CherryML: scalable maximum likelihood estimation of phylogenetic models.

Phylogenetic models of molecular evolution are central to numerous biological applications spanning diverse timescales, from hundreds of millions of years involving orthologous proteins to just tens of days relating to single cells within an organism. A fundamental problem in these applications is estimating model parameters, for which maximum likelihood estimation is typically employed. Unfortunately, maximum likelihood estimation is a computationally expensive task, in some cases prohibitively so. To address this challenge, we here introduce CherryML, a broadly applicable method that achieves several orders of magnitude speedup by using a quantized composite likelihood over cherries in the trees. The massive speedup offered by our method should enable researchers to consider more complex and biologically realistic models than previously possible. Here we demonstrate CherryML's utility by applying it to estimate a general 400 × 400 rate matrix for residue-residue coevolution at contact sites in three-dimensional protein structures; we estimate that using current state-of-the-art methods such as the expectation-maximization algorithm for the same task would take >100,000 times longer.

Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Children are susceptible to severe or fatal enterovirus 71 (EV71) infections. We aimed to evaluate the efficacy, safety, and immunogenicity of EV71vac, an aluminium phosphate-adjuvanted inactivated EV71 vaccine in children aged 2-71 months. METHODS: We did a randomised, double-blinded, placebo-controlled, phase 3 trial at five hospitals in Taiwan and two in Vietnam. Children aged 2-71 months were stratified by country and age, and randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart. Children aged 2-23 months received a third booster dose on day 366. The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases during the follow-up period, from 14 days after the second dose to when 15 cases of EV71 infections were confirmed in the per-protocol population. Our safety analysis included all participants who received at least one dose of EV71vac. This trial is registered with ClinicalTrials.gov, NCT03865238, and is complete. FINDINGS: Between April 23 and Dec 25, 2019, of 3663 children assessed, 3061 were randomly assigned, of whom 3049 were vaccinated: 1521 children in the EV71vac group and 1528 in the placebo group. By May 20, 2021, our primary efficacy analysis included 2959 children, with 1476 children in the EV71vac group and 1483 children in the placebo group. The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5-100) against EV71 associated diseases (p<0·0001). The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%) in the EV71vac group and 852 (55·8%) in the placebo group. Almost all reported solicited adverse events were mild and self-limited. INTERPRETATION: EV71vac is safe, well-tolerated, and highly effective in preventing EV71 associated diseases in children aged 2-71 months. FUNDING: Medigen Vaccine Biologics and A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan.

Surgical Outcomes and Quality of Care Among Adult Appendicitis Patients: A Comparative Study of Tertiary Care Hospitals and Regional Hospitals.

BACKGROUND: Acute appendicitis is one of the most common abdominal emergencies, with management approaches that vary depending on the available resources and setting. However, there is a lack of studies on the differences of surgical outcomes and quality of care between tertiary care hospitals and regional hospitals. METHODS: This multicenter retrospective study included 2158 consecutive adult patients between January 2014 and June 2018 at three hospitals. The patient cohort was divided into regional hospital group (N = 1223) and tertiary care hospital group (N = 935). Baseline characteristics and perioperative outcomes were compared, and factors associated with surgical delay and postoperative complication were investigated. RESULTS: Patients in tertiary care hospital group had longer surgical waiting time (17.3 vs. 12.0 h, p < 0.001), higher risks of surgical delay exceeding 24 h (OR = 2.94, 95% CI 2.17-4.01, p < 0.001), longer operation time (64 vs. 50 min, p < 0.001), more appendix perforation (22.4 vs. 13.3%, p < 0.001), and higher hospital cost compared with regional hospital group. In multivariate analysis, factors associated with surgical delay were tertiary care hospital (OR = 2.94, 95% CI 2.18-4.01, p < 0.001) and delay diagnosis (OR = 18.7, 95% CI 11.7-30.1, p < 0.001), while those associated with postoperative complications were older age (OR = 1.02, 95% CI 1.00-1.04, p = 0.013), male sex (OR = 2.38, 95% CI 1.11-5.52, p = 0.031), surgical delay (OR = 2.99, 95% CI 1.30-6.47, p = 0.007), and appendix perforation (OR = 5.61, 95% CI 2.72-11.85, p < 0.001). CONCLUSIONS: Patients at tertiary care hospitals had longer waiting time, more surgical delays, and appendix perforations, and these were risk factors of postoperative complications. Establishing an effective referral system to redirect appendicitis patients with less complex medical histories from tertiary care hospitals to regional hospitals may enhance the quality of patient care and outcomes, while also reducing medical costs.

Hypomethylated RRBP1 Potentiates Tumor Malignancy and Chemoresistance in Upper Tract Urothelial Carcinoma.

Ribosome-binding protein 1 (RRBP1) is a potential oncogene in several cancer types. However, the correlation between RRBP1 expression and the prognosis of patients with upper tract urothelial carcinoma (UTUC) remains unclear. In this study, we identified that RRBP1 is associated with carcinogenesis and metastasis in UTUC using a methylation profiling microarray. High correlations between RRBP1 and cancer stages, nodal metastasis status, molecular subtypes, and prognosis in bladder urothelial cancer (BLCA) were found. Aberrant DNA methylation in the gene body region of RRBP1 was determined in UTUC tissues by methylation-specific PCR. RRBP1 expression was significantly increased in UTUC tissues and cell lines, as determined by real-time PCR and immunohistochemistry. RRBP1 depletion significantly reduced BFTC909 cell growth induced by specific shRNA. On the other hand, molecular subtype analysis showed that the expression of RRBP1 was associated with genes related to cell proliferation, epithelial-mesenchymal transition, and basal markers. A patient-derived organoid model was established to analyze patients' responses to different drugs. The expression of RRBP1 was related to chemoresistance. Taken together, these results provide the first evidence that RRBP1 gene body hypomethylation predicts RRBP1 high expression in UTUC. The data highlight the importance of RRBP1 in UTUC malignancy and chemotherapeutic tolerance.

High-Ecological Cognitive Intervention to Improve Cognitive Skills and Cognitive-Functional Performance for Older Adults With Mild Cognitive Impairment.

IMPORTANCE: Evidence of the effectiveness of cognitive activity and preparatory tasks in improving the cognitive skills and functional performance of people with cognitive decline is limited. OBJECTIVE: To examine the efficacy of a high-ecological cognitive intervention. DESIGN: Quasi-experimental, pretest-posttest design with nonequivalent control. SETTING: Community. PARTICIPANTS: Older adults with mild cognitive impairment from two senior centers. INTERVENTION: Twelve 90-min weekly group sessions of a high-ecological cognitive intervention using simulated everyday cognitive tasks (experimental group) and of nutrition education (active control group). Outcomes and Measures: Cognitive skills were measured with the Color Trails Test (CTT), the Contextual Memory Test (CMT; Immediate Recall [CMT-Im] and Delayed Recall [CMT-De] tasks), and the Wechsler Adult Intelligence Scale-Fourth Edition Digit Span subtest (Digits Forward and Digits Backward). Cognitive-functional performance was measured with the Rivermead Behavioural Memory Test-Third Edition (RBMT-3; Immediate Recall [RBMT-3-Im] and Delayed Recall [RBMT-3-De] tasks) and the Cognitive Failures Questionnaire (CFQ). RESULTS: Thirty-seven participants (M age = 70.84 yr; 70.3% women) met the inclusion criteria for analysis (20 participants in the intervention group, 17 participants in the control group). Multivariate linear regression showed that the intervention group improved significantly more than the control group on the CTT, CMT-Im, and RBMT-3-Im but not on the CMT-De, RBMT-3-De, and CFQ. CONCLUSIONS AND RELEVANCE: Twelve 90-min weekly group sessions of a high-ecological cognitive intervention improved attention, executive function, immediate memory, and objective cognitive-functional performance with immediate-memory task demands. What This Article Adds: Carefully designed and structured simulated everyday cognitive tasks can be used as a cognitive training agent to improve both cognitive skills and objective cognitive-functional performance. The effectiveness of group-based cognitive interventions depends on the skills of occupational therapy practitioners in activity analysis and grading.

Correlation between Nanoscale Elasticity, Semiconductivity, and Structural Order in Functionalized Polyaniline Thin Films.

The correlation between structural order, elasticity, and semiconductivity for butylthio-functionalized polyaniline (PANI-SBu) thin films was investigated using atomic force microscopy (AFM)-based techniques with X-ray diffraction (XRD) and scanning electron microscopy (SEM). After different stirring times, the thin films were cast from the solution of PANI-SBu in N-methyl-2-pyrrolidone that was continuously stirred at a constant rate of 150 rpm in an airtight round-bottom flask. According to the XRD and SEM results, the cross-sectional film structure evolved from being generally holey to highly lamellar with an increase in the stirring time. However, some new types of disordered structures began emerging beyond the optimal stirring time, possibly caused by the formation of disordered packing structures as contributed from the overoxidized polyaniline backbones during the additional stirring time. Moreover, according to the investigation results obtained using AFM-based techniques, the out-of-plane elastic moduli and charge mobilities of the PANI-SBu films were consistently smaller for disordered thin films and larger for structurally more ordered ones. The shear force resulting from the mechanical stirring of the PANI-SBu solution may gradually disentangle the polymer chains and thus help transform the individual polyaniline molecule from a coil-like chain conformation to a better extended rodlike chain conformation. Therefore, when cast into a film, the stretched polymer chains facilitate self-organization among the PANI-SBu backbones during the film formation process. Thus, an improved structural order in the film is attained. Our results demonstrate an unambiguous correlation between the structure order, elasticity, and conductivity in PANI-SBu thin films, which may have useful applications in conducting polymer-based flexible electronics.

Risk Factors for Myocardial Infarction and Stroke Among Sepsis Survivors: A Competing Risks Analysis.

OBJECTIVES: Predictors for post-sepsis myocardial infarction (MI) and stroke are yet to be identified due to the competing risk of death. METHODS: This study included all hospitalized patients with sepsis from National Health Insurance Research Database of Taiwan between 2000 and 2011. The primary outcome was the first occurrence of MI and stroke requiring hospitalization within 180 days following hospital discharge from the index sepsis episode. The association between predictors and post-sepsis MI and stroke were analyzed using cumulative incidence competing risk model that controlled for the competing risk of death. RESULTS: Among 42 316 patients with sepsis, 1012 (2.4%) patients developed MI and stroke within 180 days of hospital discharge. The leading 5 predictors for post-sepsis MI and stroke are prior cerebrovascular diseases (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.74-2.32), intra-abdominal infection (HR: 1.94, 95% CI: 1.71-2.20), previous MI (HR: 1.81, 95% CI: 1.53-2.15), lower respiratory tract infection (HR: 1.62, 95% CI: 1.43-1.85), and septic encephalopathy (HR: 1.61, 95% CI: 1.26-2.06). CONCLUSIONS: Baseline comorbidities and sources of infection were associated with an increased risk of post-sepsis MI and stroke. The identified risk factors may help physicians select a group of patients with sepsis who may benefit from preventive measures, antiplatelet treatment, and other preventive measures for post-sepsis MI and stroke.

Urine catecholamines in children with severe Enterovirus A71 infection: comparison with paediatric septic shock.

Purpose: Hypercatecholaminemia-related heart failure has been proposed as the main cause of enterovirus A71-related (EV-A71) early mortality. The purpose of this study was to measure urine catecholamine concentrations in severe EV-A71-infected children. Methods: A total of 35 children, aged 2.5 ± 2.1 years, were divided into three groups. Group I: 15 septic shock patients, group II: 17 EV-A71-stage-2 patients, and group III: 3 EV-A71-stage-4 patients. The laboratory results, cardiac biomarkers and urine catecholamine concentrations were statistically analysed. Results: Group I had the highest C-reactive protein (CRP) levels and group II had the lowest B-type natriuretic peptide (BNP) and its N-terminal prohormone among the groups (p = 0.039, <0.01 and <0.01, respectively). Group III patients had significantly higher urine catecholamine and troponin-I values among the groups. If urine epinephrine (Epi) >134 ug/gCr, norepinephrine (NE) >176 ug/gCr and vanillylmandelic acid (VMA) >11.7 mg/gCr were used as the cutoff points to differentiate groups II and III, the sensitivities and specificity were all 100%. Conclusions: The significantly elevated urine catecholamine concentrations in EV-A71-stage-4 patients support the hypothesis that hypercatecholaminemia-related heart failure is involved in severe EV-A71 infection. Urine catecholamines could be used as reliable biomarkers for differentiation of severe EV-A71 infection with or without heart failure and septic shock.

Simulated image doubling and visual acuity: effects of doubling magnitude, orientation, and ghost image intensity.

PURPOSE: The effects of image doubling on logarithmic progression chart visual acuity were investigated by simulating diplopia on a computer monitor. METHODS: Ten participants (6M, 4F) aged 21-28 years (mean 22.4 ± 2.3) were assessed viewing with their left eye while wearing their best correction. Stimuli were eight rows of five Sloan letters, from 0.4 to -0.3 logMAR (6/15 to 6/3) arranged in logarithmic progression format, generated on an HD monitor. Stimuli were generated with different magnitudes of doubling, different directions of doubling, and different intensity ratios between the ghost image and main images. RESULTS: When the ghost image had the same intensity as the main image, there was a significant effect of doubling magnitude on visual acuity, with the mean acuity being -0.11 logMAR (6/4.7) for no doubling. Acuity thresholds (logMAR) increased when doubling exceeded 1 min of arc, reaching a level of 0.12 logMAR (6/7.9) for doubling of 16 min of arc. There were no significant effects of orientation on acuity, nor were there significant orientation-doubling magnitude interaction effects of visual acuity. Image doubling magnitude level affected visual acuity differently for different ghost image intensities, with the highest acuity elevation occurring when ghost and main images were equal or nearly equal. For faint ghost image intensities (10% and 20%) image doubling did not significantly affect visual acuity. CONCLUSIONS: Image doubling will degrade visual acuity if doubling is greater than 1 min of arc, and ghost images are sufficiently intense. However, even with very obvious visually-disturbing image doubling, visual acuity remains only slightly reduced.

New Dammarane-type Saponins from Gynostemma pentaphyllum.

Six new dammarane-type saponins, gypenosides CP1-6 (16), along with 19 known compounds 7⁻25, were isolated and characterized from the aerial parts of Gynostemma pentaphyllum. Among these compounds, eight dammarane-type saponins, 2, 5, 6, 7, 11, 12, 13, and 15, exhibited the greatest antiproliferative effects against two human tumor cell lines (A549 and HepG2).

Crumpling and Unfolding of Montmorillonite Hybrid Nanocoatings as Stretchable Flame-Retardant Skin.

Flame-retardant coatings are widely used in a variety of personnel or product protection, and many applications would benefit from film stretchability if suitable materials are available. It is challenging to develop flame-retardant coatings that are stretchable, eco-friendly, and capable of being integrated on mechanically dynamic devices. Here, a concept is reported that uses pretextured montmorillonite (MMT) hybrid nanocoatings that can undergo programed unfolding to mimic the stretchability of elastomeric materials. These textured MMT coatings can be transferred onto an elastomeric substrate to achieve an MMT/elastomer bilayer device with high stretchability (225% areal strain) and effective flame retardancy. The bilayer composite is utilized as flame-retardant skin for a soft robotic gripper, and it is demonstrated that the actuated response can manipulate and rescue irregularly shaped objects from a fire scene. Furthermore, by depositing the conformal MMT nanocoatings on nitrile gloves, the firefree gloves can endure direct flame contact without ignition.

Primary whole-gland ablation for localized prostate cancer with high-intensity focused ultrasound: The important predictors of biochemical recurrence.

OBJECTIVES: To identify predictive factors of biochemical recurrence for patients undergoing high-intensity focused ultrasound treatment for localized prostate cancer. METHODS: We retrospectively identified patients receiving whole-gland prostate ablation with high-intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre-high-intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate-specific antigen, T stage, postoperative prostate-specific antigen nadir, Gleason score, time to prostate-specific antigen nadir and the presence of prostate-specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan-Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut-off values of prostate-specific antigen nadir. RESULTS: Among 182 patients, 26.9% had prostate-specific antigen biochemical recurrence after high-intensity focused ultrasound during the median follow-up period of 32.21 months. Gleason score ≥7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage ≥T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate-specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate-specific antigen. We posit that a cut-off level of prostate-specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate-specific antigen biochemical recurrence in high-intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56-15.37), and created a new nadir-related prediction model for biochemical recurrence prediction. CONCLUSIONS: Postoperative prostate-specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole-prostate gland high-intensity focused ultrasound treatment, and the nadir-related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score ≥7, stage ≥T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate-specific antigen appear not to be associated with biochemical recurrence for the high-intensity focused ultrasound treatment.

Biochemical and Physiological Characteristics of Photosynthesis in Plants of Two Calathea Species.

Plants of the genus Calathea possess many leaf colors, and they are economically important because they are widely used as ornamentals for interior landscaping. Physiological performances and photosynthetic capacities of C. insignis and C. makoyana were investigated. The photosynthetic efficiencies of C. insignis and C. makoyana were significantly increased when the photosynthetic photon flux density (PPFD) increased from 0 to 600 µmol photons·m-2·s-1 and became saturated with a further increase in the PPFD. The two Calathea species had lower values of both the light saturation point and maximal photosynthetic rate, which indicated that they are shade plants. No significant differences in predawn Fv/Fm values (close to 0.8) were observed between dark-green (DG) and light-green (LG) leaf sectors in all tested leaves. However, the effective quantum yield of photosystem II largely decreased as the PPFD increased. An increase in the apparent photosynthetic electron transport rate was observed in both species to a maximum at 600 µmol·m-2·s-1 PPFD, following by a decrease to 1500 µmol·m-2·s-1 PPFD. Compared to LG leaf extracts, DG leaf extracts contained higher levels of chlorophyll (Chl) a, Chl b, Chls a + b, carotenoids (Cars), anthocyanins (Ants), flavonoids (Flas), and polyphenols (PPs) in all plants, except for the Ant, Fla and PP contents of C. insignis plants. Calathea insignis also contained significantly higher levels of total protein than did C. makoyana. The adjusted normalized difference vegetation index (NDVI), photochemical reflectance index (PRI), red-green, and flavonol index (FlavI) were significantly correlated to leaf Chls a + b, Cars, Ants, and Flas in C. makoyana, respectively, and can be used as indicators to characterize the physiology of these plants.

Stereoselective Synthesis of Spiro Bis-C,C-α-arylglycosides by Tandem Heck Type C-Glycosylation and Friedel-Crafts Cyclization.

Spiro bis-C,C-α-arylglycosides were synthesized in three steps in 78-85% overall yields starting from exo-glycals. The initial Heck type C-aryl addition of exo-glycals with arylboronic acids afforded α-aryl-ß-substituted C-glycosides with exclusive α-stereoselectivity. Among the products, ß-ethanal α-aryl C-glycosides further reacted with alkylthiol in the presence of InCl3, followed by in situ Friedel-Crafts cyclization to yield the desirable final products. We proposed a mechanism to explain how the α-aryl group serves as a main determinant of the cyclization.

Application of an Integrated Omics Approach for Identifying Host Proteins That Interact With Odontoglossum ringspot virus Capsid Protein.

The glutamic acid at position 100 (E(100)) in the capsid protein (CP) of Odontoglossum ringspot virus (ORSV) plays an important role in long-distance viral movement in Nicotiana benthamiana. The ORSV(E100A) mutant, which has a glutamic acid to alanine substitution, shows a loss of systemic infectivity in N. benthamiana. Transmission electron microscopy and size-exclusion chromatography assays showed that E(100) is essential for CP-CP interaction and viral particle assembly. To identify the ORSV triggering or response genes and CP-interacting proteins (CP-IP), an integrated omics approach based on next-generation sequencing and proteomics profiling was used in this study. The whole-transcriptomes of healthy and ORSV-infected leaves of N. benthamiana were analyzed, and the gene information was used to create a N. benthamiana protein database that was used for protein identification following mass spectrometry analysis. The integrated omics approach identified several putative host proteins that interact with ORSV CP(WT) and were categorized as photosystem subunits, defense-associated proteins, and cell division components. The expression pattern and CP interaction of these CP-IP were examined by semiquantitative reverse transcription polymerase chain reaction and an in vitro binding assay, respectively, to verify the in silico data. Among these proteins, a proteinase inhibitor of N. benthamiana (NbPI2) was highly associated with CP(E100A) as compared with CP(WT), and NbPI1 and NbPI2 were highly induced in ORSV-infected plants. NbPI1- and NbPI2-silenced plants (via a Tobacco rattle virus-induced gene-silencing system) did not exhibit a difference in ORSV infection. Thus, whether NbPI1 and NbPI2 play a role in plant immunity requires further investigation. In summary, the integrated omics approach provides massive and valuable information to identify the ORSV CP-IP and these CP-IP will help us to understand the movement of this virus and plant-virus interaction.

Mode competition of two bandedge lasing from dye doped cholesteric liquid crystal laser.

Mode competition of two-lasing modes at the photonic bandedge from dye-doped cholesteric liquid crystal lasing was studied by the alternation of temperatures. The increase or decrease of the wavelengths from photonic bandedges versus the alternation of temperature is attributed to the variation of helical twist power (HTP) and thus it shows the completely different result by choosing two of different nematic liquid crystals (MDA-981602 and MDA-3970). At certain temperature, the intensity contrast and slope efficiency between long and short emission lasing peaks were dominated from the experienced gain or loss of laser for the position of the photonic bandedge. By the linear combination of these two lasing modes with different emission wavelengths and intensity contrast at distinct temperature, the wide tuning of the output colors can be revealed from the CIE chromaticity diagram and thus it has opportunity to be used in the display technology in the near future.

Tunable localized surface plasmon-enabled broadband light-harvesting enhancement for high-efficiency panchromatic dye-sensitized solar cells.

In photovoltaic devices, light harvesting (LH) and carrier collection have opposite relations with the thickness of the photoactive layer, which imposes a fundamental compromise for the power conversion efficiency (PCE). Unbalanced LH at different wavelengths further reduces the achievable PCE. Here, we report a novel approach to broadband balanced LH and panchromatic solar energy conversion using multiple-core-shell structured oxide-metal-oxide plasmonic nanoparticles. These nanoparticles feature tunable localized surface plasmon resonance frequencies and the required thermal stability during device fabrication. By simply blending the plasmonic nanoparticles with available photoactive materials, the broadband LH of practical photovoltaic devices can be significantly enhanced. We demonstrate a panchromatic dye-sensitized solar cell with an increased PCE from 8.3% to 10.8%, mainly through plasmon-enhanced photoabsorption in the otherwise less harvested region of solar spectrum. This general and simple strategy also highlights easy fabrication, and may benefit solar cells using other photoabsorbers or other types of solar-harvesting devices.

Comparison between dynamic versus static models and real-time monitoring of neuronal dysfunction in an amyloid-ß induced neuronal toxic model on a chip platform.

Microfluidics-based organs-on-a-chip offer a promising method for dynamic and 3-dimensional (3D) cell culture to evaluate the cell behaviors within the biomimetic environment. The purpose of this study was to establish neural network connections in a 3D neural stem cell (NSC)-based system with an interstitial level of flow for simulating the brain microenvironment toward a dynamic amyloid-ß (Aß) induced neuronal toxic model on a chip and to compare the biological effects and neurite dysfunction between static and dynamic systems. The brain-on-a-chip system consisted of an impedance analyzing layer, a structured well with a connected channel, and an interface coating with polypeptide films fabricated with modification based on our previous study. The cytotoxicity and percentage of neuron/astrocyte differentiation were all compared in both static and dynamic brain-on-a-chip systems. Reactive oxygen species production, neuron marker expression and neurotransmitter-acetylcholine release were all compared to evaluate functional neurite losses in both static and dynamic systems with/without Aß addition. Moreover, real-time impedance recording was used to consecutively monitor the neurite connection/disconnection in both static and dynamic brain-on-a-chip systems. The NSC-based dynamic brain-on-a-chip may enable the application of different neurodegenerative disease in vitro models for pathogenesis studies, drug discovery and novel therapeutic method development.

Machine intelligence accelerated design of conductive MXene aerogels with programmable properties.

Designing ultralight conductive aerogels with tailored electrical and mechanical properties is critical for various applications. Conventional approaches rely on iterative, time-consuming experiments across a vast parameter space. Herein, an integrated workflow is developed to combine collaborative robotics with machine learning to accelerate the design of conductive aerogels with programmable properties. An automated pipetting robot is operated to prepare 264 mixtures of Ti3C2Tx MXene, cellulose, gelatin, and glutaraldehyde at different ratios/loadings. After freeze-drying, the aerogels' structural integrity is evaluated to train a support vector machine classifier. Through 8 active learning cycles with data augmentation, 162 unique conductive aerogels are fabricated/characterized via robotics-automated platforms, enabling the construction of an artificial neural network prediction model. The prediction model conducts two-way design tasks: (1) predicting the aerogels' physicochemical properties from fabrication parameters and (2) automating the inverse design of aerogels for specific property requirements. The combined use of model interpretation and finite element simulations validates a pronounced correlation between aerogel density and compressive strength. The model-suggested aerogels with high conductivity, customized strength, and pressure insensitivity allow for compression-stable Joule heating for wearable thermal management.

Machine intelligence-accelerated discovery of all-natural plastic substitutes.

One possible solution against the accumulation of petrochemical plastics in natural environments is to develop biodegradable plastic substitutes using natural components. However, discovering all-natural alternatives that meet specific properties, such as optical transparency, fire retardancy and mechanical resilience, which have made petrochemical plastics successful, remains challenging. Current approaches still rely on iterative optimization experiments. Here we show an integrated workflow that combines robotics and machine learning to accelerate the discovery of all-natural plastic substitutes with programmable optical, thermal and mechanical properties. First, an automated pipetting robot is commanded to prepare 286 nanocomposite films with various properties to train a support-vector machine classifier. Next, through 14 active learning loops with data augmentation, 135 all-natural nanocomposites are fabricated stagewise, establishing an artificial neural network prediction model. We demonstrate that the prediction model can conduct a two-way design task: (1) predicting the physicochemical properties of an all-natural nanocomposite from its composition and (2) automating the inverse design of biodegradable plastic substitutes that fulfils various user-specific requirements. By harnessing the model's prediction capabilities, we prepare several all-natural substitutes, that could replace non-biodegradable counterparts as exhibiting analogous properties. Our methodology integrates robot-assisted experiments, machine intelligence and simulation tools to accelerate the discovery and design of eco-friendly plastic substitutes starting from building blocks taken from the generally-recognized-as-safe database.