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We present crystal structures of a new NAD+-binding riboswitch termed NAD+-II, bound to nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD+) and nicotinamide riboside (NR). The RNA structure comprises a number of structural features including three helices, one of which forms a triple helix by interacting with an A5 strand in its minor-groove, and another formed from a long-range pseudoknot. The core of the structure (centrally located and coaxial with the triplex and the pseudoknot) includes two consecutive quadruple base interactions. Unusually the riboswitch binds two molecules of ligand, bound at distinct, non-overlapping sites in the RNA. Binding occurs primarily through the nicotinamide moiety of each ligand, held by specific hydrogen bonding and stacking interactions with the pyridyl ring. The mode of binding is the same for NMN, NR and the nicotinamide moiety of NAD+. In addition, when NAD+ is bound into one site it adopts an elongated conformation such that its diphosphate linker occupies a groove on the surface of the RNA, following which the adenine portion inserts into a pocket and makes specific hydrogen bonding interactions. Thus the NAD+-II riboswitch is distinct from the NAD+-I riboswitch in that it binds two molecules of ligand at separate sites, and that binding occurs principally through the nicotinamide moiety.

Ribozymes are excellent systems in which to study ‘sequence - structure - function’ relationships in RNA molecules. Understanding these relationships may greatly help structural modeling and design of functional RNA structures and some functional structural modules could be repurposed in molecular design. At present, there is no comprehensive database summarising all the natural ribozyme families. We have therefore created Ribocentre, a database that collects together sequence, structure and mechanistic data on 21 ribozyme families. This includes available information on timelines, sequence families, secondary and tertiary structures, catalytic mechanisms, applications of the ribozymes together with key publications. The database is publicly available at https://www.ribocentre.org.

Optimal treatment for resectable esophageal squamous cell carcinoma (ESCC) is controversial, especially in the context of potential benefit of combining PD-1 blockade with neoadjuvant therapy. This phase 2 study aimed to assess neoadjuvant camrelizumab plus chemotherapy in this population. Patients (clinical stage II-IVA) received two cycles of neoadjuvant chemoimmunotherapy (NIC) with camrelizumab (200 mg on day 1) plus nab-paclitaxel (260 mg/m2 in total on day 1 and day 8) and cisplatin (75 mg/m2 in total on days 1-3) of each 21-day cycle. Surgery was performed approximately 6 weeks after completion of NIC. Primary endpoint was complete pathologic response (CPR) rate in primary tumor. Secondary endpoints were objective response rate (ORR) per RECIST v1.1, 2-year progression-free survival (PFS) rate after surgery, PFS, overall survival (OS) and safety during NIC and perioperative period. Between 17 January 2020 and 8 December 2020, 56 patients were enrolled, and 51 received esophagectomy. Data cutoff date was 25 August 2021. The CPR rate was 35.3% (95% CI, 21.7%-48.9%). NIC had an ORR of 66.7% (95% CI, 40.0%-70.4%) and treatment-related adverse events (TRAEs) of low severity (grade 1-2, 75.0%; grade 3, 10.7%; grade 4-5, no). No perioperative mortality occurred. Three (5.9%) patients had tumor recurrence and one (2.0%) patient died. The 2-year PFS rate, median PFS and median OS had not been reached yet. Camrelizumab plus neoadjuvant chemotherapy in resectable ESCC demonstrates promising efficacy with acceptable toxicity, providing a feasible and effective option. Study is ongoing for long-term survival analyses. ispartof: INTERNATIONAL JOURNAL OF CANCER vol:151 issue:1 pages:128-137 ispartof: location:United States status: published

Known ribozymes in contemporary biology perform a limited range of chemical catalysis, but in vitro selection has generated species that catalyze a broader range of chemistry; yet, there have been few structural and mechanistic studies of selected ribozymes. A ribozyme has recently been selected that can catalyze a site-specific methyl transfer reaction. We have solved the crystal structure of this ribozyme at a resolution of 2.3 Å, showing how the RNA folds to generate a very specific binding site for the methyl donor substrate. The structure immediately suggests a catalytic mechanism involving a combination of proximity and orientation and nucleobase-mediated general acid catalysis. The mechanism is supported by the pH dependence of the rate of catalysis. A selected methyltransferase ribozyme can thus use a relatively sophisticated catalytic mechanism, broadening the range of known RNA-catalyzed chemistry.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

In the fiberglass industry, Pt–Rh bushings made of platinum and rhodium have very good characteristics, such as high temperature resistance, corrosion resistance, oxidation resistance, and creep resistance. In this paper, a semi-infinite lath structure model is constructed, and the expression of the surface temperature distribution of a Pt–Rh alloy plate with a circular through hole is obtained based on the non-Fourier heat conduction equation, complex function method and conformal mapping method. At the same time, the influence of the position of the circular through hole in the Pt–Rh bushing and the parameters of the incident light source (Non-diffusion incident wave number and relative thermal diffusion length) on the surface temperature distribution of the Pt–Rh bushing is studied by using this formula. It is found that: 1. heat concentration and fracture are occur easily at the through hole; 2. when the through hole is in the asymmetric center, the greater the asymmetry, the smaller the maximum temperature amplitude; 3. when the buried depth of the through hole increases, the maximum temperature amplitude decreases; 4. when the incident wave number and the relative thermal diffusion length of the incident light source are larger, the maximum temperature amplitude is smaller. The numerical results are almost consistent with those of ANSYS thermal simulation. The expression of the surface temperature distribution of the semi-infinite lath structure proposed in this paper can effectively reduce the loss of precious metal materials and the time of thermal simulation in the experimental process, as well as provide important significance for structural design, quality inspection, process optimization, and service life improvement of Pt–Rh bushings.

The reference effect of consumers’ product quality and service quality is an important behavioral factor that affects consumers’ purchase decisions. In this paper, considering the inherent dynamics of the operation mode, the two were combined into a product-service supply chain composed of a manufacturer and two competitive retailers, and the service reference effect was further divided into horizontal and vertical service reference effects. Differential game models between the manufacturer and the retailers were constructed. Using the continuous dynamic programming theory, the manufacturer’s quality level strategy, retailer’s service level strategy and supply chain system performance under the modes of no cost sharing decision, cost sharing decision and centralized decision were analyzed and compared. Main findings: The optimal strategy of product quality under centralized decision is greater than the corresponding value under cost sharing contract decision. Compared with decentralized decision making of no cost sharing, cost sharing contract cannot promote the manufacturer to improve product quality. Different from previous studies, the service quality under centralized decision making is not higher than other decisions. When the horizontal reference effect of service quality meets a certain condition, the supply chain profit under centralized decision making is lower than the corresponding value under decentralized decision making.

As a new type of pollutant, microplastics have attracted much attention. As the third largest freshwater lake in China, Taihu Lake is characterized by severe eutrophication caused by external pollution and frequent occurrence of cyanobacterial blooms. Although there have been previous investigations into the spatial distribution of microplastics in Taihu Lake, research on the relationships among microplastics, pollutants, and cyanobacterial blooms, as well as the spatiotemporal distribution and changing characteristics of microplastics, is deficient. This study investigated the characteristics of microplastics, pollutants, and cyanobacterial blooms in the surface water and sediments of Taihu Lake. The abundances of microplastics were 0-3.7 items/L in the surface water and 44.42-417.56 items/kg (dry weight) in the sediments. Microplastics are most abundant in the western, southern, and northern lake areas. The northern and western lake areas are severely polluted, and cyanobacterial blooms are prone to occur in these areas. This study found that microplastics exist in the surface water of the southeastern lake area, which is a source of drinking water, and the microplastics may thus have adverse effects on drinking water quality. As the main organisms in the cyanobacterial blooms, Microcystis and microplastics have similar spatial distributions in Taihu Lake and are both affected by wind. Based on a combination of the investigations of this paper with the existing research on the microplastics in Taihu Lake, the spatiotemporal distribution of microplastics was obtained: the abundance of microplastics in surface water has continuously decreased, there are no obvious spatial distribution differences, and the spatial distribution of microplastics in the sediments is the same as that in the surface water.

Nowadays, in such a competitive business environment, under the pursuit of high quality and high standards, every enterprise has clearly realized that the quality of products is directly related to the interests of the enterprise, the development of the enterprise, and the survival of the enterprise. The idea that quality is life has long been deeply rooted in every enterprise. Based on the aforementioned reality, this paper first constructs a demand function affected by product quality, service quality, reference effect and quality competition, and studies the optimal product quality and service quality under centralized decision-making and decentralized decision-making. By comparing the decision values and profit difference between centralized decision making and decentralized decision making, a bilateral cost sharing contract is proposed, and its application scope is discussed. The major findings entail that the centralized decision-making mode of supply chain will be more conducive to improving service quality. However, it is not necessarily conducive to improving product quality, which depends on the marginal profits of competitors, since supply chain decision-makers are more willing to invest resources in products with high marginal profits, thereby improving product quality. The increase of reference effect is conducive to improving the quality of products and services, but it may also lead to higher production costs in the case of centralized decision-making. Therefore, when the reference effect is high, supply chain enterprises should adopt decentralized decision-making mode. Excessive competition is not conducive to improving the profits and increases internal friction among enterprises. Therefore, when the competition is fierce, enterprise alliance is a better choice. Finally, the bilateral cost sharing contract can coordinate the supply chain, that is to say, the system profit is equal to the profit of centralized decision-making. However, only when the supplier’s share rate meets certain conditions can the bilateral cost sharing contract achieve Pareto optimization, that is to say, when it is greater than the profit of the enterprise under decentralized decision-making.

Due to the sudden surge of orders, it is difficult for suppliers with a limited capacity to ensure that all orders are delivered in time and all the products are qualified. Suppliers are likely to put more limited capacity into completing orders, thus ignoring the quality of products. This will easily lead to the occurrence of product quality events, and then affect the goodwill of enterprise products. The innovations of this paper are as follows: first, based on the above facts, a negative and dynamic correlation between the delivery level and the quality level is established, which has been involved in previous studies. Second, the joint decision model of timely delivery, product quality, and marketing is constructed. Thirdly, centralized decision-making is the best way of supply chain cooperation, and cost sharing contracts can coordinate the supply chain. This paper provides guidance for enterprise managers when making decisions on quality, marketing and delivery. It also provides the basis for enterprise managers to formulate effective cooperation models. We can draw some research implications: when consumers are less sensitive to timely delivery, enterprises should give some coupons and small gifts to consumers in exchange for the extension of delivery time and put their limited capacity into improving the product quality. When consumers are highly sensitive to timely delivery, they can outsource some orders to cost-effective and professional third-party enterprises, which not only improves the delivery rate but also improves the product quality.

Quality is not only the basis for business survival and development but also a key issue that cannot be ignored in supply chain management decisions. In practice, the impact of quality on goodwill does not show an immediate effect, and there is a dynamic delayed effect. Therefore, we developed a dynamic model that considers the delayed effect of quality on goodwill. Firstly, we constructed a delayed differential equation for the effect of quality on goodwill based on the Nerlove–Arrow model for a two-channel supply chain in a competitive environment and studied the dynamic quality decision problem of manufacturers and retailers under the delay effect. Secondly, we constructed the manufacturer and retailer Hamilton functions based on the principles of being of great value, solving and comparing the optimal product quality level, having an optimal service quality level, product goodwill, and overall profit of the supply chain under both decentralized and centralized decision modes, and investigated the effect of delay time on the profit and quality decisions of supply chain members. The conclusions show that: (i) delay time is an important reference for supply chain members when choosing the decision mode, and the overall profit size of the supply chain has different relationships with the different values of delay time taken into account with the two decision scenarios. (ii) Adopting a centralized decision mode can motivate manufacturers and retailers to improve the quality level, which in turn promotes the sales of products and the accumulation of brand goodwill.