Bioactive Phenylpropanoid Glycosides, Dimers, and Heterodimers from the Bark of Cinnamomum cassia (L.) J.Presl.

Six new phenylpropanoid glycosides (1-6), two new phenylethanol glycosides (7 and 8), one new phenylmethanol glycoside (9), three new phenylpropanoid dimers (10-12), two new phenylpropanoid-flavan-3-ol heterodimers (13 and 14), and six known relevant compounds (15-20) were isolated and identified from the well-liked edible and medicinal substance (the bark of Cinnamomum cassia (L.) J.Presl). The structures of these isolates were determined by using spectroscopic analyses, chemical methods, and quantum chemical calculations. Notably, compounds 4-9 were rare apiuronyl-containing glycosides, and compounds 13 and 14 were heterodimers of phenylpropanoids and flavan-3-ols linked through C-9″-C-8 bonds. The antioxidant and α-glucosidase inhibitory activities of all isolates were evaluated. Compounds 10 and 12 exhibited DPPH radical scavenging capacities with IC50 values of 20.1 and 13.0 µM, respectively (vitamin C IC50 value of 14.3 µM). In the ORAC experiment, all these compounds exhibited different levels of capacity for scavenging free radicals, and compound 10 displayed extraordinary free radical scavenging capacity with the ORAC value of 6.42 ± 0.01 µM TE/µM (EGCG ORAC value of 1.54 ± 0.02 µM TE/µM). Compound 12 also showed significant α-glucosidase inhibitory activity with an IC50 of 56.3 µM (acarbose IC50 of 519.4 µM).

A Functional Switch Between Asperfumene and Fusicoccadiene Synthase and Entrance to Asperfumene Biosynthesis through a Vicinal Deprotonation-Reprotonation Process.

The diterpene synthase AfAS was identified from Aspergillus fumigatiaffinis. Its amino acid sequence and - according to a structural model - active site architecture are highly similar to those of the fusicocca-2,10(14)-diene synthase PaFS, but AfAS produces a structurally much more complex diterpene with a novel 6-5-5-5 tetracyclic skeleton called asperfumene. The cyclisation mechanism of AfAS was elucidated through isotopic labelling experiments and DFT calculations. The reaction cascade proceeds in its initial steps through similar intermediates as for the PaFS cascade, but then diverges through an unusual vicinal deprotonation-reprotonation process that triggers a skeletal rearrangement at the entrance to the steps leading to the unique asperfumene skeleton. The structural model revealed only one major difference between the active sites: The PaFS residue F65 is substituted by I65 in AfAS. Intriguingly, site-directed mutagenesis experiments with both diterpene synthases revealed that position 65 serves as a bidirectional functional switch for the biosynthesis of tetracyclic asperfumene versus structurally less complex diterpenes.

Core-shell structured alginate-based hydrogel beads modified by starch and protocatechuic acid: Preparation, characterization, phenolic slow release and stable antioxidant potential.

A novel core-shell structured alginate-based hydrogel bead modified by co-gelatinizing with starch and protocatechuic acid (PA), was designed to modulate physical properties of beads, release behavior and antioxidant stability of encapsulated bioactives. Core was fabricated by ionotropic gelation, and its formulation (ratio of sodium alginate/starch) was determined by particle size/starch distribution, texture and bioactive encapsulation capacity of core. Then, coating core with shell-forming solution co-gelatinized with different doses of PA, and subsequently cross-linked with Ca2+ to obtain core-shell structured beads. Surface microstructure, mechanical characteristics, and swelling ratio of beads were affected by concentrations of PA. Besides, core-shell structure containing PA could enhance delivery and sustained release of encapsulated phenolic bioactives during in vitro digestion, and improve their antioxidant potential stability. Furthermore, interaction between PA and polysaccharide components was elucidated by FTIR and TGA. The present information was beneficial for the advancement of functional food materials and bioactive delivery systems.

A novel treatment planning method via scissor beams for uniform-target-dose proton GRID with peak-valley-dose-ratio optimization.

BACKGROUND: Proton spatially fractionated RT (SFRT) can potentially synergize the unique advantages of using proton Bragg peak and SFRT peak-valley dose ratio (PVDR) to reduce the radiation-induced damage for normal tissues. Uniform-target-dose (UTD) proton GRID is a proton SFRT modality that can be clinically desirable and conveniently adopted since its UTD resembles target dose distribution in conventional proton RT (CONV). However, UTD proton GRID is not used clinically, which is likely due to the lack of an effective treatment planning method. PURPOSE: This work will develop a novel treatment planning method using scissor beams (SB) for UTD proton GRID, with the joint optimization of PVDR and dose objectives. METHODS: The SB method for spatial dose modulation in normal tissues with UTD has two steps: (1) a primary beam (PB) is halved with interleaved beamlets, to generate spatial dose modulation in normal tissues; (2) a complementary beam (CB) is added to fill in previously valley-dose positions in the target to generate UTD, while the CB is angled slightly from the PB, to maintain spatial dose modulation in normal tissues. A treatment planning method with PVDR optimization via the joint total variation and L1 (TVL1) regularization is developed to jointly optimize PVDR and dose objectives. The plan optimization solution is obtained using an iterative convex relaxation algorithm. RESULTS: The new methods SB and SB-TVL1 were validated in comparison with CONV. Compared to CONV of relatively homogeneous dose distribution, SB had modulated spatial dose pattern in normal tissues with UTD and comparable plan quality. Compared to SB, SB-TVL1 further maximized PVDR, with comparable dose-volume parameters. CONCLUSIONS: A novel SB method is proposed that can generate modulated spatial dose pattern in normal tissues to achieve UTD proton GRID. A treatment planning method with PVDR optimization capability via TVL1 regularization is developed that can jointly optimize PVDR and dose objectives for proton GRID.

NucMap 2.0: An Updated Database of Genome-wide Nucleosome Positioning Maps Across Species.

Nucleosome dynamics plays important roles in many biological processes, such as DNA replication and gene expression. NucMap (https://ngdc.cncb.ac.cn/nucmap) is the first database of genome-wide nucleosome positioning maps across species. Here, we present an updated version, NucMap 2.0, by incorporating more species and MNase-seq samples. In addition, we integrate other related omics data for each MNase-seq sample to provide a comprehensive view of nucleosome positioning, such as gene expression, transcription factor binding sites, histone modifications and DNA methylation. In particular, NucMap 2.0 integrates and pre-analyzes RNA-seq data and ChIP-seq data of human-related samples, which facilitates the interpretation of nucleosome positioning in humans. All processed data are integrated into an in-built genome browser, and users can make comprehensive side-by-side analyses. In addition, more online analytical functions are developed, which allows researchers to identify differential nucleosome regions and explore potential gene regulatory regions. All resources are open access with a user-friendly web interface.

Simultaneous dose and dose rate optimization via dose modifying factor modeling for FLASH effective dose.

BACKGROUND: Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV). PURPOSE: This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED. METHODS: SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method. RESULTS: SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26 Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10 mm ring expansion of CTV). CONCLUSION: We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO.

Cardinality-constrained plan-quality and delivery-time optimization method for proton therapy.

BACKGROUND: While minimizing plan delivery time is beneficial for proton therapy in terms of motion management, patient comfort, and treatment throughput, it often poses a tradeoff with optimizing plan quality. A key component of plan delivery time is the energy switching time, which is approximately proportional to the number of energy layers, that is, the cardinality. PURPOSE: This work aims to develop a novel optimization method that can efficiently compute the pareto surface between plan quality and energy layer cardinality, for the planner to navigate through this quality-and-efficiency tradeoff and select the appropriate plan of a balanced tradeoff. METHODS: A new IMPT method CARD is proposed that (1) explicitly incorporates the minimization of energy layer cardinality as an optimization objective, and (2) automatically generates a set of plans sequentially with a descending order in number of energy layers. The energy layer cardinality is penalized through the l1,0-norm regularization with an upper bound, and the upper bound is monotonically decreased to compute a series of treatment plans with gradually decreased energy layer cardinality on the quality-and-efficiency pareto surface. For any given treatment plan, the plan optimality is enforced using dose-volume planning objectives and the plan deliverability is imposed through minimum-monitor-unit (MMU) constraints, with optimization solution algorithm based on iterative convex relaxation. RESULTS: The new method CARD was validated in comparison with the benchmark plan of all energy layers (P0), and a state-of-the-art method called MMSEL, using prostate, head-and-neck (HN), lung, pancreas, liver and brain cases. While labor-intensive and time-consuming manual parameter tuning was needed for MMSEL to generate plans of predefined energy layer cardinality, CARD automatically and efficiently computed all plans with sequentially decreasing predefined energy layer cardinality all at once. With the acceptable plan quality (i.e., no more than 110% of total optimization objective value from P0), CARD achieved the reduction of number of energy layers to 52% (from 77 to 40), 48% (from 135 to 65), 59% (from 85 to 50), 67% (from 52 to 35), 80% (from 50 to 40), and 30% (from 66 to 20), for prostate, HN, lung, pancreas, liver, and brain cases, respectively, compared to P0, with overall better plan quality than MMSEL. Moreover, due to the nonconvexity of the MMU constraint, CARD provided the similar or even smaller optimization objective than P0, at the same time with fewer number of energy layers, that is, 55 versus 77, 85 versus 135, 45 versus 52, and 25 versus 66 for prostate, HN, pancreas, and brain cases, respectively. CONCLUSIONS: We have developed a novel optimization algorithm CARD that can efficiently and automatically compute a series of treatment plans of any given energy layer sequentially, which allows the planner to navigate through the plan-quality and energy-layer-cardinality tradeoff and select the appropriate plan of a balanced tradeoff.

A lumped parameter model for evaluating coronary artery blood supply capacity.

The coronary artery constitutes a vital vascular system that sustains cardiac function, with its primary role being the conveyance of indispensable nutrients to the myocardial tissue. When coronary artery disease occurs, it will affect the blood supply of the heart and induce myocardial ischemia. Therefore, it is of great significance to numerically simulate the coronary artery and evaluate its blood supply capacity. In this article, the coronary artery lumped parameter model was derived based on the relationship between circuit system parameters and cardiovascular system parameters, and the blood supply capacity of the coronary artery in healthy and stenosis states was studied. The aortic root pressure calculated by the aortic valve fluid-structure interaction (AV FSI) simulator was employed as the inlet boundary condition. To emulate the physiological phenomenon of sudden pressure drops resulting from an abrupt reduction in blood vessel radius, a head loss model was connected at the coronary artery's entrance. For each coronary artery outlet, the symmetric structured tree model was appended to simulate the terminal impedance of the missing downstream coronary arteries. The particle swarm optimization (PSO) algorithm was used to optimize the blood flow viscous resistance, blood flow inertia, and vascular compliance of the coronary artery model. In the stenosis states, the relative flow and fractional flow reserve (FFR) calculated by numerical simulation corresponded to the published literature data. It was anticipated that the proposed model can be readily adapted for clinical application, serving as a valuable reference for diagnosing and treating patients.

Genotypic-phenotypic landscape computation based on first principle and deep learning.

The relationship between genotype and fitness is fundamental to evolution, but quantitatively mapping genotypes to fitness has remained challenging. We propose the Phenotypic-Embedding theorem (P-E theorem) that bridges genotype-phenotype through an encoder-decoder deep learning framework. Inspired by this, we proposed a more general first principle for correlating genotype-phenotype, and the P-E theorem provides a computable basis for the application of first principle. As an application example of the P-E theorem, we developed the Co-attention based Transformer model to bridge Genotype and Fitness model, a Transformer-based pre-train foundation model with downstream supervised fine-tuning that can accurately simulate the neutral evolution of viruses and predict immune escape mutations. Accordingly, following the calculation path of the P-E theorem, we accurately obtained the basic reproduction number (${R}_0$) of SARS-CoV-2 from first principles, quantitatively linked immune escape to viral fitness and plotted the genotype-fitness landscape. The theoretical system we established provides a general and interpretable method to construct genotype-phenotype landscapes, providing a new paradigm for studying theoretical and computational biology.

Analysis of risk factors, pathogenic bacteria characteristics, and drug resistance of postoperative surgical site infection in adults with limb fractures.

PURPOSE: We carried out the study aiming to explore and analyze the risk factors, the distribution of pathogenic bacteria, and their antibiotic-resistance characteristics influencing the occurrence of surgical site infection (SSI), to provide valuable assistance for reducing the incidence of SSI after traumatic fracture surgery. METHODS: A retrospective case-control study enrolling 3978 participants from January 2015 to December 2019 receiving surgical treatment for traumatic fractures was conducted at Tangdu Hospital of Air Force Medical University. Baseline data, demographic characteristics, lifestyles, variables related to surgical treatment, and pathogen culture were harvested and analyzed. Univariate analyses and multivariate logistic regression analyses were used to reveal the independent risk factors of SSI. A bacterial distribution histogram and drug-sensitive heat map were drawn to describe the pathogenic characteristics. RESULTS: Included 3978 patients 138 of them developed SSI with an incidence rate of 3.47% postoperatively. By logistic regression analysis, we found that variables such as gender (males) (odds ratio (OR) = 2.012, 95% confidence interval (CI): 1.235 - 3.278, p = 0.005), diabetes mellitus (OR = 5.848, 95% CI: 3.513 - 9.736, p < 0.001), hypoproteinemia (OR = 3.400, 95% CI: 1.280 - 9.031, p = 0.014), underlying disease (OR = 5.398, 95% CI: 2.343 - 12.438, p < 0.001), hormonotherapy (OR = 11.718, 95% CI: 6.269 - 21.903, p < 0.001), open fracture (OR = 29.377, 95% CI: 9.944 - 86.784, p < 0.001), and intraoperative transfusion (OR = 2.664, 95% CI: 1.572 - 4.515, p < 0.001) were independent risk factors for SSI, while, aged over 59 years (OR = 0.132, 95% CI: 0.059 - 0.296, p < 0.001), prophylactic antibiotics use (OR = 0.082, 95% CI: 0.042 - 0.164, p < 0.001) and vacuum sealing drainage use (OR = 0.036, 95% CI: 0.010 - 0.129, p < 0.001) were protective factors. Pathogens results showed that 301 strains of 38 species of bacteria were harvested, among which 178 (59.1%) strains were Gram-positive bacteria, and 123 (40.9%) strains were Gram-negative bacteria. Staphylococcus aureus (108, 60.7%) and Enterobacter cloacae (38, 30.9%) accounted for the largest proportion. The susceptibility of Gram-positive bacteria to Vancomycin and Linezolid was almost 100%. The susceptibility of Gram-negative bacteria to Imipenem, Amikacin, and Meropenem exceeded 73%. CONCLUSION: Orthopedic surgeons need to develop appropriate surgical plans based on the risk factors and protective factors associated with postoperative SSI to reduce its occurrence. Meanwhile, it is recommended to strengthen blood glucose control in the early stage of admission and for surgeons to be cautious and scientific when choosing antibiotic therapy in clinical practice.

Effectiveness and safety of augmentative plating technique in managing nonunion following intramedullary nailing of long bones in the lower extremity: A systematic review and meta-analysis.

PURPOSE: To methodically assess the effectiveness of augmentative plating (AP) and exchange nailing (EN) in managing nonunion following intramedullary nailing for long bone fractures of the lower extremity. METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library were searched to gather clinical studies regarding the use of AP and EN techniques in the treatment of nonunion following intramedullary nailing of lower extremity long bones. The search was conducted up until May 2023. The original studies underwent an independent assessment of their quality, a process conducted utilizing the Newcastle-Ottawa scale. Data were retrieved from these studies, and meta-analysis was executed utilizing Review Manager 5.3. RESULTS: This meta-analysis included 8 studies involving 661 participants, with 305 in the AP group and 356 in the EN group. The results of the meta-analysis demonstrated that the AP group exhibited a higher rate of union (odds ratio: 8.61, 95% confidence intervals (CI): 4.12 - 17.99, p < 0.001), shorter union time (standardized mean difference (SMD): -1.08, 95 % CI: -1.79 - -0.37, p = 0.003), reduced duration of the surgical procedure (SMD: -0.56, 95 % CI: -0.93 - -0.19, p = 0.003), less bleeding (SMD: -1.5, 95 % CI: -2.81 - -0.18), p = 0.03), and a lower incidence of complications (relative risk: -0.17, 95 % CI: -0.27 - -0.06, p = 0.001). In the subgroup analysis, the time for union in the AP group in nonisthmal and isthmal nonunion of lower extremity long bones was shorter compared to the EN group (nonisthmal SMD: -1.94, 95 % CI: -3.28 - -0.61, p < 0.001; isthmal SMD: -1.08, 95 % CI: -1.64 - -0.52, p = 0.002). CONCLUSION: In the treatment of nonunion in diaphyseal fractures of the long bones in the lower extremity, the AP approach is superior to EN, both intraoperatively (with reduced duration of the surgical procedure and diminished blood loss) and postoperatively (with an elevated union rate, shorter union time, and lower incidence of complications). Specifically, in the management of nonunion of lower extremity long bones with non-isthmal and isthmal intramedullary nails, AP demonstrated shorter union time in comparison to EN.

Electroacupuncture treatment improves postoperative ileus by inhibiting the Th1 cell-mediated inflammatory response through the vagus nerve.

BACKGROUND: Electroacupuncture (EA) has been reported to improve intestinal motility in mice with postoperative ileus (POI). Previous studies, however, have yielded heterogeneous results regarding the effect of EA on POI. METHODS: Herein, a POI mouse model was constructed by intestinal manipulation. To evaluate the effect of EA treatment on colonic transit, the levels of inflammatory markers (macrophage inflammatory protein (MIP)-1α, interleukin (IL)-1ß, IL-6, monocyte chemotactic protein (MCP)-1 and intercellular adhesion molecule (ICAM)-1) were detected by enzyme-linked immunosorbent assay (ELISA); immune cell infiltration was detected by immunohistochemical staining of myeloperoxidase (MPO), ectodysplasin (ED)-1 and ED-2, and the percentage of CD4+ interferon (IFN)-γ+ Th1 cells and IFN-γ secretion levels were determined. Activated Th1 cells and pentoxifylline, a cell differentiation inhibitor, were used to assess the role of Th1 cells in EA treatment of POI. Neostigmine administration and unilateral vagotomy were performed to confirm whether the effects of EA treatment on Th1 cells were mediated by the vagus nerve (VN). RESULTS: The results revealed that EA treatment at ST36 improved POI, as indicated by a decreased level of inflammatory-related markers and immune cell infiltration and shortened colonic transit time. The activated Th1 cells abolished the effects of EA treatment on POI. The effects of EA treatment on POI were enhanced by stimulation of the VN along with a decreased level of Th1 cells, but these effects were abolished by vagotomy along with an increased percentage of Th1 cells; this result indicates that the VN mediates the role of Th1 cells in the effects of EA treatment of POI. CONCLUSION: Our findings showed that the effects of EA treatment of POI were mainly mediated by Th1 cells through the stimulation of the VN and inhibition of the inflammatory response.

Functional and structural dissection of glycosyltransferases underlying the glycodiversity of wolfberry-derived bioactive ingredients lycibarbarspermidines.

Lycibarbarspermidines are unusual phenolamide glycosides characterized by a dicaffeoylspermidine core with multiple glycosyl substitutions, and serve as a major class of bioactive ingredients in the wolfberry. So far, little is known about the enzymatic basis of the glycosylation of phenolamides including dicaffeoylspermidine. Here, we identify five lycibarbarspermidine glycosyltransferases, LbUGT1-5, which are the first phenolamide-type glycosyltransferases and catalyze regioselective glycosylation of dicaffeoylspermidines to form structurally diverse lycibarbarspermidines in wolfberry. Notably, LbUGT3 acts as a distinctive enzyme that catalyzes a tandem sugar transfer to the ortho-dihydroxy group on the caffeoyl moiety to form the unusual ortho-diglucosylated product, while LbUGT1 accurately discriminates caffeoyl and dihydrocaffeoyl groups to catalyze a site-selective sugar transfer. Crystal structure analysis of the complexes of LbUGT1 and LbUGT3 with UDP, combined with molecular dynamics simulations, revealed the structural basis of the difference in glycosylation selectivity between LbUGT1 and LbUGT3. Site-directed mutagenesis illuminates a conserved tyrosine residue (Y389 in LbUGT1 and Y390 in LbUGT3) in PSPG box that plays a crucial role in regulating the regioselectivity of LbUGT1 and LbUGT3. Our study thus sheds light on the enzymatic underpinnings of the chemical diversity of lycibarbarspermidines in wolfberry, and expands the repertoire of glycosyltransferases in nature.

Potential of polyphenols from Ligustrum robustum (Rxob.) Blume on enhancing the quality of starchy food during frying.

The increasing concerns about health have led to a growing demand for high-quality fried foods. The potential uses of Ligustrum robustum (Rxob.) Blume, a traditional tea in China, as natural additives to enhance the quality of starchy food during frying was studied. Results indicated that L. robustum polyphenols extract (LREs) could improve the quality of fried starchy food, according to the tests of color, moisture content, oil content, texture property, and volatile flavor. The in vitro digestion results demonstrated that LRE reduced the final glucose content from 11.35 ± 0.17 to 10.80 ± 0.70 mmol/L and increased the phenolic content of fried starch foods from 1.23 ± 0.04 to 3.76 ± 0.14 mg/g. The appearance and polarizing microscopy results showed that LRE promoted large starch bulges on the surface of fried starchy foods. Meanwhile, X-ray diffraction results showed that LRE increased the intensity of characteristic diffraction peak of fried starch with a range of 21.8%-28%, and Fourier transform infrared results showed that LRE reduced the damage to short-range order structure of starch caused by the frying process. In addition, LRE increased the aggregation of starch granules according to the SEM observation and decreased the enthalpy of starch gelatinization based on the differential scanning calorimetry results. The present results suggest that LREs have the potential to be utilized as a natural additive for regulating the quality of fried starchy food in food industries. PRACTICAL APPLICATION: The enhancement of L. robustum polyphenols on the quality of starchy food during frying was found, and its mechanisms were also explored. This work indicated that L. robustum might be used as a novel economic natural additive for producing high-quality fried foods.

Biological optimization for hybrid proton-photon radiotherapy.

Objective.Hybrid proton-photon radiotherapy (RT) is a cancer treatment option to broaden access to proton RT. Additionally, with a refined treatment planning method, hybrid RT has the potential to offer superior plan quality compared to proton-only or photon-only RT, particularly in terms of target coverage and sparing organs-at-risk (OARs), when considering robustness to setup and range uncertainties. However, there is a concern regarding the underestimation of the biological effect of protons on OARs, especially those in close proximity to targets. This study seeks to develop a hybrid treatment planning method with biological dose optimization, suitable for clinical implementation on existing proton and photon machines, with each photon or proton treatment fraction delivering a uniform target dose.Approach.The proposed hybrid biological dose optimization method optimized proton and photon plan variables, along with the number of fractions for each modality, minimizing biological dose to the OARs and surrounding normal tissues. To mitigate underestimation of hot biological dose spots, proton biological dose was minimized within a ring structure surrounding the target. Hybrid plans were designed to be deliverable separately and robustly on existing proton and photon machines, with enforced uniform target dose constraints for the proton and photon fraction doses. A probabilistic formulation was utilized for robust optimization of setup and range uncertainties for protons and photons. The nonconvex optimization problem, arising from minimum monitor unit constraint and dose-volume histogram constraints, was solved using an iterative convex relaxation method.Main results.Hybrid planning with biological dose optimization effectively eliminated hot spots of biological dose, particularly in normal tissues surrounding the target, outperforming proton-only planning. It also provided superior overall plan quality and OAR sparing compared to proton-only or photon-only planning strategies.Significance.This study presents a novel hybrid biological treatment planning method capable of generating plans with reduced biological hot spots, superior plan quality to proton-only or photon-only plans, and clinical deliverability on existing proton and photon machines, separately and robustly.

Elucidating the influence and mechanism of different phenols on the properties, food quality and function of maize starch.

This study discusses interaction differences between three phenols (protocatechuic acid, naringin and tannic acid) and starch helix, investigates influences of phenols at different doses on properties of maize starch, and further determines their effects on quality and function of maize-starchy foods. Simulated results indicate variations of phenolic structure (phenolic hydroxyl group amount, glycoside structure and steric hindrance) and dose induce phenols form different complexes with starch helix. Formation of different starch-phenols complexes alters gelatinization (1.65-5.63 J/g), pasting form, water binding capacity (8.83-12.69 g/g) and particle size distribution of starch. Meanwhile, differences in starch-phenols complexes are reflected in fingerprint area (R1045/1022: 0.920 to 1.047), crystallinity (8.3% to 17.0%), rheology and gel structure of starch. Additionally, phenols change texture and color of cold maize cake, giving them different antioxidant capacity and lower digestibility. Findings are beneficial for understanding interaction between starch and different phenols and their potential application.

Biosynthesis of Enfumafungin-type Antibiotic Reveals an Unusual Enzymatic Fusion Pattern and Unprecedented C-C Bond Cleavage.

Enfumafungin-type antibiotics, represented by enfumafungin and fuscoatroside, belong to a distinct group of triterpenoids derived from fungi. These compounds exhibit significant antifungal properties with ibrexafungerp, a semisynthetic derivative of enfumafungin, recently gaining FDA's approval as the first oral antifungal drug for treating invasive vulvar candidiasis. Enfumafungin-type antibiotics possess a cleaved E-ring with an oxidized carboxyl group and a reduced methyl group at the break site, suggesting unprecedented C-C bond cleavage chemistry involved in their biosynthesis. Here, we show that a 4-gene (fsoA, fsoD, fsoE, fsoF) biosynthetic gene cluster is sufficient to yield fuscoatroside by heterologous expression in Aspergillus oryzae. Notably, FsoA is an unheard-of terpene cyclase-glycosyltransferase fusion enzyme, affording a triterpene glycoside product that relies on enzymatic fusion. FsoE is a P450 enzyme that catalyzes successive oxidation reactions at C19 to facilitate a C-C bond cleavage, producing an oxidized carboxyl group and a reduced methyl group that have never been observed in known P450 enzymes. Our study thus sets the important foundation for the manufacture of enfumafungin-type antibiotics using biosynthetic approaches.

Operando Characterization and Molecular Simulations Reveal the Growth Kinetics of Graphene on Liquid Copper During Chemical Vapor Deposition.

In recent years, liquid metal catalysts have emerged as a compelling choice for the controllable, large-scale, and high-quality synthesis of two-dimensional materials. At present, there is little mechanistic understanding of the intricate catalytic process, though, of its governing factors or what renders it superior to growth at the corresponding solid catalysts. Here, we report on a combined experimental and computational study of the kinetics of graphene growth during chemical vapor deposition on a liquid copper catalyst. By monitoring the growing graphene flakes in real time using in situ radiation-mode optical microscopy, we explore the growth morphology and kinetics over a wide range of CH4-to-H2 pressure ratios and deposition temperatures. Constant growth rates of the flakes' radius indicate a growth mode limited by precursor attachment, whereas methane-flux-dependent flake shapes point to limited precursor availability. Large-scale free energy simulations enabled by an efficient machine-learning moment tensor potential trained to density functional theory data provide quantitative barriers for key atomic-scale growth processes. The wealth of experimental and theoretical data can be consistently combined into a microkinetic model that reveals mixed growth kinetics that, in contrast to the situation at solid Cu, is partly controlled by precursor attachment alongside precursor availability. Key mechanistic aspects that directly point toward the improved graphene quality are a largely suppressed carbon dimer attachment due to the facile incorporation of this precursor species into the liquid surface and a low-barrier ring-opening process that self-heals 5-membered rings resulting from remaining dimer attachments.

Development and characterization of the first proton minibeam system for single-gantry proton facility.

BACKGROUND: Minibeam represents a preclinical spatially fractionated radiotherapy modality with great translational potential. The advantage lies in its high therapeutic index (compared to GRID and LATTICE) and ability to treat at greater depth (compared to microbeam). Proton minibeam radiotherapy (pMBRT) is a synergy of proton and minibeam. While the single-gantry proton facility has gained popularity due to its affordability and compact design, it often has limited beam time available for research purposes. Conversely, given the current requirement of pMBRT on specific minibeam hardware collimators, necessitates a reproducible and fast setup to minimize pMBRT treatment time and streamline the switching time between pMBRT and conventional treatment for clinically translation. PURPOSE: The contribution of this work is the development and characterization of the first pMBRT system tailored for single-gantry proton facility. The system allows for efficient and reproducible plug-and-play setup, achievable within minutes. METHODS: The single room pMBRT system is constructed based on IBA ProteusONE proton machine. The end of nozzle is attached with beam modifying accessories though an accessory drawer. A small snout is attached to the accessory drawer and used to hold apertures and range shifters. The minibeam aperture consists of two components: a fitting ring and an aperture body. Three minibeam apertures were manufactured. The first-generation apertures underwent qualitatively analysis with film, and the second generation aperture underwent more comprehensive quantitative measurement. The reproducibility of the setup is accessed, and the film measurements are performed to characterize the pMBRT system in cross validation with Monte Carlo (MC) simulations. RESULTS: We presented initial results of large field pMBRT aperture and the film measurements indicates the effect of source-to-isocenter distance = 930 cm in Y proton scanning direction. Consistent with TOPAS MC simulation, the dose uniformity of pMBRT field <2 cm is demonstrated to be better than 2%, rendering its suitability for pre-clinical studies. Subsequently, we developed the second generation of aperture with five slits and characterized the aperture with film dosimetry studies and compared the results to the benchmark MC. Comprehensive film measurements were also performed to evaluate the effect of divergence, air gap and gantry-angle dependency and repeatability and revealing a consistent performance within 5%. Furthermore, the 2D gamma analysis indicated a passing rate exceeding 99% using 3% dose difference and 0.2 mm distance agreement criteria. We also establish the peak valley dose ratio and the depth dose profile measurements, and the results are within 10% from MC simulation. CONCLUSIONS: We have developed the first pMBRT system tailored for a single-gantry proton facility, which has demonstrated accuracy in benchmark with MC simulations, and allows for efficient plug-and-play setup, emphasizing efficiency.

Mixed-size spot scanning with a compact large momentum acceptance superconducting (LMA-SC) gantry beamline for proton therapy.

Objective. Lowering treatment costs and improving treatment quality are two primary goals for next-generation proton therapy (PT) facilities. This work will design a compact large momentum acceptance superconducting (LMA-SC) gantry beamline to reduce the footprint and expense of the PT facilities, with a novel mixed-size spot scanning method to improve the sparing of organs at risk (OAR).Approach. For the LMA-SC gantry beamline, the movable energy slit is placed in the middle of the last achromatic bending section, and the beam momentum spread of delivered spots can be easily changed during the treatment. Simultaneously, changing the collimator size can provide spots with various lateral spot sizes. Based on the provided large-size and small-size spot models, the treatment planning with mixed spot scanning is optimized: the interior of the target is irradiated with large-size spots (to cover the uniform-dose interior efficiently), while the peripheral of the target is irradiated with small-size spots (to shape the sharp dose falloff at the peripheral accurately).Main results. The treatment plan with mixed-size spot scanning was evaluated and compared with small and large-size spot scanning for thirteen clinical prostate cases. The mixed-size spot plan had superior target dose homogeneities, better protection of OAR, and better plan robustness than the large-size spot plan. Compared to the small-size spot plan, the mixed-size spot plan had comparable plan quality, better plan robustness, and reduced plan delivery time from 65.9 to 40.0 s.Significance. The compact LMA-SC gantry beamline is proposed with mixed-size spot scanning, with demonstrated footprint reduction and improved plan quality compared to the conventional spot scanning method.