An Analysis of Accessibility of Representative Psychotropic Medicine From the World Health Organization Model List of Essential Medicines in Developing Countries With Different Income Levels.

OBJECTIVES: The objective of this study was to analyze the accessibility of psychotropic medicine in developing countries based on the availability, price, and affordability indicators to create international evidence to guide the development of policies on the accessibility of medicines. METHODS: This study included 5 types of psychotropic medicines listed in the 22nd edition of the World Health Organization Model List of Essential Medicines published by the World Health Organization in 2021. Derived from 84 surveys in 59 countries, this study summarizes the availability, price, and affordability of originator branded drugs (OBs) and lowest-price generic drugs (LPGs) in the public and private sectors and compares them based on income levels in different countries. RESULTS: The average availability of psychotropic medicine was 45% in low- and lower-middle-income countries (LLMICs) compared with 49% in high- and upper-middle-income countries (HUMICs) whereas the availability of LPGs was higher than that of OBs in all country groups. The average patient price for OBs and LPGs was 94.0 and 23.2, respectively, and the overall patient price of psychotropic medicine in LLMICs was higher than that in HUMICs. The affordability of psychotropic medicine in LLMICs was lower than that in HUMICs. CONCLUSIONS: Psychotropic medicines in lower-middle-income countries have lower availability, a higher average patient price, and lower average affordability than in HUMICs, which requires lower-middle-income countries to take effective and various measures to improve the accessibility of psychotropic medicine.

Adhesion, proliferation, and detachment of various cell types on thermoresponsive microgel coatings.

Cutting-edge biomedical applications require increasingly complex and fastidious cell systems, for example, various classes of primary or stem cells. Their cultivation, however, still differs little from 30 years ago. This especially applies to the use of indiscriminative proteases for nonspecific cell detachment. A far more gentle alternative changes the adhesive properties of the cell culture substrates through coatings based on thermoresponsive polymers. Such polymers mediate cell adhesion at 37°C, but become repulsive upon a cell-compatible temperature drop to, for example, 32°C. While the high functionality of this method has already been well proven, it must also be easy and reproducible to apply. Here, we emphasize the potential of standard cell culture materials coated by spraying with thermoresponsive microgels for routine cultivation and beyond. On these surfaces, we successfully cultivated and detached various cell types, including induced pluripotent stem cells and cells in serum-free culture. In addition, we evaluated the compatibility of the microgel-sprayed surfaces with adhesion-promoting proteins, which are essential for, for example, stem cells or neuronal cells. Finally, we demonstrate that the microgel surfaces do not impair proliferation and show their long-term stability. We conclude that for cell detachment, thermoresponsive cell culture substrates can fully substitute proteases, like trypsin, by employing a comparably straightforward protocol that is compatible with many industrial processing lines.

Long period fiber grating in two-core hollow eccentric fiber.

Long period fiber gratings (LPGs) in a two-core hollow eccentric fiber (TCHF) have been demonstrated experimentally. Two LPGs have been fabricated into the respective core of the TCHF by a high frequency CO2 laser. The coupling characteristics in the TCHF-LPG have been studied using the coupling mode theory (CMT). The resonant peak is mainly caused by the coupling between the core mode LP01 and cladding mode LP81. The experimental results agree well with the simulation results. Furthermore, the sensing properties of the TCHF-LPG have been investigated with respect to bending, temperature and axial strain. Compared with the LPG in the single mode fiber (SMF), the experimental results indicate that the sensitivity of the TCHF-LPGs to bending curvature is low and even very small at some bending directions. In addition, TCHF-LPGs are insensitive to the axial strain while sensitive to the temperature. Therefore, the proposed TCHF-LPGs can efficiently sense the changing temperature that is independent of the strain. Moreover, the TCHF-LPGs can also be applied to two-channel filters without signal crosstalk between two cores.

Bending characteristics of a long-period fiber grating in a hollow eccentric optical fiber.

In this paper, the bending characteristics of a long-period fiber grating (LPFG) in a hollow eccentric optical fiber (HEOF) have been investigated. Two samples fabricated under different laser exposure directions have been studied experimentally. The results show that the HEOF-LPFG can distinguish specific bending directions. The resonant peak shifts linearly with increasing curvature, but its sensitivity is lower than that of the LPFGs in single-mode fibers. In addition, the exposure direction shows a great influence on the bending characteristics due to the asymmetry of the fiber core. Furthermore, the responses of the HEOF-LPFG to temperature, axial strain, and external refractive index have been measured.

Joining of metallic glasses in liquid via ultrasonic vibrations.

Joining processes especially for metallic materials play critical roles in manufacturing industries and structural applications, therefore they are essential to human life. As a more complex technique, under-liquid joining has far-reaching implications for national defense, offshore mining. Furthermore, up-to-now, the effective joining of metals in extreme environments, such as the flammable organo-solvent or the arctic liquid nitrogen, is still uninvestigated. Therefore, an efficient under-liquid joining approach is urgently called for. Here we report a method to join different types of metallic glasses under water, seawater, alcohol and liquid-nitrogen. The dynamic heterogeneity and liquid-like region expansion induces fluid-like behavior under ultrasonic vibration to promote oxide layer dispersion and metal bonding, allowing metallic glasses to be successfully joined in heat-free conditions, while still exhibiting excellent tensile strength (1522 MPa), bending strength (2930 MPa) and improved corrosion properties. Our results provide a promising strategy for manufacturing under offshore, polar, oil-gas and space environments.

Dissolvable templates to prepare Pt-based porous metallic glass for the oxygen reduction reaction.

Oxygen reduction reaction (ORR) plays a crucial role in electrochemical energy conversion and storage devices such as metal-air batteries and water electrolyzers. Herein, a hierarchical nanoporous platinum-based metallic glass (NPMG) was developed by a facile fabrication method by dissolving in a liquid. The surface topography of the sample can be easily modulated by controlling the particle size of sodium chloride. As a result, the NPMG was proved to be efficient and robust as the ORR catalysts with super hydrophilicity and self-renewal capacity. The half-wave potential of the platinum-based porous material was 835 mV at 0.1 M KOH, even higher than that of the commercial Pt/C catalyst (823 mV) and the previously reported platinum material. In particular, platinum-based porous materials have extremely long stability (more than 500 h) through the self-renewal surface, which perfectly meets the requirements of catalyst stability in batteries. Our study has a better inspiration for developing and applying novel catalysts to prepare metal-air batteries.

Longitudinal characterization of TK6 cells sequentially adapted to animal product-free, chemically defined culture medium: considerations for genotoxicity studies.

Introduction: In vitro approaches are an essential tool in screening for toxicity of new chemicals, products and therapeutics. To increase the reproducibility and human relevance of these in vitro assessments, it is advocated to remove animal-derived products such as foetal bovine serum (FBS) from the cell culture system. Currently, FBS is routinely used as a supplement in cell culture medium, but batch-to-batch variability may introduce inconsistency in inter- and intra-lab assessments. Several chemically defined serum replacements (CDSR) have been developed to provide an alternative to FBS, but not every cell line adapts easily and successfully to CDSR-supplemented medium, and the long-term effect on cell characteristics remains uncertain. Aim: The aim of this study was to adapt the TK6 cell line to animal-product free CDSR-supplemented medium and evaluate the long-term effects on cell health, growth, morphology, phenotype, and function. This included a provisional assessment to determine the suitability of the transitioned cell line for standardised genotoxicity testing using the "in vitro mammalian cell micronucleus test" (OECD TG 487). Materials and methods: Gradual adaptation and direct adaptation methodologies were compared by assessing the cell proliferation, size and viability every passage until the cells were fully adapted to animal-free CDSR. The metabolic activity and membrane integrity was assessed every 4-8 passages by PrestoBlue and CytoTox-ONE™ Homogeneous Membrane Integrity Assay respectively. A detailed morphology study by high content imaging was performed and the expression of cell surface markers (CD19 and CD20) was conducted via flow cytometry to assess the potential for phenotypic drift during longer term culture of TK6 in animal-free conditions. Finally, functionality of cells in the OECD TG 487 assay was evaluated. Results: The baseline characteristics of TK6 cells cultured in FBS-supplemented medium were established and variability among passages was used to set up acceptance criteria for CDSR adapted cells. TK6 were adapted to CDSR supplemented medium either via direct or gradual transition reducing from 10% v/v FBS to 0% v/v FBS. The cell growth rate was compromised in the direct adaptation and therefore the gradual adaptation was preferred to investigate the long-term effects of animal-free CDSR on TK6 cells. The new animal cells showed comparable (p > 0.05) viability and cell size as the parent FBS-supplemented cells, with the exception of growth rate. The new animal free cells showed a lag phase double the length of the original cells. Cell morphology (cellular and nuclear area, sphericity) and phenotype (CD19 and CD20 surface markers) were in line (p > 0.05) with the original cells. The new cells cultured in CDSR-supplemented medium performed satisfactory in a pilot OECD TG 487 assay with compounds not requiring metabolic activation. Conclusion: TK6 cells were successfully transitioned to FBS- and animal product-free medium. The new cell cultures were viable and mimicked the characteristics of FBS-cultured cells. The gradual transition methodology utilised in this study can also be applied to other cell lines of interest. Maintaining cells in CDSR-supplemented medium eliminates variability from FBS, which in turn is likely to increase the reproducibility of in vitro experiments. Furthermore, removal of animal derived products from cell culture techniques is likely to increase the human relevance of in vitro methodologies.

OECD workshop consensus report: Ethical considerations with respect to human derived products, specifically human serum, in OECD test guidelines.

The ethical needs and concerns with use and sourcing of human materials, particularly serum, in OECD in vitro test guidelines were explored in a dedicated international workshop held in 2019. The health-related aspects of the donation procedure, including tissue screening, donor health, laboratory work health protection, permission from the donor for commercial use, payment of the donors and the potential for exploitation of low-income populations and data protection of the donors; supply, availability, and competition with clinical needs; traceability of the serum and auditability/GLP needs for the Test Guideline Programme, were examined. Here we provide the recommendations of the workshop with respect to the use of human serum, and potentially other human reagents, specifically with regard to test method development for OECD Test Guideline utility as part of the Mutual Acceptance of Data requirement across all OECD member countries. These include informed donor consent terminology, a checklist of human serum information requirements to be included with the Good Laboratory Practise report, and suitable sources for human serum to ensure waste supplies are used, that can no longer be used for medical purposes, ensuring no competition of supply for essential medical use.

The Role of Jinhuang Powder to Prevent Adverse Effects of Subcutaneous Injection of Enoxaparin Sodium.

Objective: To determine the role of Jinhuang Powder to prevent adverse effects of subcutaneous injection of enoxaparin sodium. Methods: The clinical data of 97 patients with cervical cancer who were treated with subcutaneous injection of enoxaparin through the lower margin of the deltoid muscle of the upper arm in Zhejiang Tumor Hospital from August 2020 to August 2021 were retrospectively analyzed. All patients were divided into the control group (n = 39) and the research group (n = 58) according to the different use time periods of Jinhuang Powder. The research group was treated with Jinhuang Powder and enoxaparin sodium at the same time. The control group started to use Jinhuang Powder after the adverse reactions occurred. The induration, subcutaneous bleeding events, and pain were statistically analyzed. Results: The incidence of induration (3.4% vs 15.4%, P=0.036) and subcutaneous hemorrhage (37.9% vs 76.9%, P=0.003) in the research group was significantly lower than that in the control group. The pain in the research group was lighter than that in the control group (grade 0-4 pain: 70% vs 28.2%, 19% vs 30.8%, 8.6% vs 23.1%, 1.7% vs 12.8%, 1.7% vs 5.1%, P=0.001). Conclusion: Preventive use of Jinhuang Powder can significantly reduce the incidence of subcutaneous induration and subcutaneous bleeding and can effectively alleviate the local pain of injection. It is worthy of further study to clarify its role and mechanism.

Carbon metabolism limits recombinant protein production in Pichia pastoris.

The yeast Pichia pastoris enables efficient (high titer) recombinant protein production. As the molecular tools required are well established and gene specific optimizations of transcription and translation are becoming available, metabolism moves into focus as possible limiting factor of recombinant protein production in P. pastoris. To investigate the impact of recombinant protein production on metabolism systematically, we constructed strains that produced the model protein ß-aminopeptidase BapA of Sphingosinicella xenopeptidilytica at different production yields. The impact of low to high BapA production on cell physiology was quantified. The data suggest that P. pastoris compensates for the additional resources required for recombinant protein synthesis by reducing by-product formation and by increasing energy generation via the TCA cycle. Notably, the activity of the TCA cycle was constant with a rate of 2.1 ± 0.1 mmol g CDW-1 h(-1) irrespective of significantly reduced growth rates in high BapA producing strains, suggesting an upper limit of TCA cycle activity. The reduced growth rate could partially be restored by providing all 20 proteinogenic amino acids in the fermentation medium. Under these conditions, the rate of BapA synthesis increased twofold. The successful supplementation of the growth medium by amino acids to unburden cellular metabolism during recombinant protein production suggests that the metabolic network is a valid target for future optimization of protein production by P. pastoris.

Metallic glue for designing composite materials with tailorable properties.

Developing materials with tailorable properties has been the long-sought goal of humankind. Forming composite materials with superior properties by combining two or more materials has emerged as a competitive means in the search and design of new materials. However, it is still a grand challenge to use metallic materials as a binder for composites because of their lack of adhesion. In the present work, we proposed a facile and flexible route to synthesize composites using metallic glass as a glue to bond various materials, ranging from conductors to insulators, and metals to nonmetals, together. The mechanical, magnetic and electrical performances of the composites can be manually regulated by changing the addition ratios of the metallic glass glue and the corresponding admixture. In addition, porous structures were also obtained and tuned by dissolving the soluble admixture in water. In principle, our approach provides a new idea for the fabrication and optimization of composites using metallic materials as binders. The outcome of our current research opens up a window not only to synthesize composite materials with tailorable properties universally and flexibly, but also towards the discovery of potential multi-functional metal containing composites.

Quantitative physiology of Pichia pastoris during glucose-limited high-cell density fed-batch cultivation for recombinant protein production.

Pichia pastoris has become one of the major microorganisms for the production of proteins in recent years. This development was mainly driven by the readily available genetic tools and the ease of high-cell density cultivations using methanol (or methanol/glycerol mixtures) as inducer and carbon source. To overcome the observed limitations of methanol use such as high heat development, cell lysis, and explosion hazard, we here revisited the possibility to produce proteins with P. pastoris using glucose as sole carbon source. Using a recombinant P. pastoris strain in glucose limited fed-batch cultivations, very high-cell densities were reached (more than 200 g(CDW) L(-1)) resulting in a recombinant protein titer of about 6.5 g L(-1). To investigate the impact of recombinant protein production and high-cell density fermentation on the metabolism of P. pastoris, we used (13)C-tracer-based metabolic flux analysis in batch and fed-batch experiments. At a controlled growth rate of 0.12 h(-1) in fed-batch experiments an increased TCA cycle flux of 1.1 mmol g(-1) h(-1) compared to 0.7 mmol g(-1) h(-1) for the recombinant and reference strains, respectively, suggest a limited but significant flux rerouting of carbon and energy resources. This change in flux is most likely causal to protein synthesis. In summary, the results highlight the potential of glucose as carbon and energy source, enabling high biomass concentrations and protein titers. The insights into the operation of metabolism during recombinant protein production might guide strain design and fermentation development.

Correlation between TCA cycle flux and glucose uptake rate during respiro-fermentative growth of Saccharomyces cerevisiae.

Glucose repression of the tricarboxylic acid (TCA) cycle in Saccharomyces cerevisiae was investigated under different environmental conditions using (13)C-tracer experiments. Real-time quantification of the volatile metabolites ethanol and CO(2) allowed accurate carbon balancing. In all experiments with the wild-type, a strong correlation between the rates of growth and glucose uptake was observed, indicating a constant yield of biomass. In contrast, glycerol and acetate production rates were less dependent on the rate of glucose uptake, but were affected by environmental conditions. The glycerol production rate was highest during growth in high-osmolarity medium (2.9 mmol g(-1) h(-1)), while the highest acetate production rate of 2.1 mmol g(-1) h(-1) was observed in alkaline medium of pH 6.9. Under standard growth conditions (25 g glucose l(-1) , pH 5.0, 30 degrees C) S. cerevisiae had low fluxes through the pentose phosphate pathway and the TCA cycle. A significant increase in TCA cycle activity from 0.03 mmol g(-1) h(-1) to about 1.7 mmol g(-1) h(-1) was observed when S. cerevisiae grew more slowly as a result of environmental perturbations, including unfavourable pH values and sodium chloride stress. Compared to experiments with high glucose uptake rates, the ratio of CO(2) to ethanol increased more than 50 %, indicating an increase in flux through the TCA cycle. Although glycolysis and the ethanol production pathway still exhibited the highest fluxes, the net flux through the TCA cycle increased significantly with decreasing glucose uptake rates. Results from experiments with single gene deletion mutants partially impaired in glucose repression (hxk2, grr1) indicated that the rate of glucose uptake correlates with this increase in TCA cycle flux. These findings are discussed in the context of regulation of glucose repression.

3D Hollow Quasi-Graphite Capsules/Polyaniline Hybrid with a High Performance for Room-Temperature Ammonia Gas Sensors.

Designing sensing materials with novel morphologies and compositions is eminently challenging to achieve high-performance gas sensor devices. Herein, an in situ oxidative polymerization approach is developed to construct three-dimensional (3D) hollow quasi-graphite capsules/polyaniline (GCs/PANI) hierarchical hybrids by decorating protonated PANI on the surface of GCs; as a result, an immensely active and sensitive material was developed for sensing ammonia gas at room temperature. Moreover, the GCs possessed a capsule-like hollow/open structure with partially graphitized walls, and PANI nanospheres were uniformly decorated on the GC surfaces. Furthermore, the inflexible and rigid 3D ordered chemistry of these materials provides the resulting hybrids with a large interfacial surface area, which not only allows for rapid adsorption and charge transfer but also provides the necessary structural stability. The 3D hollow GCs/PANI hybrids exhibit excellent performance; the GCs/PANI-3 hybrid is highly sensitive (with a response value of 1.30) toward 10 ppm NH3 gas and has short response and recovery times of 34 and 42 s, respectively. The GCs/PANI-3 hybrid also demonstrates a good selectivity, repeatability, and long-term stability, which are attributed to the substantial synergistic effect of the GCs and PANI. The design of such a unique 3D ordered framework provides a promising pathway to achieve room-temperature gas sensors for commercial applications.

Fetal Bovine Serum (FBS): Past - Present - Future.

The supplementation of culture medium with fetal bovine serum (FBS, also referred to as "fetal calf serum") is still common practice in cell culture applications. Due to a number of disadvantages in terms of quality and reproducibility of in vitro data, animal welfare concerns, and in light of recent cases of fraudulent marketing, the search for alternatives and the development of serum-free medium formulations has gained global attention. Here, we report on the 3rd Workshop on FBS, Serum Alternatives and Serum-free Media, where regulatory aspects, the serum dilemma, alternatives to FBS, case-studies of serum-free in vitro applications, and the establishment of serum-free databases were discussed. The whole process of obtaining blood from a living calf fetus to using the FBS produced from it for scientific purposes is de facto not yet legally regulated despite the existing EU-Directive 2010/63/EU on the use of animals for scientific purposes. Together with the above-mentioned challenges, several strategies have been developed to reduce or replace FBS in cell culture media in terms of the 3Rs (Refinement, Reduction, Replacement). Most recently, releasates of activated human donor thrombocytes (human platelet lysates) have been shown to be one of the most promising serum alternatives when chemically-defined media are not yet an option. Additionally, new developments in cell-based assay techniques, advanced organ-on-chip and microphysiological systems are covered in this report. Chemically-defined serum-free media are shown to be the ultimate goal for the majority of culture systems, and examples are discussed.

[Nutrient Exchange Between Meixi River and Yangtze River Due to the Typical Interaction Process of the Three Gorges Reservoir and Its Tributary].

Frequent algal blooms have been observed in the Meixi bay of the Three Gorges Reservoirs (TGR) since its initial filling. In order to understand the effects of intrusions from Changjiang mainstream on the nutrient supply of the Meixi Bay, a detailed field monitoring was conducted from August 2012 to July 2013. The results showed that there were significant intrusions from the mainstream to the Meixi Bay during the different water level scheduling periods of the TGR. As a result, the invading flow from the mainstream of the Changjiang caused a significant effect on the nutrient distribution in the Meixi River. Annually, the mainstream transportednet fluxes of 5 478.02 t DIN, 234.04 t DIP and 5 935.22 t DSi to the Meixi Bay, which were 2.37 times, 4.32 times and 1.33 times of the corresponding fluxes from the upstream, respectively. The influence on the nutrient distributions was not only limited in the estuary area but also in the upper reaches, the supply of DIP changed the nutrient structure and relieved the P restrictions on phytoplankton growth.