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The emergence of Klebsiella pneumoniae carbapenemases (KPCs), β-lactamases that inactivate “last-line” antibiotics such as imipenem, represents a major challenge to contemporary antibiotic therapies. The combination of ceftazidime (CAZ) and avibactam (AVI), a potent β-lactamase inhibitor, represents an attempt to overcome this formidable threat and to restore the efficacy of the antibiotic against Gram-negative bacteria bearing KPCs. CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging. We engineered 19 KPC-2 variants bearing targeted mutations at amino acid residue Ambler position 179 in Escherichia coli and identified a unique antibiotic resistance phenotype. We focus particularly on the CAZ-AVI resistance of the clinically relevant Asp179Asn variant. Although this variant demonstrated less hydrolytic activity, we demonstrated that there was a prolonged period during which an acyl-enzyme intermediate was present. Using mass spectrometry and transient kinetic analysis, we demonstrated that Asp179Asn “traps” β-lactams, preferentially binding β-lactams longer than AVI owing to a decreased rate of deacylation. Molecular dynamics simulations predict that (i) the Asp179Asn variant confers more flexibility to the Ω-loop and expands the active site significantly; (ii) the catalytic nucleophile, S70, is shifted more than 1.5 Å and rotated more than 90°, altering the hydrogen bond networks; and (iii) E166 is displaced by 2 Å when complexed with ceftazidime. These analyses explain the increased hydrolytic profile of KPC-2 and suggest that the Asp179Asn substitution results in an alternative complex mechanism leading to CAZ-AVI resistance. The future design of novel β-lactams and β-lactamase inhibitors must consider the mechanistic basis of resistance of this and other threatening carbapenemases. IMPORTANCE Antibiotic resistance is emerging at unprecedented rates and threatens to reach crisis levels. One key mechanism of resistance is the breakdown of β-lactam antibiotics by β-lactamase enzymes. KPC-2 is a β-lactamase that inactivates carbapenems and β-lactamase inhibitors (e.g., clavulanate) and is prevalent around the world, including in the United States. Resistance to the new antibiotic ceftazidime-avibactam, which was designed to overcome KPC resistance, had already emerged within a year. Using protein engineering, we uncovered a mechanism by which resistance to this new drug emerges, which could arm scientists with the ability to forestall such resistance to future drugs. Antibiotic resistance is emerging at unprecedented rates and threatens to reach crisis levels. One key mechanism of resistance is the breakdown of β-lactam antibiotics by β-lactamase enzymes. KPC-2 is a β-lactamase that inactivates carbapenems and β-lactamase inhibitors (e.g., clavulanate) and is prevalent around the world, including in the United States. Resistance to the new antibiotic ceftazidime-avibactam, which was designed to overcome KPC resistance, had already emerged within a year. Using protein engineering, we uncovered a mechanism by which resistance to this new drug emerges, which could arm scientists with the ability to forestall such resistance to future drugs.

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)–infected individuals, (2) organ transplant recipients, and (3) non–HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

The Nose cone is an integral part of the missile, with the role of protecting the self-guided head from the effects of the environment during the flight. However, the Nose cone also causes the error component of the angle due to the electromagnetic refraction effect when passing through the Nose cone, causing the missile guidance error. This article will analyze the relationship among the angular components during the proximity to the target of the missile, thereby using filters along with the dither signal to determine the angular error component caused by the Nose cone to eliminate the effect of the said error component This article proposes a simple compensation and rejection scheme based on the dither signal. With the proposed compensation scheme, the calculated volume is significantly reduced when compared to the method of compensation by the Kalman filter. The Nose cone error compensation ability of the compensation scheme proposed in this article will be verified through simulations on the MATLAB software. The results of the article will show that the Nose cone coefficient can be quickly estimated using a dither signal, bandpass filter and notch filter, so that we could get information about the Nose cone coefficient. With the practicality of the article results, it can be applied to radio self-guided head of the self-guided missile system to improve the quality of proximity to the target, reduce slippage at the time of meeting.

This paper presents a low-error, low-area FPGA-based hardware logarithm generator for digital signal processing systems which require high-speed, real time logarithm operations. The proposed logarithm generator employs the modified quasi-symmetrical approach for an efficient hardware implementation. The error analysis and implementation results are also presented and discussed. The achieved results show that the proposed approach can reduce the approximation error and hardware area compared with traditional methods.

Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings. In this personal perspective, we discuss the future role stewardship can play in stimulating innovation, a need to move away from a pharmacy budget dominated view of antibiotic use, and the impact of the ever-increasing sophistication and interdisciplinary nature of antimicrobial control programs. Changes are needed to optimize clinical outcomes for patients.

Klebsiella pneumoniae remains an important cause of intrapulmonary infection and invasive disease worldwide. K. pneumoniae can evade serum killing and phagocytosis primarily through the expression of a polysaccharide capsule, but its pathogenicity is also influenced by host factors. We examined whether CD36, a scavenger receptor that recognizes pathogen and modified self ligands, is a host determinant of K. pneumoniae pathogenicity. Despite differences in serum sensitivity and virulence of 3 distinct K. pneumoniae (hypermucoviscous K1, research K2, and carbapenemase-producing ST258) strains, the absence of CD36 significantly increased host susceptibility to acute intrapulmonary infection by K. pneumoniae, regardless of strain. We demonstrate that CD36 enhances LPS responsiveness to K. pneumoniae to increase downstream cytokine production and macrophage phagocytosis that is independent of polysaccharide capsular antigen. Our study provides new insights into host determinants of K. pneumoniae pathogenicity and raises the possibility that functional mutations in CD36 may predispose individuals to K. pneumoniae syndromes.

Bacterial exopolysaccharides (EPSs) are an essential group of compounds secreted by bacteria. These versatile EPSs are utilized individually or in combination with different materials for a broad range of biomedical field functions. The various applications can be explained by the vast number of derivatives with useful properties that can be controlled. This review offers insight on the current research trend of nine commonly used EPSs, their biosynthesis pathways, their characteristics, and the biomedical applications of these relevant bioproducts.

Hydrolyzed collagen with different fractions is broadly applied in various industries due to its functional properties. The study aimed to purify and fractionate the hydrolyzed collagen from yellowfin tuna skin by ultrafiltration and evaluate the functional properties of its fractions. The effect of temperature, pH, and pressure on membrane flux, nitrogen recovery efficiency, and degree of separation was investigated. Afterward, several functional properties of hydrolyzed collagen fractions including solubility, emulsification, foaming, and antioxidant properties were evaluated. The optimum ultrafiltration conditions for hydrolyzed collagen were temperature 25 °C, pH 6.5 and pressure 12 psi provided optimum membrane flux (3.4 L/m2.h) and nitrogen recovery efficiency (80.81%), and the smallest degree of separation (27.45%). The products after ultrafiltration were separated into two fractions, F1 (< 3 kDa), and F2 (3-5 kDa), with the volume of 10% and 90%, respectively. Both hydrolyzed collagen fractions were more than 96% soluble at pH below 8.0, where the F2 fraction dissolved better than F1. As pH was higher than 8.0, both fractions were almost completely dissolved. In addition, the emulsifying and foaming abilities of the F1 fraction were better than the F2. However, the F2 fraction was more resistant to oxidation with higher antioxidant activity. In conclusion, this research indicates that different fractions from hydrolyzed collagen from yellowfin tuna skin have various functional properties that could be applied in food, cosmetic and pharmaceutical industries.

This research explores the relationship between the recruitment process and turnover intentions, with the mediating role of affective commitment among Generation Z working in European enterprises operating in Vietnam. The study examines the relationship between job description, job evaluation, job specification, job analysis, and affective commitment of Generation Z, while also identifying the influence of affective commitment on turnover intentions. A quantitative analysis was conducted on a sample of 250 Generation Z respondents working for European businesses in Vietnam using snowball sampling. Questionnaires were distributed via an online survey. Data were analyzed using SPSS v.22 and AMOS software. Results reveal that job description, job evaluation, job specification, and job analysis all contribute to enhancing affective commitment, and that affective commitment negatively influences turnover intentions. Managerial policy implications for Central European enterprises are proposed to increase employee affective commitment, including regularly reviewing job descriptions, overcoming cultural barriers, creating a flexible workplace, and emphasizing a supportive team environment. The insights are particularly relevant for Central European enterprises expanding into Southeast Asia.

As 3D-printed (3DP) patterns are solid and durable, they can be used to create thin wall castings, which is complicated with wax patterns because of the wax’s fragility and high shrinkage ratio. According to this study’s experiment results, polylactic acid (PLA), polyvinyl butyral (PVB), and castable wax (CW) are suitable materials for preparing investment casting (IC) cavities. The results indicate that the casting product with the highest-quality surface is obtained using a cavity prepared using a CW-printed pattern. PLA- and PVB-printed patterns provide a good surface finish for casted products. In addition, the roughness of both the printed and casted surfaces increases as the printing layer height increases. The roughness of the casted surface varies from 2.25 μm to 29.17 μm. This investigation also considers the correlation between the infill ratio and mechanical properties of PLA-printed patterns. An increase in the infill ratios from 0% to 100% leads to a significant increase in the tensile properties of the PLA-printed pattern. The obtained results can be practically used.