Continuous Production Research Articles

Utilizing Engineered Bacteria as "Cell Factories" In Vivo for Intracellular RNA-Loaded Outer Membrane Vesicles' Self-Assembly in Tumor Treatment.

Delivery systems play a crucial role in RNA therapy. However, the current RNA delivery system involves complex preparation and transport processes, requiring RNA preassembly in vitro, transportation at low temperatures throughout, and possibly multiple injections for improved therapeutic efficacy. To address these challenges, we developed a simple and efficient RNA delivery system. This system only requires the injection of engineered bacteria, which serve as in vivo "cell factories" for continuous production of the target RNA. The RNA can self-assemble with engineered bacteria's outer membrane vesicles (OMVs), facilitating in vivo RNA delivery. Experimental results demonstrated that this system allowed effective delivery with excellent stability and continuity for various types of RNA, including mRNA, miRNA, and siRNA. And the relative abundance of target RNA in the OMVs was 104-107 times higher than that in the mock group. We took the delivery of PD-L1 siRNA for tumor treatment as an example and found that this system could effectively downregulate the gene expression of PD-L1 by approximately twofold. Notably, a single injection of engineered bacteria achieved a significant tumor suppression of 49.37% in vivo. This research provides promising insights into the RNA delivery system for tumor therapy.

A Review on 3D Printing Technology Used in Pharmaceutical Industry

Three-dimensional printing (3DP) makes it possible to create a variety of geometries using computer-aided design with various materials and procedures for intended uses, such pharmaceutical drug delivery systems. Despite the fact that 3D printing was patented in 1986, 3DP research did not gain traction until the past 10 years. The expectations of regulatory bodies, constraints, challenges in setting up such facilities for the manufacturing of pharmaceutical goods, benefits, drawbacks, uses, techniques, and related manufacturing hazards are all presented here. FDA. When compared to conventional drug preparation methods, 3D printing technology offers substantial benefits for customized drug production, making it simple to create preparations with intricate structures or drug release characteristics and enabling quick production of tiny quantities of medications. It also offers a thorough analysis of the state of this platform's research and development at the moment. The present review aims to provide an overview of the benefits, limitations, and uses of 3D printing in pharmaceutical technology by outlining several techniques (such as thermal ink jet printing, ink jet printing, fused deposition modeling, extrusion 3D printing, zip dose, hot melt extrusion, 3D printer, stereolithography, selective laser sintering, laser-based writing system, continuous layer interface production, and powder-based 3D printing). [15]

Evaluation of the Efficacy of the Vaccine Production Process in Removing Residual Host Cell DNA from the Vero Cell Rabies Vaccine

Background: The Vero cell rabies vaccine is currently the most widely used human rabies vaccine. However, owing to the presence of residual host cell DNA (HCD) in the final product and the potential tumorigenicity of the DNA of high-passage Vero cells, the WHO not only sets a limit on the number of times cells used in production can be passaged, but also imposes strict requirements on the amount of residual HCD in the final vaccine product. Objectives: To systematically reduce the HCD level in the final vaccine product, multiple purification steps are included in the vaccine production process. This study investigated the effectiveness of key production steps in antigen recovery and DNA removal. Methods: The residual HCD fragment content and size distribution were detected using fluorescence quantitative PCR (qPCR) and capillary gel electrophoresis (CGE), and the rabies virus glycoprotein antigen content was detected using enzyme-linked immunosorbent assay (ELISA). The antigen recovery rate and HCD removal rate in each key process were calculated to evaluate the scientific basis and effectiveness of each production step. Additionally, the stability of the process was studied using multiple commercial batches of the product. Results: The results revealed that the total antigen recovery rate in the production process described in this report was no less than 8.5%, and the effective removal rate of residual HCD was not lower than 99.99%. Moreover, the amount of residual HCD in the final product was far below the quality standard of 2 ng/dose, and most of the residual HCD fragments were smaller than 200 bp. The results of the process stability studies on multiple commercial batches showed that the bulk human rabies vaccine produced by this process had excellent safety and efficacy and that the production process was stable and thus suitable for large-scale batch production. Conclusions: The production process described in this study achieved effective recovery of viral antigens and efficient removal of residual HCD, and the process was stable and controllable, enabling the continuous and stable production of vaccine products that meet WHO recommendations and the relevant requirements of the current edition of the Chinese Pharmacopeia. In addition, this study provides theoretical guidance for optimizing the vaccine production process.

A CFT dual for evaporating black holes: boundary continuous matrix product states

Tensor network states, especially Matrix Product States (MPS), are crucial tools for studying how particles in large quantum systems are entangled with each other. MPS are particularly effective for modeling systems in one-dimensional space. Their continuous version, known as continuous Matrix Product States (cMPS), extends this approach to more complex quantum field theories that describe systems with an infinite number of interacting particles. This paper introduces a novel extension, boundary continuous Matrix Product States (BCMPS), which incorporate boundary states from conformal field theory (TFD state of two CFTs, let). We construct BCMPS and explore their potential holographic duals, linking them to black hole microstates with end-of-the-world branes in AdS/CFT. This connection hints at a deeper relationship between tensor networks and spacetime geometry, potentially offering new insights into the interplay between quantum information and gravity.

The performance and mechanism of friction-promoted two-electron fully water splitting of boron carbide

The decomposition of hydrogen peroxide is an essential intermediate step in the kinetically advantageous two electrons in the process of splitting water (2H2O =H2O2+H2,H2O2→12O2+H2O). Although it is an exothermic reaction, the reaction rate is slow without catalyst. It is possible to significantly improve the efficiency of water splitting if hydrogen peroxide can be decomposed in a timely and rapid manner. Hydrogen peroxide can be quickly decomposed by tribocatalysis process to solve the above problems. In the process of friction catalysis, when external force is applied to piezoelectric material B4C, internal charge separation will be generated and local electric field will be formed. Tribocatalysis can continuously generate rapidly separated electrons and positive charges, which provide sufficient electrons for the two-electron water splitting process. At the same time, under the tribocatalysis of boron carbide (B4C), water molecules are easily combined with positive charges to form hydroxyl radicals and release hydrogen ions. It provides a continuous source of hydrogen ions for the generation of hydrogen, which consumes positive charges and improves the utilization efficiency of electrons. Finally, two moles of hydroxyl radicals quickly form hydrogen peroxide, which is rapidly decomposed by tribocatalysis, thus solving the bottleneck problem of two-electron water splitting. Under tribocatalytic-driven, the dual function of B4C: catalytic water splitting and decomposition of hydrogen peroxide is the key to its efficient catalytic continuous production of hydrogen and oxygen.

High temperature fencing for continuous steelmaking unit

A new method of iron recovery and continuous steel production with in-line vacuuming is described. Constructive solutions for refractory fencing are proposed, as well as the evaluation and selection of materials for the multilayer lining of the proposed installation. Technical solutions have been selected to extend the service life of high-temperature fencing using water-cooled panels that ensure the formation of a garnish. Numerical modeling of the process of the growth of the garnish layer is carried out.

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy

Globally, nearly half of all pregnancies are unintended, ∼1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy and two highly prevalent sexually transmitted infections (STIs).

Research Productivity Among Applicants Who Matched into an Integrated Thoracic Surgery Residency Program: A Bibliographic Review

ObjectiveResearch productivity is an important factor in candidate selection by Integrated thoracic surgery residency programs. It is necessary to track the research output of applicants who match into an Integrated program. This study sought to examine the research productivity of matched Integrated applicants prior to residency and assess demographic, bibliographic, and institutional variables associated with continued research productivity during residency. MethodsBibliographic records of applicants who matched into an Integrated program from 2015 to 2022 were manually reviewed (e.g., PubMed/MEDLINE, Scopus, Google Scholar, ResearchGate) to identify studies published until January 2024. Publications were stratified by publication type and first-authorship relative to the applicants’ match year. Individuals were analyzed by demographics, medical school ranking, and affiliated residency programs’ research infrastructure. ResultsThree hundred matched Integrated applicants were identified. Among applicants who matched into an Integrated program, the number of total (p = 0.001) and first-author (p = 0.006) publications prior to residency significantly increased from 2015 to 2022. Over the same period, the rate of total (p = 0.2) and first-author (p = 0.3) publications during residency remained relatively unchanged. Matched Integrated applicants with a higher number of total and first-author publications prior to residency had a higher rate of total (1.17; 95% confidence interval (CI) 1.09 – 1.25; p < 0.001) and first-author (1.19; 95% CI 1.13 – 1.26; p < 0.001) publications during residency, respectively. ConclusionResearch productivity among applicants who matched into an Integrated program from 2015 to 2022 has increased and is a strong predictor of sustained scholarly output during residency.

Spatial confinement of MoS2 nanoparticles in jellyfish-inspired open-mouthed spheres for high-capacity and ultrafast-rate sodium-ion capture

Rational nanoscale structure engineering of electroactive nanoarchitecture is a very promising strategy for designing advanced capacitive deionization (CDI) materials. Herein, inspired by jellyfish physiological structure, open-mouthed MoS2/C hierarchical porous spheres were fabricated via direct-spray pyrolysis by adopting a strategy of coupling defective MoS2 with locally conductive network graphene quantum dots. Such a well-developed open-mouthed interconnected porous structure significantly stimulated the permeation of electrolyte ion the deep internal spaces of electrode, facilitated fast ion diffusion and provided abundant electrochemical adsorption sites, endowing the MoS2/C electrode with a remarkable desalination capacity of 118.83 mg g−1, an impressively rapid desalination rate of 51.35 mg g−1 min−1, and a good long-term cycle stability of 82 % after 50 cycles. This work inspires the design hierarchically porous composite materials with unique micro-nanostructures, offering a new viable route for the continuous and efficient production of CDI electrode materials.

In-situ synthesis of a heterogeneous NHC–CO2 catalyst for continuous DMC production

In-situ synthesis of a heterogeneous NHC–CO2 catalyst for continuous DMC production

Thermally-assisted reformation of spray-printed polymer channel layer for improved transistor performance and device-to-device uniformity

Bulk and surface morphology of a channel layer needs to be controlled to obtain desirable electrical performance of organic transistors and circuits based on them. Although spray coating is widely used in industry for continuous production of thin films, the microscopically rough nature of the spray-printed films makes it challenging to apply in electronics. Herein, we demonstrate a simple, scalable, and general approach by combining solvent mixing and thermal annealing to improve surface flatness, and therefore device reproducibility, without additional apparatuses attached to the spraying tools. We find that a small amount (2–5 vol%) of a high-boiling-point solvent, which can dissolve the channel material only at an elevated temperature, reduces surface roughness and rearranges the internal microstructure of the channel layer via dissolution and re-solidification during heat treatment. Thermally-assisted reformation of the channels of representative polymers (P3HT and PDPP2T-TT) results in 1.5–2.1 times enhancement of charge-carrier mobility in organic electrochemical transistors compared to as-printed films. At the same time, the device-to-device variation is significantly reduced with about 4–5 times lower coefficient variation in electrical characteristics.

An in-depth study of the strengthening mechanism in wood scrimber prepared via roller-pressing impregnation technology

Wood scrimber, a new type of wood composite material, can replace nature high-quality wood. To improve the mechanical properties and dimensional stability of scrimber for wider applications, a negative pressure resin-absorption method called “roller-pressing impregnation” was developed to produce wood scrimber in this study. Compared to the properties of wood scrimber prepared using the cage impregnation method (CWS), roller-pressing impregnated wood scrimber (RWS) exhibited significantly reduced surface roughness and wettability. Moreover, the thickness and width swelling rate of RWS decreased by 26.15 % and 18.77 % respectively, while the modulus of rupture increased by 12.45 %. Microscopic observation demonstrated that the weak tissue (middle lamella and vessels) in the oriented wood fiber mats (OWFMs) were damaged during the roller-pressing process. Meanwhile, these cleaved cellular helped the resin be absorbed more uniformly into the vessel cavities by the negative pressure, which enhanced the strength of the resin bonding between cells and also strengthened the hardness and elastic modulus of the cell wall. Therefore, the dimensional stability and mechanical properties of the scrimber were successfully enhanced. The in-depth exploration of the mechanism behind the roller impregnation technology was expected to accelerate the accurate controlling of the wood scrimber properties for continuous production.

Effect of Gypsum, Cover Crop, and Crop Rotation on Bulk Density and Aggregate Properties of Soils

ABSTRACT Soybean production, worldwide, typically involves full tillage resulting in much less biomass than other crops, leading to decreased soil organic matter and increased soil degradation. The goal of this study was to evaluate the potential benefits of an innovative management system that includes the combinations of no-till, crop rotation, cover crop, and gypsum application on continuous soybean production. The response of soil physical properties, i.e. bulk density and water-stable aggregates, was evaluated across a range of soil types and climatic conditions. Treatments consisted of comparing (1) continuous soybean to a soybean-corn and corn-soybean rotation, (2) cereal rye [Secale cereale (L.)] cover crop to no cover crop, and (3) gypsum surface‐applied at 0, 1.1, and 2.2 Mg ha−1. The study was replicated at four different sites in the United States, including Shorter (AL), Farmland (IN), Hoytville (OH), and Piketon (OH). At the end of the 5-year study, soil bulk density and aggregate stability were determined. Soil bulk density and water-stable aggregates were unaffected by gypsum addition regardless of the location. Including cereal rye as a winter cover increased soil aggregation and bulk density at the Hoytville location only. Rotating the soybeans with corn (compared to continuous soybeans) resulted in soil aggregation and bulk density improvements at all research locations. Results indicated that soybean production that included crop rotation into management system improved soil aggregate stability, whereas cover crop benefits were less effective and amending the soil with gypsum did not significantly affect these soil properties.

Biofilm-based immobilized fermentation of engineered Komagataella phaffii for xylanase production

This study presented an immobilized fermentation process of engineered Komagataella phaffii with improved biofilm-forming abilities for continuous xylanase production and provided the first insights into the molecular basis of biofilm-based immobilized fermentation of K. phaffii. Overexpression of PAS_chr2-2_0178 and PAS_FragB_0067 in K. phaffii facilitated biofilm formation with 31.6% and 113.8% increasement, respectively. Subsequently, a biofilm-based immobilized fermentation process was developed for the PAS_FragB_0067-overexpressing strain. Xylanase production over five batches by GS115-0067* was better than that of GS115-xyn, with an overall average of 35.4% higher enzyme activity. PAS_FragB_0067 overexpression resulted in better adhesion of K. phaffii cells on the carrier, and enhanced biofilms could provide more active cells in the immobilized fermentation process. Transcriptome analysis revealed that overexpression of the biofilm-related gene promoted central carbon metabolism. These findings offer a valuable reference strategy to improve production efficiency of K. phaffii cells in continuous fermentation processes.

Climate change and poultry production: Enhancing resilience and sustainability through climate-smart practices, a review

Chicken production plays a vital role in global food systems, providing essential protein to billions of people, particularly in developing nations. However, climate change poses significant challenges to the poultry industry, including temperature stress, water scarcity, feed supply disruptions, disease prevalence, and economic impacts. This review examines the intricate effects of climate change on chicken production, highlighting primary challenges and exploring potential solutions. Proactive measures such as improved housing, water management, feed innovation, disease control, and genetic selection are crucial for enhancing the resilience of poultry farming systems. Collaborative efforts among industry stakeholders, researchers, and policymakers are essential to effectively implement these strategies and safeguard food security, economic stability, and environmental sustainability. By prioritizing adaptation and mitigation efforts, stakeholders can mitigate the adverse effects of climate change on chicken production, ensuring continued productivity and profitability in a changing climate. It is imperative that decisive action is taken to address these challenges, fostering innovation, sustainability, and resilience in chicken production systems worldwide.

Dynamic scheduling for flexible job shop based on MachineRank algorithm and reinforcement learning

This paper investigates the Dynamic Flexible Job Shop Scheduling Problem (DFJSP), which is based on new job insertion, machine breakdowns, changes in processing time, and considering the state of Automated Guided Vehicles (AGVs). The objective is to minimize the maximum completion time and improve on-time completion rates. To address the continuous production status and learn the most suitable actions (scheduling rules) at each rescheduling point, a Dueling Double Deep Q Network (D3QN) is developed to solve this problem. To improve the quality of the model solutions, a MachineRank algorithm (MR) is proposed, and based on the MR algorithm, seven composite scheduling rules are introduced. These rules aim to select and execute the optimal operation each time an operation is completed or a new disturbance occurs. Additionally, eight general state features are proposed to represent the scheduling status at the rescheduling point. By using continuous state features as the input to the D3QN, state-action values (Q-values) for each scheduling rule can be obtained. Numerical experiments were conducted on a large number of instances with different production configurations, and the results demonstrated the superiority and generality of the D3QN compared to various composite rules, other advanced scheduling rules, and standard Q-learning agents. The effectiveness and rationality of the dynamic scheduling trigger rules were also validated.

Poly(vinyl alcohol)-Assisted Exfoliation and Grafting Modification of Boron Nitride Nanosheets with a High Aspect Ratio via a Continuous Production Method for Energy Storage and Thermal Management.

Hexagonal boron nitride nanosheets (BNNS) integrating many extraordinary properties are usually combined with polymers to fabricate multifunctional dielectric materials for energy storage and thermal management. Unfortunately, the existing technologies for producing BNNS generally have the disadvantages of inefficiency and low product quality, which significantly hinder the wide application of high-value nanocomposites. Herein, a novel poly(vinyl alcohol) (PVA)-assisted pan-milling method based on the innovative solid-state shear milling (S3 M) technology is reported for the production of high-quality BNNS. The uniform three-dimensional (3D) shear force field generated by pan milling not only ensured the high aspect ratio of BNNS (the average lateral size of ∼954 nm and the average thickness of ∼3.7 nm) but also induced the mechanochemical reaction between PVA and BNNS to achieve in situ grafting modification on the BNNS surface. The simultaneous high-quality exfoliation and surface modification of BNNS positively contributed to the mechanical, dielectric, and thermal conduction properties of BNNS/PVA nanocomposites. At the BNNS content of 10 wt %, the BNNS/PVA composite film exhibited excellent robustness (Young's modulus of 5305 MPa and the tensile strength of 83 MPa), with a satisfactory breakdown strength (Eb of 134.7 MV/m) and dielectric constant (∼5 at 1000 Hz). In addition, the substantial improvement of thermal conductivity (from 0.88 to 5.59 W·m-1·K-1) guaranteed the stability of the dielectric properties of the nanocomposites at high temperatures. This pan-milling method characterized by green and efficiency is highly scalable to other two-dimensional (2D) layered materials, providing a practical strategy for the industrial fabrication of nanocomposites in elevated-temperature energy storage.

In situ Fe-doped thin carbon wires via AC high voltage arc discharge

This study explores the controlled, continuous production of thin carbon rods between graphite electrodes (continued electrode deposits) during an arc discharge of high voltage alternating current with a frequency of 50 Hz in liquid paraffin, along with in situ doping of the resulting material using a suspension of liquid paraffin and iron powder ( <10 μm). The surface morphology of the obtained carbon rod nanomaterials was characterized using scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectroscopy (EDX), scanning transmission electron microscopy (STEM) with EDX chemical composition analysis, X-ray microtomography (micro-CT), and atomic force microscopy (AFM). The AFM technique in scanning thermal microscopy (SThM) and conductive probe (CP) modes was employed to determine the temperature and electrical conductivity of the obtained nanostructures. Qualitative analysis was conducted using Raman spectroscopy, X-ray powder diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). This simple system for producing thin, stable carbon wires (< 1.2 mm thick) enables efficient and low-cost production and doping of these materials. The high-voltage alternating current (HVAC) arc discharge method for growing controlled, metal-doped electrode deposits presents a new approach to producing inexpensive, porous carbon nanomaterials for various scientific and technological applications.

Design of China first pilot plant for supercritical hydrothermal synthesis of AgNPs

Supercritical hydrothermal synthesis (SCHS) is an eco-friendly and efficient method for synthesizing nanomaterials. China's first pilot plant for SCHS of silver nanoparticles (AgNPs) has been successfully built, producing AgNPs with controllable particle sizes through reactor and system optimizations. This manuscript systematically explores the challenges of low heating and mixing efficiency and clogging, and proposes targeted solutions, including efficient warming, heat reuse and mixer structure optimisation. The detailed system components, evident properties, advanced control methods and primary experiment results of the pilot scale plant are described objectively, achieving high-purity AgNPs with an average particle size of 36.1 nm. These findings will contribute to the commercialisation of the SCHS pilot plant for continuous batch production of nanoparticles.

Thermal Vacuum Synthesis: Physical Processes in Nanomaterial Production

The thermovacuum process offers an efficient and cost-effective method for producing nanomaterials by ensuring the continuous flow of dispersed material inside a spiral heating element. This is achieved by introducing the material into the heating element&amp;apos;s cavity along with air, forming a two-phase gas-solid particle system. The material moves upward through the heated space, where pressure gradually decreases. Experimental studies on materials like carbon, brown coal, and zirconium dioxide indicate specific conditions are necessary for the system&amp;apos;s continuous operation. One key requirement is that the mass of solid particles should not exceed 1.0 to 1.2 grams per liter of air entering the heating element. This limit ensures that nanodispersed and finely dispersed particles can move freely, avoiding collisions and allowing faster-moving particles to overtake slower ones. These particles increase in velocity and temperature as they pass through the heating element, with changes in heat capacity and particle motion contributing to wave motion and pulsed heat loads. The velocity at which the material particles travel depends on the thermal radiation from the heater walls and the energy generated by local pulse steam explosions, which create shock waves. Higher explosion energy results in increased particle velocity, greater impact angles against the heater walls, and higher environmental temperatures. These conditions lead to accelerated electron, proton, and other charged particle flows, forming plasma clots and neutrino clouds. The nanoparticles take various forms, including nanotubes, fullerenes, thin films, and crystals, reaching velocities up to a thousand kilometers per second and heating temperatures of up to 17 million degrees during pulses. This process consistently subjects the material to force, heat, deformation, and ionization, expediting the creation of nanodispersed materials with enhanced physicochemical and mechanical properties. The thermovacuum process not only improves the efficiency of thermotechnological equipment but also reduces energy consumption, production time, and costs. The research findings support its use in the continuous and effective production of high-quality nanomaterials.