High-sensitivity heat-capacity measurements on Sr2RuO4 under uniaxial pressure

A key question regarding the unconventional superconductivity of Sr2RuO4 remains whether the order parameter is single- or two-component. Under a hypothesis of two-component superconductivity, uniaxial pressure is expected to lift their degeneracy, resulting in a split transition. The most direct and fundamental probe of a split transition is heat capacity. Here, we report measurement of heat capacity of samples subject to large and highly homogeneous uniaxial pressure. We place an upper limit on the heat-capacity signature of any second transition of a few percent of that of the primary superconducting transition. The normalized jump in heat capacity, ΔC/C, grows smoothly as a function of uniaxial pressure, favoring order parameters which are allowed to maximize in the same part of the Brillouin zone as the well-studied van Hove singularity. Thanks to the high precision of our measurements, these findings place stringent constraints on theories of the superconductivity of Sr2RuO4.

Obtaining a full understanding of the superconductivity of Sr2RuO4 is a core challenge for condensed-matter physics. Since soon after its discovery over a quarter of a century ago (1), the superconducting order parameter of Sr2RuO4 has been known to be unconventional (2, 3) and to condense from a well-understood and fairly simple quasi-two-dimensional Fermi liquid metallic state (4–7). Given the profound advances in theoretical techniques in recent decades a full understanding of its superconductivity is an important, and attainable, challenge for the field. The form of the wave-vector-dependent susceptibility of Sr2RuO4 leads to the prediction of a rich superconducting phase diagram in weak-coupling calculations which aim to perform a bias-free estimate of the condensation energies of different order parameters. A notable feature of the results is how close a number of different odd- and even-parity solutions are seen to be in energy (8–10). On the one hand, this emphasizes the potential of Sr2RuO4 as a test-bed material on which to refine the predictive capabilities of modern theories of unconventional superconductivity (11). On the other hand, realizing this potential will likely first require a conclusive experimental determination of which of the many possible order parameters wins out in the real material. This is a particularly exciting stage of the quest to complete this empirical determination, for reasons that we will now outline.For over 20 y the large majority of attention was paid to odd-parity order parameter candidates for Sr2RuO4 (12), because of NMR measurements of spin susceptibility in the superconducting state that seemed to be inconsistent with any even-parity order parameter (13). However, thanks to the discovery of a systematic error in the original NMR measurements (14, 15), that situation has now been more or less completely reversed. Taking into account the most recent measurements of the magnetic field dependence of the spin susceptibility (16), it seems clear that the order parameter must be even-parity or at least dominated by an even-parity component. The spin susceptibility results would be most easily describable in terms of a single-component, likely d-wave, order parameter, but recent thermodynamic evidence from ultrasound experiments is most straightforwardly interpreted in terms of an order parameter with two degenerate components (17, 18). Such order parameters do not of necessity break time-reversal symmetry, but they can, if the two degenerates have the appropriate phase relationship. In the context it is significant that long-standing muon-spin relaxation (μSR) (19, 20) and magneto-optic Kerr rotation measurements (21) have indicated time-reversal symmetry breaking in the superconducting state.To investigate any order parameter with two degenerate components, whether or not it breaks time-reversal symmetry, uniaxial pressure is a powerful probe because it can split the degeneracy, creating a split superconducting phase transition (22). In a significant experimental advance, the muon-spin relaxation experiments have recently been extended to high uniaxial pressures (23). In line with naive expectation, the temperature at which time-reversal symmetry is broken (TTRSB) splits from the main superconducting transition (Tc), with TTRSB remaining nearly pressure-independent while Tc increases under the application of the pressure. However, there has been a long-standing question about whether the Kerr and muon signals correspond to bulk thermodynamic transitions, so it is highly desirable to compare the new muon-spin relaxation data with those from a bulk thermodynamic probe. In this context, it is natural to look at heat capacity, because it has an intrinsic sensitivity to transitions within the superconducting state, as is well known from work on UPt3 (24, 25).     

Structural Variations of the Cell Wall Precursor Lipid II and Their Influence on Binding and Activity of the Lipoglycopeptide Antibiotic Oritavancin

Oritavancin is a semisynthetic derivative of the glycopeptide antibiotic chloroeremomycin with activity against Gram-positive pathogens, including vancomycin-resistant staphylococci and enterococci. Compared to vancomycin, oritavancin is characterized by the presence of two additional residues, a hydrophobic 4′-chlorobiphenyl methyl moiety and a 4-epi-vancosamine substituent, which is also present in chloroeremomycin. Here, we show that oritavancin and its des-N-methylleucyl variant (des-oritavancin) effectively inhibit lipid I- and lipid II-consuming peptidoglycan biosynthesis reactions in vitro. In contrast to that for vancomycin, the binding affinity of oritavancin to the cell wall precursor lipid II appears to involve, in addition to the d-Ala-d-Ala terminus, other species-specific binding sites of the lipid II molecule, i.e., the crossbridge and d-isoglutamine in position 2 of the lipid II stem peptide, both characteristic for a number of Gram-positive pathogens, including staphylococci and enterococci. Using purified lipid II and modified lipid II variants, we studied the impact of these modifications on the binding of oritavancin and compared it to those of vancomycin, chloroeremomycin, and des-oritavancin. Analysis of the binding parameters revealed that additional intramolecular interactions of oritavancin with the peptidoglycan precursor appear to compensate for the loss of a crucial hydrogen bond in vancomycin-resistant strains, resulting in enhanced binding affinity. Augmenting previous findings, we show that amidation of the lipid II stem peptide predominantly accounts for the increased binding of oritavancin to the modified intermediates ending in d-Ala-d-Lac. Corroborating our conclusions, we further provide biochemical evidence for the phenomenon of the antagonistic effects of mecA and vanA resistance determinants in Staphylococcus aureus, thus partially explaining the low frequency of methicillin-resistant S. aureus (MRSA) acquiring high-level vancomycin resistance.     

Myopia in young patients with type 1 diabetes mellitus

INTRODUCTION

This study aimed to evaluate the proportion of young patients with type 1 diabetes mellitus (T1DM) who have myopia, as well as the risk factors associated with myopia in this group.

METHODS

In this cross-sectional study, patients aged < 21 years with T1DM for ≥ 1 year underwent a comprehensive eye examination. Presence of parental myopia, and average hours of near-work and outdoor activity were estimated using a questionnaire. Annualised glycosylated haemoglobin (HbA1c), defined as the mean of the last three HbA1c readings taken over the last year, was calculated. Multivariate analysis using genetic, environmental and diabetes-related factors was done to evaluate risk factors associated with myopia.

RESULTS

Of the 146 patients (mean age 12.5 ± 3.6 years) recruited, 66.4% were Chinese and 57.5% were female. Myopia (i.e. spherical equivalent [SE] of –0.50 D or worse) was present in 96 (65.8%) patients. The proportion of patients with myopia increased from 25.0% and 53.6% in those aged < 7.0 years and 7.0–9.9 years, respectively, to 59.2% and 78.4% in those aged 10.0–11.9 years and ≥ 12.0 years, respectively. Higher levels of SE were associated with lower parental myopia (p = 0.024) and higher annualised HbA1c (p = 0.011).

CONCLUSION

Compared to the background population, the proportion of myopia in young patients with T1DM was higher in those aged < 10 years but similar in the older age group. Myopia was associated with a history of parental myopia. Environmental risk factors and poor glycaemic control were not related to higher myopia risk.     

Narrow-band imaging optical chromocolonoscopy： Advantages and limitations

Narrow-band imaging （NBI） is an innovative optical technology that modifies the center wavelength and bandwidth of an endoscope＇s light into narrow-band illumination of 415 ：1： 30 nm. NBI markedly improves capillary pattern contrast and is an in vivo method for visualizing microvessel morphological changes in superficial neoplastic lesions. The scientific basis for NBI is that short wavelength light falls within the hemoglobin absorption band, thereby facilitating clearer visualization of vascular structures. Several studies have reported advantages and limitations of NBI colonoscopy in the colorectum. One difficulty in evaluating results, however, has been nonstandardization of NBI systems （Sequential and nonsequential）. Utilization of NBI technology has been increasing worldwide, but accurate pit pattern analysis and sufficient skill in magnifying colonoscopy are basic fundamentals required for proficiency in NBI diagnosis of colorectal lesions. Modern optical technology without proper image interpretation wastes resources, confuses untrained endoscopists and delays interinstitutional validation studies. Training in the principles of ＂optical image-enhanced endoscopy＂ is needed to close the gap between technological advancements and their clinical usefulness. Currently available evidence indicates that NBI constitutes an effective and reliable alternative to chromocolonoscopy for in vivo visualization of vascular structures, but further study assessing reproducibility and effectiveness in the colorectum is ongoing at various medical centers.     

Comparison of Two Commercial Tick-Borne Encephalitis Virus IgG Enzyme-Linked Immunosorbent Assays

Despite the availability of protective vaccines, tick-borne encephalitis virus (TBEV) infections have been increasingly reported to the European Centre for Disease Prevention and Control in the past 2 decades. Since the diagnosis of TBEV exposure relies on serological testing, we compared two commercial enzyme-linked immunosorbent assays (ELISAs), i.e., Immunozym FSME IgG assay (ELISA-1) and Euroimmun FSME Vienna IgG assay (ELISA-2). Both assays use whole TBEV antigens, but they differ in viral strains (Neudoerfl for ELISA-1 and K23 for ELISA-2) and cutoff values. In testing of samples from 398 healthy blood donors, ELISA-1 showed higher reactivity levels than ELISA-2 (P < 0.001), suggesting different assay properties. This finding was supported by Bland-Altman analysis of the optical density at 450 nm (OD₄₅₀) (mean bias, +0.32 [95% limits of agreement, −0.31 to +0.95]) and persisted after transformation into Vienna units. Concordant results were observed for 276 sera (69%) (44 positive and 232 negative results). Discordant results were observed for 122 sera (31%); 15 were fully discordant, all being ELISA-1 positive and ELISA-2 negative, and 107 were partially discordant (101 being ELISA-1 indeterminate and ELISA-2 negative and 6 having positive or indeterminate reactivity in both ELISAs). Neutralization testing at a 1:10 dilution yielded positive results for 33 of 44 concordant positive sera, 1 of 15 fully discordant sera, and 1 of 33 partially discordant sera. Indirect immunofluorescence testing revealed high antibody titers of ≥100 for yellow fever virus in 18 cases and for dengue virus in one case, suggesting that cross-reactivity contributed to the ELISA-1 results. We conclude that (i) cross-reactivity among flaviviruses remains a limitation of TBEV serological testing, (ii) ELISA-2 revealed reasonable sensitivity and specificity for anti-TBEV IgG population screening of human sera, and (iii) neutralization testing is most specific and should be reserved for selective questions.     

Lineage fate of ductular reactions in liver injury and carcinogenesis

Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.     

Disentangling the lifespans of hepatitis C virus‐infected cells and intracellular vRNA replication‐complexes during direct‐acting anti‐viral therapy

The decay rate of hepatitis C virus (HCV)‐infected cells during therapy has been used to determine the duration of treatment needed to attain a sustained virologic response, but with direct‐acting anti‐virals (DAA), this rate has been difficult to estimate. Here, we show that it is possible to estimate it, by simultaneously analysing the viral load and alanine aminotransferase (ALT) kinetics during combination DAA therapy. We modelled the HCV RNA and ALT serum kinetics in 26 patients with chronic HCV genotype 1b infection, under four different sofosbuvir‐based combination treatments. In all patients, ALT decayed exponentially to a set point in the normal range by 1‐3 weeks after initiation of therapy. The model indicates that the ALT decay rate during the first few weeks after initiation of therapy reflects the death rate of infected cells, with an estimated median half‐life of 2.5 days in this patient population. This information allows independent estimation of the rate of loss of intracellular replication complexes during therapy. Our model also predicts that the final ALT set point is not related to the release of ALT by dying HCV‐infected cells. Using ALT data, one can separately obtain information about the rate of ‘cure’ of HCV‐infected cells versus their rate of death, something not possible when analysing only HCV RNA data. This information can be used to compare the effects of different DAA combinations and to rationally evaluate their anti‐viral effects.     

Matrix Metalloproteinase Inhibition Lowers Mortality and Brain Injury in Experimental Pneumococcal Meningitis

Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1β (IL-1β) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.