Features of financing of small business and microenterprises

In this article, we examined the specifics of financing small businesses and microenterprises

Torsional Force Microscopy of Van der Waals Moir\'es and Atomic Lattices

In a stack of atomically-thin Van der Waals layers, introducing interlayer twist creates a moir\'e superlattice whose period is a function of twist angle. Changes in that twist angle of even hundredths of a degree can dramatically transform the system's electronic properties. Setting a precise and uniform twist angle for a stack remains difficult, hence determining that twist angle and mapping its spatial variation is very important. Techniques have emerged to do this by imaging the moir\'e, but most of these require sophisticated infrastructure, time-consuming sample preparation beyond stack synthesis, or both. In this work, we show that Torsional Force Microscopy (TFM), a scanning probe technique sensitive to dynamic friction, can reveal surface and shallow subsurface structure of Van der Waals stacks on multiple length scales: the moir\'es formed between bilayers of graphene and between graphene and hexagonal boron nitride (hBN), and also the atomic crystal lattices of graphene and hBN. In TFM, torsional motion of an AFM cantilever is monitored as the it is actively driven at a torsional resonance while a feedback loop maintains contact at a set force with the surface of a sample. TFM works at room temperature in air, with no need for an electrical bias between the tip and the sample, making it applicable to a wide array of samples. It should enable determination of precise structural information including twist angles and strain in moir\'e superlattices and crystallographic orientation of VdW flakes to support predictable moir\'e heterostructure fabrication.Comment: 28 pages, 14 figures including supplementary material

BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance

<p>Abstract</p> <p>Background</p> <p>The <it>BCR-ABL1 </it>translocation occurs in chronic myeloid leukemia (CML) and in 25% of cases with acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKI) has fundamentally changed the treatment of CML. However, TKI are not equally effective for treating ALL. Furthermore, <it>de novo </it>or <it>secondary </it>TKI-resistance is a significant problem in CML. We screened a panel of <it>BCR-ABL1 </it>positive ALL and CML cell lines to find models for imatinib-resistance.</p> <p>Results</p> <p>Five of 19 <it>BCR-ABL1 </it>positive cell lines were resistant to imatinib-induced apoptosis (KCL-22, MHH-TALL1, NALM-1, SD-1, SUP-B15). None of the resistant cell lines carried mutations in the kinase domain of <it>BCR-ABL1 </it>and all showed resistance to second generation TKI, nilotinib or dasatinib. STAT5, ERK1/2 and the ribosomal S6 protein (RPS6) are <it>BCR-ABL1 </it>downstream effectors, and all three proteins are dephosphorylated by imatinib in sensitive cell lines. TKI-resistant phosphorylation of RPS6, but responsiveness as regards JAK/STAT5 and ERK1/2 signalling were characteristic for resistant cell lines. PI3K pathway inhibitors effected dephosphorylation of RPS6 in imatinib-resistant cell lines suggesting that an oncogene other than <it>BCR-ABL1 </it>might be responsible for activation of the PI3K/AKT1/mTOR pathway, which would explain the TKI resistance of these cells. We show that the TKI-resistant cell line KCL-22 carries a PI3Kα E545G mutation, a site critical for the constitutive activation of the PI3K/AKT1 pathway. Apoptosis in TKI-resistant cells could be induced by inhibition of AKT1, but not of mTOR.</p> <p>Conclusion</p> <p>We introduce five Philadelphia-chromosome positive cell lines as TKI-resistance models. None of these cell lines carries mutations in the kinase domain of <it>BCR-ABL1 </it>or other molecular aberrations previously indicted in the context of imatinib-resistance. These cell lines are unique as they dephosphorylate ERK1/2 and STAT5 after treatment with imatinib, while PI3K/AKT1/mTOR activity remains unaffected. Inhibition of AKT1 leads to apoptosis in the imatinib-resistant cell lines. In conclusion, Ph+ cell lines show a form of imatinib-resistance attributable to constitutive activation of the PI3K/AKT1 pathway. Mutations in <it>PIK3CA</it>, as observed in cell line KCL-22, or PI3K activating oncogenes may undelie TKI-resistance in these cell lines.</p

Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma

<p>Abstract</p> <p>Background</p> <p>Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a hallmark of cancer. To assay its extent in human lymphoma, methylation of 24 TSG was analyzed in lymphoma-derived cell lines as well as in patient samples.</p> <p>Methods</p> <p>We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated <it>CD44 </it>was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of <it>CD44 </it>and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.</p> <p>Results</p> <p>On average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that <it>CD44 </it>was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: <it>CD44 </it>was not methylated in MCL patients (0/11) whereas <it>CD44 </it>was frequently hypermethylated in BL patients (18/29). In cell lines with <it>CD44 </it>hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of <it>CD44</it>. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44⁺lymphoma cells. <it>CD44 </it>hypermethylated, CD44^-lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.</p> <p>Conclusion</p> <p>Our data show that <it>CD44 </it>is epigenetically regulated in lymphoma and undergoes <it>de novo </it>methylation in distinct lymphoma subtypes like BL. Thus <it>CD44 </it>may be a promising new epigenetic marker for diagnosis and a potential therapeutic target for the treatment of specific lymphoma subtypes.</p

Harvest volume optimization with linear programming

The paper presents a linear programming method of harvest volume determination including calculations of net present value (NPV) of standing timber. NPV was computed taking into account the costs of harvesting and skidding and a discount rate of 2.5%. Harvest volume was determined for three 10−year management periods according to the following four scenarios: (1) Vol_max – timber volume maximization within constraints concerning harvest area (4 ha), cutting interval (5 year), felling a maximum of two adjacent cutting plots over a 10−year period, combined harvest area per decade (a quarter of the total area of near−mature, mature, and overmature stands), and minimum stand age (starting with near−mature stands); (2) RA – as in the Vol_max scenario plus the harvest area per decade should be smaller than or equal to the regulated area; (3) NPV_max – NPV maximization while respecting all constraints from the Vol_max scenario; and (4) IUL – pursuant to the Instrukcja… [2012]. Calculations included allowable cuts by maturity for mature stands (the last age class) and near−mature and mature stands (two last age classes), as well as the allowable cut for mean age equalization. Subsequently, the optimum allowable cut was determined and particular stands were designated for felling, starting with the oldest ones, and taking into consideration spatial layout. An optimization case study was done for the Seredzice forest unit designated for clearcutting, consisting of pine stands or stands with a predominance of Scots pine growing on coniferous and mixed coniferous habitat types with a total area of 813.20 ha in the Marcule Forest District (C Poland). The total harvest volume determined using linear programming for a 30−year period was 81.17, 74.70, and 80.84 thousand m3 in the Vol_max, RA, and NPV_max scenarios, respectively, which was greater by 29%, 19%, and 28% than in the IUL scenario (62.95 thousand m3). The total NPV of stands designated for harvesting in the 30−year period was 9423, 8824, and 9483 thousand PLN for the Vol_max, RA, and NPV_max scenarios, respectively, as compared to 7492 thousand PLN in the IUL scenario. The simultaneous determination of harvest volume for several management periods by analyzing the parameters of individual stands and selecting the optimum harvest period for them makes it possible to better exploit the production potential of the forest and increase both the volume and value of the harvested timber over a long time horizon

Time series decomposition of timber production volume and prices using the example of the Marcule Forest District

The objective of the study was to identify and analyze long−term trends as well as cyclic, seasonal, and irregular effects in timber volume and prices by means of time series decomposition. The adopted multiplicative model was the product of all the time series components identified using the Census X11 method. The study material consisted of quarterly data on the volume and prices of timber sold by the Marcule Forest District (central Poland) in the years 2006−2018. Analysis was performed for the overall timber production volume, as well as separately for pine timber (constituting 86% of the total) and oak timber (5%), taking into account large−diameter saw timber (WC0) and medium−diameter industrial and general purpose timber (pulpwood, S2A). Over the analyzed period, the nominal prices of timber rose on average by 39% from 165 to 229 PLN/m3. The greatest price increase was recorded for large−diameter oak timber (by 100%), while the prices of WC0 pine timber, which accounted for the greatest proportion of the production volume, increased by 23% on average. Production characterized marked seasonality throughout the year, depending on the species. Pine timber sales were the lowest in 1st quarter and the highest in 3rd one, while oak timber sales were the lowest in 3rd quarter and the highest in 4th one. The seasonal effect accounted for the largest proportion of variation in timber production volume. The seasonality of timber prices was negatively correlated with production. The highest prices for pine and oak timber were obtained in 1st and 2nd quarters respectively, when the production volume of those timber species was the lowest. Conversely, the lowest prices were recorded in seasons characterized by the greatest production volume, i.e., in 3rd quarter for pine and in 4th quarter for oak. The decomposition of overall variation in timber prices into its components, which can be predicted (cyclic and seasonal fluctuations as well as long−term trend), and those that are difficult to forecast (irregular effect) is of great significance for timber sales management as the results can be used to improve timber price forecasting

Determining the value of standing timber for harvest planning optimization

Forest managers conducting sustainable forest management are guided by the principles of sustainable use of natural resources, which involve the need for long and short-term planning in organizational units of the State Forests. Plans often differ from reality by the time individual treatments and cuts are to be performed. For economic reasons, it is important to optimize harvest planning, not only focusing on the volume of timber to be harvested, but also the price differences of individual tree species and sort types of wood. The purpose of this study was to present methods evaluating standing timber and to assess their usefulness in optimizing the harvest volume using linear programming. Stands designated to be cut were evaluated using transaction value methods, i.e. “the stumpage value method” M1, the “con- sumption value” method M2, as well as the net present value (NPV) method M3. The research material was obtained from the State Forests Information System (SILP) for the Marcule Forest District covering the years 2014–2018. The stand values were determined at the beginning and end of the 10-year planning period. We observed that the stand value (standing timber) differed significantly between method M2 as compared to method M1. The value of stands determined by method M3, on the other hand, decreased as the discount rate increased. In the process of optimizing the selection of stands for felling, economic criteria should also be taken into account and this is a direct measure of obtainable standing timber in terms of the cutting possibility in the given planning period. In stands where one species dominates, a simplified method of determining the value (M1) can be used, whereas in stands with significant species diversity, method M2 provides a significantly more accurate value for the cutting timber. Howe- ver, if harvest volume optimization using linear programming methods is to take longer time periods into account, e.g. 30 years (three 10-year economic planning periods), the most reasonable method for determining the value of stands is the net present value method M3