Supramolecular amplification of amyloid self-assembly by iodination

Amyloid supramolecular assemblies have found widespread exploitation as ordered nanomaterials in a range of applications from materials science to biotechnology. New strategies are, however, required for understanding and promoting mature fibril formation from simple monomer motifs through easy and scalable processes. Noncovalent interactions are key to forming and holding the amyloid structure together. On the other hand, the halogen bond has never been used purposefully to achieve control over amyloid self-assembly. Here we show that single atom replacement of hydrogen with iodine, a halogen-bond donor, in the human calcitonin-derived amyloidogenic fragment DFNKF results in a super-gelator peptide, which forms a strong and shape-persistent hydrogel at 30-fold lower concentration than the wild-type pentapeptide. This is remarkable for such a modest perturbation in structure. Iodination of aromatic amino acids may thus develop as a general strategy for the design of new hydrogels from unprotected peptides and without using organic solvents

A synthetically modified hydrophobin showing enhanced fluorous affinity

Hydrophobins are natural surfactant proteins endowed with exceptional surface activity and film-forming capabilities and their use as effective “fluorine-free fluorosurfactants” has been recently reported. In order to increase their fluorophilicity further, here we report the preparation of a unique fluorous-modified hydrophobin, named F-HFBI. F-HFBI was found to be more effective than its wild-type parent protein HFBI at reducing interface tension of water at both air/water and oil/water interfaces, being particularly effective at the fluorous/water interface. F-HFBI was also found to largely retain the exceptionally good capability of forming strong and elastic films, typical of the hydrophobin family. Further studies by interface shear rheology and isothermal compression, alongside Quartz Crystal Microbalance and Atomic Force Microscopy, demonstrated the tendency of F-HFBI to form thicker films compared to the wild-type protein. These results suggest that F-HFBI may function as an effective compatibilizer for biphasic systems comprising a fluorous phase

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both

Importance Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. Objective To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. Design, Setting, and Participants The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. Interventions Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. Main Outcomes and Measures Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression–free interval, total SREs, and overall survival (OS). Results Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). Conclusions and Relevance Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy

A baseline survey of potentially toxic elements in the soil of north-west Syria following a decade of conflict

We present the first region-wide chemical survey of soils in NW Syria following more than a decade of ongoing conflict. We sampled topsoil at 66 sites, typically located in marginal agricultural (orchards, arable) or peri-urban settings, grouped around 21 localities covering the whole area of NW Syria currently under Syrian Opposition control. Samples were analysed in the UK using ICP-MS and ICP-OES. Topsoil total concentrations of heavy metals are broadly consistent with pre-war data from Aleppo and recent data from nearby Turkey. Principal Components Analysis (PCA) of associations among the sampling sites identified three groupings. Ni (133.30 ± 72.12 mg/kg) and Cr (122.14 ± 52.25 mg/kg) exist in all samples at levels in excess of typical European guideline thresholds for agricultural soil. Observed Cd (0.57 ± 0.93 mg/kg), Co (23.07 ± 18.48 mg/kg) and As (6.65 ± 4.51 mg/kg) concentrations are up to three times comparable values from nearby agricultural regions in southern Turkey. Maximum observed values for Cd, As, and Co, which exceed EU thresholds, are concentrated in a corridor around Sarmada to the west of Aleppo which has seen some of the most intense conflict-related impacts. Cu (28.33 ± 17.11 mg/kg), Pb (15.65 ± 10.85 mg/kg) and Zn (73.64 ± 40.15 mg/kg) also observe maxima in the Sarmada corridor, but show a more even distribution across the region, widely at values above comparable regional values for agriculture but below EU threshold concentrations. We interpret the occurrence of Ni-Cr as consistent with intensive agriculture using wastewater-contaminated irrigation and fertilisers. Cd-As-Co and Cu-Pb-Zn are likely anthropogenic and reflect intense pressures of conflict, informal settlement, unregulated industry and untreated wastewater irrigation on a historically agricultural region. The sampling method was designed to capture regional variations from a minimal dataset and it is likely that local topsoil concentrations at specific points of impact (proximal to locations of shelling, industry, effluent release or population) will be considerably higher than those reported here. This study establishes an important baseline reference for further targeted studies to identify and mitigate specific pollution hazards in this region of ongoing, extreme humanitarian and ecological threat

Examining the immunological effects of COVID-19 vaccination in patients with conditions potentially leading to diminished immune response capacity – the OCTAVE trial

SARS-COV-2 vaccines have been shown to be efficacious primarily in healthy volunteer populations and population level studies. Immune responses following SARS-CoV-2 vaccination are less well characterised in potentially immune vulnerable patient groups, including those with immune-mediated inflammatory and chronic diseases (inflammatory arthritis [IA] incorporating rheumatoid arthritis [RA] and psoriatic arthritis [PsA]; ANCA-Associated Vasculitis [AAV]; inflammatory bowel disease [IBD]); hepatic disease (HepD), end stage kidney disease requiring haemodialysis (HD) without or with immunosuppression (HDIS); solid cancers (SC) and haematological malignancies (HM), and those that have undergone haemopoietic stem cell transplant (HSCT). The OCTAVE trial is a multi-centre, multi-disease, prospective cohort that will comprehensively assess SARS-CoV-2 vaccine responses within and between the abovementioned disease cohorts using common analytical platforms in patients recruited across the United Kingdom (UK). The majority of subjects received either COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) or ChAdOx1 Vaccine (AstraZeneca formerly AZD1222) as part of the UK National COVID19 vaccination programme. As of 13 th August 2021; 2,583 patients have been recruited. We report herein the humoral and T cell immune response results from the first 600 participants recruited where serology data are available at baseline, pre-second vaccine dose (boost) and/or 4 weeks post second dose. We also include in the analysis, data obtained from 231 healthy individuals from the PITCH (Protective Immunity from T cells in Healthcare workers) study. Overall, in comparison to PITCH where 100% of tested individuals (n=93) generated anti-Spike antibodies after vaccine doses, 89% of patients within OCTAVE seroconverted 4 weeks after second vaccine dose. By corollary, approximately 11% of patients across all disease cohorts fail to generate antibodies that react to SARS-CoV-2 spike 4 weeks after two vaccines. Failure to generate spike reactive antibodies was found at a higher proportion in some specific patient subgroups, particularly AAV (72.4%), HD-IS (16.7%) and HepD (16.7%). Importantly, all recruited AAV patients had received Rituximab; a targeted B cell depletion therapy. Furthermore, even in those who seroconverted, 40% of patients across disease cohorts generate lower levels of SARS-CoV-2 antibody reactivity compared to healthy subjects after two SARS-CoV-2 vaccines; the functional significance of these findings in providing protection from subsequent SARS-CoV-2 exposure is not currently known. In contrast to the observed serological response, evaluation of the Spike-specific T cell response revealed that across all patient sub-groups (including AAV) a response similar to healthy individuals was generated. Our data argue strongly for further vaccination strategies to optimise humoral immune responses against SARS-CoV-2 in patients with chronic diseases and/or patients on immune suppressive therapies. Trial Registration: The trial is registered on ISRCTN 12821688.Funding: This work was supported by the Medical Research Council COVID-19 Immunity – National Core Study (IMM-NCS) [grant number MC-PC-20031]. Staff at the Cancer Research UK Clinical Trials Unit (CRCTU) are supported by a core funding grant from Cancer Research UK (C22436/A25354). PK and EB are supported by the NIHR Birmingham Biomedical Research Centres at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham Biomedical Research Centres. EB and PK are supported by an NIHR Senior Investigator award. PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z), the U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. The PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, is funded by the UK Department of Health and Social Care with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UKCIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS).Declaration of Interest: None to declare. Ethical Approval: This study was approved by the UK Medicines and Healthcare Products Regulatory Agency on the 5th February 2021 and the London and Chelsea Research Ethics Committee (REC Ref:21/HRA/0489) on 12th February 2021, with subsequent amendments approved on 3rd March 2021, 19th April 2021 and 26th April 2021)

Sodium Chloride Inhibits the Growth and Infective Capacity of the Amphibian Chytrid Fungus and Increases Host Survival Rates

The amphibian chytrid fungus Batrachochytrium dendrobatidis is a recently emerged pathogen that causes the infectious disease chytridiomycosis and has been implicated as a contributing factor in the global amphibian decline. Since its discovery, research has been focused on developing various methods of mitigating the impact of chytridiomycosis on amphibian hosts but little attention has been given to the role of antifungal agents that could be added to the host's environment. Sodium chloride is a known antifungal agent used routinely in the aquaculture industry and this study investigates its potential for use as a disease management tool in amphibian conservation. The effect of 0–5 ppt NaCl on the growth, motility and survival of the chytrid fungus when grown in culture media and its effect on the growth, infection load and survivorship of infected Peron's tree frogs (Litoria peronii) in captivity, was investigated. The results reveal that these concentrations do not negatively affect the survival of the host or the pathogen. However, concentrations greater than 3 ppt significantly reduced the growth and motility of the chytrid fungus compared to 0 ppt. Concentrations of 1–4 ppt NaCl were also associated with significantly lower host infection loads while infected hosts exposed to 3 and 4 ppt NaCl were found to have significantly higher survival rates. These results support the potential for NaCl to be used as an environmentally distributed antifungal agent for the prevention of chytridiomycosis in susceptible amphibian hosts. However, further research is required to identify any negative effects of salt exposure on both target and non-target organisms prior to implementation

Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma

Background: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. Methods: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. Results: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. Conclusions: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC

Stable isotope and minor element proxies for Eocene climate of Seymour Island, Antarctica

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94846/1/palo900.pd