of the chosen approach and its implementation (IV.) as well as an outlook summarising our conclusions (V.) will complete this article. By detailing the German approach to transposing the CSR Directive, this paper intends to provide an example of the challenges member state legislators face when complying with modern governance concepts such as Corporate Social Responsibility by way of non-financial reporting obligations.
[1] Federal Law Gazette, Part I 2017, 802 et seq.
[2] Directive 2014/95/EU of the European Parliament and of the Council 22 October 2014 amending Directive 2013/34/EU as regards disclosure of non-financial and diversity information by certain large undertakings and groups, OJ EU No. L 330, p. 1.
Design and Analysis of an OFDM-Based Orthogonal Chaotic Vector Shift Keying Communication System
(2018)
We propose a new non-coherent multicarrier spread-spectrum system that combines orthogonal chaotic vector shift keying (OCVSK) and orthogonal frequency-division multiplexing (OFDM). The system enhances OCVSK by sending multiple groups of information sequences with the same orthogonal chaotic vector reference sequences over the selected subcarriers. Each group carries M information bits and is separated from other groups by orthogonal chaotic reference signals. We derive the information rate enhancement (IRE) and the energy saving enhancement (ESE) factors as well as the bit error rate theory of OFDM-OCVSK under additive white Gaussian noise and multipath Rayleigh fading channels and compare the results with conventional OCVSK systems. For large group numbers, the results show that the IRE and ESE factors approachM×100% andM/(M+1)×100%, respectively, and thus outperform OCVSK systems. The complexity analysis of the proposed scheme as compared with OFDM-DCSK shows a significant reduction in the number of complex multiplications required.
After replanting apple (Malus domestica Borkh.) on the same site severe growth suppressions, and a decline in yield and fruit quality are observed in all apple producing areas worldwide. The causes of this complex phenomenon, called apple replant disease (ARD), are only poorly understood up to now which is in part due to inconsistencies in terms and methodologies. Therefore we suggest the following definition for ARD: ARD describes a harmfully disturbed physiological and morphological reaction of apple plants to soils that faced alterations in their (micro-) biome due to the previous apple cultures. The underlying interactions likely have multiple causes that extend beyond common analytical tools in microbial ecology. They are influenced by soil properties, faunal vectors, and trophic cascades, with genotype-specific effects on plant secondary metabolism, particularly phytoalexin biosynthesis. Yet, emerging tools allow to unravel the soil and rhizosphere (micro-) biome, to characterize alterations of habitat quality, and to decipher the plant reactions. Thereby, deep insights into the reactions taking place at the root rhizosphere interface will be gained. Counteractions are suggested, taking into account that culture management should emphasize on improving soil microbial and faunal diversity as well as habitat quality rather than focus on soil disinfection.
The elucidation of conformations and relative potential energies (rPEs) of small molecules has a long history across a diverse range of fields. Periodically, it is helpful to revisit what conformations have been investigated and to provide a consistent theoretical framework for which clear comparisons can be made. In this paper, we compute the minima, first- and second-order saddle points, and torsion-coupled surfaces for methanol, ethanol, propan-2-ol, and propanol using consistent high-level MP2 and CCSD(T) methods. While for certain molecules more rigorous methods were employed, the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pV5Z theory level was used throughout to provide relative energies of all minima and first-order saddle points. The rPE surfaces were uniformly computed at the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ level. To the best of our knowledge, this represents the most extensive study for alcohols of this kind, revealing some new aspects. Especially for propanol, we report several new conformations that were previously not investigated. Moreover, two metrics are included in our analysis that quantify how the selected surfaces are similar to one another and hence improve our understanding of the relationship between these alcohols.
Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.
The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research.
We present the performance of the upGREAT heterodyne array receivers on the SOFIA telescope after several years of operations. This instrument is a multi-pixel high resolution (R≳107) spectrometer for the Stratospheric Observatory for Far-Infrared Astronomy (SOFIA). The receivers use 7-pixel subarrays configured in a hexagonal layout around a central pixel. The low frequency array receiver (LFA) has 2×7 pixels (dual polarization), and presently covers the 1.83–2.07THz frequency range, which allows to observe the [CII] and [OI] lines at 158μm and 145μm wavelengths. The high frequency array (HFA) covers the [OI] line at 63μm and is equipped with one polarization at the moment (7 pixels, which can be upgraded in the near future with a second polarization array). The 4.7THz array has successfully flown using two separate quantum-cascade laser local oscillators from two different groups. NASA completed the development, integration and testing of a dual-channel closed-cycle cryocooler system, with two independently operable He compressors, aboard SOFIA in early 2017 and since then, both arrays can be operated in parallel using a frequency separating dichroic mirror. This configuration is now the prime GREAT configuration and has been added to SOFIA’s instrument suite since observing cycle 6.
Females are influenced more than males by visual cues during many spatial orientation tasks; but females rely more heavily on gravitational cues during visual-vestibular conflict. Are there gender biases in the relative contributions of vision, gravity and the internal representation of the body to the perception of upright? And might any such biases be affected by low gravity? 16 participants (8 female) viewed a highly polarized visual scene tilted ±112° while lying supine on the European Space Agency's short-arm human centrifuge. The centrifuge was rotated to simulate 24 logarithmically spaced g-levels along the long axis of the body (0.04-0.5g at ear-level). The perception of upright was measured using the Oriented Character Recognition Test (OCHART). OCHART uses the ambiguous symbol "p" shown in different orientations. Participants decided whether it was a "p" or a "d" from which the perceptual upright (PU) can be calculated for each visual/gravity combination. The relative contribution of vision, gravity and the internal representation of the body were then calculated. Experiments were repeated while upright. The relative contribution of vision on the PU was less in females compared to males (t=-18.48, p≤0.01). Females placed more emphasis on the gravity cue instead (f:28.4%, m:24.9%) while body weightings were constant (f:63.0%, m:63.2%). When upright (1g) in this and other studies (e.g., Barnett-Cowan et al. 2010, EJN, 31,1899) females placed more emphasis on vision in this task than males. The reduction in weight allocated by females to vision when in simulated low-gravity conditions compared to when upright under normal gravity may be related to similar female behaviour in response to other instances of visual-vestibular conflict. Why this is the case and at which point the perceptual change happens requires further research.
Analytical redundancy relations are fundamental in model-based fault detection and isolation. Their numerical evaluation yields a residual that may serve as a fault indicator. Considering switching linear time-invariant system models that use ideal switches, it is shown that analytical redundancy relations can be systematically deduced from a diagnostic bond graph with fixed causalities that hold for all modes of operation. Moreover, as to a faultless system, the presented bond graph–based approach enables to deduce a unique implicit state equation with coefficients that are functions of the discrete switch states. Devices or phenomena with fast state transitions, for example, electronic diodes and transistors, clutches, or hard mechanical stops are often represented by ideal switches which give rise to variable causalities. However, in the presented approach, fixed causalities are assigned only once to a diagnostic bond graph. That is, causal strokes at switch ports in the diagnostic bond graph reflect only the switch-state configuration in a specific system mode. The actual discrete switch states are implicitly taken into account by the discrete values of the switch moduli. The presented approach starts from a diagnostic bond graph with fixed causalities and from a partitioning of the bond graph junction structure and systematically deduces a set of equations that determines the wanted residuals. Elimination steps result in analytical redundancy relations in which the states of the storage elements and the outputs of the ideal switches are unknowns. For the later two unknowns, the approach produces an implicit differential algebraic equations system. For illustration of the general matrix-based approach, an electromechanical system and two small electronic circuits are considered. Their equations are directly derived from a diagnostic bond graph by following causal paths and are reformulated so that they conform with the matrix equations obtained by the formal approach based on a partitioning of the bond graph junction structure. For one of the three mode-switching examples, a fault scenario has been simulated.