The cellular serine protease TMPRSS2, a member of the type II transmembrane serine protease (TTSP) family, cleaves and activates the hemagglutinin of influenza A viruses (FLUAV) in cell culture and ...is essential for spread of diverse FLUAV in mice. Non-human primates (NHP), in particular rhesus and cynomolgus macaques, serve as animal models for influenza and experimental FLUAV infection of common marmosets has recently also been reported. However, it is currently unknown whether the NHP orthologues of human TMPRSS2 cleave and activate FLUAV hemagglutinin and contribute to viral spread in respiratory tissue. Here, we cloned and functionally analyzed the macaque and marmoset orthologues of human TMPRSS2. In addition, we analyzed the macaque orthologues of human TMPRSS4 and HAT, which also belong to the TTSP family. We found that all NHP orthologues of human TMPRSS2, TMPRSS4 and HAT cleave and activate HA upon directed expression and provide evidence that endogenous TMPRSS2 is expressed in the respiratory epithelium of rhesus macaques. Finally, we demonstrate that a serine protease inhibitor active against TMPRSS2 suppresses FLUAV spread in precision-cut lung slices of human, macaque and marmoset origin. These results indicate that FLUAV depends on serine protease activity for spread in diverse NHP and in humans. Moreover, our findings suggest that macaques and marmosets may serve as models to study FLUAV activation by TMPRSS2 in human patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) has been reported to be superior in inducing protective ...immunity compared to repeated application of the same vaccine. However, data comparing immunity decline after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. Here we show longitudinal monitoring of ChAd/ChAd (n = 41) and ChAd/BNT (n = 88) vaccinated individuals and the impact of a third vaccination with BNT. The third vaccination greatly augments waning anti-spike IgG but results in only moderate increase in spike-specific CD4 + and CD8 + T cell numbers in both groups, compared to cell frequencies already present after the second vaccination in the ChAd/BNT group. More importantly, the third vaccination efficiently restores neutralizing antibody responses against the Alpha, Beta, Gamma, and Delta variants of the virus, but neutralizing activity against the B.1.1.529 (Omicron) variant remains severely impaired. In summary, inferior SARS-CoV-2 specific immune responses following homologous ChAd/ChAd vaccination can be compensated by heterologous BNT vaccination, which might influence the choice of vaccine type for subsequent vaccination boosts.
Microsatellites (MSs) are DNA markers with high analytical power, which are widely used in population genetics, genetic mapping, and forensic studies. Currently available software solutions for ...high-throughput MS design (i) have shortcomings in detecting and distinguishing imperfect and perfect MSs, (ii) lack often necessary interactive design steps, and (iii) do not allow for the development of primers for multiplex amplifications. We present a set of new tools implemented as extensions to the STADEN package, which provides the backbone functionality for flexible sequence analysis workflows. The possibility to assemble overlapping reads into unique contigs (provided by the base functionality of the STADEN package) is important to avoid developing redundant markers, a feature missing from most other similar tools.
Our extensions to the STADEN package provide the following functionality to facilitate microsatellite (and also minisatellite) marker design: The new modules (i) integrate the state-of-the-art tandem repeat detection and analysis software PHOBOS into workflows, (ii) provide two separate repeat detection steps - with different search criteria - one for masking repetitive regions during assembly of sequencing reads and the other for designing repeat-flanking primers for MS candidate loci, (iii) incorporate the widely used primer design program PRIMER3 into STADEN workflows, enabling the interactive design and visualization of flanking primers for microsatellites, and (iv) provide the functionality to find optimal locus- and primer pair combinations for multiplex primer design. Furthermore, our extensions include a module for storing analysis results in an SQLite database, providing a transparent solution for data access from within as well as from outside of the STADEN Package.
The STADEN package is enhanced by our modules into a highly flexible, high-throughput, interactive tool for conventional and multiplex microsatellite marker design. It gives the user detailed control over the workflow, enabling flexible combinations of manual and automated analysis steps. The software is available under the OpenBSD License 12. The high efficiency of our automated marker design workflow has been confirmed in three microsatellite development projects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Childhood maltreatment is associated with the development and maintenance of mental disorders. The purpose of this naturalistic study was (a) to identify different patterns of childhood maltreatment, ...(b) to examine how these patterns are linked to the severity of mental disorders and (c) whether they are predictive of treatment outcome.
742 adult patients of a university hospital for psychotherapy and psychosomatics were assessed at intake and discharge by standardized questionnaires assessing depression (Beck Depression Inventory, BDI) and general mental distress (Symptom Check List-90-R, SCL-90-R). Traumatic childhood experience (using the Childhood Trauma Questionnaire, CTQ) and ICD-10 diagnoses were assessed at intake.
The patients could be allocated to three different patterns of early childhood trauma experience: mild traumatization, multiple traumatization without sexual abuse and multiple traumatization with sexual abuse. The three patterns showed highly significant differences in BDI, General Severity Index (GSI) and in the number of comorbidity at intake. For both BDI and GSI a general decrease in depression and general mental distress from intake to discharge could be shown. The three patterns differed in BDI and GSI at intake and discharge, indicating lowest values for mild traumatization and highest values for multiple traumatization with sexual abuse. Patients with multiple traumatization with sexual abuse showed the least favourable outcome.
The results provide evidence that the severity of childhood traumatization is linked to the severity of mental disorders and also to the treatment outcome in inpatient psychotherapy. In the study, three different patterns of childhood traumatization (mild traumatization, multiple traumatization without sexual abuse, multiple traumatization with sexual abuse) showed differences in the severity of mental disorder and in the course of treatment within the same therapy setting.
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that ...syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy.
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•Syrosingopine inhibits lactate export by MCT1 and MCT4•Combined MCT1 and MCT4 inhibition elicits synthetic lethality with metformin•Synthetic lethality is due to loss of NAD+-regenerating capacity•Syrosingopine reduces metformin concentration required for anti-cancer activity
Benjamin et al. show that the clinical drug syrosingopine potently inhibits the lactate transporters MCT1 and MCT4 and is thus a clinically relevant MCT4 inhibitor. Intracellular lactate accumulation by syrosingopine elicits synthetic lethality with metformin and potentiates metformin’s anti-cancer efficacy.
Nowadays, feed axes are often equipped with multiple parallel-acting actuators in order to increase the dynamics of the machine tool. Also, additional actuators for active damping are widely used. ...Normally, the drives or actuators are controlled independently without consideration for the impact on each other. In contrast, by using the modal space control, the system can be decoupled and the modal control loops can be adjusted independently. This control approach is particularly suitable for motion systems, such as machine tools, which have more drives or actuators than degrees of freedom of movement. This paper deals with the pre-investigation of the modal-based vibration control for machine tools with additional actuators. The object of investigation is an elastic system with a movable saddle. The modal-based control is compared with a local control approach. The results obtained experimentally on the test rig are presented. The modal control is superior since, with the modal approach, each control loop corresponds to a specific vibration mode, and the control law for this loop is designed to provide
the desired performance of the control system at the corresponding resonance frequency. The parameterisation of the control loops is simplified by modal control, since the modes can be controlled independently.
GPR15 is a G protein-coupled receptor (GPCR) proposed to play a role in mucosal immunity that also serves as a major entry cofactor for HIV-2 and simian immunodeficiency virus (SIV). To discover ...novel endogenous GPR15 ligands, we screened a hemofiltrate (HF)-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of cystatin C (CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2, and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4
T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this GPCR.
The present study in Quezon, Philippines, assessed the sustainability of small-scale production systems, based either on native or on exotic sow breeds, using different survey tools in a ...socio-economic approach. In two research periods, data sets with 49 and 68 households, respectively, all smallholder farmers keeping <= 5 sows, were compiled. In 2016, four municipalities were purposively selected, each representing one of Quezon’s four districts. In 2017, two municipalities, both with larger populations of native pigs, were re-visited in order to review and supplement the previously obtained information. Small-scale pig production based on native sow breeds could result in less local environmental load than that based on exotic sows, as indicated by a significantly closer approximation to organic standards, and a reduced public health impact. However, native sows were less productive than exotic sows, thus allowing only a reduced live weight offtake per household and year (274 vs. 607 kg). Regarding economic viability, both pig production systems were equally cost-effective and required similar weekly labour hours. The advantage of basing production on exotic sows was the possibility to make larger investments, a financial function that could not be met by native sows. The revenues from marketing piglets and porkers from native sows were low, preventing a better outcome. Conversion to organic production and certification could represent one strategy for development given that increasing the value added is putatively the only way to improve the cost-effectiveness of the production from native pigs in Quezon.
We show spin lifetimes of 12.6 ns and spin diffusion lengths as long as 30.5 μm in single layer graphene nonlocal spin transport devices at room temperature. This is accomplished by the fabrication ...of Co/MgO-electrodes on a Si/SiO2 substrate and the subsequent dry transfer of a graphene-hBN-stack on top of this electrode structure where a large hBN flake is needed in order to diminish the ingress of solvents along the hBN-to-substrate interface. Interestingly, long spin lifetimes are observed despite the fact that both conductive scanning force microscopy and contact resistance measurements reveal the existence of conducting pinholes throughout the MgO spin injection/detection barriers. Compared to previous devices, we observe an enhancement of the spin lifetime in single layer graphene by a factor of 6. We demonstrate that the spin lifetime does not depend on the contact resistance area products when comparing all bottom-up devices indicating that spin absorption at the contacts is not the predominant source for spin dephasing.
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