Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated cell and process engineering for improved transient production of a “difficult‐to‐express“ fusion protein by CHO cells

Based on an optimized electroporation protocol, we designed a rapid, milliliter‐scale diagnostic transient production assay to identify limitations in the ability of Chinese hamster ovary (CHO) cells to produce a model “difficult‐to‐express” homodimeric Fc‐fusion protein, Sp35Fc, that exhibited very low volumetric titer and intracellular formation of disulfide‐bonded oligomeric aggregates post‐transfection. As expression of Sp35Fc induced an unfolded protein response in transfected host cells, we utilized the transient assay to compare, in parallel, multiple functionally diverse strategies to engineer intracellular processing of Sp35Fc in order to increase production and reduce aggregation as two discrete design objectives. Specifically, we compared the effect of (i) co‐expression of ER‐resident molecular chaperones (BiP, PDI, CypB) or active forms of UPR transactivators (ATF6c, XBP1s) at varying recombinant gene load, (ii) addition of small molecules known to act as chemical chaperones (PBA, DMSO, glycerol, betaine, TMAO) or modulate UPR signaling (PERK inhibitor GSK2606414) at varying concentration, (iii) a reduction in culture temperature to 32°C. Using this information, we designed a biphasic, Sp35Fc‐specific transient manufacturing process mediated by lipofection that utilized CypB co‐expression at an optimal Sp35Fc:CypB gene ratio of 5:1 to initially maximize transfected cell proliferation, followed by addition of a combination of PBA (0.5 mM) and glycerol (1% v/v) at the onset of stationary phase to maximize cell specific production and eliminate Sp35Fc aggregation. Using this optimal, engineered process transient Sp35Fc production was significantly increased sixfold over a 12 day production process with no evidence of disulfide‐bonded aggregates. Finally, transient production in clonally derived sub‐populations (derived from parental CHO host) screened for a heritably improved capability to produce Sp35Fc was also significantly improved by the optimized process, showing that protein‐specific cell/process engineering can provide a solution that exceeds the limits of genetic/functional diversity within heterogeneous host cell populations. Biotechnol. Bioeng. 2015;112: 2527–2542. © 2015 Wiley Periodicals, Inc.
Measuring New Product Portfolio Innovativeness: How Differences in Scale Width and Evaluator Perspectives Affect its Relationship with Performance

Portfolio innovativeness is a central variable in innovation management. However, the impact of portfolio innovativeness on new product development (NPD) performance is unclear, which may partly be due to the construct's multifaceted nature. Different facets may reflect different degrees of innovativeness and may have different relationships with performance. In addition, firm members with different functional backgrounds may perceive and thus assess these facets differently, which again may influence the performance effect of portfolio innovativeness. Based on a sample of 746 CEOs and marketing as well as technology professionals from 117 firms and using Item Response Theory (IRT), a multifaceted scale of portfolio innovativeness, whose facets are able to cover the entire innovativeness spectrum, is developed. In addition, it is shown that the performance impact of portfolio innovativeness is dependent on the facets included in the scale, and on the specialization of the professional assessing the facets. Inverted U-shaped performance effects are found when the scale covers the entire spectrum of innovativeness, and linear positive or zero effects with different types of more narrowly modeled scales. Inverted U-shaped performance effects are also found when technology professionals assess the facets, while the assessments by marketing professionals lead to linear positive effects.
Out-of-State Holding Company Affiliation and Small Business Lending

Opponents of interstate banking and branching assert that larger organizations, particularly those headquartered outside local markets, are either less willing or less able to make small business loans than smaller competitors. The expected outcome of ongoing acquisition activity by companies with interstate operations is higher prices and reduced volumes of credit to small business borrowers in affected local markets. This study attempts to determine whether or not these effects are evident. Small business lending levels, prices, and margins for a sample of 1,377 banks located in the states of Illinois, Kentucky, and Montana are examined using simple univariate statistical tests and regression analysis. In general, the results are not consistent with the assertions of those opposed to interstate banking and branching. Analysis of the available data for these states indicates that the volume of small business lending by out-of-state bank holding company (OSHC) subsidiaries compares favorably with both independent banks and in-state bank holding company subsidiaries. The analysis also shows that out-of-state holding company subsidiaries do not systematically discourage small business borrowing through their loan pricing. Small loan rates at OSHC bank subsidiaries generally are lower than those at other types of banks. OSHC subsidiaries also appear to be willing to accept lower margins on small commercial loans. The results demonstrate that independents do not appear to be at a competitive disadvantage relative to OSHC subsidiaries, at least in this particular product line.
That’s Entertainment - scale and scope economies in the location and clustering of the entertainment economy

It is argued that the introduction of new technology is leading toward the decentralization of the production and consumption of creative products and industries. But creative industries and workers may benefit from being around large markets, access to shared labor, network interactions and economies of scale as well as scope. We hypothesize that the combined effects of scale and scope economies shape significant geographic concentration of the entertainment industry. We test for this using data for 297 U.S. metropolitan areas from 1970-2000 for the entertainment industry overall and its key sub-segments. The findings indicate show that the entertainment industry is concentrated in New York and Los Angeles which significantly outperform other large regions. We further note the rise of one or two highly specialized locations in individual segments of the entertainment industry such as Nashville in music or Las Vegas for dancers. We also find some dispersal of entertainment activity to smaller centers. We conclude that the entertainment industry is characterized by a biurificated spatial structure – with concentration driven by the conjoined effects of scale and scope economies growing at the very top (among the very largest city-regions) and dispersal growing at the bottom.
Pivotal Advance: Peritoneal cavity B‐1 B cells have phagocytic and microbicidal capacities and present phagocytosed antigen to CD4+ T cells

Breaking the long‐held paradigm that primary B cells are not phagocytic, several studies have demonstrated recently that B cells from fish, amphibians, and reptilians have a significant phagocytic capacity. Whether such capacity has remained conserved in certain mammalian B cell subsets is presently an enigma. Here, we report a previously unrecognized ability of PerC B‐1a and B‐1b lymphocytes to phagocytose latex beads and bacteria. In contrast, B‐2 lymphocytes had an almost negligible ability to internalize these particles. Upon phagocytosis, B‐1a and B‐1b cells were able to mature their phagosomes into phagolysosomes and displayed the ability to kill internalized bacteria. Importantly, B‐1a and B‐1b cells effectively present antigen recovered from phagocytosed particles to CD4+ T cells. However, these cells showed a much lower competence to present soluble antigen or antigen from large, noninternalized particles. B‐1 B cells presented particulate and soluble antigen to CD4+ T cells more efficiently than macrophages, whereas DCs were the most potent APCs. The novel phagocytic and microbicidal abilities identified in B‐1 B lymphocytes strengthen the innate nature that has long been attributed to these cells. In the context of adaptive immunity, we show that these innate immune processes are relevant, as they enable B‐1 B cells to present phagocytosable particulate antigen. These capacities position these cells at the crossroads that link innate with adaptive immune processes. In a broader context, these newly identified capacities of B‐1 B cells further support the previously recognized functional, developmental, and evolutionary relationships between these cells and macrophages.
APC-Independent Activation of NK Cells by the Toll-Like Receptor 3 Agonist Double-Stranded RNA

Toll-like receptors (TLRs) play a fundamental role in the recognition of bacteria and viruses. TLR3 is activated by viral dsRNA and polyinosinic-polycytidylic acid (poly(I:C)), a synthetic mimetic of viral RNA. We show that NK cells, known for their capacity to eliminate virally infected cells, express TLR3 and up-regulate TLR3 mRNA upon poly(I:C) stimulation. Treatment of highly purified NK cells with poly(I:C) significantly augments NK cell-mediated cytotoxicity. Poly(I:C) stimulation also leads to up-regulation of activation marker CD69 on NK cells. Furthermore, NK cells respond to poly(I:C) by producing proinflammatory cytokines like IL-6 and IL-8, as well as the antiviral cytokine IFN-γ. The induction of cytokine production by NK cells was preceded by activation of NF-κB. We conclude that the ability of NK cells to directly recognize and respond to viral products is important in mounting effective antiviral responses.
Membranous nephropathy and central retinal vein occlusion

second dose (1000 mg) in order to prevent a relapse. However, 5 months later, while still being B-cell depleted (CD19 count 0.0026 × 10/L (2.6 cells/mm)), there was recurrence of proteinuria associated with increase of serum creatinine from 141 μmol/L to 233 μmol/L. Based on our previous experience, a new course of rituximab was started. Because of the severity of the clinical presentation with acute kidney injury, we added three pulses of methylprednisolone to rapidly induce a remission. Also, we decided to give two doses of rituximab, although the literature does not provide evidence that this is always necessary. The treatment resulted in a partial remission and 6 months later a preventive dose of 1000 mg was administered. During the treatment period oral prednisone was maintained in a dose of 5–10 mg a day. Few patients have been described with a relapse of nephrotic syndrome before recovery of peripheral B-cells (reviewed in). None of the patients received renewed therapy with rituximab. Our case shows that even in the absence of peripheral B-cells, treatment with rituximab can induce a remission. Therefore, we feel that rituximab should not be withheld to these patients. Possible explanations for the efficacy of treatment are the presence of residual B-cells in lymphoid nodes or B-cell independent mechanisms.
Numerical dosimetry at power-line frequencies using anatomically based models.

We have used the finite-difference time-domain (FDTD) method to calculate induced current densities in a 1.31-cm (nominal 1/2 in) resolution anatomically based model of the human body for exposure to purely electric, purely magnetic, and combined electric and magnetic fields at 60 Hz. This model based on anatomic sectional diagrams consists of 45,024 cubic cells of dimension 1.31 cm for which the volume-averaged tissue properties are prescribed. It is recognized that the conductivities of several tissues (skeletal muscle, bone, etc.) are highly anisotropic for power-line frequencies. This has, however, been neglected in the first instance and will be included in future calculations. Because of the quasi-static nature of coupling at the power-line frequencies, a higher quasi-static frequency f' may be used for irradiation of the model, and the internal fields E' thus calculated can be scaled back to the frequency of interest, e.g., 60 Hz. Since in the FDTD method one needs to calculate in the time domain until convergence is obtained (typically 3-4 time periods), this frequency scaling to 5-10 MHz for f' reduces the needed number of iterations by over 5 orders of magnitude. The data calculated for the induced current and its variation as a function of height are in excellent agreement with the data published in the literature. The average current densities calculated for the various sections of the body for the magnetic field component (H) are considerably smaller (by a factor of 20-50) than those due to the vertically polarized electric field component when the ratio E/H is 377 ohms. We have also used the previously described impedance method to calculate the induced current densities for the anatomically based model of the human body for the various orientations of the time-varying magnetic fields, namely from side to side, front to back, or from top to bottom of the model, respectively.
Transmit Antenna Selection with Alamouti Coding and Power Allocation in MIMO Wiretap Channels

In this work, we propose a new transmit antenna selection (TAS) scheme which examines the trade-off between feedback overhead and secrecy performance in multiple-input multiple-output wiretap channels. Our new scheme is carried out in two steps. First, the transmitter selects the first two strongest antennas to maximize the instantaneous signal-to-noise ratio (SNR) of the transmitter-receiver channel. Second, Alamouti coding is employed at the selected antennas in order to perform secure data transmission. When equal power is applied to the selected antennas, we refer to our new scheme as TAS-Alamouti. To provide valuable insights into TAS-Alamouti, we derive new closed-form expressions for the secrecy performance metrics. In terms of these metrics, we show how in a Rayleigh fading channel that our TAS-Alamouti scheme outperforms the traditional single TAS scheme conditioned on the SNR of the transmitter-receiver channel being larger than a specific value. We show how in some antenna configurations no additional feedback, relative to single TAS, is required in order to realize such performance enhancements. Furthermore, we show how optimal power allocation (OPA) across the selected antennas at the transmitter leads to a new scheme, which we refer to as TAS-Alamouti-OPA, that outperforms single TAS unconditionally. Relative to TAS-Alamouti, TAS-Alamouti-OPA requires only one additional feedback bit.
Origins of knowledge creation and multinational firm performance

Knowledge creation is one of the most important instruments of firm survival and growth (Grant, 1996; Kogut and Zander, 1992; Kogut and Zander, 1993). Firms make decisions on whether to create knowledge using single country or international strategies, individually or in collaboration with various internal and external partners such as units, universities or research centres, which may operate in different countries (Arora et al., 2014; Berry, 2014; He and Wong, 2004; Kogut and Zander, 1992; Kogut and Zander, 1993; Van de Vrande, 2013). Therefore, firms make strategic choices regarding the locational and organisational origins of knowledge creation. Despite a growing body of research suggesting that firms increasingly create knowledge using international, multi-country strategies (Berry, 2014; Patel et al., 2014; Van de Vrande, 2013), many aspects of these strategies remain unclear. Using insights from knowledge of the firm and subsidiary evolution theory as well as interrelated theories, this thesis aims to show the value of different international knowledge creation strategies, how firms combine them in their overall knowledge strategy and align them to different contexts in which they operate. Based on a sample of 46,712 patents as indicators of knowledge creation granted to 150 UK headquartered manufacturing sector multinational firms and their 5,352 first level subsidiaries during the 2003 to 2012 period, the findings show that international internal and external knowledge creation strategies have a U-shaped relationship with performance. Also, this thesis offers evidence that multinational firms need to combine single country and international as well as internal and external international knowledge creation strategies in a balanced way in their overall strategy. Finally, these effects depend significantly on the characteristics of the environment in which multinational firms operate.
Generalized Euler method for Hamilton Jacobi differential functional systems

Nonlinear first order partial functional differential systems are considered in the paper. Classical solutions of the local Cauchy problem on the Haar pyramid are approximated by solutions of suitable quasilinear systems of difference functional equations. The proposed numerical methods are difference schemes of the Euler type. A complete convergence analysis is given and it is shown by examples that the new methods are considerable better than the classical methods. It is shown that the Lax scheme is superfluous for the numerical approximations of classical solutions to nonlinear functional differential problems. The proof of the stability is based on a comparison technique with nonlinear estimates of the Perron type for given operators.
Neuropathology of the Mcoln1−/− Knockout Mouse Model of Mucolipidosis Type IV

The recently developed Mcoln1−/− knockout mouse provides a novel model for analyzing mucolipin 1 function and mucolipidosis type IV disease. Here we characterize the neuropathology of Mcoln1−/− mouse at the end stage. Evidence of ganglioside accumulation, including increases in GM2, GM3, and GD3 and redistribution of GM1, was found throughout the central nervous system (CNS) independent of significant cholesterol accumulation. Unexpectedly, colocalization studies using immunofluorescence confocal microscopy revealed that GM1 and GM2 were present in separate vesicles within individual neurons. While GM2 was significantly colocalized with LAMP2, consistent with late-endosomal/lysosomal processing, some GM2-immunoreactivity occurred in LAMP2-negative sites, suggesting involvement of other vesicular systems. P62/Sequestosome 1 (P62/SQSTM1) inclusions were also identified in the CNS of the Mcoln1−/− mouse, suggesting deficiencies in protein degradation. Glial cell activation was increased in brain, and there was evidence of reduced myelination in cerebral and cerebellar white matter tracts. Autofluorescent material accumulated throughout the brains of the knockout mice. Finally, axonal spheroids were prevalent in white matter tracts and Purkinje cell axons. This neuropathological characterization of the Mcoln1−/− mouse provides an important step in understanding how mucolipin 1 loss of function affects the CNS and contributes to mucolipidosis type IV disease.
Estimates of capital stocks and capital productivity in Austrian manufacturing industries: 1978-1994

We present gross, net and productive capital stock estimates for 20 industries of the Austrian manufacturing sector based on the perpetual inventory method for the period 1969-1994. The estimation of the net capital stocks and the volume index of capital services follows an integrated method derived from the neoclassical theory of investment. Based on the estimates we calculate capital intensity and capital productivity measures for the 20 industries and provide estimates of capital productivity developments. We find that capital productivity decreased only for 5 out of the 20 industries. The other industries showed in part marked increases in both capital and labor productivity. (author's abstract)
EMISSION CERTIFICATE TRADE AND COSTS UNDER REGIONAL BURDEN-SHARING REGIMES FOR A 2°C CLIMATE CHANGE CONTROL TARGET

In this article we explore regional burden-sharing regimes for the allocation of greenhouse gas emission reduction obligations needed to reach a 2°C long-term global climate change control target by performing an integrated energy-economy-climate assessment with the bottom–up TIAM-ECN model. Our main finding is that, under a burden-sharing scheme based on the allowed emissions per capita, the sum of merchandized carbon certificates yields about 2000 billion US$/yr worth of inter-regional trade around 2050, with China and Latin America the major buyers, respectively Africa, India, and other Asia the main sellers. Under a burden-sharing regime that aims at equal cost distribution, the aggregated amount of transacted carbon certificates involves less than 500 billion US$/yr worth of international trade by 2050, with China and other Asia representing the vast majority of selling capacity. Restrictions in the opportunities for international certificate trade can have significant short- to mid-term impact, with an increase in global climate policy costs of up to 20%.
Inconsistency in the Assessment of China's Domestic and Foreign Patents

Stronger intellectual property rights (IPR) protection is usually acknowledged beneficial for a country’s technology progress (Briggs, 2008; Dinopoulos and Kottaridi, 2008; Grossman and Lai, 2004; Li, 2008; Sequeira, 1998; Tvedt, 2010). However, what if the IPR protection is carried out unequally towards domestic and foreign patents? More specifically, do some national patent offices’ impose strong IPR protection to domestic patents but weak ones to foreign patents? If it is true, then why and how does a patent office treat native and foreign patent applicants differently? Many scholars have recognized the malfunction of patent offices. It can be caused by the congestion of mass applications, inconsistent standards among different patent examiners, incapability of examiners in updating their science and background knowledge over time, or budgetary constraints of patent offices (Abbott, 2004; Burke and Reitzig, 2007; Caillaud and Duchene, 2011; Mack, 2006; Thomas, 2002). However, these failures, due to imperfections of examiners and institutions, should be distinguished from deliberate discrimination against non-citizen patent applications. If foreign patent applications receive such deliberate non-national treatment, which is used as a strategy to protect domestic innovations, we identify it as a kind of strategic patent policy. This chapter exploits the possible strategic patent policy or inconsistency in the assessment of domestic and foreign patents in the Chinese patent office by the analysis of patent data. The content is organized as follows. We first review the literature in Section 13.2, then specify the econometric models in Section 13.3
Leadership in Virtual Teams: An Exploratory Study

This paper discusses a “research in progress” study. Exploratory research is presently being conducted to learn more about the role of leadership in distributed teams. Thirteen distributed teams are being studied over a period of fifteen weeks. Each team consists of four members. The participants in the study are distance learners in an executive MBA program. The study will combine qualitative and quantitative research methods to address the following questions: Are there common characteristics associated with leadership emergence in distributed teams (e.g., trust)? ; What strategies (e.g., communication behaviors) do emerging leaders use to establish leadership and lead others in a distributed environment? ; and Do leadership characteristics have an impact on distributed team performance?