High-fidelity single logical qubit encoding scheme assisted by single-sided quantum dot-cavity systems.

We present an encoding scheme of a single logical qubit with single-sided quantum dot (QD)-cavity systems, which is immune to the collective decoherence. By adjusting the Purcell factor to satisfy the balanced reflection condition, the detrimental effects of unbalanced reflection between the coupled and uncoupled QD-cavity systems can be effectively suppressed. Furthermore, the fidelity of each step can be increased to unity regardless of the strong coupling regime and the weak coupling regime of cavity quantum electrodynamics (QED) with the assistance of waveform correctors. The scheme requires QD-cavity systems and simple linear optical elements, which can be implemented with the currently experimental techniques.

Comparative genomic analysis provides insights into the genetic diversity and pathogenicity of the genus Brucella.

Some Brucella spp. are important pathogens. According to the latest prokaryotic taxonomy, the Brucella genus consists of facultative intracellular parasitic Brucella species and extracellular opportunistic or environmental Brucella species. Intracellular Brucella species include classical and nonclassical types, with different species generally exhibiting host preferences. Some classical intracellular Brucella species can cause zoonotic brucellosis, including B. melitensis, B. abortus, B. suis, and B. canis. Extracellular Brucella species comprise opportunistic or environmental species which belonged formerly to the genus Ochrobactrum and thus nowadays renamed as for example Brucella intermedia or Brucella anthropi, which are the most frequent opportunistic human pathogens within the recently expanded genus Brucella. The cause of the diverse phenotypic characteristics of different Brucella species is still unclear. To further investigate the genetic evolutionary characteristics of the Brucella genus and elucidate the relationship between its genomic composition and prediction of phenotypic traits, we collected the genomic data of Brucella from the NCBI Genome database and conducted a comparative genomics study. We found that classical and nonclassical intracellular Brucella species and extracellular Brucella species exhibited differences in phylogenetic relationships, horizontal gene transfer and distribution patterns of mobile genetic elements, virulence factor genes, and antibiotic resistance genes, showing the close relationship between the genetic variations and prediction of phenotypic traits of different Brucella species. Furthermore, we found significant differences in horizontal gene transfer and the distribution patterns of mobile genetic elements, virulence factor genes, and antibiotic resistance genes between the two chromosomes of Brucella, indicating that the two chromosomes had distinct dynamics and plasticity and played different roles in the survival and evolution of Brucella. These findings provide new directions for exploring the genetic evolutionary characteristics of the Brucella genus and could offer new clues to elucidate the factors influencing the phenotypic diversity of the Brucella genus.

Monkeypox: Can we count on the current smallpox immunization?

Two vaccines ACAM 2000 and JYNNEOS have obtained approval from the Food and Drug Administration as preventive measures against monkeypox, contributing significantly to the management of the monkeypox epidemic. Nonetheless, research has demonstrated that smallpox vaccination offers approximately 88.8% protection against monkeypox, while immunization with these vaccines generates relatively low levels of neutralizing antibodies. In this work, we performed a comprehensive comparison of antigens between the 2022-2023 monkeypox strains and the smallpox vaccine strains. Our analysis has revealed considerable amino acid changes in all 27 antigens, including core and envelope proteins. Amino acid substitutions within B cell epitopes were observed in 26 of these antigens, with at least half of the antigen substitutions occurring within B cell epitopes in 20 out of the 26 antigens analyzed. These findings may raise potential concerns regarding the efficacy of these vaccines.

Discovery of conformationally constrained c-Abl inhibitors with potential neuroprotective effects against Parkinson's disease.

Abelson tyrosine kinase (c-Abl) is involved in various biological processes in neurodegenerative diseases and is an attractive target for anti-PD (Parkinson's disease) drug discovery. Based on our previous work, we designed several novel c-Abl inhibitors through a conformational constrained strategy and evaluated their pharmacological activities. Among them, compound A6 exhibited superior inhibitory activity against c-Abl than nilotinib in the homogenous time-resolved fluorescence (HTRF) assay. Furthermore, A6 displayed higher neuroprotective effects against SH-SY5Y cell death induced by MPP+ and lower cytotoxicity than that of nilotinib. Molecular modeling revealed that the 1H-pyrrolo[2,3-B]pyridine ring may contribute to the high affinity of A6 for binding to c-Abl. Collectively, these results suggest that A6 deserves further investigation as a c-Abl inhibitor for neurodegenerative disorders.

Evolution of the ability to evade host innate immune defense by Talaromyces marneffei.

Talaromyces (Penicillium) marneffei is an intracellular pathogenic fungus. Some strains of this fungus have been misidentified due to the similarity between Talaromyces and Penicillium. T. marneffei has mainly been found to afflict immunocompromised individuals, causing respiratory, skin, and systemic mycosis. Mp1p is a key virulence factor that can help T. marneffei evade clearance by the normally functioning immune system. Understanding how novel functions arise is an intriguing question in many fields of biology. Mp1p has two homologous domains (Mp1p-LBD1 and Mp1p-LBD2). Sequence similarity searches with Mp1p-LBD sequences revealed Mp1p homologs in many other pathogenic fungi. Integrated information on the taxonomic distribution, phylogenetic relationships, and sequence similarity of Mp1p domains revealed that the ancestor of Mp1p-LBDs was acquired through horizontal gene transfer (HGT). Additional evidence revealed that Mp1p homologs have undergone extensive gene duplications in T. marneffei. Mp1p might be a result of gene fusion following gene duplication. Furthermore, we propose a new method for identifying Talaromyces and identify 4 strains with misclassification errors. Our results characterize the evolutionary mechanism of T. marneffei evasion of host innate immune defense and clearly demonstrate the role of gene duplication and HGT in the evolution of host immune escape by T. marneffei.

Characterization and Diversity of Klebsiella pneumoniae Prophages.

Klebsiella pneumoniae is a common human commensal and opportunistic pathogen. In recent years, the clinical isolation and resistance rates of K. pneumoniae have shown a yearly increase, leading to a special interest in mobile genetic elements. Prophages are a representative class of mobile genetic elements that can carry host-friendly genes, transfer horizontally between strains, and coevolve with the host's genome. In this study, we identified 15,946 prophages from the genomes of 1437 fully assembled K. pneumoniae deposited in the NCBI database, with 9755 prophages on chromosomes and 6191 prophages on plasmids. We found prophages to be notably diverse and widely disseminated in the K. pneumoniae genomes. The K. pneumoniae prophages encoded multiple putative virulence factors and antibiotic resistance genes. The comparison of strain types with prophage types suggests that the two may be related. The differences in GC content between the same type of prophages and the genomic region in which they were located indicates the alien properties of the prophages. The overall distribution of GC content suggests that prophages integrated on chromosomes and plasmids may have different evolutionary characteristics. These results suggest a high prevalence of prophages in the K. pneumoniae genome and highlight the effect of prophages on strain characterization.

Effects of low-dose furosemide combined with aminophylline on the renal function in septic shock patients.

BACKGROUND: To investigate the effects of low-dose furosemide and aminophylline on the renal function in patients with septic shock. METHODS AND RESULTS: A total of 109 eligible septic shock patients in the intensive care unit were randomly divided into a control group (n = 55) and an intervention group (n = 54). The control group received normal saline, and the intervention group received low-dose furosemide (0.048 mg/kg.h-1) with aminophylline (0.3 mg/kg.h-1). The primary outcomes included the levels of serum creatinine (Scr), creatinine clearance rate (Ccr), blood urea nitrogen (BUN), glomerular filtration rate (GFR), and urine output on admission and on days 3, 7 and 14. The secondary outcomes were the sequential organ failure assessment (SOFA) scores, continuous renal replacement therapy (CRRT) time and intensive care unit (ICU) mortality, hospital mortality and 28-day mortality. There were no significant differences in the levels of Scr, Ccr, BUN, or GFR between the two groups, while the urine output was higher in the intervention group on days 3, 7, and 14. Compared with the control group, the SOFA scores, ICU mortality, hospital mortality and 28-day mortality were significantly lower in the intervention group on days 3, 7, and 14, the CRRT time was shorter, and the cumulative fluid balance was lower on days 3 and 7 in the intervention group. CONCLUSIONS: Although low-dose furosemide and aminophylline have fewer protective effects on the renal function in septic shock patients, they could reduce the CRRT time and improve the prognosis.

Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine.

Both reversible noncovalent inhibitors and irreversible covalent inhibitors targeting tyrosine kinases have their disadvantages. The reversible covalent inhibitors with electrophilic group cyanoacrylamide as warheads reacting with cysteine residues could solve the dilemmas. However, there are still several unresolved issues regarding the electrophilic groups. In this manuscript, a series of EGFR inhibitors with double electron-withdrawing substituents introduced into the Cα position on the olefin bond were designed and synthesized. The binding structures and characteristics of inhibitors with the kinase in both the first noncovalent binding phase and the second covalent binding step were explored and combined with molecular docking and molecular dynamics simulations. Then, the reverse ß-elimination reactions of the thiol-Michael adducts were investigated by applying density functional theory calculations. In addition, the effects of different electrophilic substituents of Cα on the binding between the inhibitors and kinase were elucidated. The results suggested that the electrophilicity and size of the electron-withdrawing groups play an important role in the specific interactions during the reaction. The compounds with the electron-withdrawing groups that had medium electrostatic and steric complementarity to the kinase active site could cooperatively stabilize the complexes and showed relatively good potent activities in the kinase assay experiment. The mechanical and structural information in this study could enhance our understanding of the functioning of the electron-withdrawing groups in the covalent inhibitors. The results might help to design efficient cysteine targeting inhibitors in the future.

TREM-1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway.

Sepsis often causes cell death via pyroptosis and hence results in septic cardiomyopathy. Triggering receptors expressed in myeloid cells-1 (TREM-1) may initiate cellular cascade pathways and, in turn, induce cell death and vital organ dysfunction in sepsis, but the evidence is limited. We set to investigate the role of TREM-1 on nucleotide-binding oligomerization domain-like receptors with pyrin domain-3 (NLRP3) inflammasome activation and cardiomyocyte pyroptosis in sepsis models using cardiac cell line (HL-1) and mice. In this study, TREM-1 was found to be significantly increased in HL-1 cells challenged with lipopolysaccharide (LPS). Pyroptosis was also significantly increased in the HL-1 cells challenged with lipopolysaccharide and an NLRP3 inflammasome activator, nigericin. The close interaction between TREM-1 and structural maintenance of chromosome 4 (SMC4) was also identified. Furthermore, inhibition of TREM-1 or SMC4 prevented the upregulation of NLRP3 and decreased Gasdermin-D, IL-1ß and caspase-1 cleavage. In mice subjected to caecal ligation and puncture, the TREM-1 inhibitor LR12 decreased the expression of NLRP3 and attenuated cardiomyocyte pyroptosis, leading to improved cardiac function and prolonged survival of septic mice. Our work demonstrates that, under septic conditions, TREM-1 plays a critical role in cardiomyocyte pyroptosis. Targeting TREM-1 and its associated molecules may therefore lead to novel therapeutic treatments for septic cardiomyopathy.

Discovery of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as C-Abl inhibitors with potential neuroprotective effect.

C-Abl is involved in various biological processes and plays an important role in neurodegenerative diseases, especially Parkinson's disease (PD). Previous studies have found that nilotinib shows a neuroprotective effect in cell and animal models of PD by inhibiting the activation of c-Abl. But the low blood-brain barrier permeability and potential toxicity limit the further use of nilotinib in PD. Based on molecular modeling studies, a series of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives were designed and synthesized. In particular, compound 9a exhibited significant inhibitory activity against c-Abl and a potent neuroprotective effect against MPP+-induced SH-SY5Y cell death. Moreover, 9a not only displayed lower cell toxicity compared with nilotinib, but also showed higher oral bioavailability and proper permeability of the blood-brain barrier. This paper provides 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as a new scaffold for c-Abl inhibitor with potential neuroprotective effect.

Metachronous Multiple Primary Carcinoma With Acute Promyelocytic Leukemia: 2 Cases Report and Literature Review.

The co-occurrence of multiple primary cancers with hematological malignancies is uncommon, and acute promyelocytic leukemia (APL) with MPC is even rarer, with only a few cases reported in the literature. Herein, we introduce the diagnosis and treatment of 2 cases of MPC complicated with APL in our hospital and review the relevant literature. Both patients were primary solid tumor patients and were treated with surgery and chemotherapy, and had stable disease (SD). However, more than 1 year after the primary tumor was diagnosed, clinical symptoms were found and APL was diagnosed. Both patients received standard remission-induction therapy, but unfortunately died in the short term due to hemorrhagic complications. In conclusion, treatment of hematological neoplasms, especially acute leukemia combined with multiple primary cancers, is challenging. The prognostic factors and survival analysis of MPC patients with combined APL still need further clinical research and analysis.

Association between Procalcitonin and Acute Kidney Injury in Patients with Bacterial Septic Shock.

OBJECTIVE: The objective of this study was to assess the relationship between serum procalcitonin (PCT) and acute kidney injury (AKI) induced by bacterial septic shock. METHODS: A retrospective study was designed which included patients who were admitted to the ICU from January 2015 to October 2018. Multiple logistic regression and receiver operating characteristic (ROC) as well as smooth curve fitting analysis were used to assess the relationship between the PCT level and AKI. RESULTS: Of the 1,631 patients screened, 157 patients were included in the primary analysis in which 84 (53.5%) patients were with AKI. Multiple logistic regression results showed that PCT (odds ratio [OR] = 1.017, 95% confidence interval [CI] 1.009-1.025, p < 0.001) was associated with AKI induced by septic shock. The ROC analysis showed that the cutoff point for PCT to predict AKI development was 14 ng/mL, with a sensitivity of 63% and specificity 67%. Specifically, in multivariate piecewise linear regression, the occurrence of AKI decreased with the elevation of PCT when PCT was between 25 ng/mL and 120 ng/mL (OR 0.963, 95% CI 0.929-0.999; p = 0.042). The AKI increased with the elevation of PCT when PCT was either <25 ng/mL (OR 1.077, 95% CI 1.022-1.136; p = 0.006) or >120 ng/mL (OR 1.042, 95% CI 1.009-1.076; p = 0.013). Moreover, the PCT level was significantly higher in the AKI group only in female patients aged ≤75 years (p = 0.001). CONCLUSIONS: Our data revealed a nonlinear relationship between PCT and AKI in septic shock patients, and PCT could be used as a potential biomarker of AKI in female patients younger than 75 years with bacterial septic shock.

Platelet count as a new biomarker for acute kidney injury induced by hemorrhagic shock.

The aim of this study was to investigate the association between nadir platelet count and acute kidney injury (AKI) or 28-day all-cause mortality induced by hemorrhagic shock (HS), and to determine the cutoff value of nadir platelet count in HS clinical practice. This retrospective study included hospitalized patients enrolled in a tertiary-care teaching hospital from January 1, 2010 to December 31, 2015. Clinical data from HS admitted to the intensive care unit (ICU) were evaluated. Nadir platelet count was defined as the lowest values in the first 48 h. Multivariate logistic regression and Cox proportional hazards regression were used to assess the correlation between nadir platelet count and AKI or 28-day all-cause mortality induced by HS, respectively; the area under receiver operating characteristic (AU-ROC) and Youde's index were used to determine the optimal cutoff value of nadir platelet count. Kaplan-Meier's method and log-rank test were assessed for the 28-day all-cause mortality in AKI and non-AKI groups. Of 1589 patients screened, 84 patients (mean age,37.1 years; 58 males) were included in the primary analysis in which 30 patients with AKI. Multiple logistic results indicated that nadir platelet count was a risk factor of AKI (OR = 0.71,95% confidence interval [CI] 0.54-0.93, P < 0.05). Cox regression analysis revealed that nadir platelet count was independent risk factors for 28-day all-cause mortality (Hazard ratios [HR]0.89,95%CI 0.76-0.99, P < 0.05). Kaplan-Meier curve showed that 28-day all-cause mortality was significantly higher in patients with AKI than non-AKI (P < 0.001).These results suggest that nadir platelet count in the first 48 h is a new biomarker for AKI and 28-day all-cause mortality induced by HS. Moreover, the risk for AKI and 28-day all-cause mortality in HS patients decreased by 29% and 11%, respectively, for every 10 × 109/L increase in platelet count. Additional studies are needed to investigate whether elevation of nadir platelet count reduces the risk in different genders.