Synchronized wearables for the detection of haemodynamic states via electrocardiography and multispectral photoplethysmography.

Cardiovascular health is typically monitored by measuring blood pressure. Here we describe a wireless on-skin system consisting of synchronized sensors for chest electrocardiography and peripheral multispectral photoplethysmography for the continuous monitoring of metrics related to vascular resistance, cardiac output and blood-pressure regulation. We used data from the sensors to train a support-vector-machine model for the classification of haemodynamic states (resulting from exposure to heat or cold, physical exercise, breath holding, performing the Valsalva manoeuvre or from vasopressor administration during post-operative hypotension) that independently affect blood pressure, cardiac output and vascular resistance. The model classified the haemodynamic states on the basis of an unseen subset of sensor data for 10 healthy individuals, 20 patients with hypertension undergoing haemodynamic stimuli and 15 patients recovering from cardiac surgery, with an average precision of 0.878 and an overall area under the receiver operating characteristic curve of 0.958. The multinodal sensor system may provide clinically actionable insights into haemodynamic states for use in the management of cardiovascular disease.

High-yield production of FK228 and new derivatives in a Burkholderia chassis.

FK228 (romidepsin) is the only natural histone deacetylases (HDACs) inhibitor approved by FDA to treat cutaneous and peripheral T-cell lymphoma. However, the limited supply and severe cardiotoxicity of FK228 underscore the importance to develop an effective synthetic biology platform for the manufacturing and fine-tuning of this drug lead. In this work, we constructed a Burkholderia chassis for the high-yield production of FK228-family (unnatural) natural products. By virtue of the optimized Burkholderia-specific recombineering system, the biosynthetic gene cluster (BGC) encoding the FK228-like skeleton thailandepsins (tdp) in Burkholderia thailandensis E264 was replaced with an attB integration site to afford the basal chassis KOGC1. The tdp BGC directly captured from E264 was hybridized with the FK228-encoding BGC (dep) using the versatile Red/ET technology. The hybrid BGC (tdp-dep) was integrated into the attB site of KOGC1, resulting in the heterologous expression of FK228. Remarkably, the titer reached 581 mg/L, which is 30-fold higher than that of native producer Chromobacterium violaceum No. 968. This success encouraged us to further engineer the NRPS modules 4 or 6 of hybrid tdp-dep BGC by domain units swapping strategy, and eight new FK228 derivatives (1-8) varying in the composition of amino acids were generated. Especially, the titers of 2 and 3 in KOGC1 were up to 985 mg/L and 453 mg/L, respectively. 2 and 3 displayed stronger cytotoxic activity than FK228. All in all, this work established a robust platform to produce FK228 and its new derivatives in sufficient quantities for anticancer drug development.

Patterned Aluminum/Polydimethylsiloxane-Laminated Film for a Solvent-Driven Soft Actuator with Programmable and Multistable Shape Morphing.

Recently, soft actuators capable of deforming in predictable ways under external stimuli have attracted increasing attention by showing great potential in emerging industries. However, limited efforts are being spent on the untethered actuators with multistable deformations. Also, there is a lack of mechanically guiding design principles for multistable structures. Here, the patterned aluminum/polydimethylsiloxane (Al/PDMS)-laminated films with surface wrinkles are fabricated by magnetron sputtering the Al layer on the PDMS substrate. By tuning the geometric parameters and surface constraints of the patterned Al/PDMS-laminated films, a series of solvent-driven actuators with multiform stable configurations (such as monostable arc, multistable cylinder, and monostable/bistable spiral) are proposed. The deformation mechanism is revealed using a linear elastic theory. Combined with the finite element analysis method, the deformations of Al/PDMS-laminated films with different surface constraints and geometric configurations are visually predicted. Besides, we modulate the deformation of different parts of the Z-shaped actuators by tuning the surface constraints in different regions of the Z-shaped Al/PDMS bilayer films to achieve multiple stable deformations in a single actuator. The concept offers a huge design scope for reconfigurable soft robots. Finally, two bionic applications are proposed to demonstrate the practical applications of the soft solvent-driven actuator based on the patterned Al/PDMS films in artificial muscles and bionic robotics. This work provides a strategy for the design and fabrication of programmable and controllable soft actuators, laying the foundation for a wide range of applications in smart materials.

Soft skin-interfaced mechano-acoustic sensors for real-time monitoring and patient feedback on respiratory and swallowing biomechanics.

Swallowing is a complex neuromuscular activity regulated by the autonomic nervous system. Millions of adults suffer from dysphagia (impaired or difficulty swallowing), including patients with neurological disorders, head and neck cancer, gastrointestinal diseases, and respiratory disorders. Therapeutic treatments for dysphagia include interventions by speech-language pathologists designed to improve the physiology of the swallowing mechanism by training patients to initiate swallows with sufficient frequency and during the expiratory phase of the breathing cycle. These therapeutic treatments require bulky, expensive equipment to synchronously record swallows and respirations, confined to use in clinical settings. This paper introduces a wireless, wearable technology that enables continuous, mechanoacoustic tracking of respiratory activities and swallows through movements and vibratory processes monitored at the skin surface. Validation studies in healthy adults (n = 67) and patients with dysphagia (n = 4) establish measurement equivalency to existing clinical standard equipment. Additional studies using a differential mode of operation reveal similar performance even during routine daily activities and vigorous exercise. A graphical user interface with real-time data analytics and a separate, optional wireless module support both visual and haptic forms of feedback to facilitate the treatment of patients with dysphagia.

Thermally switchable, crystallizable oil and silicone composite adhesives for skin-interfaced wearable devices.

Continuous health monitoring is essential for clinical care, especially for patients in neonatal and pediatric intensive care units. Monitoring currently requires wired biosensors affixed to the skin with strong adhesives that can cause irritation and iatrogenic injuries during removal. Emerging wireless alternatives are attractive, but requirements for skin adhesives remain. Here, we present a materials strategy enabling wirelessly triggered reductions in adhesive strength to eliminate the possibility for injury during removal. The materials involve silicone composites loaded with crystallizable oils with melting temperatures close to, but above, surface body temperature. This solid/liquid phase transition occurs upon heating, reducing the adhesion at the skin interface by more than 75%. Experimental and computational studies reveal insights into effects of oil mixed randomly and patterned deterministically into the composite. Demonstrations in skin-integrated sensors that include wirelessly controlled heating and adhesion reduction illustrate the broad utility of these ideas in clinical-grade health monitoring.

Docking-guided rational engineering of a macrolide glycosyltransferase glycodiversifies epothilone B.

Glycosyltransferases typically display acceptor substrate flexibility but more stringent donor specificity. BsGT-1 is a highly effective glycosyltransferase to glycosylate macrolides, including epothilones, promising antitumor compounds. Here, we show that BsGT-1 has three major regions significantly influencing the glycodiversification of epothilone B based on structural molecular docking, "hot spots" alanine scanning, and site saturation mutagenesis. Mutations in the PSPG-like motif region and the C2 loop region are more likely to expand donor preference; mutations of the flexible N3 loop region located at the mouth of the substrate-binding cavity produce novel epothilone oligosaccharides. These "hot spots" also functioned in homologues of BsGT-1. The glycosides showed significantly enhanced water solubility and decreased cytotoxicity, although the glycosyl appendages of epothilone B also reduced drug permeability and attenuated antitumor efficacy. This study laid a foundation for the rational engineering of other GTs to synthesize valuable small molecules.

Intramuscular Near-Infrared Spectroscopy for Muscle Flap Monitoring in a Porcine Model.

BACKGROUND: Current near-infrared spectroscopy (NIRS)-based systems for continuous flap monitoring are limited to flaps which carry a cutaneous paddle. As such, this useful and reliable technology has not previously been applicable to muscle-only free flaps where other modalities with substantial limitations continue to be utilized. METHODS: We present the first NIRS probe which allows continuous monitoring of local tissue oxygen saturation (StO2) directly within the substance of muscle tissue. This probe is flexible, subcentimeter in scale, waterproof, biocompatible, and is fitted with resorbable barbs which facilitate temporary autostabilization followed by easy atraumatic removal. This novel device was compared with a ViOptix T.Ox monitor in a porcine rectus abdominus myocutaneous flap model of arterial and venous occlusions. During these experiments, the T.Ox device was affixed to the skin paddle, while the novel probe was within the muscle component of the same flap. RESULTS: The intramuscular NIRS device and skin-mounted ViOptix T.Ox devices produced very similar StO2 tracings throughout the vascular clamping events, with obvious and parallel changes occurring upon vascular clamping and release. The normalized cross-correlation at zero lag describing correspondence between the novel intramuscular NIRS and T.Ox devices was >0.99. CONCLUSION: This novel intramuscular NIRS probe offers continuous monitoring of oxygen saturation within muscle flaps. This experiment demonstrates the potential suitability of this intramuscular NIRS probe for the task of muscle-only free flap monitoring, where NIRS has not previously been applicable. Testing in the clinical environment is necessary to assess durability and reliability.

Merging the Versatile Functionalities of Boronic Acid with Peptides.

Peptides inherently feature the favorable properties of being easily synthesized, water-soluble, biocompatible, and typically non-toxic. Thus, boronic acid has been widely integrated with peptides with the goal of discovering peptide ligands with novel biological activities, and this effort has led to broad applications. Taking the integration between boronic acid and peptide as a starting point, we provide an overview of the latest research advances and highlight the versatile and robust functionalities of boronic acid. In this review, we summarize the diverse applications of peptide boronic acids in medicinal chemistry and chemical biology, including the identification of covalent reversible enzyme inhibitors, recognition, and detection of glycans on proteins or cancer cell surface, delivery of siRNAs, development of pH responsive devices, and recognition of RNA or bacterial surfaces. Additionally, we discuss boronic acid-mediated peptide cyclization and peptide modifications, as well as the facile chemical synthesis of peptide boronic acids, which paved the way for developing a growing number of peptide boronic acids.

Sub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples.

The human metabolome provides a window into the mechanisms and biomarkers of various diseases. However, because of limited availability, many sample types are still difficult to study by metabolomic analyses. Here, we present a mass spectrometry (MS)-based metabolomics strategy that only consumes sub-nanoliter sample volumes. The approach consists of combining a customized metabolomics workflow with a pulsed MS ion generation method, known as triboelectric nanogenerator inductive nanoelectrospray ionization (TENGi nanoESI) MS. Samples tested with this approach include exhaled breath condensate collected from cystic fibrosis patients as well as in vitro-cultured human mesenchymal stromal cells. Both test samples are only available in minimum amounts. Experiments show that picoliter-volume spray pulses suffice to generate high-quality spectral fingerprints, which increase the information density produced per unit sample volume. This TENGi nanoESI strategy has the potential to fill in the gap in metabolomics where liquid chromatography-MS-based analyses cannot be applied. Our method opens up avenues for future investigations into understanding metabolic changes caused by diseases or external stimuli.

Effects of glycosylation on the bioactivity of rapamycin.

The macrolactone rapamycin (RAP) presents a broad range of bioactivities, but its clinical applications are compromised due to the poor water solubility and low bioavailability, which could probably be overcome by glycosylation. In this study, we tested a set of promiscuous glycosyltransferases (GTs) to modify rapamycin with four different sugar donors. BsGT-1 displayed the best glycosylation activity with a preference for UDP-glucose, and the glycosylation happened at C-28 or C-40 of rapamycin, producing rapamycin-40-O-ß-D-glucoside (RG1), and two new compounds rapamycin-28-O-ß-D-glucoside (RG2) and rapamycin-28,40-O-ß-D-diglucoside (RG3). The glycosylation remarkably improved water solubility and almost completely abolished cytotoxicity but simultaneously attenuated the antifungal, antitumor, and immunosuppression bioactivities of rapamycin. We found the glycosylation at C-40 had less effect on the bioactivities than that at C-28. The molecular docking analysis revealed that the glycosylation, especially the glycosylation at C-28, weakened the hydrophobic and hydrogen bonding contacts between the rapamycin glucosides and the binding proteins: the FK506-binding protein (FKBP12) and the FKBP12-rapamycin binding (FRB) domain. This study highlights a succinct approach to expand the chemical diversity of the therapeutically important molecule rapamycin by using promiscuous glycosyltransferases. Moreover, the fact that glycosyl moieties at different positions of rapamycin affect bioactivity to different extents inspires further glycosylation engineering to improve properties of rapamycin. KEY POINTS: • Rapamycin was glycosylated efficiently by some promiscuous GTs. • Glycosylation improved water solubility, attenuated cytotoxicity, and bioactivities. • Glycosylation affected the interactions between ligand and binding proteins.

Eleven healthy live births: a result of simultaneous preimplantation genetic testing of α- and ß-double thalassemia and aneuploidy screening.

PURPOSE: To evaluate the efficacy of preimplantation genetic testing (PGT) for α- and ß-double thalassemia combined with aneuploidy screening using next-generation sequencing (NGS). METHODS: An NGS-based PGT protocol was performed between 2017 and 2018 for twelve couples, each of which carried both α- and ß-thalassemia mutations. Trophectoderm biopsy samples underwent whole-genome amplification using multiple displacement amplification (MDA), followed by NGS for thalassemia detection and aneuploidy screening. A selection of several informative single nucleotide polymorphisms (SNPs) established haplotypes. Aneuploidy screening was performed only on unaffected noncarriers and carriers. Unaffected and euploid embryos were transferred into the uterus through frozen-thawed embryo transfer (FET). RESULTS: A total of 280 oocytes were retrieved following 18 ovum pick-up (OPU) cycles, with 182 normally fertilized and 112 cultured to become blastocysts. One hundred and seven (95.5%, 107/112) blastocysts received conclusive PGT results, showing 56 (52.3%, 56/107) were unaffected. Thirty-seven (66.1%, 37/56) of the unaffected were also identified as euploid. One family had no transferable embryos. Unaffected and euploid embryos were then transferred into the uterus of the other 11 couples resulting in 11 healthy live births. The clinical pregnancy rate was 61.1% (11/18) per OPU and 68.8% (11/16) per FET, with no miscarriage reported. Seven families accepted the prenatal diagnosis and received consistent results with the NGS-based PGT. CONCLUSION: This study indicated that NGS could realize the simultaneous PGT of double thalassemia and aneuploidy screening in a reliable and accurate manner. Moreover, it eliminated the need for multiple biopsies, alleviating the potential damages to the pre-implanted blastocysts.

Signal Output of Triboelectric Nanogenerator at Oil-Water-Solid Multiphase Interfaces and its Application for Dual-Signal Chemical Sensing.

A liquid-solid contact triboelectric nanogenerator (TENG) based on poly(tetrafluoroethylene) (PTFE) film, a copper electrode, and a glass substrate for harvesting energy in oil/water multiphases is reported. There are two distinctive signals being generated, one is from the contact electrification and electrostatic induction between the liquid (water/oil) and the PTFE film (VTENG and ITENG ); and the other is from the electrostatic induction in the copper electrode by the oil/water interfacial charges (ΔVinterface and Iinterface ), which is generated only when the liquid-solid contact TENG is inserted across the oil/water interface. The two signals show interesting opposite changing trends that the VTENG and ITENG decrease while the oil/water interfacial signals of ΔVinterface and Iinterface increase after coating a layer of polydopamine on the surfaces of PTFE and glass via self-polymerization. As an application of the observed phenomena, both the values of ITENG and Iinterface have a good linear relationship versus the natural logarithm of the concentration of the dopamine. Based on this, the first self-powered dual-signal detection of dopamine using TENG is demonstrated.

Phylogeny-guided characterization of glycosyltransferases for epothilone glycosylation.

Glycosylation of natural products can influence their pharmacological properties, and efficient glycosyltransferases (GTs) are critical for this purpose. The polyketide epothilones are potent anti-tumour compounds, and YjiC is the only reported GT for the glycosylation of epothilone. In this study, we phylogenetically analysed 8261 GTs deposited in CAZy database and revealed that YjiC locates in a subbranch of the Macrolide I group, forming the YjiC-subbranch with 160 GT sequences. We demonstrated that the YjiC-subbranch GTs are normally efficient in epothilone glycosylation, but some showed low glycosylation activities. Sequence alignment of YjiC-subbranch showed that the 66th and 77th amino acid residues, which were close to the catalytic cavity in molecular docking model, were conserved in five high-active GTs (Q66 and P77) but changed in two low-efficient GTs. Site-directed residues swapping at the two positions in the two low-active GTs (BssGT and BamGT) and the high-active GT BsGT-1 demonstrated that the two amino acid residues played an important role in the catalytic efficiency of epothilone glycosylation. This study highlights that the potent GTs for appointed compounds are phylogenetically grouped with conserved residues for the catalytic efficiency.

Silicon Nanowire/Polymer Hybrid Solar Cell-Supercapacitor: A Self-Charging Power Unit with a Total Efficiency of 10.5.

An integrated self-charging power unit, combining a hybrid silicon nanowire/polymer heterojunction solar cell with a polypyrrole-based supercapacitor, has been demonstrated to simultaneously harvest solar energy and store it. By efficiency enhancement of the hybrid nanowire solar cells and a dual-functional titanium film serving as conjunct electrode of the solar cell and supercapacitor, the integrated system is able to yield a total photoelectric conversion to storage efficiency of 10.5%, which is the record value in all the integrated solar energy conversion and storage system. This system may not only serve as a buffer that diminishes the solar power fluctuations from light intensity, but also pave its way toward cost-effective high efficiency self-charging power unit. Finally, an integrated device based on ultrathin Si substrate is demonstrated to expand its feasibility and potential application in flexible energy conversion and storage devices.

Anti-tumor and immunomodulatory activity of iron hepta-tungsten phosphate oxygen clusters complex.

Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2]·44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5µM (ca. 300µg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-γ and IL-2 production, and up-regulated the mRNA expression levels of IFN-γ, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell-mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity.

Metabolomics-Driven Discovery of a Prenylated Isatin Antibiotic Produced by Streptomyces Species MBT28.

Actinomycetes are a major source of antimicrobials, anticancer compounds, and other medically important products, and their genomes harbor extensive biosynthetic potential. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known molecules. Here we report the identification of a previously unidentified isatin-type antibiotic produced by Streptomyces sp. MBT28, following a strategy based on NMR-based metabolomics combined with the introduction of streptomycin resistance in the producer strain. NMR-guided isolation by tracking the target proton signal resulted in the characterization of 7-prenylisatin (1) with antimicrobial activity against Bacillus subtilis. The metabolite-guided genome mining of Streptomyces sp. MBT28 combined with proteomics identified a gene cluster with an indole prenyltransferase that catalyzes the conversion of tryptophan into 7-prenylisatin. This study underlines the applicability of NMR-based metabolomics in facilitating the discovery of novel antibiotics.

Expanding the chemical space for natural products by Aspergillus-Streptomyces co-cultivation and biotransformation.

Actinomycetes and filamentous fungi produce a wide range of bioactive compounds, with applications as antimicrobials, anticancer agents or agrochemicals. Their genomes contain a far larger number of gene clusters for natural products than originally anticipated, and novel approaches are required to exploit this potential reservoir of new drugs. Here, we show that co-cultivation of the filamentous model microbes Streptomyces coelicolor and Aspergillus niger has a major impact on their secondary metabolism. NMR-based metabolomics combined with multivariate data analysis revealed several compounds that correlated specifically to co-cultures, including the cyclic dipeptide cyclo(Phe-Phe) and 2-hydroxyphenylacetic acid, both of which were produced by A. niger in response to S. coelicolor. Furthermore, biotransformation studies with o-coumaric acid and caffeic acid resulted in the production of the novel compounds (E)-2-(3-hydroxyprop-1-en-1-yl)-phenol and (2E,4E)-3-(2-carboxy-1-hydroxyethyl)-2,4-hexadienedioxic acid, respectively. This highlights the utility of microbial co-cultivation combined with NMR-based metabolomics as an efficient pipeline for the discovery of novel natural products.

Phenolic compounds with NF-κB inhibitory effects from the fungus Phellinus baumii.

Chemical investigation of the fungus Phellinus baumii has resulted in characterization of five previously undescribed hispidin derivatives, phellibaumins A-E (1-5), as well as two pairs of new non-equivalent epimeric benzyl dihydroflavones, methylphelligrin A (9), epi-methylphelligrin A (10), methylphelligrin B (11), and epi-methylphelligrin B (12), together with five known compounds, interfungin B (6), phelligridin H (7), phelligridimer A (8), phelligrin A (13), and epi-phelligrin A (14). Phellibaumin A (1) was a novel hispidin derivative with a unique 3,4-dihydroxybenzofuran unit. These compounds exhibited NF-κB inhibitory activity with IC(50) values of 52.96 µM (1), 41.40 µM (2), 52.92 µM (5), 36.44 µM (9 and 10), and 22.46 µM (11 and 12), respectively.