Cutting Edge: l-Arginine Transfer from Antigen-Presenting Cells Sustains CD4+ T Cell Viability and Proliferation.

Metabolomics analyses suggest changes in amino acid abundance, particularly l-arginine (L-ARG), occur in patients with tuberculosis. Immune cells require L-ARG to fuel effector functions following infection. We have previously described an L-ARG synthesis pathway in immune cells; however, its role in APCs has yet to be uncovered. Using a coculture system with mycobacterial-specific CD4+ T cells, we show APC L-ARG synthesis supported T cell viability and proliferation, and activated T cells contained APC-derived L-ARG. We hypothesize that APCs supply L-ARG to support T cell activation under nutrient-limiting conditions. This work expands the current model of APC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.

Test-dose pharmacokinetics guided melphalan dose adjustment in reduced intensity conditioning allogeneic transplant for non-malignant disorders.

AIMS: We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan. METHODS: Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m2 or 4.7 mg/kg in patients <10 kg). Melphalan concentration was measured by liquid chromatography electrospray ionization tandem mass-spectrometry assay and data were analysed using a population-PK model and Bayesian estimation. Test and full-dose melphalan clearance estimates were evaluated by pairwise Wilcoxon test and Bland-Altman plot. RESULTS: Twenty-four patients undergoing 25 transplants were included in the final analysis. Patients received standard full-dose melphalan in 17 transplants, with median area under the concentration-time curve (AUC) of 5.5 mg*h/L (range, 3.0-9.5 mg*h/L). Patients received test-dose melphalan in 23 transplants with a test-dose PK predicted full-dose AUC range of 2.9-16.8 mg*h/L. In seven transplants where patients had baseline organ impairment, test-dose PK predicted higher exposure for standard full-dose (median AUC 13.8 mg*h/L). Melphalan full-dose was adjusted in these patients, with achievement of desired target AUC (3.6-5.4 mg*h/L) and no excess toxicity. Mean ratio of test-dose clearance to full-dose clearance was 1.03. Twenty of 22 patients (91%) were within the 95% confidence intervals of the clearance ratio. CONCLUSION: Melphalan test-dose PK reliably predicts full-dose PK and allows for accurate adjustment of full-dose melphalan in RIC-HCT for NMD. This approach can avoid excess toxicity from increased systemic exposure, especially in patients with organ impairment.

Prognostic validity of the American joint committee on cancer eighth edition staging system for well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: The American Joint Committee on Cancer (AJCC) made improvements for staging pancreatic neuroendocrine tumors (pNETs) in its 8th Edition; however, multicenter studies were not included. METHODS: We collected multicenter datasets (n = 1,086, between 2004 and 2018) to validate the value of AJCC 8 and other coexisting staging systems through univariate and multivariate analysis for well-differentiated (G1/G2) pNETs. RESULTS: Compared to other coexisting staging systems, AJCC 7 only included 12 (1.1%) patients with stage III tumors. Patients with European Neuroendocrine Tumor Society (ENETS) stage IIB disease had a higher risk of death than patients with stage IIIA (hazard ratio [HR]: 4.376 vs. 4.322). For the modified ENETS staging system, patients with stage IIB disease had a higher risk of death than patients with stage III (HR: 6.078 vs. 5.341). According to AJCC 8, the proportions of patients with stage I, II, III, and IV were 25.7%, 40.3%, 23.6%, and 10.4%, respectively. As the stage advanced, the median survival time decreased (NA, 144.7, 100.8, 72.0 months, respectively), and the risk of death increased (HR: II = 3.145, III = 5.925, and IV = 8.762). CONCLUSION: These findings suggest that AJCC 8 had a more reasonable proportional distribution and the risk of death was better correlated with disease stage.

Bile Acid Profiling Reveals Distinct Signatures in Undernourished Children with Environmental Enteric Dysfunction.

BACKGROUND: Intestinal inflammation and malabsorption in environmental enteric dysfunction (EED) are associated with early childhood growth faltering in impoverished settings worldwide. OBJECTIVES: The goal of this study was to identify candidate biomarkers associated with inflammation, EED histology, and as predictors of later growth outcomes by focusing on the liver-gut axis by investigating the bile acid metabolome. METHODS: Undernourished rural Pakistani infants (n = 365) with weight-for-height Z score (WHZ) < -2 were followed up to the age of 24 mo and monitored for growth, infections, and EED. Well-nourished local children (n = 51) were controls, based on consistent WHZ > 0 and height-for-age Z score (HAZ) > -1 on 2 consecutive visits at 3 and 6 mo. Serum bile acid (sBA) profiles were measured by tandem MS at the ages of 3-6 and 9 mo and before nutritional intervention. Biopsies and duodenal aspirates were obtained following upper gastrointestinal endoscopy from a subset of children (n = 63) that responded poorly to nutritional intervention. BA composition in paired plasma and duodenal aspirates was compared based on the severity of EED histopathological scores and correlated to clinical and growth outcomes. RESULTS: Remarkably, >70% of undernourished Pakistani infants displayed elevated sBA concentrations consistent with subclinical cholestasis. Serum glycocholic acid (GCA) correlated with linear growth faltering (HAZ, r = -0.252 and -0.295 at the age of 3-6 and 9 mo, respectively, P <0.001) and biomarkers of inflammation. The proportion of GCA positively correlated with EED severity for both plasma (rs = 0.324 P = 0.02) and duodenal aspirates (rs = 0.307 P = 0.06) in children with refractory wasting that underwent endoscopy, and the proportion of secondary BA was low in both undernourished and EED children. CONCLUSIONS: Dysregulated bile acid metabolism is associated with growth faltering and EED severity in undernourished children. Restoration of intestinal BA homeostasis may offer a novel therapeutic target for undernutrition in children with EED. This trial was registered at clinicaltrials.gov as NCT03588013.

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo.

Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline-generating (i.e., iNOS) and l-citrulline-using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.

Model-Informed Bayesian Estimation Improves the Prediction of Morphine Exposure in Neonates and Infants.

BACKGROUND: Pain control in infants is an important clinical concern, with potential long-term adverse neurodevelopmental effects. Intravenous morphine is routinely administered for postoperative pain management; however, its dose-concentration-response relationship in neonates and infants has not been well characterized. Although the current literature provides dosing guidelines for the average infant, it fails to control for the large unexplained variability in morphine clearance and response in individual patients. Bayesian estimation can be used to control for some of this variability. The authors aimed to evaluate morphine pharmacokinetics (PKs) and exposure in critically ill neonates and infants receiving standard-of-care morphine therapy and compare a population-based approach to the model-informed Bayesian techniques. METHODS: The PKs and exposure of morphine and its active metabolites were evaluated in a prospective opportunistic PK study using 221 discarded blood samples from 57 critically ill neonates and infants in the neonatal intensive care unit. Thereafter, a population-based PK model was compared with a Bayesian adaptive control strategy to predict an individual's PK profile and morphine exposure over time. RESULTS: Among the critically ill neonates and infants, morphine clearance showed substantial variability with a 40-fold range (ie, 2.2 to 87.1, mean 23.7 L/h/70 kg). Compared with the observed morphine concentrations, the population-model based predictions had an R of 0.13, whereas the model-based Bayesian predictions had an R of 0.61. CONCLUSIONS: Model-informed Bayesian estimation is a better predictor of morphine exposure than PK models alone in critically ill neonates and infants. A large variability was also identified in morphine clearance. A further study is warranted to elucidate the predictive covariates and precision dosing strategies that use morphine concentration and pain scores as feedbacks.

Downregulation of MicroRNA-551b Correlates With Dissemination of Human Oral Squamous Cell Carcinoma.

PURPOSE: Altered expression of microRNAs contributes to invasion and metastasis of many human cancers; however, the importance of microRNAs in head and neck cancers remains to be elucidated. In this study, we examined whether altered microRNA (miR)-551b expression correlated with invasive phenotypes of human oral squamous cell carcinoma (OSCC) in vivo and in vitro. MATERIALS AND METHODS: Real-time polymerase chain reaction was used to detect the expression level of miR-551b in 71 OSCC tissues with lymph node metastasis and 50 nonmetastatic OSCC tissues. We also constructed miR-551b mimic-transfected cell lines HN4 and HN12. The effects of overexpressing miR-551b on the proliferation, migration, and invasion of OSCC cells were examined using Cell Counting Kit 8 (Dojindo, Kumamoto, Japan), plate clone formation, wound healing, and Transwell invasion experiments (Corning, Corning, NY). The association between clinical pathologic parameters and the expression level of miR-551b was analyzed using Kaplan-Meier survival analysis. RESULTS: The expression of miR-551b measured 0.33 ± 0.11 in the 71 OSCC tissues with lymph node metastasis versus 0.54 ± 0.06 in the 50 tissues with non-lymph node metastasis (P = .021). Regarding OSCC patients, the expression of miR-551b negatively correlated with patients' overall survival (P = .035). The ectopic expression of miR-551b inhibited the invasion and migration of OSCC cells. CONCLUSIONS: This is the first report showing that reduced miR-551b expression may be an event leading to OSCC invasion and metastasis.

Development and Characterization of MDR1 (Mdr1a/b) CRISPR/Cas9 Knockout Rat Model.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 [MDR1 (also known as P-glycoprotein)] is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (Mdr1a/b) double-knockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (-/-) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (-/-) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation.

A two-photon fluorescent probe for basal formaldehyde imaging in zebrafish and visualization of mitochondrial damage induced by FA stress.

The detection of mitochondrial formaldehyde (FA) is of great significance because FA is generated through a one-carbon formaldehyde cycle in mitochondria, and abnormal elevations in FA levels can damage mitochondria by decreasing the mitochondrial membrane potential and inhibiting mitochondrial respiration. Herein, a mitochondria-targetable two-photon probe (Mito-FA-FP) has been well demonstrated. Mito-FA-FP is conjugated with hydrazine as the FA-reactive site and a pyridine derivate as the mitochondria-targetable moiety. After reacting with FA, Mito-FA-FP exhibits dramatic fluorescence enhancement (12-fold) due to suppression of the PET process in the probe and presents good selectivity as well as high sensitivity (LOD: 12.4 µM). Moreover, Mito-FA-FP can be utilized to monitor endogenous FA in mitochondria and evaluate mitochondrial damage caused by FA stress through observing mitochondrial morphology changes. With good two-photon absorption cross-section and high two-photon fluorescence contrast, Mito-FA-FP has been successfully employed for the two-photon fluorescence imaging of basal FA in zebrafish.

Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases.

BACKGROUND: An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM). METHODS: Patients who received neoadjuvant chemotherapy and underwent partial hepatectomy for CRLM between 2008 and 2014 were included. Liver and tumour specimens were histologically examined for CALI (steatosis, steatohepatitis, sinusoidal dilatation [SD], nodular regeneration) and tumour regression grade (TRG). TRG 1-2 was defined as complete tumour response. RESULTS: 166 consecutive patients were included with a median survival of 30 and 44 months for recurrence-free and overall survival, respectively. Grade 2-3 SD was found in 44 (27%) and TRG 1-2 was observed in 33 (20%) patients. Of studied CALI, only grade 2-3 SD was associated with increased TRG 3-5 (odds ratio 3.99, 95% CI 1.17-13.65, p = 0.027). CALI was not significantly related to survival. TRG 1-2 was associated with prolonged recurrence-free (hazard ratio 0.47, 95% CI 0.25-0.89, p = 0.020) and overall survival (hazard ratio 0.35, 95% CI 0.18-0.68, p = 0.002). CONCLUSION: CALI was not directly related to survival. CALI was, however, associated with diminished complete tumour response, and diminished complete tumour response, in turn, was associated with decreased survival.

Differential Requirements for L-Citrulline and L-Arginine during Antimycobacterial Macrophage Activity.

Microbicidal NO production is reliant on inducible NO synthase-mediated L-arginine metabolism in macrophages (MΦs). However, L-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting L-citrulline to L-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied L-arginine, L-citrulline, or both amino acids. Using liquid chromatography-tandem mass spectrometry, we determined that L-arginine synthesized from L-citrulline was less effective as a substrate for arginase-mediated L-ornithine production compared with L-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette-Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from L-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in L-arginine. Furthermore, we found that arginase-expressing MΦs preferred L-citrulline over L-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of L-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.

Radical-induced dissociation leading to the loss of CO2 from the oxazolone ring of [b5- H]˙(+) ions.

Macrocyclization is commonly observed in large bn(+) (n≥ 4) ions and as a consequence can lead to incorrect protein identification due to sequence scrambling. In this work, the analogous [b5- H]˙(+) radical cations derived from aliphatic hexapeptides (GA5˙(+)) also showed evidence of macrocyclization under CID conditions. However, the major fragmentation for [b5- H]˙(+) ions is the loss of CO2 and not CO loss, which is commonly observed in closed-shell bn(+) ions. Isotopic labeling using CD3 and (18)O revealed that more than one common structure underwent dissociations. Theoretical studies found that the loss of CO2 is radical-driven and is facilitated by the radical being located at the Cα atom immediately adjacent to the oxazolone ring. Comparable energy barriers against macrocyclization, hydrogen-atom transfer, and fragmentations are found by DFT calculations and the results are consistent with the experimental observations that a variety of dissociation products are observed in the CID spectra.

Dysregulated miR-645 affects the proliferation and invasion of head and neck cancer cell.

BACKGROUND AND PURPOSE: Dysregulated miRNAs play an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we identified the differentially expressed miR-645 in the progressing of head and neck squamous cell carcinoma (HNSCC) and investigated its biological function. METHODS: The association between clinicopathological parameters and the expression levels of the candidated miRNAs were analyzed by using the Kaplan-Meier survival analysis. The cell growth, invasion and migration potential, and clone formation were observed to detect the functions of the miRNAs in HNSCC cells. RESULTS: In the 34 HNSCC tissues with lymph node metastasis, the expression level of miR-645 was 0.54 ± 0.12, and the expression level was 0.22 ± 0.05 in the 28 tissues with non lymph node metastasis (p = 0.017). In patients with HNSCC, higher level of miR-645 expression significantly correlates with worse overall survival (p = 0.04). Ectopic expression of miR-645 promoted cell invasion and migration. CONCLUSIONS: miR-645 play a key role in cell invasion and metastasis and their expression correlates with overall survival in the patients with HNSCC.

Radical-induced, proton-transfer-driven fragmentations in [b(5)-H]˙(+) ions derived from pentaalanyl tryptophan.

The collision-induced dissociation (CID) of [b5 - H]˙(+) ions containing four alanine residues and one tryptophan give identical spectra regardless of the initial location of the tryptophan indicating that, as proposed for b5(+) ions, sequence scrambling occurs prior to dissociation. Cleavage occurs predominantly at the peptide bonds and at the N-Cα bond of the alanine residue that is attached to the N-terminus of the tryptophan residue. The product of the latter pathway, an ion at m/z 240, is the base peak in all the mass spectra. With the exception of one minor channel giving a b3(+) ion, the product ions retain both the tryptophan residue and the radical. Experiments with one trideuterated alanine established the sequences of loss of alanine residues. Formation of identical products implies a common intermediate, a [b5 - H]˙(+) ion that has a 'linear' structure in which the tryptophan residue is present as an α-radical located in the oxazolone ring, structure Ie. Density functional theory calculations show this structure to be at the global minimum, 14.6 kcal mol(-1) below the macrocyclic structure, ion II. Loss of CO from the [b5 - H]˙(+) ions is inhibited by the presence of the radical centre in the oxazolone ring and migration of the proton from the oxazolone ring onto the peptide backbone induces cleavage of an N-Cα or peptide bond. Three calculated structures for the ion at m/z 240 all have an oxazolone ring. Two of these structures may be formed from Ie, depending upon which proton migrates onto the peptide chain prior to the dissociation. The barrier to interconversion between these two structures requires a 1,3-hydrogen atom shift and is high (51.0 kcal mol(-1)), but both can convert into a third isomer that readily loses CO2 (barrier 38.7 kcal mol(-1)). The lowest barrier to the loss of CO, the usual fragmentation path observed for protonated oxazolones, is 47.0 kcal mol(-1).

Subtractive screen of potential limb regeneration related genes from Pachytriton brevipes.

Regeneration capacity varies greatly among different animal species. In vertebrate, amphibian especially the Urodela, has been used as a powerful model system to study the mechanism of tissue regeneration because of the strong ability to regenerate their damaged or lost appendages. Pachytriton brevipes, a species of newt, which is widely distributed in south of China, can completely restore their damaged limbs within several months. In this study, we use modified suppression subtractive hybridization assay and dot-blot screening to identify candidate genes involved in tissue regeneration in P. brevipes. We successfully isolated 81 ESTs from a forward regeneration subtraction library. And we further verified the differential expression of four candidate genes, Rpl11, Cirbp, Ag2 and Trimx, between regenerating blastema and non-regeneration tissues by in situ hybridization. These genes were also be further characterized by phylogenetic and bioinformatic analysis. In general, we provided a comparative experimental approach to study the mechanisms of vertebrate regeneration.

Bifurcations of orbit and inclination flips heteroclinic loop with nonhyperbolic equilibria.

The bifurcations of heteroclinic loop with one nonhyperbolic equilibrium and one hyperbolic saddle are considered, where the nonhyperbolic equilibrium is supposed to undergo a transcritical bifurcation; moreover, the heteroclinic loop has an orbit flip and an inclination flip. When the nonhyperbolic equilibrium does not undergo a transcritical bifurcation, we establish the coexistence and noncoexistence of the periodic orbits and homoclinic orbits. While the nonhyperbolic equilibrium undergoes the transcritical bifurcation, we obtain the noncoexistence of the periodic orbits and homoclinic orbits and the existence of two or three heteroclinic orbits.

Use of volumetric absorptive microsampling and parallel reaction monitoring mass spectrometry for tacrolimus blood trough measurements at home in pediatric heart transplant patients.

Background: Measurement of trough levels for calcineurin inhibitors by venipuncture sampling is a mainstay of patient management in solid organ transplant recipients but challenging in pediatric patients. Volumetric Absorptive Microsampling (VAMS) is a patient-friendly, minimally invasive sampling technique to accurately collect blood. An assay for measurement of tacrolimus in blood using VAMS, coupled with parallel reaction monitoring (PRM) mass spectrometry, was validated in pediatric heart transplant patients. Methods: Tacrolimus was measured by a newly developed high-resolution PRM assay and compared with low-resolution tandem mass spectrometry (MRM). Dried blood samples were collected from pediatric heart transplant patients (n = 35) using VAMS devices and a satisfaction survey was completed by patients/guardians. Tacrolimus concentrations were compared across whole liquid blood, dried blood spots, and capillary blood, and shipping stability determined. Results: The PRM assay was linear over a range 1-50 ng/mL, similar to MRM but had greater specificity due to reduced background noise. No significant differences in tacrolimus concentrations were observed between VAMS and venous blood. Tacrolimus dried on VAM tips was stable for 14 days and concentrations were unaffected by postal shipping. The variability in two simultaneously collected at-home patient samples was minimal - average concentration difference was 0.12 ± 0.94 ng/mL (p = 0.6) between paired samples. Conclusion: A high resolution PRM mass spectrometry assay was developed for home-based dried blood collections for therapeutic monitoring of tacrolimus. The advantage of PRM was enhanced specificity and the VAMS devices provided a simple and convenient approach to blood sampling at home in pediatric heart transplant patients.

Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease.

We evaluated the pharmacokinetics (PK) of oral ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) (age <12 years) and chronic GVHD (cGVHD) (age ≤18 years) using our published pediatric dosing. PK sampling was performed before and 2 hours after ruxolitinib administration in patients with established cGVHD. More extensive PK analyses were performed in patients with newly diagnosed aGVHD or cGVHD before and .5, 1, 2, 4, and 6 hours after ruxolitinib administration in patients weighing >10 kg and before, 3+, and 6+ hours in children weighing <10 kg. pSTAT1, pSTAT3, and pSTAT5 expression levels were measured on CD4+ and CD8+ T cells before and 2 hours after ruxolitinib administration as a pharmacodynamic marker of JAK/STAT inhibition. Thirteen patients were prospectively enrolled, including 8 with existing cGVHD (age 0 to ≤18 years), 4 with new-onset steroid-refractory aGVHD (age 0 to <12 years) and 1 with newly diagnosed steroid-refractory cGVHD. Great variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (range, 3.1 to 15.3 L/h). The average elimination half-life was 2.32 ± 1.0 hours. Mean ruxolitinib clearance was higher in children age <2 years versus those age >2 years (12.1 ± 3.0 L/h versus 5.7 ± 2.8 L/h; P = .005) and was reduced with concurrent treatment with azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T cells at time of peak ruxolitinib absorption (2 hours after dosing). Children <10 kg had lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variability in dosing methods, leading to decreased drug absorption.

Carbon budget of different forests in China estimated by an individual-based model and remote sensing.

Forests play a key role in the regional or global carbon cycle. Determining the forest carbon budget is of great significance for estimating regional carbon budgets and formulating forest management policies to cope with climate change. However, the carbon budget of Chinese different forests and their relative contributions are not completely clear so far. We evaluated the carbon budget of different forests from 1981 to 2020 in China through combining model with remote sensing observation. In addition, we also determined the relative contribution of carbon budget of each forest type to all forests in China. Eight forest types were studied: evergreen coniferous forest (ECF), deciduous coniferous forest (DCF), coniferous and broad-leaved mixed forest (CBF), deciduous broad-leaved forest (DBF), evergreen broad-leaved forest (EBF), evergreen deciduous broad-leaved mixed forest (EDBF), seasonal rain forest (SRF), and rain forest (RF). The results indicated that the Chinese forests were mainly carbon sink from 1981 to 2020, particularly the annual average carbon budget of forest from 2011 to 2020 was 0.191 PgC·a-1. Spatially, the forests' carbon budget demonstrated obvious regional differences, gradually decreasing from Southeast China to Northwest China. The relative contributions of carbon budget in different forests to all forests in China were different. During 2011-2020, the ECF forests contributed the most carbon budget (34.45%), followed by DBF forests (25.89%), EBF forests (24.82%), EDBF forests (13.10%), RF forests (2.23%), SRF forests (3.14%) and CBF forests (1.14%). However, the DCF forests were found mainly as carbon source. These results contribute to our understanding of regional carbon budget of forests.

Corrigendum: Changes and net ecosystem productivity of terrestrial ecosystems and their influencing factors in China from 2000 to 2019.

[This corrects the article DOI: 10.3389/fpls.2023.1120064.].