Quaternized Acridine Maleimide MALDI Probe Enables Mass Spectrometry Imaging of Thiols.

Thiols are essential metabolites associated with redox imbalances and metabolic disorders in diseases. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) facilitates imaging of metabolites in tissue, but imaging of thiols remains challenging. Here we developed a method to visualize thiols using a stable isotope-labeled (SIL) MALDI probe, a mixture of unlabeled and deuterium-labeled reagents that provided adduct signals at [M]+ and [M + 3]+, to identify endogenous thiols in tissue. A series of MALDI probe candidates were rationally designed, and the structure-effect relationships were determined. First, the reactivity of different warheads toward the thiol group was evaluated, and maleimide was the best for in situ derivatization. Second, an acridine fragment showed the best improvement in MS responses. Third, a permanent charge was introduced for detection improvement in the positive mode. Finally, the hydrogens of methyl group were replaced by deuterium atoms, obtaining the novel SIL MALDI probe and thus facilitating significantly the annotation of thiols. The finally obtained D0/D3-9-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)carbamoyl)-10-methylacridin-10-ium iodide (D0/D3-MaI-MADA) enabled direct MSI of thiols in the fine structures of human liver tumors without a reduction procedure. Our work built a SIL MALDI probe for the first time and provided a strategy for the rational design of MALDI probes.

Neutralizing monoclonal antibody in patients with coronavirus disease 2019: an observational study.

BACKGROUND: Clinical data on patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant are limited, especially on clinical status after the application of antibody therapy. METHODS: We evaluated clinical status in patients with the SARS-CoV-2 delta variant after BRII-196 and BRII-198 treatment in an infectious disease hospital in China. We collected data on clinical symptoms, laboratory tests, radiological characteristics, viral load, anti-SARS-CoV-2 antibodies, treatment, and outcome. RESULTS: In mid-June 2021, 36 patients with delta variant infection were identified in Shenzhen. The most common symptoms at illness onset were cough (30.6%), fever (22.2%), myalgia (16.7%), and fatigue (16.7%). A small number of patients in this study had underlying diseases, including diabetes (5.6%) and hypertension (8.3%). The application of BRII-196 and BRII-198 can rapidly increase anti-SARS-CoV-2 IgG. The median peak IgG levels in the antibody treatment group were 32 times higher than those in the control group (P < 0.001). The time from admission to peak IgG levels in the antibody treatment group (mean: 10.2 days) was significantly shorter than that in the control group (mean: 17.7 days). Chest CT score dropped rapidly after antibody therapy, with a mean duration of 5.74 days from admission to peak levels. CONCLUSION: The results of this study suggest that the application of BRII-196 and BRII-198 antibody therapy improved clinical status in patients with SARS-CoV-2 delta variant infection.

COVID-19 in a designated infectious diseases hospital outside Hubei Province, China.

BACKGROUND: The clinical characteristics of novel coronavirus disease (COVID-2019) patients outside the epicenter of Hubei Province are less understood. METHODS: We analyzed the epidemiological and clinical features of all COVID-2019 cases in the only referral hospital in Shenzhen City, China, from January 11, 2020, to February 6, 2020, and followed until March 6, 2020. RESULTS: Among the 298 confirmed cases, 233 (81.5%) had been to Hubei, while 42 (14%) did not have a clear travel history. Only 218 (73.15%) cases had a fever as the initial symptom. Compared with the nonsevere cases, severe cases were associated with older age, those with underlying diseases, and higher levels of C-reactive protein, interleukin-6, and erythrocyte sedimentation rate. Slower clearance of the virus was associated with a higher risk of progression to critical condition. As of March 6, 2020, 268 (89.9%) patients were discharged and the overall case fatality ratio was 1.0%. CONCLUSIONS: In a designated hospital outside Hubei Province, COVID-2019 patients could be effectively managed by properly using the existing hospital system. Mortality may be lowered when cases are relatively mild, and there are sufficient medical resources to care and treat the disease.

A rapid and convenient derivatization method for quantitation of short-chain fatty acids in human feces by ultra-performance liquid chromatography/tandem mass spectrometry.

RATIONALE: Short-chain fatty acids (SCFAs) are associated with intestinal microbiota and diseases in humans. SCFAs have a low response in mass spectrometry, and in order to increase sensitivity, reduce sample consumption, shorten analysis time, and simplify sample preparation steps, a derivatization method was developed. METHODS: We converted seven SCFAs into amide derivatives with 4-aminomethylquinoline. The reaction occurred for 20 min at room temperature. The analytes were separated on a reversed-phase C18 column and quantitated in the positive ion electrospray ionization mode using multiple reaction monitoring. Acetic acid-d4 was used as the stable-isotope-labeled surrogate analyte for acetic acid in the working solutions, while the other stable-isotope-labeled standards were used as internal standards (ISs). RESULTS: Method validation showed that the intra-day and inter-day precision of quantitation for the seven SCFAs over the whole concentration range was ≤3.8% (n = 6). The quantitation accuracy ranged from 85.5% to 104.3% (n = 6). Most important, the collected feces were vortexed immediately with ethanol. CONCLUSIONS: This study provides a new derivatization method for a precise, accurate, and rapid quantitation of SCFAs in human feces using ultra-performance liquid chromatography/tandem mass spectrometry. This method successfully determined the concentration of SCFAs in human feces and could assist in the exploration of intestinal microbiota and diseases.

Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver.

In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg-1· d-1, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.

Omicron variants escape the persistent SARS-CoV-2-specific antibody response in 2-year COVID-19 convalescents regardless of vaccination.

With the ongoing COVID-19 pandemic and the emergence of various SARS-CoV-2 variants, a comprehensive evaluation of long-term efficacy of antibody response in convalescent individuals is urgently needed. Several longitudinal studies had reported the antibody dynamics after SARS-CoV-2 acute infection, but the follow-up was mostly limited to 1 year or 18 months at the maximum. In this study, we investigated the durability, potency, and susceptibility to immune evasion of SARS-CoV-2-specific antibody in COVID-19 convalescents for 2 years after discharge. These results showed the persistent antibody-dependent immunity could protect against the WT and Delta variant to some extent. However, the Omicron variants (BA.1, BA.2, and BA.4/5) largely escaped this preexisting immunity in recovered individuals. Furthermore, we revealed that inactivated vaccines (BBIBP-CorV, CoronaVac, or KCONVAC) could improve the plasma neutralization and help to maintain the broadly neutralizing antibodies at a certain level. Notably, with the time-dependent decline of antibody, 1-dose or 2-dose vaccination strategy seemed not to be enough to provide immune protection against the emerging variants. Overall, these results facilitated our understanding of SARS-CoV-2-induced antibody memory, contributing to the development of immunization strategy against SARS-CoV-2 variants for such a large number of COVID-19 survivors.

Benefit of Nasal Douche in COVID-19 Patients with Recurrence of Positive SARS-CoV-2 Viral RNA.

Purpose: The purpose was to review relevant clinical data and formulate recommendations supporting the use of saline as a simple rinse for an early reassuring intervention to reduce the occurrence of re-positive COVID-19 patients. Methods: We conducted a single-centre retrospective cohort study, which enrolled patients with confirmed re-testing positive COVID-19 during 7-60 days after discharge from Third People's Hospital of Shenzhen. By one-to-two propensity score matching for age and sex, the control group of those not re-testing positive during the same period served as matched control. Results: A total of 223 patients were included in our study, 94 in re-positive group and 129 in non-re-positive group. The result shows that the rates of nasal douche treatment in the non-re-positive group were considerably higher than that of the re-positive group. And the Ct value of nasal douche group increased faster than that of non-nasal douche group after the Ct value reaching ≥35. Further analysis revealed that the higher the Ct value at the time of readmission, the shorter the time of average Ct values to reach ≥35. Conclusion: These findings suggest that nasal douche is beneficial to shorten the time of virus nucleic acid turning negative, thereby reducing the incidence of re-positive. The prevention and control of epidemics focuses on re-positive patients with Ct values <35.

12-Month Post-Discharge Liver Function Test Abnormalities Among Patients With COVID-19: A Single-Center Prospective Cohort Study.

Objective: The longitudinal effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the liver are unknown. This study aimed to characterize dynamic changes in liver function test abnormalities in patients with COVID-19 at the acute phase and recovery phase. Methods: A prospective cohort study involved patients with COVID-19 who were admitted to Shenzhen Third People's Hospital between January 11, 2020, and April 27, 2020. Patients underwent liver function tests at hospitalization and at the outpatient visit at the 1-month, 3-month, 6-month, and 12-month follow-ups. Results: Among 461 patients, 28.4% of patients had any kind of liver function tests abnormality at admission, manifested as elevated ALT (13.0%), AST (17.6%), and GGT (15.8%) levels. The trajectory analysis indicated a marked improvement in liver function after discharge, with any kind of liver function test abnormalities of 25.1% at 1 month, 13.2% at 3 months, 16.7% at 6 months, and 13.2% at 12 months after discharge. Persistent liver function abnormalities were observed in patients with pre-existing conditions during follow-up. A significantly higher prevalence of ultrasound determined fatty liver disease was found in those patients with more frequent LFT abnormalities at follow-up. Conclusion: In this study of patients with COVID-19, liver damage in COVID-19 was usually temporary and could return to normal at the end of the 12-month follow-up.

Clinical status of patients 1 year after hospital discharge following recovery from COVID-19: a prospective cohort study.

BACKGROUND: The long-term clinical status of coronavirus disease 2019 (COVID-19) in recovered patients remains largely unknown. This prospective cohort study evaluated clinical status of COVID-19 and explored the associated risk factors. METHODS: At the outpatient visit, patients underwent routine blood tests, physical examinations, pulmonary function tests, 6-min walk test, high-resolution computed tomography (CT) of the chest, and extrapulmonary organ function tests. RESULTS: 230 patients were analyzed. Half (52.7%) reported at least one symptom, most commonly fatigue (20.3%) and sleep difficulties (15.8%). Anxiety (8.2%), depression (11.3%), post-traumatic symptoms (10.3%), and sleep disorders (26.3%) were also reported. Diffusion impairments were found in 35.4% of the patients. Abnormal chest CT scans were present in 63.5% of the patients, mainly reticulation and ground-glass opacities. Further, a persistent decline in kidney function was observed after discharge. SARS-CoV-2-specific antibodies of IgA, IgG, and IgM were positive in 56.4%, 96.3%, and 15.2% of patients, respectively. Multivariable logistic regression showed that disease severity, age, and sex were closely related to patient recovery. CONCLUSIONS: One year after hospital discharge, patients recovered from COVID-19 continued to experience both pulmonary and extrapulmonary dysfunction. While paying attention to pulmonary manifestations of COVID-19, follow-up studies on extrapulmonary manifestations should be strengthened.

Healthy outcomes of patients with COVID-19 two years after the infection: a prospective cohort study.

The long-term effect of coronavirus disease 2019 (COVID-19) has been rarely known. This study aimed to investigate healthy outcomes of COVID-19 survivors up to 2 years after the infection. A total of 155 COVID-19 patients, who were discharged from Shenzhen Third People's Hospital from February 2020 to April 2020, were enrolled and followed up until March 4, 2022. COVID-19 survivors received questionnaires of long COVID symptoms and psychological symptoms, pulmonary function tests, chest computed tomography (CT) scans and routine laboratory tests. Two years after infection, 36.6% of patients had at least one symptom of long COVID. Vision impairment and fatigue were the most common symptom. 35.0% of participants still had at least one psychological symptom of anxiety, depression, post-traumatic stress symptoms, and sleep difficulties. Radiographic abnormalities were presented in 50.7% of patients, with the most common features of fibrosis-like lesions and residual ground-glass opacity. Diffuse dysfunction (24.0%) was the main abnormalities of pulmonary function tests. Most laboratory parameters returned to normal range, while persistent abnormalities in kidney and liver function test were observed in a subset of participants after discharge. Two years after COVID-19 infection, persistent symptoms of long COVID and psychological symptoms, as well as abnormalities in pulmonary function tests and CT, were still common in a subset of recovering individuals. These findings were limited by the lack of a healthy control group and pre-COVID assessments, which should be confirmed by further large-scale studies.

Long-term sequelae of different COVID-19 variants: The original strain versus the Omicron variant.

Although Omicron appears to cause less severe acute illness than the original strain, the potential for large numbers of patients to experience long COVID is a major concern. Little is known about the recovery phase in cases of Omicron, highlighting the importance of dynamically monitor long COVID in those patients. Subjects of the current study were patients available for a three-month follow-up who were admitted from January 13 to May 22, 2020 (period of the original strain) and from January 1 to May 30, 2022 (period of Omicron). Twenty-eight-point-four percent of patients infected with the original strain had long-term symptoms of COVID-19 and 5.63% of those infected with the Omicron strain had such symptoms. The most common symptom was a cough (18.5%), followed by tightness in the chest (6.5%), in patients infected with the original strain. Fatigue (2.4%) and dyspnea (1.7%) were the most commonly reported symptoms in patients infected with the Omicron strain. The respiratory system is the primary target of SARSCoV-2. Supportive treatment is the basis for the treatment of respiratory symptoms in patients with COVID-19. Quality sleep and good nutrition may alleviate fatigue and mental issues. Further knowledge about a long-term syndrome due to Omicron needs to be discussed and assembled so that healthcare and workforce planners can rapidly obtain information to appropriately allocate resources.

Three-Month Pulmonary Function and Radiological Outcomes in COVID-19 Survivors: A Longitudinal Patient Cohort Study.

BACKGROUND: This study aimed to investigate pulmonary function and radiological outcomes in a group of coronavirus disease 2019 (COVID-19) survivors. METHODS: One hundred seventy-two COVID-19 survivors in a follow-up clinic in a referral hospital underwent high-resolution computed tomography (CT) of the thorax and pulmonary function at 3 months after hospital discharge. RESULTS: The median duration from hospital discharge to radiological and pulmonary function test (interquartile range) was 90 (88-95) days. Abnormal pulmonary function was found in 11 (6.40%) patients, and abnormal small airway function (FEF25-75%) in 12 (6.98%). Six (3.49%) patients had obstructive ventilation impairment, and 6 (3.49%) had restrictive ventilatory impairment. No significant differences in lung function parameters were observed between the nonsevere and severe groups. Of 142 COVID-19 patients who underwent CT scan, 122 (85.91%) showed residual CT abnormalities and 52 (36.62%) showed chronic and fibrotic changes. The ground-glass opacities absorption in the lungs of severe cases was less satisfactory than that of nonsevere patients. The severe patients had higher CT scores than the nonsevere cases (2.00 vs 0.00; P < .001). CONCLUSIONS: Of the COVID-19 survivors in our study, 6.40% still presented pulmonary function abnormality 3 months after discharge, which did not vary by disease severity during hospitalization; 85.91% of patients had abnormalities on chest CT, with fibrous stripes and ground-glass opacities being the most common patterns.

Pulmonary Sequelae in Patients After Recovery From Coronavirus Disease 2019: A Follow-Up Study With Chest CT.

Objective: The pulmonary sequelae of coronavirus disease 2019 (COVID-19) have not been comprehensively evaluated. We performed a follow-up study analyzing chest computed tomography (CT) findings of COVID-19 patients at 3 and 6 months after hospital discharge. Methods: Between February 2020 and May 2020, a total of 273 patients with COVID-19 at the Shenzhen Third People's Hospital were recruited and followed for 6 months after discharge. Chest CT scanning was performed with the patient in the supine position at end-inspiration. A total of 957 chest CT scans was obtained at different timepoints. A semi-quantitative score was used to assess the degree of lung involvement. Results: Most chest CT scans showed bilateral lung involvement with peripheral location at 3 and 6 months follow-up. The most common CT findings were ground-glass opacity and parenchymal band, which were found in 136 (55.3%) and 94 (38.2%) of the 246 patients at 3 months follow-up, and 82 (48.2%) and 76 (44.7%) of 170 patients at 6 months follow-up, respectively. The number of lobes involved and the total CT severity score declined over time. The total CT score gradually increased with the increasement of disease severity at both 3 months follow-up (trend test P < 0.001) and 6 months follow-up (trend test P < 0.001). Patients with different disease severity represented diverse CT patterns over time. Conclusions: The most common CT findings were ground-glass opacity and parenchymal bands at the 3 and 6 months follow-up. Patients with different disease severity represent diverse CT manifestations, indicating the necessary for long-term follow-up monitoring of patients with severe and critical conditions.

[Extraction of evoked related potentials by using the combination of independent component analysis and wavelet analysis].

In this paper we present a new method of combining Independent Component Analysis (ICA) and Wavelet de-noising algorithm to extract Evoked Related Potentials (ERPs). First, the extended Infomax-ICA algorithm is used to analyze EEG signals and obtain the independent components (Ics); Then, the Wave Shrink (WS) method is applied to the demixed Ics as an intermediate step; the EEG data were rebuilt by using the inverse ICA based on the new Ics; the ERPs were extracted by using de-noised EEG data after being averaged several trials. The experimental results showed that the combined method and ICA method could remove eye artifacts and muscle artifacts mixed in the ERPs, while the combined method could retain the brain neural activity mixed in the noise Ics and could extract the weak ERPs efficiently from strong background artifacts.

Soil microbial community shifts with long-term of different straw return in wheat-corn rotation system.

Despite the integral role of the soil microbial community in straw decomposition, we still have a limited understanding of the complex response of microbial community to long-term of crop straw return in rotation system. Here we report on the structural and functional response of the soil bacterial and fungal community to more than 10 years of straw return in wheat-corn rotation system. Compared with single-season straw return, soil microbial phosphor lipid fatty acids (PLFAs) and catabolic activity were improved more greatly with double-season straw return. The relative abundance of bacteria and fungi decreased with double-season straw return, but increased with single-season straw return. The copiotrophic bacteria were more represented in the soils with corn straw return, while oligotrophic groups were more represented in soils with wheat straw return. Compared with wheat straw return, lower fungal community diversity and higher abundance of fungal pathogen (identified to be Leptosphaeria) were observed with corn straw return, especially at high return rates. Redundancy analysis showed that soil available potassium (P = 0.008) and ratio of C to N (P = 0.048) significantly affected the soil bacterial community, while soil electric conductivity (P = 0.04) was the significant factor impacting soil fungal community. It suggests that full corn straw return might have positive impact on soil mineral nutrient but negative impact on soil fungal community diversity and pathogenic risk, mainly due to the change in soil electric conductivity.

Gigantol ameliorates CCl4-induced liver injury via preventing activation of JNK/cPLA2/12-LOX inflammatory pathway.

Arachidonic acid (AA) signaling pathway is an important constituent of inflammatory processes. In our previous study, it was found that dihydro-stilbene gigantol relieved hepatic inflammation in mice with CCl4-induced acute liver injury. This study aimed to investigate the involvement of arachidonate metabolic cascade in this process. Our results showed CCl4 activated AA metabolism with the evidence of cPLA2 phosphorylation, which was dependent on the MAPK/JNK activation. Pretreatment with JNK inhibitor SU3327 or gigantol abolished the cPLA2 activation, along with the attenuation of liver damage. Besides, gigantol markedly decreased immune cells activation. Metabolomic analysis revealed that gigantol universally reversed the upregulation of major AA metabolites in injured mouse livers induced by CCl4, especially 12-hydroxyeicosatetraenoic acid (12-HETE). Gigantol also decreased the mRNA and protein expression of platelet-, and leukocyte-type 12-lipoxxygenase (LOX) in the liver. Furthermore, pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) and specific 12-LOX inhibitors baicalein and ML351 attenuated the liver injury to the same extent as gigantol. Overall, our study elucidated a comprehensive profile of AA metabolites during hepatic inflammation caused by CCl4, highlighting the role of 12-LOX-12-HETE pathway in this process. And gigantol alleviated liver inflammation partly through inhibiting the JNK/cPLA2/12-LOX pathway.

[Progress in single-trial extraction of evoked potential].

The robust extracting of evoked potential (EP) has become a vexed question in the process of electroencephalogram owing to the faint signal-to-noise ratio of EP. This paper presents the single trial of EP in time, transform and space field. Several methods such as adaptive filter, wavelet transform, principal component analysis (PCA) and independent component analysis (ICA) have been applied to the process of EP.

Responses of Wheat Yield, Macro- and Micro-Nutrients, and Heavy Metals in Soil and Wheat following the Application of Manure Compost on the North China Plain.

The recycling of livestock manure in cropping systems is considered to enhance soil fertility and crop productivity. However, there have been no systematic long-term studies of the effects of manure application on soil and crop macro- and micro-nutrients, heavy metals, and crop yields in China, despite their great importance for sustainable crop production and food safety. Thus, we conducted field experiments in a typical cereal crop production area of the North China Plain to investigate the effects of compost manure application rates on wheat yield, as well as on the macro-/micro-nutrients and heavy metals contents of soil and wheat. We found that compost application increased the soil total N and the available K, Fe, Zn, and Mn concentrations, whereas the available P in soil was not affected, and the available Cu decreased. In general, compost application had no significant effects on the grain yield, biomass, and harvest index of winter wheat. However, during 2012 and 2013, the N concentration decreased by 9% and 18% in straw, and by 16% and 12% in grain, respectively. With compost application, the straw P concentration only increased in 2012 but the grain P generally increased, while the straw K concentration tended to decrease and the grain K concentration increased in 2013. Compost application generally increased the Fe and Zn concentrations in straw and grain, whereas the Cu and Mn concentrations decreased significantly compared with the control. The heavy metal concentrations increased at some compost application rates, but they were still within the safe range. The balances of the macro-and micro-nutrients indicated that the removal of nutrients by wheat was compensated for by the addition of compost, whereas the level of N decreased without the application of compost. The daily intake levels of micronutrients via the consumption of wheat grain were still lower than the recommended levels when sheep manure compost was applied, except for that of Mn.

[Assessment of groundwater vulnerability to nitrate in He'nan Province of China based on principal component regression].

According to the hydrological and morphological characteristics, He'nan Province was divided into mountainous region and plain region. The level of rich water, infiltration modulus of precipitation, fertilization level per unit area, proportions of vegetable planting area, and soil texture were selected as the common indices, and the slope and groundwater depth were selected as specific indices to assess the groundwater vulnerability to nitrate. Principal component regression analysis was adopted to determine the index weights, and the spatial distribution of groundwater vulnerability to nitrate in He'nan Province was assessed with ArcGIS 9.2. In the Province, the groundwater vulnerability to nitrate was mainly at low and medium level, and the region with this vulnerability level accounted for 68.4% of the total. The high vulnerability region accounted for 19.8%, and the extremely high vulnerability region occupied 11.8%. The main factors affecting the groundwater vulnerability to nitrate in plain region were soil texture, fertilization level, and infiltration modulus of precipitation, while those in mountainous region were fertilization level, soil texture, and slope. This study provided a theoretical basis for reasonable fertilization and agricultural environment management.