Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues

Potential and costs of carbon dioxide removal by enhanced weathering of rocks

The chemical weathering of rocks currently absorbs about 1.1 Gt CO2 a−1 being mainly stored as bicarbonate in the ocean. An enhancement of this slow natural process could remove substantial amounts of CO2 from the atmosphere, aiming to offset some unavoidable anthropogenic emissions in order to comply with the Paris Agreement, while at the same time it may decrease ocean acidification. We provide the first comprehensive assessment of economic costs, energy requirements, technical parameterization, and global and regional carbon removal potential. The crucial parameters defining this potential are the grain size and weathering rates. The main uncertainties about the potential relate to weathering rates and rock mass that can be integrated into the soil. The discussed results do not specifically address the enhancement of weathering through microbial processes, feedback of geogenic nutrient release, and bioturbation. We do not only assess dunite rock, predominantly bearing olivine (in the form of forsterite) as the mineral that has been previously proposed to be best suited for carbon removal, but focus also on basaltic rock to minimize potential negative side effects. Our results show that enhanced weathering is an option for carbon dioxide removal that could be competitive already at 60 US $t−1 CO2 removed for dunite, but only at 200 US$ t−1 CO2 removed for basalt. The potential carbon removal on cropland areas could be as large as 95 Gt CO2 a−1 for dunite and 4.9 Gt CO2 a−1 for basalt. The best suited locations are warm and humid areas, particularly in India, Brazil, South-East Asia and China, where almost 75% of the global potential can be realized. This work presents a techno-economic assessment framework, which also allows for the incorporation of further processes

A Holistic Comparative Analysis of Different Storage Systems using Levelized Cost of Storage and Life Cycle Indicators

AbstractIn this study, a detailed economic analysis is combined with an ecological analysis of electricity storage systems. On the economic side, a “Levelized Cost of Storage (LCOS)” analysis is conducted, which assesses the cost of stored electricity. The LCOS is determined for a specific case of a private household in combination with a PV system. On the ecological side a “Life Cycle Assessment” (LCA) is used to calculate the environmental impact of electricity storage as well as the CO2 abatement costs. In the parameterized LCA the energy generation process used to feed the storage system, the material and the energy demand during the life cycle of the storage options is considered. With the parameterized LCA approach, the ecologically most rational storage systems can be identified. Results show that PV storage systems at household level are an environmental friendly option to increase the self-consumption and will be economically attractive in about ten years

Understanding efficient phosphorus-functionalization of graphite for vanadium flow batteries

Numerous surface treatment methods are known to enhance the electrochemical activity of graphite felt (GF), such as thermal activation or attachment of nanoparticulate catalysts. The integration of heteroatoms into the graphite lattice at the surface could be a promising technique for reliable and efficient electrode activation. However, these functionalization techniques are based on thermochemical activation, which makes it difficult to distinguish between activity effects other than foreign atom integration, such as defects and other surface groups that must be considered. In this work, we analyzed commercial and synthetic phosphorus-doped graphene and GF using different electrochemical and physicochemical techniques. Despite a high doping concentration, the activity of the commercial powder bonded to GF and coated on glassy carbon remained limited due to the low degree of graphitization and high oxygen content. Instead, a low phosphorus concentration of <1 at% combined with a high degree of graphitization increased the catalytic activity. Building on these findings, GF was rationally modified, resulting in twice the power density compared to the original material in full cell tests

Price Relationships along the Value Chain: An Analysis of the Hake Market in France

In this paper we use cointegration analysis and the Law of One Price to test for proportionality between hake prices at different stages along the value chain in the French hake market. Cointegration analysis is an appropriate means of testing for price proportionality when price series are non-stationary, as was found to be the case for hake prices in France. Estimates of the relative size of mark-ups along the value chain are calculated by applying the Law of One Price to the cointegrated price series. Finally, we test for weak exogeneity of hake prices in order to determine how price information is transmitted through the value chain

Efficacy and safety of medications for antihistamine-refractory chronic spontaneous urticaria: a systematic review and network meta-analysis

Purpose Most medications for antihistamine-refractory chronic spontaneous urticaria (CSU) have not been compared head-to-head. This systematic review and network meta-analysis evaluates their relative efficacy and safety. Methods Electronic databases were searched until 05 May 2022 for randomized controlled trials investigating systemic medications for antihistamine-refractory CSU. The change in the urticaria activity score over seven days (UAS7) and occurrence of adverse events were compared between treatments using random-effects network meta-analysis models. Results In all, 32 studies with 3641 patients receiving 31 different systemic medical interventions were included. Among currently available drugs, omalizumab 300 mg injected every 4 weeks and cyclosporine 3–5 mg/kg daily per os were most effective in reducing the UAS7 with a reduction of −10.45 (95% confidence interval [CI]: −12.35, −8.55) and of −10.40 (95% CI: −19.4, −1.4) compared to placebo. Similar efficacies were shown by the nonapproved agents ligelizumab 72 mg injected every 4 weeks (−11.67, 95% CI: −16.80, −7.15) and fenebrutinib 400 mg daily per os (−9.50, 95% CI: −17.56, −1.44). The odds ratio for the occurrence of an adverse event with placebo as comparator was 1.09 for omalizumab (95% CI: 0.83, 1.42), 2.16 for cyclosporine (95% CI: 0.77, 6.07: GRADE; moderate certainty), 0.89 for ligelizumab (95% CI: 0.47, 1.69), and 2.14 for fenebrutinib (95% CI: 0.62, 7.38) in the mentioned dosages. Conclusion Omalizumab 300 mg injected every 4 weeks and cyclosporine 3–5 mg/kg daily per os are the most effective currently available drugs for antihistamine-refractory CSU. Cyclosporine shows a relatively less favorable safety profile

Practical and Robust Secure Logging from Fault-Tolerant Sequential Aggregate Signatures

Keeping correct and informative log files is crucial for system maintenance, security and forensics. Cryptographic logging schemes offer integrity checks that protect a log file even in the case where an attacker has broken into the system. A relatively recent feature of these schemes is resistance against truncations, i.e. the deletion and/or replacement of the end of the log file. This is especially relevant as system intruders are typically interested in manipulating the later log entries that point towards their attack. However, there are not many schemes that are resistant against truncating the log file. Those that are have at least one of the following disadvantages: They are memory intensive (they store at least one signature per log entry), or fragile (i.e. a single error in the log renders the signature invalid and useless in determining where the error occurred). We obtain a publicly-verifiable secure logging scheme that is simultaneously robust, space-efficient and truncation secure with provable security under simple assumptions. Our generic construction uses forward-secure signatures, in a plain and a sequential aggregate variant, where the latter is additionally fault-tolerant, as recently formalized by Hartung et al. (PKC 2016). Fault-tolerant schemes can cope with a number of manipulated log entries (bounded a priori) and offer strong robustness guarantees while still retaining space efficiency. Our implementation and the accompanying performance measurements confirm the practicality of our scheme

GluA4-Targeted AAV Vectors Deliver Genes Selectively to Interneurons while Relying on the AAV Receptor for Entry

Selective gene delivery into subtypes of interneurons remains an important challenge in vector development. Adeno-associated virus (AAV) vector particles are especially promising for intracerebral injections. For cell entry, AAV2 particles are supposed to attach to heparan-sulfate proteoglycans (HSPGs) followed by endocytosis via the AAV receptor (AAVR). Here, we assessed engineered AAV particles deficient in HSPG attachment but competent in recognizing the glutamate receptor 4 (GluA4, also known as GluRD or GRIA4) through a displayed GluA4-specific DARPin (designed ankyrin repeat protein). When injected into the mouse brain, histological evaluation revealed that in various regions, more than 90% of the transduced cells were interneurons, mainly of the parvalbumin-positive subtype. Although part of the selectivity was mediated by the DARPin, the chosen spleen focus-forming virus (SFFV) promoter had contributed as well. Further analysis revealed that the DARPin mediated selective attachment to GluA4-positive cells, whereas gene delivery required expression of AAVR. Our data suggest that cell selectivity of AAV particles can be modified rationally and efficiently through DARPins, but expression of the AAV entry receptor remains essential