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This research aims to shed light on the formulation of returns management strategies and to identify key returns management components in developing more effective returns management strategies. Anchored in supply chain orientation and supply chain alignment research, we use a multiple confirmatory case study of six retailers operating in online commerce. Interviews with fifteen managers provided the primary empirical data source for the study. The results confirm the presence of alignment in establishing effective strategies for managing product returns and suggest a return policy. The findings provide detailed insights into seven existing misalignments that curb the strength of alignment. These serve as strategic elements for managers to consider in formulating returns management strategies and goals. The results may assist retail and supply chain professionals in their quest to develop effective strategies for managing product returns. Research on returns management strategy is scarce. This study offers a conceptual framework and provides new empirical insights into returns management strategy formulation and, in particular, potential misalignments.

Diamond-Blackfan anemia is a rare genetic bone marrow failure disorder which is usually caused by mutations in ribosomal protein genes. In the present study, we generated a traceable RPS19-deficient cell model using CRISPR-Cas9 and homology-directed repair to investigate the therapeutic effects of a clinically applicable lentiviral vector at single-cell resolution. We developed a gentle nanostraw delivery platform to edit the RPS19 gene in primary human cord bloodderived CD34+ hematopoietic stem and progenitor cells. The edited cells showed expected impaired erythroid differentiation phenotype, and a specific erythroid progenitor with abnormal cell cycle status accompanied by enrichment of TNFα/NF-κB and p53 signaling pathways was identified by single-cell RNA sequencing analysis. The therapeutic vector could rescue the abnormal erythropoiesis by activating cell cycle-related signaling pathways and promoted red blood cell production. Overall, these results establish nanostraws as a gentle option for CRISPR-Cas9- based gene editing in sensitive primary hematopoietic stem and progenitor cells, and provide support for future clinical investigations of the lentiviral gene therapy strategy.

How customers develop purchase intentions in online shopping has been an area of recent interest. In this study, we ask whether males and females leverage trust into and perceived reputation of online retailers differently in reporting purchase intentions. Drawing on the literature on differences in males and females in online shopping behaviors, we propose that females rely on reputation in developing purchase intentions whereas males rely on perceived trust in developing purchase intentions. In a sample of 727 respondents in Sweden, we find support for the proposed associations. Implications for online retailers are discussed.

For a series of conventional soda-lime-silicate glasses with increasing Al2O3 content, we investigated the thermal, mechanical, and structural properties before and after K+-for-Na+ ion-exchange strengthening by exposure to molten KNO3. The Al-for-Si replacement resulted in increased glass network polymerization and lowered compactness. The glass transition temperature (Tg), hardness (H) and reduced elastic modulus (Er), of the pristine glasses enhanced monotonically for increasing Al2O3 content. H and Er increased linearly up to a glass composition with roughly equal stoichiometric amounts of Na2O and Al2O3 where a nonlinear dependence on Al2O3 was observed, whereas H and Er of the chemically strengthened (CS) glasses revealed a strictly linear dependence. Tg, on the other hand, showed linear increase with Al-for-Si for pristine glasses while for the CS glasses a linear to nonlinear trend was observed. Solid-state 27Al nuclear magnetic resonance (NMR) revealed the sole presence of AlO4 groups in both the pristine and CS glasses. 23Na NMR and wet-chemical analysis manifested that all Al-bearing glasses had a lower and near-constant K+-for-Na+ ion exchange ratio than the soda-lime-silicate glass. Differential thermal analysis of CS glasses revealed a “blurred” glass transition temperature (Tg) and an exothermic step below Tg; the latter stems from the relaxation of residual compressive stresses. The nanoindentation-derived hardness at low loads and

Gaucher disease type 1 (GD1) is an inherited lysosomal disorder with multisystemic effects in patients. Hallmark symptoms include hepatosplenomegaly, cytopenias, and bone disease with varying degrees of severity. Mutations in a single gene, glucosidase beta acid 1 (GBA1), are the underlying cause for the disorder, resulting in insufficient activity of the enzyme glucocerebrosidase, which in turn leads to a progressive accumulation of the lipid component glucocerebroside. In this study, we treat mice with signs consistent with GD1, with hematopoietic stem/progenitor cells transduced with a lentiviral vector containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the genome encodes for functional human glucocerebrosidase. Five months after gene transfer, a highly significant reduction in glucocerebroside accumulation with subsequent reversal of hepatosplenomegaly, restoration of blood parameters, and a tendency of increased bone mass and density was evident in vector-treated mice compared to non-treated controls. Furthermore, histopathology revealed a prominent reduction of Gaucher cell infiltration after gene therapy. The vector displayed an oligoclonal distribution pattern but with no sign of vector-induced clonal dominance and a typical lentiviral vector integration profile. Cumulatively, our findings support the initiation of the first clinical trial for GD1 using the lentiviral vector described here.

Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder in which pure red blood cell aplasia is associated with physical malformations and a predisposition to cancer. Twentyfive percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene, self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1a short promoter, which can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy and safety of the vector in a Rps19-deficient DBA mouse model and in human primary RPS19-deficient CD34+ cord blood cells. We observed that transduced Rps19-deficient bone marrow cells could reconstitute mice long-term and rescue the bone marrow failure and severe anemia observed in Rps19-deficient mice, with a low risk of mutagenesis and a highly polyclonal insertion site pattern. More importantly, the vector can also rescue impaired erythroid differentiation in human primary RPS19-deficient CD34+ cord blood hematopoietic stem cells. Collectively, our results demonstrate the efficacy and safety of using a clinically applicable lentiviral vector for the successful treatment of Rps19-deficient DBA in a mouse model and in human primary CD34+ cord blood cells. These findings show that this vector can be used to develop clinical gene therapy for RPS19-deficient DBA patients.

The paper presents basis and experimental results of a non-destructive method aimed at determination of the presence of large surface cracks in glass samples by measurements with NAW® technology (Nonlinear Acoustic Wave). The method is based on a transmitted ultrasonic wave in the material from which the non-linear content of the signal can be analysed. A sample containing defects presents nonlinearities in the form of distortions, such as, higher order harmonics that are detected. Nonlinearities in the signal are primarily formed at crack-tips and the number of nonlinearities is proportional to the amount of damage, or defects, in the sample that is investigated. The result of the measurement and evaluation, that only takes a few seconds, is a damage value that is easy to understand and to use for immediate application. A number of preliminary test results and comparisons with destructive testing for various test setups, as well as a recent test strategy including fabricated defects with a nanoindenter will be discussed.

Life-long production of blood from hematopoietic stem cells (HSCs) is a process of strict modulation. Intrinsic and extrinsic signals govern fate options like self-renewal - a cardinal feature of HSCs. Bone morphogenetic proteins (BMP) have an established role in embryonic hematopoiesis, but less is known about its functions in adulthood. Previously, SMAD-mediated BMP signaling has been proven dispensable for HSCs. However, the BMP Type II receptor (BMPR-II) is highly expressed in HSCs, leaving the possibility that BMPs function via alternative pathways. Here, we establish that BMP signaling is required for self-renewal of adult HSCs. Through conditional knockout we show that BMPR-II deficient HSCs have impaired self-renewal and regenerative capacity. BMPR-II deficient cells have reduced p38 activation, implying that non-SMAD pathways operate downstream of BMPs in HSCs. Indeed, a majority of primitive hematopoietic cells do not engage in SMAD-mediated responses downstream of BMPs in vivo. Furthermore, deficiency of BMPR-II results in increased expression of TJP1, a known regulator of self-renewal in other stem cells, and knockdown of TJP1 in primitive hematopoietic cells partly rescues the BMPR-II null phenotype. This suggests TJP1 may be a universal stem cell regulator. In conclusion, BMP signaling, in part mediated through TJP1, is required endogenously by adult HSCs to maintain self-renewal capacity and proper resilience of the hematopoietic system during regeneration.

Purpose - The purpose of this paper is to identify the impact of enterprise systems (ESs), in particular radio frequency identification (RFID) and enterprise resource planning (ERP) systems, on supply chain management (SCM). The results of this conceptual paper demonstrate that ERP and RFID systems contribute to SCM by improving supply chain integration. Supply chain integration occurs to facilitate the flow of financing, products, and information throughout the chain. In this regard, ERP and RFID contribute to integration by enhancing the information flow across the supply chain. Design/methodology/approach - This paper proposes a conceptual model developed from the findings of literature review within the research domains of SCM, ESs, and supply chain integration. Findings - This conceptual study contributes to the existing theory by linking the concept of information technology, ESs to SCM. The conceptual model in this paper may provide insights for executives who wish to implement ERP or RFID systems in their businesses in order to achieve higher integration, both within internal sectors and also with supply chain partners. Originality/value - The findings in this study contribute to the theory base by linking the concept of information technologies, ESs to SCM. The conceptual model presented in this paper can provide insights for executives who wish to implement ERP or RFID systems in their businesses in order to achieve higher integration within internal sectors and with supply chain partners. This study offers new understandings by investigating the impact of ERP and RFID together on SCM.

Thermal strengthening of glass is common for many different purposes including architecture, automotive, glasses for solar energy, tableware and occasionally also containers. It is an easy and relatively cheap method to make glasses stronger, however, with an Achilles heel that it can spontaneously fracture without the slightest applied external force. Though, fracture due to applied external force is the most common case, spontaneous fracture is rare. The current paper reviews the literature of spontaneous fracture and NiS inclusions and what kind of mitigation measures that have been done in order to reduce the frequency of spontaneous fracture. Finally is also an outlook for the alternative mitigation measures and their advantages as well as disadvantages. A personal perspective is given in discussions and gives an outlook to the most promising alternative methods to reduce and hopefully eliminate the NiS inclusions. These include multi-functional methods where not only the NiS inclusion issue is solved.

Failure of PV modules frequently occurs as a result of degradation of their encapsulation material by destructive UV radiation. Both the life expectancy and efficiency of PV modules can be improved by reducing the transmittance of the destructive UV radiation through the cover glass without compromising the transmittance in the visible wavelength region. In addition, if the absorbed UV photons can be down-shifted to wavelengths that can be more efficiently converted to electrical energy, an additional increase of the PV efficiency could be achieved. In this study we have investigated transparent ZnO and TiO2 thin films deposited by spray pyrolysis on soda lime silicate float glass as functional layers on PV cover glass. The optical bandgap, UV-cutoff, UV-Vis transmittance, reflectivity (total and diffuse) and photoluminescence have been determined. The ZnO coating shifted the optical bandgap to longer wavelengths, resulting in a reduction of the transmittance of destructive UV radiation by up to ~85%. Distinct photoluminescence peaks at 377 nm and at 640 nm were observed for one of the ZnO samples. The TiO2 coated glasses also showed an increased UV cutoff, which resulted in a reduction of transmittance of destructive UV radiation by up to 75%. However, no photoluminescence peaks could be observed from the TiO2 films with 325 nm excitation laser, which can be explained by the fact that only indirect interband transitions are accessible at this excitation wavelength. Deposition of both ZnO and TiO2 coatings resulted in a reduction of the transmitted light convertible by PV modules, by up to 12.3 and 21.8%, respectively. The implication of the results is discussed in terms of lifetime expectancy and efficiency of PV modules.

The local structures of Cu(I) and Cu(II) in (20-x)Na2O-xK2O-10CaO-70SiO2 glasses with a copper content of 0.4 mol% have been investigated by Cu K-edge extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES). Complementary data for Cu(II) was derived using UV–Vis-NIR spectroscopy. Indication for mainly linear two-fold coordination of the Cu+ ion was found by both EXAFS and XANES, but other coordination between Cu+ and O2– cannot be excluded. The Cu(I)O bond lengths were found to be 1.79–1.83 ± 0.02 Å. EXAFS results showed that Cu(II) was mostly present in a Jahn-Teller distorted environment with oxygen, an octahedron with four shorter Cu(II)O bonds and two longer in axial position. The equatorial bond lengths were found to be 1.89–1.91 ± 0.02 Å and the axial 2.20–2.24 ± 0.02 Å with no effect of the Jahn-Teller distortion of the octahedron when the glass composition was altered. Keywords: Mixed alkali, Ligand field theory, UV–Vis-NIR, EXAFS, XANES and Jahn-Teller distortion

Cutaneous squamous cell carcinomas is a growing problem but the driver genes causing this remain poorly defined. Here, the authors demonstrate that inactivating driver mutations in TGFBR1 and TGFBR2occur in vemurafenib-induced and sporadic cutaneous squamous cell carcinomas.

The membrane lipid glucosylceramide (GlcCer) is continuously formed and degraded. Cells express two GlcCer-degrading β-glucosidases, glucocerebrosidase (GBA) and GBA2, located in and outside the lysosome, respectively. Here we demonstrate that through transglucosylation both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol, and vice versa. Furthermore, the natural occurrence of 1-O-cholesteryl-β-D-glucopyranoside (GlcChol) in mouse tissues and human plasma is demonstrated using LC-MS/MS and 13C6-labeled GlcChol as internal standard. In cells, the inhibition of GBA increases GlcChol, whereas inhibition of GBA2 decreases glucosylated sterol. Similarly, in GBA2-deficient mice, GlcChol is reduced. Depletion of GlcCer by inhibition of GlcCer synthase decreases GlcChol in cells and likewise in plasma of inhibitor-treated Gaucher disease patients. In tissues of mice with Niemann-Pick type C disease, a condition characterized by intralysosomal accumulation of cholesterol, marked elevations in GlcChol occur as well. When lysosomal accumulation of cholesterol is induced in cultured cells, GlcChol is formed via lysosomal GBA. This illustrates that reversible transglucosylation reactions are highly dependent on local availability of suitable acceptors. In conclusion, mammalian tissues contain GlcChol formed by transglucosylation through β-glucosidases using GlcCer as donor. Our findings reveal a novel metabolic function for GlcCer.

Monovalent cations enable efficient ion-exchange processes due to their high mobility in silicate glasses. Numerous properties can be modified in this way, e.g., mechanical, optical, electrical, or chemical performance. In particular, alkali cation exchange has received significant attention, primarily with respect to introducing compressive stress into the surface region of a glass, which increases mechanical durability. However, most of the present applications rely on specifically tailored matrix compositions in which the cation mobility is enhanced. This largely excludes the major area of soda-lime-silicates (SLS) such as are commodity in almost all large-scale applications of glasses. Basic understanding of the relations between structural parameters and the effective diffusion coefficients may help to improve ion-exchanged SLS glass products, on the one hand in terms of obtainable strength and on the other in terms of cost. In the present paper, we discuss the trends in the effective diffusion coefficients when exchanging Na+ for various monovalent cations (K+, Cu+, Ag+, Rb+, and Cs+) by drawing relations to physicochemical properties. Correlations of effective diffusion coefficients were found for the bond dissociation energy and the electronic cation polarizability, indicating that localization and rupture of bonds are of importance for the ion-exchange rate.

Developmental pluripotency-associated 5 (Dppa5) is an RNA binding protein highly expressed in undifferentiated pluripotent stem cells. Here, we demonstrate that Dppa5 is a regulator of hematopoietic stem cells (HSCs) that critically governs reconstitution capacity after bone marrow transplantation. Ectopic expression of Dppa5 followed by in vitro culture robustly increased HSC reconstitution levels through suppression of endoplasmic reticulum (ER) stress and apoptosis. Remarkably, a chemical chaperone that decreases ER stress in HSCs also increases HSC engraftment. Conversely, knockdown of Dppa5 impaired the long-term reconstitution ability of HSCs due to elevated ER stress levels, suggesting that ER stress regulation is physiologically important for proper HSC function in vivo. Thus, Dppa5 represents a pivotal connection between ER stress regulation and stem cell properties in HSCs. The findings also demonstrate that protein quality control is critical for the maintenance, survival, and function of HSCs in vivo and ex vivo.

Prospective isolation is critical for understanding the cellular and molecular aspects of stem cell heterogeneity. Here, we identify the cell surface antigen CD9 as a positive marker that provides a simple alternative for hematopoietic stem cell isolation at high purity. Crucially, CD9 affords the capture of all hematopoietic stem cells in murine bone marrow in the absence of contaminating populations that lack authentic stem cell function. Using CD9 as a tool to subdivide hematopoietic stem-cell-containing populations, we provide evidence for heterogeneity at the cellular, functional, and molecular levels.