Intracellular Accumulation of Linezolid and Florfenicol in OptrA-Producing Enterococcus faecalis and Staphylococcus aureus

The optrA gene, which confers transferable resistance to oxazolidinones and phenicols, is defined as an ATP-binding cassette (ABC) transporter but lacks transmembrane domains. The resistance mechanism of optrA and whether it involves antibiotic efflux or ribosomal protection remain unclear. In this study, we determined the MIC values of all bacterial strains by broth microdilution, and used ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry to quantitatively determine the intracellular concentrations of linezolid and florfenicol in Enterococcus faecalis and Staphylococcus aureus. Linezolid and florfenicol both accumulated in susceptible strains and optrA-carrying strains of E. faecalis and S. aureus. No significant differences were observed in the patterns of drug accumulation among E. faecalis JH2-2, E. faecalis JH2-2/pAM401, and E. faecalis JH2-2/pAM401+optrA, but also among S. aureus RN4220, S. aureus RN4220/pAM401, and S. aureus RN4220/pAM401+optrA. ANOVA scores also suggested similar accumulation conditions of the two target compounds in susceptible strains and optrA-carrying strains. Based on our findings, the mechanism of optrA-mediated resistance to oxazolidinones and phenicols obviously does not involve active efflux and the OptrA protein does not confer resistance via efflux like other ABC transporters

VIVO: Visual Vocabulary Pre-Training for Novel Object Captioning

It is highly desirable yet challenging to generate image captions that can describe novel objects which are unseen in caption-labeled training data, a capability that is evaluated in the novel object captioning challenge (nocaps). In this challenge, no additional image-caption training data, other thanCOCO Captions, is allowed for model training. Thus, conventional Vision-Language Pre-training (VLP) methods cannot be applied. This paper presents VIsual VOcabulary pretraining (VIVO) that performs pre-training in the absence of caption annotations. By breaking the dependency of paired image-caption training data in VLP, VIVO can leverage large amounts of paired image-tag data to learn a visual vocabulary. This is done by pre-training a multi-layer Transformer model that learns to align image-level tags with their corresponding image region features. To address the unordered nature of image tags, VIVO uses a Hungarian matching loss with masked tag prediction to conduct pre-training. We validate the effectiveness of VIVO by fine-tuning the pre-trained model for image captioning. In addition, we perform an analysis of the visual-text alignment inferred by our model. The results show that our model can not only generate fluent image captions that describe novel objects, but also identify the locations of these objects. Our single model has achieved new state-of-the-art results on nocaps and surpassed the human CIDEr score.Comment: AAAI 202

DSHGT: Dual-Supervisors Heterogeneous Graph Transformer -- A pioneer study of using heterogeneous graph learning for detecting software vulnerabilities

Vulnerability detection is a critical problem in software security and attracts growing attention both from academia and industry. Traditionally, software security is safeguarded by designated rule-based detectors that heavily rely on empirical expertise, requiring tremendous effort from software experts to generate rule repositories for large code corpus. Recent advances in deep learning, especially Graph Neural Networks (GNN), have uncovered the feasibility of automatic detection of a wide range of software vulnerabilities. However, prior learning-based works only break programs down into a sequence of word tokens for extracting contextual features of codes, or apply GNN largely on homogeneous graph representation (e.g., AST) without discerning complex types of underlying program entities (e.g., methods, variables). In this work, we are one of the first to explore heterogeneous graph representation in the form of Code Property Graph and adapt a well-known heterogeneous graph network with a dual-supervisor structure for the corresponding graph learning task. Using the prototype built, we have conducted extensive experiments on both synthetic datasets and real-world projects. Compared with the state-of-the-art baselines, the results demonstrate promising effectiveness in this research direction in terms of vulnerability detection performance (average F1 improvements over 10\% in real-world projects) and transferability from C/C++ to other programming languages (average F1 improvements over 11%)

Physiology of quantal norepinephrine release from somatodendritic sites of neurons in locus coeruleus

Norepinephrine (NE) released from the nerve terminal of locus coeruleus (LC) neurons contributes to about 70% of the total extracellular NE in primates brain. In addition, LC neurons also release NE from somatodendritic sites. Quantal NE release from soma of LC neurons has the characteristics of long latency, nerve activity-dependency, and autoinhibition by α2-adrenergic autoreceptor. The distinct kinetics of stimulus-secretion coupling in somata is regulated by action potential patterns. The physiological significance of soma and dendritic release is to produce negative-feedback and to down-regulate neuronal hyperactivity, which consequently inhibit NE release from axon terminal of LC projecting to many brain areas. Recent discoveries about the LC somatodendritic release may provide new insights into the pathogenesis of clinic disease involving LC-NE system dysfunction, and may help developing remedy targeted to the LC area

Controlled synthesis of mussel-inspired Ag nanoparticle coatings with demonstrated in vitro and in vivo antibacterial properties

The in-situ formation of silver nanoparticles (AgNPs) via dopamine-reduction of Ag+ has been widely utilized for titanium implants to introduce antibacterial properties. In previous studies, the preparation of AgNPs has focused on controlling the feeding concentrations, while the pH of the reaction solution was ignored. Herein, we systematically determined the influence of various pH (4, 7, 10) and Ag+ concentrations (0.01, 0.1 mg/mL) on the AgNPs formation, followed by the evaluation of the antibacterial properties in vitro and in vivo. The results revealed that an alkaline environment was favourable for AgNP formation and resulted in more particles. Although the AgNPs bearing Ti had lower biocompatibilities, it was significantly improved after 7 days of mineralization in simulated body fluid. The outstanding antibacterial property of the AgNPs was well maintained after one day and seven days of implantation. Moreover, 3D micro-CT modelling showed that the pH 10/0.1 group exhibited remarkable osteogenesis, which may be due to their strong antibacterial properties and ability to promote mineralization. Therefore, we have demonstrated that the solution pH was as important as the feeding Ag+ concentration in determining AgNP formation, and it has paved the way for developing various AgNP-loaded surfaces that could meet different antibacterial needs

Pharmacological Effects of Two Novel Bombesin-Like Peptides from the Skin Secretions of Chinese Piebald Odorous Frog (Odorrana schmackeri) and European Edible Frog (Pelophylax kl. esculentus) on Smooth Muscle

Bombesin-like peptides, which were identified from a diversity of amphibian skin secretions, have been demonstrated to possess several biological functions such as stimulation of smooth muscle contraction and regulation of food intake. Here, we report two novel bombesin-like peptides, bombesin-OS and bombesin-PE, which were isolated from Odorrana schmackeri and Pelophylax kl. esculentus, respectively. The mature peptides were identified and structurally confirmed by high performance Scliquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Subsequently, the effects of these purified chemically-synthetic peptides on smooth muscle were determined in bladder, uterus, and ileum. The synthetic replications were revealed to have significant pharmacological effects on these tissues. The EC50 values of bombesin-OS for bladder, uterus and ileum, were 10.8 nM, 33.64 nM, and 12.29 nM, respectively. Furthermore, compared with bombesin-OS, bombesin-PE showed similar contractile activity on ileum smooth muscle and uterus smooth muscle, but had a higher potency on bladder smooth muscle. The EC50 value of bombesin-OS for bladder was around 1000-fold less than that of bombesin-PE. This suggests that bombesin-OS and bombesin-PE have unique binding properties to their receptors. The precursor of bombesin-OS was homologous with that of a bombesin-like peptide, odorranain-BLP-5, and bombesin-PE belongs to the ranatensin subfamily. We identified the structure of bombesin-OS and bombesin-PE, two homologues peptides whose actions may provide a further clue in the classification of ranid frogs, also in the provision of new drugs for human health

Study on the bearing characteristics of overrun hydraulic support under impact loading

In order to study the effects of stress change and adaptability of the overrun hydraulic stent under impact load, the rigid–flexible coupling numerical model of the stent is established using multi-body dynamics simulation software ADAMS. In the model, the stent is flexibilized using the HyperMesh module, and the column and jack are equivalently replaced with a spring damping system. By applying impact loads to different positions above the front roof beam of the stent, the dynamic response characteristics of the column and the articulation point are obtained at different positions with different strengths. The results show that when the impact load is applied to different positions of the front roof beam, the steady-state response force of the column shows an overall “M" distribution, and along the length direction of the roof beam, the steady-state response force of the column shows an upward trend, and the maximum steady-state response force of the column is 547 kN at point (1, 6); when the impact load is applied to both sides of the front roof beam, the response at the articulation point is greater, resulting in a higher maximum simple harmonic response at that articulation point. When the impact load acts on both sides of the front roof beam, the response of the articulation point is greater, with a maximum simple harmonic response coefficient of 0.75 and a maximum excitation response coefficient of 0.28; when the impact loads of different strengths act on the whole front roof beam, the force acting on the column and pin shaft at the articulation point will produce a large impact, reducing its adaptability. To address this, we can consider changing the top plate stress conditions using methods like high-pressure injection of water and control the gradual and slow release of the top plate stresses. The results of the study provide a reference for the structural strength design and reliability analysis of the hydraulic support, which is of practical significance and value for improving the safe mining of the coal mining face