Listeria-vectored cervical cancer vaccine candidate strains reduce MDSCs via the JAK-STAT signaling pathway.

BACKGROUND: Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. RESULTS: The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. CONCLUSIONS: Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.

Electrochemical coupling in subnanometer pores/channels for rechargeable batteries.

Subnanometer pores/channels (SNPCs) play crucial roles in regulating electrochemical redox reactions for rechargeable batteries. The delicately designed and tailored porous structure of SNPCs not only provides ample space for ion storage but also facilitates efficient ion diffusion within the electrodes in batteries, which can greatly improve the electrochemical performance. However, due to current technological limitations, it is challenging to synthesize and control the quality, storage, and transport of nanopores at the subnanometer scale, as well as to understand the relationship between SNPCs and performances. In this review, we systematically classify and summarize materials with SNPCs from a structural perspective, dividing them into one-dimensional (1D) SNPCs, two-dimensional (2D) SNPCs, and three-dimensional (3D) SNPCs. We also unveil the unique physicochemical properties of SNPCs and analyse electrochemical couplings in SNPCs for rechargeable batteries, including cathodes, anodes, electrolytes, and functional materials. Finally, we discuss the challenges that SNPCs may face in electrochemical reactions in batteries and propose future research directions.

Reducing the degree of crosslinking of peptidoglycan in Listeria monocytogenes promoted the secretion of membrane vesicles.

Listeria monocytogenes (LM) is a Gram-positive (G+) bacterium that secretes nanoscale membrane vesicles (MVs). LM MVs comprise various bacterial components and may have potential as an antigen or drug-delivery vehicle; however, the low yield of the LM MVs limits related research. G+-bacterial MVs germinate from the bacterial plasma membrane and must pass through a thick crosslinked peptidoglycan layer for release. Herein, we aimed to increase the release of MVs by reducing the degree of crosslinking of peptidoglycan. We knocked out two genes related to the longitudinal crosslinking of peptidoglycan, dal and dat, and supplemented the knocked-out dal gene through plasmid expression to obtain a stably inherited recombinant strain LMΔdd::pCW633. The structure, particle size, and main protein components of MVs secreted by this recombinant strain were consistent with those secreted from the wild strain, but the yield of MVs was considerably increased (p < 0.05). Furthermore, Listeria ivanovii (LI) was found to secrete MVs that differed in the composition of the main proteins compared with those of LM MVs. The abovementioned method was also feasible for promoting the secretion of MVs from the attenuated LM strain and LI wild-type and attenuated strains. Our study provides a new method to increase the secretion of MVs derived from Listeria that could be extended to other G+ bacteria.

Learning QM/MM potential using equivariant multiscale model.

The machine learning (ML) method emerges as an efficient and precise surrogate model for high-level electronic structure theory. Its application has been limited to closed chemical systems without considering external potentials from the surrounding environment. To address this limitation and incorporate the influence of external potentials, polarization effects, and long-range interactions between a chemical system and its environment, the first two terms of the Taylor expansion of an electrostatic operator have been used as extra input to the existing ML model to represent the electrostatic environments. However, high-order electrostatic interaction is often essential to account for external potentials from the environment. The existing models based only on invariant features cannot capture significant distribution patterns of the external potentials. Here, we propose a novel ML model that includes high-order terms of the Taylor expansion of an electrostatic operator and uses an equivariant model, which can generate a high-order tensor covariant with rotations as a base model. Therefore, we can use the multipole-expansion equation to derive a useful representation by accounting for polarization and intermolecular interaction. Moreover, to deal with long-range interactions, we follow the same strategy adopted to derive long-range interactions between a target system and its environment media. Our model achieves higher prediction accuracy and transferability among various environment media with these modifications.

Rigid ureteroscopic lithotripsy with a pressure-controlling ureteral access sheath for complex steinstrasse.

OBJECTIVE: To evaluate the safety and efficacy of rigid ureteroscopic lithotripsy with a pressure-controlling ureteral access sheath (PC-UAS) for complex steinstrasse. METHODS: Thirty-one consecutive patients (male: 18; female: 13) with steinstrasse were enrolled, six of whom had concurrent kidney stones. The mean cumulative stone size was 2.7 ± 1.3 cm. The patients were treated with rigid ureteroscopic lithotripsy using a PC-UAS. The cavity pressure parameters were set as follows: control value at -15 mmHg to -2 mmHg, warning value at 20 mmHg, and limit value at 30 mmHg. The infusion flow rate was set at 150-200 ml/min. A holmium laser (550 µm) was used to powderize the stone at 2.0-2.5 J/pulse with a frequency of 20-30 pulses/s. Analyses included cavity pressure, operative time, stone-free rates, and complications. RESULTS: Among the 31 patients, 29 were successfully treated with PC-UAS, with nine requiring adjunctive flexible ureteroscopy for stone migration to the kidney. Two procedures were converted to percutaneous nephrolithotomies due to failure of sheath placement. The cavity pressure of all 29 patients was well-maintained below 20 mmHg, with clear vision. The mean operative time was 48.2 ± 17.7 min. No complications, such as ureteral perforation, mucosal avulsion, or hemorrhage, occurred. Two cases of Clavien-Dindo grade I complications occurred. No major complications (Clavien-Dindo grade II-V) occurred. The mean postoperative hospitalization time was 1.7 days. The stone-free rates 1 day and 1 month after surgery were 93.1% and 96.6%, respectively. One patient with residual stones underwent extracorporeal shockwaves. CONCLUSIONS: Rigid ureteroscopic lithotripsy with PC-UAS can effectively control the cavity pressure, shorten the operation time, and improve the efficiency of broken stones, thus reducing the complication rate.

Lower Reoperation Rate and Superior Patient-reported Outcome Following Arthroscopic Rotator Cuff Repair with Concomitant Acromioplasty: An Updated Systematic Review of Randomized Controlled Trials.

PURPOSE: This study aims to systematically assess the postoperative outcomes in patients undergoing arthroscopic rotator cuff repairs with or without concomitant acromioplasty through a rigorous systematic review of randomized controlled trial s (RCTs). METHODS: This systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, aimed to identify RCTs comparing clinical outcomes of patients with full thickness rotator cuff tears undergoing arthroscopic rotator cuff repair with acromioplasty versus those without at a minimum of 12 months follow-up. Databases searched included PubMed, Web of Science, Embase, and the Cochrane Library. The risk of bias in the included studies was assessed using the revised Cochrane Risk of Bias 2 (RoB2). Meta-analysis was conducted for outcomes with at least three studies reporting, with pooled effect estimates calculated using either fixed-effect or random-effects models based on heterogeneity levels. Results were presented as the weighted mean difference (WMD) or odds ratio (OR) with 95% confidence intervals (CIs). For outcomes with fewer than three studies reporting, a Fisher exact test was conducted, with continuity correction applied if necessary. Primary outcomes include rates of retear and reoperation, while secondary outcomes included improvement in American Shoulder and Elbow Surgeons (ASES) score, range of motion (ROM), and complication rate. RESULTS: Five high-quality RCTs, with low bias risk, involving 409 patients, revealed demographics of 58.4% males, mean age 58.4 years, and acromion types: 12.2% type I, 70.7% type II, and 17.1% type III. Mean follow-up was 52.2 months. Retear (12.5% versus 16.1%, P = 0.536) and complication rates (OR, 3.11; 95% CI, 0.31-30.73; P=0.33) were comparable between the two groups. However, reoperation rate (5.3% versus 15.9%, P < 0.001) and improvement in ASES score (WMD, 3.99; 95% CI, 1.00-6.99; P=0.009) favored the acromioplasty group. Both groups showed significant improvements in ROM, but insufficient data prevented a comparison. CONCLUSIONS: Compared to arthroscopic rotator cuff repair alone, arthroscopic rotator cuff repair with acromioplasty demonstrated similar rates of retear and complications, but a significantly lower reoperation rate and superior improvement in ASES score. The available data were insufficient to draw a definitive conclusion regarding ROM. This conclusion is fragile due to a limited sample size.

Transcriptomic Features of systemic lupus erythematosus Patients in Flare and Changes during Acute In-Hospital Treatment.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varying symptoms and multi-organ damage. Relapse-remission cycles often persist for many patients for years with the current treatment. Improved understanding of molecular changes caused by SLE flare and intensive treatment may result in more targeted therapies. METHODS: RNA-sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 65 SLE patients in flare, collected both before (SLE1) and after (SLE2) in-hospital treatment, along with 15 healthy controls (HC). Differentially expressed genes (DEGs) were identified among the three groups. Enriched functions and key molecular signatures of the DEGs were analyzed and scored to elucidate the transcriptomic changes during treatment. RESULTS: Few upregulated genes in SLE1 vs HC were affected by treatment (SLE2 vs SLE1), mostly functional in interferon signalling (IFN), plasmablasts, and neutrophils. IFN and plasmablast signatures were repressed, but the neutrophil signature remained unchanged or enhanced by treatment. The IFN and neutrophil scores together stratified the SLE samples. IFN scores correlated well with leukopenia, while neutrophil scores reflected relative cell compositions but not cell counts. CONCLUSIONS: In-hospital treatment significantly relieved SLE symptoms with expression changes of a small subset of genes. Notably, IFN signature changes matched SLE flare and improvement, while enhanced neutrophil signature upon treatment suggested the involvement of low-density granulocytes (LDG) in disease development.

Study on the effect of additives on microbial diversity, predicted functional profiles, and fermentation quality of Broussonetia papyrifera and Pennisetum sinese mixed ensilage in the karst region.

In this research, we evaluated the effect of exogenous lactic acid bacteria and Amomum villosum essential oil (AVEO) on the chemical composition, microbial community composition, microbial functional diversity, and fermentation quality of Broussonetia papyrifera (BP) and Pennisetum sinese (PS) mixed silages. The BP:PS mixing ratios were 100:0, 70:30, 50:50, 30:70, and 0:100. After 3 and 30 days of ensiling at 22°C-25°C, microbial diversity and function, and fermentation quality, were assessed. Increasing PS content resulted in decreased ammoniacal nitrogen and pH, increased water-soluble carbohydrate content, increased relative abundance of Lactococcus and Acinetobacter, and reduced relative abundance of Caproiciproducens and Pseudomonas. A 50:50 BP:PS ratio effectively improved the fermentation quality compared to anaerobic fermentation with BP or PS alone, while AVEO treatment further improved fermentation quality by increasing Lactococcus relative abundance. Moreover, as fermentation proceeded, ensiling enhanced the 'Human diseases', 'Environmental information processing', and 'Cellular processes' functions at the first level, as well as the 'Two-component system' and 'ABC transporters' functions at the third level. Different additives affected the fermentation of BP and PS mixed silage by regulating microbial community succession and metabolic pathways during ensiling.

Phytochemical Engineered Bacterial Outer Membrane Vesicles for Photodynamic Effects Promoted Immunotherapy.

Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.

HDAC3 promotes pulmonary fibrosis by activating NOTCH1 and STAT1 signaling and up-regulating inflammasome components AIM2 and ASC.

BACKGROUND: Pre-clinical studies suggest that pan-inhibitors for histone deacetylases (HDACs) may benefit the treatment of pulmonary fibrosis (PF). However, HDAC3-specific roles or mechanisms during PF development are poorly understood. METHODS: The expression of HDAC3 and the impacts of RGFP966, a selective HDAC3 inhibitor, were examined in a bleomycin-induced PF mouse model and in TGF-ß-challenged MRC-5 cells. H&E and Masson staining were employed to reveal the pathological changes in lung; Western blot to assess expressions of biomarkers related to fibrosis and epithelial-mesenchymal transition (EMT), activations of Notch1 and signal transducer and activator of transcription 1 (STAT1) signaling, and levels of inflammasome components, absent in melanoma 2 (AIM2) and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC); ELISA to measure productions of proinflammatory interleukin (IL)-1ß and IL-18; cycloheximide chase assay and coimmunoprecipitation to monitor the protein stability and acetylation of Notch intracellular domain 1 (NICD1) and STAT1, respectively. RESULTS: HDAC3 was induced in in vitro and in vivo PF models, which was associated with elevated expressions of fibrosis-related biomarkers, EMT markers, and pro-inflammatory cytokines, activations of Notch1 and STAT1 signaling, and up-regulated inflammasome components, AIM2 and ASC. All the fibrotic phenotypes were potently inhibited by RGFP966, which boosted the acetylation of NICD1 and STAT1, accelerated the degradation of NICD1, and inhibited STAT1 phosphorylation. Overexpressing NICD1 or STAT1 restored the fibrotic phenotypes suppressed by RGFP966. CONCLUSIONS: HDAC3 promoted EMT, inflammation, and PF development by activating Notch1 and STAT1 signaling. Therefore, targeting HDAC3, Notch1 or STAT1 signaling may ameliorate PF development.

Synthesis of spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones through gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered indoles.

A variety of functionalized spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones were prepared in good to excellent yields through a gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered C2-substituted indoles. This reaction features a broad substrate scope, good functional group tolerance, and easy gram-scale preparation and transformations. Furthermore, biological activity studies showed that most of the obtained spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinone scaffolds showed potential as good anti-inflammatory agents.

A Chimeric Plasmodium vivax Merozoite Surface Protein Antibody Recognizes and Blocks Erythrocytic P. cynomolgi Berok Merozoites In Vitro.

Research on erythrocytic Plasmodium vivax merozoite antigens is critical for identifying potential vaccine candidates in reducing P. vivax disease. However, many P. vivax studies are constrained by its inability to undergo long-term culture in vitro Conserved across all Plasmodium spp., merozoite surface proteins are essential for invasion into erythrocytes and highly expressed on erythrocytic merozoites, thus making it an ideal vaccine candidate. In clinical trials, the P. vivax merozoite surface protein 1 (PvMSP1-19) vaccine candidate alone has shown to have limited immunogenicity in patients; hence, we incorporate the highly conserved and immunogenic C terminus of both P. vivax merozoite surface protein 8 (PvMSP8) and PvMSP1-19 to develop a multicomponent chimeric protein rPvMSP8+1 for immunization of mice. The resulted chimeric rPvMSP8+1 antibody was shown to recognize native protein MSP8 and MSP1-19 of mature P. vivax schizonts. In the immunized mice, an elevated antibody response was observed in the rPvMSP8+1-immunized group compared to that immunized with single-antigen components. In addition, we examined the growth inhibition of these antibodies against Plasmodium cynomolgi (Berok strain) parasites, which is phylogenetically close to P. vivax and sustains long-term culture in vitro Similarly, the chimeric anti-rPvMSP8+1 antibodies recognize P. cynomolgi MSP8 and MSP1-19 on mature schizonts and showed strong inhibition in vitro via growth inhibition assay. This study provides support for a new multiantigen-based paradigm rPvMSP8+1 to explore potential chimeric vaccine candidates against P. vivax malaria using sister species P. cynomolgi.

Genome-wide association study on Northern Chinese identifies KLF2, DOT1L and STAB2 associated with systemic lupus erythematosus.

OBJECTIVES: To identify novel genetic loci associated with systemic lupus erythematosus (SLE) and to evaluate potential genetic differences between ethnic Chinese and European populations in SLE susceptibility. METHODS: A new genome-wide association study (GWAS) was conducted from Jining, North China, on 1506 individuals (512 SLE cases and 994 matched healthy controls). The association results were meta-analysed with existing data on Chinese populations from Hong Kong, Guangzhou and Central China, as well as GWAS results from four cohorts of European ancestry. A total of 26 774 individuals (9310 SLE cases and 17 464 controls) were included in this study. RESULTS: Meta-analysis on four Chinese cohorts identifies KLF2 as a novel locus associated with SLE [rs2362475; odds ratio (OR) = 0.85, P=2.00E-09]. KLF2 is likely an Asian-specific locus as no evidence of association was detected in the four European cohorts (OR = 0.98, P =0.58), with evidence of heterogeneity (P=0.0019) between the two ancestral groups. Meta-analyses of results from both Chinese and Europeans identify STAB2 (rs10082873; OR= 0.89, P=4.08E-08) and DOT1L (rs4807205; OR= 1.12, P=8.17E-09) as trans-ancestral association loci, surpassing the genome-wide significance. CONCLUSIONS: We identified three loci associated with SLE, with KLF2 a likely Chinese-specific locus, highlighting the importance of studying diverse populations in SLE genetics. We hypothesize that DOT1L and KLF2 are plausible SLE treatment targets, with inhibitors of DOT1L and inducers of KLF2 already available clinically.

Deep reinforcement learning of transition states.

Combining reinforcement learning (RL) and molecular dynamics (MD) simulations, we propose a machine-learning approach, called RL‡, to automatically unravel chemical reaction mechanisms. In RL‡, locating the transition state of a chemical reaction is formulated as a game, and two functions are optimized, one for value estimation and the other for policy making, to iteratively improve our chance of winning this game. Both functions can be approximated by deep neural networks. By virtue of RL‡, one can directly interpret the reaction mechanism according to the value function. Meanwhile, the policy function allows efficient sampling of the transition path ensemble, which can be further used to analyze reaction dynamics and kinetics. Through multiple experiments, we show that RL‡ can be trained tabula rasa hence allowing us to reveal chemical reaction mechanisms with minimal subjective biases.

Clairvoyant Melon Maturity Detection Enabled by Doctor-Blade-Coated Photonic Crystals.

Climacteric fruits are harvested before they are ripened to avoid adverse damages during transport. The unripe fruits can undergo ripening processes associated with rind color changes on exposure to ethanol vapors. Although rind coloration is a common indicator showing fruit maturity, the attribute does not provide reliable assessment of maturity especially for melons. Herein, we report the achievement of sensitive and reversible melon maturity detection using macroporous hydrogel photonic crystals self-assembled by a roll-to-roll compatible doctor-blade-coating technology. The consumption of applied ethanol vapor during melon ripening results in less condensation of ethanol vapor in the pores (250 nm in diameter), leading to a distinct blue-shift of the optical stop band from 572 to 501 nm and an obvious visual colorimetric readout from yellow green to blue. Moreover, the dependence of the color change on Brix value within the melon has also been evaluated in the study.

Immunogenicity analysis of conserved fragments in Plasmodium ovale species merozoite surface protein 4.

BACKGROUND: There is an urgent need for an effective vaccine to control and eradicate malaria, one of the most serious global infectious diseases. Plasmodium merozoite surface protein 4 (MSP4) has been listed as a blood-stage subunit vaccine candidate for malaria. Infection with Plasmodium ovale species including P. ovale wallikeri and P. ovale curtisi, is also a source of malaria burden in tropical regions where it is sometimes mixed with other Plasmodium species. However, little is known about P. ovale MSP4. METHODS: The msp4 gene was amplified through polymerase chain reaction using genomic DNA extracted from blood samples of 46 patients infected with P. ovale spp. and amplified products were sequenced. Open reading frames predicted as immunogenic peptides consisting of 119 and 97 amino acids of P. ovale curtisi MSP4 (PocMSP4) and P. ovale wallikeri MSP4 (PowMSP4), respectively, were selected for protein expression. Recombinant proteins (rPoMSP4) were expressed in Escherichia coli, purified, analysed, and immunized in BALB/c mice. The specificity of anti-MSP4-immunoglobulin (Ig) G antibodies was evaluated by Western blot and enzyme-linked immunosorbent assays, and cellular immune responses were analysed via lymphocyte proliferation assays. RESULTS: Full peptide sequences of PocMSP4 and PowMSP4 were completely conserved in all clinical isolates, except in the epidermal growth factor-like domain at the carboxyl terminus where only one mutation was observed in one P. o. wallikeri isolate. Further, truncated PoMSP4 segments were successfully expressed and purified as ~ 32 kDa proteins. Importantly, high antibody responses with end-point titres ranging from 1:10,000 to 1:2,560,000 in all immunized mouse groups were observed, with high IgG avidity to PocMSP4 (80.5%) and PowMSP4 (92.3%). Furthermore, rPocMSP4 and rPowMSP4 cross-reacted with anti-PowMSP4-specific or anti-PocMSP4-specific antibodies. Additionally, anti-PoMSP4 IgG antibodies showed broad immuno-specificity in reacting against rPoMSP1 and rPoAMA1. Lastly, PocMSP4- and PowMSP4-immunized mice induced cellular immune responses with PocMSP4 (36%) and PowMSP4 cells (15.8%) during splenocyte proliferation assays. CONCLUSION: Findings from this study suggest conservation in PoMSP4 protein sequences and high immunogenicity was observed in rPoMSP4. Furthermore, induction of immune responses in PocMSP4- and PowMSP4-immunized mice informed that both humoral and cellular immune responses play crucial roles for PoMSP4 in protection.

A high-sensitive sensor with HEPES-enhanced electrochemiluminescence of benzo[3]uril for Fe3+ and its application in human serum.

An electrochemiluminescence (ECL) sensor based on a benzo[3]uril-modified glassy carbon electrode with sensitized luminescence, with the coexistence of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) as the coreactant, was successfully constructed. The sensitization mechanism was proposed by analyzing the results of the control experiments for establishing the relationship of the luminescence effect with the concentration of HEPES. Under the optimized conditions, the fabricated sensor system was applied for the detection of Fe3+ in an aqueous solution with good sensitivity and selectivity. A low detection limit of 0.41 nM was achieved, indicating superior sensor performance over the previous analytical methods. The ECL sensor system was employed for the detection of Fe3+ in human serum samples to produce excellent recoveries ranging from 96.17% to 101.81%.

A Perspective on Deep Learning for Molecular Modeling and Simulations.

Deep learning is transforming many areas in science, and it has great potential in modeling molecular systems. However, unlike the mature deployment of deep learning in computer vision and natural language processing, its development in molecular modeling and simulations is still at an early stage, largely because the inductive biases of molecules are completely different from those of images or texts. Footed on these differences, we first reviewed the limitations of traditional deep learning models from the perspective of molecular physics and wrapped up some relevant technical advancement at the interface between molecular modeling and deep learning. We do not focus merely on the ever more complex neural network models; instead, we introduce various useful concepts and ideas brought by modern deep learning. We hope that transacting these ideas into molecular modeling will create new opportunities. For this purpose, we summarized several representative applications, ranging from supervised to unsupervised and reinforcement learning, and discussed their connections with the emerging trends in deep learning. Finally, we give an outlook for promising directions which may help address the existing issues in the current framework of deep molecular modeling.

Deep learning for variational multiscale molecular modeling.

Molecular simulations are widely applied in the study of chemical and bio-physical problems. However, the accessible timescales of atomistic simulations are limited, and extracting equilibrium properties of systems containing rare events remains challenging. Two distinct strategies are usually adopted in this regard: either sticking to the atomistic level and performing enhanced sampling or trading details for speed by leveraging coarse-grained models. Although both strategies are promising, either of them, if adopted individually, exhibits severe limitations. In this paper, we propose a machine-learning approach to ally both strategies so that simulations on different scales can benefit mutually from their crosstalks: Accurate coarse-grained (CG) models can be inferred from the fine-grained (FG) simulations through deep generative learning; in turn, FG simulations can be boosted by the guidance of CG models via deep reinforcement learning. Our method defines a variational and adaptive training objective, which allows end-to-end training of parametric molecular models using deep neural networks. Through multiple experiments, we show that our method is efficient and flexible and performs well on challenging chemical and bio-molecular systems.

A Comparison of Intranasal Dexmedetomidine and Dexmedetomidine-Ketamine Combination Sedation for Transthoracic Echocardiography in Pediatric Patients With Congenital Heart Disease: A Randomized Controlled Trial.

OBJECTIVES: To compare the effects of intranasal dexmedetomidine (DEX) and DEX-ketamine (KET) on hemodynamics and sedation quality in children with congenital heart disease. DESIGN: A randomized controlled, double-blind, prospective trial. SETTING: A tertiary care teaching hospital. PARTICIPANTS: The study comprised 60 children undergoing transthoracic echocardiography (TTE). INTERVENTIONS: Patients were randomly allocated into the DEX group (group D [n = 30]) or the DEX-KET group (group D-K [n = 30]). Group D received 2 µg/kg of intranasal DEX; group D-K received 2 µg/kg of DEX and 1 mg/kg of KET intranasally. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in hemodynamics, measured using mean arterial pressure (MAP) and heart rate (HR). Secondary outcomes were onset time, wake-up time, and discharge time. No differences were found in mean arterial pressure or heart rate. The onset time was significantly shorter in group D-K than in group D (9.6 ± 2.9 minutes v 14.3 ± 3.4 minutes; p = 0.031). The wake-up time was longer in group D-K than in group D (52 ± 14.7 minutes v 39.6 ± 12.1 minutes; p = 0.017). The discharge time was longer in group D-K than in group D (61.33 ± 11.59 minutes v 48.17 ± 8.86 minutes; p < 0.001). No differences in hemodynamics were found between the 2 groups. Intranasal DEX was found to be as effective for TTE sedation as intranasal DEX-KET, with longer onset time and shorter recovery and discharge times. CONCLUSION: No differences in hemodynamics were found between the 2 groups. Intranasal DEX was found to be as effective for TTE sedation as is intranasal DEX-KET, with longer onset time and shorter recovery and discharge times.