Ethnic Concentration, Cultural Identity and Immigrant Self-Employment in Switzerland

Immigrant self-employment rates vary considerably across regions in Switzerland. Business ownership provides an alternative to wage labour, where immigrants have to face structural barriers such as the limited knowledge of the local language, or difficulties in fruitfully making use of their own human capital. Despite their historically high unemployment rates with respect to natives, immigrants in Switzerland are less entrepreneurial. It is therefore important to uncover factors that may facilitate the transition from the status of immigrant to the one of economic agent. Among others factors, concentration in ethnic enclaves, as well as accumulated labour market experience and time elapsed since immigration, have been associated to higher business ownership rates. In this paper, we use a cross-section of 2,490 Swiss municipalities in order to investigate the role played by the ethnic concentration of immigrants, as well as cultural factors, in determining self-employment rates

Transient receptor potential canonical 4 and 5 proteins as targets in cancer therapeutics

Novel approaches towards cancer therapy are urgently needed. One approach might be to target ion channels mediating Ca²+ entry because of the critical roles played by Ca²+ in many cell types, including cancer cells. There are several types of these ion channels, but here we address those formed by assembly of transient receptor potential canonical (TRPC) proteins, particularly those which involve two closely related members of the family: TRPC4 and TRPC5. We focus on these proteins because recent studies point to roles in important aspects of cancer: drug resistance, transmission of drug resistance through extracellular vesicles, tumour vascularisation, and evoked cancer cell death by the TRPC4/5 channel activator (−)-englerin A. We conclude that further research is both justified and necessary before these proteins can be considered as strong targets for anti-cancer cell drug discovery programmes. It is nevertheless already apparent that inhibitors of the channels would be unlikely to cause significant adverse effects, but, rather, have other effects which may be beneficial in the context of cancer and chemotherapy, potentially including suppression of innate fear, visceral pain and pathological cardiac remodelling

The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication

Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (MPro, 3CLPro, NSP5). Its therapeutic application reduces but does not abolish the progression of COVID-19 in humans. Here we report a strong synergy of Nirmatrelvir with inhibitors of the ER chaperone GRP78 (HSPA5, BiP). Combining Nirmatrelvir with the GRP78-antagonizing drug candidate HA15 strongly inhibits the replication of SARS-CoV-2, to a far greater extent than either drug alone, as observed by diminished cytopathic effect, levels of detectable virus RNA, TCID50 titers, and reduced accumulation of the non-structural proteins, as well as Spike and N proteins. The original SARS-CoV-2 strain as well as an Omicron variant were similarly susceptible towards the drug combination. Other GRP78 inhibitors or siRNAs targeting GRP78 also fortified the antiviral effect of Nirmatrelvir. In a hamster model of COVID-19, the combination of Nirmatrelvir with HA15 alleviated pneumonia-induced pulmonary atelectasis more effectively than the single drugs. In conclusion, inhibition of the virus Main protease and cellular GRP78 cooperatively diminishes virus replication and may improve COVID-19 therapy

Grexit News and Stock Returns

During the first eight months of 2015, there was an ongoing debate about whether or not Greece should remain in the euro area. Using an event study approach, we quantify the effects of Grexit-related statements made by six important euro area politicians (Merkel, Schaeuble, Tsipras, Varoufakis, Juncker, and Schulz) on intraday stock returns in Germany, Greece, and the euro area during the period of January 1, 2015 - August 19, 2015. We show that positive statements indicating that a Grexit is less likely lead to higher returns, and negative statements to lower returns. The overall impact of negative statements is more pronounced. The cumulative absolute effects on stock returns are sizeable as the statements contribute to a variation of up to 58 percentage points in the ATHEX. These large effects are of particular relevance as our study only captures an eight month snapshot of the Greek government debt crisis

Synergistic interference with SARS-CoV-2 replication by molnupiravir-derived N⁴-hydroxycytidine and inhibitors of CTP synthetase in cell culture

N4-hydroxycytidine (NHC), the active metabolite of molnupiravir, is incorporated into nascent RNA of SARS-CoV-2 and interferes with subsequent virus replication. We have previously described synergy between NHC and inhibitors of dehydroorotate dehydrogenase (DHODH), an enzyme required for pyrimidine synthesis. Upon DHODH inhibition, the lack of endogenous pyrimidines conceivably enhances NHC incorporation. However, the question remains whether preventing the synthesis of just one pyrimidine base, cytidine, might as well augment the antiviral efficacy of NHC. We tested this by inhibiting CTP synthetases (CTPSs), the cellular enzymes that directly catalyze the synthesis of a cytidine nucleotide. We observed that inhibitors of CTP synthetase (CTPSis), namely cyclopentenyl cytosine (CPEC) as well as STP938 and STP720, display a strong synergy with NHC for diminishing SARS-CoV-2 replication in cell culture, as shown earlier for DHODH inhibitors. NHC and CTPSis in combination prevented the cytopathic effect of SARS-CoV-2 and strongly reduced the release of viral RNA and infectious particles, as well as the synthesis of viral proteins. This combination was also active against an Omicron variant of SARS-CoV-2. Addition of cytidine, but not uridine, rescued virus growth under these conditions. Surprisingly, this synergy was not confirmed in the SARS-CoV-2 animal model in Syrian hamsters. While treatment with the CTPS1 inhibitor STP938 alone strongly diminished virus propagation and COVID pathology, addition of molnupiravir did not augment this effect and even counteracted the benefits of STP938 in vivo. We propose that, if further developed, CTPS inhibitors might represent candidates for antiviral therapy

Critical Epitopes in the Nucleocapsid Protein of SFTS Virus Recognized by a Panel of SFTS Patients Derived Human Monoclonal Antibodies

BACKGROUND: SFTS virus (SFTSV) is a newly discovered pathogen to cause severe fever with thrombocytopenia syndrome (SFTS) in human. Successful control of SFTSV epidemic requires better understanding of the antigen target in humoral immune responses to the new bunyavirus infection. METHODOLOGY/PRINCIPAL FINDINGS: We have generated a combinatorial Fab antibody phage library from two SFTS patients recovered from SFTSV infection. To date, 94 unique human antibodies have been generated and characterized from over 1200 Fab antibody clones obtained by screening the library with SFTS purified virions. All those monoclonal antibodies (MAbs) recognized the nucleocapsid (N) protein of SFTSV while none of them were reactive to the viral glycoproteins Gn or Gc. Furthermore, over screening 1000 mouse monoclonal antibody clones derived from SFTSV virions immunization, 462 clones reacted with N protein, while only 16 clones were reactive to glycoprotein. Furthermore, epitope mapping of SFTSV N protein was performed through molecular simulation, site mutation and competitive ELISA, and we found that at least 4 distinct antigenic epitopes within N protein were recognized by those human and mouse MAbs, in particular mutation of Glu10 to Ala10 abolished or significantly reduced the binding activity of nearly most SFTS patients derived MAbs. CONCLUSIONS/SIGNIFICANCE: The large number of human recombinant MAbs derived from SFTS patients recognized the viral N protein indicated the important role of the N protein in humoral responses to SFTSV infection, and the critical epitopes we defined in this study provided molecular basis for detection and diagnosis of SFTSV infection

Different Whole-Brain Functional Connectivity Correlates of Reactive-Proactive Aggression and Callous-Unemotional Traits in Children and Adolescents with Disruptive Behaviors

Background: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. Methods: The large sample of children and adolescents aged 8–18 years (n = 207; mean age = 13.30 ± 2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. Results: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled. For cases, reactive and proactive aggression scores related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. Conclusions: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control

Temporal Controls of the Asymmetric Cell Division Cycle in Caulobacter crescentus

The asymmetric cell division cycle of Caulobacter crescentus is orchestrated by an elaborate gene-protein regulatory network, centered on three major control proteins, DnaA, GcrA and CtrA. The regulatory network is cast into a quantitative computational model to investigate in a systematic fashion how these three proteins control the relevant genetic, biochemical and physiological properties of proliferating bacteria. Different controls for both swarmer and stalked cell cycles are represented in the mathematical scheme. The model is validated against observed phenotypes of wild-type cells and relevant mutants, and it predicts the phenotypes of novel mutants and of known mutants under novel experimental conditions. Because the cell cycle control proteins of Caulobacter are conserved across many species of alpha-proteobacteria, the model we are proposing here may be applicable to other genera of importance to agriculture and medicine (e.g., Rhizobium, Brucella)

EU Structural Funds and Regional Income Convergence A Sobering Experience

The European Structural and Investment Funds (ESIF) are the prime instrument of EU regional policy. European policy makers place considerable hope into their growth stimulating funding measures to overcome current economic stagnation. Consequently, there is a strong need for credible evidence regarding the programs' effectiveness. Based on an empirical identification strategy linked to modern growth theory, we find that the disbursement of EU structural funds is negatively correlated with regional growth. Incorporating spatial dynamics and decomposing this correlation into a direct and a spatially-indirect component, it is particularly the latter which determines this 'sobering' finding. Regarding the economics behind these results, the obtained negative spatial effect may reflect the role played by policy-induced spatial competition among neighboring regions. It could also highlight the backwardness in technological endowment and economic structures of highly funded regions. In any case, EU structural funding does not seem to contribute effectively to foster income convergence across regions.Die europäischen Struktur und Investmentfonds (ESIF) sind das wichtigste Instrument der EU-Regionalpolitik; die europäische Politik setzt große Hoffnungen in die wachstumsstimulierende Wirkung dieser Fördermaßnahmen zur Überwindung der aktuellen wirtschaftlichen Stagnation. Basierend auf einer empirischen Identifikationsstrategie können in diesem Papier keine Belege für positive Förderwirkungen gefunden werden. Werden räumliche Strukturen berücksichtigt, zeigt sich, dass räumlich indirekte Effekte dieses Ergebnis beeinflussen - also solche Regionen weniger wachsen, deren Nachbarn stark gefördert werden. Neben der potenziellen Erklärung, dass Nachbarn gegenseitig ihre Investoren abwerben, legt dieses Resultat nahe, dass hochgeförderte regionale Cluster unter struktureller und technologischer Rückständigkeit leiden, die durch Wachstumsprogramme nicht überwunden werden. Beide möglichen Erklärungen lassen den Schluss zu, dass die Förderung ihr eigentliches Ziel, die Konvergenz der Regionen, verfehlt