Institute for Small Business Economics

Heat shock proteins (hsps) are intracellular chaperones that play a key role in the recovery from stress. Hsp70, the major stress-induced hsp, has been found in the extracellular medium and is capable of activating immune cells. The mechanism involved in Hsp70 release is controversial because this protein does not present a consensual secretory signal. In this study, we have shown that Hsp70 integrates into artificial lipid bilayer openings of ion conductance pathways. In addition, this protein was found inserted into the plasma membrane of cells after stress. Hsp70 was released into the extracellular environment in a membrane-associated form, sharing the characteristics of this protein in the plasma membrane. Extracellular membranes containing Hsp70 were at least 260-fold more effective than free recombinant protein in inducing TNF-alpha production as an indicator of macrophage activation. These observations suggest that Hsp70 translocates into the plasma membrane after stress and is released within membranous structures from intact cells, which could act as a danger signal to activate the immune system.

Gilbert et al. conclude that evidence from the Open Science Collaboration's Reproducibility Project: Psychology indicates high reproducibility, given the study methodology. Their very optimistic assessment is limited by statistical misconceptions and by causal inferences from selectively interpreted, correlational data. Using the Reproducibility Project: Psychology data, both optimistic and pessimistic conclusions about reproducibility are possible, and neither are yet warranted.

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

OBJECTIVE: Based on findings in animal models of autoimmune optic nerve inflammation, we have assessed the safety and efficacy of erythropoietin in patients presenting with a first episode of optic neuritis. METHODS: Patients with optic neuritis who attended the University Hospitals of Homburg/Saar, Göttingen, or Hamburg (Germany) were included in this double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov, NCT00355095). They were randomly assigned to groups receiving either 33,000IU recombinant human erythropoietin intravenously daily for 3 days or placebo as an add-on therapy to methylprednisolone. The primary outcome parameter was change in retinal nerve fiber layer (RNFL) thickness after 16 weeks. Secondary outcome parameters included optic nerve atrophy as assessed by magnetic resonance imaging, and changes in visual acuity, visual field, and visual evoked potentials (VEPs). RESULTS: Forty patients were assigned to the treatment groups (21/19 erythropoietin/placebo). Safety monitoring revealed no relevant issues. Thirty-seven patients (20/17 erythropoietin/placebo) were analyzed for the primary endpoint according to the intention-to-treat protocol. RNFL thinning was less apparent after erythropoietin treatment. Thickness of the RNFL decreased by a median of 7.5μm by week 16 (mean ± standard deviation, 10.55 ± 17.54μm) compared to a median of 16.0μm (22.65 ± 29.18μm) in the placebo group (p = 0.0357). Decrease in retrobulbar diameter of the optic nerve was smaller in the erythropoietin group (p = 0.0112). VEP latencies at week 16 were shorter in erythropoietin-treated patients than in the placebo group (p = 0.0011). Testing of visual functions revealed trends toward an improved outcome after erythropoietin treatment. INTERPRETATION: These results give the first indications that erythropoietin might be neuroprotective in optic neuritis.

The Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome presenting as an association of imperforate anus, triphalangeal and supernumerary thumbs, malformed ears and sensorineural hearing loss. Mutations in SALL1, a gene mapping to 16q12.1, were identified as a cause for TBS. To elucidate how SALL1 mutations lead to TBS, we have performed a series of functional studies with the SALL1 protein. Using epifluorescence and confocal microscopy it could be shown that a GFP-SALL1 fusion protein localizes to chromocenters and smaller heterochromatin foci in transiently transfected NIH-3T3 cells. Chromocenters consist of clustered pericentromeric heterochromatin and contain telomere sequences. Indirect immunofluorescence revealed a partial colocalization of GFP-SALL1 with M31, the mouse homolog of the Drosophila heterochromatic protein HP1. It was further demonstrated that SALL1 acts as a strong transcriptional repressor in mammalian cells. Transcriptional repression could not be relieved by the addition of the histone deacetylase inhibitor Trichostatin-A. In a yeast two-hybrid screen we identified PIN2, an isoform of telomere-repeat-binding factor 1 (TRF1), as an interaction partner of SALL1, and showed that the N-terminus of SALL1 is not necessary for the interaction with PIN2/TRF1. The interaction was confirmed in vitro in a GST-pulldown assay. The association of the developmental regulator SALL1 with heterochromatin is striking and unexpected. Our results propose an involvement of SALL1 in the regulation of higher order chromatin structures and indicate that the protein might be a component of a distinct heterochromatin-dependent silencing process. We have also provided new evidence that there is a close functional link between the centromeric and telomeric heterochromatin domains not only in Drosophila and yeast, but also in mammalian cells.

Various groups of innovating German small and medium enterprises (SMEs) are identified according to their use (or nonuse) of in-house research and development (R&D), their reliance on external sources of knowledge, and the degree of interactive learning within the firm that they employ. Our findings confirm that SMEs can compensate for a lack of R&D by placing a strong emphasis on internal and external interactive learning, at least to some degree. Another observation is that each learning mode is likely to positively affect company performance. Hence, in large parts of the SME sector, it is economically rational to follow a non-R&D-oriented mode of learning and innovation. The article concludes with some policy implications.

The ‘doing-using-interacting’ (DUI) mode of innovation describes informal innovative activities and it can be juxtaposed with the ‘science-technology-innovation’ (STI) mode based on deliberate research and development. While both modes contribute substantially but differently to technological progress, our empirical understanding of DUI mode innovative activity suffers from the lack of a comprehensive measurement approach. While empirical measurement of the STI mode is well established, empirical indicators for DUI activities are scarce and no consensus has emerged concerning its constituting learning processes. We propose a new measurement conception for innovative activity and based on 81 in-depth interviews with German firms and regional innovation consultants. We derive fifteen categories of DUI mode learning processes and a comprehensive set of 47 indicators comprising both established and new DUI indicators for empirical measurement. This new measurement conception and the respective indicators provide a holistic perspective and their application can be used to increase our understanding of the importance of DUI mode innovative activity, as well as guiding policy-makers.

Innovation processes comprise interactive learning mechanisms by combining different knowledge sources. Using a set of 80 exploratory interviews with small and medium-sized enterprises (SMEs) and regional innovation consultants, this paper analyzes the mechanisms through which firms combine an STI (science-technology – innovation) and DUI (learning-by-doing, -using and -interacting) mode of innovation. We show that the innovation mode concept ought to be applied as a continuum of combinations. Thus, SMEs integrate STI-based knowledge into DUI-routines through mechanisms with varying levels of complexity. The described mechanisms differ with respect to their effects on innovativeness, the required absorptive capacities, and costs incurred. Depending on the level of integration, cognitive, organizational and financial barriers impede a combination of innovation modes. At this point, regional innovation consultants can affect a successful combination. We derive implications for innovation policy regarding absorptive capacities in SMEs, showing that policy support extends beyond financial services.

The adaptor complexes AP-1 and AP-3 are localized to endosomes and/or the trans Golgi network (TGN). Because of limitations in analysing intracellular adaptor function directly, their site of function is a matter of ongoing uncertainty. To overcome this problem and to analyse adaptor sorting at the TGN, we reconstituted vesicle formation from Golgi/TGN-enriched membranes in a novel in vitro budding assay. Melanocytes were metabolically labelled followed by a 19 degrees C temperature block to accumulate newly synthesized proteins in Golgi membranes, which were then enriched by subcellular fractionation and used as donor membranes for vesicle formation in vitro. The incorporation of the melanosomal proteins tyrosinase and tyrosinase-related protein 1 (TRP-1) as well as Lamp-1 and 46 kDa mannose-6-phosphate receptor (MPR46) into Golgi/TGN-derived vesicles was temperature, nucleotide, cytosol, ADP ribosylation factor 1 and adaptor dependent. We show that sorting of TRP-1 and MPR46 was AP-1 dependent, while budding of tyrosinase and Lamp-1 required AP-3. Depletion of clathrin inhibited sorting of all four cargo proteins, suggesting that AP-1 and AP-3 are involved in the formation of distinct types of clathrin-coated vesicles, each of which is characterized by the incorporation of specific cargo membrane proteins.

; however, broader connectivity rules remain unknown. Here we leverage the millimetre-scale MICrONS dataset to analyse synaptic connectivity and functional properties of neurons across cortical layers and areas. Our results reveal that neurons with similar response properties are preferentially connected within and across layers and areas-including feedback connections-supporting the universality of 'like-to-like' connectivity across the visual hierarchy. Using a validated digital twin model, we separated neuronal tuning into feature (what neurons respond to) and spatial (receptive field location) components. We found that only the feature component predicts fine-scale synaptic connections beyond what could be explained by the proximity of axons and dendrites. We also discovered a higher-order rule whereby postsynaptic neuron cohorts downstream of presynaptic cells show greater functional similarity than predicted by a pairwise like-to-like rule. Recurrent neural networks trained on a simple classification task develop connectivity patterns that mirror both pairwise and higher-order rules, with magnitudes similar to those in MICrONS data. Ablation studies in these recurrent neural networks reveal that disrupting like-to-like connections impairs performance more than disrupting random connections. These findings suggest that these connectivity principles may have a functional role in sensory processing and learning, highlighting shared principles between biological and artificial systems.

Understanding the relationship between circuit connectivity and function is crucial for uncovering how the brain implements computation. In the mouse primary visual cortex (V1), excitatory neurons with similar response properties are more likely to be synaptically connected, but previous studies have been limited to within V1, leaving much unknown about broader connectivity rules. In this study, we leverage the millimeter-scale MICrONS dataset to analyze synaptic connectivity and functional properties of individual neurons across cortical layers and areas. Our results reveal that neurons with similar responses are preferentially connected both within and across layers and areas - including feedback connections - suggesting the universality of the 'like-to-like' connectivity across the visual hierarchy. Using a validated digital twin model, we separated neuronal tuning into feature (what neurons respond to) and spatial (receptive field location) components. We found that only the feature component predicts fine-scale synaptic connections, beyond what could be explained by the physical proximity of axons and dendrites. We also found a higher-order rule where postsynaptic neuron cohorts downstream of individual presynaptic cells show greater functional similarity than predicted by a pairwise like-to-like rule. Notably, recurrent neural networks (RNNs) trained on a simple classification task develop connectivity patterns mirroring both pairwise and higher-order rules, with magnitude similar to those in the MICrONS data. Lesion studies in these RNNs reveal that disrupting 'like-to-like' connections has a significantly greater impact on performance compared to lesions of random connections. These findings suggest that these connectivity principles may play a functional role in sensory processing and learning, highlighting shared principles between biological and artificial systems.

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.

Generalized trust represents an important regional resource for a firm. It increases human capital, fosters frequent interaction and information sharing, and lowers transaction costs. We provide empirical evidence on the impact of generalized trust among people on firm innovation in German regions. Our observation period ranges from 2004 to 2018. A trust measure is generated by using survey data from the German Socio-Economic Panel, firm-level data is obtained from the Mannheim Innovation Panel and regional data is retrieved from the INKAR database. We apply a 3-level multilevel model, with yearly observations nested in firms, which are nested in regions. Our results show that the relationship between trust and firm innovation has an inverted U-shape. An increase in trust is particularly beneficial for firms inside regions with very low levels of trust, and in small and medium-sized enterprises, especially those that operate in the doing-using-interacting mode of innovation (DUI) with an emphasis on employee freedom and creativity.

The Big Five personality traits and their influence on entrepreneurial action have been repeatedly studied using a trait-based approach. The present paper partly deviates from this perspective by analysing the role of personality prototypes in relation to entrepreneurship. This person-centred approach suggests that combinations of Big Five traits form individual personalities. By using data from the German Socio-Economic Panel (SOEP), we show that at least three prototypes can be identified, one of which - the resilient type - can be hypothesized to significantly increase the likelihood of entrepreneurial action. Our regression results provide evidence of a positive impact of this prototype on the likelihood of and transitioning into self-employment but not the likelihood of exit. We also show that the prototyping approach explains individual self-employment decisions over and above what can already be explained by the profiling approach, another person-centred Big Five approach. The paper concludes with implications for policy and research.

Die Gliederung der Betriebswirtschaftslehre in Teildisziplinen hat in den vergangenen Jahren mehrere Veränderungen erfahren. Einmal sind einzelne Bereiche stärker in den Vordergrund getreten1. Zum anderen entstanden neue, wie die Betriebsinformatik, die Logistik und das Controlling, die vor wenigen Jahrzehnten noch weitgehend unbekannt waren. Gegenüber dem Controlling besteht in der Betriebswirtschaftslehre eine gewisse Zurückhaltung2. Dagegen zeigt die Praxis immer stärker die Neigung, diese Bezeichnung für einen wichtigen Unternehmensbereich zu übernehmen3.

Abstract We describe the development of a Web‐based rainfall atlas for southern Africa, a decision support system for the management of water resources. The rainfall atlas, which is accessible online at the URI http://134.76.173.220/rainfall/index.html , was constructed in a number of phases over some 20 years. In the first phase, a 16 parameter model was developed, validated for representative sites, and then fitted to daily rainfall data from 2550 sites. Eight years later the estimates of the model parameters were updated, extended to 5070 sites, and interpolated on a grid of 1 minute of a degree of latitude and longitude over the entire region of southern Africa, namely South Africa, Lesotho and Swaziland. The method of kriging with external drift was used for the interpolation. The interpolated estimates were used to generate long artificial daily rainfall sequences at a spatial resolution of 1 minute of degree square. The sequences were used to compute rainfall‐related statistics, such as percentiles of annual and monthly rainfall distributions, probabilities associated with droughts, and additional measures relating to the timing and intensity of rainfall. The final phase, information transfer, was the construction of the Atlas website, which offers online access to a wide range of rainfall‐related statistics and some 5000 maps. To facilitate the computation of statistics that are not available in the database, the Atlas enables users to generate, and then import, artificial sequences online, for any grid point in southern Africa. These sequences are designed to mirror the properties of real rainfall records (seasonality, serial dependence, distributional properties, etc.) at the required grid point and can be used to compute quantities of interest empirically. Copyright © 2006 John Wiley & Sons, Ltd.

Las publicaciones acadmicas en revistas cientficas son la viva representacin de la generacin de conocimiento, proceso que constituye uno de los principales roles que debe cumplir una universidad; sin embargo, a la hora de publicar los hallazgos de las investigaciones realizadas, se pueden presentar determinados problemas. En este orden de cosas, el objetivo central de este trabajo es efectuar ciertas reflexiones en relacin con la relevancia que tienen las publicaciones acadmicas en la sociedad del conocimiento, y adicionalmente presentar algunas dificultades que se evidencian en el correspondiente proceso, complementadas con sugerencias para afrontar estos obstculos. Desde el punto de vista de los contenidos se comienza por presentar aspectos contextuales que posibilitan plantear la problemtica, luego se pasa revista a los problemas ms habituales que enfrentan los autores, a la hora de presentar un artculo para una posible publicacin; entre estos se citan: tiempo de demora de la publicacin, abuso de las autocitas, opacidad en la aceptacin de artculos, incompetencias en la revisin de los artculos y faltas de rigor en el clculo del factor de impacto. Finalmente, sobre la base de los problemas identificados, se entregan algunas recomendaciones

Pelota (Pelo) is an evolutionarily conserved gene, and its deficiency in Drosophila affects both male and female fertility. In mice, genetic ablation of Pelo leads to embryonic lethality at the early implantation stage as a result of the impaired development of extra-embryonic endoderm (ExEn). To define the consequences of Pelo deletion on male germ cells, we temporally induced deletion of the gene at both embryonic and postnatal stages. Deletion of Pelo in adult mice resulted in a complete loss of whole-germ cell lineages after 45 days of deletion. The absence of newly emerging spermatogenic cycles in mutants confirmed that spermatogonial stem cells (SSCs) were unable to maintain spermatogenesis in the absence of PELO protein. However, germ cells beyond the undifferentiated SSC stage were capable of completing spermatogenesis and producing spermatozoa, even in the absence of PELO. Following the deletion of Pelo during embryonic development, we found that although PELO is dispensable for maintaining gonocytes, it is necessary for the transition of gonocytes to SSCs. Immunohistological and protein analyses revealed the attenuation of FOXO1 transcriptional activity, which induces the expression of many SSC self-renewal genes. The decreased transcriptional activity of FOXO1 in mutant testes was due to enhanced activity of the PI3K/AKT signaling pathway, which led to phosphorylation and cytoplasmic sequestration of FOXO1. These results suggest that PELO negatively regulates the PI3K/AKT pathway and that the enhanced activity of PI3K/AKT and subsequent FOXO1 inhibition are responsible for the impaired development of SSCs in mutant testes.

Abstract The possibility to fail is inherent to entrepreneurial existence. The risk of a system – a company losing stability increases especially in economic crisis as well as in times of social change. Is it possible for companies to develop their own ‘immunity’ which would make it easier to minimize these risks? This paper examines German breweries during the structural change after ‘the boom’. First, the theory of resilience, here in the sense of crisis robustness, is critically analysed and the value for business research considered. Although the term ‘resilience’ was not used by contemporaries, it was, however, an already established concept of action, based on the interaction between anticipatory preparedness and situational flexibility.

AIM: Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. METHODS: Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. RESULTS: We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. CONCLUSIONS: IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.