Programmable Chemical Evolution with Natural/non-natural Building Blocks.

Non-natural building blocks (BBs) present a vast reservoir of chemical diversity for molecular recognition and drug discovery. However, leveraging evolutionary principles to efficiently generate bioactive molecules with a larger number of diverse BBs poses challenges within current laboratory evolution systems. Here, we introduce programmable chemical evolution (PCEvo) by integrating chemoinformatic classification and high-throughput array synthesis/screening. PCEvo initiates evolution by constructing a diversely combinatorial library to create ancestral molecules, streamlines the molecular evolution process and identifies high-affinity binders within 2-4 cycles. By employing PCEvo with 108 BBs and exploring >10^17 chemical space, we identify bicyclic peptidomimetic binders against targets SAR-CoV-2 RBD and Claudin18.2, achieving nanomolar affinity. Remarkably, Claudin18.2 binders selectively stain gastric adenocarcinoma cell lines and patient samples. PCEvo achieves expedited evolution in a few rounds, marking a significant advance in utilizing non-natural building blocks for rapid chemical evolution applicable to targets with or without prior structural information and ligand preference.

Formation of Size-Controllable Tetragonal Nanoprisms by Crystallization-Directed Ionic Self-Assembly of Anionic Porphyrin and PEO-Containing Triblock Cationic Copolymer.

The creation of anisotropic nanostructures with precise size control is desirable for new properties and functions, but it is challenging for ionic self-assembly (ISA) because of the non-directional electrostatic interactions. Herein, the formation of size-controllable tetragonal nanoprisms is reported via crystallization-directed ionic self-assembly (CDISA) through evaporating a micellar solution on solid substrates. First, ISA is designed with a crystalline polyethylene oxide (PEO) containing cationic polymer poly(2-(2-guanidinoethoxy)ethyl methacrylate)-b-poly(ethyleneoxide)-b-poly(2-(2-guanidinoethoxy)-ethylmethacrylate) (PGn -PEO230 -PGn ) and an anionic 5,10,15,20-Tetrakis(4-sulfonatophenyl) porphyrin (TPPS) to form micelles in aqueous solution. The PG segments binds excessive TPPS with amplenet chargeto form hydrophilic corona, while the PEO segments are unprecedentedly dehydrated and tightly packed into cores. Upon naturally drying the micellar solution on a silicon wafer, PEO crystallizationdirects the micelles to aggregate into square nanoplates, which are further connected to nanoprisms. Length and width of the nanoprisms can be facilely tuned by varying the initial concentration. In this hierarchical process, the aqueous self-assembly is prerequisite and the water evaporation rate is crucial for the formation of nanostructures, which provides multiple factors for morphology regulating. Such precise size-control strategy is highly expected to provide a new vision for the design of advanced materials with size controllable anisotropic nanostructures.

The Role of TGF-ß during Pregnancy and Pregnancy Complications.

Transforming growth factor beta (TGF-ß), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays significant roles in hormone secretion, placental development, and embryonic growth during pregnancy. TGF-ß is implicated in embryo implantation and inhibits the invasion of extraepithelial trophoblast cells. It also moderates the mother-fetus interaction by adjusting the secretion pattern of immunomodulatory factors in the placenta, consequently influencing the mother's immune cells. The TGF-ß family regulates the development of the nervous, respiratory, and cardiovascular systems by regulating gene expression. Furthermore, TGF-ß has been associated with various pregnancy complications. An increase in TGF-ß levels can induce the occurrences of pre-eclampsia and gestational diabetes mellitus, while a decrease can lead to recurrent miscarriage due to the interference of the immune tolerance environment. This review focuses on the role of TGF-ß in embryo implantation and development, providing new insights for the clinical prevention and treatment of pregnancy complications.

A Self-Assembled Matrix System for Cell-Bioengineering Applications in Different Dimensions, Scales, and Geometries.

Stem cell bioengineering and therapy require different model systems and materials in different stages of development. If a chemically defined biomatrix system can fulfill most tasks, it can minimize the discrepancy among various setups. By screening biomaterials synthesized through a coacervation-mediated self-assembling mechanism, a biomatrix system optimal for 2D human mesenchymal stromal cell (hMSC) culture and osteogenesis is identified. Its utility for hMSC bioengineering is further demonstrated in coating porous bioactive glass scaffolds and nanoparticle synthesis for esiRNA delivery to knock down the SOX-9 gene with high delivery efficiency. The self-assembled injectable system is further utilized for 3D cell culture, segregated co-culture of hMSC with human umbilical vein endothelial cells (HUVEC) as an angiogenesis model, and 3D bioprinting. Most interestingly, the coating of bioactive glass with the self-assembled biomatrix not only supports the proliferation and osteogenesis of hMSC in the 3D scaffold but also induces the amorphous bioactive glass (BG) scaffold surface to form new apatite crystals resembling bone-shaped plate structures. Thus, the self-assembled biomatrix system can be utilized in various dimensions, scales, and geometries for many different bioengineering applications.

Se4P4nanoparticles confined within porous carbon as a lithium-ion battery anode with superior electrochemical performance.

The exploration of advanced anode materials through rational structure/phase design is the key to developing high-performance rechargeable batteries. Herein, tetraphosphorus tetraselenide (Se4P4) nanoparticles confined within porous carbon (named SeP@C) are developed for lithium-ion batteries. The designed SeP@C shows a set of structural/compositional advantages as lithium-ion battery anodes including high electrical conductivity, low ion diffusion barrier, and relieved lithiation stress. Consequently, the SeP@C electrode displays superior comprehensive lithium storage performance, e.g., high reversible capacity (640.8 mA h g-1at 0.1 A g-1), excellent cycling stability (500 cycles with respective capacity retention of over or nearly 100%), and good rate capability, representing a comparable lithium storage performance in reported phosphide-based anodes. More significantly, it shows excellent energy storage properties in lithium-ion full cells which can light up 85 red LEDs for over 3.2 h. This work offers an advanced electrode construction guidance of phosphorous-based anodes for the development of high-performance energy storage devices.

Adjunctive dexmedetomidine infusion in open living donor hepatectomy: A way to enhance postoperative analgesia and recovery.

BACKGROUND: Open living donor hepatectomy (OLDH) is a highly painful procedure. Advanced strategies for enhancing perioperative analgesia and accelerating recovery are needed for patients undergoing OLDH. This study evaluated the effects of intravenous infusion of dexmedetomidine (DEX) during OLDH on postoperative analgesia and recovery. METHODS: This prospective, randomised, double-blinded, and placebo-controlled study included 34 patients randomised to a control group (group C) and a DEX group (group D). Utilisation of intravenous patient-controlled analgesia (IV-PCA) pump, pain intensity, and postoperative recovery variables were recorded. Moreover, intraoperative anaesthetic consumption, hemodynamic parameters, and fluid status were also recorded. RESULTS: During the first 24 hours after surgery, patients in group D had a lower pain intensity. The cumulative numbers of IV-PCA pump presses and fentanyl consumption within 24 and 48 hours postoperatively in group C were significantly higher than in group D. The time to first IV-PCA attempt was prolonged in group D. In addition, faster flatus passage was observed in group D. Intraoperatively, fewer anaesthetic agents were required in group D. Less fluctuation in hemodynamics and reduced bleeding were also found in group D. CONCLUSIONS: The present study revealed that the addition of intravenous infusion of DEX during OLDH provided several benefits in relieving postoperative pain and promoting recovery. Therefore, we concluded that intraoperative DEX infusion may play an important role in enhancing the recovery of patients undergoing OLDH.

Comparison of maternal and fetal outcomes between delayed and immediate pushing in the second stage of vaginal delivery: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The second stage of labor begins with complete dilatation of the cervix until delivery of the fetus. After the cervix has fully dilated, the caregiver/nurse will provide guidance to the mother regarding the push technique for delivering the fetus (immediate pushing, IP). Because some women receive analgesic medications during labor, they might not be able to push correctly. Therefore, some obstetricians choose to postpone guiding the patient to push until the cervix is fully dilated and the fetal head has begun to descend. At this point, there is an involuntary exertion sensation (delayed pushing, DP) that saves energy and, at the same time, decreases tiredness and fatigue. The best timing for pushing during the second stage of labor is still controversial. The aim of this study was to investigate the different maternal and neonatal outcomes with IP and DP in the second stage of labor. METHODS: The Cochrane Library, EMBASE, PubMed, and Airiti Library (a Chinese database) were searched up to July 2019. Search keywords included: "labor stage, second", "delayed pushing", and "immediate pushing". Gray literature and bibliographies of articles were checked. No language restrictions were applied. Only randomized controlled trials were included. Two independent reviewers identified relevant studies and extracted data. The quality of the studies was assessed using the Cochrane's Risk of Bias tool. A random-effects meta-analysis was used to pool results. Mean differences and risk ratios were calculated with 95% confidence intervals (CIs) using Review Manager 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark, 2014). The risk of heterogeneity was reported as I2, and publication bias was visually assessed by funnel plots. RESULTS: In total, 15 studies (n = 6121 participants) were identified. Pooled results demonstrated the following. (1) As to maternal outcomes, in comparison, IP shortened the length of the second stage of labor by 40.9 (95% CI 23.6-58.2) min; however, DP decreased the total length of pushing by 25.4 (95% CI 13.9-37.0) min. The incidence of instrument-assisted vaginal delivery was significantly lower in the DP group in western countries (RR 0.85, 95% CI 0.74-0.97). In addition, the maternal postpartum fatigue score was 0.67 points lower in the DP group (95% CI - 1.09 to - 0.26). There was no statistical significance of the cesarean section rate or blood loss. (2) As to neonatal outcomes (Apgar score at 1 min), the DP group showed a higher score (by 0.19; 95% CI 0.10-0.27 points) than the IP group. CONCLUSIONS: Delayed pushing can decrease the total pushing time and decrease the fatigue score after delivery without significant adverse events compared to the early pushing group. Therefore, we recommend that caregivers instruct the pushing time at the optimal moment, which allows women to have more resting time and save energy during labor.

Specificity from nonspecific interaction: regulation of tumor necrosis factor-α activity by DNA.

As anionic biopolymers, oligonucleotides can have biological functions independent from their roles as the medium for the storage and flow of genetic information. In this paper, we investigated the interaction between DNA and the pro-inflammatory cytokine tumor necrosis factor-α (TNFα). Although various forms of DNA bind to TNFα with low µm dissociation constants, the interaction stabilizes the trimeric form of TNFα and enhances its cytotoxic effect. Based on this mechanism, a photoswitchable TNFα (TNFα-2-nitroveratryloxycarbonyl) has been designed whose sensitivity to DNA-mediated up-regulation of TNFα activity can be tuned by light irradiation. The mechanism described in this study represents a general model to understand the involvement of nonspecific interactions among biomolecules in regulating their biological functions. Because the interaction is not DNA sequence-specific, the resulting effect should be considered for oligonucleotide-based therapeutics in general.

Using a PCR-Based Method To Analyze and Model Large, Heterogeneous Populations of DNA.

The study of populations of large size and high diversity is limited by the capability of collecting data. Moreover, for a pool of individuals, each associated with a unique characteristic feature, as the pool size grows, the possible interactions increase exponentially and quickly go beyond the limit of computation and experimental studies. Herein, the design of DNA libraries with various diversity is reported. By using a facile analytical method based on real-time PCR, the diversity of a pool of DNA can be evaluated to allow extraordinarily high heterogenicity (e.g., >1 trillion). It is demonstrated that these DNA libraries can be used to model heterogeneous populations; these libraries exhibit functions such as self-protection, suitability for biased expansion, and the possibility to evolve into amorphous structures. The method has shown the remarkable power of parallel computing with DNA, since it can resemble an analogue computer and be applied in selection-based biotechnology methods, such as DNA-encoded chemical libraries. As a chemical approach to solve problems traditionally for genetic and statistical analysis, the method provides a quick and cost-efficient evaluation of library diversity for intermediate steps through a selection process.

Does hyoscine N-butylbromide shorten the active phase in labor? A meta-analysis of randomized controlled trials.

OBJECTIVES: The objective of the study is to evaluate the therapeutic effect of hyoscine N-butylbromide (HBB) in active phase of labor and its safety to mother and fetus. METHODS: A systematic literature search was conducted on Cochrane Library, Pubmed, EMBASE, CINAHL, ClinicalTrials.gov and three databases in Chinese up to March 31, 2020. Randomized controlled trials (RCTs) of HBB administration during the active phase for shortening of spontaneous labor at term compared with placebo were included. Two reviewers assessed the methodological quality and data extraction independently. We calculated pooled risk ratios (RRs), mean differences (MDs) and 95% confidence intervals (CIs) using Review Manager 5.3 software. Intention-to-treat principles and random-effects model were adopted for analysis and pool results. RESULTS: In total, 1448 women from 9 RCTs were included in the meta-analysis. The HBB group exhibited significantly decreased durations of active phase (MD -61.1 min; 95% CI: -87.7 to -34.4, I2 : 96%), the second stage (MD -2.0 min; 95% CI: -3.4 to -0.5, I2 : 62%), and third stage (MD -0.7 min; 95% CI: -1.1 to -0.3, I2 : 51%). Intravenous (IV) HBB group and intramuscularly (IM) HBB group were compared to the control group (MD -60.9 min; 95% CI -87.7 to -34.1, I2 : 96%). No significant differences were observed in Cesarean section, post-partum hemorrhage, instrumental labor, Apgar scores or any adverse effects. CONCLUSION: Hyoscine N-butylbromide had a significant effect of shortening the duration of the active phase of labor without adverse effects. We recommend a single dose of intravenous administrated HBB when a woman undergoes labor augmentation.

Evaluation of thirty patients with eustachian tube dysfunction in Taiwan by questionnaire survey.

BACKGROUND: Eustachian tube dysfunction (ETD) is a common otolaryngological disorder. The seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) was used for the assessment of symptoms related to ETD and treatment outcome. Currently, there is no traditional Chinese version of the ETDQ-7 to diagnose ETD in Taiwan. We aim to verify the reliability and validity of the traditional Chinese version of the ETDQ-7 in a clinical setting. METHODS: The traditional Chinese version of the ETDQ-7 was completed by 60 adult subjects composed of 30 healthy controls and 30 subjects diagnosed with ETD. The internal consistency was evaluated using the Cronbach's α coefficient. The discriminant validity was calculated by receiver operating characteristic (ROC) curve as an accuracy measure. RESULTS: The overall Cronbach's α coefficient of the traditional Chinese version ETDQ-7 was 0.717. The mean ETDQ-7 total score was 26.97 in the ETD group and 9.27 in the control group. The area under the ROC curve (AUC) was 99.8%, and the sensitivity and specificity of the traditional Chinese ETDQ-7 was 100% and 99.9%, respectively. CONCLUSION: The traditional Chinese version of the ETDQ-7 is a valid and reliable, disease-specific rating scale that can be used to quantitatively evaluate the severity of subjective symptoms of ETD in adult patients.

Highly Conductive, Stretchable, and Cell-Adhesive Hydrogel by Nanoclay Doping.

Electrically conductive materials that mimic physical and biological properties of tissues are urgently required for seamless brain-machine interfaces. Here, a multinetwork hydrogel combining electrical conductivity of 26 S m-1 , stretchability of 800%, and tissue-like elastic modulus of 15 kPa with mimicry of the extracellular matrix is reported. Engineering this unique set of properties is enabled by a novel in-scaffold polymerization approach. Colloidal hydrogels of the nanoclay Laponite are employed as supports for the assembly of secondary polymer networks. Laponite dramatically increases the conductivity of in-scaffold polymerized poly(ethylene-3,4-diethoxy thiophene) in the absence of other dopants, while preserving excellent stretchability. The scaffold is coated with a layer containing adhesive peptide and polysaccharide dextran sulfate supporting the attachment, proliferation, and neuronal differentiation of human induced pluripotent stem cells directly on the surface of conductive hydrogels. Due to its compatibility with simple extrusion printing, this material promises to enable tissue-mimetic neurostimulating electrodes.

Thioxylated cyclosporin A for studying protein-drug interactions.

Single atom substitution of cyclosporin A (CsA) through thioxylation has been used to study the structure-activity relationship of the immunosuppressive complex, involving the CsA receptor protein cyclophilin 18 (Cyp18) and the immunological target protein phosphatase calcineurin (CaN), illustrating the contributions of peptide backbone in protein-drug interaction. Moreover, the subtle difference between thioxylation positions in CsA has led to a remarkable change in the quenching effect on Cyp18 intrinsic fluorescence. Using the thioxylated compound Cs7 as an isosteric derivative of CsA in competition assay, the experiment has led to the determination of koff value in solution. Whereas the conformational heterogeneity of CsA has been found to be associated with its two-phase binding kinetics to Cyp18, the dissociation rate of CsA from complex is independent from the initial ligand structure.

Predicting Optimal Insertion Depth of a Left-sided Double-Lumen Endobronchial Tube.

OBJECTIVE: Appropriate placement of the double-lumen endobronchial tube (DLT) is essential for one-lung ventilation. Several formulae based on body height (BH) have been used for estimating the optimal insertion depth of a left-sided DLT. In this study, the authors examined the following 5 formulae for accuracy of prediction: 0.11×BH+10.53 (cm) from Brodsky et al(1); 0.15×BH+3.96 (cm) from Bahk and Oh(2); 0.148×BH+3.8 (cm) from Chow et al;(3) 0.1×BH+12.5 (cm) from Takita et al(4); and 0.1977×BH - 4.2423 (cm) (authors' formula). DESIGN: Single-center, retrospective, observational study. SETTING: University hospital. PARTICIPANTS: Anesthetic records of patients older than 20 years who received one-lung ventilation using a left-sided DLT were included. INTERVENTIONS: The patients' sex, age, body weight, BH, and the final correct insertion depth of the left-sided DLT after fiberscope verification were recorded. Linear regression and correlation were used to analyze the data. MEASUREMENTS AND MAIN RESULTS: One hundred seventy anesthetic records were analyzed. The insertion depth was distributed normally in 4 groups with different BH intervals. The correlations between the correct insertion depth and all the lengths calculated using each formula were significant (p<0.001), with a similar high coefficient of determination (r = 0.809). The regression line derived from the authors' formula-0.1977×BH - 4.2423 (cm)-showed the most accuracy in predicting the correct insertion depth. CONCLUSIONS: The height-based formula of 170 - 29.5 - 5 - 1 (the insertion depth is 29.5 cm for patients who are 170 cm tall, and the insertion length is increased or decreased by 1 cm for every 5 cm increase or decrease in BH) modified by the equation of 0.1977×BH - 4.2423 is a useful tool to predict the optimal insertion depth in initially blind left-sided DLT insertion.

Characterization of DNA-conjugated compounds using a regenerable chip.

DNA-encoded chemical library (DECL) technology has emerged as a new avenue in the field of drug discovery. Combined with high-throughput sequencing, DECL selection experiments can provide not only many lead compounds but also insights into the structure-affinity relationship. However, the counts of individual DNA codes reflect, but cannot be used to precisely rank, the binding affinities of the corresponding compounds to protein targets. Herein, we describe a chip-based approach to realize an automated high-throughput assay for the kinetic characterization of the interaction between DNA-conjugated small organic compounds and protein targets. Importantly, this method can be applied to both single-pharmacophore DECLs and self-assembled dual-pharmacophore DECLs.

DNA-Encoded Dynamic Combinatorial Chemical Libraries.

Dynamic combinatorial chemistry (DCC) explores the thermodynamic equilibrium of reversible reactions. Its application in the discovery of protein binders is largely limited by difficulties in the analysis of complex reaction mixtures. DNA-encoded chemical library (DECL) technology allows the selection of binders from a mixture of up to billions of different compounds; however, experimental results often show low a signal-to-noise ratio and poor correlation between enrichment factor and binding affinity. Herein we describe the design and application of DNA-encoded dynamic combinatorial chemical libraries (EDCCLs). Our experiments have shown that the EDCCL approach can be used not only to convert monovalent binders into high-affinity bivalent binders, but also to cause remarkably enhanced enrichment of potent bivalent binders by driving their in situ synthesis. We also demonstrate the application of EDCCLs in DNA-templated chemical reactions.

A repertoire of peptide tags for controlled drug release from injectable noncovalent hydrogel.

A repertoire of conjugable tags for controlling the release of drugs from biomaterials is highly interesting for the development of combinatorial drug administration techniques. This paper describes such a system of 11 peptide tags derived from our previous work on a physical hydrogel system cross-linked through peptide-heparin interactions. The release kinetics of the tags correlate well with their affinity to heparin and obey Fick's second law of diffusion, with the exception of the ATIII peptide, which displays a stable release profile close to a zero-order reaction. A system for release experiments over seven months was built, using the hydrogel matrix as a barrier between the reservoirs of tagged compounds and supernatant. The gel matrix can be injected without affecting the releasing properties. A tagged cyclosporin A derivative was also tested, and its release was monitored by measuring its biological activity. This work represents a design of biomaterials with an integral system of drug delivery, where both the assembly process of the matrix and affinity capture/release of tagged compounds are based on the noncovalent interaction of heparin with one class of peptides.

A Highly Sustainable Supramolecular Bioplastic Film with Superior Hydroplasticity and Biodegradability.

Massive accumulation of postconsumer plastic waste in eco-system has raised growing environmental concerns. Sustainable end-of-life managements of the indispensable plastic are highly demanding and challenging in modern society. To relieve the plastic menace, herein we present a full life cycle sustainable supramolecular bioplastic made from biomass-derived polyelectrolyte (chitosan quaternary ammonium salt, QCS) and natural sodium fatty acid (sodium laurate, SL) through solid-phase molecular self-assembly (SPMSA), by which the QCS-SL complexes, precipitated from mixing the aqueous solutions, self-assemble to form bioplastic film by mildly pressing at room temperature. The QCS-SL bioplastic films display superior hydroplasticity owing to the water-activated molecular rearrangement and electrostatic bond reconstruction, which allows facile self-healing and reprocessing at room temperature to significantly extend the service lifetime of both products and raw materials. With higher water content, the dynamic electrostatic interactions and precipitation-dissolution equilibrium endow the QCS-SL bioplastic films with considerable solubility in water, which is promising to mitigate the plastic accumulation in aquatic environment. Because both QCS and SL are biocompatible and biodegradable, the dissolved QCS-SL films are nontoxic and environmentally friendly. Thus, this novel supramolecular bioplastic is highly sustainable throughout the whole life cycle, which is expected to open a new vista in sustainable plastic materials.

Practice Algorithm of Rotational Thromboelastometry-Guided (ROTEM-Guided) Bleeding Management in Liver Transplantation.

Liver transplantation (LT) is frequently complicated by coagulopathy associated with end-stage liver disease, which is often multifactorial and associated with hemostatic disturbances affecting both the procoagulant and anticoagulant systems. This rebalanced coagulation system may lead to bleeding diathesis or increased clot formation. Conventional coagulation tests cannot reflect these complex changes because they can only illustrate deficiencies in the procoagulant system. Viscoelastic tests such as rotational thromboelastometry (ROTEM) have been used in LT and have shown useful for detecting coagulopathy and guiding transfusions. Implementation of ROTEM-guided bleeding management algorithms has proven effectiveness in reducing bleeding, transfusion needs, complication rates, and healthcare costs in LT. This document is intended to provide a practice algorithm for the management of major bleeding and coagulopathy during LT and to encourage adaptation of the guidelines to individual institutional circumstances and resources.