Biological Characterization and Genomic Analysis of Novel Phages DLDT_So2 and BHDT_So9 Against Pseudomonas solanacearum, an Infectious Agent in Tomato in Vietnam.

Tomato (Solanum lycopersicum L.) is an important grown vegetable in Vietnam. Bacterial wilt caused by Pseudomonas solanacearum has been considered to be an important disease resulting in a harvest loss up to 90% and significant economic loss to farmers. In this study, two bacteriophages DLDT_So2 and BHDT_So9 specific to P. solanacearum were isolated. Morphological analysis indicated that DLDT_So2 and BHDT_So9 had podovirus morphology and were classified into Autographiviridae family. The latent period and burst size of DLDT_So2 was found to be approximately 120 min and 20.0 ± 2.4 virions per infected cell. Meanwhile, the latent period of BHDT_So9 was 140 min with a burst size of 11.5 ± 2.8 virions per infected cell. Of the 23 bacterial strains tested, the phages infected 7/11 strains of P. solanacearum and none of the other bacteria tested were susceptible to the phages. Stability of the phages at different temperatures, pHs, solvents was also investigated. The genomes of DLDT_So2 and BHDT_So9 are 41,341 bp and 41,296 bp and long with a total GC content of 63%, contains 48 and 46 predicted protein-encoding CDSs. No virulence or antibiotic resistance genes were found in the genomes, suggesting they would be useful biocontrol agents against P. solanacearum. Classification of the phage using average nucleotide identity, phylogenetic analysis was also carried out. The two phages represented new species when they had overall average nucleotide identity of < 95%. This is first report of the isolation and characterization of P. solanacearum-specific phages from tomato farms in Vietnam. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01090-9.

Bacteriophage PVN06 protected catfish Pangasianodon hypophthalmus from Edwardsiella ictaluri infection.

Bacillary necrosis of pangasius (BNP) is a disease caused by Edwardsiella ictaluri bacteria in striped catfish Pangasianodon hypophthalmus that results in high mortality rates. To control this disease, bacteriophages have been considered as alternatives to antibiotics. In this study, we applied the lytic bacteriophage PVN06 in striped catfish fingerlings to prevent E. ictaluri infection. In an experimental trial, the phage was administered to fish by feeding phage-coated feed with doses of 7.17±0.09, 8.17±0.09 and 9.17±0.09 log PFU/g feed per day before bacterial infection. Fish were infected by bacteria once with concentrations ranging from 3.01 to 7.01 log CFU/ml tank water. A day after infection, phage treatment resumed at a rate of once per day until the end of the trial. The results of the trial show that bacterial infection caused typical symptoms of BNP in fish with the cumulative fish death rate of 36.7±2.9 to 75.0±5.0%, depending on the bacterial concentration used for infection. Phage treatment with 9.17±0.09 log PFU/g significantly reduced the mortality rate, while treatments with 8.17±0.09 and 7.17±0.09 log PFU/g did not. This phage dose resulted in a 61.7-fold reduction in the toxicity of the bacterial pathogen and the survival rate of 15-23.3% in fish. Our study has demonstrated that the bacteriophage PVN06 protected striped catfish from BNP.

Complete genome sequence of a novel lytic phage of Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen in rice.

Bacteriophage L522, which infects Xanthomonas oryzae pv. oryzae, was isolated from a paddy leaf sample collected in Long An province, Vietnam. The phage shows myovirus morphology based on transmission electron microscopy. It displays a latent period and burst size of approximately 3 h and 63 new virions per infected cell (PFU/infected cell), respectively. The genome of L522 is 44,497 bp in length, with 52% GC content. Of the 63 genes identified, functions were predicted for 26. No virulence or antibiotic-resistance genes were detected. The results of a BLASTn search showed similarity to a previously reported Xanthomonas phage, with 85% average nucleotide sequence identity and 87.15% query coverage. Thus, this L522 is a representative of a new species in the genus Xipdecavirus.

Changes in Generalized and Particularized Trust and Their Link to Depressive Symptoms: Exploring the Roles of Changes in Self-Rated Health, Family Support and Life Satisfaction Among Chinese Older Adults.

This study aimed to examine whether changes in generalized trust (GT) and particularized trust (PT) predict changes in depressive symptoms (CES-D 8), and whether changes in self-rated health (SRH), family support (FS), and life satisfaction (LS) mediate the relationship between changes in the two types of trust and depressive symptoms in Chinese older adults. Structural equation modeling was employed to analyze two-wave data on 3770 participants aged 65 and over. Our results showed that in a context where GT was low and PT was high, an increase in GT was associated with more depressive symptoms, while an increase in PT was associated with fewer depressive symptoms. As such, GT cannot be viewed as protective against depression in older adults in a given context. LS partially mediated the relationship between changes in PT and depressive symptoms. The findings support psychosocial processes rather than health-problem and support pathways.

Diverse Bacteriophages Infecting the Bacterial Striped Catfish Pathogen Edwardsiella ictaluri.

Bacteriophages infecting Edwardsiella ictaluri have been less investigated, although the host bacterium is one of the most important fish pathogens causing enteric septicemia of catfish (ESC). We present here two distinctly novel bacteriophages vB_EiM_PVN06 and vB_EiA_PVN09 infecting Edwardsiella ictaluri E1, with their geographical origins from the Mekong Delta, Vietnam. Bacteriophage vB_EiM_PVN06 native to a mud sample reveals complete differences of biological properties with the phage vB_EiA_PVN09 originated from a viscus of a healthy catfish (Pangasianodon hypophthalmus) cultured in the same area. Morphological analyses combined with genomic data indicate that phage vB_EiM_PVN06 is classified to Myoviridae family and shares high similarity with E. ictaluri phage PEi21 genome, while vB_EiA_PVN09 is a member of Teseptimavirus genus, Autographiviridae family, and mostly closes to phage vB_EcoP_IME390. The vB_EiA_PVN09 is a T7-like bacteriophage, which has been firstly found infecting to E. ictaluri, and host range analysis also evidences for the cross-infection of this phage to Escherichia coli K12 and Escherichia coli DH5α. Together, our research highlights the diversity of bacteriophages infecting the pathogen E. ictaluri and suggests further explorations of lytic phages in environmental niches, to be exploited in feasible strategies of phage therapy in ESC disease control.

Demonstration of Single-Shot Picosecond Time-Resolved MeV Electron Imaging Using a Compact Permanent Magnet Quadrupole Based Lens.

We present the results of an experiment where a short focal length (∼1.3 cm), permanent magnet electron lens is used to image micron-size features (of a metal sample) with a single shot from an ultrahigh brightness picosecond-long 4 MeV electron beam emitted by a radio-frequency photoinjector. Magnification ratios in excess of 30× were obtained using a triplet of compact, small gap (3.5 mm), Halbach-style permanent magnet quadrupoles with nearly 600 T/m field gradients. These results pave the way towards single-shot time-resolved electron microscopy and open new opportunities in the applications of high brightness electron beams.

Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

WHAT IS KNOWN AND OBJECTIVE: The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. METHODS: The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24 . RESULTS AND DISCUSSION: Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331 µg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 µg/mL. WHAT IS NEW AND CONCLUSION: Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 µg/mL, this level should ideally not be exceeded.

Surface-plasmon resonance-enhanced multiphoton emission of high-brightness electron beams from a nanostructured copper cathode.

We experimentally investigate surface-plasmon assisted photoemission to enhance the efficiency of metallic photocathodes for high-brightness electron sources. A nanohole array-based copper surface was designed to exhibit a plasmonic response at 800 nm, fabricated using the focused ion beam milling technique, optically characterized and tested as a photocathode in a high power radio frequency photoinjector. Because of the larger absorption and localization of the optical field intensity, the charge yield observed under ultrashort laser pulse illumination is increased by more than 100 times compared to a flat surface. We also present the first beam characterization results (intrinsic emittance and bunch length) from a nanostructured photocathode.

Malaria parasite induces tryptophan-related immune suppression in mice.

Plasmodium spp. cause the worst parasitic diseases in humans and evade host immunity in complicated ways. Activated catabolism of tryptophan in dendritic cells is thought to suppress immunity, which is mediated by an inducible rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3 dioxygenase (IDO), via both tryptophan depletion and production of toxic metabolites. In various infections, including malaria, IDO is known to be activated but its biological significance is unclear; therefore, we investigated whether malaria parasites induce IDO to suppress host immune responses. We found that enzymatic activity of IDO was elevated systematically in our mouse malaria model, and was abolished by in vivo IDO inhibition with 1-methyl tryptophan. Experimental infection with Plasmodium yoelii showed that IDO inhibition slightly suppressed parasite density in association with enhanced proliferation and IFN-gamma production by CD4+ T cells in response to malaria parasites. Our observations suggest that induction of IDO is one of the immune mechanisms of malaria parasites.

Chronopharmacology of oral prednisolone in rats.

The chronopharmacology of oral prednisolone (PSL) was studied in rat models. Differences in the dosing-time-dependent toxicity were evaluated at four time points (3, 9, 15 and 21 HALO) in adult male Wistar rats and confirmed in an inbred strain of Lewis rats (MHC haplotype; RTIl) at two time points (9 and 21 HALO). The total body weight and that of the immunologic-related organs were maximally reduced when PSL was repeatedly administered during the late active phase (21 HALO). This chronotoxicity was independent of plasma concentrations of PSL, adrenocorticotropic hormone, and corticosterone. Repeated administration of PSL prolonged cardiac allograft survival in a DA (RTIa) -to-Lewis combination, and there was a tendency to be more effective in the 21 HALO trial. These results suggested that single dose therapy of PSL at the selected point of the day may be less harmful, protecting against allograft rejection.

Simplified method of heterotopic rat heart transplantation using the cuff technique: application to sublethal dose protocol of methotrexate on allograft survival.

Rodent heterotopic heart transplantation (HHT) models have been developed for the study of transplantation immunology. Most of these transplantations are performed by hand-suture techniques, requiring several months of training. We describe a modified technique of rat HHT in the neck, using a cuff method that can be mastered by beginners within a few weeks. Our main modification of the rat HHT in the neck is that the right superior vena cava of the graft is chosen as an outflow duct, while the pulmonary artery has been taken as an effluent drainage in the ordinary HHT models. The aorta of the donor is anastomosed with the carotid artery of the recipient. Donation can be completed within 5 min and vascular connections in the recipient done within 3 min, resulting in a minimum of ischemia time. Using this minimum surgical intervention model, we tested the immunosuppressive effect of a sublethal dose of methotrexate (MTX), which has been widely used in cancer therapy. Our results showed that high doses of MTX severely suppressed the recipient bone marrow, but prolonged heart allografts for more than 365 days after HHT. In conclusion, the new model simplified the rat HHT procedure and made it possible for the beginner of rodent transplantation to master this skill within a few weeks. Using this minimized intervention technique, we found that the high doses of MTX can significantly prolong the survival of fully mismatched DA heart graft in PVG/c recipient.

Dosing time-dependent pharmacological effects of anti-metabolites for rat cardiac graft.

Antimetabolites such as methotrexete and 6-mercaptopurine have been shown to have circadian variations in their toxicities. However, chronopharmacological profiles of mizoribine (Miz) that is newly synthesized as an anti-metabolic agent for immunosuppression, have not been evaluated. In this study, we examined the dosing time-dependent alterations in the pharmacokinetics and pharmacodynamics of Miz. In addition, chronopharmacology of azathiopurine (Aza) was also evaluated to compare with that of Miz. Initially, Miz (10 and 20 mg/kg) or Aza (20 mg/kg) was orally administered at 8:00 hr or 20:00 hr for 3 weeks to rats. To reveal the dosing time-dependent difference of pharmacokinetics, Miz (20 mg/kg) was orally given at 8:00 hr or 20:00 hr and blood was obtained for 12 hours. Finally, Miz (20 mg/kg) or Aza (20 mg/kg) was administered at 8:00 hr or 20:00 hr to rats with heterotopic allogeneic heart grafts. The Miz group treated at 8:00 hr and Aza group treated at 20:00 hr showed severe myelosuppression compared with their each opposite dosing time. AUC of Miz in the morning trial was twice as high as that in the evening trial. The graft survival durations of the Miz- and Aza-treated groups were significantly longer than those of the respective control groups, but were not affected by dosing time of each agent. These results suggest that the toxicity, but not efficacy of Miz is varied with the dosing time. The chronotoxicological phenomenon of Miz might be, at least in part, explained by the dosing time-dependent difference in serum drug concentrations and apparent clearance.

Cisplatin-induced vomiting depends on circadian timing.

We examined whether the clock time of cisplatin plus antiemetic and diuretic administration affects the amount of cisplatin-associated emesis and severity of renal toxicity. We treated 22 patients with urogenital cancer with two courses of chemotherapy containing 70 mg/m2 of cisplatin. Cisplatin together with furosemide was administered in the morning (05:00) or evening (17:00) during two courses 1 month apart in a crossover fashion. Ondansetron was given either before or after cisplatin to control nausea and vomiting. The number of vomiting episodes, serum creatinine, serum urea nitrogen (BUN), creatinine clearance, and urinary beta-N-acetyl glucosamidase (NAG) concentration were evaluated before and after each treatment course. Regardless of the timing of ondansetron, morning compared to evening cisplatin was always associated with greater vomiting in the first treatment course. However, prophylactic administration of ondansetron markedly diminished the impact of the clock time of cisplatin administration. Serum creatinine transiently decreased rather than increased 14 days after cisplatin and furosemide administration, while NAG excretion increased 3 days after cisplatin and furosemide administration. In the first course, serum creatinine levels were similar regardless of the clock time of cisplatin and furosemide administration. However, in the second course, serum creatinine rose in patients given evening cisplatin and furosemide, while it remained unchanged in those given morning cisplatin and furosemide. Moreover, the first course morning cisplatin and furosemide treatment was associated with less change in NAG excretion (less kidney toxicity) than the first course of evening cisplatin and furosemide treatment. The second course evening cisplatin and furosemide treatment was associated with an increase in NAG excretion compared to the first course of treatment, while morning cisplatin and furosemide treatment in the second course showed less change in NAG excretion compared to the first course. The clock time of cisplatin administration had an impact on the frequency of emesis. Prophylactic ondansetron, however, diminished the time-of-day dependency of cisplatin-induced vomiting. Administration of cisplatin and furosemide in the morning rather than evening appears to cause less renal damage, and this damage may be further reduced with aggressive hydration and routine administration of furosemide.

Effects of dosing time and schedule on cisplatin-induced nephrotoxicity in rats.

Renal dysfunction induced by a single injection of cisplatin depends on the timing of the dose. However, the effects of repeated administration of cisplatin on time-dependent toxicity have not been evaluated despite the fact that in clinical practice high doses are repeatedly injected at intervals or low doses are administered daily. We studied chrononephrotoxicity in rats after weekly or daily cisplatin injections. Weekly high doses (5 mg kg(-1)) or daily low doses (1.2 mg kg(-1)) of cisplatin were injected at four time points (3, 9, 15 and 21 h after the light was turned on (HALO)) for 3 weeks. Changes in body weight after weekly cisplatin administration were independent of the timing of the doses. In the group that received daily cisplatin, the loss in body weight in the 3 HALO group was smaller than in animals receiving injections at 15 and 21 HALO (P < 0.05 and 0.001, respectively). The blood urea nitrogen and serum creatinine levels in the control rats showed a significant circadian change (peak at 15 HALO and trough at 9 HALO), but these parameters were markedly elevated in both trials and their circadian variations were disturbed. In conclusion, cisplatin-induced nephrotoxicity was the lowest at 3HALO compared with other time points of both dose regimens.

Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice.

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6mg kg(-1)) for 5 days at four time points (04:00, 10:00, 16:00 and 22:00h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04:00 and 16:00h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04:00 and 16:00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04:00 and the 16:00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16:00 h group than in the 04:00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.