The controlled synthesis and surface engineering of inorganic nanomaterials hold great promise for the design of functional nanoparticles for a variety of applications, such as drug delivery, bioimaging, biosensing, and catalysis. However, owing to the inadequate and unstable mass/heat transfer, conventional bulk synthesis methods often result in the poor uniformity of nanoparticles, in terms of microstructure, morphology, and physicochemical properties. Microfluidic technologies with advantageous features, such as precise fluid control and rapid microscale mixing, have gathered the widespread attention of the research community for the fabrication and engineering of nanomaterials, which effectively overcome the aforementioned shortcomings of conventional bench methods. This review summarizes the latest research progress in the microfluidic fabrication of different types of inorganic nanomaterials, including silica, metal, metal oxides, metal organic frameworks, and quantum dots. In addition, the surface modification strategies of nonporous and porous inorganic nanoparticles based on microfluidic method are also introduced. We also provide the readers with an insight on the red blocks and prospects of microfluidic approaches, for designing the next generation of inorganic nanomaterials. Inorganic nanoparticles show prospect for an array of fields, such as imaging , optoeleBy taking into consideration the physical state, the conventional bulk synthesis of inorganic nanomaterials can be classified into three methods: gas phase, liquid phase, and solid phase. Due to the lack of the accurate control of the mixing and separation process of reactants, the nucleation, growth, and agglomeration processes occur simultaneously in the conventional bulk synthesis method. Consequently, the structural, physicochemical, and functional properties of inorganic nanoparticles vary from batch-to-batch and nanostructures with the desired structure and features cannot be precisely achieved . In addi−9 to 10−8 L) . S. S2O3-Si synergy b 87]..2O3-SiO22@TiO2 hybrids, by using a one-step emulsification process in a coaxial microfluidic system  were used as protective and reducing agents, respectively. The gold nanosheets with thickness ranging from less than 1 to several nanometers could be obtained by adjusting the flow rate.Gold nanoparticles are widely used in various fields, such as disease diagnostics ,101,102,Multi-functional gold nanoparticles can also be fabricated in a microfluidic device. Functionalized gold nanoparticles have been synthesized by Santamaria and coworkers . Differe2), hydrazine hydrate, and sodium hydroxide in an oil bath-heated capillary-type mixer, to obtain crystalline nickel nanoparticles with an average particle size of 80 nm and particles size distribution in the range of 60–114 nm , oleylamine, trioctylphosphine, and 1-octadecene precursors could nucleate rapidly after entering into the microfluidic chamber at 220 °C. The average diameter of nickel nanoparticles and the yield were found to be 11.1 ± 3.1 nm and 62%, respectively. Moreover, it was estimated that more than 27 g of nickel nanoparticles could be produced in one day.High-quality and scale-up production of nickel nanoparticles is critical to the industrial development, because these nanoparticles have important applications in catalysis and magnetic materials ,111. Zha0–114 nm a 45]. T. T2), hyeal time b 46]. T. T2), hy4 in a microfluidic reactor, consisting of three different types of micromixers . T. T49]. T4 , bismuth nitrate (Bi(NO3)3), and ethylene glycol into the channels. It was demonstrated that the phase and morphology of nanoparticles can be tuned by increasing the heating. Typically, V-shaped Pt1Bi1 nanostructures with an arm diameter of approximately 17 nm were obtained at 260 °C. On the other hand, spherical-shaped Pt1Bi2 nanostructures with an average diameter of 33.5 nm were synthesized at 360 °C. Meanwhile, bimetallic Au-Pd nanoclusters were prepared by using a single-phase multilayer flow mixing device for the catalytic aerobic oxidation of benzyl alcohol , Ni(acac)2 and tungsten hexacarbonyl (W(CO)6) were afforded in a mixture of oleic acid, oleylamine and benzyl ether and preheated to 70 °C before introduction into the microfluidic reaction system heated at 230 °C. In this process, W(CO)6 decomposes to immediately release carbon monoxide (CO) gas, which may (1) separate the liquid phase into uniformly distributed discrete droplets and (2) act as a reducing agent for the synthesis of Pt-Ni nanoparticles. In addition, by using air as a continuous phase and sodium tetrachloropalladate (II) (Na2PdCl4) and PVP dispersed diethylene glycol solution as a dispersed phase, the palladium icosahedra nanoparticles coated with platinum monolayer were obtained . T. T70]. Tus phase d 138]. . 4O was decorated with gold nanoparticles  by using a microfluidic device  during the microfluidic synthesis, which has highly shortened the reaction time as compared to the conventional extrusion method d 153]. . 153]. TPorous inorganic nanomaterials have gathered considerable research interest in biomedical sector owning to their rich and adjustable nanoporous structure, high specific surface area, and improved physicochemical properties ,156,157.2O2) to trigger the release of atorvastatin, which was maintained for more than 24 h. Moreover, the multifunctional oxidized dextran nanocarriers consisting of drug-loaded PSi and gold nanoparticles have been synthesized by using a similar approach, which can be used for controlled drug delivery and X-ray computed tomography (CT) imaging for liver failure theranostics (Mesoporous silica and porous silicon (PSi) nanoparticles have been hot spots for disease diagnosis and drug delivery for a long time ,158. Theanostics c 166]. . 2O2) toanostics d 167]. . 2O2) toMicrofluidic platforms have shown promising potential to design a myriad of inorganic nanomaterials with an improved trait of physico-chemical properties. Rapid and efficient mixing, as well as simplicity and reversibility, pose microfluidics as an ideal platform for the cost-effective mass production of inorganic nanomaterials with narrow size distribution and high monodispersity than that of the bulk method. Likewise, the application of microfluidic technology for the synthesis of core-shell nanostructures avoids complicated coating and purification steps, in marked contrast to the conventional methods, which encompass separate steps for the nucleation, growth, and modification.In recent years, although the progress has been made in the synthesis of various types of inorganic nanoparticles  and their applications in a wide range of fields; the development of the microfluidic-based synthetic strategy for inorganic nanoparticles is still at its infancy. In order to further promote the rapid development of this technology, several issues need to be carefully addressed, which include, but are not limited to: (1) a comprehensive understanding of the synthesis mechanism of inorganic nanoparticles. At present, the formation processes of inorganic nanomaterials as well as the correlation between particle morphology/structure and reaction conditions in microfluidic scale are not yet fully understood. We look forward to more in-depth investigations of the differences in basic principles between the bulk and microfluidic synthesis. (2) There is few research studies on the effect of liquid evaporation caused by high temperature on the synthesis process of nanomaterials in microfluidic system, which need to be further studied. (3) Increase of the yield of inorganic nanoparticles. One of the advantages of microfluidic technology is that it can accurately process a trace amount of samples, thereby reducing the reagent cost while avoiding the wastage of precious chemicals. However, due to the small channel size and the high hydraulic pressure of the microfluidic device, the current maximum productivity of this technology is only about in grams per hour. In order to meet industrial demands, it is pertinent to develop effective stackable microreactor systems and industrial-scale fluid control devices to achieve a manufacturing efficiency for up to kilograms per hour or even higher. (4) Modulation of the morphology of inorganic nanoparticle. Anisotropic nanoparticles or nanoparticles with different layers have received enormous interest of the scientific community, partly due to their unique morphology and diverse potential applications. However, most of the nanoparticles prepared by using microfluidics are of symmetrical shape. The controllable synthesis of complex shaped nanoparticles based on microfluidic technology has yet to be achieved, and considerable efforts should be made in this field in the near future. (5) Industrial design and development of microfluidic devices. Currently, the manufacturing process of the microfluidic device is very expensive, complicated, and tedious. Companies including Lonza, Corning, and Syrris have conducted groundbreaking research to manufacture robust and flexible microreactors, which provide useful guidance for the industrial development of microfluidics. However, there is still a long way to go to achieve cost-effective yet robust microfluidic devices.Taken together, microfluidic technology is a promising approach for overcoming the current challenges in the synthesis and modification of inorganic nanomaterials and realizing the well-controlled, cost-effective and reproducible synthesis of inorganic nanoparticles. In the future, with the rapid development of the multi-scale material design, sol-gel chemistry, microfabrication, and microfluidic technology, an array of functional inorganic nanoparticles, with different sizes, shapes, and properties are expected to be realized to meet the growing demand in different fields.


Desmodium uncinatum is one of the most important legume forage which distributes in tropical and subtropical regions of the world. In our study, we obtained the complete chloroplast genome of D. uncinatum with a length of 148,853 bp, including a large single copy region of 84,019 bp, small single copy region of 18,223 bp, and a pair of inverted repeat regions of 20,672 bp. The GC content in the whole chloroplast genome of D. uncinatum is 35.16%. Among the 133 unique genes in the circular genome, 37 tRNA, 12 rRNA and 84 protein-coding genes were successfully annotated. We constructed the Maximum likelihood (ML) tree with 11 species, and came to the conclusion that D. uncinatum was phylogenetically closely related to the genus of Glycine and Trifolium. Desmodium uncinatum, important perennial forage legume native to Argentina, Bolivia, Brazil, Peru, and Venezuela, provides forage of high protein content to livestock . The voucher specimen (FR001) were deposited at the Herbarium of the Institute of Animal Sciences of the Chinese Academy of Agricultural Sciences, Beijing, China. After germinate in lab, genomic DNA from young leaves was extracted using a DNA Extraction Kit from Tiangen Bio Tech Co., Ltd . The sequencing was carried out on the Illumina Novaseq PE150 platform , and 150 bp paired-end reads were generated. The software GetOrganelle v1.5  as a reference. The chloroplast genome annotation was performed through the online program CPGAVAS2  of 20,672 bp that were separated by a large single copy  and a small single copy . The GC content of the whole chloroplast genome is 35.16%. The chloroplast genome is identified to have genes of 133 in total, including 84 protein-coding genes, 37 tRNA genes, and 12 rRNA genes. Among them, 36 genes encoding amino acid transfer protein , 25 genes encoding ribosomal structural proteins protein , 16 genes encoding electron transport protein , 14 genes encoding light collection structural protein (PSII)  are found in the chloroplast genome of D. uncinatum (In the present study, the complete chloroplast genome of ncinatum .Vachellia flava as outgroup species was downloaded from the NCBI GenBank database to identify the phylogenetic relationship of D. uncinatum. The sequences were aligned using MAFFT v7 (Katoh et al. Trifolium meduseum and Desmodium renifolium are closely related to D. uncinatum (The chloroplast genomes of 10 species from Fabaceae and as well as ncinatum . This st


This study aimed to explore factors may affect the length of hospital stay after laparoscopic appendectomy.The data of 636 patients undergoing laparoscopic appendectomy between July 2016 and July 2019 in Beijing Tsinghua Changgung Hospital were retrospectively analyzed. The patients were divided into group A  and group B  according to their hospital stay.Sex, age, disease onset time(time from onset to admission), nausea, vomiting, diarrhea, peritonitis, comorbidities, and history of appendicitis; preoperative body temperature (T), white blood cell (WBC) count, percentage of neutrophilic granulocytes, and preoperative C-reactive protein (CRP) level; time from diagnosis to surgery. appendix diameter, appendicolith, and ascites in ultrasound or CT; surgical time, intraoperative blood loss , intraoperative adhesions or effusions, and stump closure methods, convert to open appendectomy, appendix pathology(perforated or gangrenous appendicitis were defined as complicated appendicitis and simple or suppurative appendicitis were defined as uncomplicated appendicitis) and antibiotic treatment schemes were analyzed.P<0.01), disease onset time , time from diagnosis to surgery ; surgical time; peritonitis, comorbidities , appendicolith , ascites before the surgery, intraoperative adhesions or effusions; preoperative temperature ; preoperative WBC count ;preoperative CRP level; appendix diameter; intraoperative blood loss ; using Hem-o-lok for stump closure; complicated appendicitis ; and using ertapenem for antibiotic treatment after the surgery. Multivariate analysis demonstrated that age , peritonitis , preoperative WBC count , preoperative CRP level , time from diagnosis to surgery , appendicolith , complicated appendicitis , surgical time , use of Hem-o-lok for stump closure , and use of ertapenem for antibiotic treatment  were the risk factors for a prolonged hospital stay.Significant differences were detected between group A and group B in age (37.10 ± 13.52y vs 42.94 ± 15.57y, The patient with appendicitis was older and had peritonitis, higher preoperative WBC count or CRP level, longer time from diagnosis to surgery, appendicolith, and complicated appendicitis, predicting a prolonged hospital stay. Shorter surgical time and the use of silk ligation for stump closure and cephalosporins + metronidazole for antibiotic treatment might be better choices to obtain a shorter hospital stay. Acute appendicitis is the most common acute abdominal surgical emergency with a worldwide incidence of 6.7%-8.6% . The morLaparoscopic appendectomy has become the preferred surgical method for appendicitis due to less trauma and faster recovery –6. PreviThe study was conducted in accordance with the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of Beijing Tsinghua Changgung Hospital (20277-0-01). Because of the retrospective nature of the study, patient consent for inclusion was waived.This was a retrospective study of patients with acute appendicitis who underwent laparoscopic appendectomy between July 2016 and July 2019 at the Beijing Tsinghua Changgung Hospital. Data of 636 patients who underwent laparoscopic appendectomy between July 2016 and July 2019 were retrospectively reviewed.The inclusion criteria were as follows: (1) patients diagnosed with acute appendicitis, (2) patients undergoing laparoscopic appendectomy, and (3) patients aged more than 15 years.The exclusion criteria were as follows: (1) patients diagnosed with periappendicular abscess, because we followed the 2017 WESE guidelines for appendticitis treatment and choose non-operative management with antibiotics or percutaneous drainage as the first choice for it, (2) aged less than 15 years or more than 80 years, and (3) negative explorations.The diagnostic criteria for acute appendicitis was as follows: pain in the right lower quadrant; a physical examination showing tenderness in the right lower quadrant with maximum severity at the McBurney point; a blood test showing increased white blood cell (WBC) count or C-reactive protein (CRP) level or percentage of neutrophils; and ultrasound or abdominal computed tomography (CT) suggesting swelling in the appendix.The patients were divided into 2 groups according to the hospital stay: 348 with a hospital stay ≤3 days in group A and 288 with a hospital stay >3 days in group B.All surgeries were performed by the same group of doctors, who had 3–5 years of experience in laparoscopic appendectomy and performed more than 50 laparoscopic appendectomies every year. The patients were placed in the supine position and received general anesthesia by tracheal intubation. A 1-cm arc incision was made on the umbilicus, and a pneumoperitoneum needle was used to puncture into the abdominal cavity. A 12–14 mm Hg pneumoperitoneum was formed by inflation with carbon dioxide. The pneumoperitoneum needle was pulled out. A 10-mm trocar was used to puncture the abdominal cavity, and the inner core was pulled out to allow the entry of a laparoscope. Under laparoscopy, 1-cm and 0.5-cm small incisions were made at the anti-McBurney point and 3 cm on the pubic symphysis, and 10-mm and 5-mm trocars were placed, respectively. After changing to a left lateral position with head down and legs up, laparoscopic instruments were placed in to find and resect the appendix. A nipper was used to lift the mesenterium near the root of the appendix, and a separating plier was used to bluntly separate and penetrate the root of the appendix mesentery connected to the appendix. Either suture ligation or Hem-o-lok occlusion was performed to close the root mesentery of the appendix. The appendix root was 1igated with a 7# silk thread  0.5 cm from the root of the appendix if the root of appendix was not edema and the root diameter with in 5mm. Otherwise it was occluded with a Hem-o-lok  0.5 cm from the root of the appendix. The appendix was cut at a distance of 0.5 cm from the ligation position or the distal end of the Hem-o-lok. The appendix was removed by placing it in a fetching bag from the trocar in the left lower abdomen. The abdominal pelvic fluid was suctioned, and the incision was sutured.The postoperative diet was gradually restored according to the conditions during the surgery. Ceftriaxone 2g qd + metronidazole 0.5g tid or ertapenem 1g qd were used for intravenous antibiotic treatment according to the severity of infection. The wound dressing was changed 2–3 days after the surgery. The patients were discharged if the blood test results were basically normal , the patients tolerated semi-liquid food, they had no fever or wound infection, and they had controlled pain.The following indicators were monitored: sex, age, disease onset time (time from onset to admission), nausea, vomiting, diarrhea, peritonitis, comorbidities, and history of appendicitis; preoperative T, WBC count, percentage of neutrophilic granulocytes, and CRP level; time from diagnosis to surgery. appendix diameter, appendicolith, and ascites in ultrasound or CT; surgical time , intraoperative blood loss , intraoperative adhesions or effusions, and stump closure methods; convert to open appendectomy, appendix pathology and antibiotic treatment schemes and hospital stay.All the results were analyzed using SPSS 16.0 software . Continuous variables were compared using the Mann–Whitney test, while the chi-square test was used for comparing the frequency data. Binary logistic regressions were performed using the hospital stay (cutoff = 3 days) as the outcome, and related factors were investigated. A P <0.05 indicated a statistically significant difference.The surgeries were successfully completed, with 37 cases (15 cases in group A and 22 cases in group B) converted into open surgeries. Group A comprised 169 male and 179 female patients aged 37.10 ± 13.52 years, while group B comprised 142 male and 146 female patients aged 42.94 ± 15.57 years. Compared with patients in group A, patients in group B had longer disease onset time , longer time from diagnosis to surgery , longer surgical time , higher incidence of peritonitis , comorbidities , appendicolith , ascites before the surgery , intraoperative adhesions or effusions , higher temperature , higher preoperative WBC count , higher preoperative CRP level , higher appendix diameter , more intraoperative blood loss , higher rate of using Hem-o-lok for stump closure , higher ratio of complicated appendicitis , and higher rate of using ertapenem for antibiotic treatment after the surgery . No significant differences were found between the two groups in sex, presence or absence of symptoms, presence or absence of history of appendicitis, temperature, preoperative neutrophil percentage, neutrophil percentage on the second postoperative day, CRP level on the second postoperative day, or postoperative wound infection rate. None of the patients in the two groups had stump fistula within 3 months after the surgery, as shown in Logistic regression was performed and demonstrated that age , peritonitis , preoperative WBC count , preoperative CRP level , time from diagnosis to surgery , appendicolith , complicated appendicitis , surgical time , use of Hem-o-lok for stump closure , and use of ertapenem for antibiotic treatment  were the risk factors for a prolonged hospital stay, as shown in The shorter hospital stay can lead to less cost and a higher percentage of bed utilization. Therefore, it is important to investigate its influencing factors.This study demonstrated that the length of hospital stay increased with the age of patients. The patients in the group with a prolonged hospital stay were older than the patients in other groups. Elder people are at higher risk of malnutrition which will lead to a higher risk of post operation infection. Therefore, the elderly patients took more time to return to normal after the surgery.Preoperative high WBC count and CRP level and peritonitis indicated severe appendicitis. Regarding the AIR scores, the WBC count >15 × 109/L and the CRP level>50 mg/L were used as the criteria for the diagnosis of severe abdominal infection. The accuracy rate of these criteria in distinguishing severe acute abdominal infection was as high as 85% . The posThe key to the successful treatment of acute appendicitis is timely surgery after diagnosis. How long it will be safe from diagnosis to surgery is still controversial. The hospital stays of patients with the diagnosis to surgical time more than 24 h was significantly longer . MoreoveThe present study demonstrated that patients with appendicolith had a significantly longer hospital stay. Appendicolith can cause the obstruction of the appendiceal lumen, contributes to bacterial overgrowth and continued secretion of mucus, leading to intraluminal distention and increased wall pressure. Subsequent impairment of lymphatic and venous drainage leads to mucosal ischemia. These processes in combination promote a localized inflammatory process that may progress to gangrene and perforation. Appendicolith was found to be an independent risk factor for appendiceal perforation , 22. PerThe surgeons involved in the study were all experienced doctors. Therefore, the extension of the surgical time was attributable to the severity of infection and abdominal adhesion. Severe adhesion leads to more severe trauma after extended dissection and more local exudation, eventually leading to prolonged postoperative recovery time. Therefore, the present study demonstrated that prolonged surgical time was a risk factor for the prolongation of hospital stay.The treatment of the appendix stump is the key to a successful surgery. The commonly used methods are silk ligation, Endoloop ligation, Hem-o-lok vascular clamp occlusion, and endo-gastrointestinal anastomosis (Endo-GIA) stapler cutting and closure , 23–28. Escherichia coli and anaerobes. Ceftriaxone, metronidazole, and ertapenem are commonly used antibiotics for appendicitis [The main pathogens causing appendicitis are ndicitis . Ertapenndicitis , 31. TheThis study had some limitations. It was a single-center study with a small sample size. Therefore, the results need to be confirmed in larger groups of patients. Further, it was a retrospective study, and the patients were not randomly assigned to their treatment groups, leading to some bias. The findings of the multivariate analysis should be confirmed with a randomized controlled trial.In summary, patients with appendicitis were older and had peritonitis, higher preoperative WBC count or CRP level, longer time from diagnosis to surgery, appendicolith, and complicated appendicitis, which might predict a prolonged hospital stay. Shorter surgical time and the use of silk ligation for stump closure and cephalosporins + metronidazole for antibiotic treatment might be better choices to obtain shorter hospital stay.S1 File(XLS)Click here for additional data file.


Realizing the promise of precision medicine in psychiatry is a laudable and beneficial endeavor, since it should markedly reduce morbidity and mortality and, in effect, alleviate the economic and social burden of psychiatric disorders. This review aims to summarize important issues on pharmacogenomics in psychiatry that have laid the foundation towards personalized pharmacotherapy and, in a broader sense, precision medicine. We present major pharmacogenomic biomarkers and their applications in a variety of psychiatric disorders, such as depression, attention-deficit/hyperactivity disorder (ADHD), narcolepsy, schizophrenia, and bipolar disorder. In addition, we extend the scope into epilepsy, since antiepileptic drugs are widely used to treat psychiatric disorders, although epilepsy is conventionally considered to be a neurological disorder. The World Health Organization (WHO) estimates that about 25% of the population around the world will suffer from at least one mental disorder at some time in their lives ,2. DepreMedications can be used in order to reduce the intensity of symptoms or treat several psychiatric disorders. A patient’s response to the many medications used to treat various psychiatric disorders can be highly variable . Drug reFor an increasing number of drugs, pharmacogenomic testing is available and used to pre-screen patients and help them in selecting drug choice and drug dose accordingly ,7. Now, HLA-B*15:02 before treatment [HLA-B variant alleles are just one example of such adverse drug reactions (ADRs). In fact, there is a plethora of genetic variants that are associated with ADRs. As an evident example, carriers of a variant of MT-RNR1 , an RNA-coding gene, are at high risk of irreversible hearing loss by a single dose of gentamicin [There are solid reasons for pharmacogenomic testing (PGx testing). Some drugs are only effective for specific genotypes and the testing can avoid unpredictable, severe, and potentially fatal drug reactions. Furthermore, for some drugs, a patient’s ancestry is the essential consideration. For example, for carbamazepine, a commonly used antiepileptic drug, the FDA recommends that, if patients are descendants of genetically high-risk populations, they should take PGx testing for the presence of reatment ,9,10. Cantamicin ,12.For a growing number of drugs, PGx testing provide a means of optimizing the drug choice and drug dose. Drug labels include not only standard dosing information, but also guidelines for adjusting the drug dose or selecting an alternative drug, when necessary, based on a patient’s genetic makeup if gene-drug interrelationships are well understood. Dosing adjustment requirements or recommendations are mostly in variants of genes that encode drug-metabolizing enzymes or drug transporters . Thus, PAccumulated data are then noted to FDA and its Table of Pharmacogenomic Biomarkers in Drug Labeling is widely used as a standard guideline . PGx infCYP genes are quite polymorphic and they can lead to increased, decreased, or completely absent drug metabolism activity. Among these genes, CYP2D6 is particularly important and heavily studied. More than 100 CYP2D6 variants have been reported and catalogued at the Pharmacogene Variation Consortium database [The cytochrome P450s (CYPs) comprise a large superfamily of a variety of enzymes that serve as major workhorses for metabolizing steroid hormones, lipids, toxins, and xenobiotics. The CYP superfamily genes encode enzymes that function as monooxygenases and catalyze the modification of about 25–30% commonly used drugs ,23. The database . In addiMany of these variants cause the enzyme to change activity at different levels. The level of CYP2D6 activity decides how an individual responds to the substrate drugs. A standard dosage of the drug may show inadequate efficacy in some individuals and serious toxicity in others. To name a few, the drug substrates of CYP2D6 include atomoxetine (a non-stimulant for ADHD), clozapine (an antipsychotic for schizophrenia), and venlafaxine (an antidepressant), among psychiatric medications, as in CYP2D6 allele frequencies among different populations [There are substantial variations in ulations ,27. The ulations . Intermeulations . Thus, aulations . The Afrulations ,31,32. Iulations . In contulations ,34,35. Culations . When inulations . Becauseulations .CYP2D6 genes [CYP2D6 active allele—have been reported. These carriers are CYP2D6 ultrarapid metabolizers. In the case of 13 functional copies, the rate was up to 17 times higher than for individuals with no active CYP2D6 enzyme [Interestingly, copy-number variants were also found in D6 genes . In othe6 enzyme . If the Depression  is a common and serious psychiatric disorder that affects more than 350 million people each year across the world . People Depending on the drug target, the neurotransmitter and/or its metabolizing enzyme, antidepressants can be categorized into four major classes—two older ones, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), and two newer ones, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) Individual response to some antidepressants varies for reasons not yet well understood. Once a patient starts to take antidepressants, it is advisable not to stop taking them without the recommendation of a doctor. Therefore, it is necessary to know which medicine works for them beforehand. Some antidepressants may result in more adverse effects than others. Common ADRs include diarrhea, nausea and vomiting, weight gain, sleepiness, and sexual problems.SLC6A4, the serotonin transporter gene, is a well-characterized gene that is associated with the treatment outcome of depression [SLC6A4 gene is polymorphic in its length [s) allele or the long (l) allele, respectively, depending on the occurrence of a deletion or an insertion of 6–8 units. The l allele is 44 bp shorter than the s allele and it is associated with higher levels of transcription of the SLC6A4 gene in human cell lines. Some studies suggest that the l-allele patients respond better to antidepressants, even if this needs to be further investigated [pression ,44,45,46s length . 5-HTTLPstigated ,49.Amitriptyline (brand name Elavil) is a TCA that is used to treat many psychiatric disorders, including obsessive-compulsive disorder . TCAs moThe FDA’s guideline on amitriptyline states that CYP2D6 poor metabolizers will have higher plasma levels of the medication than expected when normal doses are given. The FDA also recommends that monitoring TCA plasma levels is necessary whenever a TCA is co-administered with another medication, which is known to be a CYP2D6 inhibitor. The CPIC has also made recommendations that the dosages of TCAs need to be adjusted, depending on CYP2C19 and CYP2D6 genotypes . CYP2D6 One important precaution in increasing amitriptyline dose for CYP2D6 metabolizers is the fact that, when the level of hydroxyl-metabolites increases, it can lead to cardiotoxicity ,53. PresCYP2D6 gene contains decreased-function allele(s).Venlafaxine (brand name Effexor) is an antidepressant that is used to treat the depression, anxiety, and panic disorder ,55. BothThe FDA’s guideline on venlafaxine indicates that neither specific dose recommendations for CYP2D6 poor metabolizers nor dose adjustment in the case of coadministration of venlafaxine and any CYP2D6 inhibitor. Instead, the drug label includes the statement that imipramine partially inhibits the metabolism of venlafaxine, but the total concentration of active compounds (both venlafaxine and ODV) remains unchanged. On the other hand, the DPWG provides recommendations on venlafaxine dosing based on the CYP2D6 genotype. According to the guideline, CYP2D6 poor and intermediate metabolizers needs to use an alternative drug. When ADRs occur and an alternative medication is not available, then venlafaxine can be used after a dose reduction based on clinical progress. The DPWG recommends that CYP2D6 ultrarapid metabolizers need to take an increased dose of venlafaxine up to 50% from the standard dose or use an alternative drug when treatment effects of dose adjustment cannot be monitored, as they will have lower plasma levels in the sum of venlafaxine and ODV .CYP2D6 genotype can affect individual’s risk of ADRs from taking venlafaxine. CYP2D6 poor metabolizers have higher levels of venlafaxine and lower levels of ODV, and this can be interpreted as a higher risk of side effects and a reduced efficacy of the medication, respectively . Old peoAnti-anxiety medications help to alleviate the symptoms of anxiety, such as intense and persistent fear and worry and panic attacks . BenzodiAttention-deficit/hyperactivity disorder (ADHD) is a common psychiatric and neurodevelopmental disorder in children, which is estimated to affect 5% of children and 2.5% of adults around the world ,73,74,75Narcolepsy is a psychiatric disorder of hypersomnolence, which is characterized by disturbed sleep, sleep paralysis, hallucinations, and direct onset of REM sleep from wakefulness ,64,65. Nd-amphetamine and l-amphetamine) and it can be composed of various types of salts, including d-methamphetamine salts, dexamfetamine, and a d-amphetamine prodrug, lisdexamfetamine dimesylate. In the 1930s, it was first noted that amphetamine relaxes hyperactivity, despite its stimulant nature [Amphetamine is a central nervous system stimulant that is approved for the treatment of ADHD and it is also used to treat narcolepsy as a third-line therapy ,82,83. At nature . Later, t nature . Amphetat nature . Althougt nature . TherefoAtomoxetine is a non-stimulant, which is approved to treat ADHD . AlthougModafinil is approved for improving wakefulness in adult patients with excessive sleepiness that is related to narcolepsy, obstructive sleep apnea (OSA), or shift work sleep disorder (SWSD) . It is c®) is approved for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. As a psychostimulant, pitolisant is a histamine-3 (H3) receptor antagonist and inverse agonist, which activates histamine release [Pitolisant , when taken in the long term . TD causAccording to the WHO, schizophrenia is a chronic and severe neurodevelopmental disorder, and it affects 20 million people worldwide. Etiology of schizophrenia remains unclear, but genetic and environmental factors seem to work together . The patOne genome-wide association study in 2014 identified 108 SNPs that were associated with schizophrenia, 83 of which were new. Not surprisingly, most of these SNPs occurred in genes that are highly expressed in the brain. However, surprisingly, some associated SNPs were found in genes that are expressed in tissues that are involved in the immune system .DTNBP1 gene. Its genetic variants can affect the availability of dopamine D2 receptors. Recently, one study revealed that some genetic variants in the DTNBP1 gene are associated with individual cognitive response to antipsychotics [Dysbindin-1 regulates the transport and release of synaptic vesicles and is encoded by the ychotics ,106. PGxAripiprazole is an atypical antipsychotic that is used for managing schizophrenia, bipolar disorder, major depressive disorder, and Tourette’s disorder. Two enzymes, CYP2D6 and CYP3A4, are the mainstay of its metabolism and elimination. The FDA’s Table of PGx Biomarkers for aripiprazole states that CYP2D6 poor metabolizers need to take half of the usual dose . When CYClozapine is among the most effective antipsychotics available in treating schizophrenia and, in treatment-resistant schizophrenia, this is the only option to be effective. Schizophrenia patients show high risk of recurrent suicidal behavior and clozapine can function to reduce this condition . When coCYP2D6 alleles. In contrast, CYP2D6 ultrarapid metabolizers may show a decreased response to therapy. The FDA’s Table of PGx Biomarkers for risperidone states that poor and extensive/normal metabolizers show no significant differences in the rates of adverse effects. Additionally, the DPWG recently revised its dosing guidelines as “no action is needed” for CYP2D6 poor metabolizers taking risperidone.Risperidone, which is an atypical antipsychotic, is the most commonly prescribed among antipsychotics in the US ,111. It KCNH7 variants reveals that two SNPs in the KCNH7/Kv11.3 gene were significantly associated with risperidone responses [KCNH7/Kv11.3 gene encodes one subunit of the potassium voltage-gated channel Kv11 family.A recent association study of esponses ,113. TheThioridazine is particularly used for patients who have failed to respond to, or cannot tolerate, other antipsychotics . ThioridMood stabilizers are used mainly in treating bipolar disorder and mood swings and in augmenting the treatment effect of antidepressants, through decreasing abnormal activity in the brain ,117. LitEpileptic seizures are a malfunction of the brain, like major depression, anxiety disorders, and other psychoses. Thus, epilepsy has psychiatric aspects, and some psychiatric disorders are highly associated with epilepsy. Patients with mood disorders tend to experience seizures of both kinds—epileptic seizures and non-epileptic seizures. This relationship seems to flow in both directions: mood disorders increase the risk of seizures and seizures increase the risk of mood disorders. This is why some mood stabilizers are also used as antiepileptic drugs, and these will be described in the next section.According to the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy , epilepsBrivaracetam is approved for partial-onset seizures in patients four years of age and older . It bindCarbamazepine is approved for partial seizures, tonic-clonic seizures, mixed seizures patterns, and pain control for trigeminal neuralgia . It is aA receptor agonist, which binds to postsynaptic GABAA receptors in the brain, causes hyperpolarization, and creates an inhibitory signal [Clobazam is approved for adjunctive treatment of seizures associated with Lennox–Gastaut syndrome (LGS) in patients two years of age or older . LGS is y signal . It is py signal ,127. Thuy signal . Thirty-y signal ,130. Cloy signal .A receptor agonist, which creates an inhibitory signal in the vertebrate central nervous system [Diazepam is approved for various clinical uses, including anxiety disorders, symptomatic relief of acute agitation, tremor, hallucinosis, and skeletal muscle spasm. It is also indicated for use as an adjunctive therapy for convulsive disorder . It is as system ,132. CYPs system . It is fs system . Both acs system . Genetics system . On the s system .Lacosamide is a third-generation anticonvulsant, which is approved for partial-onset seizures in patients four years of age and older . As a fuAs a structural analogue of carbamazepine, oxcarbazepine shows a similar mechanism of action with carbamazepine by blocking voltage-gated sodium channels ,136. OxcPhenytoin is approved for the control of generalized-onset tonic-clonic  and complex partial  seizures and the prevention and treatment of seizures occurring during or following neurosurgery . It reduPOLG) gene is strongly associated with acute liver failure and consequent death [POLG1 gene and it changes several mitochondria genes, which affect mitochondria genesis [Valproic acid is approved for monotherapy and adjunctive therapy of complex partial seizures, simple and complex absence seizures, and adjunctive therapy of multiple seizure types that include absence seizures . It is ant death ,142. Val genesis . Additio genesis .Precision medicine targets providing the optimal diagnoses and treatments for each patient based on the categorization of biomarkers ,145,146.AI has been used in predicting diagnosis, treatment outcome, and prognosis. As of psychiatry and neurology, multiple studies have used models, including deep learning architecture, random forest, tree-based ensemble, elastic net, and linear regression in order to evaluate and predict lithium treatment response on major depressive disorder . To predVarious research efforts are ongoing in order to improve diagnosis, prognosis, and treatment in neuropsychiatry: PGx data and their treatment outcomes have been collected to support data-driven clinical decision-making for the patient. To this end, relations between genetic variation and variable drug responses to psychiatric medications should be well established . The use


This prospective crossover study compared the effects of intramuscular administration of medetomidine for sedation on parameters of the abdominal vascular system, measured by enhancement computed tomography (CT), to those of propofol-induced sevoflurane maintenance anesthesia, as a control, in five clinically healthy adult male beagle dogs (11.4–12.8 kg). Each animal underwent both protocols at a 1-week interval. The enhancement (HU) and time to peak enhancement on CT were measured for the aorta (AO), caudal vena cava (CVC), portal vein (PV), and hepatic parenchyma (HP). The contrast effects in the AO, PV, and HP were significantly delayed under medetomidine sedation compared to the control anesthesia protocol. Particularly, the contrast effect in the PV and HP was significantly delayed under sedation, appearing approximately 1 min after contrast medium injection. This delay likely reflects the peripheral vasoconstrictive effect of medetomidine. We noted a generally early high contrast enhancement of the CVC under medetomidine sedation, likely contributed by the induced bradycardia. Therefore, findings obtained on contrast enhancement CT under medetomidine sedation may be different from those obtained under propofol-induced sevoflurane maintenance anesthesia. These differences are important to consider when using the findings to inform diagnosis. In veterinary medicine, multiphasic multi-detector computed tomography (CT) angiography, including triple-phase helical CT, is currently used as a diagnostic tool for vascular disorders, such as portosystemic shunts , arterio2-agonist that is widely used for sedation, produces cardiovascular effects, including vasoconstriction, a change in blood pressure, and bradycardia [CT imaging further requires that the animal be immobilized, with anesthesia or sedation used to achieve this ,15,16,17dycardia ,19,20. Idycardia ,22. The This was a prospective, randomized crossover study. The study protocol strictly followed the Rules for Animal Care and Use of the Laboratory Animal Center, Imabari Campus, Okayama University of Science, and was compliant with the Guide for the Care and Use of Laboratory Animals (8th ed). Experimental protocols were approved by the Animal Care and Use Committee of Okayama University of Science .Five adult male beagle dogs (11.4–12.8 kg) were used in this study. These animals had not been used for any prior research. The dogs were housed in our Laboratory Animal Center at Imabari Campus, Okayama University of Science, under a 12:12 h light-dark cycle . The room temperature was maintained between 24 and 26 °C and the humidity between 40–60%. For inclusion, all dogs had to be clinically healthy, based on a physical examination, complete blood count, and results from biochemical testing, abdominal radiography, and echocardiography. Needle catheters (22 G) were placed in the right or left cephalic vein for propofol injection and contrast medium infusion, with the side randomly allocated between animals before induction of anesthesia and sedation. After this study, all dogs were maintained in our Laboratory Animal Center.2O; and end expiratory carbon dioxide concentration, 40 mmHg). For the sedation protocol, a 40 µg/kg dose of medetomidine hydrochloride was administered IM in the right semitendinosus or semimembranosus muscle. Spontaneous breathing was maintained under sedation, with no requirement for intubation; flow-by oxygen (100%) was provided (5 L/min). Each animal underwent both the anesthesia and sedation protocols at a 1-week interval. The vaporizer was calibrated before each experiment.Whether anesthesia or sedation was used first was randomly determined for each dog. The animals were fasted for approximately 12 h before anesthesia or sedation. For the control anesthesia protocol, dogs were induced using propofol , administered intravenously (IV), and intubated using a tracheal tube. General anesthesia was maintained using sevoflurane (2.5%: vaporizer setting) and oxygen (2 L/min) under mechanical ventilation . All dogs were placed in the dorsal recumbent position. The CT scan was started after immobilization was stable . The scanning position was localized at the level of T13. For the anesthesia protocol, the dynamic scanning parameters were as follows: rotation time, 1 s; slice thickness, 1 mm; reconstruction interval, 1 s; X-ray tube potential, 120 kV; and X-ray tube current, 100 mA; with a total scanning time of 60 s (60 slices). For the sedation protocol, the dynamic scanning parameters were as follows: rotation time, 1 s; slice thickness, 1 mm; reconstruction interval, 2 s; X-ray tube potential, 120 kV; and X-ray tube current, 100 mA; with a total scanning time of 120 s (60 slices). A single CT scan was performed at 2, 3, 4, and 5 min after the start of the contrast medium infusion for all sessions. The parameters for this single scan were as follows: rotation time, 1 s; slice thickness, 1 mm; X-ray tube potential, 120 kV; and X-ray tube current, 100 mA.A non-ionic, low osmolar iodinated contrast material, Iohexol  was used, administered at a dose of 2 mL/kg (600 mgL/kg) via injection into the cephalic vein, using a power injector. The injection time was 15 s and the dynamic scan was initiated at the time the injection of the contrast medium. During scanning, heart rate was measured at 1-min intervals, while blood pressure was measured and recorded at two time-points, before anesthesia or sedation, and at the start of the scanning. Heart rate was measured by counting the QRS complex on the electrocardiogram over a 60 s period. Blood pressure was non-invasively measured using the oscillometric method with a multiparameter monitor , with the size of the blood pressure cuff selected to be about 40% of the limb circumference, applied to the forelimb (radius) for all measurements.2 area at the center of the AO, PV, and CVC, and a 200 mm2 area in either the left of right lateral lobe of the liver for HP measures, avoiding the hepatic vessels. All measures in the regions of interest (ROIs) were recorded in Hounsfield units (HU). The following time-based parameters were also measured from the time of contrast medium injection: first appearance of AO enhancement (AO-EA) and the AO enhancement peak (AO-EP); first appearance of CVC enhancement (CVC-EA) and the CVC enhancement peak (CVC-EP); first appearance of PV enhancement (PV-EA) and the PV enhancement peak (PV-EP); and first appearance of HP enhancement (HP-EA) and HP enhancement peak (HP-EP). The time-attenuation curve (TAC) was calculated based on all measured values in the ROIs.All CT images were reviewed on a dedicated DICOM viewer . Contrast enhancement measures were obtained at the following regions of interest ROIs; : 40 mm2 p-value < 0.05 was considered significant.Statistical analyses were performed using commercially available statistical analysis software . All ROI measurements and time-based parameters were reported as a median and range. The normality of the distribution of data was confirmed prior to analyses. The Kruskal–Wallis H test was used to evaluate the relationships among all measured values and time-based parameters, as well as body weight, heart rate, blood pressure, the injection time, and the speed of the contrast medium. A Mann–Whitney U test was used to evaluate the contrast values between the anesthesia and sedation protocols, as well as for between-group comparison of blood pressure before anesthesia or sedation and the time to the start of scanning. For all statistical analyses, a All measurements obtained are summarized in Compared to the sedation protocol, all time-based parameters  were earlier for the anesthesia protocol , while pWith regard to time-based parameters, in four dogs under the sedation protocol, CVC enhancement occurred earlier than AO enhancement, with a strong peak of CVC enhancement . We noteIn veterinary medicine, the effects of contrast medium in abdominal vessels have been widely investigated ,14,15. TThe rotation time and total time of dynamic scanning were 1 s and 60 s, respectively, under anesthesia and 2 s and 120 s, respectively, under sedation. Of note, under anesthesia, the effects of the contrast medium appeared early  and were tightly coupled, as previously reported ,14,15. TIn humans, the timing of contrast effects is affected by cardiac output ,22. ConsWith sedation, except in one dog, contrast enhancement of the CVC appeared earlier than the effect in the AO. Moreover, contrast enhancement values of the CVC were the highest among all measured contrast enhancement values, with this state persisting for at least 40 s after the administration of contrast medium. This finding is indicative of a sedation-induced bradycardia and a weakened cardiac output; therefore, the contrast medium may have stagnated in the CVC without entering the pulmonary circulation. In humans, this characteristic effect is known as the “inferior vena cava level contrast” or “dependent pooling sign” and is observed clinically in patients who are in shock due to cardiac arrest, cardiac tamponade, or myocardial infarction ,29,30. TIn veterinary medicine, CT angiography, including dual-phase and triple-phase helical CT, is widely used in clinical and experimental fields ,10,11,12The limitations of our study need to be acknowledged. Foremost, with regard to cardiac parameters, we only measured heart rate and blood pressure. As such, the underlying cause of observed differences in contrast enhancement effects with medetomidine sedation could only be inferred. A detailed examination of circulation parameters, including cardiac parameters, is necessary to clarify the mechanisms underlying the observed effects of medetomidine sedation on contrast enhancement. We also note that while we used propofol and sevoflurane for the anesthesia protocol and medetomidine for the sedation protocol, in practice, various opioid and sedative agents  are widely used as premedication for general anesthesia. These agents do exert a dose- and drug-dependent effect on the cardiovascular system and, therefore, could have an impact on the results of CT angiography. We did not use such premedication drugs in our study and, as such, cannot predict their effect on measured outcomes under IM medetomidine sedation. Further studies are needed to investigate the influence of other sedative and anesthetic agents on measured contrast effects during CT angiography.In conclusion, our results demonstrate that contrast enhancement measured under IM medetomidine sedation was greatly delayed compared to measures under anesthesia. In addition, peak contrast effects in the AO, PV, and HP were significantly lower under sedation than under anesthesia. Of note was the early high contrast enhancement of the CVC under sedation. Therefore, findings on CT angiography will be very different under medetomidine sedation from those obtained under anesthesia. These differences need to be considered when using contrast enhancement findings to inform diagnosis.


The metastatic cascade is a highly plastic and dynamic process dominated by cellular heterogeneity and varying metabolic requirements. During this cascade, the three major metabolic pillars, namely biosynthesis, RedOx balance, and bioenergetics, have variable importance. Biosynthesis has superior significance during the proliferation-dominated steps of primary tumour growth and secondary macrometastasis formation and only minor relevance during the growth-independent processes of invasion and dissemination. Consequently, RedOx homeostasis and bioenergetics emerge as conceivable metabolic key determinants in cancer cells that disseminate from the primary tumour. Within this review, we summarise our current understanding on how cancer cells adjust their metabolism in the context of different microenvironments along the metastatic cascade. With the example of one-carbon metabolism, we establish a conceptual view on how the same metabolic pathway can be exploited in different ways depending on the current cellular needs during metastatic progression. The term metastasis originates from the Greek words meta, meaning next, and stasis, meaning placement  and descTo date, most traditional anti-neoplastic chemotherapeutics have been specifically designed to target rapidly dividing cells . To illuIn chapter 2 of this review, we briefly revisit the general concept of metastatic progression and metabolic adaptation. In chapter 3, this concept is exemplified with a specific emphasis on the effects of oxygen and nutrient availability in respect of varying tumour microenvironments (TMEs). In chapter 4, we provide a comprehensive insight on the biochemical potential of metabolic pathways that capacitate tumour cells to coordinate their available carbon units for biosynthesis, RedOx balance, and energy production. The potential of metabolic pathways is explored in detail within the context of one-carbon (1C) metabolism.During their journey, metastatic cancer cells are described to acquire four specific hallmarks which signify a cell that traverses the metastatic cascade and are indicative of eventual effective secondary tumour formation. Such specific traits include motility and invasion, the ability to modulate the secondary site or local microenvironments, plasticity and the ability to colonise secondary tissues .2), nutrients, and mechanical stress [Cancer cell invasion is a complex sequential and interrelated process, which is initiated by the migration and local invasion of cells from the primary tumour into the surrounding extracellular matrix (ECM). Subsequently, cells that detached from the primary tumour and invaded through the tissue of origin have to intravasate into the vascular system, survive within the bloodstream, extravasate into a distant organ, adapt to the new microenvironment, and multiply to form macrometastases ,10. Throl stress . Only cel stress . MammaliMetabolic plasticity is not only characteristic to cancer cells but is also a common phenomenon in non-malignant cells. For example, both macrophages and lymphocytes strongly rewire their metabolism upon activation. The way this rewiring takes place depends however on the activating stimulus and cell type and can be directed towards an anabolic or catabolic program . In a siAs cells traverse the metastatic cascade, key microenvironmental conditions are constantly altering and may change drastically from solid primary tumour to final macrometastasis establishment in a different organ. In the confined local primary tumour, poor vascularisation has been shown to promote hypoxic regions , reactiv2, there is significant heterogeneity reported between individual primary tumours in different tissues of origin [2 in comparison to normal tissue was reported for human pancreatic (19.1–22.7-fold), prostate (2.8–12.5-fold), breast (5.2-fold) and liver cancer (5.0-fold) [2 is independent of clinical size, histology and grade for many tumour types [2 within tumour tissue can herein be either chronically reduced due to locally prolonged diffusion distances for oxygen within the tissue upon tumour growth (chronic hypoxia) or acutely reduced due to ischemic perfusion limitation in intratumoural blood vessels (acute hypoxia) [Although median oxygen levels in most primary tumours are <2% Of origin . Hereby,.0-fold) . Such vatic 19.1–.7-fold, ur types . The pO2hypoxia) ,23. Signhypoxia) . Upon hyhypoxia) . The subtic 19.1–.7-fold, hypoxia) ,37,38,39hypoxia) . Therefo+. This can limit the catabolism of nutrients as it requires NAD+. Therefore, a way to increase the ATP production rate is to increase glycolysis at the cost of lactate (carbon) overflow. In the case of glucose fermentation, no net production of NADH occurs and the only product that remains in the cell is ATP. When speed and cellular space are the constraints, glycolysis seems to outperform OXPHOS [Furthermore, HIF-dependent signalling in hypoxic regions of primary tumours is well known to reprogram tumour metabolism. HIF induces glucose metabolism via upregulation of glucose transporters and glycolytic enzymes ,44,45,46m OXPHOS ,61,62. TRas and BCR/ABL [FH and FOXO3a [ND5 [Upon escape from the primary site and intravasation to blood or lymph vessels, cells are challenged with enhanced oxygen concentrations, which increase from <2% in hypoxic tumour regions to concentrations as high as 4.5% in the lymphatic system and 14% in the blood vasculature . Promine BCR/ABL ,64,65,66d FOXO3a ,68, mitoO3a [ND5 , inflammO3a [ND5 ,68,69,70O3a [ND5 ,51,71. IO3a [ND5 ,72,73,74The gatekeeper to control cellular ROS homeostasis is the transcription factor NRF2 . Upon ROIn summary, the shortage of oxygen within hypoxic regions of the primary tumour as well as the enhanced availability of oxygen in lymph and blood vessels and secondary organ sites, have the potential to support cancer progression towards a more malignant phenotype. However, as these oxygen-dependent pro-malignant effects are also on the edge of cell survival, they might be one factor that explains the overall inefficient process of metastasis formation.In addition to adaptation to variable oxygen saturation within the different TMEs, the extracellular nutrient availability influences the phenotypic characteristics of cancer cells undergoing metastasis. The TME is thought to be scarce in the availability of nutrients due to the high proliferative activity of the primary tumour and inefficient vascularisation. In a very recent, elegant study, it was demonstrated that in PDAC, nutrient availability in the TME does not reflect what is usually observed from in vitro studies . Even gl+-dependent enzyme in serine de novo synthesis. Thereby, the cells circumvent a potential dismal depletion of serine in the TME, an amino acid that is essential for protein, lipid and nucleotide synthesis [2 into the TME from metabolically active cancer cells impacts the pH. This can in turn prompt invasion, e.g., via NFκB, leading to the release of MMP9 and the degradation of the ECM [Another advantage gained by tumours in response to stressful nutrient-poor conditions is the selection of clones within the tumour that harbour genetic mutations that offer them survival advantage over other cells in the TME. One example is the selection for cells overexpressing GLUT1 in glucose-reduced conditions . Furtherynthesis ,103,104.ynthesis . Additioynthesis ,107,108. the ECM ,110.In addition, the TME itself can also support cancer progression. A key aspect of that is sustenance, by which different cell types deposit metabolites that cancer cells use for their proliferation and growth . GlutamaIn order to enter the bloodstream, metastasising cells show traits of EMT, allowing them to escape from the primary tumour and to intravasate . The EMTAs detailed in Organotropic metastasis describes the tendency of defined primary tumours to form metastasis in specific secondary organs . While tm values of the respective modifying enzymes [In addition to acting as substrates within specific metabolic pathways, metabolites can also have roles beyond their metabolic function. One example for this dual role is the usage of abundant pulmonary pyruvate by metastasising breast cancer cells. On the one hand, pyruvate can anaplerotically re-fill the tricarboxylic acid (TCA) cycle via the activity of pyruvate carboxylase ,138. On  enzymes .In conclusion, pathways in central carbon metabolism can be dynamically altered to adjust to metabolic constraints during the metastatic cascade. Hereby, engagement of the same central pathways can lead to distinctively different metabolic outputs. For example, cancer cells can utilise glucose as carbon-source for bioenergetics, biosynthesis or RedOx balance generating in the process different and proportionally variable amounts of co-factors, building blocks and ATP. Hereby, cancer cells in the primary tumour are for instance able to adapt their metabolism to proliferation rates that exceed the capacity limit of the ETC . MetastaIn 2, one ATP, four NADH, and one FADH2 [2 molecule. Subsequently, each acetyl-CoA enters the TCA cycle to be fully oxidised producing two CO2, three NADH, one FADH2, and one ATP [ne FADH2 . Serine ne FADH2 . This cane FADH2 . Of notene FADH2 . Complet one ATP . Glutami one ATP ,146,147.2 and acetyl-CoA in a ROS-dependent manner [t manner . This alt manner ,79,80. Ct manner ,149,150.t manner  and costt manner , the enet manner . In addi2. NADPH is used by cells as a reducing power to reduce the oxidised form of GSH, which is then in turn utilised to reduce ROS and maintain RedOx balance [ balance . In cons balance . Apart f balance ,155. Red balance ,156. Add balance ,158. ThiIt should be noted that the purpose of these tables is to illustrate how one pathway can be potentially maximised towards a certain constraint. In reality, different intermediate combinations will exist depending on the cellular and microenvironmental context. This concept of metabolic flexibility and adaptation occurs in the cell as one complex system. For the sake of simplicity, it is possible to zoom into one metabolic pathway and dissect its potential with respect to different metabolic sinks. Chapter 4 of this review will take an in-depth look into 1C metabolism and exemplarily highlight its potential in supporting each of the above-discussed constraints.2) under production of reducing equivalents and ATP. In the second cytoplasmic part of the cycle, both glycine and formate can subsequently serve as precursors for anabolic reactions or serine can be re-synthesised which then closes the 1C cycle. Thus, 1C metabolism is an example of a pathway in which catabolic and anabolic reactions are separated from each other by cellular compartmentalisation.Folate-mediated 1C metabolism describes a series of biochemical reactions that governs the transfer of 1C units from donor metabolites to different acceptors  144,159159,160. 3-THF for the remethylation of homocysteine to methionine + to NAD(P)H, a RedOx-relevant reaction. As oxidation of CH2-THF is located in the mitochondrion, the generated NADH can readily be oxidised at complex I of the ETC, which generates 2.5 mol ATP per mol NADH. It is under debate if the oxidation of CH2-THF in cancer cells is coupled to NAD+ or NADP+. Early in vitro results pointed towards NAD+ [2-THF [2-THF depends on NAD+ and active respiration. This is supported by a recent study showing that MTHFD2 can still oxidise 1C units at decreasing NAD+/NADH levels at which enzymes of the TCA cycle are already inhibited [To generate formate, the 1C unit CHrds NAD+ , while l+ [2-THF . Yet, a + [2-THF ,168 indinhibited . In suchnhibited ,170. Thunhibited ,161. Hen2-THF by the activity of MTHFD2, formate can either be further oxidised by ALDH1L2 to CO2 under production of NADPH or released from THF under production of ATP. Hence, depending on the environmental condition, the fate of 1C units can differ and the catabolism of serine can support RedOx and/or bioenergetics. Under standard cell culture conditions, it was observed that in proliferating cells the largest fraction of generated 1C units are excreted in the form of formate in a process designated as formate overflow despite the cell’s high demand of 1C units for nucleotide synthesis [Once formyl-THF (CHO-THF) has been generated from CHynthesis . In a suynthesis . Releaseynthesis . Whetherynthesis .In summary, the overall balance of mitochondrial serine catabolism is:2 via glycolysis and TCA cycle. Compared to glutamine oxidation, serine catabolism has also a reduced NADH burden, which could be of advantage in cancer cells that are likely to struggle to regenerate sufficient NAD+. Thus, in growth-independent conditions or glucose-deprived TME, catabolism of serine could be an attractive pathway to exploit serine as an energy substrate. Alternatively, if, e.g., the level of oxidative stress and therefore the demand for reducing equivalents rises, formate could instead be directed to ALDH1L2 for full oxidation and concomitant NADPH production [In the case of NADH oxidation via the ETC and formate excretion, the catabolism of serine generates 3.5 ATP with only four enzymatic reactions, which equals 0.88 mol ATP per reaction . This isoduction ,154.2-THF by cytosolic MTHFD1. CH2-THF is required for the synthesis of the pyrimidine thymine and it has been shown that most CH2-THF for dTMP synthesis is derived from the mitochondrion [+-dependent [2-THF in the cytoplasm results in net consumption of NADPH. Experimental evidence showing that a significant fraction of serine-derived 1C units are resynthesized to serine in the cytoplasm indicates that 1C cycle consumes NADPH [2 by ALDH1L2 or ALDH1L1, if maintenance of the RedOx balance is the major cellular constraint (If formate is not excreted from the cytoplasm, it can be bound again to THF under consumption of 1 ATP, which renders the ATP balance of the 1C cycle zero. Cytosolic CHO-THF can then be used for purine synthesis or alternatively be reduced to CHhondrion . Interesependent . Thus, res NADPH . Followinstraint  as in thGiven these biochemical relations, it nevertheless remains debatable if 1C metabolism represents a general major source for cellular NADPH. At first, in a pioneering study, 1C metabolism got into the spotlight for being a major contributor to cellular NADPH metabolism . HoweverEven if not critical for the cytosolic NADPH pool, 1C metabolism could be of relevance for NADPH homeostasis in the mitochondrion under certain environmental conditions as has been shown previously . However1C metabolism has also a significance on a systemic level. In a nutshell, most oxidative organs show glycine and formate overflow, while the kidney and especially the liver are thought to be glycine and formate sinks and to re-synthesise serine ,170,173.By in-depth discussion of the example of 1C metabolism flexibility, it was illustrated how a single metabolic pathway can play different roles in bioenergetics, biosynthesis and RedOx homeostasis. It highlights thereby that cellular metabolism has the potential to adapt to different constraints within the TME. The observation that nutrient availability can crucially alter the directionality and output of a plethora of metabolic pathways shows how vital the microenvironment is in dictating metabolic rewiring.It appears that, during dissemination, nutrient catabolism is not used for proliferation but instead can be exploited for survival and motility. During metastasis, cells are in cell cycle phase G0/G1  and consWe are just now starting to understand how the detailed metabolic adaptations towards these metastatic constraints and demands look like. However, we currently lack sufficient in-depth knowledge and quantitative insight on these adaptation processes. Being able to comprehensively understand the dimensionality of metabolic adaptations and the intricate ways they manifest will allow for the design of tailored intervention strategies directed specifically against more dormant, metastasis-prone tumour cells. As potential interventions can vary from patient to patient, precision medicine and appendant patient-specific analysis of cancer metabolism may open new possibilities to define individual treatment regimens, even though there is still a long way to go to attain this final goal.


As the most basic governmental unit in China, counties could better capture the regional heterogeneity than provinces and prefecture-level city, and county-level CO2 emissions could be used for the development of strategic policies tailored to local conditions. However, most of the previous accounts of CO2 emissions in China have only focused on the national, provincial, or city levels, owing to limited methods and smaller-scale data. In this study, a particle swarm optimization-back propagation (PSO-BP) algorithm was employed to unify the scale of DMSP/OLS and NPP/VIIRS satellite imagery and estimate the CO2 emissions in 2,735 Chinese counties during 1997–2017. Moreover, as vegetation has a significant ability to sequester and reduce CO2 emissions, we calculated the county-level carbon sequestration value of terrestrial vegetation. The results presented here can contribute to existing data gaps and enable the development of strategies to reduce CO2 emissions in China.With the implementation of China’s top-down CO Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.13090370 An increasing number of studies have focused on topics such as CO2 emissions accounts9, driving forces of CO2 emissions11, forecasting future emissions, and more13. However, most of this research has been conducted at the national, provincial16, or city level18. Actually, even within the same province or the same prefecture-level city, there can be obvious differences in CO2 emissions among counties. Research at the county-level is important for capturing regional heterogeneity and developing policies that can effectively lead to reductions in CO2 emissions.As one of the largest carbon emitters globally, China has pledged to reach the peak of its carbon emissions by 20302 emissions are required, which could help to fill the gaps in China’s CO2 emission data and could be used for the development of strategic policies that propose county specific emission reduction actions. However, very few studies have investigated the county-level emissions in China owing to low availability of data sources, and the corresponding studies have limitations in methodology, time span, and geographical coverage. These studies can be classified into two main categories:2 emissions on the basis of the published energy use data20. For example, Cai et al.19 estimated CO2 emissions of 16 counties in Tianjin, China in 2007 based on the construction of a CO2 emissions grid, which was derived from the spatial distributions of energy use from the industrial sector, agricultural sector, and residential sector. Additionally, Guan et al.20 adopted the CO2 emission coefficients provided by the IPCC and 11 types of energy use, such as coal, coke, coal gas, and natural gas, to calculate the CO2 emissions of 18 counties in the Ningxia Hui Autonomous Region during 1991–2011. The county-level CO2 emissions estimated by these studies relied on the published energy use data. Hence, the estimated emissions are always limited to a small coverage and short period, owing to the insufficient and often incomparable county-level energy use information.Previous studies calculated the county-level CO2 emissions22. Although some scholars have used several socioeconomic variables (such as urbanization ratio and population density) as the cutting index23; also the nighttime light data are always selected as proxies to downscale the total energy-related CO2 emissions22. For example, Meng et al.21 used the brightness data from Defense Meteorological Satellite Program/Operational Linescan System (DMSP/OLS) satellite imagery to downscale and estimate CO2 emissions of 287 prefecture-level cities in China during 1995–2010. Similarly, Su et al.22 calculated city-level CO2 emissions in China during 1992–2012 based on the DMSP/OLS imagery. In the present case, there are primarily two reasons for selecting lighting data: first, the brightness distribution on the surface of the earth at night is closely related to human activities; second, with advancements in remote sensing interpretation technologies, a wider time-span and coverage of global lighting data can be extracted and used. In addition, considering the advantages above, nighttime light data have also been widely accepted and applied in other research fields, such as energy use forecasting, gross domestic productivity evaluation, and population distribution estimation26.When dealing with the lack of data in cities and counties, some studies used a top-down approach to calculate their COTherefore, records of county-level CO2 emissions can be calculated at micro-level administration. However, because the DMSP/OLS images are only available up to 2013, the research period was limited. Additionally, even though Suomi National Polar-Orbiting Partnership/Visible Infrared Imaging Radiometer Suite (NPP/VIIRS) images provide another source of nighttime light brightness data after 2012, the evident gaps between the two sets of satellites’ data have hindered the construction of long-term nighttime light data sets and calculations of CO2 emissions. Thus, several studies have made attempts to unify the two sets of satellite data29. But matching the results proved difficult, and other problems involving discontinuity and saturation were encountered. Hence, there is room for further improvements.Thus, based on the available nighttime light data provided by DMSP/OLS images, China’s energy-related CO2 emissions reduction has only focused on the energy-related carbon emissions, and the influence of carbon sequestration of vegetation have always been ignored. With regard to the concept of plant carbon sequestration capacity, it is a natural carbon sequestration process, which directly counteracts the processes of emitting CO2 into the atmosphere. In addition, the natural processes mainly originate from vegetation net primary productivity (NPP) or net ecosystem productivity– vegetation in the ecosystem absorb CO2 from the air, produce carbohydrates such as glucose through photosynthesis, and release oxygen. Actually, vegetation has a significant effect on CO2 sequestration, and can account for a major part of the CO2 emissions associated with energy use. Among them, terrestrial vegetation plays a significant role in CO2 sequestration, and methods of estimation of its sequestration capacity have advanced and have been widely adopted29. Therefore, we also estimate the county-level carbon sequestration values of terrestrial vegetation, which facilitates more comprehensive research on reducing CO2 emissions in China and evaluating sustainable develoment30.In addition, existing literature on CO2 emissions mitigation.Thus, our present study makes the following marginal contributions to this field of research: (1) we developed a new model and employed a particle swarm optimization-back propagation (PSO-BP) algorithm to unify the scale of DMSP/OLS and NPP/VIIRS images during 1997–2017, which obtain superior fitting effects than those of previous studies based on original models and normal econometrics; (2) we adopted the PSO-BP algorithm to downscale the provincial energy-carbon emissions based on the nighttime light data, and calculated 2,735 county-level energy-related carbon emissions during 1997–2017; and (3) we estimated the corresponding county-level carbon sequestration values of terrestrial vegetation, which is an issue that has rarely been considered in previous studies and plays a significant role in CO2 emitter globally, our aim was to facilitate the determination of carbon reduction status in China and to address current data gaps in China. In addition, our research results could facilitate energy saving and emissions reduction activities and efforts in other countries, especially in other developing countries.Since China is one of the largest CO2 emissions as a research focus. Our study areas cover 2,735 counties of 30 provinces in China mainland  based on the accessibility of data sets, which cover approximately 87% of China’s land area, over 90% of the population, and 90% of the GDP.As the most basic governmental unit in China, counties should play important roles in the implementation of emission reduction policies from the central, provincial, and municipal governments. Therefore, we selected county-level CO2 emissions (1997–2017) and carbon sequestration values for terrestrial vegetation (2000–2017). The estimated boundary for energy-related CO2 emissions lies in Scope 2 proposed by the Climate Action Registry (CAR) and other institutes, which is consistent with Meng et al.21, Su et al.22, and Zhao et al.28.Our estimated and provided data sets include energy-related CO32 and NPP/VIIRS33 images) and net primary productivity data of terrestrial vegetation (which were provided by the MODIS NPP products34). Considering that there are several problems in the satellite images, such as discontinuities, the white noise, and fill values, these data sets need to be pre-processed before they can be further used.Three satellite data sets were used in our study: two types of nighttime light data  used by Chen et al.30, we obtained the carbon sequestration values of terrestrial vegetation, including Evergreen Needleleaf Forest (ENF), Evergreen Broadleaf Forest (EBF), Deciduous Needleleaf Forest (DNF), Deciduous Broadleaf Forest (DBF), Mixed forests (MF), Closed Shrublands (CShrub), Open Shrublands (OShrub), Woody Savannas (WSavanna), Savannas (Savanna), grassland (Grass), and Croplands (Crop). Based on vector cutting, we obtained the county-level nighttime light values and carbon sequestration values of vegetation. The vector map of county-level cities in China in 2015 was derived from the National Geomatics Center of China, which is consistent with the work of Lv et al.27 and Zhao et al.28.The MOD17A3 products provided by the National Aeronautics and Space Administration (NASA) have fill values and need to be multiplied by a 0.0001 conversion factor. Next, following the user guides36. However, the mechanisms for explaining the differences remain like a “Black Box,” and any fixed functional form for the inter-calibration between DMSP/OLS and NPP/VIIRS data may fail to produce a good match between the two sets of data and lead to large errors. Therefore, in the present study, we used an artificial neural network (ANN) to explore the relationship between the DMSP/OLS and NPP/VIIRS data rather than conventional econometric methods, because the conventional methods often fail to model the non-linear relationships41.Because the DMSP/OLS and NPP/VIIRS images were derived from different types of satellites, there are evident gaps in the two sets of data. Specifically, there are discrepancies caused by various factors such as the use of different sensors, different spatial resolutions, different spread functions, and so on43, the BP algorithm was adopted in this research. However, given that the BP algorithm can lead to data at local extremes and training failures, we also combined the BP algorithm with particle swarm optimization (PSO)—PSO has shown great potential in exploring the global optimistic results45.Additionally, because the back-propagation (BP) algorithm has performed well in previous studies for constructing regressions and obtaining local optimistic resultset al.28 and selected the county-level mean pixel values of NPP/VIIRS in 2013 .As for the input parameters, we followed the approach of Zhao C1 and C2 both as 2.0, the maximum iteration number as 50, and the population size as 2046. Additionally, the structure of the model was set as one hidden layer with five nodes in the hidden layer, which is consistent with the work of Mohamad et al.45 The total number of samples was 2,826. Among these, 2,000 samples were randomly selected as training samples, whereas the other 826 samples were used as testing samples. The calculation procedure for the PSO-BP model was consistent with the work of Mohamad et al.45 and Yin et al.47.Based on initializing the ANN weights with the PSO technique, we set values of To test the validity of the PSO-BP algorithm and the proposed supplementary input parameters, we also trained the BP algorithm and corresponding algorithm without the supplementary input parameters as control groups. The best training results are presented in Fig. a for the testing dataset indicated that the proposed PSO-BP algorithm reliably matched the DMSP/OLS images with NPP/VIIRS images in later years . The correlation coefficient, R2, based on our method, was 0.955, which was significantly higher than values obtained previously, including the 0.8354 of Lv et al.27, 0.9154 of Zhao et al.28, and 0.91 of Li et al.36.Figure Furthermore, the matching work has not yet been completed. Although the correlation coefficient is close to 1, there were evident and unavoidable faults in some counties in 2013  and 2014 , which also exist in previous studies. Therefore, we make use of the annual increase amounts of converted NPP/VIIRS data during 2013–2017 to obtain the final simulated DMSP/OLS data during 2014–2017, avoiding the shortcoming of faults and discontinuities in some regions during 2013–2014.2 emissions.In summary, based on the PSO-BP algorithm, we could confidently convert the scale of NPP/VIIRS data during 2013–2017 to the scales of DMSP/OLS data and obtain stable and continuous county-level nighttime light data during 1997–2017, which lay a foundation for further calculations of county-level CO2 emissions and nighttime light data  in this study; then, the sum of the DN values was used as a proxy to estimate the county-level carbon emissions.Because provincial energy balance tables were available and there was a lack of energy use data for various counties, we first established the relationship between provincial CO2 emissions were carried out based on the following method provided by the Intergovernmental Panel on Climate Change (IPCC), which has been widely adopted49:2 emissions from energy use (unit: million tons); jth type of energy use in province i; jth energy consumption; jth energy source; and jth energy source. In addition, 17 types of fossil fuel used are considered, including raw coal, cleaned coal, other washed coal, briquettes, gangue, coke, coke oven gas, blast furnace gas, converter gas, other gases, other coking products, crude oil, gasoline, kerosene, diesel oil, fuel oil, naphtha, lubricants, paraffin, white spirit, bitumen asphalt, petroleum coke, other petroleum products, liquefied petroleum gas (LPG), refinery gas, and natural gas.First, the estimations of provincial CO2 emissions c, and sum of DN values sdn. The results are presented in Table 50, which has been widely accepted in the field of econometrics53. The majority of tests led to the rejection of the null hypothesis of no co-integration, thus suggesting that there was significant co-integration among the provincial carbon emissions and sum of DN values.Subsequently, to avoid spurious regression problems, we adopted the unit root test to verify the relationship between provincial CO2 emissions and nighttime light data is non-linear, the normal econometric methods may lead to relatively high errors27; here, we employed the PSO-BP algorithm to fit and train the relationship. We selected the sum of DN values, dummy variables of identity, and year as the input parameters, and the provincial CO2 emissions were the output parameter. In addition, the other initialized parameters were consistent with those discussed in the earlier section on the inter-calibration. The results are presented in Fig. Furthermore, considering that the relationship between provincial CO2 of 0.9895 was higher than the 0.94 of Meng et al.21 and 0.6922 of Lv et al.27 estimated based on conventional econometric methods. Then, based on the concept of the top-down method and a DN value-based weighted-average strategy41, we obtained the county-level carbon emissions.The test and training results showed great fitting effects, which were indicative of the high effectiveness of the algorithm. Notably, the coefficient of determination R2 emissions caused by energy use and carbon sequestration values of terrestrial vegetation). Among them, there were 2,735 CO2 emission county data records associated with energy use (1997–2017), and corresponding 2,735 carbon sequestration values associated with terrestrial vegetation (2000–2017).A total of 5470 data records  after the inter-calibration based on the PSO-BP algorithm. Evidently, there was a gap between the scale of DMSP/OLS and NPP/VIIRS images before the matching. Additionally, the trend of our inter-calibrated results continuously increased, which is consistent with previous studies28.On the basis of the inter-calibration method described earlier, we were able to obtain continuous and stable county-level nighttime light DN values during 1997 to 2017, and the sum of DN values is presented in Fig. 56 and power consumption data59, we used the provincial cross-sectional gross domestic product (GDP) and power consumption to individually perform linear regressions with the sum of DN values (sdn) during 1997–2017. These results are presented in Table Subsequently, because nighttime light data tend to be highly consistent with economic outputsdn during 1997–2017. All of the R2 values were over 0.87, and the AIC values were small, thus implying that inter-calibrated nighttime light data characterized the economic output well. Simultaneously, in regard to the Model (2) results shown in Table 2 values were high, and the AIC values were small.With regard to the Model (1) results shown in Table et al.30 and, therefore, was deemed a reliable measure. With regard to the validity of energy-related carbon emissions based on the nighttime light data, we made use of the national and provincial energy-related CO2 emissions provided by existing studies61 to conduct a comparison with the summary of our simulated energy-related carbon emissions. These results are presented in Fig. 2 emissions with the CO2 emissions based on existing literature during 1997–2017. The results in each graph were highly consistent, thus indicating that the simulated CO2 emissions based on the nightlight data are reliable.The method of calculation of carbon sequestration value of terrestrial vegetation is consistent with that in Chen 2 emissions are based only on the nighttime light data, overlooking other factors such as urbanization rate, population, and earth surface temperature. Secondly, our estimated carbon sequestration values only include carbon sequestration capacity of terrestrial vegetation, without taking into account ocean carbon sequestration capacity62.Our datasets have several limitations, which we will address in the future to improve the accuracy of China’s county-level emission accounts. First, our estimated county-level COet al.63, to improve the accuracy of the calculated county-level carbon emissions. We will further analyze the carbon sequestration capacity of mangrove vegetation to enrich the estimated county-level carbon sequestration data.Therefore, our future work will include two aspects: first, we will combine night light data with other satellite data such as earth surface temperature provided by MOD11A2, and impervious surface data provided by Gong 2 emissions at county-level rather than the nation3, province5 or prefecture-level27. Additionally, it can be used to further evaluate the emission reductions20 or construct budget allocation of CO2 emission rights in the county.First, the China mainland’s 2,735 county-level energy-related carbon emissions data is provided and has the advantages of wide coverage and long time-span. The data set can help fill the existing data gaps and be further used in future research. For example, scholars can use the data to further analyze the driving forces of the CO2 emissions, the dataset of the 2,735 county-level carbon sequestration values of vegetation can be combined with our provided county-level energy-related CO2 emissions. Evidently, the dataset could facilitate further comprehensive analyses and research on China’s emissions mitigation65, the gap between CO2 emissions and carbon sequestration, and comprehensive evaluation of sustainable development65.Second, considering that vegetation plays a significant role in sequestrating and reducing CO2 emissions and carbon sequestration values for vegetation. Because of the availability of the original data, the energy-related CO2 emissions data span 1997–2017, while the carbon sequestration values of vegetation data span 2000–2017. Similarly, we have to point out that our study areas only include China mainland. The units of county-level CO2 emissions and carbon sequestration values provided are million tons.Additionally, the present study was limited by differences in time spans of the energy-related COSupplementary File 1