Complement receptor type 1 and 2 (CR1 and CR2) gene polymorphisms and plasma protein levels are associated with the Dengue disease severity.

The pathological outcome of dengue disease results from complex interactions between dengue virus (DENV) and host genetics and immune response. Complement receptor types 1 and 2 (CR1 and CR2) mediate complement activation through the alternative pathway. This study investigated the possible association of genetic polymorphisms and plasma levels of CR1 and CR2 with dengue disease. A total of 267 dengue patients and 133 healthy controls were recruited for this study. CR1 and CR2 gene polymorphisms were analyzed by Sanger sequencing, while plasma CR1 and CR2 levels were measured by ELISA. The frequency of the CR1 minor allele rs6691117G was lower in dengue patients and those with severe dengue compared to healthy controls. Plasma CR1 and CR2 levels were decreased in dengue patients compared to healthy controls (P < 0.0001) and were associated with platelet counts. CR1 levels were lower in dengue patients with warning signs (DWS) compared to those without DWS, while CR2 levels were decreased according to the severity of the disease and after 5 days (T1) and 8 days (T2) of follow-up. CR2 levels were decreased in dengue patients positive for anti-DENV IgG and IgM and patients with bleeding and could discriminate DWS and SD from dengue fever patients (AUC = 0.66). In conclusion, this study revealed a reduction in CR2 levels in dengue patients and that the CR1 SNP rs6691117A/G is associated with the dengue severity. The correlation of CR2 levels with platelet counts suggests that CR2 could be an additional biomarker for the prognosis of severe dengue disease.

Establishment of cancer cell line originating from a patient with high-grade serous ovarian carcinoma.

Aim: Ovarian cancer is a serious malignancy with high prevalence and mortality. Methods: We isolated and characterized an ovarian high-grade serous cancer cell line (M4) from a tumor of a Vietnamese patient with ovarian carcinoma. Results: The M4 cancer cell line showed good proliferation and stability in culture. Morphologically, the M4 cells showed similar characteristics to tumor cells such as a polyhedral shape, large irregular nuclei, high nuclear/cytoplasmic ratio, high nuclear density and expressing cancer markers like CA125, p53 and Ki67 markers. Conclusion: We have successfully isolated and characterized the M4 cell line from a Vietnamese patient with ovarian carcinoma.

Effect of substituting glutamine with lysine on structural and biological properties of antimicrobial peptide Polybia-MP1.

The natural antimicrobial peptide Polybia-MP1 is a promising candidate for developing new treatment therapy for infection and cancer. It showed broad-spectrum antimicrobial and anticancer activity with high safety on healthy cells. However, previous sequence modification usually resulted in at least one of two consequences: a notable increase in hemolytic activity or a considerable decrease in activity against Gram-negative bacteria and cancer cells. Herein, a new approach was applied by replacing the amino acid Glutamine at position 12 with Lysine and generating the MP1-Q12K analog. Our preliminary data suggested an enhancement in antibacterial and antifungal activity, whereas the anticancer and hemolytic activity of the two peptides were comparable. Moreover, MP1-Q12K was found to be less self-assembly than Polybia-MP1, which further supports the enhancement of antimicrobial properties. Hence, this study provides new information regarding the structure-activity relationships of Polybia-MP1 and support for the development of potent, selective antimicrobial peptides.

Association of PSORS1C3, CARD14 and TLR4 genotypes and haplotypes with psoriasis susceptibility.

Psoriasis is a common chronic, immune-mediated inflammatory disease of the skin. PSORS1C3 is a non-protein coding gene, of which the RNA transcript is found in psoriatic patients. CARD14 is mainly expressed in epidermal keratinocytes. TLR4 is a transmembrane protein to recognize microbial antigens. Our study aimed to assess the relationship among PSORS1C3, CARD14 and TLR4 polymorphisms, inflammatory expression and psoriasis susceptibility. To the end, 71 patients with psoriasis and 46 healthy individuals with the well-characterized clinical profiles were enrolled. Gene polymorphisms were determined by Sanger DNA sequencing and secretion of cytokines by ELISA. As a result, genetic analysis of PSORS1C3 gene identified nine SNPs and three haplotype blocks. Sequencing of the CARD14 gene determined eight SNPs and one haplotype block. Sequencing of TLR4 gene identified nine SNPs, in which a SNP rs1018673641 was found to exert deleterious effect. The linkage disequilibrium analysis showed that seven variants in PSORS1C3 gene and three SNPs in CARD14 gene were in tightly linked. More importantly, a significant association between IL-6 level and rs1018673641 AT genotype in TLR4 gene was detected in psoriatic patients. In conclusion, the PSORS1C3, CARD14 and TLR4 polymorphisms and haplotypes may be correlated with risk of suffering psoriasis and the IL-6-mediated chronic inflammation in psoriasis could be partially regulated by the TLR4 functional variant.

Nutrients, temperature, and oxygen mediate microbial antibiotic resistance in sea bass (Lateolabrax maculatus) ponds.

Antibiotic resistance genes (ARGs) have drawn increasing attention as novel environmental pollutants because of the threat they impose on human and animal health. The sea bass (Lateolabrax maculatus) is the third most cultured marine fish in China. Therefore, a study of ARG pollution in the sea bass culture environment is of great significance for the healthy and sustainable development of the sea bass industry. Here, we systematic investigated the contents of 23 antibiotic resistance-related genes (ARRGs), including 19 ARGs and four mobile genetic elements, and analyzed bacterial community composition and environmental parameters in sea bass ponds. The relative abundance (ARRG copies/16S ribosomal RNA gene copies) of ARRGs was up to 3.83 × 10-2. Sul1 was the most abundant ARRG, followed by ereA, intI-1, sul2, dfrA1, and aadA. Both the ARRG changes and aquatic microbiota succession were mainly driven by water temperature (WT), dissolved oxygen (DO), and NO3-. WT is positively correlated with the most ARGs and some of the top 38 Operational Taxonomic Units (OTUs) belonging to the orders of Frankiales, Micrococcales, Chitinophagales, and Sphingomonadales. Furthermore, WT is negatively related with some other OTUs of the orders Frankiales, Xanthomonadales, Micrococcales, and Rhizobiales. However, DO and NO3- have the opposite function with WT on specific taxa and ARGs. These results indicate that sea bass ponds are reservoirs of ARGs, and are driven mainly by the nutrient, temperature, and oxygen with inducing specific microbial taxa. The regulation of environmental factors (increasing DO and NO3-) can be conducted to reduce drug resistance risk in aquaculture ponds. Therefore, environmental factors and specific taxa could be the indicators of ARG contamination and can be used to establish an antibiotic elimination system and consequently realize a sustainable aquaculture industry.

Establishment and characterization of a liver cell line, ALL, derived from yellowfin sea bream, Acanthopagrus latus, and its application to fish virology.

Yellowfin sea bream (Acanthopagrus latus) is an important economic fish, which is seriously threatened by various fish viruses. In this study, a cell line designated as ALL derived from the liver of yellowfin sea bream was developed and characterized. The cell line grew well in Dulbecco's modified Eagle's medium containing 10%-20% foetal bovine serum at 28°C. Amplification of the cytochrome B gene indicated that ALL cells originated from yellowfin sea bream. The modal chromosome number of ALL cells was 48. ALL cells were efficiently transfected with pEGFP-N3 plasmids, indicating the potential application of ALL cells in exogenous gene manipulation studies. ALL cells were susceptive to three main fish viruses, including viral haemorrhagic septicaemia virus (VHSV), red-spotted grouper nervous necrosis virus (RGNNV) and largemouth bass virus (LMBV). The replication of VHSV, RGNNV and LMBV in ALL cells was confirmed by quantitative real-time polymerase chain reaction, virus titre and transmission electron microscopy assays. Moreover, ALL cells could respond to VHSV, RGNNV and LMBV infections, as indicated by the differential expression of antiviral genes involving in the innate immune response. In conclusion, the newly established ALL cell line will be an excellent in vitro platform for the study of the virus-yellowfin sea bream interaction.

Prognostic significance of the angiopoietin-2 for early prediction of septic shock in severe sepsis patients.

Aim: The current study investigated the plasma levels of angiopoietin-1/-2 and their association with clinical outcomes of sepsis. Methods: Angiopoietin-1 and -2 levels were quantified in plasma from 105 patients with severe sepsis by ELISA. Results: Angiopoietin-2 levels elevated according to the severity of sepsis progression. Angiopoietin-2 levels were correlated with mean arterial pressure and platelets counts, total bilirubin, creatinine, procalcitonin, lactate levels and SOFA score. Angiopoietin-2 levels accurately discriminated for sepsis with an AUC = 0.97 and septic shock from severe sepsis patients (AUC = 0.778). Conclusion: Plasma angiopoietin-2 levels may serve as an additional biomarker for severe sepsis and septic shock.

The study investigated the plasma levels of angiopoietin-1/-2 and their association with clinical outcomes of sepsis in plasma from 105 patients with severe sepsis by ELISA. The results showed that angiopoietin-2 levels elevated according to the severity of sepsis progression and were correlated with important clinical parameters such as mean arterial pressure and platelets counts, procalcitonin, lactate levels and SOFA score. Angiopoietin-2 levels accurately discriminated for sepsis and septic shock. Thus, plasma angiopoietin-2 levels may serve as an additional biomarker for severe sepsis and septic shock.

Effects of Vinblastine and Vincristine on the function of chronic myeloid leukemic cells through expression of A20 and CYLD.

Chronic myelogenous leukemia (CML) is characterised by the translocation of regions of the BCR and ABL genes, leading to the fusion gene BCR-ABL forming the Philadelphia (Ph) chromosome. Vinblastine (Vinb) and Vincristine (Vinc) are Vinca alkaloids and frequently used in combination chemotherapy in leukemias and lymphomas. Deubiquitinating enzyme (DUB) genes such as A20, Otubain 1 and CYLD are known as inhibitors of functional activation of immune cells mediated through the NF-κB/STAT pathway. Little is known about the regulatory role of Vinb/Vinc on the function of CML cells and the contribution of the DUBs to those effects. In the end, the gene expression profile was determined by quantitative RT-PCR, physiological properties of CML cells by flow cytometry and cytokine production by ELISA. As a result, inactivated expression of the DUBs A20, CYLD, Otubain 1 and Cezanne and enhanced activation of CD11b+ and CD4T cells were observed in CML patients. Importantly, Vinc enhanced the expression of A20 and CYLD and inhibited the proliferation and survival of CML (K562) cells. The effects were abolished in the presence of A20 siRNA, while cell proliferation only depended on the presence of CYLD. In conclusion, the up-regulation of A20 by Vinc could involve inhibitory effects on the proliferation and survival of K562 cells. The events might contribute to the anticancer effect of Vinc on A20-sensitive CML cells.

Low Prevalence of HEV Infection and No Associated Risk of HEV Transmission from Mother to Child among Pregnant Women in Vietnam.

Infections with HEV in low- and middle-income countries (LMICs) are associated with increased rates of preterm birth, miscarriage, and stillbirth. The aim of the present study was to investigate HEV infections in pregnant women and the possibility of mother-to-child transmission, and associated outcomes. A total of 183 pregnant women in their third trimester were recruited and followed until delivery. Anti-HEV IgG and IgM were determined via enzyme-linked immunosorbent assay (ELISA), and HEV nucleic acids were detected in stool and cord blood samples. HEV genotypes were identified by Sanger sequencing, and phylogenetic analyses were performed. Mother-to-child transmission and associated adverse outcomes were not observed. Only 2% of patients (n = 4/183) tested positive for anti-HEV IgM, and 8% (n = 14/183) tested positive for anti-HEV IgG antibodies. Cord blood (n = 150) analysis showed that there was no IgM detected, while 4% (n = 6/150) tested positive for anti-HEV IgG, which was consistent with mothers testing positive for anti-HEV IgG. Nucleic acid tests for HEV RNA yielded 2% (n = 4/183) from the serum and stool of pregnant women, and none from cord blood. The HEV isolates belonged to the genotype HEV-3a, with 99% homology with humans and 96% with pigs. No association was found between the risk of HEV infection and pregnancy outcomes or HEV transmission from mother to child. HEV-3 infections of zoonotic origin in pregnancy might have eventually resolved without complications.

Antimicrobial resistance in colonizing group B Streptococcus among pregnant women from a hospital in Vietnam.

Few studies have been conducted on group B Streptococcus (GBS) in Vietnam. We determined the GBS colonization and antimicrobial resistance vaginal-rectal profile of 3863 Vietnamese pregnant women over 5 years. Maternal GBS colonization was characterized by antibiotic susceptibility. Overall, the GBS colonization rate was 8.02% (95% CI: 7.20-8.94%). Compared to sampling ≥ 35 weeks of gestation, the GBS colonization rate was statistically higher (p = 0.004) with sampling < 35 weeks. Among 272 antimicrobial susceptibility testing isolates, all were susceptible to ampicillin, penicillin, ceftriaxone, cefotaxime, vancomycin, and quinupristin/dalfopristin. Resistance was highest for tetracycline (89.66%), followed by erythromycin (76.23%) and clindamycin (58.21%). Multidrug resistance and resistance to ≥ 6 different antibiotics were 60.66% and 8.82%, respectively. Resistance to clindamycin but not erythromycin (L phenotype) was 2.2%. The clindamycin resistance rate was significantly increased (p = 0.005) during the study period. These data demonstrate a low rate of maternal GBS colonization. The high rate of erythromycin, clindamycin, and multidrug resistance to GBS that can be transmitted to neonates is an important risk factor to consider. ß-lactams continue to be appropriate for first-line treatment and prophylaxis in the study area. Ongoing monitoring should be considered in the future.

Maternal Vaginal Colonization and Extended-Spectrum Beta-Lactamase-Producing Bacteria in Vietnamese Pregnant Women.

Extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) resistance to commonly prescribed drugs is increasing in Vietnam. During pregnancy, ESBL-E may predispose women to reproductive tract infections and increases the risk for neonatal morbidity. Vaginal colonization and infections by Escherichia coli and Klebsiella pneumoniae are seldom studied in Vietnam. In this study, we investigated ESBL-producing Enterobacterales in the birth canal of pregnant women. Between 2016 and 2020, vaginal swabs were collected from 3104 pregnant women (mean gestational age of 31 weeks) and inoculated onto MacConkey agar plates. Colonies were subjected to direct identification and antimicrobial susceptibility testing using the VITEK®-2 automated compact system and disk diffusion. ESBL production was determined phenotypically. E. coli, Klebsiella species were identified in 30% (918/3104) of the vaginal swabs, with E. coli being the most common (73%; 667/918). ESBL-production was detected in 47% (432/918) of Enterobacterales, with frequent multidrug-resistant phenotype. The overall prevalence of carbapenem resistance was low (8%). Over 20% of Klebsiella spp. were carbapenem-resistant. Pregnant women had a high prevalence of colonization and may transmit ESBL-E to neonates at birth, an important risk factor to be considered. The high rate of ESBL-producers and carbapenem resistance in Enterobacterales in Vietnam emphasizes the need for consequent surveillance and access to molecular typing.

What drives putative bacterial pathogens removal within seagrass meadows?

To analyze the mechanism of bacterial pathogen removal in seagrass meadows, we compared bacterial pathogens abundance in trapped particles in different seagrass meadows under different intensities of human activities. We compared the particle deposition rates and abundances of bacterial pathogen in Thalassia hemprichii, Enhalus acoroides stands and adjacent unvegetated patches. The bacterial pathogens abundance was much higher in E. acoroides than in adjacent unvegetated patches, however, the trapped particles under T. hemprichii were lower than in nearby unvegetated areas with the exception of the pristine seagrass meadow. These results indicate that seagrass, at least E. acoroides, can remove bacterial pathogens by trapping particles. What is unknown, nevertheless, is how the trapped bacterial pathogens are removed by T. hemprichii. We put forward that antibacterial chemical compounds release from seagrass was stimulated by stress from human activities for inhibition of bacterial pathogen. This putative mechanism needs to be explored in future studies.

Isolation and Differentiation of Amniotic Membrane Stem Cells Into Keratinocytes.

The human amniotic membrane is a highly abundant and readily available tissue that may be useful for regenerative medicine and cell therapy. The amniotic membrane stem cells can differentiate into multiple cell lineages; they have low immunogenicity and anti-inflammatory functions. This research aims to examine the protocols for the isolation of human amniotic membrane stem cells, including their phenotypic characterization and in vitro potential for differentiation toward keratinocytes. Human placentas were obtained from selected cesarean-sectioned births. We isolated amniotic stem cells by trypsin and collagenase B digestion and centrifuged with Percoll. After monolayer expansion of adherent cells, the cells were characterized by immunocytology with octamer-binding transcription factor 4 and differentiated into keratinocytes by treating the cells with insulin, hydrocortisone, BMP-4, and vitamin C. Protocol for isolation of stem cells from amniotic membrane has high efficiency. Differentiation markers of stem cells into keratinocytes, such as vimentin, cytokeratin (CK) 14, and CK19, were determined by reverse transcription-polymerase chain reaction increase over time in culture. Stem cells isolated from the amniotic membrane can differentiate into keratinocytes. It has opened the prospect of using stem cells to regenerate skin and clinical applications.

Complement protein levels and MBL2 polymorphisms are associated with dengue and disease severity.

The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (- 550L/H, MBL2 codon 54), MBL2 diplotypes (XA/XO, YA/XO) and MBL2 haplotypes (LXPB, HXPA, XO) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.

Association of FCN2 polymorphisms and Ficolin-2 levels with dengue fever in Vietnamese patients.

BACKGROUND AND OBJECTIVE: The human ficolin-2, encoded by FCN2, recognizes pathogen-associated acetylated residues on their cell surfaces and activates the lectin complement cascade. This study aimed to investigate the contribution of human ficolin-2 and the functional FCN2 genetic variants in dengue virus (DENV) infection and in clinical progression. METHODS: FCN2 genetic polymorphisms in the promoter, intron 7 and exon 8 were genotyped in 279 patients with dengue fever and in 200 healthy controls by direct Sanger sequencing. The ficolin-2 levels were measured in serum samples by ELISA and correlated with clinical data. RESULTS: The frequencies of +6031GG, +6220GG and +6424TT genotypes were significantly higher in dengue patients compared to healthy controls indicating an increased risk of dengue fever. The SNPs rs11103563 (+6031A/G), rs7872508 (+6220 T/G), and rs7851696 (+6424G/T) significantly regulated ficolin-2 levels in dengue patients (P < 0.0001). Ficolin-2 levels were increased in patients with dengue and Dengue with Warning Signs (DWS) compared to healthy controls (P < 0.0001 and P = 0.038, respectively). Ficolin-2 levels were significantly increased after 10-14 days of admission in both dengue and DWS patients and then slightly decreased after three weeks of discharge, indicating that ficolin-2 levels were modulated during the progression of dengue fever. In addition, ficolin-2 levels were negatively correlated with AST levels and positively correlated with platelet counts. CONCLUSIONS: FCN2 polymorphisms are associated with dengue fever in the Vietnamese population. Ficolin-2 levels are modulated during the progression of dengue fever and correlated with clinical parameters and thus may play a possible role in the pathogenesis of DENV infection.

A First Report of Aeromonas veronii Infection of the Sea Bass, Lateolabrax maculatus in China.

The sea bass, Lateolabrax maculatus is commercially farmed in Zhuhai, located in the Guangdong Province of China. L. maculatus in aquaculture have suffered acute death, characterized by ulcerations on the body surface, congestion, and hemorrhage in internal organs such as liver, kidney, and spleen. The dominant infecting strain of bacteria isolated from the kidneys of diseased fish was identified as Aeromonas veronii (strain 18BJ181). This identification was based on analysis of morphological, physiological, and biochemical features, as well as 16S rRNA and gyrB gene sequences. Drug sensitivity testing showed that the strain 18BJ181 isolate was resistant to four antibacterial drugs, including amoxicillin, madinomycin, penicillin and sulfamethoxazole, while moderately sensitive to erythromycin and rifampicin. The detection of growth characteristics showed that the strain 18BJ181 exhibited adaptability to the environment. In addition, some virulence genes, such as aer, act, gcaT, tapA and fla, were detected in the strain 18BJ181. The median lethal dosage of the strain 18BJ181 isolate in L. maculatus was 8.5 × 105 and 4.2 × 105 cfu/g under the conditions of intraperitoneal injection and intramuscular injection, respectively. The experimentally induced infection showed that the 18BJ181 isolate caused considerable histological lesions in L. maculatus, including tissue degeneration, necrosis, and different degrees of hemorrhage. These results provided evidence for a more comprehensive understanding of A. veronii strain 18BJ181 infection in L. maculatus.

Regulation of dendritic cell function by A20 through high glucose-induced Akt2 signaling.

A20 is a negative regulator of nuclear factor (NF)-κB-dependent inflammatory reaction in response to different stimuli by immune cells including dendritic cells (DCs), the most potent antigen-presenting cells involved in both the innate and adaptive immune response. Dendritic cells use glucose as carbon source to synthesize fatty acid and generate energy. Glucose enhances cell apoptosis mediated through PI3K/Akt, ERK1/2, and Bax/Bcl-2 pathways. The protein kinase Akt2/PKBß is expressed in DCs and a regulator of Ca2+ influx, Na+/H+ exchanger activity, and migration of DCs. This study explored whether regulation of high glucose-induced DC function through Akt2 signaling is influenced by overexpression of A20. To this end, A20 protein expression was determined by western blotting and immunoprecipitation, secretion of inflammatory cytokines by ELISA, and expression of apoptotic markers by flow cytometry. As a result, treatment of mice with 10% high glucose enriched water increased secretion of insulin/IGF1 and reduced A20 protein level, the effects were blunted in Akt2-/- mice. Incubation of DCs with high glucose significantly decreased A20 protein expression in both control and Akt1-silenced DCs, but not in Akt2-/- DCs. Importantly, treatment of DCs with high glucose increased ceramide synthesis, caspase 8 activity, and annexin V binding in control DCs, the effects were abolished in Akt2-/- DCs or by A20 overexpression. In conclusion, regulation of A20 sensitive DC function by high glucose is mediated through insulin/IGF-1/Akt2 signaling.

Combination of Vaccine Strain Measles Virus and Nimotuzumab in the Treatment of Laryngeal Cancer.

BACKGROUND/AIM: This study aims to investigate whether the combination of oncolytic viruses with chemoradiotherapy or other therapies is a promising strategy for cancer treatment. MATERIALS AND METHODS: The anticancer effects of measles virus (MeV) in combination with nimotuzumab in the treatment of laryngeal cancer were evaluated in vitro and in nude mice inoculated with Hep2 tumors. MTT assay and flow cytometry were used to examine cell death. RESULTS: Laryngeal cancer cells treated with MeV+nimotuzumab combination had a significantly lower survival rate compared to those treated with MeV or nimotuzumab alone (p<0.0001). In an animal model bearing human laryngeal tumor, the treated group had a higher survival rate (60%) compared to a untreated group (20%) (p<0.05), and the survival rate of the group treated with MeV+nimotuzumab combination was higher compared to the groups received single treatment. CONCLUSION: The MeV+nimotuzumab combination has greater anticancer activities in both laryngeal cancer cells and an animal model.

Diversity and abundance of antibiotic resistance of bacteria during the seedling period in marine fish cage-culture areas of Hainan, China.

Antibiotic resistance has become an important focus of research in the aquaculture environment. However, few studies have evaluated antibiotic resistance during the seedling period in marine fish cage-culture areas. In this study, culture-dependent methods and quantitative polymerase chain reaction were used to identify and detect cultivable heterotrophic antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs), respectively, during the seedling period in a marine fish cage-culture areas of Hainan, China. Bacterial resistance to amoxicillin, erythromycin, and gentamicin was generally high (average on 27.67%, 23.61% and 37.32%, respectively), whereas resistance to furazolidone and nitrofurantoin was generally low (average on 0.14% and 7.425%). Alteromonas (32.72%) and Vibrio (24.77%) were the dominant genus of ARB. Most ARB were opportunistic pathogens, belonging to the phylum Proteobacteria (96.02%). The abundance of sul family genes was higher than that of tet family genes. Overall, the abundance of ARGs and the resistance rates in HW was highest.

Identification of novel azaindazole CCR1 antagonist clinical candidates.

Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.