Decrease in osteoporotic fracture in the western Kitakyushu region by the STOP-Fx study.

INTRODUCTION: The Seamless Treatment of Osteoporosis against Fractures (STOP-Fx) study was initiated to provide and continue therapeutic interventions for registered patients with osteoporotic fractures. MATERIALS AND METHODS: Women who visited six hospitals in the western Kitakyushu area for osteoporotic fractures between October 2016 and December 2018 were included in the study. Data collection for primary and secondary outcomes was conducted from October 2018 to December 2020, 2 years after STOP-Fx study enrollment. The primary outcome included the number of surgeries for osteoporotic fractures after the STOP-Fx study intervention, while secondary outcomes were the intervention rate of osteoporosis treatment, incidence and timing of secondary fractures, and factors associated with secondary fractures and loss to follow-up. RESULTS: Concerning the primary outcome, the number of surgeries for osteoporotic fractures decreased since the STOP-Fx study initiation: 813 in 2017, 786 in 2018, 754 in 2019, 716 in 2020, and 683 in 2021. Regarding the secondary outcome, of the 805 patients enrolled, 445 were available for follow-up at 24 months. Of the 279 patients who were untreated for osteoporosis at enrollment, 255 (91%) were on treatment at 24 months. There were 28 secondary fractures, which were associated with increased tartrate-resistant acid phosphatase-5b and decreased lumbar spine bone mineral density during enrollment in the STOP-Fx study. CONCLUSION: As the demographics and medical area served by six hospitals in the western Kitakyushu region have not changed significantly since the STOP-Fx study initiation, the STOP-Fx study may have contributed in decreasing the number of osteoporotic fractures.

Behavioral correlates of cortical semantic representations modeled by word vectors.

The quantitative modeling of semantic representations in the brain plays a key role in understanding the neural basis of semantic processing. Previous studies have demonstrated that word vectors, which were originally developed for use in the field of natural language processing, provide a powerful tool for such quantitative modeling. However, whether semantic representations in the brain revealed by the word vector-based models actually capture our perception of semantic information remains unclear, as there has been no study explicitly examining the behavioral correlates of the modeled brain semantic representations. To address this issue, we compared the semantic structure of nouns and adjectives in the brain estimated from word vector-based brain models with that evaluated from human behavior. The brain models were constructed using voxelwise modeling to predict the functional magnetic resonance imaging (fMRI) response to natural movies from semantic contents in each movie scene through a word vector space. The semantic dissimilarity of brain word representations was then evaluated using the brain models. Meanwhile, data on human behavior reflecting the perception of semantic dissimilarity between words were collected in psychological experiments. We found a significant correlation between brain model- and behavior-derived semantic dissimilarities of words. This finding suggests that semantic representations in the brain modeled via word vectors appropriately capture our perception of word meanings.

Decoding naturalistic experiences from human brain activity via distributed representations of words.

Natural visual scenes induce rich perceptual experiences that are highly diverse from scene to scene and from person to person. Here, we propose a new framework for decoding such experiences using a distributed representation of words. We used functional magnetic resonance imaging (fMRI) to measure brain activity evoked by natural movie scenes. Then, we constructed a high-dimensional feature space of perceptual experiences using skip-gram, a state-of-the-art distributed word embedding model. We built a decoder that associates brain activity with perceptual experiences via the distributed word representation. The decoder successfully estimated perceptual contents consistent with the scene descriptions by multiple annotators. Our results illustrate three advantages of our decoding framework: (1) three types of perceptual contents could be decoded in the form of nouns (objects), verbs (actions), and adjectives (impressions) contained in 10,000 vocabulary words; (2) despite using such a large vocabulary, we could decode novel words that were absent in the datasets to train the decoder; and (3) the inter-individual variability of the decoded contents co-varied with that of the contents of scene descriptions. These findings suggest that our decoding framework can recover diverse aspects of perceptual experiences in naturalistic situations and could be useful in various scientific and practical applications.

Acinetobacter baumannii Lipopolysaccharide Influences Adipokine Expression in 3T3-L1 Adipocytes.

Acinetobacter baumannii is one of the most important nosocomial opportunistic pathogen worldwide. In addition, obesity has been associated with an increased risk of nosocomial infection, suggesting that there may be an association between A. baumannii and white adipose tissue. However, the effects of A. baumannii on adipocytes have not been well studied at the molecular level. Here, we investigated the potential role of A. baumannii-derived lipopolysaccharides (LPS) as signaling molecules that affect adipocyte functionality. We tested the effect of increasing concentrations of A. baumannii-derived LPS (10, 100, or 1000 ng/mL) on the 3T3-L1 adipocyte cell line. Exposure to LPS was found to increase the expression of several adipokines (e.g., MIP-2, MCP-1, TNF-α, IL-6, lipocalin-2, and FABP4) in 3T3-L1 adipocytes and significantly reduced the expression of leptin and adiponectin. The effects of A. baumannii-derived LPS on MIP-2 expression were similar in comparison with that of LPS prepared from Pseudomonas aeruginosa and Escherichia coli in our cell culture-based system. This study suggests that A. baumannii-derived LPS functions as a signaling molecule that impacts the inflammatory function of white adipose tissue on the level of gene expression.

Different target-discrimination times can be followed by the same saccade-initiation timing in different stimulus conditions during visual searches.

The neuronal processes that underlie visual searches can be divided into two stages: target discrimination and saccade preparation/generation. This predicts that the length of time of the prediscrimination stage varies according to the search difficulty across different stimulus conditions, whereas the length of the latter postdiscrimination stage is stimulus invariant. However, recent studies have suggested that the length of the postdiscrimination interval changes with different stimulus conditions. To address whether and how the visual stimulus affects determination of the postdiscrimination interval, we recorded single-neuron activity in the lateral intraparietal area (LIP) when monkeys (Macaca fuscata) performed a color-singleton search involving four stimulus conditions that differed regarding luminance (Bright vs. Dim) and target-distractor color similarity (Easy vs. Difficult). We specifically focused on comparing activities between the Bright-Difficult and Dim-Easy conditions, in which the visual stimuli were considerably different, but the mean reaction times were indistinguishable. This allowed us to examine the neuronal activity when the difference in the degree of search speed between different stimulus conditions was minimal. We found that not only prediscrimination but also postdiscrimination intervals varied across stimulus conditions: the postdiscrimination interval was longer in the Dim-Easy condition than in the Bright-Difficult condition. Further analysis revealed that the postdiscrimination interval might vary with stimulus luminance. A computer simulation using an accumulation-to-threshold model suggested that the luminance-related difference in visual response strength at discrimination time could be the cause of different postdiscrimination intervals.

Discharge-rate persistence of baseline activity during fixation reflects maintenance of memory-period activity in the macaque posterior parietal cortex.

Recent evidence has demonstrated that spatiotemporal patterns of spontaneous activity reflect the patterns of activity evoked by sensory stimuli. However, few studies have examined whether response profiles of task-evoked activity, which is not related to external sensory stimuli but rather to internal processes, are also reflected in those of spontaneous activity. To address this, we recorded activity of neurons in the lateral intraparietal area (LIP) when monkeys performed reaction-time and delayed-response visual-search tasks. We particularly focused on the target location-dependent modulation of delay-period activity (delay-period modulation) in the delayed-response task, and the discharge-rate persistency in fixation-period activity (baseline-activity maintenance) in the reaction-time task. Baseline-activity maintenance was assessed by the correlation between the spike counts of 2 separate bins. We found that baseline-activity maintenance, calculated from bins separated by a long interval (200-500 ms), was correlated with delay-period modulation, whereas that calculated from bins separated by a short interval (~100 ms) was correlated with trial-to-trial fluctuations in baseline activity, suggesting a link between the capability to hold task-related information in delay-period activity and the degree of baseline-activity maintenance in a timescale-dependent manner.

Mechanism-independent method for predicting response to multidrug combinations in bacteria.

Drugs are commonly used in combinations larger than two for treating bacterial infection. However, it is generally impossible to infer directly from the effects of individual drugs the net effect of a multidrug combination. Here we develop a mechanism-independent method for predicting the microbial growth response to combinations of more than two drugs. Performing experiments in both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria, we demonstrate that for a wide range of drugs, the bacterial responses to drug pairs are sufficient to infer the effects of larger drug combinations. To experimentally establish the broad applicability of the method, we use drug combinations comprising protein synthesis inhibitors (macrolides, aminoglycosides, tetracyclines, lincosamides, and chloramphenicol), DNA synthesis inhibitors (fluoroquinolones and quinolones), folic acid synthesis inhibitors (sulfonamides and diaminopyrimidines), cell wall synthesis inhibitors, polypeptide antibiotics, preservatives, and analgesics. Moreover, we show that the microbial responses to these drug combinations can be predicted using a simple formula that should be widely applicable in pharmacology. These findings offer a powerful, readily accessible method for the rational design of candidate therapies using combinations of more than two drugs. In addition, the accurate predictions of this framework raise the question of whether the multidrug response in bacteria obeys statistical, rather than chemical, laws for combinations larger than two.

Transition of target-location signaling in activity of macaque lateral intraparietal neurons during delayed-response visual search.

Neurons in the lateral intraparietal area (LIP) are involved in signaling the location of behaviorally relevant objects during visual discrimination and working memory maintenance. Although previous studies have examined these cognitive processes separately, they often appear as inseparable sequential processes in real-life situations. Little is known about how the neural representation of the target location is altered when both cognitive processes are continuously required for executing a task. We investigated this issue by recording single-unit activity from LIP of monkeys performing a delayed-response visual search task in which they were required to discriminate the target from distractors in the stimulus period, remember the location at which the extinguished target had been presented in the delay period, and make a saccade to that location in the response period. Target-location signaling was assessed using response modulations contingent on whether the target location was inside or opposite the receptive field. Although the population-averaged response modulation was consistent and changed only slightly during a trial, the across-neuron pattern of response modulations showed a marked and abrupt change around 170 ms after stimulus offset due to concurrent changes in the response modulations of a subset of LIP neurons, which manifested heterogeneous patterns of activity changes during the task. Our findings suggest that target-location signaling by the across-neuron pattern of LIP activity discretely changes after the stimulus disappearance under conditions that continuously require visual discrimination and working memory to perform a single behavioral task.

Genomic analysis of extensively drug-resistant Acinetobacter baumannii harbouring a conjugative plasmid containing aminoglycoside resistance transposon TnaphA6.

The occurrence of multidrug-resistant Acinetobacter baumannii (MDRA) has increased rapidly and is associated with severe nosocomial infections. MDRA has emerged in the hospital setting and has evolved into extensively drug-resistant A. baumannii (XDRA). A clinical XDRA isolate obtained from a hospitalised patient in 2016 was evaluated for antibiotic susceptibility and whole-genome sequence. The XDRA isolate was resistant to ß-lactams, including broad-spectrum cephalosporins and carbapenems, and to aminoglycosides, fosfomycin, fluoroquinolones, tetracyclines, tigecycline, and trimethoprim-sulfamethoxazole. The isolate harboured abaF, ant(3″)-II-c, aph(3″)-Ib, aph(6)-Id, armA, blaADC-73, blaTEM-1, blaOXA-66, blaOXA-23, mphE, msrE and tet(B). Quinolone resistance was associated with mutations gyrA S81L and parC S84L. Tigecycline resistance was associated with a mutation in adeS. The isolate belonged to Oxford and Pasteur scheme sequence type 1050 and 2, respectively, and harboured a conjugative plasmid containing the aminoglycoside resistance transposon TnaphA6. Our study demonstrates that the isolate is closely related to a recent MDRA identified in Australia and the USA, in which a similar conjugative plasmid is not observed. Although the MDRA in Australia caused an outbreak, our hospital's surveillance protocol managed to prevent a further outbreak. Our finding suggests that this XDRA isolate is of concern in hospital and community care settings. The gpi allele could be a marker for discriminating this isolate from clonal complex 92 isolates.

Efficacy of Cefiderocol, a Novel Siderophore Cephalosporin, against Multidrug Resistant Acinetobacter baumannii Clinical Isolates in Japan.

Multidrug-resistant Acinetobacter baumannii (MDRAB) is an important pathogen that causes nosocomial infections and is resistant to almost all antibiotics, including carbapenems. Cefiderocol is a novel siderophore cephalosporin active against a broad spectrum of gram-negative bacteria. However, the susceptibility of MDRAB to cefiderocol has not yet been reported in Japan. In this study, we measured the minimum inhibitory concentrations (MICs) of antibiotics including cefiderocol against MDRAB clinical isolates collected during a nosocomial outbreak between 2009 and 2010 at the Teikyo University Hospital in Japan. We found that all 10 MDRAB clinical isolates tested were susceptible to cefiderocol, with an MIC range of 0.12 to 1 µg/mL. All the isolates also exhibited resistance to ampicillin-sulbactam and an intermediate resistance to colistin, whereas nine of them were susceptible to tigecycline. DNA sequencing revealed that all strains harbored an OXA-51-like carbapenemase, a major cause of carbapenem resistance in A. baumannii in Japan. In conclusion, this study showed that the cefiderocol susceptibility of MDRAB clinical isolates in Japan was equivalent to that to colistin or tigecycline, and thus cefiderocol is a potential treatment option for MDRAB infections.

Separate evaluation of target facilitation and distractor suppression in the activity of macaque lateral intraparietal neurons during visual search.

During visual search, neurons in the lateral intraparietal area (LIP) discriminate the target from distractors by exhibiting stronger activation when the target appears within the receptive field than when it appears outside the receptive field. It is generally thought that such target-discriminative activity is produced by the combination of target-related facilitation and distractor-related suppression. However, little is known about how the target-discriminative activity is constituted by these two types of neural modulation. To address this issue, we recorded activity from LIP of monkeys performing a visual search task that consisted of target-present and target-absent trials. Monkeys had to make a saccade to a target in the target-present trials, whereas they had to maintain fixation in the target-absent trials, in which only distractors were presented. By introducing the activity from the latter trials as neutral activity, we were able to separate the target-discriminative activity into target-related elevation and distractor-related reduction components. We found that the target-discriminative activity of most LIP neurons consisted of the combination of target-related elevation and distractor-related reduction or only target-related elevation. In contrast, target-discriminative activity composed of only distractor-related reduction was observed for very few neurons. We also found that, on average, target-related elevation was stronger and occurred earlier compared with distractor-related reduction. Finally, we consider possible underlying mechanisms, including lateral inhibitory interactions, responsible for target-discriminative activity in visual search. The present findings provide insight into how neuronal modulations shape target-discriminative activity during visual search.

Visual response of neurons in the lateral intraparietal area and saccadic reaction time during a visual detection task.

During visual detection with saccades, a target with higher luminance is detected with reduced reaction times. In such visual detection behaviors, luminance-related sensory signals should be converted into movement-related signals for saccade initiation. At the site where the visuomotor transformation takes place, there is the possibility that visual activity not only encodes the target luminance but also affects the generation of an upcoming saccade. To assess this possibility, we recorded single-cell activity from visually responsive neurons in the lateral intraparietal area (LIP) when monkeys made a saccade to an isolated target over five luminance levels. We found that as stimulus luminance increased, visual response strength increased, and response onset latency decreased. These luminance-related changes in activity were significantly correlated with changes in reaction time. In particular, changes in response onset latency accounted for a substantial part of the observed changes in reaction time, suggesting that luminance-related changes in response onset latency may propagate to the saccade generation process. However, the length of time from response onset to saccade onset was not constant but increased as luminance was reduced, suggesting the existence of other luminance-dependent processing in downstream and/or parallel pathways before saccade generation. Additionally, we failed to find strong covariance between response strength or latency and reaction time when the effect of luminance changes was removed. Thus, the present results reveal how visually responsive LIP neurons contribute to saccade generation in visual detection.

Disorganization of Semantic Brain Networks in Schizophrenia Revealed by fMRI.

OBJECTIVES: Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts since the term "schizophrenia" was first coined by Bleuler. However, a mechanistic account of this cardinal disturbance in terms of functional dysconnection has been lacking. To evaluate how aberrant semantic connections are expressed through brain activity, we characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). STUDY DESIGN: We quantified various concept representations in patients' brains from fMRI activity evoked by movie scenes using encoding modeling. We then constructed semantic brain networks by evaluating the similarity of these semantic representations and conducted graph theory-based network analyses. STUDY RESULTS: Neurotypical networks had small-world properties similar to those of natural languages, suggesting small-worldness as a universal property in semantic knowledge networks. Conversely, small-worldness was significantly reduced in networks of schizophrenia patients and was correlated with psychological measures of delusions. Patients' semantic networks were partitioned into more distinct categories and had more random within-category structures than those of controls. CONCLUSIONS: The differences in conceptual representations manifest altered semantic clustering and associative intrusions that underlie thought disorders. This is the first study to provide pathophysiological evidence for the loosening of associations as reflected in randomization of semantic networks in schizophrenia. Our method provides a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively.

Functions of consciousness: conceptual clarification.

There are many theories of the functions of consciousness. How these theories relate to each other, how we should assess them, and whether any integration of them is possible are all issues that remain unclear. To contribute to a solution, this paper offers a conceptual framework to clarify the theories of the functions of consciousness. This framework consists of three dimensions: (i) target, (ii) explanatory order, and (iii) necessity/sufficiency. The first dimension, target, clarifies each theory in terms of the kind of consciousness it targets. The second dimension, explanatory order, clarifies each theory in terms of how it conceives of the explanatory relation between consciousness and function. The third dimension, necessity/sufficiency, clarifies each theory in terms of the necessity/sufficiency relation posited between consciousness and function. We demonstrate the usefulness of this framework by applying it to some existing scientific and philosophical theories of the functions of consciousness.

Evaluation of an immunological assay for the identification of multiple carbapenemase-producing Gram-negative bacteria.

Carbapenemase-producing Gram-negative organisms (CPOs) frequently gain multidrug-resistant phenotypes and thereby limit the therapeutic options available. Colonisation and infection with CPOs are critical risks for mortality in clinical settings, especially in critical care medicine. Carbapenemase genes on plasmids have transferred to many Gram-negative species, and these species have spread, leading to global concern regarding antimicrobial resistance. A molecular rapid diagnostic test (mRDT) for CPOs is urgently required in critical care medicine. Here, we evaluated a rapid lateral flow immunoassay (LFIA) for CPOs isolated from patients at university hospitals, including intensive care units, and compared the results with those obtained using the multiplex polymerase chain reaction (PCR) method. NG-test CARBA 5 detected multiple carbapenemases, KPC, OXA-48, NDM, VIM, and IMP variants expressed in clinical isolates. Quick Chaser IMP detected IMP variants. The LFIAs exhibited 100% sensitivity and specificity relative to clinical isolates on agar plates. By contrast, the multiplex PCR method exhibited a limited ability to detect IMP-7-producing isolates not belonging to the IMP1 group, which resulted in 97% sensitivity and 100% specificity for IMP-producing isolates. Our results demonstrate that the LFIA is a useful mRDT to identify CPOs and has an advantage over the PCR method for both detection time and sensitivity to the IMP groups. LFIA could complement the nucleic acid amplification test used to identify CPOs. In conclusion, we evaluated sensitive and specific LFIAs capable of detecting carbapenemase production in Gram-negative bacteria. We anticipate that LFIAs will become a point-of-care test enabling rapid detection of carbapenemases in hospital settings, particularly in intensive care units.

Expert Programmers Have Fine-Tuned Cortical Representations of Source Code.

Expertise enables humans to achieve outstanding performance on domain-specific tasks, and programming is no exception. Many studies have shown that expert programmers exhibit remarkable differences from novices in behavioral performance, knowledge structure, and selective attention. However, the underlying differences in the brain of programmers are still unclear. We here address this issue by associating the cortical representation of source code with individual programming expertise using a data-driven decoding approach. This approach enabled us to identify seven brain regions, widely distributed in the frontal, parietal, and temporal cortices, that have a tight relationship with programming expertise. In these brain regions, functional categories of source code could be decoded from brain activity and the decoding accuracies were significantly correlated with individual behavioral performances on a source-code categorization task. Our results suggest that programming expertise is built on fine-tuned cortical representations specialized for the domain of programming.

Automatic measurement of mandibular cortical bone width on cone-beam computed tomography images.

OBJECTIVE: The computed tomography cortical index (CTCI), computed tomography mandibular index (CTMI), and computed tomography index (inferior) [CTI(I)] are indexes obtained from cone-beam computed tomography images for the assessment of the mandibular cortex quality for implant planning or osteoporosis. However, cross-sectional image reconstruction for the measurements is labor-intensive. This study aimed to develop and evaluate a method to automatically reconstruct cross-sectional images and measure the cortex width in all areas inferior to the mental foramen (MF). METHODS: Seventy-one women (mean age: 52.4 years; range: 20-78 years) were enrolled. They were divided into four age and CTCI groups, including females younger (FY) and females older (FO) than 50 years (C1: normal, C2: mild/moderate erosion, and C3: severe porosity). Automatic and manual measurements of CTMI and CTI(I) were compared, and the inter- and intraobserver agreements were assessed using the intraclass correlation coefficient (ICC). The relationships between CTMI or CTI(I) and CTCI were also assessed. RESULTS: The mean processing times for reconstruction and measurements were 31.9 s and 1.22 s, respectively. ICCs for the comparison of automatic and manual measurements were 0.932 and 0.993 in the C1 and C2/C3 groups, respectively. Significant differences in CTMI and CTI(I) were observed between the FY or the FO-C1 and FO-C3 groups (p < 0.05). CONCLUSION: The automatic and manual measurements showed a strong agreement. The new method could drastically reduce routine clinical workload. Additionally, our method enables the measurement of the cortex width in all the mandibular bones inferior to the MF.

Histopathological Analysis of Acinetobacter baumannii Lung Infection in a Mouse Model.

Acinetobacter baumannii is the main causative pathogen of nosocomial infections that causes severe infections in the lungs. In this study, we analyzed the histopathological characteristics of lung infection with two strains of A. baumannii (ATCC 19606 and the clinical isolate TK1090) and Pseudomonas aeruginosa PAO-1 in C3H/HeN mice to evaluate the virulence of A. baumannii. Survival was evaluated over 14 days. At 1, 2, 5, or 14 days postinfection, mice of C3H/HeN were sacrificed, and histopathological analysis of lung specimens was also performed. Histopathological changes and accumulation of neutrophils and macrophages in the lungs after infection with A. baumannii and P. aeruginosa were analyzed. Following intratracheal inoculation, the lethality of ATCC 19606- and TK1090-infected mice was lower than that of PAO-1-infected mice. However, when mice were inoculated with a sub-lethal dose of A. baumannii, the lung bacterial burden remained in the mice until 14 days post-infection. Additionally, histopathological analysis revealed that macrophages infiltrated the lung foci of ATCC 19606-, TK1090-, and PAO-1-infected mice. Although neutrophils infiltrated the lung foci of ATCC 19606- and TK1090-infected mice, they poorly infiltrated the lung foci of PAO-1-infected mice. Accumulation of these cells in the lung foci of ATCC 19606- and TK1090-infected mice, but not PAO-1-infected mice, was observed for 14 days post-infection. These results suggest that A. baumannii is not completely eliminated despite the infiltration of immune cells in the lungs and that inflammation lasts for prolonged periods in the lungs. Further studies are required to understand the mechanism of A. baumannii infection, and novel drugs and vaccines should be developed to prevent A. baumannii infection.

A rabbit monoclonal antibody-mediated lateral flow immunoassay for rapid detection of CTX-M extended-spectrum ß-lactamase-producing Enterobacterales.

Infections of CTX-M extended-spectrum ß-lactamase-producing Enterobacterales are a severe threat in clinical settings. CTX-M genes on plasmids have been transferred to many Enterobacterales species, and these species have spread, leading to the global problem of antimicrobial resistance. Here, we developed a lateral flow immunoassay (LFIA) based on an anti-CTX-M rabbit monoclonal antibody. This antibody detected CTX-M variants from the CTX-M-9, CTX-M-2, and CTX-M-1 groups expressed in clinical isolates. The LFIA showed 100% sensitivity and specificity with clinical isolates on agar plates, and its limit of detection was 0.8 ng/mL recombinant CTX-M-14. The rabbit monoclonal antibody did not cross-react with bacteria producing other class A ß-lactamases, including SHV. In conclusion, we developed a highly sensitive and specific LFIA capable of detecting CTX-M enzyme production in Enterobacterales. We anticipate that our LFIA will become a point-of-care test enabling rapid detection of CTX-M in hospital and community settings as well as a rapid environmental test.

A new oxidative sensing and regulation pathway mediated by the MgrA homologue SarZ in Staphylococcus aureus.

Oxidative stress serves as an important host/environmental signal that triggers a wide range of responses from the human pathogen Staphylococcus aureus. Among these, a thiol-based oxidation sensing pathway through a global regulator MgrA controls the virulence and antibiotic resistance of the bacterium. Herein, we report a new thiol-based oxidation sensing and regulation system that is mediated through a parallel global regulator SarZ. SarZ is a functional homologue of MgrA and is shown to affect the expression of approximately 87 genes in S. aureus. It uses a key Cys residue, Cys-13, to sense oxidative stress and to co-ordinate the expression of genes involved in metabolic switching, antibiotic resistance, peroxide stress defence, virulence, and cell wall properties. The discovery of this SarZ-mediated regulation, mostly independent from the MgrA-based regulation, fills a missing gap of oxidation sensing and response in S. aureus.