DNA G-quadruplexes are not only attractive drug targets for cancer therapeutics, but also have important applications in supramolecular assembly. Here, we report a platinum(II)-based tripod ...(Pt-tripod) specifically binds the biological relevant hybrid-1 human telomeric G-quadruplex (Tel26), and strongly inhibits telomerase activity. Further investigations illustrate Pt-tripod induces the formation of monomeric and multimeric Pt-tripod‒Tel26 complex structures in solution. We solve the 1:1 and the unique dimeric 4:2 Pt-tripod-Tel26 complex structures by NMR. The structures indicate preferential binding of Pt-tripod to the 5'-end of Tel26 at a low Pt-tripod/Tel26 ratio of 0-1.0. After adding more Pt-tripod, the Pt-tripod binds the 3'-end of Tel26, unexpectedly inducing a unique dimeric 4:2 structure interlocked by an A:A non-canonical pair at the 3'-end. Our structures provide a structural basis for understanding the dynamic binding of small molecules with G-quadruplex and DNA damage mechanisms, and insights into the recognition and assembly of higher-order G-quadruplexes.
Energy systems are increasingly exposed to the threats of extreme events like floods, earthquakes and hurricanes. In practice, the behaviors of the systems affected by these extreme events are often ...modeled by multistate models to facilitate the analysis. In this paper, we develop a generic framework for resilience modeling and analysis of multistate energy systems. A multistate resilience model is developed based on a Markov reward process model, where the degradation and recovery of system performance are characterized by a continuous time discrete state Markov chain and the losses caused by the extreme event is modeled by the reward rates associated with the sojourns in the degradation states and the transitions among the states. Four numerical metrics are defined to describe different aspects of system resilience, i.e. the resistant, absorption, recovery and overall resilience. A simulation-based algorithm is proposed for resilience analysis of multistate energy systems. The developed methods are applied for resilience modeling and analysis of a Nuclear Power Plant (NPP) under the threat of earthquakes. The Markov reward process model is developed following a probabilistic seismic hazard analysis, a fragility analysis and an event tree modeling of accident evolutions. Both a time-static and time-dependent resilience analysis are conducted and the results show that the developed model is able to comprehensively describe the resilience of multistate energy systems under the threats of extreme events.
•A resilience model is developed for multistate systems based on Markov reward processes.•Four resilience metrics are defined to measure different aspects of resilience.•A simulation-based algorithm is developed for resilience analysis of multistate systems.
Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral ...organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.
Antibody drug conjugates (ADC) are an emerging class of pharmaceuticals consisting of cytotoxic agents covalently attached to an antibody designed to target a specific cancer cell surface molecule ...followed by internalization and intracellular release of payload to exhibit its anticancer activity. Targeted delivery of cytotoxic payload to a variety of specific cells has been demonstrated to have significant enhancement in clinical efficacy and dramatic reduction in off‐target toxicity. Site‐specific conjugation of payload to the antibody is highly desirable for development of ADC with well‐defined antibody‐to‐drug ratio, enhanced internalization, reduced toxicity, improved stability, desired pharmacological profile and optimal therapeutic index. Here, we reported a site‐specific conjugation strategy for evaluation of antibody internalization and efficacy of ADC designed to target SSEA4 on solid tumors. This strategy stems from the azido‐fucose tag of a homogeneous antibody Fc‐glycan generated via in vitro glycoengineering approach for site‐specific conjugation and optimization of antibody‐drug ratio to exhibit optimal efficacy. The ADC consisting of a chimeric anti‐SSEA4 antibody chMC813‐70, conjugated to the antineoplastic agent monomethyl auristatin E via both cleavable and non‐cleavable linkers showed excellent cytotoxicity profile towards SSEA4‐bearing cancer cells. A clear distinction in cytotoxicity was observed among cancer cells with different SSEA4 expression levels.
Local pathogens can accumulate as asymptomatic endophytes, making it difficult to detect the impacts of invasive species as propagators of disease in the invaded range.
We used the invasive plant ...Ageratina adenophora to assess such accumulation. We intensively collected foliar fungal endophytes and leaf spot pathogens of A. adenophora and co-occurring neighbours and performed an inoculation experiment to evaluate their pathogenicity and host range.
Ageratina adenophora harboured diverse necrotrophic pathogens; its communities of endophytes and leaf spot pathogens were different in composition and shared only a small number of fungal species. In the pathogen communities of local plant hosts, 21% of the operational taxonomic units (OTUs), representing 50% of strains, also occurred as leaf spot pathogens and/or endophytes of A. adenophora. The local pathogen community was more similar to the endophytes than to the pathogens of A. adenophora. The inoculation experiment showed that local pathogens could infect A. adenophora leaves asymptomatically and that local plant hosts were susceptible to both A. adenophora endophytes and pathogens.
Ageratina adenophora is a highly competent host for local pathogens, and its asymptomatic latent pathogens are fungi primarily shared with local neighbours. This poses challenges for understanding the long-term ecological consequences of plant invasion.
A comprehensive structure-activity relationship study on antibody Fc-glycosylation has been performed using the chimeric anti-SSEA4 antibody chMC813-70 as a model. The α-2,6 sialylated biantennary ...complex type glycan was identified as the optimal Fc-glycan with significant enhancement in antibody effector functions, including binding to different Fc receptors and ADCC.
A comprehensive structure-activity relationship study on antibody Fc-glycosylation has been performed using the chimeric anti-SSEA4 antibody chMC813-70 as a model.
A new class of broadly neutralizing antibodies (bNAbs) from HIV donors has been reported to target the glycans on gp120--a glycoprotein found on the surface of the virus envelope--thus renewing hope ...of developing carbohydrate-based HIV vaccines. However, the version of gp120 used in previous studies was not from human T cells and so the glycosylation pattern could be somewhat different to that found in the native system. Moreover, some antibodies recognized two different glycans simultaneously and this cannot be detected with the commonly used glycan microarrays on glass slides. Here, we have developed a glycan microarray on an aluminium-oxide-coated glass slide containing a diverse set of glycans, including homo- and mixed N-glycans (high-mannose, hybrid and complex types) that were prepared by modular chemo-enzymatic methods to detect the presence of hetero-glycan binding behaviours. This new approach allows rapid screening and identification of optimal glycans recognized by neutralizing antibodies, and could speed up the development of HIV-1 vaccines targeting cell surface glycans.
Clonorchiasis is an important food-borne parasitic disease caused by Clonorchis sinensis infection. The evaluation of long-term cost-effectiveness of control strategies is important for disease ...control and prevention. The present study aimed to assess the cost-effectiveness of the three recommended strategies (i.e., WHO, Chinese and Guangdong strategies) and different combinations of commonly used measures (i.e., preventive chemotherapy, information, education, and communication (IEC) and environmental improvement) on clonorchiasis. The study area, Fusha town in Guangdong Province, was a typical high endemic area in China. The analysis was based on a multi-group transmission model of C. sinensis infection. We set the intervention duration for 10 years and post-intervention period for 50 years. The corresponding costs and DALYs were estimated. Strategies with incremental cost-effectiveness ratios (ICERs) less than 1/5 of the willingness-to-pay threshold were identified as highly cost-effective strategies. The optimal control strategy was obtained using the next best comparator method. The ICERs of Guangdong strategy were $172 (95% CI: $143-$230) US for praziquantel and $106 (95% CI: $85-$143) US for albendazole, suggesting the highest cost-effectiveness among the three recommended strategies. For praziquantel, 470 sets of control strategies were identified as highly cost-effective strategies for achieving infection control (prevalence<5%). The optimal strategy consisted of chemotherapy targeted on at-risk population, IEC and environmental improvement, with coverages all being 100%, and with the ICER of $202 (95% CI: $168-$271) US. The results for transmission control (prevalence<1%) and albendazole were obtained with the same procedures. The findings may help to develop control policies for C. sinensis infection in high endemic areas. Moreover, the method adopted is applicable for assessment of optimal strategies in other endemic areas.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An 8‐wk feeding trial was conducted to evaluate the effects of replacing fishmeal with rapeseed meal (RM) on growth, feed utilization, antioxidant capacity, nonspecific immunity, and growth‐related ...gene expression of Pseudobagrus ussuriensis (initial body weight 14.0 g). Six isonitrogenous and isoenergetic diets were formulated to contain RM to replace fishmeal at 0 (R0), 10 (R10), 20 (R20), 30 (R30), 40 (R40), and 50% (R50), respectively. The results showed that final body weight, specific growth rate (SGR), feed intake, feed efficiency, and protein efficiency ratio decreased with increasing dietary RM levels. Fish fed the diets with 30% or more fishmeal replaced by RM had significantly lower SGR (P < 0.05). The apparent digestibility coefficient of dry matter, crude protein, and crude lipid decreased with increasing dietary RM levels. Similar trends were observed in immune parameters and the activities of superoxide dismutase and catalase. However, an increasing trend was observed in malondialdehyde. Fish fed the diets with 30% or more fishmeal replaced by RM had significantly lower hepatic aspartate aminotransferase and alanine aminotransferase activities than the control group R0 (P < 0.05). Hepatic insulin‐like growth factor I (IGF‐I) gene expression level significantly decreased in fish fed Diet R50 compared with the R10 group (P < 0.05). However, the IGF‐I gene expression level in muscles significantly increased in fish fed Diet R50 compared with other groups (P < 0.05). Broken‐line model analysis based on SGR against dietary RM substitution level indicated that the appropriate substitution level was 17%.
•The topology of the coupling interface between interdependent critical infrastructures is optimized to enhance their combined resilience•A distributionally robust optimization approach is used to ...avoid excessively conservative solution.•The results are compared with traditional stochastic and robust solutions.•The results highlight the potential of optimal coupling interfaces in terms of resilience enhancement.
Critical infrastructures (CIs), such as energy systems, transportation networks and telecommunications networks, are the backbone of any advanced society, and ensuring their resilience is a fundamental task. CIs are often interconnected to, and interdependent on, each other through complex coupling interfaces. Failures can propagate among different CIs through these coupling interfaces, causing multi-sectoral disruption. The design of the coupling interface can strongly impact the cascading effect between different CIs. In this paper, we propose a data-driven distributionally robust approach for the optimal coupling of interdependent CIs. Our model obtains an optimal coupling interface that maximizes the expected combined performance of interdependent CIs under random failure scenarios with ambiguous probability distributions. We demonstrate the validity of the proposed approach using an ambiguity set built upon a synthetic data set of historical contingency scenarios. Interdependent power and gas networks (IPGNs) are used as an illustrative case study. We show that our proposed approach leads to better coupling interfaces with higher expected performance under disruptive scenarios.
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