This study explores the fabrication of nanofibers using different types of gelatins, including bovine, porcine, and fish gelatins. The gelatins exhibited distinct molecular weights and apparent viscosity values, leading to different entanglement behavior and nanofiber production. The electrospinning technique produced nanofibers with diameters from 47 to 274 nm. The electrospinning process induced conformational changes, reducing the overall crystallinity of the gelatin samples. However, porcine gelatin nanofibers exhibited enhanced molecular ordering. These findings highlight the potential of different gelatin types to produce nanofibers with distinct physicochemical properties. Overall, this study sheds light on the relationship between gelatin properties, electrospinning process conditions, and the resulting nanofiber characteristics, providing insights for tailored applications in various fields. Traditionally, bovine and porcine skin and bones have been the primary sources of gelatin production4. However, fish skin has emerged as a promising and extensively studied alternative7. The hydrolysis of collagen leads to the cleavage of hydrogen, peptide, and covalent bonds in tropocollagen, forming free α chains, β chains, and γ chains. These chains consist mostly of repeated sequences of the amino acids Gly-X-Y10. The specific amino acids X and Y vary depending on the collagen source, influencing gelatin's final amino acid sequence2. Importantly, gelatin can restore collagen-like triple helix structures at temperatures within the range of 25–35 °C. These unique or aggregated segments act as junction zones, promoting enhanced intra- and intermolecular interactions along the polypeptide chains. However, above this temperature range, the triple helix dissociates, allowing the solvation of gelatin chains12.Gelatin is a heterogeneous mixture of polypeptides obtained through controlled hydrolysis of collagen. In industrial processes, gelatin is produced through acid, base, or mixed pre-treatment, followed by thermal treatment16. These unique characteristics, combined with gelatin's properties, especially the presence of nonpolar functional groups, allow for effective interaction with hydrophobic bioactive compounds in developing nanocarriers18.Among the diverse types of gelatin-based biomaterials, gelatin nanofibers offer several advantages due to their high surface area. These advantages include increased digestibility of pharmaceutical/bioactive compounds, adsorption of bioactive compounds at the intestinal mucosa, adsorption of organic compounds at adsorbents, and enhanced solubility of nonpolar bioactive compounds19. Different molecular weights of gelatin can be obtained depending on the source of raw materials and operational conditions employed. Type B gelatin typically has a molecular weight range of 40–90 kDa20, while type A gelatin has a higher tendency to maintain the integrity of the α chain, with a molecular weight of approximately 90–100 kDa18. The variability in gelatin molecular weight underscores the importance of characterizing gelatin to understand its influence on developing novel gelatin nanofibers. Previous studies have predominantly centered on investigating the influence of solution concentration, solvent type, and operational parameters on gelatin nanofiber formation26. However, the molecular weight of gelatin, a critical factor with potential far-reaching effects, has not been a focal point of these investigations. To the best of our knowledge, no previous studies have investigated the effect of different types of gelatins and their molecular weights on nanofiber formation. For instance, this study seeks to address this gap by exploring the impact of bovine, porcine, and fish gelatin on the physicochemical properties of nanofibers.In the development of gelatin-based nanofibers, the molecular weight of the polypeptide chain plays a significant role in determining the physicochemical properties of the final nanomaterial MW) . The intrinsic viscosity (η) was calculated by Huggin’s equation, Eq. (ηSP/c is the reduced viscosity (mL g−1), ηSP is the specific viscosity which compares the viscosity of the gelatin in solution to that of the solvent (dimensionless), c is the gelatin concentration (g mL−1), k is the Huggins constant (dimensionless), K and a are constants, which depends on the system solvent-polymer (K = 0.16 mL g−1 and a = 0.82)27.Bovine gelatin , porcine gelatin , and cold-water fish skin (without gel strength) were commercially purchased . Cannon–Fenske viscometer evaluated gelatin's viscosity-average molecular weight (−1) were dissolved in a 30% (v v−1) acetic acid solution for 2 h under stirring (300 rpm)  at 50 °C. The gelatin nanofibers were produced by electrospinning technique . Based on preliminary tests, the solutions were electrospun using a metallic capillary with a diameter of 0.7 mm, a capillary-to-collector distance of 7 cm, an applied voltage of 25 kV, and a flow rate of 1.2 mL h−1. The nanofiber synthesis occurred at a temperature of 25 ± 1 °C and relative humidity of 40 ± 1%.Different concentrations of gelatin   operating at 10 kV. Before imaging, the samples were coated with a 1 nm layer of gold ζ) were acquired using the Kalliope™ software program .ηe is electrolyte viscosity (Pa s−1), ε is the relative dielectric constant (F m−1), εo is the vacuum dielectric constant (F m−1), dU/dp is the slope of streaming potential versus differential pressure (V Pa−1), k is the electric conductivity of solution (S m−1).The samples without dilution were subjected to electrophoretic light scattering (ELS) analysis (triplicate) at 25 °C to measure the zeta potential of bovine, porcine, and fish gelatin solutions  at 25 °C. The electrolytes present in the emulsions flowed through a capillary channel, leading to different electrophoretic mobilities. These mobilities were determined by analyzing the Doppler frequency shift in scattered light, employing the Helmholtz-Smoluchowski equation Eq. . Zeta po−1), porcine (20% w v−1), and fish (35% w v−1) gelatin solutions were assessed by measuring their apparent viscosity (ηa) using a rheometer , equipped with a cone-plate sensor (C60/2°) with a gap set at 0.104 mm. The measurements were conducted at a range of shear rates from 1 to 200 s−1 at 25 °C. The experimental data were fitted to the power law model, described by Eq.  was estimated considering the power law and tubular geometry according to Eq. (30.τ is the shear stress (Pa), Ki is the consistency index (Pa sn), γ is the shear rate (s−1), and n is the flow behavior index (dimensionless).γmax is the maximum shear rate (s−1), n is the flow behavior index (dimensionless), Q is the volumetric flow rate of the gelatin solution (m3 s−1), and R is the radius of the metallic capillary (m).The rheological properties of bovine  . The ATR-FTIR analysis was performed at 20 °C, covering a range of 650–4000 cm32.n is the reflection order (dimensionless), λ is X-ray wavelength (1.5418 Å), and θ is the angle of incidence (°).The evaluation of crystalline modifications in the bovine, porcine, and fish gelatin nanofibers was performed using X-ray diffraction (XRD) . The XRD analysis was conducted at 40 kV and 40 mA, with a diffraction angle 2θ ranging from 5° to 90° in steps of 0.05°. The distance between consecutive layers of atoms, represented as d (Å), was calculated using Bragg’s Law Eq. 32.6\docu−1 (from 25 to 500 °C) and a heating rate of 10 °C min−1. TGA analysis, on the other hand, assessed the thermal stability of the samples and was conducted under a nitrogen flow rate of 30 mL min−1 (from 25 to 500 °C) at a heating rate of 10 °C min−1.The thermal properties of bovine, porcine, and fish gelatin nanofibers were investigated by differential scanning calorimetry (DSC) , as well as thermogravimetric analysis (TGA) . DSC analysis was employed to examine the physical transitions and was performed with a nitrogen flow rate of 50 mL minp < 0.05). Parameter estimation for the power law was performed using the nonlinear Quasi-Newton method in Statistica 7.0 . Graphical representations were generated using OriginPro 8.5 software .Statistical analysis included the comparison of nanofibers' diameter. Mean differences were determined using Statistica 7.0 software , with significance set at a 95% confidence level , and γ-type chains 35. Therefore, lower molecular weight values can be attributed to implementing more rigorous operating conditions  and applying basic pre-treatment, both of which contribute to increased hydrolysis along the collagen chains.The bovine, porcine, and fish gelatins exhibited a viscosity-average molecular weight of 48.8 ± 2.8, 98.4 ± 1.3, and 24.8 ± 1.5 kDa, respectively. The disparity in these values can primarily be attributed to the gelatin extraction processes. The covalent bonds between aldehyde and free amine groups within tropocollagen chains undergo denaturation during gelatin production−1). These images revealed that a concentration of 20% w v−1 yielded a combination of droplets and fibers, while higher concentrations (25–30% w v−1) resulted in uniformly structured fibers. Moreover, concentrations starting from 20% w v−1 represent the minimum threshold for polymer chains to overlap and form fibers. The increase in concentration (25–30% w v−1) promotes enhanced interaction and entanglement among the chains, crucial for maintaining a stable jet and preventing the formation of droplet-laden or spherical fibers as observed at 20% w v−1 . Notably, a concentration of 20% w v−1exclusively yielded fibers, unlike the results observed with bovine gelatin. This distinction can be attributed to the higher molar weight of porcine gelatin. Consequently, lower concentrations enable the necessary entanglement of polymer chains for fiber formation. Figure 37.Figure −1). In Fig. −1, higher than the minimum concentration required for bovine and porcine gelatin. This difference can be directly attributed to fish gelatin's lower molar weight than the other types. Consequently, a higher concentration of fish gelatin is necessary to achieve the required entanglement of polymer chains for fiber formation. The effect of the reduced molecular weight of fish gelatin also contributed to an increase in the minimum concentration (35% w v−1) necessary for forming a stable polymeric jet and, subsequently, producing droplet-free fibers.Figure p < 0.05) increase in the average diameter of nanofibers across various concentrations and gelatin types38. This behavior can be attributed to the heightened entanglement of polymer chains, which influences both the jet's stability and the fibers' final diameter19. Furthermore, for the same solvent, an augmented concentration curtails the mobility between polymer chains, thereby limiting the stretching of the jet and leading to the formation of larger-diameter fibers40. Moreover, under the conditions of 25% (w v−1), it was observed that all types of gelatin produced nanofibers. Porcine gelatin exhibited the largest nanofibers diameters, followed by bovine and fish gelatins. This difference in nanofibers diameters can be attributed to their distinct molecular weights, as previously mentioned.Table −1and 30% w v-−1 for bovine gelatin, 20% w v−1 for porcine gelatin, and 35% w v−1 for fish gelatin. The bovine gelatin samples at 25% w v−1and 30% w v−1exhibited production rates of 0.1 and 0.5 g h−1, respectively. The porcine gelatin sample at 20% w v−1 had a production rate of 0.1 g h−1, while the fish gelatin sample at 35% w v−1 had a production rate of 0.3 g h−1. It should be mentioned that these values surpass the average nanofiber production (0.01–0.1 g h−1) achieved through the traditional electrospinning process with a single capillary42. Considering the smaller average diameter, absence of droplets, and higher production rate, the samples with 30% w v−1 bovine gelatin, 20% w v−1 porcine gelatin, and 35% w v−1 fish gelatin were selected for subsequent analyses of structural, crystallinity, and thermal properties.The samples that yielded the smallest average diameter and were free of droplets were obtained at concentrations of 25% w v44. These differences can be mainly attributed to the partial deamination of glutamine and asparagine to glutamic acid and aspartic acid during the alkaline pre-treatment of gelatin45. Therefore, the enhanced electrophoretic and zeta potential values in porcine gelatin solution could be associated with increased amino acids with positively charged side chains, such as arginine, histidine, and lysine, through gelatin structure.Table −1) revealed that the porcine gelatin solution exhibited the highest viscosity, followed by bovine and fish gelatin solutions. Despite fish gelatin having the highest concentration (35% w v−1), followed by bovine (30% w v−1) and porcine gelatins (20% w v−1), the molecular weight of the gelatins appeared to have a pronounced effect on their viscosity.Table 46. On the other hand, fish gelatin exhibited reduced apparent viscosity values, indicating a higher proportion of free α-type chains and depolymerized α chains48. Furthermore, the higher positive charge observed in porcine gelatin, followed by bovine and fish gelatins, as indicated by the electrophoretic and zeta potential values, increases electrostatic repulsion. This electrostatic repulsion expands the gelatin chains in the solution, consequently increasing the overall size and volume occupied by the gelatin chains51. These results suggest that a higher concentration of fish gelatin is required to achieve the necessary chain entanglement to produce nanofibers, as previously discussed.The results suggest that porcine gelatin may possess greater structural integrity, particularly concerning β-type and γ-type chains. The presence of these chains introduces additional physical entanglements and constraints that impede the flow of the polymer, resulting in higher apparent viscosityKi) than the other types, consistent with its higher apparent viscosity values. Additionally, the flow behavior index (n) was approximately 1 for all samples, indicating the Newtonian behavior of the fluids29. This behavior is reflected in Table −1 for bovine, porcine, and fish gelatin solutions was 1.23, 1.24, and 1.22 s−1, respectively.The power law parameters for bovine, porcine, and fish gelatin solutions are presented in Table 52. These findings hold significance as viscous forces exert a stronger influence with decreasing feed rate in the electrospinning process. Considering these results, it can be argued that the importance of feed rate in electrospinning extends beyond jet velocity, solution transfer rate, and solvent evaporation; it also affects the viscoelastic forces. Lower feeding rates are desirable for solvent evaporation and to surpass the surface tension, avoiding Rayleigh instability54. On the other hand, increasing the apparent viscosity leads to heightened viscoelastic forces that need to be overcome by the electric forces involved and need to55.Decreasing the feed rate reduces the fluid supply to the syringe system, resulting in a lower shear rate as there is less movement between adjacent fluid layersFigure −1, the band corresponds to the stretching of NH bonding and hydrogen bonding of amide A. The band at 1750 cm−1 represents the stretching of C=O and hydrogen bonding coupled with the COO of amide I. Furthermore, the band at 1518 cm−1 indicates the vibration of N–H groups and the stretching of C–N groups of amides II57. In the vibrational spectra of the gelatin nanofiber samples  occurring at 60 °C according to the first derivative of the TGA curves.Figures v) values for bovine gelatin powder, porcine gelatin powder, and fish gelatin powder were determined as 1.1, 2.0, and 20.5 J g−1, respectively. The disparity in these values may be attributed to the increased interaction between water and the functional groups of fish gelatin. This trend could result from a higher proportion of smaller-sized polypeptide chains in fish gelatin, such as free α chains and depolymerized α chains, which provide a larger contact surface and greater availability of side chains for interaction with water molecules.The enthalpy of vaporization (∆Hv (69.0 J g−1), with Temax occurring at two temperatures (58 and 218 °C). These observations may be attributed to conformational changes in the structure of porcine gelatin during the electrospinning process.Comparison between the DSC curves of gelatin powder samples Fig. d, e, f ag), while the second is a first-order endothermic transition called melting61. The glass transition corresponds to the shift from a glassy state, where polymeric chains lack sufficient internal energy for mobility, to a higher energy state, allowing chains in the amorphous region to become flexible and mobile. However, the glass transition was not observed in the gelatin powder samples  of gelatin. Similar to the glass transition, this peak comprehends the transition from an ordered molecular state to a more disordered state in the crystalline regions of gelatin.Gelatin exhibits two well-established physical transitions. The first is a second-order transition known as the glass transition temperature (TM) values for bovine gelatin powder, porcine gelatin powder, and fish gelatin powder were found to be 124.2 J g−1 (108 °C), 169.8 J g−1 (110 °C), and 266.7 J g−1 (118 °C), respectively. As mentioned earlier, the higher ∆HM value in fish gelatin powder compared to bovine gelatin powder could be attributed to the increased interaction between water molecules and functional groups. The adsorbed water molecules could enhance intermolecular interactions and produce a more ordered structure within the fish gelatin61. On the other hand, the higher ∆HM value in porcine gelatin powder compared to bovine gelatin powder may be attributed to the preparation process. The acid pre-treatment step can lead to less hydrolysis along the collagen chain, thereby preserving the integrity of the crystalline regions related to β and γ chains.The melting enthalpy  and the reduction in mass percentage in the TGA curves  and 170–270 °C (Temax = 218 °C). The second water evaporation range may be associated with increased water adsorption at the active sites of gelatin. The initial temperature of degradation (TID) for the polymeric chains of bovine gelatin powder, porcine gelatin powder, and fish gelatin powder (Fig. ID values were measured at 269, 287, and 252 °C, respectively. These results indicate that the electrospinning process did not affect the thermal stability of the nanofibers.In the nanofiber sample from porcine gelatin, a higher amount of residual solvent may act as an anti-plasticizer, leading to interactions between water molecules and gelatin functional groups. This interaction could intensify intermolecular associations and limit the mobility of smaller chains within the amorphous region of the biopolymerves Fig. f within This study focused on developing nanofibers using different gelatins, namely bovine, porcine, and fish gelatins. The gelatins exhibited distinct molecular weight values: 48.8 ± 2.8, 98.4 ± 1.3, and 24.8 ± 1.5 kDa, respectively. Successful nanofiber formation was achieved for all gelatins, with fiber diameters from 47 to 274 nm. The variations in molecular weight and apparent viscosity among the gelatins indicated that porcine gelatin required lower concentrations to achieve the necessary entanglement for nanofiber production, followed by bovine and fish gelatins. The differences in molecular weight, apparent viscosity, electrophoretic and zeta potential values suggest that the process conditions not only affect the gelatin's chemical structure, including the presence of free α-type chains, depolymerized α chains, β-type chains, and γ-type chains but also impact the side chains of amino acids.Moreover, the electrospinning process may induce conformational alterations within the gelatin nanofibers, disrupting the remaining helical structure and modifying the junction zones responsible for maintaining the triple helix. This behavior ultimately results in reduced overall crystallinity of the gelatin samples. However, the electrospinning process induced a new conformational state characterized by enhanced molecular ordering in the nanofibers of porcine gelatin. Consequently, this study demonstrates how different gelatins can produce nanofibers with distinct physicochemical properties, influencing their potential applications.The unique properties of gelatin-based nanofibers make them versatile materials for various industries. Bovine and fish gelatins, with lower crystallinity, increased flexibility and reduced molecular order hold promise for applications requiring higher mass transfer rates, such as oral delivery carriers and membranes for organic compound purification. These nanofibers have higher solubility rate, making them ideal for delivering medications or nutrients in the oral mucosa. Moreover, they can enable higher adsorption capacities, facilitating the separation and purification of valuable compounds in industrial processes. On the other hand, porcine gelatin nanofibers, with increased crystallinity, offer benefits for applications involving prolonged drug/food delivery, food packaging, and biomedical scaffold fabrication. Their dense and structured architecture lends itself to sustained release formulations, ensuring a controlled and extended release of drugs or nutrients over time. In the food packaging industry, these nanofibers can enhance shelf life and protect products from external contaminants. Furthermore, these nanofibers find their place in biomedical engineering, where their structural integrity are critical for the fabrication of tissue scaffolds, promoting cell growth and tissue regeneration. Thus, the selection of gelatin sources during nanofibers production opens up a world of possibilities for tailoring nanofiber properties to specific applications across diverse domains.


Glycyrrhiza uralensis extract exhibited ~50% inhibition of sEH at 100 μg/mL, and column chromatography yielded compounds 1–11. Inhibitors 1, 4–6, 9, and 11 were non-competitive; inhibitors 3, 7, 8, and 10 were competitive. The IC50 value of inhibitor 10 was below 2 μM. Molecular simulation was used to identify the sEH binding site. Glycycoumarin (10) requires further evaluation in cells and animals.Soluble epoxide hydrolase (sEH) is a target enzyme for the treatment of inflammation and cardiovascular disease. A  Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid, which is metabolized by cytochrome P450 (CYP) epoxygenase enzymes . The CYPIn particular, sEH is an enzyme mainly expressed in the liver, and alcohol-induced inflammation, injury, and steatosis were reduced in hepatic sEH-knockout mice . MoreoveGancao) prepared from the roots of Glycyrrhiza species (Fabaceae) is widely used to treat various human ailments -benzamide were excluded from the A-chain. The revised A-chain was hydrogenated using AutoDockTools ; the Gasteiger charge model was then applied. Flexible ligand docking was evaluated using a torsion tree that detected torsion roots and rotatable bonds. The grid box sizes were 126 × 126 × 126 at 0.375 Å and 60 × 60 × 60  for blinded docking and ligand docking to the active site, respectively. Molecular docking was evaluated using a Lamarckian algorithm and the maximum possible evaluation number. The resulting values were calculated and visualized using AutoDockTools, Chimera ver. 1.14 , and LIGPLOT .3D ligand structures were built using the GlycoBioChem server. The sEH Gro was developed using the GROMOS96 45a3 force field. All complexes were surrounded by water molecules (cubic size 12 × 12 × 12) and six Cl anions. The energy level attained 10.0 kJ/mol via steepest descent minimization. Each inhibitor–sEH complex was sequentially subjected to NVT equilibration at 300 K, NPT and Particle Mesh Ewald evaluation of long-range electrostatics at 1 bar, and MD simulation for 30 ns.All measurements were performed in triplicate (three independent experiments) and the results are means ± standard errors of the means (SEMs). The results were compared using Sigma Plot 10.0 .G. uralensis roots inhibited sEH, but the main compound, glycyrrhizin, lacked such an effect. In this study, eleven polyphenol compounds, 1–11, were isolated from G. uralensis. Among them, compounds 1, 3–9, and 11 were found to exert moderate inhibitory effects, and inhibitor 10 showed a potent effect, with an IC50 value of 1.9 ± 0.2 μM. Molecular simulation was used to study the binding of 1, and 3–11 to sEH and it was found that the potential inhibitor 10 maintained a stable fluidic bond with the enzyme. Therefore, of the polyphenols, compound 10 was the strongest sEH inhibitor.Bioactivity screening revealed that an ethanol extract of


The AWaRe classification categorizes antibiotics and is a tool for antimicrobial stewardship. To combat antimicrobial resistance, prescribers must adhere to the AWaRe framework, which promotes the rational use of antibiotics. Therefore, increasing political will, dedicating resources, building capacity, and improving awareness and sensitization campaigns may promote adherence to the framework. Addressing AMR requires the establishment and implementation of antimicrobial stewardship (AMS) programs.Antimicrobial resistance (AMR) is a significant global health threat to humans, animals, agriculture, and the environment. This was a great milestone in the fight against AMR because a more objective, user-friendly tool became available to organize the antibiotics. The WHO AWaRe framework categorizes antibiotics according to their spectrum of activity and potential to develop resistance. The Access group contains antibiotics used in the first- and second-line treatment of infections. The Watch group contains broad-spectrum antibiotics with a higher potential of developing resistance. The Reserve group contains last-resort antibiotics used for multidrug-resistant infections. Furthermore, the framework promotes the responsible use of antibiotics by classifying them according to their importance in human medicine and promoting their appropriate use. The framework also includes key components such as prescribing guidelines and surveillance systems to monitor antimicrobial use (AMU) and AMR, as well as promoting research and development of new antibiotics and alternative treatment options. By 2023, the WHO AWaRe tool recommends that 60% of all prescribed antibiotics must belong to the Access group. Therefore, developing, implementing, and adhering to the WHO AWaRe framework promotes AMS and reduces the inappropriate use of antibiotics.In 2017, the World Health Organization (WHO) developed the Access, Watch, and Reserve (AWaRe) classification system of antibiotics as part of AMS. Significant progress has been reported by countries that have adopted national policies and guidelines on AMS and have implemented measures such as prescribing guidelines and surveillance systems to monitor AMU and AMR. Thus, countries that implemented the AWaRe framework are fully guided on the antibiotic to use for specific diseases. Additionally, prescribers are guided on the dosage of antibiotics for specific infections. This guidance has improved adherence to the recommended antibiotic prescribing guidelines. From the Zambian point of view, implementation of the AWaRe tool is still in its infancy, but hospitals where prescribers adhered to this AMS strategy reported low AMR challenges. Therefore, the political will demonstrated by the Government of the Republic of Zambia to support the implementation of this AMS strategy will further prevent and reduce AMR cases.Since its introduction, progress has been made in different regions of the world in implementing the AWaRe framework. Another major challenge is limited resources and capacity to implement the framework in many countries, especially in lower- and middle-income countries. Additionally, the low availability of affordable and good-quality antibiotics affects the sustainable implementation of the AWaRe system. A lack of political will in many countries continues to be a barrier to the implementation of the AWaRe framework of antibiotics. Therefore, these challenges may affect the strengthening of AMS, surveillance and monitoring systems of AMU and AMR, including the research and development of new antibiotics and alternative treatment options.The challenges reported here were from various countries but also apply to Zambia. One major challenge has been lack of awareness and education about appropriate antibiotic use. Many healthcare providers and patients are still not fully aware of the risks associated with the nonprudent AMU and the consequences of AMR. This lack of awareness is one of the reasons why AMR continues to be a serious global public health concern. Additionally, the lack of awareness of the WHO AWaRe framework of antibiotics influences healthcare workers to prescribe and dispense antibiotics without following the guidelines, worsening the AMR challenge.To push for further progress, continued collaborative efforts are needed to improve AMS. These efforts include increasing awareness and education about appropriate antibiotic use, strengthening surveillance and monitoring systems, and promoting research and development of new antibiotics and alternative treatment options. Healthcare authorities must increase awareness and sensitization campaigns and educational activities that may promote the use of and adherence to the WHO AWaRe classification of antibiotics. Healthcare workers, such as physicians, pharmacists, nurses, dental surgeons, and clinical officers, must be educated about the framework because they are the main prescribers and dispensers of antibiotics both in public and private healthcare facilities.Additionally, it is important to explore the potential role of global collaborations and partnerships in promoting AMS. Implementing and sustaining the WHO AWaRe classification of antibiotics may require additional resources such as human and funding needs. Thus, we urge countries to collaborate with other countries and organizations and learn from other nations that have successfully implemented the AWaRe framework of antibiotics.It is also important to address the social determinants of health, such as poverty, education, and access to healthcare, in addressing AMR and promoting the prudent use of antibiotics. This attention to social issues may help reduce the burden of infections and noncommunicable diseases, leading to a reduction in the use of antibiotics.Furthermore, the One Health approach should be promoted when tackling AMR as guided by the Global Action Plan (GAP) on AMR. This approach ensures that AMR is addressed across all sectors, including human, animal, agriculture, the environment and all its ecological systems. Therefore, professionals from the human, animal, agriculture, and environmental sectors must collaborate for the common good of tackling AMR. Furthermore, management of infections across sectors should be conducted according to the WHO AWaRe framework of antibiotics.AMS programs need to be extended from centralized, larger healthcare facilities to smaller healthcare facilities. With many patients seen in smaller healthcare facilities like clinics and first-level hospitals, the risks of misusing and overusing antibiotics are high and require the adoption of the AWaRe framework of antibiotics in such settings. A key component in the development and sustainability of these programs needs a strong research and development framework that will respond to the needs of individual countries. This will ensure that the programs evolve and are current.Political will from governments is critical in establishing, implementing, and sustaining healthcare programs such as AMS. The need for healthcare workers to adhere to the WHO AWaRe framework of antibiotics requires political will because policies are developed and implemented by authorities. Successful implementation of the AWaRe framework of antibiotics may require many political players, such as those in leadership politics, bureaucratic politics, interest group politics, beneficiary politics, budget politics, and external actor politics.To tackle these challenges and further the progress in the future, we recommend the following measures: In all studies, ceftriaxone, a Watch antibiotic, was being overused (Table In Zambia, there are gaps and lack of knowledge among healthcare workers on the use the AWaRe tool because studies have reported high prescribing of Watch antibiotics.ed Table . This coIn conclusion, the WHO AWaRe classification of antibiotics provides a valuable framework for monitoring AMU and addressing AMR. Nevertheless, there is still much work to be done to ensure the widespread implementation of this classification framework and its effectiveness in reducing AMU and AMR. By addressing the challenges and adopting a multifaceted approach, we can make progress in the fight against AMR.


We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity, and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, ‘off-the-shelf’ tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [ The mesocorticolimbic dopamine system plays a key role in a range of cognitive functions, including cognitive control processes, such as working memory , attenti18F]fluoro-l-m-tyrosine ([18F]-FMT) PET imaging, and striatal dopamine release, estimated with [11C]-raclopride PET imaging  in humans indicates that working memory capacity is positively associated with both striatal dopamine synthesis capacity, assessed with 6--FDOPA PET imaging in a much larger sample of healthy volunteers (N = 94) to establish the predictive link with three commonly used putative proxy measures of striatal dopamine: working memory capacity, trait impulsivity, and sEBR. In addition, we explored the potential correlation between striatal dopamine synthesis capacity and a questionnaire index of subjective reward sensitivity, a process that is intimately linked with dopamine function  for our three striatal ROIs  of the null hypotheses that dopamine synthesis capacity values and the different trait measures are not positively correlated (H0) versus the alternative hypotheses that they are positively correlated . For sEBR, the analysis revealed moderate evidence for the null hypothesis of no positive correlation with dopamine synthesis capacity in the caudate nucleus and putamen (BF01 ≈ 6), but only weak, inconclusive evidence in the nucleus accumbens (BF01 ≈ 2). The data for the correlation between subjective reward sensitivity and dopamine synthesis capacity were equally likely under H0 or H1 (BF01 ≈ 1), indicating that the Bayesian analysis was inconclusive about the evidence for the existence of a positive correlation.Because of the lack of statistically significant correlations, we sought to quantify the evidence in our data for the absence of correlations between the trait measures and dopamine synthesis capacity using a Bayesian analysis of the associations. We calculated the Bayes factors , trait impulsivity (BF01 ≈ 6), or sEBR (BF01 ≈ 4–8). For subjective reward sensitivity, the relative evidence for the null hypothesis remained inconclusive (BF01 ≈ 2).We also assessed Bayes factors quantifying the relative evidence for the non-directional hypotheses of no correlation (H0) versus a (positive or negative) correlation (H1) between the trait measures and dopamine synthesis capacity . This reOf note, previous studies that used smaller sample sizes typically reported much larger correlation coefficients than those observed in this study . To illuα = 0.05), using G*Power  and permutation testing, to estimate to what extent each of the trait measures could predict striatal dopamine synthesis capacity, using simple linear regression models (see ‘Methods’ for details). We indexed predictive accuracy with the out-of-sample coefficient of determination (R2) and provide the root mean square error (RMSE) as an additional performance measure  function with PET measurements. While such links are supported by evidence from patient or genetic studies and experimental animals, the interpretation of these behavioural indices as proxies for striatal dopamine levels requires robust direct evidence in humans for the existence of at least a strong correlation. The absence of such correlations observed here provides a strong cautionary message for future studies that may be tempted to use these relatively simple behavioural indices of working memory capacity, trait impulsivity, sEBR, or subjective reward sensitivity as a proxy for striatal dopamine synthesis capacity.https://www.proefbunny.nl/; 5%; a participant recruiting website that is not available anymore), and advertisement flyers around Nijmegen or word of mouth (together 18%). Prerequisites for participation were age between 18 and 45 y, Dutch as native language, and right-handedness. Before admission to the study, participants were extensively screened for adverse medical and psychiatric conditions. Exclusion criteria included any current or previous psychiatric or neurological disorders, having a first-degree family member with a current or previous psychiatric disorder, clinically significant hepatic, cardiac, renal, metabolic, or pulmonary disease, epilepsy, hyper- or hypotension, habitual smoking or drug use, pregnancy, and MRI contraindications, such as unremovable metal parts in the body or claustrophobia.This study is part of a larger project  for whicSix participants dropped out before completion of the study because of discomfort in the MRI or PET scanner (N = 4), personal reasons (N = 1), or technical failure of the PET scanner (N = 1). Therefore, PET data were available for a total of N = 94 participants . For a detailed description of the testing sessions and tasks and measures collected, see Data were collected as part of a large PET, pharmaco-fMRI study on the effects of methylphenidate and sulpiride on brain and cognition, employing a within-subject, placebo-controlled, double-blind cross-over design . The mean time difference between the intake session and PET session was 90.16 d, standard error of mean = 3.13 d.On the intake session, a whole-brain structural image was acquired to use for within-subject registration with the PET images, using a T1-weighted magnetization prepared, rapid-acquisition gradient echo sequence . The MRI experiment was performed on a 3T Siemens Magnetom Skyra MRI scanner at the Donders Institute using a 32-channel head coil.18F]-FDOPA, which was synthesized at Radboud Translational Medicine BV (RTM BV) in Nijmegen. The tracer is a substrate for aromatic amino acid decarboxylase, the enzyme that converts DOPA into dopamine. The rate of conversion of [18F]-FDOPA into dopamine provides an estimate of dopamine synthesis capacity. It is a stable measure with good test–retest reliability (intraclass correlation coefficients range from about 0.7–0.94 in the striatum) even after a 2-yr time interval between acquisitions of scans , respectively, thereby increasing signal-to-noise ratio in the brain  at the Department of Medical Imaging of the Radboud University Medical Center. We used the well-validated radiotracer [of scans . 50 min he brain .18F]-FDOPA tracer was administered (approximately 185 MBq) via a bolus injection in the antecubital vein and the PET scan was started. Dynamic PET data  were acquired over 89 min and divided into 24 frames . Data were reconstructed with weighted attenuation correction and time-of-flight recovery, scatter corrected, and smoothed with a 3 mm full-width-at-half-maximum (FWHM) kernel.The procedure started with a low-dose CT scan to use for attenuation correction of the PET images. Then, the -FDOPA PET measurements of striatal dopamine synthesis capacity and a series of measures, including behavioral readouts, proposed to index dopamine function. The frequentist and Bayesian analyses together provide compelling evidence for an absence of any relationship between striatal dopamine synthesis capacity and external measures, questioning the interpretation of studies using such measures to index dopamine function. These findings will not only be of great interest to cognitive neuroscientists but also inform future studies of neuropsychiatric diseases. public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Our editorial process produces two outputs: (i) Decision letter after peer review:eLife. Your article has been reviewed by 2 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Christian Büchel as the Senior Editor. The following individuals involved in the review of your submission have agreed to reveal their identity: Mitul Mehta (Reviewer #1); David Zald (Reviewer #2).Thank you for submitting your article "Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity" for consideration by The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.Essential revisions:1) The study is seated in the empirical use of 'baseline' assessments and the theoretical and mechanistic plausibility of this position is only briefly highlighted in the introduction. The use of the terms 'linked' and 'link' are handy but can hide a more complex relationship that may be non-linear. It would be great if you could expand a little here on the precise relationships which have been suggested and described previously.2) The study is focused on striatal dopamine assessment whereas in the introduction subcortical and cortical dopamine is discussed. A much clearer separation might be helpful here, arguably dismissing the cortical element briefly and leaving this for the discussion, with a more critically evaluative assessment of the subcortical processes predicted to be mediated by dopamine transmission. In addition, the 'functional' subdivisions and their importance should be introduced.3) Please provide more information on the group included. Multiple sources of recruitment are described. Please indicate the number included from each source. Please include a table of participant characteristics. Any measure of the social status of participants , and ethnicity, would also be appreciated.4) Please indicate the n for each of the DA synthesis studies mentioned in lines 107-113 (p. 6). Similarly in the discussion (lines 331-334), it is reasonable for a reader to wonder what the sample size was for studies of the value of cognitive effort , with the impact of average reward value on response vigor  and with dopaminergic drug-related changes in prediction error-related BOLD signal in the striatum. If these are of similarly small samples as the working memory studies it would suggest as much suspicion should be applied to these other findings.5) Please discuss additional reasons why the presented index of dopamine synthesis might not prove informative. A discussion of how dopamine synthesis capacity relates to other dopaminergic parameters such as dopamine release warrants discussion given that the core hypothesis driving the study is that individual differences in synthesis capacity within the normal range are functionally impactful. If, for instance, dopamine synthesis capacity is detached from actual amounts of dopamine released, then it may be less surprising that it is not showing relations to constructs that are impacted by dopamine within a healthy population.6) It is very much appreciated that the authors have provided information on the predictive power of the observed effect sizes. Given a negative finding, it may also be useful to articulate what statistical power the study had in the first place in relation to possible effect sizes (Cohen's D). Similarly, it would be useful to articulate the test-retest reliability of synthesis capacity metrics, since unreliability would naturally lower the ability to observe correlates of synthesis capacity, and thus alter statistical power.Reviewer #1 (Recommendations for the authors):I only have a small number of recommendations for the authors.- The study is seated in the empirical use of 'baseline' assessments and the theoretical and mechanistic plausibility of this position is only briefly highlighted in the introduction. The use of the terms 'linked' and 'link' are handy but can hide a more complex relationship that may be non-linear. It is worth expanding a little here on the precise relationships which have been theorised and described previously. This speaks directly to what the authors are attempting to model.- The study is focussed on striatal dopamine assessment whereas in the introduction subcortical and cortical dopamine is discussed. The authors should attempt a much clearer separation here, arguably dismissing the cortical element briefly and leaving this for the discussion, with a more critically evaluative assessment of the subcortical processes predicted to be mediated by dopamine transmission. In addition, the 'functional' subdivisions and their importance need to be introduced.- The authors do not provide sufficient information on the group included. Multiple sources of recruitment are described. Please indicate the number included from each source. Please include a table of participant characteristics. If you have any measure of the social status of participants , and ethnicity, please also include this.Congratulations on this work.Reviewer #2 (Recommendations for the authors):Because the methods are sound and the paper is well-written, my comments are relatively limited. Nevertheless, there are a few things that might further improve the paper.1) Since a major argument for this study is that many of the existing papers on the topic have small samples relative to the current one, on page 6 it would be useful to indicate the n for each of the DA synthesis studies mentioned in lines 107-113. Similarly in the discussion (lines 331-334), it is reasonable for a reader to wonder what the sample size was for studies of the value of cognitive effort , with the impact of average reward value on response vigor  and with dopaminergic drug-related changes in prediction error-related BOLD signal in the striatum, since if these are of similarly small samples as the working memory studies it would suggest as much suspicion should be applied to these other findings.2) The authors may wish to discuss if there are additional reasons why their index of dopamine synthesis might not prove informative. They note in the discussion that F-Dopa is subject to dopamine turnover. This is true, and of course, could potentially be measured with the proper methodology, so it is probably worth an explanation of why they do not specifically model turnover. The issue of low signal-to-noise ratios for their FDOPA measures that they raise in the discussion seems a less likely culprit and hardly seems worth describing. However, a consideration of how dopamine synthesis capacity relates to other dopaminergic parameters such as dopamine release warrants discussion given that the core hypothesis driving the study is that individual differences in synthesis capacity within the normal range are functionally impactful. If, for instance, dopamine synthesis capacity is detached from actual amounts of dopamine released, then it may be less surprising that it is not showing relations to constructs that are impacted by dopamine within a healthy population.3) I appreciate that the authors have provided information on the predictive power of the observed effect sizes. Given a negative finding, it may also be useful to also articulate what statistical power the study had in the first place in relation to a small or moderate effect size (Cohen's D). Similarly, it would be useful to articulate the test-retest reliability of synthesis capacity metrics, since unreliability would naturally lower the ability to observe correlates of synthesis capacity, and thus alter statistical power. Essential revisions:1) The study is seated in the empirical use of 'baseline' assessments and the theoretical and mechanistic plausibility of this position is only briefly highlighted in the introduction. The use of the terms 'linked' and 'link' are handy but can hide a more complex relationship that may be non-linear. It would be great if you could expand a little here on the precise relationships which have been suggested and described previously.We have now expanded the precise observations of previous studies regarding the relationships between the trait variables and striatal dopamine. With this, we have replaced instances of our use of the term ‘link’ with more explicit statements like ‘positive correlation’.More specifically, for working memory we explain that greater caudate nucleus dopamine synthesis capacity and release has been associated with greater working memory capacity and that this prior observation pertained in particular to the updating of working memory. For impulsivity, we now open the paragraph with the key findings of positive correlations between impulsivity and human PET indices of dopamine function, rather than starting with another instance of the word ‘link’. In addition, we have moved the two animal study references more appropriately to the counter-evidence section and decided to include here some compelling evidence from studies on Parkinson’s disease. For sEBR, we have rephrased the paragraph, keeping the explicit mention of positive correlation findings, and have added the clause that the exact mechanism by which sEBR and striatal dopamine activity are connected remains unclear.2) The study is focused on striatal dopamine assessment whereas in the introduction subcortical and cortical dopamine is discussed. A much clearer separation might be helpful here, arguably dismissing the cortical element briefly and leaving this for the discussion, with a more critically evaluative assessment of the subcortical processes predicted to be mediated by dopamine transmission. In addition, the 'functional' subdivisions and their importance should be introduced.The introduction was in fact already focused on subcortical dopamine. We have now made this explicit by rewriting the opening paragraph and including a sentence stating our focus on striatal dopamine:“The mesocorticolimbic dopamine system plays a key role in a range of cognitive functions, including cognitive control processes, such as working memory , attention , and flexible behaviour . While such processes have classically been associated with prefrontal dopamine function, they also critically depend on the basal ganglia and dopamine activity in the striatum . Accordingly, individual differences in striatal dopamine function have been associated with various behavioural and physiological trait characteristics, including working memory capacity, impulsivity, and spontaneous eye-blink rate (sEBR). We focused on striatal dopamine and investigated the relationships suggested by prior literature between these trait characteristics and individual variation in striatal dopamine function.”In addition, we suspect that phrasings like “dopamine function” might be taken to mean dopamine processes in general, including cortical dopamine, which might have made the focus on specifically striatal dopamine less clear. Therefore, we have rephrased those instances to “striatal dopamine function”.To better introduce the relevance of striatal subdivisions, as well as for a more precise discussion of previous findings, we have now also referred to the specific striatal locus of the observed relationships with dopamine within the striatum. At the end of the introduction we have added a section explaining the rationale and origin of our striatal ROIs:“The subcortical dopamine system is not a single entity and the striatum is a functionally heterogeneous structure with a distinct connectionist anatomy with the cortex, involving a functional gradient in the connections between the cortex and ventral striatum (primarily nucleus accumbens), dorsolateral striatum (putamen), and dorsomedial striatum . To take this heterogeneity into account, we performed our analyses in three striatal regions of interest (ROIs), defined using a parcellation based on intra-striatal functional connectivity in an independent sample . The ROIs approximately matched the anatomical subdivision of the striatum into caudate nucleus, putamen, and nucleus accumbens . We tested the hypotheses that the trait measures were positively correlated with, and predictive of, estimates of striatal dopamine synthesis capacity in these striatal ROIs.”3) Please provide more information on the group included. Multiple sources of recruitment are described. Please indicate the number included from each source. Please include a table of participant characteristics. Any measure of the social status of participants , and ethnicity, would also be appreciated.18% of the participants approached us after seeing the advertisement on flyers or heard about the study via word of mouth, 5% found us on proefbunny.nl, the rest were recruited via the university’s electronic participant database. We have now added this information to the text in the Methods section. We have also added a table (Supplementary Table 1 in Supplementary File 1) with participants characteristics specifying the already provided information on sex and age distribution, and we also added education level and current occupation. However, we did not collect information on income or ethnicity.4) Please indicate the n for each of the DA synthesis studies mentioned in lines 107-113 (p. 6). Similarly in the discussion (lines 331-334), it is reasonable for a reader to wonder what the sample size was for studies of the value of cognitive effort , with the impact of average reward value on response vigor  and with dopaminergic drug-related changes in prediction error-related BOLD signal in the striatum. If these are of similarly small samples as the working memory studies it would suggest as much suspicion should be applied to these other findings.We have added the N for each of these studies in the introduction and discussion.In the introduction: “.”18F]-FDOPA uptake in the striatum was associated positively with the value of cognitive effort , with the impact of average reward value on response vigour  and with dopaminergic drug-related changes in prediction error-related BOLD signal in the striatum . The implication of this body of work is that more sophisticated and quantitative indices of value-based learning, motivation, and even daily logs of participants’ social activity on their smartphone  might be better proxy measures of striatal dopamine synthesis capacity than the simple trait measures reported here.”In the discussion: “More specifically, -DOPA PET imaging, was found to correlate negatively with dopamine D2/3-receptor availability, as indexed with [11C]raclopride , but no relationship was observed in other studies . Conversely, another recent study (N=40) that used [18F]-FMT found striatal dopamine synthesis capacity to be positively correlated with striatal dopamine D2/3-receptor availability but not with striatal dopamine release . If dopamine synthesis capacity is detached from actual amounts of dopamine released, then it may be less surprising that it does not show direct correlations with constructs that are impacted by dopamine within a healthy population. While dopamine synthesis capacity has been associated with a host of cognitive functions and tasks, understanding the mechanisms behind these effects will ultimately require a deeper understanding of how the various aspects of the dopamine system interact.”“On a more fundamental level, future work is needed to clarify how the various PET imaging measures that index different aspects of dopamine system activity relate to each another. Investigating multiple aspects of the dopamine system is challenging, as it requires different radiotracers and separate PET scans. Therefore they are rarely studied within the same individuals. Nevertheless, a few small-scale studies have been conducted. In one such study, striatal dopamine synthesis capacity, as indexed by L-[B-18F]-FDOPA versus [18F]-FMT to index dopamine synthesis capacity and added an explanation of why we do not model dopamine turnover, even though [18F]-FDOPA is subject to dopamine turnover: “… the impact of dopamine turnover on the signal is only significant when longer scan times are used than we have presently used .”We have also rewritten the paragraph on the use of [6) It is very much appreciated that the authors have provided information on the predictive power of the observed effect sizes. Given a negative finding, it may also be useful to articulate what statistical power the study had in the first place in relation to possible effect sizes (Cohen's D). Similarly, it would be useful to articulate the test-retest reliability of synthesis capacity metrics, since unreliability would naturally lower the ability to observe correlates of synthesis capacity, and thus alter statistical power.We thank the reviewers for this suggestion. We have added these details to the end of the first Results section in the following paragraph:“To further inspect the impact of sample size and power, we calculated the effect size that we would be able to reliably detect with the one-sided Pearson correlation tests at acceptable levels of statistical power in our sample of N=94 , using G*Power . With power of 0.9 we would be able to reliably detect correlations with a coefficient of ρ = 0.29 (which corresponds to a sample Cohen’s d of 0.61). For a power of 0.8 the coefficients would have to be ρ = 0.25 (sample Cohen’s d = 0.52). The hypothesized correlations between striatal dopamine synthesis capacity and working memory capacity, impulsivity, and sEBR were all much weaker than that in the current sample: all but one correlation with ρ < 0.1. For an effect size of ρ = 0.1 and power of 0.8 a sample size of N=614 would have been needed (N=850 for power of 0.9).”We also slightly rewrote the second paragraph of the Discussion to add a short discussion of these numbers, also including an acknowledgement of the potential existence of true correlations undetected by our sample:“The current work provides a direct assessment using human brain PET imaging of the relationships between these trait measures and striatal dopamine synthesis capacity on a much larger scale than previous work. Despite this, the strength of the correlations that we observed was far below the threshold of what we could reliably detect with an acceptable level of statistical power, should a true correlation exist. However, our sample size was more than adequate to reliably detect effects of magnitudes that were previously observed, as the previous smaller-scale studies reported coefficients of 0.6 or higher for the correlations between dopamine synthesis capacity and working memory capacity , impulsive behaviour , and sEBR . Instead, our results corroborate findings of a lack of significant correlations between striatal dopamine synthesis capacity and working memory capacity , self-reported trait impulsivity , and sEBR . Moreover, our Bayesian analyses demonstrated not just a lack of evidence for the presence of correlations, but also the presence of evidence for the absence of correlations. Nevertheless, genuine correlations may exist, undetected by the current study, for example because our relatively young and highly educated participant sample may not be representative enough of the general population. While uncovering such potential relationships would be relevant for our understanding of the links between striatal dopamine and trait characteristics, it seems unlikely those correlations would be strong enough to validate use of the trait measures as approximations of striatal dopamine function if they were not detected with the current participant sample.”Finally, we have included specific previous findings on the test-retest reliability of FDOPA in the methods section :“It is a stable measure with good test-retest reliability (intraclass correlation coefficients range from about 0.7 to 0.94 in the striatum) even after a 2-year time interval between acquisitions of scans .”


The Src family kinases (SFKs) play indispensable roles in multiple signal transduction pathways. SFKs are activated by autophosphorylation (human Src: Tyr419) in the trans-molecular mode and abnormal SFK activation often leads to cancer and other diseases. C-terminal Src kinase (CSK) phosphorylates SFKs at their C-terminal tyrosine and inactivates SFKs. CSK homologous kinase (CHK) shares same SH2-SH3-SH1 structure and 53% amino acid identity with CSK. There is evidence suggesting CSK may be a dominant player in contrast to an auxiliary role of CHK in certain tissue or cells . A uniquRegulation and Dysfunction of CSK and CHK” consists of 5 review articles contributed by 17 authors in the fields of CSK and CHK. The Research Topic collects different research aspects including molecular structures of CSK and CHK, major signaling pathways such as apoptosis and integrin signaling in cancers affected by CSK and CHK and comprehensive overviews of CSK and CHK highlighting their regulation, molecular targets and functional roles.This Research Topic “Sun et al. have reviewed the structure-function relationship of CSK and CHK with an emphasis on catalysis, substrate recognition, and the interactions between domain and domain/key phosphorylation site. This review not only summarizes the current understanding of CSK/CHK enzymology but also sheds light on the general mechanism of regulation and catalysis of protein tyrosine kinases. This will be helpful in bolstering protein phosphorylation as a key methodology for the development of anti-cancer therapeutics.In addition to the general features of phosphorylating substrates, CSK and CHK have unique structural motifs determining their substrate specificity and enzymatic efficiencies. CSK and CHK are also subject to regulation by different regulators and/or post-translational modifications. To understand the roles of CSK and CHK and their functional differences in inactivating SFKs, Fortner et al. provide an overview of the apoptosis mechanisms induced by CSK. CSK suppresses MAPK, STAT3 and PI3K signaling respectively, all of which are involved in promoting cell survival through upregulation of pro-survival molecules such as Myc and Bcl-2, and downregulation of pro-apoptotic molecules such as Bim and FOXO. The Src-dependent pro-apoptotic effect of CSK has been further confirmed by a novel Src inhibitor (Apoptosis, a form of programmed cell death, plays a key role in multiple biological processes . The extnhibitor . Therefonhibitor .Maldonado et al. reviewed how CSK regulates integrin signaling through SFKs. These authors focuse on the crucial role of integrins in sensing and responding to mechanical changes in the surrounding environment by emphasizing their mechanosensing and mechanotransduction functions (As a part of the focal adhesion, integrins can sense and send extracellular signals to the cytosol to regulate different processes such as cell migration, invasion, proliferation, and survival. Therefore, integrins play crucial roles in cancer progression and metastasis. unctions . They haZhu et al. have provided overviews of how CSK and CHK are regulated, their molecular targets, and novel biological functions involved. Among many interesting new features of CSK/CHK, it is noteworthy that CHK not only phosphorylates SFKs to inactivate them, CHK also serves as a non-enzymatic inhibitor for many Src family members; Unlike CSK which is expressed ubiquitously, expression of CHK is limited in several tissues; Novel targets of CHK including SHPS-1, paxillin, and synuclein have been identified. Therefore, CHK may complement or strengthen CSK’s effect in inhibiting SFKs in certain tissues. CHK silencing due to DNA methylation (Besides the above specific Research Topic focuses, hylation  in certahylation  and novehylation , and theIn conclusion, the “Regulation and Dysfunction of CSK and CHK” Research Topic highlights the recent discoveries of molecular structure, targets, regulation and biological function of CSK/CHK. This not only furthered our understanding in basic research but also paved the way for the development of new therapies and diagnosis.


Digital technology coupled with the quarantines caused by the COVID-19 pandemic has made working from anywhere (WFA)—a modern form of remote working—a widespread phenomenon. Given that WFA brings new career challenges to and engenders paradoxes of knowledge exchange among employees, this research aims to examine how the interactions of remote work time (RWT), knowledge sharing (KS), and knowledge hiding (KH) affect career development (CD) from a culturally grounded paradoxical framing of yin–yang harmonizing. The data were collected from Chinese manufacturing employees, and a moderated hierarchical regression analysis was used to examine the hypotheses. The results show an inverted U-shaped relationship between RWT and CD. The interaction of KS and KH is significantly related to CD, and the inverted U-shaped RWT–CD relationship is moderated by the interaction term, in which RWT exerts the most substantial positive impact on CD when KS is high and KH is low. This study offers valuable implications for coping with perplexing employment relationships and increasing career challenges in volatile work environments. The primary originality is to adopt a novel cognitive frame of yin–yang harmonizing to examine the nonlinear effect of remote working and the symbiotic impact of KS and KH on CD, which not only enriches the understanding of flexible work arrangements in the digital economy but also provides novel insights into the interconnectedness of KS and KH and their interacting effects on HRM-related outcomes. The rapid advancement in information and communication technology (ICT), coupled with the mandated quarantines caused by the COVID-19 pandemic, has compelled numerous employees across the globe to engage in part- or full-time remote work. Thus, working from anywhere  to address the tensions of KS and KH in the ICT-enabled WFA context, in which HRM systems must syncretize office, remote, and a variety of mixed job designs. This advances the traditional binary analysis of on-site and online work to a new, contemporary understanding of the dynamics of work arrangements in the digital economy. Related to this point, our research also adds value to the knowledge management (KM) literature because we provide novel insights into the interconnectedness and synergic mechanisms of employee KS and KH in HRM-related outcomes. Practically, our findings offer valuable implications for global managers and workers in coping with perplexing employment relationships and increasing career challenges in a digitalized, volatile work environment.The present paper is structured as follows: The section “Theoretical foundation” provides the theoretical foundations for yin–yang harmonizing, paradox framing, and KS and KH in CD. Section “Methodology” describes the methodology used, section “Results” explores the results, and section “Discussion” provides the conclusion, managerial implications, limitations, and future research directions.paradoxical framing are deeply rooted in ancient Western and Eastern cultures, as characterized by Socrates’ dialectical approach and Chinese yin–yang harmonizing dialectics  and Compendium and Materia Medica (本草纲目), yin and yang elements were used as metaphors for Chinese herbs and human organs to decipher their attributes and prescribe treatments for disease. In contrast, the latter favors the use of different metonymic and metaphorical models to map different paradoxes.The philosophical origins of ics Lai, . Yin–yanics Lai, . The onlics Lai, , 2021c. a persistent symbiosis of multiple opposing yet interdependent elements that can be adopted as a cognitive approach to social science sense-making , CD refers to “a mechanism of ensuring the match between the needs of both individual and the organization while developing individuals’ capacity to exercise control over the quality and nature of their career conditions”  indicates the coexistence of two opposing cognitions as yin and yang elements of a whole that could enable individuals to develop or inhibit their careers, depending on which element is dominant. In other words, RWT can be regarded as a motivator or demotivator for individuals to achieve the set goals of their careers.H1. The relationship between RWT and CD is curvilinear (inverse U-shaped), with the highest CD performed at an intermediate degree of RWT.The impromptu, ever-changing restrictions caused by the evolving pandemic have detached numerous workers from traditional fixed places of work. In the beginning, workers may feel very motivated when they perceive greater flexibility and autonomy in terms of work time and space. However, after a certain period, individuals may also feel demotivated because they are disassociated with and disengaged from their previous social relationships constructed in the office setting. This implies that, when RWT is lower or higher, individuals are very likely to be affected by initial disruptions or the prolonged effects of remote work fatigue. Following this logic, we assume a curvilinear relationship between RWT and employee CD:The definition of knowledge has deep historical and philosophical roots. Many philosophers in the West and East, including Plato, Aristotle, Confucius, and Laozi, have put forward various conceptions covering a wide range of doxastic notions, such as belief, ethics, esthetics, and intellectual virtues  department helped distribute the online questionnaires. The questionnaires were distributed among workers in the sample firms by applying simple random sampling techniques —to distribute the questionnaires to participating workers via WeChat. We also provided clear guidelines for how the respondents should fill out the questionnaire and how their anonymity was protected. A WeChat account/ID was offered to answer the participants’ inquiries.In terms of carrying out the formal online survey, we employed a reliable online service provider in China—Sojump (To reduce the likelihood of common method variance (CMV), we collected data at two time points to meet the conditions of the time lag research design .Given that Chinese employees may not be able to truthfully report their behavior, we used a peer rating rather than a self-report measure Chin, . We adopα = 0.935).As mentioned above, we also adjusted Connelly et al.’s  scale toα = 0.911).Because of the lack of mature scales for CD, we referred to Yoon et al.’s  suggestiWe controlled for age (in years), gender , marriage , type of firm , and firm size .α for all measures were above 0.70, indicating acceptable reliability. The values of construct reliability (CR) and average variance extracted (AVE) were above the acceptable values of 0.7 and 0.5, respectively . According to Podsakoff et al. , the new model with the latent CMV factor still fit the data well  and did not show any significant differences . Hence, CMV is unlikely to be a major threat.We conducted the CFA marker method . In Model 3, the square term of RWT was added. The results revealed that the square term of RWT had a significantly negative relationship with CD , indicating that RWT had an inverse U-shaped relationship with CD; hypothesis 1 was supported. Model 4 indicated that KS was positively related to CD , while KH was negatively related to CD . Model 5 added the interaction term of KS and KH, and the results showed that the interaction term of KS and KH was positively related to CD ; hypothesis 2 was supported ; hypothesis 3 was supported.To verify the relationship between the three-way interaction terms of RWT, KS, and KH in the employees’ CD, Model 6 through Model 10 conducted hierarchical regressions. According to Model 10, the U-shaped relationship between RWT and CD was moderated by the joint effect of KS and KH (2 × KS × KH); the interaction term of KS and KH has the strongest moderating effect on the relationship between RWT and CD when KS is at the highest level and KH at the lowest level. The plot further confirmed hypothesis 4.In addition, referring to Dawson , we alsoThe empirical analysis showed that all four hypotheses were fully supported. A curvilinear (inverted U-shaped) relationship exists between RWT and CD, where the highest CD is found at the intermediate degree of RWT. The interaction of KS and KH is significantly related to CD. Moreover, the relationship between RWT and CD is moderated by the interaction of KS and KH; thus, the interacting term of KS and KH has the strongest positive moderating effect on the relationship between RWT and CD when KS is at the highest level and KH is at the lowest level. In terms of the control variables, the results suggest a positive association between employees’ age (older), gender , and type of firm (state-owned company), as well as a negative association between employees’ marriage status (nonmarried) and their CD. Overall, the current research enriches our understanding of a new form of job design—WFA—by linking it to the intersection of the career and KM domains through an unorthodox paradoxical lens. We elaborate on the main contributions below.First, based on the cognitive frame of yin–yang harmonizing, we contribute to the HRM literature by examining the nonlinear effect of remote working and symbiotic impact of KS and KH on CD. The results highlight the emergence and existence of a variety of micro-level paradoxes in terms of developing careers during the COVID-19 pandemic. Specifically, the inverted U-shaped relationship between RWT and CD partly echoes the autonomy control view , KS and KH are actually not opposing notions, but two independent yet interconnected concepts in social interactions (Connelly et al., Related to the points above, we have adopted the paradoxical cognition of yin–yang harmonizing to investigate the synergistic interaction of KS and KH, thus advancing the traditional binary analysis of on-site and remote works to an unorthodox, contemporary understanding of flexible and dynamic work arrangements in the digital economy. To a certain extent, these initial findings can inspire scholars to dig deeper into this very important yet underexplored area of inquiry in the “new normal.”The findings of the present study offer valuable implications for global managers and workers in coping with bewildering work relationships and growing career challenges in a digitized and volatile workplace.First, the present study highlights that remote work acts as a nonlinear relationship with respect to the CD of employees in need of support and cooperation. This means that managers should build a hybrid work community based on shared values, both physically and digitally, to foster support and cohesion within the team. Targeting employees who do not need access to hardware that is difficult to move or whose job duties have little or no coordination with coworkers, companies could eye policies that balance the amount of time employees work at home and in the office during the week, which may be more ideal for companies and employees than full time in the office or full time at home.Second, the present study confirmed that flexibility in places and times of work increases the personal satisfaction of employees who can organize and manage their day according to their needs. Therefore, even if there is indirect environmental interference while employees work remotely, work flexibility and ICT can still favor the exchange of knowledge through the interaction between KS and KH in proportion to the time spent working remotely. In accordance with the view of autonomy control (Bathini and Kandathil, However, the study also revealed that WFA is likely to reduce KS and increase KH under conditions of low physical embodiment. Therefore, the results suggest that managers should take various measures to enhance the connection and cohesion of employees and teams, as well as to deal with the problem of “information islands” in the WFA setting. For example, instead of simple voice or chat messages, employees should be encouraged to connect with their workmates in online meetings with their cameras on because such face-to-face meetings increase physical embodiment and build trust and a sense of teamwork. Furthermore, managers should adopt dynamic organizational strategies capable of spreading the work culture based on the results. Several studies have examined the propensity of distance workers to be promoted, despite the career development they have provided to the organization because they are believed to be underutilized. This implies that managers should adopt reward systems based on the recognition of the performance achieved by remote workers.Despite the originality of this contribution to the HRM literature, the present study has some limitations that pave the way for new avenues of research. First, the current research has identified the paradoxical mechanisms of RWT–KS–KH interactions in CD in a novel, ICT-enabled WFA context. However, given that knowledge exchange is context specific (Chin et al., a multitiered, smart infrastructure of employee knowledge exchange, where KS and KH also go beyond the original work and job premises and time. However, the impact on HRM-related outcomes remains somewhat puzzling. For instance, as shown by some empirical surveys, employees hailed this shift as surprisingly productive in the beginning, but after a while, they became frustrated with the difficulties of converging on the meaning of complex information through virtual meetings and the lack of division between their work and private lives. Thus, we believe that, over time, coupled with the rapid advancement of ICT, the WFA model may continuously evolve into more configurations in the contemporary career landscape. It entails the building of more sophisticated knowledge networks that allow for kaleidoscopic knowledge exchange activities and polychronic knowledge creation among employees with diverse forms of employment.Distinct from typical dehumanized remote working conditions, the modern ICT-enabled WFA context transcends the traditional spatiotemporal boundaries of work structures and characterizes