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In this work, we focus on the model-mismatch problem for model-based subspace channel tracking in the correlated underwater acoustic channel. A model based on the underwater acoustic channel’s correlation can be used as the state-space model in the Kalman filter to improve the underwater acoustic channel tracking compared that without a model. Even though the data support the assumption that the model is slow-varying and uncorrelated to some degree, to improve the tracking performance further, we cannot ignore the model-mismatch problem because most channel models encounter this problem in the underwater acoustic channel. Therefore, in this work, we provide a dynamic time-variant state-space model for underwater acoustic channel tracking. This model is tolerant to the slight correlation after decorrelation. Moreover, a forward-backward Kalman filter is combined to further improve the tracking performance. The performance of our proposed algorithm is demonstrated with the same at-sea data as that used for conventional channel tracking. Compared with the conventional algorithms, the proposed algorithm shows significant improvement, especially in rough sea conditions in which the channels are fast-varying.

The application of aerobic denitrifying bacteria in biological nitrogen removal has been of great interest. However, the mechanism of nitrogen conversion by aerobic denitrifying bacteria is unclear due to the lack of stoichiometry and kinetic studies. Therefore, this study aimed to investigate the stoichiometry and kinetics of aerobic denitrification using Pseudomonas mosselii H6 as a model strain. The results showed that the stoichiometric equations of strain H6 under different nitrogen source conditions were obtained by nitrogen balance analysis; the concentrations of different limiting substrates were set and combined with the multi-substrate Monod kinetic equation to fit the half-saturation constants of COD, ammonia, nitrate and nitrite nitrogen for strain H6, which were 230.1008, 25.3435, 4.1009 and 23.4601 mg/L, respectively; based on the model of “two-step denitrification”, the numerical simulation of the growth and aerobic denitrification of strain H6 under different limiting substrate concentrations was carried out by using AQUASIM software to test the validity of stoichiometric coefficients and kinetic constants and perfect fitting results were obtained. These parameters will help to simulate the growth and denitrification performance of aerobic denitrifying bacteria and provide an experimental basis for further quantitatively elucidating the mechanism of action in the aerobic denitrification process.

Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of translation elongation for protein biosynthesis as well as a plethora of non-translational moonlighting functions for cellular homeostasis. In malignant cells, however, eEF1A becomes a pleiotropic driver of cancer progression via a broad diversity of pathways, which are not limited to hyperactive translational output. In the past decades, mounting studies have demonstrated the causal link between eEF1A and carcinogenesis, gaining deeper insights into its multifaceted mechanisms and corroborating its value as a prognostic marker in various cancers. On the other hand, an increasing number of natural and synthetic compounds were discovered as anticancer eEF1A-targeting inhibitors. Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics.

The development of messenger RNA (mRNA) vaccines and therapeutics necessitates the production of high-quality in vitro-transcribed mRNA drug substance with specific critical quality attributes (CQAs), which are closely tied to the uniformity of linear DNA template. The supercoiled plasmid DNA is the precursor to the linear DNA template, and the supercoiled DNA percentage is commonly regarded as a key in-process control (IPC) during the manufacturing of linear DNA template. In this study, we investigate the influence of supercoiled DNA percentage on key mRNA CQAs, including purity, capping efficiency, double-stranded RNA (dsRNA), and distribution of poly(A) tail. Our findings reveal a significant impact of supercoiled DNA percentage on mRNA purity and in vitro transcription yield. Notably, we observe that the impact on mRNA purity can be mitigated through oligo-dT chromatography, alleviating the tight range of DNA supercoiled percentage to some extent. Overall, this study provides valuable insights into IPC strategies for DNA template chemistry, manufacturing, and controls (CMC) and process development for mRNA drug substance.

In this paper, we consider steady Euler flows in a planar bounded domain in which the vorticity is sharply concentrated in a finite number of disjoint regions of small diameter. Such flows are closely related to the point vortex model and can be regarded as desingularization of point vortices. By an adaption of the vorticity method, we construct a family of steady Euler flows in which the vorticity is concentrated near a global minimum point of the Robin function of the domain, and the corresponding stream function satisfies a semilinear elliptic equation with a given profile function. Furthermore, for any given isolated minimum point (x1, . . ., xk) of the Kirchhoff-Routh function of the domain, we prove that there exists a family of steady Euler flows whose vorticity is supported in k small regions near xi, and near each xi the corresponding stream function satisfies a semilinear elliptic equation with a given profile function. [ABSTRACT FROM AUTHOR]

Objective The adjusted mechanical alignment (aMA) technique is an extension of conventional mechanical alignment (MA), which has rarely been reported. The purpose of this study was to evaluate mid‐term outcomes of navigation‐assisted total knee arthroplasty (TKA) using aMA. Methods This retrospective cohort study enrolled 63 consecutive patients (77 knees) who underwent navigation‐assisted TKA using aMA between September 2017 and October 2019. Fifty‐two consecutive patients (61 knees) who underwent TKA using MA during the same period were assessed as the controlled group. The demographic data and perioperative data were recorded. The parameters of resection and soft tissue balance including tibia resection angle, frontal femoral angle, axial femoral angle, joint line translation, medial and lateral gap in extension and flexion position were recorded. Radiographic parameters and functional scores including the Hospital for Special Surgery (HSS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Forgotten Joint Score‐12 (FJS‐12) were evaluated. Surgery‐related complications were recorded. The average follow‐up was 3.5 years, with a minimum of 2.4 years. Results The frontal femoral angle was 2.55° ± 1.08° in aMA group versus 0.26° ± 0.60° in MA group (p

Abstract Objective To describe a new alignment technique of adjusted restricted kinematic alignment (arKA) for the treatment of severe varus deformity in total knee arthroplasty. Methods Three female patients (three severe varus knees) who underwent navigation‐assisted total knee arthroplasty (TKA) using arKA from April 2020 to September 2020 were included in this study, with an average age of 71.33 years (range, 61 to 80 years). General anesthesia was given to all patients. Intraoperative observations including tibia resection angle, frontal femoral angle, axial femoral angle, medial and lateral gap in the extension and flexion positions and joint line translation were recorded. Also, operation duration and drainage volume were recorded. Radiographic parameters including the mechanical axis (α), coronal femoral component angle (β), coronal tibial component angle (γ), sagittal femoral component angle (δ), tibial posterior slope angle (ε), femoral‐patella angle (θ), and femoral notching were assessed. Clinical evaluation was performed using the Hospital for Special Surgery (HSS) Score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Score. Both individual and mean measurement data were displayed. Results The mean tibial resection was 4.00° varus (range, 3° to 5°), and the mean frontal femoral angle was 3.67° varus (range, 3° to 4°) in extension. The flexion lateral gap was wider than the medial gap with a mean laxity of 1.34 mm. Moreover, the mean axial femoral angle was 2.67° external (range, 0° to 6°) in flexion, and the mean joint line translation was 1.00 mm proximal (range, 0 to 3 mm). In addition, the mean preoperative mechanical axis was 156.22° (range, 153.65° to 158.90°) and the mean postoperative mechanical axis was 174.04° (range, 173.83° to 174.17°) with a mean correction of 17.82°. The mean femoral angle was 92.60° (range, 91.29° to 93.30°) and the mean tibial angle was 86.95° (range, 86.83° to 87.04°) in coronal plane. The HSS score improved from an average of 46.67 points (range, 42 to 51) preoperatively to 83.67 points (range, 81 to 86) at 3 months postoperatively. The mean WOMAC score was 16.33 points at 3 months postoperatively. Conclusions The new alignment technique of arKA aims to balance the flexion and extension gap without extensive releases of soft tissue and restore the native pre‐arthritic alignment, may be a promising alignment strategy for treating severe varus deformity. However, further study and comparison with other alignment techniques is needed.

Digestive perianastomotic ulceration (DPAU) is a rare complication after intestinal resection and anastomosis occurring at or near the anastomosis site. The purpose of this review is to summarize the characteristics of DPAU, including the etiology, diagnosis and differential diagnosis, clinical manifestations, treatment, and future research. All recent literature on DPAU was searched in PubMed, Embase, and Cochrane and then reviewed. The clinical manifestations of DPAU are mainly gastrointestinal symptoms such as bloody stool and chronic anemia. The diagnosis of DPAU is difficult. Specific diseases, such as Crohn’s disease, must be ruled out before a diagnosis can be made. In addition, there are no clear treatment guidelines due to the high degree of heterogeneity in response to drugs and surgery. It is recommended to adjust medication in time and combine various treatment methods. In addition, the mechanism that causes DPAU is not well understood; however, several possible mechanisms have been proposed, such as scar tissue ischemia and underlying diseases. Moreover, there is a high risk of relapses, and a long-term follow-up is necessary. Numerous issues remain to be solved in this area; therefore, more randomized controlled trials and studies should be carried out to further understand this disease.

Salmonella 4,[5],12:i:-, a monophasic variant of S. Typhimurium, has become a global serovar causing animal and human infections since its first emergence in the late 1980's. Several previous studies showed the increasing prevalence of S. 4,[5],12:i:- in China, most of which were from swine with multidrug resistance (MDR) profiles. However, the molecular characteristic and evolution of S. 4,[5],12:i:- in the same swine farm are still unknown. In this study, a total of 54 S. enterica strains were isolated from different fattening pigs aged 1, 3, and 6 months, most of which belonged to S. 4,[5],12:i:-. Whole-genome sequencing revealed that all 45 S. 4,[5],12:i:- strains belonged to ST34 and were further divided into two different ribosomal STs and nine different core-genome STs. Phylogenetic analysis of 286 S. 4,[5],12:i:- strains in China, including 241 from the EnteroBase Salmonella database, revealed the genetic diversity of S. 4,[5],12:i:- and indicated that S. 4,[5],12:i:- in this swine farm might have multiple origins. Three different IncHI2 plasmids carrying various resistance genes were characterized by nanopore sequencing and could be conjugated to Escherichia coli. The colistin resistance gene mcr-1 and ESBLs gene blaCTX − M−14 were co-located on the chromosome of one strain. The dynamic changes in antimicrobial resistance regions and transferability of IncHI2 plasmids, as well as the chromosomal location of resistance genes, facilitated the diversity of the antimicrobial resistance characteristics in S. 4,[5],12:i:-. Since the swine farm is regarded as the important reservoir of MDR S. 4,[5],12:i:-, the prevalence and evolution of S. 4,[5],12:i:- from swine farms to pig products and humans should be continually monitored.

The 5G internet of things brings the ultimate experience to users, but it also puts forward new challenges.Users’ requirements of ultra-low latency experience, access to business without sense during movement and security guarantee have attracted much attention.Mobile edge computing can meet the strict requirements of 5G with low latency, large connection and high bandwidth.As a computing paradigm with the coexistence of multi-trust domains, multi-entities and cross-trust domains are interconnected frequently.Identity authentication is particularly important for security protection.Through the research on the identity authentication mechanism under the existing edge computing paradigm, a lightweight fast handover authentication scheme based on pre-authentication was proposed.The proposed solution moved services and calculations from the cloud to the edge.Biometric fingerprint technology was used on the client side to defend against terminal theft attacks.Edge servers in different regions used pre-authentication scheme to meet fast switching requirements.The user and the edge server established a secure channel by negotiating a shared session key in real time, and the authentication scheme ensured lightweight operation with XOR and hash operation.The proposed scheme was evaluated from two aspects of security and performance.Theoretical design analysis and formal tool verification were carried out for security evaluation.The formal analysis tool, AVISPA, was used to verify the improved security of the proposed scheme in the presence of intruders.The performance was mainly evaluated from the computing cost and communication cost of the authentication scheme.The simulation results showed that the proposed scheme reduces communication cost, and the computational overhead can meet the needs of mobile terminals with limited resources.As the future work, the scheme will be improved from two aspects: one is to strengthen the scalability to ensure that users and edge servers can join and exit at any time, and the other one is to strengthen the universality of the scheme to meet the access deployment of third-party service providers.

Abstract Background The inhibition of osteogenic differentiation is a major factor in glucocorticoid-induced bone loss, but there is currently no effective treatment. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of the neuroendocrine system in bone metabolism has emerged, the precise effects of dopamine receptor signaling on osteoblastogenesis remain unknown. Methods In vitro, western blotting and immunofluorescence staining were used to observe the expression of dopamine receptors in MC3T3-E1 and BMSCs cells treated with dexamethasone (Dex). In addition, Alizarin red S (ARS) and alkaline phosphatase (ALP) staining and western blotting were used to evaluate the effect of D1R activation on osteogenic differentiation in Dex-induced MC3T3-E1 cells via the ERK1/2 signaling pathway. In vivo, micro-CT and hematoxylin and eosin (H&E), toluidine blue and immunohistochemical staining were used to determine the effect of D1R activation on Dex-induced bone loss. Results We demonstrated that the trend in D1R but not D2-5R was consistent with that of osteogenic markers in the presence of Dex. We also demonstrated that the activation of D1R promoted Dex-induced osteogenic differentiation by activating the ERK1/2 pathway in vitro. We further demonstrated that a D1R agonist could reduce Dex-induced bone loss, while pretreatment with a D1R inhibitor blocked the effect of a D1R agonist in vivo. Conclusions Activation of D1R promotes osteogenic differentiation and reduces Dex-induced bone loss by activating the ERK1/2 pathway. Hence, D1R could serve as a potential therapeutic target for glucocorticoid-induced osteoporosis.

Copper-based nanopesticides are released into the environment during foliar spray application, and they could, on their own or in combination with microplastics (MPs), pose threats to environmental safety and human health. In this study, Cu(OH)2 nanowires greatly decreased the vigor of lettuce seeds (p< 0.01) and the root length of lettuce seedlings (p< 0.01) and significantly altered the lettuce antioxidant defence system and MDA content (p< 0.05). Released Cu2+ played a critical role in the toxicity mechanism of Cu(OH)2 nanowires in lettuce seedlings, as evidenced by the substantial accumulation of Cu in the seedling roots (p< 0.01) rather than in the leaves. Polystyrene (PS) MPs (1 mg/L) stimulated lettuce seedling growth, as shown by the (highly) significant increase in root and leaf length and in the seed vigor index (p< 0.01 or 0.05). Notably, PS MPs (1 mg/L) neutralized the hazardous effects of 1 mg/L Cu(OH)2 nanowire treatment on lettuce growth, as reflected by the vitality and root length of the seedlings returning to normal levels. The PS MPs (1 mg/L) absorbed on middle root surfaces and strongly hindered Cu accumulation in lettuce roots, which was the predominant mechanism by which PS MPs suppressed the hazardous effects of the Cu(OH)2 nanowires. This study strengthens the understanding of the toxicity and toxicity mechanisms of Cu(OH)2 nanowires with or without PS MPs in the environment.

Abstract In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

Periprosthetic osteolysis (PPO) remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles. Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses. Additionally, the NLRP3 inflammasome is activated by prosthetic particles. Sirtuin3, an NAD+-dependent deacetylase of mitochondria, regulates the function of mitochondria in diverse activities. However, whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported. Therefore, we investigated the role of SIRT3 during the process of titanium (Ti) particle-induced osteolysis. We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro. Moreover, we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3β/β-catenin signalling pathway. Collectively, these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.

Objective To evaluate mid‐ to long‐term results of revision total hip arthroplasty for massive femoral bone loss using a cementless modular, fluted, tapered stem. Methods This is a retrospective study performed at a single hospital. During the period of January 2007 to January 2015, 33 patients (34 hips) underwent primary revision surgery with cementless modular, fluted, tapered stems due to femoral bone loss. Sixteen men and 17 women were included in the study, with an average age of 63.9 ± 11.7 years (range, 27 to 88 years). Operative data including operative duration, length of incision, drainage volume and duration, blood loss and transfusion, cases of bone graft and extended trochanteric osteotomy were recorded. Clinical evaluation was performed using Harris hip score (HHS), visual analogue scale (VAS), and patients' satisfaction. Radiographic data including femoral stem fixation, subsidence, integrin of allograft bone, and leg length discrepancy were assessed. Complications and survivorship were evaluated using Kaplan–Meier survival rate. Results The mean follow‐up was 9.1 ± 2.5 years (range, 5–13 years). The Harris hip score was 43.6 ± 11.5 preoperatively and maintained at 86.5 ± 6.6 at the time of latest follow‐up (P

A micro-annulus (MA) is defined as a high permeability zone or gap initiating/occurring at the casing-cement and cement-formation interfaces during the wellbore life span. An MA can significantly compromise wellbore integrity by establishing enhanced fluid flow pathways. This study uses a staged finite element approach to simulate wellbore integrity during various loading steps of wellbore operations under downhole conditions. Particular emphasis is placed on the processes of cement poro-elastic property evolution, volume variation, and pore pressure variation as part of the cement hardening step. The resulting state of stress during the life cycle of a typical injection well (i.e. hardening, completion, and injection) is analyzed to assess the onset and evolution of micro-annuli at various interfaces of the composite wellbore system under downhole conditions. The results show that cement shear failure is observed at the casing-cement interface during pressure testing (excessive wellbore pressure); and tensile debonding failure initiates at the cement-formation interface due to cement shrinkage during hardening and injection-related cooling (thermal cycling). Sensitivity analyses considering several parameters show that: (1) the degree of poro-elastic bulk shrinkage has significant implications for both shear and tensile failure initiation – the less the cement shrinks, the less likely the failure initiation is; (2) cement integrity increases with increasing depth; (3) cement pore pressure evolution has significant implications for tensile failure – if cement pore pressure decreases more, higher temperature differences can be sustained before an MA occurs; and (4) cement temperature fluctuations during hardening promote initiation of debonding failure. In summary, the results presented indicate that establishing downhole conditions to quantitatively analyze MA generation is necessary. The results are different compared to laboratory studies without considering/simulating downhole conditions. The knowledge from this study can raise the awareness of predicting and evaluating MA under downhole conditions and can be used to supplement and improve future laboratory experiments.

This paper presents an analysis of sea surface roughness from visible images based on fractals features for the first time. We measure fractal dimensions of sea surface images by the methods of box counting, fractional Brownian motion, and area measurement. The empirical values of sea surface roughness are found from measured wind speed and an empirical relation. The correlations between wind speeds (or sea surface roughness) and fractal dimensions are evaluated based on the data from a field experiment. Further, four types of noises with different parameters are introduced to the sea surface images. Then noise suppression performances of six methods are evaluated. Our experiments have demonstrated that our fractal methods and empirical relation between wind speeds and fractal dimensions are effective for analyzing roughness changes of sea surface from visible images.

Abstract Glucocorticoids (GCs) are used in treating viral infections, acute spinal cord injury, autoimmune diseases, and shock. Several patients develop GC‐induced osteonecrosis of the femoral head (ONFH). However, the pathogenic mechanisms underlying GC‐induced ONFH remain poorly understood. GC‐directed bone marrow mesenchymal stem cells (BMSCs) fate is an important factor that determines GC‐induced ONFH. At high concentrations, GCs induce BMSC apoptosis by promoting oxidative stress. In the present study, we aimed to elucidate the molecular mechanisms that relieve GC‐induced oxidative stress in BMSCs, which would be vital for treating ONFH. The endocannabinoid system regulates oxidative stress in multiple organs. Here, we found that monoacylglycerol lipase (MAGL), a key molecule in the endocannabinoid system, was significantly upregulated during GC treatment in osteoblasts both in vitro and in vivo. MAGL expression was positively correlated with expression of the NADPH oxidase family and apoptosis‐related proteins. Functional analysis showed that MAGL inhibition markedly reduced oxidative stress and partially rescued BMSC apoptosis. Additionally, in vivo studies indicated that MAGL inhibition effectively attenuated GC‐induced ONFH. Pathway analysis showed that MAGL inhibition regulated oxidative stress in BMSCs via the Kelch‐like ECH‐associated protein 1 (Keap1)/nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway. The expression of Nrf2, a major regulator of intracellular antioxidants, was upregulated by inhibiting MAGL. Nrf2 activation can mimic the effect of MAGL inhibition and significantly reduce GC‐induced oxidative damage in BMSCs. The beneficial effects of MAGL inhibition were attenuated after the blockade of the Keap1/Nrf2 antioxidant signaling pathway. Notably, pharmacological blockade of MAGL conferred femoral head protection in GC‐induced ONFH, even after oxidative stress responses were initiated. Therefore, MAGL may represent a novel target for the prevention and treatment of GC‐induced ONFH.

Skin sensitization is an important occupational health problem and immunotoxicity endpoint. Considering animal welfare and time and cost savings, many alternative approaches, such as those conducted in vitro, in silico, and in chemo, have been proposed and applied to predict skin sensitization of compounds. Toxicologically, sensitizers can elicit excess toxicity at greater levels than non-sensitizers due to their capacity to react with proteins/peptides. Based on this understanding, calculated toxicity enhancements (Te) of 65 organic compounds from three in vitro bioassays, i.e. 48-hr ciliate (Tetrahymena pyriformis) growth inhibition, and both 96-hr fathead minnow and 48-hr Daphnia magna acute lethal toxicities, were employed to qualitatively and quantitatively predict skin sensitization potencies of the test agents. The sensitivity, specificity, and accuracy reaching 80% strongly suggested toxicity enhancement was an excellent parameter for predicting skin sensitization. Linear regressions of skin sensitization against toxicity enhancement were fitted for each bioassay, and they were improved after the sensitizers were categorized into different reaction mechanistic domains, which, in decreasing order of contribution from Te to sensitization, were SNAr > SN1 > MA. These results indicated that toxicity bioassays are useful tools and that Te could be a useful parameter that might be applied to predict skin sensitization.

Natural product total synthesis is in essence target-oriented in that a set of organic transformations are orchestrated into a workable process, leading ultimately to the target molecule with a predefined architecture. For a bioactive lead, proof of synthetic viability is merely the beginning. Ensuing effort repurposes the initial synthesis for structural diversification in order to probe structure-activity relationship (SAR). Yet accessibility is not equal to flexibility; moving from convergency to divergency, it is not always feasible to explore the chemical space around a particular substructure of interest simply by tweaking an established route. In this situation, the motif-oriented strategy becomes a superior choice, which gives priority to synthetic flexibility at the concerned site such that a route is adopted only if it is capable of implementing diversification therein. This strategy was recently devised by Fürstner et al., enabling them to achieve total synthesis of both natural and non-natural nannocystins varied at an otherwise challenging position. The present review examines seven distinctive nannocystin total syntheses reported thus far and showcases the merits of conventional (target-oriented) as well as motif-oriented strategies, concluding that these two approaches complement each other and are both indispensable for natural product based drug discovery.

The advanced tensor based concept of pore pressure-stress coupling is used to provide pre-injection analytical estimates of the maximum sustainable pore pressure change, ΔPc, for fluid injection scenarios into generic anticline geometries. The heterogeneous stress distribution for different prevailing stress regimes in combination with the Young's modulus (E) contrast between the injection layer and the cap rock and the interbedding friction coefficient, μ, may result in large spatial and directional differences of ΔPc. A single value characterizing the cap rock as for horizontal layered injection scenarios is not obtained. It is observed that a higher Young's modulus in the cap rock and/or a weak mechanical coupling between layers amplifies the maximum and minimum ΔPc values in the valley and limb, respectively. These differences in ΔPc imposed by E and μ are further amplified by different stress regimes. The more compressional the stress regime is, the larger the differences between the maximum and minimum ΔPc values become. The results of this study show that, in general compressional stress regimes yield the largest magnitudes of ΔPc and extensional stress regimes provide the lowest values of ΔPc for anticline formations. Yet this conclusion has to be considered with care when folded anticline layers are characterized by flexural slip and the friction coefficient between layers is low, i.e. μ = 0.1. For such cases of weak mechanical coupling, ΔPc magnitudes may range from 0 MPa to 27 MPa, indicating imminent risk of fault reactivation in the cap rock.

User-in-the-loop (UiL) content delivery is a recently proposed scheme for personalized content retrieval over mobile communication networks. It is a promising scheme that can better manage the overall user quality-of-experience (QoE) throughout the entire content retrieval process. The performance of the scheme, however, has only been investigated in a simplified system model that assumed synchronized user behavior, inflexible delay constraint, and identical quality-of-service (QoS) requirement among users. This paper studies the performance of UiL content delivery scheme in a generalized and realistic system model with asynchronous user behavior, flexible outage delay constraint, and customized user QoS. Heuristic algorithms and theoretical bounds are investigated for the UiL content delivery problem. The proposed system is shown to be effective in managing the user QoE in generalized practical scenarios.