A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

Vulvar Crohn's disease in an adolescent diagnosed after unsuccessful surgical treatment.

BACKGROUND: This case report presents a case of Vulvar Crohn's disease (VCD) in an adolescent, that is an uncommon manifestation of Crohn's disease (CD) without gastrointestinal symptoms. Before treating CD itself with proper medication, vulvar abscess continued to recur without improvement. CASE PRESENTATION: We report the case of an 18-year-old woman with VCD. After treatment with azathioprine 50 mg daily and mesalazine 1 g three times daily, vulvar lesions resolved after 6 weeks. We collected electronic medical data on patient characteristics, and evaluated findings of physical examinations, pelvic MRI, and biopsy specimen obtained from gastroduodenoscopy/colonoscopy. CONCLUSIONS: VCD is a rare manifestation of CD that may be misdiagnosed in the absence of gastrointestinal symptoms leading to delayed treatment. If a patient has an unexplained vulvar inflammatory lesion and with repeated failed surgical treatment, gynecologists should consider the possibility of a VCD.

Hormone autocrination by vascularized hydrogel delivery of ovary spheroids to rescue ovarian dysfunctions.

The regeneration potential of implantable organ model hydrogels is applied to treat a loss of ovarian endocrine function in women experiencing menopause and/or cancer therapy. A rat ovariectomy model is used to harvest autologous ovary cells while subsequently producing a layer-by-layer form of follicle spheroids. Implantation of a microchannel network hydrogel with cell spheroids [vascularized hydrogel with ovarian spheroids (VHOS)] into an ischemic hindlimb of ovariectomized rats significantly aids the recovery of endocrine function with hormone release, leading to full endometrium regeneration. The VHOS implantation effectively suppresses the side effects observed with synthetic hormone treatment (i.e., tissue overgrowth, hyperplasia, cancer progression, deep vein thrombosis) to the normal levels, while effectively preventing the representative aftereffects of menopause (i.e., gaining fatty weight, inducing osteoporosis). These results highlight the unprecedented therapeutic potential of an implantable VHOS against menopause and suggest that it may be used as an alternative approach to standard hormone therapy.

Non-alcoholic fatty liver disease in polycystic ovary syndrome women.

To evaluate risk factors leading to non-alcoholic fatty liver disease (NAFLD) occurrence in polycystic ovarian syndrome (PCOS) women. A retrospective cohort study of a total of 586 women diagnosed with PCOS aged 13-35 years at the gynecology department at a university hospital was done to evaluate PCOS phenotype, metabolic syndrome (MetS) diagnosis, body composition, insulin sensitivity, sex hormones, lipid profile, liver function, and transient elastography (TE). In PCOS women with NAFLD compared to those without, MetS diagnosis (Hazard ratio [HR] 5.6, 95% Confidence interval [CI] 2.2-14.4, p < 0.01) and hyperandrogenism (HA) (HR 4.4, 95% CI 1.4-13.4, p = 0.01) were risk factors significantly associated with subsequent NAFLD occurrence, whereas 2-h insulin level in 75 g glucose tolerance test (GTT) (HR 1.2, 95% CI 0.5-2.5, p = 0.70) and body mass index (BMI) > 25 kg/m2 (HR 2.2, 95% CI 0.6-8.0, p = 0.24) was not. Among NAFLD patients who underwent TE, a higher number of MetS components indicated a worse degree of fibrosis and steatosis. MetS diagnosis and HA at PCOS diagnosis were risk factors associated with NAFLD, while 2-h insulin level in 75 g GTT and obesity were not. Although elevated aspartate aminotransferase levels were significant for NAFLD risk, liver enzyme elevations may not be present until late liver damage. Further prospective studies of PCOS women with MetS or HA are warranted to determine whether patients without liver enzyme elevations should undergo preemptive liver examinations.

Effect of sex hormones on coronavirus disease 2019: an analysis of 5,061 laboratory-confirmed cases in South Korea.

OBJECTIVE: To evaluate the effect of female sex hormones on the clinical outcomes of coronavirus disease 2019 patients using national claims data. METHODS: This retrospective cohort study used the Health Insurance Review and Assessment data of 5,061 adult patients with laboratory-confirmed coronavirus disease 2019 in South Korea from January 20 to April 8, 2020. To evaluate the effect of hormone therapy on clinical outcomes among women, subgroup analyses using age-matched case-control data were performed. RESULTS: Coronavirus disease 2019 was most prevalent in women in the 20-39 years age group (1,250 [44.14%]). Men were more likely to receive oxygen therapy (144 [6.46%] vs 131 [4.63%], P = 0.004), be admitted to the intensive care unit (60 [2.69%] vs 53 [1.87%], P = 0.049), and have a longer length of stay after admission to the intensive care unit (19.70 ± 11.80 vs 14.75 ±â€Š9.23, P = 0.016). However, there was no significant difference in the mortality rate (men vs women: 42 [1.88%] vs 42 [1.48%], P = 0.267). In the multivariable Cox analysis, older age and underlying comorbidities, but not sex, were independent risk factors for mortality. Hormone therapy was not significantly associated with clinical outcomes. CONCLUSIONS: This study, using nationwide data, suggests that female sex hormones are not associated with the morbidity and clinical outcomes of coronavirus disease 2019 in South Korea.

Identification of Serum Biomarkers for Diagnosis of Endometriosis Using Multiplex Immunoassays.

Endometriosis is a common gynecologic disorder characterized by chronic pelvic pain, dysmenorrhea, and infertility. Although this condition places significant financial burden on the healthcare system and negatively affects patient's quality of life, the pathophysiology of the disease remains unclear, and noninvasive diagnostic methods are insufficient. The object of this study was to identify potential biomarkers for endometriosis from peripheral blood. We hypothesized that serum biomarkers modified in endometriosis patients would be detected by multiplex cytokine panel, and identification of a combination of these biomarkers would improve diagnostic power. A total of 141 women, aged 15-52 years with regular menstruation, participated in this study. Twenty-one serum cytokines were detected using the commercially available MILLIPLEX MAP Human Cytokine/Chemokine Kit Panel IV. Among these cytokines, breast- and kidney-expressed chemokine (BRAK)/chemokine (C-X-C motif) ligand 14 (CXCL14) was significantly decreased, and proliferation-inducing ligand (APRIL)/tumor necrosis factor ligand superfamily member 13 (TNFSF13) was significantly increased in endometriosis group. APRIL/TNFSF13 and BRAK/CXCL14 alone or in combination, however, failed to show adequate sensitivity or specificity for the diagnosis of endometriosis. Combination of APRIL/TNFSF13 and BRAK/CXCL14 with serum CA-125 levels yielded significantly higher sensitivity (71.2%) for detecting endometriosis without compromising specificity (80.8%) than CA-125 alone in a logistic regression model (P = 0.050). In conclusion, we identified a biomarker combination that detects endometriosis better than CA125 alone. Therefore, we conclude that multiplex cytokine panel is an efficient method for detecting endometriosis, and analysis of additional cytokine panels may lead to identification of a novel biomarker combination with superior diagnostic power.

Operative hysteroscopy-assisted pregnancy termination after failed surgical abortion in missed abortion of woman with complete septate uterus.

First trimester surgical abortion is an effective and safe procedure. Although its failure is uncommon, congenital uterine anomaly may be considered as one of the etiologic factors in such cases. Here, we report a rare case of surgical abortion failure that was successfully managed by operative hysteroscopy-assisted dilatation and evacuation (D&E) under ultrasound guidance in a woman with complete uterine septum. The patient was referred to Severance Hospital after two consecutive surgical abortion failures even under ultrasound guidance. A missed abortion in a left-sided hemicavity of septate uterus was noted on ultrasonography. Ultrasound-guided D&E was unsuccessful because the curette could not reach the uterine cavity with the gestational sac. Operative hysteroscopy revealed insufficient communication with the left-sided cavity just above the cervical internal os of the uterine septum. After widening the communication, ultrasound-guided D&E was successfully performed.

Clinical factors and ultrasound parameters to predict successful vaginal delivery following labour induction.

Morbidity and complications are higher with caesarean delivery after labour induction. We aimed to evaluate which maternal/neonatal pregnancy characteristics and ultrasound parameters are useful in predicting successful vaginal delivery following labour induction. In this retrospective observational study, several maternal and foetal characteristics were studied in 197 primigravidae women at 38 or more gestational weeks before induction. Multivariate analysis showed that maternal age (odds ratio [OR] 0.907, 95% confidence intervals [CI] 0.826-0.995, p = .038), term body mass index (BMI; OR 0.909, 95% CI 0.828-0.997, p = .044), and foetal engagement (OR 3.295, 95% CI 1.232-8.810, p = .017) were independent predictors for a successful vaginal delivery in an induced labour. An older maternal age, high term BMI and un-engagement were associated with a failed labour induction.IMPACT STATEMENTWhat is already known on this subject? Labour induction is being used more frequently worldwide, but it is not always easy to predict those patients who will progress to a vaginal delivery and those who will require a caesarean section. Because caesarean sections are associated with a higher mortality and morbidity in patients who have undergone a labour induction, it is important to identify the factors predictive of successful vaginal delivery after labour induction.What do the results of this study add? Multivariate analysis showed that maternal age, term BMI, and foetal engagement were independent predictors for successful vaginal delivery in an induced labour.What are the implications of these findings for clinical practice and/or further research? We found that maternal age, term body mass index and foetal engagement were important variables to consider when predicting a successful labour induction. A comprehensive assessment of these variables should be done before inducing labour to limit any unnecessary mortality and morbidity associated with a failed induction. Women should be given accurate information regarding the risks of induction based on their individual characteristics.

Polycystic ovarian morphology is associated with primary dysmenorrhea in young Korean women.

OBJECTIVE: This study was aimed at identifying a correlation between polycystic ovarian morphology (PCOM) and the severity of primary dysmenorrhea in young Korean women. METHODS: A total of 592 patients who visited a tertiary hospital from March 2008 to March 2015 for dysmenorrhea were examined. After excluding those with secondary causes of menstrual pain (for example, myoma, adenomyosis, endometriosis, and pelvic inflammatory disease), 361 women were recruited and retrospectively analyzed. Severe dysmenorrhea was defined as a visual analog scale (VAS) score ≥6. RESULTS: The mean patient age was 23.0±4.0 years, the average menstrual cycle length was 34.4±23.7 days, and the average pain intensity was VAS 6.7±0.1 at baseline. PCOM was assessed by ultrasound in 54 women (15%). Patients with severe menstrual pain were more likely to have irregular menstrual cycles (P=0.03) and heavy menstrual flow (P=0.01) than those with mild menstrual pain. After adjusting for weight, height, menstrual cycle interval, and menstrual flow in the logistic regression analysis, PCOM (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.05-4.97; P=0.04) and heavy menstrual flow (OR, 1.85; 95% CI, 1.05-3.28; P=0.04) were found to be significant independent factors influencing pain. CONCLUSION: Our study shows that PCOM may have a correlation with the severity of primary dysmenorrhea. Since PCOM may play a role in the development of menstrual pain, patients with PCOM should be under active surveillance with resources for prompt pain management readily available. It may also be necessary to further investigate the molecular mechanisms of pain development in primary dysmenorrhea.

MiR-150-5p May Contribute to Pathogenesis of Human Leiomyoma via Regulation of the Akt/p27Kip1 Pathway In Vitro.

Uterine leiomyoma is found in ~50-80% of women of a reproductive age and is the most common reason for hysterectomy. Recently, posttranscriptional gene silencing by microRNAs (miRs) has been reported as a mechanism for regulating gene expression stability in the pathogenesis of uterine leiomyomas. In this study, miR microarray analysis of leiomyomas and paired myometrial tissue revealed numerous aberrantly expressed miRs, including miR-150. In functional assays, transfection with miR-150 mimic resulted in decreased migration and fibrosis, implying an inhibition of leiomyoma growth. To identify the target genes of miR-150 in leiomyoma, gene set analysis and network analysis were performed. To overcome the limitations of in silico analysis, changes in expression levels of hallmark genes in leiomyoma after transfection with a miR-150 mimic were also evaluated using qRT-PCR. As a result, the Akt/p27Kip1 pathway was presumed to be one of the target pathways of miR-150. After transfecting cultured leiomyoma cells with the miR-150 mimic, expression levels of its target gene Akt decreased, whereas those of p27Kip1 increased significantly. Our results suggest that miR-150 affects the cell cycle regulation in uterine leiomyoma through the Akt/p27Kip1 pathway.

Comparison of congenital malformations among babies born after administration of letrozole or clomiphene citrate for infertility treatment in a Korean cohort.

This retrospective study investigated and compared the incidence of congenital foetal anomalies after letrozole versus clomiphene citrate (CC) administration for infertility treatment. Data from 142 newborns were included: letrozole group, n = 83; CC group, n = 61. Congenital anomalies were found in 7.2% (6/83) patients in the letrozole group and 18.0% (11/61) patients in the CC group, with no significant between-group difference (p = .066). Major congenital anomaly rate was 2.4% (2/83) in the letrozole group and 3.3% (2/61) in the CC group, with no significant between-group difference (p > 0.999). There was no significant difference in major and minor congenital anomalies between the groups after excluding premature infants (birth at a gestational age of <37 weeks), low birth weight, and very low birth weight. The results of this study demonstrate the stability of letrozole compared to that of CC for infertility treatment in pregnant women.

Postoperative urinary symptoms after transobturator tape in normal-weight compared with overweight and obese woman.

OBJECTIVES: To examine the clinical outcome of obesity in women who underwent the transobturator tape procedure for stress urinary incontinence and to compare postoperative urinary symptoms after transobturator tape surgery between normal-weight women and overweight and obese women. METHODS: We performed a retrospective cohort study of the risk of postoperative urinary symptoms, including recurrence after transobturator tape surgery, in normal-weight women compared with overweight and obese women at our institution from January 2009 through October 2011. We compared the body mass index (BMI) among the four groups. The primary outcome was the occurrence of postoperative urinary symptoms. RESULTS: Three hundred ten patients who underwent transobturator tape surgery were reviewed. At the 1-year follow-up, 281 women were analyzed: 89 (34%) normal-weight women, 78 (25%) overweight women, 101 (37%) obese 1 women, and 13 (3%) obese 2 women. There was a significant difference in the occurrence of postoperative urinary symptoms. They occurred in 3.4% (n=3) of normal-weight women, 5.1% (n=4) of overweight women, and 12.9% (n=13) of obese 1 women (P=0.038). The most common postoperative urinary symptom was frequent urination (n=14). There was a significant difference in leakage; it occurred in 1.1% (n=1) of normal-weight women, 3.9% (n=3) of overweight women, and 7.9% (n=8) of obese 1 women (P=0.139). Postoperative urinary symptoms were almost four times more likely to occur in obese 1 women than in normal-weight women. CONCLUSION: Transobturator tape surgery seems effective regardless of BMI, but obese women had a higher occurrence of postoperative urinary symptoms than did normal-weight women.

Cleavage of molybdopterin synthase MoaD-MoaE linear fusion by JAMM/MPN+ domain containing metalloprotease DR0402 from Deinococcus radiodurans.

Molybdenum cofactor (Moco), molybdopterin (MPT) complexed with molybdenum, is an essential cofactor required for the catalytic center of diverse enzymes in all domains of life. Since Moco cannot be taken up as a nutrient unlike many other cofactors, Moco requires de novo biosynthesis. During the synthesis of MPT, the sulfur atom on the C-terminus of MoaD is transferred to cyclic pyranopterin monophosphate (cPMP) which is bound in the substrate pocket of MoaE. MoaD is a ubiquitin-like (Ubl) protein and has a C-terminal di-Gly motif which is a common feature of Ubl proteins. Despite the importance of free C terminal di-Gly motif of MoaD as a sulfur carrier, some bacteria encode a fused MPT synthase in which MoaD- and MoaE-like domains are located on a single peptide. Although it has recently been reported that the fused MPT synthase MoaX from Mycobacterium tuberculosis is posttranslationally cleaved into functional MoaD and MoaE in M. smegmatis, the protease responsible for the cleavage of MoaD-MoaE fusion protein has remained unknown to date. Here we report that the JAMM/MPN+ domain containing metalloprotease DR0402 (JAMMDR) from Deinococcus radiodurans can cleave the MoaD-MoaE fusion protein DR2607, the sole MPT synthase in D. radiodurans, generating the MoaD having a C-terminal di-Gly motif. Furthermore, JAMMDR can also cleave off the MoaD from MoaD-eGFP fusion protein suggesting that JAMMDR recognizes the MoaD region rather than MoaE region in the cleaving process of MoaD-MoaE fusion protein.

In-bag power morcellation technique in single-port laparoscopic myomectomy.

OBJECTIVE: This study introduces and evaluates the feasibility, safety, and surgical outcomes of the in-bag power morcellation technique during single-port assisted (SPA) laparoscopic myomectomy in comparison with manual scalpel morcellation. METHODS: This is a retrospective review of a total of 58 patients who underwent SPA laparoscopic myomectomy employing in-bag power morcellation (n=27) or manual scalpel morcellation (n=31), performed between December 2014 and December 2016. Surgical outcomes, including total operation time, estimated blood loss, postoperative hemoglobin changes, postoperative hospital stay, postoperative pain (visual analog scale), perioperative and postoperative complications were evaluated. RESULTS: The demographics and patient characteristics were similar between both groups. The median patient age was 34 years and median body mass index was 20.84 kg/m2. The median specimen weight was 110 g. The median operating time was 138 minutes. The median estimated blood loss was 50 mL and the median postoperative hemoglobin change was 2.2 g/dL. The median postoperative hospital stay was 2 days and the median postoperative pain scores were 5 after 6 hours, 3 after 24 hours, and 2 after 48 hours. Occult malignancy was not identified in any patients. There were no intraoperative complications such as LapBag ruptures or gross spillage. CONCLUSION: In-bag power morcellation for SPA laparoscopic myomectomy is feasible and safe, minimizing the risks of open power morcellation. There were also no statistically significant differences in surgical outcomes.

The inability of Bacillus licheniformis perR mutant to grow is mainly due to the lack of PerR-mediated fur repression.

PerR, a member of Fur family protein, is a metal-dependent H2O2 sensing transcription factor that regulates genes involved in peroxide stress response. Industrially important bacterium Bacillus licheniformis contains three PerR-like proteins (PerRBL, PerR2, and PerR3) compared to its close relative Bacillus subtilis. Interestingly, unlike other bacteria including B. subtilis, no authentic perR BL null mutant could be established for B. licheniformis. Thus, we constructed a conditional perR BL mutant using a xylose-inducible promoter, and investigated the genes under the control of PerRBL. PerRBL regulon genes include katA, mrgA, ahpC, pfeT, hemA, fur, and perR as observed for PerRBS. However, there is some variation in the expression levels of fur and hemA genes between B. subtilis and B. licheniformis in the derepressed state. Furthermore, katA, mrgA, and ahpC are strongly induced, whereas the others are only weakly or not induced by H2O2 treatment. In contrast to the B. subtilis perR null mutant which frequently gives rise to large colony phenotype mainly due to the loss of katA, the suppressors of B. licheniformis perR mutant, which can form colonies on LB agar, were all catalase-positive. Instead, many of the suppressors showed increased levels of siderophore production, suggesting that the suppressor mutation is linked to the fur gene. Consistent with this, perR fur double mutant could grow on LB agar without Fe supplementation, whereas perR katA double mutant could only grow on LB agar with Fe supplementation. Taken together, our data suggest that in B. licheniformis, despite the similarity in PerRBL and PerRBS regulon genes, perR is an essential gene required for growth and that the inability of perR null mutant to grow is mainly due to elevated expression of Fur.

The difference in in vivo sensitivity between Bacillus licheniformis PerR and Bacillus subtilis PerR is due to the different cellular environments.

PerR, a member of Fur family of metal-dependent regulators, is a major peroxide sensor in many Gram positive bacteria, and controls the expression of genes involved in peroxide resistance. Bacillus licheniformis, a close relative to the well-studied model organism Bacillus subtilis, contains three PerR-like proteins (PerRBL, PerR2 and PerR3) in addition to Fur and Zur. In the present study, we characterized the role of PerRBL in B. licheniformis. In vitro and in vivo studies indicate that PerRBL, like PerRBS, uses either Fe2+ or Mn2+ as a corepressor and only the Fe2+-bound form of PerRBL senses low levels of H2O2 by iron-mediated histidine oxidation. Interestingly, regardless of the difference in H2O2 sensitivity, if any, between PerRBL and PerRBS, B. licheniformis expressing PerRBL or PerRBS could sense lower levels of H2O2 and was more sensitive to H2O2 than B. subtilis expressing PerRBL or PerRBS. This result suggests that the differences in cellular milieu between B. subtilis and B. licheniformis, rather than the intrinsic differences in PerRBS and PerRBLper se, affect the H2O2 sensing ability of PerR inside the cell and the H2O2 resistance of cell. In contrast, B. licheniformis and B. subtilis expressing Staphylococcus aureus PerR (PerRSA), which is more sensitive to H2O2 than PerRBL and PerRBS, were more resistant to H2O2 than those expressing either PerRBL or PerRBS. This result indicates that the sufficient difference in H2O2 susceptibility of PerR proteins can override the difference in cellular environment and affect the resistance of cell to H2O2.

Bacillus licheniformis Contains Two More PerR-Like Proteins in Addition to PerR, Fur, and Zur Orthologues.

The ferric uptake regulator (Fur) family proteins include sensors of Fe (Fur), Zn (Zur), and peroxide (PerR). Among Fur family proteins, Fur and Zur are ubiquitous in most prokaryotic organisms, whereas PerR exists mainly in Gram positive bacteria as a functional homologue of OxyR. Gram positive bacteria such as Bacillus subtilis, Listeria monocytogenes and Staphylococcus aureus encode three Fur family proteins: Fur, Zur, and PerR. In this study, we identified five Fur family proteins from B. licheniformis: two novel PerR-like proteins (BL00690 and BL00950) in addition to Fur (BL05249), Zur (BL03703), and PerR (BL00075) homologues. Our data indicate that all of the five B. licheniformis Fur homologues contain a structural Zn2+ site composed of four cysteine residues like many other Fur family proteins. Furthermore, we provide evidence that the PerR-like proteins (BL00690 and BL00950) as well as PerRBL (BL00075), but not FurBL (BL05249) and ZurBL (BL03703), can sense H2O2 by histidine oxidation with different sensitivity. We also show that PerR2 (BL00690) has a PerR-like repressor activity for PerR-regulated genes in vivo. Taken together, our results suggest that B. licheniformis contains three PerR subfamily proteins which can sense H2O2 by histidine oxidation not by cysteine oxidation, in addition to Fur and Zur.

Staphylococcus aureus PerR Is a Hypersensitive Hydrogen Peroxide Sensor using Iron-mediated Histidine Oxidation.

In many Gram-positive bacteria PerR is a major peroxide sensor whose repressor activity is dependent on a bound metal cofactor. The prototype for PerR sensors, the Bacillus subtilis PerRBS protein, represses target genes when bound to either Mn(2+) or Fe(2+) as corepressor, but only the Fe(2+)-bound form responds to H2O2. The orthologous protein in the human pathogen Staphylococcus aureus, PerRSA, plays important roles in H2O2 resistance and virulence. However, PerRSA is reported to only respond to Mn(2+) as corepressor, which suggests that it might rely on a distinct, iron-independent mechanism for H2O2 sensing. Here we demonstrate that PerRSA uses either Fe(2+) or Mn(2+) as corepressor, and that, like PerRBS, the Fe(2+)-bound form of PerRSA senses physiological levels of H2O2 by iron-mediated histidine oxidation. Moreover, we show that PerRSA is poised to sense very low levels of endogenous H2O2, which normally cannot be sensed by B. subtilis PerRBS. This hypersensitivity of PerRSA accounts for the apparent lack of Fe(2+)-dependent repressor activity and consequent Mn(2+)-specific repressor activity under aerobic conditions. We also provide evidence that the activity of PerRSA is directly correlated with virulence, whereas it is inversely correlated with H2O2 resistance, suggesting that PerRSA may be an attractive target for the control of S. aureus pathogenesis.