Bacterial protoplast-derived nanovesicles carrying CRISPR-Cas9 tools re-educate tumor-associated macrophages for enhanced cancer immunotherapy.

The CRISPR-Cas9 system offers substantial potential for cancer therapy by enabling precise manipulation of key genes involved in tumorigenesis and immune response. Despite its promise, the system faces critical challenges, including the preservation of cell viability post-editing and ensuring safe in vivo delivery. To address these issues, this study develops an in vivo CRISPR-Cas9 system targeting tumor-associated macrophages (TAMs). We employ bacterial protoplast-derived nanovesicles (NVs) modified with pH-responsive PEG-conjugated phospholipid derivatives and galactosamine-conjugated phospholipid derivatives tailored for TAM targeting. Utilizing plasmid-transformed E. coli protoplasts as production platforms, we successfully load NVs with two key components: a Cas9-sgRNA ribonucleoprotein targeting Pik3cg, a pivotal molecular switch of macrophage polarization, and bacterial CpG-rich DNA fragments, acting as potent TLR9 ligands. This NV-based, self-assembly approach shows promise for scalable clinical production. Our strategy remodels the tumor microenvironment by stabilizing an M1-like phenotype in TAMs, thus inhibiting tumor growth in female mice. This in vivo CRISPR-Cas9 technology opens avenues for cancer immunotherapy, overcoming challenges related to cell viability and safe, precise in vivo delivery.

Tooth brushing with fluoridated toothpaste and associated factors among Chinese adolescents: a nationwide cross-sectional study.

BACKGROUND: Tooth brushing with fluoridated toothpaste has become the most important way to provide the anti-caries effect of fluoride around the world. China has promoted the use of fluoridated toothpaste since 1989. However, there are few studies on the national profile of use of fluoridated toothpaste and related factors in Chinese adolescents. We carried out this study to investigate oral hygiene behaviours, especially the status of tooth brushing with fluoridated toothpaste and its correlates among adolescents, based on data from the latest Nation Oral Health Survey in mainland China. METHODS: This cross-sectional study recruited 118,601 participants aged 12-15 years using multistage stratified sampling. Questionnaires were completed by students at school. Data employed in analyses were extracted from the questionnaire, including information on tooth brushing, fluoridated toothpaste, dental floss, sociodemographic factors, fluoride knowledge and attitude towards regular dental check-ups. A binary logistic regression was performed to compute the odds ratios (OR). Tooth brushing twice daily with fluoridated toothpaste was the dependent variable. Sociodemographic factors, fluoride knowledge, attitude towards regular dental check-ups, dental visit experience and perceived oral health were the independent variables. P < 0.05 was considered statistically significant. RESULTS: A total of 32.6% of participants brushed their teeth twice daily, 7.4% used fluoridated toothpaste, and 3.9% cleaned their teeth twice daily with fluoridated toothpaste. The logistic regression showed the probability of twice-a-day tooth brushing with fluoridated toothpaste was higher among these groups: females (OR: 1.141; 95%CI: 1.072-1.214), 15-year-olds (OR: 1.786; 95%CI: 1.634-1.952), from urban areas (OR: 1.389; 95%CI: 1.288-1.497), without siblings (OR: 1.351; 95%CI: 1.259-1.450), with an educated father (OR: 1. 605; 95%CI: 1.442-1.788) and mother (OR: 1.706; 95%CI: 1.530-1.903), having dental visit experiences (OR: 1.702; 95%CI: 1.589-1.823), rating one's oral health as good (OR: 2.341; 95%CI: 2.083-2.631), having fluoride knowledge (OR: 4.345; 95%CI: 4.034-4.678) and having a positive attitude towards regular dental check-ups (OR: 1.589; 95%CI: 1.460-1.729). CONCLUSIONS: The oral hygiene behaviours of Chinese adolescents were undesirable. Twice daily tooth brushing with fluoridated toothpaste was significantly associated with sociodemographic factors, fluoride knowledge, and attitudes towards regular dental check-ups.

The Host E3-Ubiquitin Ligase TRIM28 Impedes Viral Protein GP4 Ubiquitination and Promotes PRRSV Replication.

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is a highly pathogenic porcine virus that brings tremendous economic losses to the global swine industry. PRRSVs have evolved multiple elegant strategies to manipulate the host proteins and circumvent against the antiviral responses to establish infection. Therefore, the identification of virus-host interactions is critical for understanding the pathogenesis of PRRSVs. Tripartite motif protein 28 (TRIM28) is a transcriptional co-repressor involved in the regulation of viral and cellular transcriptional programs; however, its precise role in regulating PRRSV infection remains unknown. In this study, we found that the mRNA and protein levels of TRIM28 were up-regulated in PRRSV-infected porcine alveolar macrophages (PAMs) and MARC-145 cells. Ectopic TRIM28 expression dramatically increased viral yields, whereas the siRNA-mediated knockdown of TRIM28 significantly inhibited PRRSV replication. Furthermore, we used a co-immunoprecipitation (co-IP) assay to demonstrate that TRIM28 interacted with envelope glycoprotein 4 (GP4) among PRRSV viral proteins. Intriguingly, TRIM28 inhibited the degradation of PRRSV GP4 by impeding its ubiquitination. Taken together, our work provides evidence that the host E3-ubiquitin ligase TRIM28 suppresses GP4 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM28, as a potential target in the development of anti-viral drugs against PRRSV.

Immune Molecules' mRNA Expression in Porcine Alveolar Macrophages Co-Infected with Porcine Reproductive and Respiratory Syndrome Virus and Porcine Circovirus Type 2.

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus 2 (PCV2) are economically important pathogens in swine, and pigs with dual infections of PCV2 and PRRSV consistently have more severe clinical symptoms and interstitial pneumonia. However, the synergistic pathogenesis mechanism induced by PRRSV and PCV2 co-infection has not yet been illuminated. Therefore, the aim of this study was to characterize the kinetic changes of immune regulatory molecules, inflammatory factors and immune checkpoint molecules in porcine alveolar macrophages (PAMs) in individuals infected or co-infected with PRRSV and/or PCV2. The experiment was divided into six groups: a negative control group (mock, no infected virus), a group infected with PCV2 alone (PCV2), a group infected with PRRSV alone (PRRSV), a PCV2-PRRSV co-infected group (PCV2-PRRSV inoculated with PCV2, followed by PRRSV 12 h later), a PRRSV-PCV2 co-infected group (PRRSV-PCV2 inoculated with PRRSV, followed by PCV2 12 h later) and a PCV2 + PRRSV co-infected group (PCV2 + PRRSV, inoculated with PCV2 and PRRSV at the same time). Then, PAM samples from the different infection groups and the mock group were collected at 6, 12, 24, 36 and 48 h post-infection (hpi) to detect the viral loads of PCV2 and PRRSV and the relative quantification of immune regulatory molecules, inflammatory factors and immune checkpoint molecules. The results indicated that PCV2 and PRRSV co-infection, regardless of the order of infection, had no effect on promoting PCV2 replication, while PRRSV and PCV2 co-infection was able to promote PRRSV replication. The immune regulatory molecules (IFN-α and IFN-γ) were significantly down-regulated, while inflammatory factors (TNF-α, IL-1ß, IL-10 and TGF-ß) and immune checkpoint molecules (PD-1, LAG-3, CTLA-4 and TIM-3) were significantly up-regulated in the PRRSV and PCV2 co-infection groups, especially in PAMs with PCV2 inoculation first followed by PRRSV. The dynamic changes in the aforementioned immune molecules were associated with a high viral load, immunosuppression and cell exhaustion, which may explain, at least partially, the underlying mechanism of the enhanced pulmonary lesions by dual infection with PCV2 and PRRSV in PAMs.

Millihertz magnetic resonance spectroscopy combining the heterodyne readout based on solid-spin sensors.

The sensitivities of quantum sensing in metrology and spectroscopy are drastically influenced by the resolution of the frequency spectrum. However, the resolution is hindered by the decoherence effect between the sensor and the environment. Along these lines, the continue-wave optically detected magnetic resonance (CWODMR) method combined with the heterodyne readout was proposed to break the limitation of the sensor's coherence time. The frequency of the magnetic field was swept to match the unknown signal, and the signal can be transformed to a real-time frequency-domain curve via the heterodyne readout, with a frequency resolution of 4.7 millihertz. Using the nitrogen-vacancy (NV) center ensemble in a diamond as the solid-spin sensors, it was demonstrated that the frequency resolution and precision could be improved proportionally to the low-pass filter parameters of Tc -1 and Tc -1.5, respectively. Furthermore, the introduced method performed the sensing of arbitrary audio signals with a sensitivity of 7.32 nT·Hz-1/2@10 kHz. Our generic approach can be extended to several fields, such as molecular structure determination and biomagnetic field detection, where high-fidelity detection properties across multiple frequency bands are required within small sensing volumes (∼ mm3).

Design and synthesis of TPP+-Mitomycin C conjugate with reduced toxicity.

Mitomycin C (MMC) is a class of alkylating anticancer drug, which non-specifically interacts with nuclear DNA and cross-links guanine and cytosine of DNA, thereby affecting DNA replication and synthesis. However, toxic effects largely impeded MMC's clinical applications. In this study, triphenylphosphine groups (TPP+) were attached to MMC via the active aziridine amine with the aim to reduce its toxicity. MTT assay suggested that 5 possessed a good anticancer activity (IC50 = 1.09 µM, A549) with negligible effects on human normal cells (IC50 > 20 µM, L02 and HUVEC), while MMC exhibited IC50 values of less than 2.5 µM on the tested human normal cells. Dose range-finding experiments suggested that 5 had little effect on the body weight and tissues in mouse at a dose of 20 mg/kg, indicating significantly reduced toxicity as compared to MMC (LD50 < 2.5 mg/kg). Collectively, these data suggested that TPP+ group could be an effective vector to reduce toxicity of MMC.

A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities.

Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF3-phenyl triphenylphosphonium-based PBA conjugate (53) with improved in vitro and in vivo anticancer activities. Compound 53 exhibited an IC50 value of 2.22 µM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for cancer therapy.

Differences in Humoral Immune Response against the Type 2 Porcine Reproductive and Respiratory Syndrome Virus via Different Immune Pathways.

The intramuscular vaccine is the principal strategy to protect pigs from porcine reproductive and respiratory syndrome virus (PRRSV), However, it is still difficult to control PRRSV effectively. This study infected piglets with PRRSV through intramuscular and intranasal inoculation. Subsequently, viral loads, anti-PRRSV antibody levels, and neutralizing antibodies (NAs) titers in both serum and saliva were monitored for 43 days. Meanwhile, tissues were obtained through necropsy at 43 days post-inoculation (dpi) to detect viral loads. The results indicated that viremia lasted from 3 to 31 dpi in both the inoculation groups, but the viruses survived in the lungs and lymph nodes after viremia clearance. The antibody response was detected from 11 dpi, but the response of NAs was delayed until 3-4 weeks. Furthermore, intranasal inoculation induced lower viral load levels than injection inoculation. In addition, positive SIgA and NAs levels were produced early, with higher levels through intranasal inoculation. Therefore, our data indicated that a more robust antibody response and lower virus loads could be induced by intranasal inoculation, and mucosal inoculation could be a suitable pathway for PRRSV vaccines.

3,3'-Diindolylmethane improves antitumor immune responses of PD-1 blockade via inhibiting myeloid-derived suppressor cells.

BACKGROUND: Immune checkpoint inhibitors that target programmed cell death protein 1 (PD-1) have obtained encouraging results, but a fraction of tumor patients failed to respond to anti-PD-1 treatment due to the existence of multiple immune suppressive elements such as myeloid-derived suppressor cells (MDSCs). Traditional Chinese medicine or natural products from medicinal plants could enhance immunity and may be helpful for cancer immunotherapy. As a digestive metabolite from cruciferous plants, 3,3'-diindolylmethane (DIM) has been widely used in chemotherapy, but its influence on cancer immunotherapy remains unclear. Here we investigate the function of DIM on MDSCs and examine the therapeutic effects of DIM in conjunction with PD-1 antibody against mouse tumors. METHODS: Flow cytometry analysis, Western blot analysis and qRT-PCR assay were used to examine the inhibitory effects and mechanisms of DIM on MDSCs in vitro and in vivo. The therapeutic effects of DIM on cancer immunotherapy by PD-1 antibody were evaluated in mouse models of breast cancer and melanoma tumor. RESULTS: DIM exerted the inhibitory effect on MDSCs via downregulating miR-21 level and subsequently activating PTEN/PIAS3-STAT3 pathways. Adoptive transfer of MDSCs impaired the therapeutic effects of DIM, indicating that the antitumor activity of DIM might be due to the suppression of MDSCs. Furthermore, in mouse models of breast cancer and melanoma tumor, the addition of DIM can enhance the therapeutic effect of PD-1 antibody through promoting T cells responses, and thereby inhibiting tumor growth. CONCLUSIONS: Overall, the strategy based on the combination treatment of anti-PD-1 antibody and DIM may provide a new approach for cancer immunotherapy. Cruciferae plants-rich diet which contains high amount of DIM precursor may be beneficial for cancer patients that undergo the anti-PD-1 treatment.

Anticoagulant activity analysis and origin identification of Panax notoginseng using HPLC and ATR-FTIR spectroscopy.

INTRODUCTION: Panax notoginseng is one of the traditional precious and bulk-traded medicinal materials in China. Its anticoagulant activity is related to its saponin composition. However, the correlation between saponins and anticoagulant activities in P. notoginseng from different origins and identification of the origins have been rarely reported. OBJECTIVES: We aimed to analyze the correlation of components and activities of P. notoginseng from different origins and develop a rapid P. notoginseng origin identification method. MATERIALS AND METHODS: Pharmacological experiments, HPLC, and ATR-FTIR spectroscopy (variable selection) combined with chemometrics methods of P. notoginseng main roots from four different origins (359 individuals) in Yunnan Province were conducted. RESULTS: The pharmacological experiments and HPLC showed that the saponin content of P. notoginseng main roots was not significantly different. It was the highest in main roots from Wenshan Prefecture (9.86%). The coagulation time was prolonged to observe the strongest effect (4.99 s), and the anticoagulant activity was positively correlated with the contents of the three saponins. The content of ginsenoside Rg1 had the greatest influence on the anticoagulant effect. The results of spectroscopy combined with chemometrics show that the variable selection method could extract a small number of variables containing valid information and improve the performance of the model. The variable importance in projection has the best ability to identify the origins of P. notoginseng; the accuracy of the training set and the test set was 0.975 and 0.984, respectively. CONCLUSION: This method is a powerful analytical tool for the activity analysis and identification of Chinese medicinal materials from different origins.

Assessment of Fish Protein Hydrolysates in Juvenile Largemouth Bass (Micropterus salmoides) Diets: Effect on Growth, Intestinal Antioxidant Status, Immunity, and Microflora.

Varying dietary inclusion levels of fish protein hydrolysates (FPH) were applied in a feeding experiment with juvenile largemouth bass (Micropterus salmoides) to assess their effects on growth, intestinal antioxidant status, immunity, and microflora. FPH were added in 4 dietary levels: 0 g/kg (control group, FPH-0), 10 g/kg (FPH-10), 30 g/kg (FPH-30), and 50 g/kg (FPH-50) dry matter, respectively substituting 0, 5.3, 16.3, and 27.3% of fish meal with dietary fish meal. Quadruplicate groups of 25 juvenile largemouth bass with initial body weight 9.51 ± 0.03 g were fed during the 56-day feeding experiment. Experimental results showed that fish fed FPH-30 obtained a significantly higher weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and significant feed conversion rate (FCR) compared to the other three groups (P < 0.05). FPH-30 group also promoted protein synthesis and deposition, as evidenced by the higher whole-body crude protein contents, the higher expressions of GH1, IGF-1, TOR, and S6K in the liver, and SLC7A5, SLC7A8, SLC38A2, and SLC15A2 in the intestine than the other three groups. FPH-30 group could also enhance intestinal health status by increasing the activities of SOD, POD, CAT, GSH-Px, and T-AOC activities by upregulating the expressions of SOD, GSH-Px, IL1ß, and TNFß, and by reducing the MDA contents and the expressions of IL15, Caspase 3, Caspase 9, and Caspase 10 than other groups. Compared to the control group, the Actinobacteriota abundance markedly decreased in FPH treatments, while the variation tendency of the phylum Proteobacteria was opposite. The peak value of Firmicutes:Bacteroidetes ratio and the lowest of Bacteroidetes abundance were seen in largemouth bass fed FPH-30 (P < 0.05). Fish in three FPH treatments had lower abundances of opportunistic pathogens Staphylococcus and Plesiomonas than fish in the control group. In conclusion, FPH is a nutritious feed ingredient for juvenile largemouth bass, and can be added to a dietary level of 30 g/kg dry matter replacing fish meal without any negative effect on growth and feed utilization. FPH supplements could also strengthen the intestinal immune mechanisms of largemouth bass to tackle the immunodeficiency produced by fish meal replacement.

Proteomic Characterization of PAMs with PRRSV-ADE Infection.

The antibody-dependent enhancement (ADE) effect of a PRRSV infection is that the preexisting sub- or non-neutralizing antibodies specific against PRRSV can facilitate the virus entry and replication, and it is likely to be a great obstacle for the selection of immune strategies and the development of high-efficiency PRRSV vaccines. However, the proteomic characterization of primary alveolar macrophages (PAMs) with a PRRSV-ADE infection has not yet been investigated so far. Therefore, we performed a tandem mass tag (TMT)-based quantitative proteomic analysis of PAMs with a PRRSV-ADE infection in this study. The results showed that a total of 3935 differentially expressed proteins (DEPs) were identified in the PAMs infected with PRRSV-ADE, including 2004 up-regulated proteins and 1931 down-regulated proteins. Further, the bioinformatics analysis for these DEPs revealed that a PRRSV-ADE infection might disturb the functions of ribosome, proteasome and mitochondria. Interestingly, we also found that the expression of the key molecules in the innate immune pathways and antiviral proteins were significantly down-regulated during a PRRSV-ADE infection. This study was the first attempt to analyze the proteomic characterization of PAMs with a PRRSV-ADE infection in vitro. Additionally, the findings will provide valuable information for a better understanding of the mechanism of virus-antibody-host interactions during a PRRSV-ADE infection.

Nutritional evaluation of fish protein hydrolysate and its application in piglet production.

This study was conducted to determine the digestible energy (DE), metabolizable energy (ME), and ileal digestibility of amino acids (AA) of fish protein hydrolysate (FPH), and to evaluate the effects of FPH on the performance of piglets. In Exp. 1, the available energy content of FPH was determined by difference methods: 12 barrows with an initial body weight (BW) of 40.0 ± 2.1 kg were randomly assigned into two dietary treatments with six replicates per treatment, the treatments contained a corn basal diet and an experimental diet in which 20% corn was replaced by FPH. The experiment lasted for 12 d, with 7 d adaptation period followed by 5 d total collection of feces and urine. In Exp. 2, the standardized ileal digestibility (SID) of AA in FPH by the N-free method was determined, 12 barrows (initial BW of 35.3 ± 1.8 kg) with ileal T-cannulas were randomly allotted into two treatments with six replicates per treatment, and the dietary treatments consisted of an experimental diet and a N-free diet. The experiment was lasted for 7 d, with 5 d adaptation period followed by 2 d collection of ileal digesta. In Exp. 3, the effect of FPH on the performance of piglets was conducted. One hundred ninety-two piglets (initial BW of 8.10 ± 1.8 kg) were randomly allotted into four treatments with six replicates per treatment. The treatments were a control diet with fish meal (FM) and part or all FM was replaced by FPH, receiving diets containing 2%, 3%, or 5% FPH. The experiment lasted for 28 d. Results showed that in Exp. 1, the DE and ME of FPH were 21.12 and 20.28 MJ/kg. In Exp. 2, the SID of Lys, Met, Thr, and Trp was 79.99%, 87.17%, 68.29%, and 71.53%, respectively. In Exp. 3, addition of 3% FPH increased nutrient digestibility and volatile fatty acid content in feces. Addition of 5% FPH increased the average daily feed intake (ADFI), significantly increased (P < 0.05) the activities of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and immunoglobulin A (IgA), while significantly decreased (P<0.05) the average daily gain (ADG). In conclusion, FPH had a high value of digestible energy and ileal digestible essential amino acids, and could improve nutrient digestibility, immunity, antioxidant capacity, and intestinal health of piglets, while adverse to nitrogen deposition in piglets.

Fish meal (FM) is often used as a feed ingredient for piglets to adapt to the digestive physiological characteristics. However, due to the rising price and uneven quality of FM, the feed industry has been searching for protein sources with the same or better qualities as FM. Fish protein hydrolysate (FPH), a new protein material rich in peptides and free amino acids, has the potential to serve as an alternative to traditional fish meal. Our study was conducted to determine the digestible energy (DE), metabolizable energy (ME), and ileal digestibility of amino acids (AA) of FPH, and to evaluate the effects of FPH on the performance of piglets. We found that FPH had a high value of digestible energy and ileal digestible essential amino acids, and could improve nutrient digestibility, immunity, antioxidant capacity, and intestinal health of piglets, while adverse to nitrogen deposition in piglets.

MicroRNA-376b-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication by Targeting Viral Restriction Factor TRIM22.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically significant pathogen and has evolved several strategies to evade host antiviral response and provide favorable conditions for survival. In the present study, we demonstrated that a host microRNA, miR-376b-3p, was upregulated by PRRSV infection through the viral components, nsp4 and nsp11, and that miR-376b-3p can directly target tripartite motif-containing 22 (TRIM22) to impair its anti-PRRSV activity, thus facilitating the replication of PRRSV. Meanwhile, we found that TRIM22 induced degradation of the nucleocapsid protein (N) of PRRSV by interacting with N protein to inhibit PRRSV replication, and further study indicated that TRIM22 could enhance the activation of the lysosomal pathway by interacting with LC3 to induce lysosomal degradation of N protein. In conclusion, PRRSV increased miR-376b-3p expression and hijacked the host miR-376b-3p to promote PRRSV replication by impairing the antiviral effect of TRIM22. Therefore, our finding outlines a novel strategy of immune evasion exerted by PRRSV, which is helpful for better understanding the pathogenesis of PRRSV. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes enormous economic losses each year in the swine industry worldwide. MicroRNAs (miRNAs) play important roles during viral infections via modulating the expression of viral or host genes at the posttranscriptional level. TRIM22 has recently been identified as a key restriction factor that inhibited the replication of a number of human viruses, such as HIV, encephalomyocarditis virus (ECMV), hepatitis C virus (HCV), HBV, influenza A virus (IAV), and respiratory syncytial virus (RSV). In this study, we showed that host miR-376b-3p could be upregulated by PRRSV and functioned to impair the anti-PRRSV role of TRIM22 to facilitate PRRSV replication. Meanwhile, we found that TRIM22 inhibited the replication of PRRSV by interacting with viral N protein and accelerating its degradation through the lysosomal pathway. Collectively, the findings reveal a novel mechanism that PRRSV used to exploit the host miR-376b-3p to evade antiviral responses and provide new insight into the study of virus-host interactions.

Effects of dietary supplementation of nucleotides from late gestation to lactation on the performance and oxidative stress status of sows and their offspring.

Increased metabolic burdens in breeding sows, which are induced by elevated systemic oxidative stress, could increase the need for nucleotides to repair lymphocyte DNA damage; however, de novo synthesis of nucleotides may be insufficient to cover this increased need. This study investigated the effects of dietary nucleotides on milk composition, oxidative stress status, and the reproductive and lactational performance of sows. Forty multiparous sows were assigned to 2 dietary treatments (Control group, and 1 g/kg Nucleotides group) based on a randomized complete block design using their BW at 85 d of gestation as a block. Sows from 2 groups were fed a restricted diet during gestation and ad libitum during lactation. The experiment lasted from 85 d of gestation to 21 d of lactation. The reproductive performance of sows and the growth performance of suckling piglets were measured. Oxidative stress parameters and milk components were also analysed. Data were analyzed using contrasts in the MIXED procedure of SAS. Sows in the Nucleotides group consumed more feed during the first week (P < 0.01) and from 1 to 21 d (P < 0.05) of lactation than those in Control group. Correspondingly, the litter weight gain of piglets showed a tendency to increase from cross-fostering to 9 d (P = 0.09) and from cross-fostering to 20 d (P = 0.10) in the Nucleotides group relative to the Control group. Additionally, the Nucleotides group was higher (P < 0.01) than the Control group in the concentrations of uridine 5'monophosphate, guanosine 5'monophosphate, inosine 5'monophosphate, adenosine 5'monophosphate and total nucleotides in milk. Furthermore, the Nucleotides group was higher (P < 0.01) than the Control group in the serum levels of total antioxidant capacity (P < 0.01) for sows at 109 d of gestation and glutathione peroxidase for weaning piglets, but lower at the levels of thiobarbituric acid-reactive substances (P < 0.05) in serum of weaning piglets. This study indicated that maternal dietary nucleotides could promote piglet growth, probably due to the higher lactational feed intake and higher concentration of nucleotides in the milk of sows, and lower oxidative stress for both sows and piglets.

Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects.

Opioid analgesics, such as morphine, are widely employed in the treatment of moderate to severe pain. However, they are notorious for abuse liability and respiratory depression. Therefore circumventing the side effects, such as euphoria, addiction, respiratory depression and gastrointestinal adverse reactions, is of extensive importance. Recently, a large number of research results have revealed that such morphine-like side effects are not inevitable, and they focus on the novel approaches to disconnecting the analgesics from adverse effects. In this review, we mainly discuss the approaches including biasing the GPCRs over ß-arrestin2 recruitment (TRV130, PZM21, HS665), the positive allosteric modulators of the MOR (BMS-986122) and multiple agonists of opioid receptors subtypes (SNC80, DPI-125). Besides these, we also introduce the key protein sites of MOR and ß-arrestin2 recruitment briefly.

A comparative study on the effects of air gap wind and walking motion on the thermal properties of Arabian Thawbs and Chinese Cheongsams.

This paper reports on an experimental investigation on the effects of air gap, wind and walking motion on the thermal properties of traditional Arabian thawbs and Chinese cheongsams. Total thermal resistance (It) and vapour resistance (Re) were measured using the sweating fabric manikin - 'Walter', and the air gap volumes of the garments were determined by a 3D body scanner. The results showed the relative changes of It and Re of thawbs due to wind and walking motion are greater than those of cheongsams, which provided an explanation of why thawbs are preferred in extremely hot climate. It is further shown that thermal insulation and vapour resistance of thawbs increase with the air gap volume up to about 71,000 cm(3) and then decrease gradually. Thawbs with higher air permeability have significantly lower evaporative resistance particularly under windy conditions demonstrating the advantage of air permeable fabrics in body cooling in hot environments. Practitioner Summary: This paper aims to better understand the thermal insulation and vapour resistance of traditional Arabian thawbs and Chinese cheongsams, and the relationship between the thermal properties and their fit and design. The results of this study provide a scientific basis for designing ethnic clothing used in hot environments.