Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo-Nitroreductase Complex.

Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru-arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox-active metal complexes for prodrug activation via bioinspired nitroreduction.

Record-high CO2 emissions from boreal fires in 2021.

Extreme wildfires are becoming more common and increasingly affecting Earth's climate. Wildfires in boreal forests have attracted much less attention than those in tropical forests, although boreal forests are one of the most extensive biomes on Earth and are experiencing the fastest warming. We used a satellite-based atmospheric inversion system to monitor fire emissions in boreal forests. Wildfires are rapidly expanding into boreal forests with emerging warmer and drier fire seasons. Boreal fires, typically accounting for 10% of global fire carbon dioxide emissions, contributed 23% (0.48 billion metric tons of carbon) in 2021, by far the highest fraction since 2000. 2021 was an abnormal year because North American and Eurasian boreal forests synchronously experienced their greatest water deficit. Increasing numbers of extreme boreal fires and stronger climate-fire feedbacks challenge climate mitigation efforts.

Protocol to develop a microfluidic human corneal barrier-on-a-chip to evaluate the corneal epithelial wound repair process.

Organs-on-chips are microfluidic devices for cell culturing to simulate tissue- or organ-level physiology, providing new solutions other than traditional animal tests. Here, we describe a microfluidic platform consisting of human corneal cells and compartmentalizing channels to achieve fully integrated human cornea's barrier effects on the chip. We detail steps to verify the barrier effects and physiological phenotypes of microengineered human cornea. Then, we use the platform to evaluate the corneal epithelial wound repair process. For complete details on the use and execution of this protocol, please refer to Yu et al. (2022).1.

Proliferative ability of circulating tumor cells is a prognostic factor in Early-Stage lung adenocarcinoma.

INTRODUCTION: Circulating tumor cells (CTCs) and their proliferative ability in lung adenocarcinoma (LUAD) were not well-investigated. We developed a protocol combining an efficient viable CTC isolation and in-vitro cultivation for the CTC enumeration and proliferation to evaluate their clinical significance. METHOD: The peripheral blood of 124 treatment-naïve LUAD patients were processed by a CTC isolation microfluidics, DS platform, followed by in-vitro cultivation. LUAD-specific CTCs were defined by immunostaining of DAPI+/CD45-/(TTF1/CK7)+ and were enumerated upon isolation and after 7-day cultivation. The CTC proliferative ability was evaluated by both the cultured number and the culture index, a ratio of cultured CTC number to the initial CTC number in 2 mL of blood. RESULT: All but two LUAD patients (98.4%) were detected with at least one CTC per 2 mL of blood. Initial CTC numbers did not correlate with metastasis (75 ± 126 for non-metastatic, 87 ± 113 for metastatic groups; P = 0.203). In contrast, both the cultured CTC number (mean: 28, 104, and 185 in stage 0/I, II/III, and IV; P < 0.001), and the culture index (mean: 1.1, 1.7 and 9.3 in stage 0/I, II/III, and IV; P = 0.043) were significantly correlated with the stages. Overall survival analysis within the non-metastatic group (N = 53) showed poor prognosis for patients with elevated cultured counts (cutoff ≥ 30; P = 0.027). CONCLUSION: We implemented a CTC assay in clinical LUAD patients with a high detection rate and cultivation capability. Cultured CTC count and proliferative ability, rather than the crude CTC numbers, highly associated with cancer prognosis.

Time domain adaptation of left ventricular diastolic intraventricular pressure in elite female ice hockey athletes.

Background: Ice hockey is a high-intensity dynamic sport for which competitive athletes train for longer than 20 hours each week for several years. The cumulative time of myocardial exposure to hemodynamic stress affects cardiac remodeling. However, the intracardiac pressure distribution of the elite ice hockey athletes' heart during adaptation to long-term training remains to be explored. This study aimed to compare the diastolic intraventricular pressure difference (IVPD) of the left ventricle (LV) between healthy volunteers and ice hockey athletes with different training times. Methods: Fifty-three female ice hockey athletes (27 elite and 26 casual) and 24 healthy controls were included. The diastolic IVPD of the LV during diastole was measured by vector flow mapping. The peak amplitude of the IVPD during isovolumic relaxation (P0), diastolic rapid filling (P1), and atrial systole (P4); the difference in the peak amplitude between adjacent phases (DiffP01, DiffP14); the time interval between the peak amplitude of adjacent phases (P0P1, P1P4); and the maximum decrease rate in diastolic IVPD were calculated. Differences between groups, as well as correlations between hemodynamic parameters and training time, were analyzed. Results: Structural parameters of the LV were significantly higher in elite athletes than in casual players and controls. No significant difference in the peak amplitude of the IVPD during the diastolic phase was found among the three groups. The analysis of covariance with heart rate as a covariate showed that P1P4 in the elite athlete and casual player groups was significantly longer than that in the healthy control group (p < 0.001 for all). An increased P1P4 was significantly associated with an increased training year (ß = 4.90, p < 0.001). Conclusions: The diastolic cardiac hemodynamics of the LV in elite female ice hockey athletes could be characterized by a prolonged diastolic IVPD, and P1P4 prolonged with an increase in the training years, reflecting a time-domain adaptation in diastolic hemodynamics after long-term training.

Effectiveness of non-pharmacological interventions for sleep disturbances in people living with dementia: A systematic review and meta-analysis.

We summarize the evidence on non-pharmacological interventions for sleep disturbances in people living with dementia(PlwD). A literature search was performed using PubMed, Embase, Cochrane library, Web of Science, PsycINFO, CINAHL, and clinicaltrials.gov. Up to August 20, 2022. Six studies met our eligibility criteria. Light therapy, the therapeutic pet-type robotic seal(PRAO), and slow-stroke back massage(SSBM) are non-pharmacological interventions for sleep disturbances in PlwD.PARO increased night-time sleep duration (p < 0.05). The benefit of SSBM for sleep disturbances in PlwD is unclear (p > 0.05). Although there is a lack of evidence for the effect of light therapy on sleep disturbances in PlwD (p > 0.05), light therapy reduced sleep disturbance (SMD = -0.38; 95% CI:1.25, 0.48), increased sleep efficiency (MD = 3.77; 95% CI:-0.23, 7.78), and also reduced depression (MD = -2.49; 95% CI: -2.92, -2.06). More large-scale randomized controlled trials are needed and consider combining multiple non-pharmacological measures for sleep interventions in PlwD.

Proportions of and trends in exposure to pro-tobacco and anti-tobacco advertisements among young adolescents aged 12-16 years in 142 countries and territories, 1999-2018: an analysis of repeated cross-sectional surveys.

BACKGROUND: The proportions and trends in exposure to pro-tobacco and anti-tobacco advertisements among young people remain unknown globally. We determined recent (2010-18) proportions of exposure to pro-tobacco and anti-tobacco advertisements among young adolescents and their secular trends from 1999 to 2018. METHODS: In this analysis of repeated cross-sectional surveys, we used the most recent data from 142 countries and territories (hereafter referred to as countries) collected between Jan 1, 2010, and Dec 31, 2018, comprising 710 191 participants, to assess the proportions of exposure to pro-tobacco and anti-tobacco advertisements among young adolescents aged 12-16 years. Data from 120 countries that had performed two or more Global Youth Tobacco Surveys between Jan 1, 1999, and Dec 31, 2018, comprising 1 482 031 participants, were used to assess trends in the proportions of exposure to pro-tobacco and anti-tobacco advertisements over time. A χ2 test analysis was used for proportion comparisons between subgroups. Exposure to pro-tobacco and anti-tobacco advertisements were calculated as proportions using sampling weights, strata, and primary sampling units. FINDINGS: The most recent global proportion of past 30-day exposure to tobacco advertisements among young adolescents was 433 585 (64·6%) of 710 191 (95% CI 63·5-65·7; all final percentages were weighted) for messages on electronic media, 206 766 (33·1%) of 710 191 (31·9-34·4) for exposure at the point of sale, and 63 385 (10·2%) of 710 191 (9·7-10·6) for owning something with a tobacco brand logo. The most recent global proportion of exposure to anti-tobacco advertisements was 431 862 (63·6%) of 710 191 (62·3-64·9) for messages on electronic media and 227 658 (34·1%) of 710 191 (32·8-35·3) for exposure to gathering activities. The majority of included countries showed a decreasing trend in exposure to tobacco advertisements (111 [93%] of 120) and anti-tobacco advertisements (110 [92%] of 120) between 1999 and 2018. INTERPRETATION: Among young adolescents, exposure to tobacco advertisements remains high, and exposure to anti-tobacco advertisements is not high enough. The proportion of young adolescents exposed to pro-tobacco and anti-tobacco advertisements had decreased over time in the majority of included countries. These findings underscore the importance of strict implementation of regulation on tobacco control including strengthening anti-tobacco marketing and prohibiting tobacco marketing. FUNDING: Youth Team of Humanistic and Social Science of Shandong University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Intrinsic RIG-I restrains STAT5 activation to modulate anti-tumor activity of CD8+ T cells.

Anti-tumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in tumor microenvironment, yet exact mechanisms remain incompletely defined. Here we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells. Mechanistically, T cell activation-induced RIG-I upregulation restrained STAT5 activation via competitively sequestering HSP90. In accordance, the frequency of RIG-I+ tumor-infiltrating CD8+ T cells in human colon cancer positively correlated with attenuated survival and effector signatures of CD8+ T cells as well as poor prognosis. Collectively, these results implicate RIG-I as a potentially druggable factor for improving CD8+ T cells-based tumor immunotherapy.

Icariin alleviates autistic-like behavior, hippocampal inflammation and vGlut1 expression in adult BTBR mice.

Autism spectrum disorder (ASD) is a complicated, heterogeneous disorder characterized by social interaction deficits and repetitive stereotypical behaviors. Neuroinflammation and synaptic protein dysregulation have been implicated in ASD pathogenesis. Icariin (ICA) has proven to exert neuroprotective function through anti-inflammatory function. Therefore, this study aimed to clarify the effects of ICA treatment on autism-like behavioral deficits in BTBR mice and whether these changes were related to modifications in the hippocampal inflammation and the balance of excitatory/inhibitory synapses. ICA supplementation (80 mg/kg, once daily for ten days, i.g.) ameliorated social deficits, repetitive stereotypical behaviors, and short-term memory deficit without affecting locomotor activity or anxiety-like behaviors of BTBR mice. Furthermore, ICA treatment inhibited neuroinflammation via decreasing microglia number and the soma size in the CA1 region of the hippocampus, as well as the protein levels of proinflammatory cytokines in the hippocampus of BTBR mice. In addition, ICA treatment also rescued excitatory-inhibitory synaptic protein imbalance by inhibiting the increased vGlut1 level without affecting the vGAT level in the BTBR mouse hippocampus. Collectively, the observed results indicate that ICA treatment alleviates ASD-like features, mitigates disturbed balance of excitatory-inhibitory synaptic protein, and inhibits hippocampal inflammation in BTBR mice, and may represent a novel promising drug for ASD treatment.

Recent findings on miR­370 expression, regulation and functions in cancer (Review).

MicroRNAs (miRNAs/miRs) are a group of small non­coding RNAs that serve as post­transcriptional gene modulators. miRNAs have been demonstrated to serve a pivotal role in carcinogenesis and the dysregulated expression of miRNAs is a well­understood characteristic of cancer. In recent years, miR­370 has been established as a key miRNA in various cancers. The expression of miR­370 is dysregulated in various types of cancer and varies markedly across different tumor types. miR­370 can regulate multiple biological processes, including cell proliferation, apoptosis, migration, invasion, as well as cell cycle progression and cell stemness. Moreover, it has been reported that miR­370 affects the response of tumor cells to anticancer treatments. Additionally, the expression of miR­370 is modulated by multiple factors. The present review summarizes the role and mechanism of miR­370 in tumors, and demonstrates its potential as a molecular marker for cancer diagnosis and prognosis.

Forecasting regional short-term freight volume using QPSO-LSTM algorithm from the perspective of the importance of spatial information.

It is of great significance to accurately and efficiently predict expressway freight volume to improving the supervision level of the transportation industry and reflect the performance of transportation. Using expressway toll system records to predict regional freight volume plays an important role in the development of expressway freight organization work; especially, the short-term (hour, daily or monthly) freight volume is directly related to the compilation of regional transportation plans. Artificial neural networks have been widely used in forecasting in various fields because of their unique structural characteristics and strong learning ability, among which the long short-term memory (LSTM) network is suitable for processing and predicting series with time interval attributes such as expressway freight volume data. Considering the factors affecting regional freight volume, the data set was reconstructed from the perspective of spatial importance; we then use a quantum particle swarm optimization (QPSO) algorithm to tune parameters for a conventional LSTM model. In order to verify the efficiency and practicability, we first selected the expressway toll collection system data of Jilin Province from January 2018 to June 2021, and then used database and statistical knowledge to construct the LSTM data set. In the end, we used a QPSO-LSTM algorithm to predict the freight volume at the future times (hour, daily or monthly). Compared with the conventional LSTM model without tuning, the results of four randomly selected grids naming Changchun City, Jilin city, Siping City and Nong'an County show that the QPSO-LSTM network model based on spatial importance has a better effect.

The Microzone Structure Regulation of Diamond/Cu-B Composites for High Thermal Conductivity: Combining Experiments and First-Principles Calculations.

The interface microzone characteristics determine the thermophysical properties of diamond/Cu composites, while the mechanisms of interface formation and heat transport still need to be revealed. Here, diamond/Cu-B composites with different boron content were prepared by vacuum pressure infiltration. Diamond/Cu-B composites up to 694 W/(mK) were obtained. The interfacial carbides formation process and the enhancement mechanisms of interfacial heat conduction in diamond/Cu-B composites were studied by HRTEM and first-principles calculations. It is demonstrated that boron can diffuse toward the interface region with an energy barrier of 0.87 eV, and these elements are energetically favorable to form the B4C phase. The calculation of the phonon spectrum proves that the B4C phonon spectrum is distributed in the range of the copper and diamond phonon spectrum. The overlapping of phonon spectra and the dentate structure together enhance the interface phononic transport efficiency, thereby improving the interface thermal conductance.

Deficient Chaperone-Mediated Autophagy in Macrophage Aggravates Inflammation of Nonalcoholic Steatohepatitis by Targeting Nup85.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH), a more severe subtype of non-alcoholic fatty liver disease, can cause cirrhosis and hepatocellular carcinoma. Macrophages play critical roles in initiating and maintaining NASH-induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone-mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage-specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment. METHODS: The CMA function of liver macrophages was detected using western blot, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and flow cytometry. By constructing myeloid-specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label-free mass spectrometry was utilised to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, western blot and RT-qPCR. RESULTS: A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte-derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver-targeted recruitment of monocyte and promoted steatosis, fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA-deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice. CONCLUSIONS: We proposed that the impaired CMA-induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH.

Limitations of gene editing assessments in human preimplantation embryos.

Range of DNA repair in response to double-strand breaks induced in human preimplantation embryos remains uncertain due to the complexity of analyzing single- or few-cell samples. Sequencing of such minute DNA input requires a whole genome amplification that can introduce artifacts, including coverage nonuniformity, amplification biases, and allelic dropouts at the target site. We show here that, on average, 26.6% of preexisting heterozygous loci in control single blastomere samples appear as homozygous after whole genome amplification indicative of allelic dropouts. To overcome these limitations, we validate on-target modifications seen in gene edited human embryos in embryonic stem cells. We show that, in addition to frequent indel mutations, biallelic double-strand breaks can also produce large deletions at the target site. Moreover, some embryonic stem cells show copy-neutral loss of heterozygosity at the cleavage site which is likely caused by interallelic gene conversion. However, the frequency of loss of heterozygosity in embryonic stem cells is lower than in blastomeres, suggesting that allelic dropouts is a common whole genome amplification outcome limiting genotyping accuracy in human preimplantation embryos.

Antimicrobial peptides for combating drug-resistant bacterial infections.

The problem of drug resistance due to long-term use of antibiotics has been a concern for years. As this problem grows worse, infections caused by multiple bacteria are expanding rapidly and are extremely detrimental to human health. Antimicrobial peptides (AMPs) are a good alternative to current antimicrobials with potent antimicrobial activity and unique antimicrobial mechanisms, which have advantages over traditional antibiotics in fighting against drug-resistant bacterial infections. Currently, researchers have conducted clinical investigations on AMPs for drug-resistant bacterial infections while integrating new technologies in the development of AMPs, such as changing amino acid structure of AMPs and using different delivery methods for AMPs. This article introduces the basic properties of AMPs, deliberates the mechanism of drug resistance in bacteria and the therapeutic mechanism of AMPs. The current disadvantages and advances of AMPs in combating drug-resistant bacterial infections are also discussed. This article provides important insights into the research and clinical application of new AMPs for drug-resistant bacterial infections.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Nivolumab-induced acute tubular injury: A case report.

Nivolumab belongs to immune checkpoint inhibitors (ICIs). ICIs-induced kidney injury is rare and acute interstitial nephritis (AIN) is the majority. A 58-year-old woman had gastric cancer treated with nivolumab. Her serum creatinine (Cr) increased to 5.94 mg/dL post 2 cycles of nivolumab and co-administered with acemetacin. A kidney biopsy showed acute tubular injury (ATI). Nivolumab rechallenge was done and Cr worsened again. The lymphocyte transformation test (LTT) indicated a strong positive for nivolumab. Although rare, ATI due to ICIs could not be ruled out, and LTT is a tool to identify the culprit.

Orthotopic Transplantation of Functional Bioengineered Livers in Rats.

Functional bioengineered livers (FBLs) are promising alternatives to orthotopic liver transplantation. However, orthotopic transplantation of FBLs has not yet been reported. This study aimed to perform the orthotopic transplantation of FBLs in rats subjected to complete hepatectomy. FBLs were developed using rat whole decellularized liver scaffolds (DLSs) with human umbilical vein endothelial cells implanted via the portal vein, and human bone marrow mesenchymal stem cells (hBMSCs) and mouse hepatocyte cell line implanted via the bile duct. FBLs were evaluated in terms of endothelial barrier function, biosynthesis, and metabolism and orthotopically transplanted into rats to determine the survival benefit. The FBLs with well-organized vascular structures exhibited endothelial barrier function, with reduced blood cell leakage. The implanted hBMSCs and hepatocyte cell line were well aligned in the parenchyma of the FBLs. The high levels of urea, albumin, and glycogen in the FBLs indicated biosynthesis and metabolism. Orthotopic transplantation of FBLs achieved a survival time of 81.38 ± 4.263 min in rats (n = 8) subjected to complete hepatectomy, whereas control animals (n = 4) died within 30 min (p < 0.001). After transplantation, CD90-positive hBMSCs and the albumin-positive hepatocyte cell line were scattered throughout the parenchyma, and blood cells were limited within the vascular lumen of the FBLs. In contrast, the parenchyma and vessels were filled with blood cells in the control grafts. Thus, orthotopic transplantation of whole DLS-based FBLs can effectively prolong the survival of rats subjected to complete hepatectomy. In summary, this work was the first to perform the orthotopic transplantation of FBLs, with limited survival benefits, which still has important value for the advancement of bioengineered livers.

Ultrathin C3N4 nanosheets-based oxidase-like 2D fluorescence nanozyme for dual-mode detection of organophosphorus pesticides.

Engineering efficient dual-mode portable sensor with built-in cross reference correction is of great significance for onsite reliable and precise detection of organophosphorus pesticides (OPs) and evading the false-positive outputs, especially in emergency case. Currently, most nanozyme-based sensors for OPs monitoring primarily replied on the peroxidase-like activity, which involved unstable and toxic H2O2. In this scenario, a hybrid oxidase-like 2D fluorescence nanozyme (PtPdNPs@g-C3N4) was yielded by in situ growing PtPdNPs in the ultrathin two-dimensional (2D) graphitic carbon nitride (g-C3N4) nanosheet. When acetylcholinesterase (AChE) hydrolyzed acetylthiocholine (ATCh) to thiocholine (TCh), it ablated O2-• from the dissolved O2 catalyzed by PtPdNPs@g-C3N4's oxidase-like activity, hampering the oxidation of o-phenylenediamine (OPD) into 2,3-diaminophenothiazine (DAP). Consequently, with the increasing concentration of OPs which inhibited the blocking effect by inactivating AChE, the produced DAP caused an apparent color change and a dual-color ratiometric fluorescence change in the response system. Through integrating into a smartphone, a H2O2-free 2D nanozyme-based onsite colorimetric and fluorescence dual-mode visual imaging sensor for OPs was proposed with acceptable results in real samples, which holds vast promise for further development of commercial point-of-care testing platform in early warning and controlling of OPs pollution for safeguarding environmental health and food safety.