Spin wave dispersion softening in the ferromagnetic Kondo lattice model for manganites

Spin dynamics is calculated in the ferromagnetic (FM) state of the generalized Kondo lattice model taking into account strong on-site correlations between e_g electrons and antiferromagnetic (AFM) exchange among t_{2g} spins. Our study suggests that competing FM double-exchange and AFM super-exchange interaction lead to a rather nontrivial spin-wave spectrum. While spin excitations have a conventional Dq^2 spectrum in the long-wavelength limit, there is a strong deviation from the spin-wave spectrum of the isotropic Heisenberg model close to the zone boundary. The relevance of our results to the experimental data are discussed.Comment: 6 RevTex pages, 3 embedded PostScript figure

Molecular basis of cullin-3 (Cul3) ubiquitin ligase subversion by vaccinia virus protein A55.

BTB-Kelch proteins are substrate-specific adaptors for cullin-3 (Cul3) RING-box-based E3 ubiquitin ligases, mediating protein ubiquitylation for subsequent proteasomal degradation. Vaccinia virus encodes three BTB-Kelch proteins: A55, C2, and F3. Viruses lacking A55 or C2 have altered cytopathic effects in cultured cells and altered pathology in vivo Previous studies have shown that the ectromelia virus orthologue of A55 interacts with Cul3 in cells. We report that the N-terminal BTB-BACK (BB) domain of A55 binds directly to the Cul3 N-terminal domain (Cul3-NTD), forming a 2:2 complex in solution. We solved the structure of an A55BB/Cul3-NTD complex from anisotropic crystals diffracting to 2.3/3.7 Å resolution in the best/worst direction, revealing that the overall interaction and binding interface closely resemble the structures of cellular BTB/Cul3-NTD complexes, despite low sequence identity between A55 and cellular BTB domains. Surprisingly, despite this structural similarity, the affinity of Cul3-NTD for A55BB was stronger than for cellular BTB proteins. Glutamate substitution of the A55 residue Ile-48, adjacent to the canonical φX(D/E) Cul3-binding motif, reduced affinity of A55BB for Cul3-NTD by at least 2 orders of magnitude. Moreover, Ile-48 and the φX(D/E) motif are conserved in A55 orthologues from other poxviruses, but not in the vaccinia virus proteins C2 or F3. The high-affinity interaction between A55BB and Cul3-NTD suggests that, in addition to directing the Cul3-RING E3 ligase complex to degrade cellular/viral target proteins that are normally unaffected, A55 may also sequester Cul3 from cellular adaptor proteins, thereby protecting substrates of these cellular adaptors from ubiquitylation and degradation.Wellcome Trust, Royal Societ

UK Environmental Change Network stakeholder consultation

During the Environmental Change Network (ECN) site mangers meeting feedback on the role of UK-SCAPE funding was sought. Representatives from collaborating institutions did not restrict their comments to only the period of UK-SCAPE, as this program is a continuation of previous national capability funding. The stakeholders present appreciated the role of UKCEH through the processes of co-design, co-delivery and co-development in shaping the ECN. They further commented on the co-dependency conferred by the network for their institutions and sites. While several stakeholders noted that they could not benefit directly from UK-SCAPE funding they recognised that funding was required for coordination of the network in addition to collecting monitoring data. They highlighted the risk of failure of the network and the lost opportunities in terms of collaborative working and data delivery to the research community if funding is not maintained in the network

The UK Environmental Change Network datasets – integrated and co-located data for long-term environmental research (1993–2015)

Long-term datasets of integrated environmental variables, co-located together, are relatively rare. The UK Environmental Change Network (ECN) was launched in 1992 and provides the UK with its only long-term integrated environmental monitoring and research network for the assessment of the causes and consequences of environmental change. Measurements, covering a wide range of physical, chemical, and biological “driver” and “response” variables are made in close proximity at ECN terrestrial sites using protocols incorporating standard quality control procedures. This paper describes the datasets (there are 19 published ECN datasets) for these co-located measurements, containing over 20 years of data (1993–2015). The data and supporting documentation are freely available from the NERC Environmental Information Data Centre under the terms of the Open Government Licence (see paper for DOIs)

Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells

The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase-1 and caspase-4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as interleukin (IL)-1β and IL-18. Here we report that the effector NleF binds the catalytic domain of caspase-4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase-4 and IL-18 processing in an NleF-dependent manner. Depletion of caspase-4 in IECs prevented the secretion of mature IL-18 in response to infection with EPECΔnleF. NleF-dependent inhibition of caspase-11 in colons of mice prevented IL-18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild-type C. rodentium nor C. rodentiumΔnleF triggered neutrophil infiltration or IL-18 secretion in Cas11 or Casp1/11-deficient mice. Thus, IECs have a key role in modulating early innate immune responses in the gut via a caspase-4/11—IL-18 axis, which is targeted by virulence factors encoded by enteric pathogens

Point-of-care serological assays for delayed SARS-CoV-2 case identification among health-care workers in the UK: a prospective multicentre cohort study

BACKGROUND: Health-care workers constitute a high-risk population for acquisition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Capacity for acute diagnosis via PCR testing was limited for individuals with mild to moderate SARS-CoV-2 infection in the early phase of the COVID-19 pandemic and a substantial proportion of health-care workers with suspected infection were not tested. We aimed to investigate the performance of point-of-care and laboratory serology assays and their utility in late case identification, and to estimate SARS-CoV-2 seroprevalence. METHODS: We did a prospective multicentre cohort study between April 8 and June 12, 2020, in two phases. Symptomatic health-care workers with mild to moderate symptoms were eligible to participate 14 days after onset of COVID-19 symptoms, as per the Public Health England (PHE) case definition. Health-care workers were recruited to the asymptomatic cohort if they had not developed PHE-defined COVID-19 symptoms since Dec 1, 2019. In phase 1, two point-of-care lateral flow serological assays, the Onsite CTK Biotech COVID-19 split IgG/IgM Rapid Test (CTK Bitotech, Poway, CA, USA) and the Encode SARS-CoV-2 split IgM/IgG One Step Rapid Test Device (Zhuhai Encode Medical Engineering, Zhuhai, China), were evaluated for performance against a laboratory immunoassay (EDI Novel Coronavirus COVID-19 IgG ELISA kit [Epitope Diagnostics, San Diego, CA, USA]) in 300 samples from health-care workers and 100 pre-COVID-19 negative control samples. In phase 2 (n=6440), serosurveillance was done among 1299 (93·4%) of 1391 health-care workers reporting symptoms, and in a subset of asymptomatic health-care workers (405 [8·0%] of 5049). FINDINGS: There was variation in test performance between the lateral flow serological assays; however, the Encode assay displayed reasonable IgG sensitivity (127 of 136; 93·4% [95% CI 87·8-96·9]) and specificity (99 of 100; 99·0% [94·6-100·0]) among PCR-proven cases and good agreement (282 of 300; 94·0% [91·3-96·7]) with the laboratory immunoassay. By contrast, the Onsite assay had reduced sensitivity (120 of 136; 88·2% [95% CI 81·6-93·1]) and specificity (94 of 100; 94·0% [87·4-97·8]) and agreement (254 of 300; 84·7% [80·6-88·7]). Five (7%) of 70 PCR-positive cases were negative across all assays. Late changes in lateral flow serological assay bands were recorded in 74 (9·3%) of 800 cassettes (35 [8·8%] of 400 Encode assays; 39 [9·8%] of 400 Onsite assays), but only seven (all Onsite assays) of these changes were concordant with the laboratory immunoassay. In phase 2, seroprevalence among the workforce was estimated to be 10·6% (95% CI 7·6-13·6) in asymptomatic health-care workers and 44·7% (42·0-47·4) in symptomatic health-care workers. Seroprevalence across the entire workforce was estimated at 18·0% (95% CI 17·0-18·9). INTERPRETATION: Although a good positive predictive value was observed with both lateral flow serological assays and ELISA, this agreement only occurred if the pre-test probability was modified by a strict clinical case definition. Late development of lateral flow serological assay bands would preclude postal strategies and potentially home testing. Identification of false-negative results among health-care workers across all assays suggest caution in interpretation of IgG results at this stage; for now, testing is perhaps best delivered in a clinical setting, supported by government advice about physical distancing. FUNDING: None

Variability in detection of SARS-CoV-2-specific antibody responses following mild infection: a prospective multicentre cross-sectional study, London, United Kingdom, 17 April to 17 July 2020

Introduction Immunoassays targeting different SARS-CoV-2-specific antibodies are employed for seroprevalence studies. The degree of variability between immunoassays targeting anti-nucleocapsid (anti-NP; the majority) vs the potentially neutralising anti-spike antibodies (including anti-receptor-binding domain; anti-RBD), particularly in mild or asymptomatic disease, remains unclear. Aims We aimed to explore variability in anti-NP and anti-RBD antibody detectability following mild symptomatic or asymptomatic SARS-CoV-2 infection and analyse antibody response for correlation with symptomatology. Methods A multicentre prospective cross-sectional study was undertaken (April–July 2020). Paired serum samples were tested for anti-NP and anti-RBD IgG antibodies and reactivity expressed as binding ratios (BR). Multivariate linear regression was performed analysing age, sex, time since onset, symptomatology, anti-NP and anti-RBD antibody BR. Results We included 906 adults. Antibody results (793/906; 87.5%; 95% confidence interval: 85.2–89.6) and BR strongly correlated (ρ = 0.75). PCR-confirmed cases were more frequently identified by anti-RBD (129/130) than anti-NP (123/130). Anti-RBD testing identified 83 of 325 (25.5%) cases otherwise reported as negative for anti-NP. Anti-NP presence (+1.75/unit increase; p < 0.001), fever (≥ 38°C; +1.81; p < 0.001) or anosmia (+1.91; p < 0.001) were significantly associated with increased anti-RBD BR. Age (p = 0.85), sex (p = 0.28) and cough (p = 0.35) were not. When time since symptom onset was considered, we did not observe a significant change in anti-RBD BR (p = 0.95) but did note decreasing anti-NP BR (p < 0.001). Conclusion SARS-CoV-2 anti-RBD IgG showed significant correlation with anti-NP IgG for absolute seroconversion and BR. Higher BR were seen in symptomatic individuals, particularly those with fever. Inter-assay variability (12.5%) was evident and raises considerations for optimising seroprevalence testing strategies/studies

Therapeutic potential of TLR8 agonist GS-9688 (selgantolimod) in chronic hepatitis B: re-modelling of antiviral and regulatory mediators

Background & Aims: GS‐9688 (selgantolimod) is a toll‐like receptor 8 (TLR8) agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS‐9688 has previously been evaluated in vitro in hepatitis B virus (HBV)‐infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS‐9688 to boost responses contributing to viral control and to modulate regulatory mediators. Approach & Results: We characterised the effect of GS‐9688 on immune cell subsets in vitro in PBMC of healthy controls and CHB patients. GS‐9688 activated dendritic cells and mononuclear phagocytes to produce IL‐12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and CHB patients. GS‐9688 increased the frequency of activated natural killer (NK) cells, mucosal‐associated invariant T‐cells (MAITs), CD4+ follicular helper T‐cells (TFH) and, in ~50% of patients, HBV‐specific CD8+T‐cells expressing interferon‐γ (IFNγ). Moreover, in vitro stimulation with GS‐9688 induced NK cell expression of IFNγ and TNFα and promoted hepatocyte lysis. We also assessed whether GS‐9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS‐9688 reduced the frequency of CD4+ regulatory T‐cells and monocytic myeloid‐derived suppressor cells (MDSC). Residual MDSC expressed higher levels of negative immune regulators, galectin‐9 and PD‐L1. Conversely, GS‐9688 induced an expansion of immunoregulatory TNF‐related apoptosis‐inducing ligand+ (TRAIL) regulatory NK cells and degranulation of arginase‐I+ polymorphonuclear‐MDSC (PMN‐MDSC). Conclusions: GS‐9688 induces cytokines in human PBMC that are able to activate antiviral effector function by multiple immune mediators (HBV‐specific CD8+T‐cells, TFH, NK cells and MAITs). Whilst reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimise the antiviral efficacy of GS‐9688

Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility study.

BACKGROUND: There is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children. OBJECTIVE: To assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA. DESIGN: (1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families' views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting. SETTING: Forty-four UK secondary and tertiary UK centres (service evaluation). PARTICIPANTS: Children with OM/SA. INTERVENTIONS: PCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study. RESULTS: Data were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral antibiotics, recurrence of infection, disability at follow-up, symptom free at 1 year, limb shortening or deformity, chronic OM or arthritis, amputation or fasciotomy, death, need for paediatric intensive care, and line infection. Oral switch criteria were identified, including resolution of fever for ≥ 48 hours, tolerating oral food and medicines, and pain improvement. LIMITATIONS: Data were collected in a 6-month period, which might not have been representative, and follow-up data for long-term complications are limited. CONCLUSIONS: A future RCT would need to recruit from all tertiary and most secondary UK hospitals. Clinicians have implemented early oral switch for selected patients with simple disease without formal clinical trial evidence of safety. However, the current criteria by which decisions to make the oral switch are made are not clearly established or evidence based. FUTURE WORK: A RCT in simple OM and SA comparing shorter- or longer-course i.v. therapy is feasible in children randomised after oral switch criteria are met after 7 days of i.v. therapy, excluding children meeting oral switch criteria in the first week of i.v. therapy. This study design meets clinician preferences and addresses parental concerns not to randomise prior to oral switch criteria being met. FUNDING: The National Institute for Health Research Health Technology Assessment programme