Direct transport between superconducting subgap states in a double quantum dot

We demonstrate direct transport between two opposing sets of Yu-Shiba-Rusinov (YSR) subgap states realized in a double quantum dot. This bound-state-to-bound-state transport relies on intrinsic quasiparticle relaxation, and the tunable gating of this quantum dot device allows us to explore also an additional relaxation mechanism based on charge transferring Andreev reflections. The transition between these two relaxation regimes is identified in the experiment as a marked gate-induced stepwise change in conductance. We present a transport calculation, including YSR bound states and multiple Andreev reflections alongside quasiparticle relaxation, due to a weak tunnel coupling to a nearby normal metal, and obtain excellent agreement with the dat

A novel vasoactive proline-rich oligopeptide from the skin secretion of the frog Brachycephalus ephippium.

Proline-rich oligopeptides (PROs) are a large family which comprises the bradykinin-potentiating peptides (BPPs). They inhibit the activity of the angiotensin I-converting enzyme (ACE) and have a typical pyroglutamyl (Pyr)/proline-rich structure at the N- and C-terminus, respectively. Furthermore, PROs decrease blood pressure in animals. In the present study, the isolation and biological characterization of a novel vasoactive BPP isolated from the skin secretion of the frog Brachycephalus ephippium is described. This new PRO, termed BPP-Brachy, has the primary structure WPPPKVSP and the amidated form termed BPPBrachyNH2 inhibits efficiently ACE in rat serum. In silico molecular modeling and docking studies suggest that BPP-BrachyNH2 is capable of forming a hydrogen bond network as well as multiple van der Waals interactions with the rat ACE, which blocks the access of the substrate to the C-domain active site. Moreover, in rat thoracic aorta BPP-BrachyNH2 induces potent endothelium-dependent vasodilatation with similar magnitude as captopril. In DAF-FM DA-loaded aortic cross sections examined by confocal microscopy, BPP-BrachyNH2 was found to increase the release of nitric oxide (NO). Moreover, BPP-BrachyNH2 was devoid of toxicity in endothelial and smooth muscle cell cultures. In conclusion, the peptide BPP-BrachyNH2 has a novel sequence being the first BPP isolated from the skin secretion of the Brachycephalidae family. This opens for exploring amphibians as a source of new biomolecules. The BPP-BrachyNH2 is devoid of cytotoxicity and elicits endothelium-dependent vasodilatation mediated by NO. These findings open for the possibility of potential application of these peptides in the treatment of endothelial dysfunction and cardiovascular diseases

Detection of ice core particles via deep neural networks

Insoluble particles in ice cores record signatures of past climate parameters like vegetation, volcanic activity or aridity. Their analytical detection depends on intensive bench microscopy investigation and requires dedicated sample preparation steps. Both are laborious, require in-depth knowledge and often restrict sampling strategies. To help overcome these limitations, we present a framework based on Flow Imaging Microscopy coupled to a deep neural network for autonomous image classification of ice core particles. We train the network to classify 7 commonly found classes: mineral dust, felsic and basaltic volcanic ash (tephra), three species of pollen (Corylus avellana, Quercus robur, Quercus suber) and contamination particles that may be introduced onto the ice core surface during core handling operations. The trained network achieves 96.8 % classification accuracy at test time. We present the system’s potentials and limitations with respect to the detection of mineral dust, pollen grains and tephra shards, using both controlled materials and real ice core samples. The methodology requires little sample material, is non destructive, fully reproducible and does not require any sample preparation step. The presented framework can bolster research in the field, by cutting down processing time, supporting human-operated microscopy and further unlocking the paleoclimate potential of ice core records by providing the opportunity to identify an array of ice core particles. Suggestions for an improved system to be deployed within a continuous flow analysis workflow are also presented

Diabetes Stimulates Osteoclastogenesis by Acidosis-Induced Activation of Transient Receptor Potential Cation Channels

Patients with type 1 diabetes have lower bone mineral density and higher risk of fractures. The role of osteoblasts in diabetes-related osteoporosis is well acknowledged whereas the role of osteoclasts (OCLs) is still unclear. We hypothesize that OCLs participate in pathological bone remodeling. We conducted studies in animals (streptozotocin-induced type 1 diabetic mice) and cellular models to investigate canonical and non-canonical mechanisms underlying excessive OCL activation. Diabetic mice show an increased number of active OCLs. In vitro studies demonstrate the involvement of acidosis in OCL activation and the implication of transient receptor potential cation channel subfamily V member 1 (TRPV1). In vivo studies confirm the establishment of local acidosis in the diabetic bone marrow (BM) as well as the ineffectiveness of insulin in correcting the pH variation and osteoclast activation. Conversely, treatment with TRPV1 receptor antagonists re-establishes a physiological OCL availability. These data suggest that diabetes causes local acidosis in the BM that in turn increases osteoclast activation through the modulation of TRPV1. The use of clinically available TRPV1 antagonists may provide a new means to combat bone problems associated with diabetes

Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. Here we report the first identification of a Danish breast and ovarian cancer family heterozygote for mutations in the BRCA1 and BRCA2 genes. The BRCA1 nucleotide 5215G > A/c.5096G > A mutation results in the missense mutation Arg1699Gln, while the BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G is novel. Exon trapping experiments and reverse transcriptase (RT)–PCR analysis revealed that the BRCA2 mutation results in skipping of exon 7, thereby introducing a frameshift and a premature stop codon. We therefore classify the mutation as disease causing. Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family double heterozygote for BRCA1 and BRCA2 mutations

Polymorphisms in immunoregulatory genes and the risk of histologic chorioamnionitis in Caucasoid women: a case control study

BACKGROUND: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. METHODS: Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. RESULTS: Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. CONCLUSION: These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis

Local Government Revenue Mobilisation in Anglophone Africa

This paper examines opportunities and constraints facing local revenue mobilisation in anglophone Africa, with an emphasis on urban settings. It discusses specific revenue instruments and their effects on economic efficiency, income distribution and accountability. In particular, it addresses political and administrative constraints facing various revenue instruments and factors affecting citizens’ compliance. The analysis is illustrated with examples from across anglophone Africa. A general conclusion emerging from the study is that local revenues mobilised in most local government authorities in Africa are necessary but not sufficient to develop and supply adequate services for the fast-growing population. On this basis, areas for further research on local government revenue mobilisation in Africa are identifiedDfI

Influence of experimental set-up and methodology for measurements of metabolic rates and critical swimming speed in Atlantic salmon Salmo salar

In this study, swim‐tunnel respirometry was performed on Atlantic salmon Salmo salar post‐smolts in a 90 l respirometer on individuals and compared with groups or individuals of similar sizes tested in a 1905 l respirometer, to determine if differences between set‐ups and protocols exist. Standard metabolic rate (SMR) derived from the lowest oxygen uptake rate cycles over a 20 h period was statistically similar to SMR derived from back extrapolating to zero swim speed. However, maximum metabolic rate (MMR) estimates varied significantly between swimming at maximum speed, following an exhaustive chase protocol and during confinement stress. Most notably, the mean (±SE) MMR was 511 ± 15 mg O2 kg−1 h−1 in the swim test which was 52% higher compared with 337 ± 9 mg O2 kg−1 in the chase protocol, showing that the latter approach causes a substantial underestimation. Performing group respirometry in the larger swim tunnel provided statistically similar estimates of SMR and MMR as for individual fish tested in the smaller tunnel. While we hypothesised a larger swim section and swimming in groups would improve swimming performance, Ucrit was statistically similar between both set‐ups and statistically similar between swimming alone v. swimming in groups in the larger set‐up, suggesting that this species does not benefit hydrodynamically from swimming in a school in these conditions. Different methods and set‐ups have their own respective limitations and advantages depending on the questions being addressed, the time available, the number of replicates required and if supplementary samplings such as blood or gill tissues are needed. Hence, method choice should be carefully considered when planning experiments and when comparing previous studies.publishedVersio

The Cryo-EM Structure of a Complete 30S Translation Initiation Complex from Escherichia coli

Formation of the 30S initiation complex (30S IC) is an important checkpoint in regulation of gene expression. The selection of mRNA, correct start codon, and the initiator fMet-tRNAfMet requires the presence of three initiation factors (IF1, IF2, IF3) of which IF3 and IF1 control the fidelity of the process, while IF2 recruits fMet-tRNAfMet. Here we present a cryo-EM reconstruction of the complete 30S IC, containing mRNA, fMet-tRNAfMet, IF1, IF2, and IF3. In the 30S IC, IF2 contacts IF1, the 30S subunit shoulder, and the CCA end of fMet-tRNAfMet, which occupies a novel P/I position (P/I1). The N-terminal domain of IF3 contacts the tRNA, whereas the C-terminal domain is bound to the platform of the 30S subunit. Binding of initiation factors and fMet-tRNAfMet induces a rotation of the head relative to the body of the 30S subunit, which is likely to prevail through 50S subunit joining until GTP hydrolysis and dissociation of IF2 take place. The structure provides insights into the mechanism of mRNA selection during translation initiation

Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes