Triple-fusion protein (TriFu): A potent, targeted, enzyme-like inhibitor of all three complement activation pathways.

The introduction of a therapeutic anti-C5 antibody into clinical practice in 2007 inspired a surge into the development of complement-targeted therapies. This has led to the recent approval of a C3 inhibitory peptide, an antibody directed against C1s and a full pipeline of several complement inhibitors in preclinical and clinical development. However, no inhibitor is available that efficiently inhibits all three complement initiation pathways and targets host cell surface markers as well as complement opsonins. To overcome this, we engineered a novel fusion protein combining selected domains of the three natural complement regulatory proteins decay accelerating factor, factor H and complement receptor 1. Such a triple fusion complement inhibitor (TriFu) was recombinantly expressed and purified alongside multiple variants and its building blocks. We analyzed these proteins for ligand binding affinity and decay acceleration activity by surface plasmon resonance. Additionally, we tested complement inhibition in several in vitro/ex vivo assays using standard classical and alternative pathway restricted hemolysis assays next to hemolysis assays with paroxysmal nocturnal hemoglobinuria erythrocytes. A novel in vitro model of the alternative pathway disease C3 glomerulopathy was established to evaluate the potential of the inhibitors to stop C3 deposition on endothelial cells. Next to the novel engineered triple fusion variants which inactivate complement convertases in an enzyme-like fashion, stoichiometric complement inhibitors targeting C3, C5, factor B, and factor D were tested as comparators. The triple fusion approach yielded a potent complement inhibitor that efficiently inhibits all three complement initiation pathways while targeting to surface markers.

In Situ MOF-74-Pyrolysis-Generated Porous Carbon Supporting Spinel Cu0.15Co2.85O4/C Boosts Ammonium Perchlorate Accelerating Decomposition: Precise Cu Doping Modulating Oxygen Vacancy Concentration.

As one of the main components of solid propellant, ammonium perchlorate (AP) shows slow sluggish decomposition kinetics with unconcentrated heat release. To achieve efficient catalytical decomposition, it is a significant challenge to design reasonable catalyst structure and explore the interaction between catalyst and AP. Herein, a series of porous carbon supported spinel-typed homogeneous heterometallic composites CuxCo3-xO4/C via pyrolysis of MOF-74-Co doped Cu. On basis of precise electronic-structure-tuning through modulating Cu/Co ratio in MOF-74, Cu0.15Co2.85O4/C with 5% Cu-doping featuring oxygen vacancy concentration of 26.25% exhibits the decrease to 261.5 °C with heat release up to 1222.1 J g-1 (456.9 °C and 669.2 J g-1 for pure AP). The detail process of AP accelerated decomposition is approved by TG-DSC-FTIR-MS technique. Density functional theory calculation revealed that in the Cu0.15Co2.85O4/C, the distinctive ability for NH3 catalyzed oxidation assisted with absorption performance of active porous C boosts accelerating AP decomposition. The findings would provide an insight for perceiving and understanding AP catalytic decomposition.

JUST-Net: Jointly unrolled cross-domain optimization based spatio-temporal reconstruction network for accelerated 3D myelin water imaging.

PURPOSE: We introduced a novel reconstruction network, jointly unrolled cross-domain optimization-based spatio-temporal reconstruction network (JUST-Net), aimed at accelerating 3D multi-echo gradient-echo (mGRE) data acquisition and improving the quality of resulting myelin water imaging (MWI) maps. METHOD: An unrolled cross-domain spatio-temporal reconstruction network was designed. The main idea is to combine frequency and spatio-temporal image feature representations and to sequentially implement convolution layers in both domains. The k-space subnetwork utilizes shared information from adjacent frames, whereas the image subnetwork applies separate convolutions in both spatial and temporal dimensions. The proposed reconstruction network was evaluated for both retrospectively and prospectively accelerated acquisition. Furthermore, it was assessed in simulation studies and real-world cases with k-space corruptions to evaluate its potential for motion artifact reduction. RESULTS: The proposed JUST-Net enabled highly reproducible and accelerated 3D mGRE acquisition for whole-brain MWI, reducing the acquisition time from fully sampled 15:23 to 2:22 min within a 3-min reconstruction time. The normalized root mean squared error of the reconstructed mGRE images increased by less than 4.0%, and the correlation coefficients for MWI showed a value of over 0.68 when compared to the fully sampled reference. Additionally, the proposed method demonstrated a mitigating effect on both simulated and clinical motion-corrupted cases. CONCLUSION: The proposed JUST-Net has demonstrated the capability to achieve high acceleration factors for 3D mGRE-based MWI, which is expected to facilitate widespread clinical applications of MWI.

Fish decay-accelerating factor (DAF) regulates intestinal complement pathway and immune response to bacterial challenge.

Decay-accelerating factor (DAF) is an essential member of the complement regulatory protein family that plays an important role in immune response and host homeostasis in mammals. However, the immune function of DAF has not been well characterized in bony fish. In this study, a complement regulatory protein named CiDAF was firstly characterized from Ctenopharyngodon idella and its potential roles were investigated in intestine following bacterial infection. Similar to mammalian DAFs, CiDAF has multiple complement control protein (CCP) functional domains, suggesting the evolutionary conservation of DAFs. CiDAF was broadly expressed in all tested tissues, with a relatively high expression level detected in the spleen and kidney. In vivo immune challenge experiments revealed that CiDAF strongly responded to bacterial pathogens (Aeromonas hydrophila and Aeromonas veronii) and PAMPs (lipopolysaccharide (LPS) or muramyl dipeptide (MDP)) challenges. In vitro RNAi experiments indicated that knockdown of CiDAF could upregulate the expression of complement genes (C4b, C5 and C7) and inflammatory cytokines (TNF-α, IL-1ß and IL-8). Moreover, 2000 ng/mL of CiDAF agonist progesterone effectively alleviated LPS- or MDP-induced intestinal inflammation by regulating expression of complement factors, TLR/PepT1 pathway genes and inflammatory cytokines. Overall, these findings revealed that CiDAF may act as a negative regulator of intestinal complement pathway and immune response to bacterial challenge in grass carp.

Effectiveness of a low-intensity static magnetic field in accelerating upper canine retraction: a randomized controlled clinical trial.

INTRODUCTION: Neodymium-iron-boron magnets have been suggested as a contemporary method for accelerating the process of orthodontic tooth movement (OTM). A limited number of clinical trials evaluated their effectiveness in accelerating OTM which is desirable for both orthodontists and patients. The present study aimed to investigate the effectiveness of a low-intensity static magnetic field (SMF) in accelerating upper canine retraction movement. MATERIALS AND METHODS: Seventeen patients (mean age 20.76 ± 2.9 years) with their orthodontic treatment decision to extract the upper and lower first premolars due to bimaxillary protrusion malocclusion were included in this split-mouth study. Canine retraction was performed using Nickel-titanium (Ni-Ti) closed-coil springs (150 g of force on each side). The experimental side received SMF via an auxiliary wire that carried 4-neodymium iron-born magnets with an air gap of 2 mm between the magnets to produce a magnetic field density of 414 mT in the region corresponding to the lateral ligament of the upper canine. To determine the rate of upper canine retraction and upper molar drift, alginate impressions were taken once a month to create plaster casts, which were analyzed digitally via a three-dimensional method. RESULTS: The rate of upper canine retraction was significantly greater (P < 0.05) on the SMF side than that on the control side during the first and second months, with an overall duration (19.16%) that was greater than that on the control side. The peak acceleration occurred during the second month (38.09%). No significant differences in upper molar drift were detected between the experimental and control sides (P > 0.05). CONCLUSION: A low-intensity static magnetic field was effective at accelerating upper canine retraction. The difference between the two sides was statistically significant but may not be clinically significant. The SMF did not affect upper molar drift during the upper canine retraction phase. TRIAL REGISTRATION: The trial was retrospectively registered at the ISRCTN registry ( ISRCTN59092624 ) (31/05/2022).

Platelet Membrane Cloaked Nanotubes to Accelerate Thrombolysis by Thrombus Clot-Targeting and Penetration.

Thrombotic diseases have a high rate of mortality and disability, and pose a serious threat to global public health. Currently, most thrombolytic drugs especially protein drugs have a short blood-circulation time, resulting in low thrombolytic efficiency. Therefore, a platelet membrane (Pm) cloaked nanotube (NT-RGD/Pm) biomimetic delivery system with enhanced thrombolytic efficiency is designed. Nanotubes (NT) with an excellent clot-penetration properties are used to load a protein thrombolytic drug urokinase (Uk). Platelet-targeting arginine glycine-aspartic peptide (RGD) is grafted onto the surface of the nanotubes (NT-RGD) prior to cloaking. Multiple particle tracking (MPT) technique and confocal laser scanning microscope (CLSM) analysis are applied and the results show that the nanotubes possess a strong penetration and diffusion capacity in thrombus clots. After the Pm cloaking on NT-RGD/Uk, it shows a thrombus microenvironmental responsive release property and the half-life of Uk is six times longer than that of free Uk. Most importantly, NT-RGD-Uk/Pm exhibits a 60% thrombolytic efficiency in the FeCl3 -induced thrombosis mouse model, and it is able to significantly reduce the bleeding side effects of Uk. This Pm-cloaked nanotube system is an effective and promising platform for the controlled and targeted delivery of drugs for the thrombus treatment.

Strain Regulating and Kinetics Accelerating of Micro-Sized Silicon Anodes via Dual-Size Hollow Graphitic Carbons Conductive Additives.

Micro-sized silicon (µSi) anode features fewer interfacial side reactions and lower costs compared to nanosized silicon, and has higher commercial value when applied as a lithium-ion battery (LIB) anode. However, the high localized stress generated during (de)lithiation causes electrode breakdown and performance deterioration of the µSi anode. In this work, hollow graphitic carbons with tailored dual sizes are employed as conductive additives for the µSi anode to overcome electrode failure. The dual-size hollow graphitic carbons (HGC) additives consist of particles with micrometer size similar to the µSi particles; these additives are used for strain regulation. Additionally, nanometer-size particles similar to commercial carbon black Spheron (SP) are used mainly for kinetics acceleration. In addition to building an efficient conductive network, the dual-size hollow graphitic carbon conductive additive prevents the fracture of the electrode by reducing local stress and alleviating volume expansion. The µSi anode with dual-size hollow graphitic carbons as conductive additives achieves an impressive capacity of 651.4 mAh g-1 after 500 cycles at a high current density of 2 A g-1 . These findings suggest that dual-size hollow graphitic carbons are expected to be superior conductive additives for micro-sized alloy anodes similar to µSi.

The active form of Helicobacter pylori vacuolating cytotoxin induces decay-accelerating factor CD55 in association with intestinal metaplasia in the human gastric mucosa.

High-level expression of decay-accelerating factor, CD55, has previously been found in human gastric cancer (GC) and intestinal metaplasia (IM) tissues. Therapeutic effects of CD55 inhibition in cancer have been reported. However, the role of Helicobacter pylori infection and virulence factors in the induction of CD55 and its association with histological changes of the human gastric mucosa remain incompletely understood. We hypothesised that CD55 would be increased during infection with more virulent strains of H. pylori, and with more marked gastric mucosal pathology. RT-qPCR and immunohistochemical analyses of gastric biopsy samples from 42 H. pylori-infected and 42 uninfected patients revealed that CD55 mRNA and protein were significantly higher in the gastric antrum of H. pylori-infected patients, and this was associated with the presence of IM, but not atrophy, or inflammation. Increased gastric CD55 and IM were both linked with colonisation by vacA i1-type strains independently of cagA status, and in vitro studies using isogenic mutants of vacA confirmed the ability of VacA to induce CD55 and sCD55 in gastric epithelial cell lines. siRNA experiments to investigate the function of H. pylori-induced CD55 showed that CD55 knockdown in gastric epithelial cells partially reduced IL-8 secretion in response to H. pylori, but this was not due to modulation of bacterial adhesion or cytotoxicity. Finally, plasma samples taken from the same patients were analysed for the soluble form of CD55 (sCD55) by ELISA. sCD55 levels were not influenced by IM and did not correlate with gastric CD55 mRNA levels. These results suggest a new link between active vacA i1-type H. pylori, IM, and CD55, and identify CD55 as a molecule of potential interest in the management of IM as well as GC treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Self-Accelerating Diels-Alder Reaction for Preparing Polymers of Intrinsic Microporosity.

It is a formidable challenge in polycondensation to simultaneously construct multiple covalent bonds to prepare double-stranded polymers of intrinsic microporosity (PIMs) with fused multicyclic linkages. To the best of our knowledge, this is the first study to develop a self-accelerating Diels-Alder reaction for successfully preparing double-stranded PIMs with fused multicyclic backbone structures. A self-accelerating Diels-Alder reaction was developed based on the [4+2] cycloaddition of sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DIBOD) and ortho-quinone compounds. In this reaction, the cycloaddition of ortho-quinone with the first alkyne of DIBOD activates the second alkyne, which reacts with ortho-quinone at a rate constant 192 times larger than that of the original alkyne. Using this self-accelerating reaction to polymerize DIBOD and spirocyclic/cyclic difunctional ortho-quinone monomers, a novel stoichiometric imbalance-promoted step-growth polymerization method was developed to prepare PIMs. The resultant PIMs possess intrinsic ultramicropores with pore sizes between 0.45 to 0.7 nm, high specific surface areas above 646 m2 g-1 , and good H2 separation performance.

A split-mouth randomized controlled trial to compare the rate of canine retraction after a soft tissue procedure compared against a corticotomy procedure for accelerated tooth movement.

Background and Aim: Various methods to accelerate the orthodontic tooth movement have been used, among which corticotomy is considered to be the most common one. The suggested reasoning for such acceleration was the regional acceleratory phenomenon (RAP). Since the RAP is a property of both the hard and soft tissues, we designed a soft tissue flap procedure to compare the effects with the conventional corticotomy procedure. A split-mouth study was conducted where the two procedures were assessed in a single participant. Patients and Methods: The total sample size was calculated to be 40 with 20 participants in each group. The rate of tooth movement was the primary outcome measure, and the secondary outcomes were dentoalveolar changes, which were studied in both the conventional corticotomy and the flap-only procedure based on a cone-beam computed tomography (CBCT) wherein the alveolar bone density (BD) around canines, tipping, and rotational changes in canines, premolars, and molars were assessed. Results: Corticotomy resulted in greater canine angulation, lesser canine rotation and premolar rotation, and greater molar rotation compared with flap elevation, but these differences were statistically insignificant. Conclusion: Though the corticotomy resulted in higher BD, the differences were statistically insignificant. There was no significant difference in the rate of space closure assessed by the two techniques compared.

Self-Accelerating Interfacial Catalytic Elimination of Gaseous Sulfur-Containing Volatile Organic Compounds as Microbubbles in a Facet-Engineered Three-Dimensional BiOCl Sponge Fenton-Like Process.

The elimination of gaseous sulfur-containing volatile organic compounds (S-VOCs) by a microbubble-assisted Fenton-like process is an innovative strategy. Herein, we established a microbubble-assisted Fenton-like process to eliminate malodorous microbubble CH3SH as representative gaseous S-VOCs, in which BiOCl nanosheets loaded on a three-dimensional sponge were exposed to (001) or (010) facets and induced Fenton-like interface reactions. Intriguingly, the microbubble-assisted Fenton-like process significantly removed 99.9% of CH3SH, higher than that of the macrobubble-assisted Fenton-like process (39.0%). The self-accelerating interfacial catalytic mechanism was in-depth identified by in situ ATR-FTIR, PTR-TOF-MS, EPR, and DFT computational study. The extraordinary elimination performance of microbubble-assisted Fenton-like process lies in the enhancing dissolution/mass transfer of gaseous CH3SH in the gas/liquid phase and the tight contact between CH3SH-microbubbles and 3D-BiOCl sponge due to the low rising velocity (0.13 mm s-1) and negative charge (-45.53 mV) of CH3SH-microbubbles, as well as the effective generation of 1O2 by activating the enriched dissolved oxygen in CH3SH-microbubble via effective electron-polarized sites on 3D-BiOCl sponge. Furthermore, CH3SH-microbubbles transferred electrons to H2O2 through electron-rich oxygen vacancy centers of the 3D-BiOCl sponge to generate more •OH, thus achieving excellent elimination performance. Overall, this study demonstrates the enhanced self-accelerating interfacial catalytic elimination by S-VOC microbubble and provides the underlying mechanisms.

Molecular engineering of an efficient four-domain DAF-MCP chimera reveals the presence of functional modularity in RCA proteins.

The complement system is highly efficient in targeting pathogens, but lack of its apposite regulation results in host-cell damage, which is linked to diseases. Thus, complement activation is tightly regulated by a series of proteins, which primarily belong to the regulators of complement activation (RCA) family. Structurally, these proteins are composed of repeating complement control protein (CCP) domains where two to four successive domains contribute to the regulatory functions termed decay-accelerating activity (DAA) and cofactor activity (CFA). However, the precise constitution of the functional units and whether these units can be joined to form a larger composition with dual function have not been demonstrated. Herein, we have parsed the functional units for DAA and CFA by constructing chimeras of the decay-accelerating factor (DAF) that exhibits DAA and membrane cofactor protein (MCP) that exhibits CFA. We show that in a four-CCP framework, a functional unit for each of the regulatory activities is formed by only two successive CCPs wherein each participates in the function, albeit CCP2 has a bipartite function. Additionally, optimal activity requires C-terminal domains that enhance the avidity of the molecule for C3b/C4b. Furthermore, by composing a four-CCP DAF-MCP chimera with robust CFA (for C3b and C4b) and DAA (for classical and alternative pathway C3 convertases), named decay cofactor protein, we show that CCP functional units can be linked to design a dual-activity regulator. These data indicate that the regulatory determinants for these two biological processes are distinct and modular in nature.

Accelerating progress towards improved mental health and healthy behaviours in adolescents living in adversity: findings from a longitudinal study in South Africa.

Adolescents exposed to high levels of adversity are vulnerable to developing mental health challenges, with long-lasting adverse consequences. Promoting the psychological well-being of adolescents and protecting them from adverse experiences is crucial for their quality of life. There is a need for evidence on which combinations of protective factors can improve the wellbeing of adolescents to inform future programming efforts. We used data from a longitudinal study that took place in Khayelitsha, South Africa, a semi-urban impoverished community in Cape Town. Data were collected from adolescents when they were 12-14 years of age (n = 333) and again at follow-up when they were aged 16-19 years (n = 314). A path analysis was used to estimate associations between access to service, food security, safe environment, family support, and social support and five outcomes related to adolescent mental health and risky behaviours. The fitted model was used to calculate adjusted mean differences comparing different combinations of risk factors. Two protective factors (food security and safe environment) were positively associated with three outcomes relating to mental health and the absence of risky behaviours. Further investigation revealed that the presence of high food security and safer environments was associated with higher adjusted mean scores: +16.2% (p < .0001) in no substance use; +16.5% (p < .0001) in no internalising behaviour, +19.5% (p < .0001) in self-esteem; +12.2% (p < .0001) in positive peer relationships; and +11.4% (p < .0001) in no suicidal ideation. Interventions targeting adolescents, that aim to improve food security together with improving the safety of their environment, are likely to impact their well-being.

CAFRI-Rice: CRISPR applicable functional redundancy inspector to accelerate functional genomics in rice.

Rice (Oryza sativa L.) is a staple crop with agricultural traits that have been intensively investigated. However, despite the variety of mutant population and multi-omics data that have been generated, rice functional genomic research has been bottlenecked due to the functional redundancy in the genome. This phenomenon has masked the phenotypes of knockout mutants by functional compensation and redundancy. Here, we present an intuitive tool, CRISPR applicable functional redundancy inspector to accelerate functional genomics in rice (CAFRI-Rice; cafri-rice.khu.ac.kr). To create this tool, we generated a phylogenetic heatmap that can estimate the similarity between protein sequences and expression patterns, based on 2,617 phylogenetic trees and eight tissue RNA-sequencing datasets. In this study, 33,483 genes were sorted into 2,617 families, and about 24,980 genes were tested for functional redundancy using a phylogenetic heatmap approach. It was predicted that 7,075 genes would have functional redundancy, according to the threshold value validated by an analysis of 111 known genes functionally characterized using knockout mutants and 5,170 duplicated genes. In addition, our analysis demonstrated that an anther/pollen-preferred gene cluster has more functional redundancy than other clusters. Finally, we showed the usefulness of the CAFRI-Rice-based approach by overcoming the functional redundancy between two root-preferred genes via loss-of-function analyses as well as confirming the functional dominancy of three genes through a literature search. This CAFRI-Rice-based target selection for CRISPR/Cas9-mediated mutagenesis will not only accelerate functional genomic studies in rice but can also be straightforwardly expanded to other plant species.

Hemopexin Modulates Expression of Complement Regulatory Proteins in Rat Glomeruli.

In systemic hemolysis and in hematuric forms of kidney injury, the major heme scavenging protein, hemopexin (HPX), becomes depleted, and the glomerular microvasculature (glomeruli) is exposed to high concentrations of unbound heme, which, in addition to causing oxidative injury, can activate complement cascades; thus, compounding extent of injury. It is unknown whether unbound heme can also activate specific complement regulatory proteins that could defend against complement-dependent injury. Isolated rat glomeruli were incubated in media supplemented with HPX-deficient (HPX-) or HPX-containing (HPX+) sera as a means of achieving different degrees of heme partitioning between incubation media and glomerular cells. Expression of heme oxygenase (HO)-1 and of the complement activation inhibitors, decay-accelerating factor (DAF), CD59, and complement receptor-related gene Y (Crry), was assessed by western blot analysis. Expression of HO-1 and of the GPI-anchored DAF and CD59 proteins increased in isolated glomeruli incubated with HPX- sera with no effect on Crry expression. Exogenous heme (hemin) did not further induce DAF but increased Crry expression. HPX modulates heme-mediated induction of complement activation controllers in glomeruli. This effect could be of translational relevance in glomerular injury associated with hematuria.

A perspective on early detection systems models for COVID-19 spreading.

The ongoing COVID-19 epidemic highlights the need for effective tools capable of predicting the onset of infection outbreaks at their early stages. The tracing of confirmed cases and the prediction of the local dynamics of contagion through early indicators are crucial measures to a successful fight against emerging infectious diseases (EID). The proposed framework is model-free and applies Early Warning Detection Systems (EWDS) techniques to detect changes in the territorial spread of infections in the very early stages of onset. This study uses publicly available raw data on the spread of SARS-CoV-2 mainly sourced from the database of the Italian Civil Protection Department. Two distinct EWDS approaches, the Hub-Jones (H&J) and Strozzi-Zaldivar (S&Z), are adapted and applied to the current SARS-CoV-2 outbreak. They promptly generate warning signals and detect the onset of an epidemic at early surveillance stages even if working on the limited daily available, open-source data. Additionally, EWDS S&Z criterion is theoretically validated on the basis of the epidemiological SIR. Discussed EWDS successfully analyze self-accelerating systems, like the SARS-CoV-2 scenario, to precociously identify an epidemic spread through the calculation of onset parameters. This approach can also facilitate early clustering detection, further supporting common fight strategies against the spread of EIDs. Overall, we are presenting an effective tool based on solid scientific and methodological foundations to be used to complement medical actions to contrast the spread of infections such as COVID-19.

Generation of a novel decay accelerating factor (DAF) knock-out rat model using clustered regularly-interspaced short palindromic repeats, (CRISPR)/associated protein 9 (Cas9), genome editing.

Decay accelerating factor (DAF), a key complement activation control protein, is a 70 kDa membrane bound glycoprotein which controls extent of formation of the C3 and C5 convertases by accelerating their decay. Using clustered regularly-interspaced short palindromic repeats, (CRISPR)/associated protein 9 (Cas9) genome editing we generated a novel DAF deficient (Daf-/-) rat model. The present study describes the renal and extrarenal phenotype of this model and assesses renal response to complement-dependent injury induced by administration of a complement-fixing antibody (anti-Fx1A) against the glomerular epithelial cell (podocyte). Rats generated were healthy, viable and able to reproduce normally. Complete absence of DAF was documented in renal as well as extra-renal tissues at both protein and mRNA level compared to Daf+/+ rats. Renal histology in Daf-/- rats showed no differences regarding glomerular or tubulointerstitial pathology compared to Daf+/+ rats. Moreover, there was no difference in urine protein excretion (ratio of urine albumin to creatinine) or in serum creatinine and urea levels. In Daf-/- rats, proteinuria was significantly increased following binding of anti-Fx1A antibody to podocytes while increased C3b deposition was observed. The DAF knock-out rat model developed validates the role of this complement cascade regulator in immune-mediated podocyte injury. Given the increasing role of dysregulated complement activation in various forms of kidney disease and the fact that the rat is the preferred animal for renal pathophysiology studies, the rat DAF deficient model may serve as a useful tool to study the role of this complement activation regulator in complement-dependent forms of kidney injury.

Avoiding extinction under nonlinear environmental change: models of evolutionary rescue with plasticity.

Rapid environmental changes are putting numerous species at risk of extinction. For migration-limited species, persistence depends on either phenotypic plasticity or evolutionary adaptation (evolutionary rescue). Current theory on evolutionary rescue typically assumes linear environmental change. Yet accelerating environmental change may pose a bigger threat. Here, we present a model of a species encountering an environment with accelerating or decelerating change, to which it can adapt through evolution or phenotypic plasticity (within-generational or transgenerational). We show that unless either form of plasticity is sufficiently strong or adaptive genetic variation is sufficiently plentiful, accelerating or decelerating environmental change increases extinction risk compared to linear environmental change for the same mean rate of environmental change.

Three Kinetic Patterns for the Oxidation of Emerging Organic Contaminants by Fe(VI): The Critical Roles of Fe(V) and Fe(IV).

For the first time, this study showed that the apparent second-order rate constants (kapp) of six selected emerging organic contaminants (EOCs) oxidation by Fe(VI) increased, remained constant, or declined with time, depending on [EOC]0/[Fe(VI)]0, pH, and EOCs species. Employing excess caffeine as the quenching reagent for Fe(V) and Fe(IV), it was found that Fe(V)/Fe(IV) contributed to 20-30% of phenol and bisphenol F degradation by Fe(VI), and the contributions of Fe(V)/Fe(IV) remained nearly constant with time under all the tested conditions. However, the contributions of Fe(V)/Fe(IV) accounted for over 50% during the oxidation of sulfamethoxazole, bisphenol S, and iohexol by Fe(VI), and the variation trends of kapp of their degradation by Fe(VI) with time displayed three different patterns, which coincided with those of the contributions of Fe(V)/Fe(IV) to their decomposition with time. Results of the quenching experiments were validated by simulating the oxidation kinetic data of methyl phenyl sulfoxide by Fe(VI), which revealed that the variation trends of kapp with time were significantly determined by the change in the molar ratio of Fe(V) to Fe(VI) with time, highlighting the key role of Fe(V) in the oxidative process. This study provides comprehensive and insightful information on the roles of Fe(V)/Fe(IV) during EOC oxidation by Fe(VI).

Mapping time use in clinical trials for vaccines against emerging infectious diseases.

BACKGROUND: Vaccines are potent tools to prevent outbreaks of emerging infectious diseases from becoming epidemics and need to be developed at an accelerated pace to have any impact on the course of an ongoing epidemic. The aim of this study was to describe time use in the execution of vaccine trials, to identify steps that could be accelerated to improve preparedness and planning for future emerging infectious diseases vaccine trials. METHODS: We used a mixed-methods approach to map time use and process steps that could be accelerated during vaccine trials. Trials for vaccines against infectious diseases registered in three global trial databases reported in the period 2011-2017 were eligible to join the survey. We invited sponsors to contribute data through a predefined structured questionnaire for clinical trial process metrics. Data were stratified by trial phase, disease type (i.e. emerging infectious diseases or not emerging infectious diseases), sponsor type, and continent. Qualitative interviews were conducted with purposively selected sponsors, and thematic analysis of the interview transcripts was performed. RESULTS: Based on data from 155 vaccine trials including 29,071 subjects, 52% were phase I, 23% phase II, and 25% phase III. We found that the regulatory approval, subject enrollment, study execution, and study close-out accounted for most of the cycle time of the vaccine trial process. Cycle times for the regulatory and ethical approvals, contract agreement, site initiation, and study execution were shorter in trials conducted during outbreaks. Qualitative interviews indicated that early engagement of the regulatory and independent ethical committee authorities in planning the vaccine trials was critical for saving time in trial approval. Furthermore, adapting the trial implementation to the reality of the study sites and active involvement of the local investigators during the planning of the trial and protocol writing were stated to be of paramount importance to successful completion of trials at an accelerated pace. CONCLUSION: The regulatory approval, subject recruitment, study execution, and close-out cycle times accounted for most of the vaccine trial time use and are activities that could be accelerated during a vaccine trial planning and implementation. We encourage tracking of key cycle time metrics and facilitating sharing of knowledge across industry and academia, as this may serve to reduce the time from index case detection to access of a vaccine during emerging infectious diseases epidemics.