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For a 300 MW coal-fired unit, the regenerative heat exchanger is used to design a regenerative heat exchanger cooling water collection and hot air reheat white smoke treatment and water recovery system. According to the system design scheme, the unit performance test is carried out under full load condition. The results show that: this system can effectively solve the white smoke phenomenon of smoke. In the process of reducing the smoke temperature from 54.1 °C to 40.2 °C, a total of 8.68 t/h of water is analyzed, and the water in the flue gas is effectively recovered. It reduces the concentration of particulate matter in the smoke, which has a certain positive impact on the ultra-low emission of flue gas. However, a certain amount of hot secondary air is extracted to heat the tail flue gas, resulting in an increase of coal consumption for power generation by 0.987 g/(kW h). Therefore, the cooling and water collection and hot air reheat technology of regenerative heat exchanger has certain limitations, and the technology of smoke waste heat recovery will be the key development and application direction in the future

In order to solve the problem of mine water treatment in the production process of coal mine enterprises, the source and characteristics of mine water are introduced, and the zero discharge technology of mine water is studied and applied in engineering, the zero discharge technology of mine water includes three stages: pretreatment, concentration and reduction, and evaporation and crystallization. The results show that: for the mine water with TDS mass concentration of 3200 mg/L, coagulation clarification process is used for pretreatment, reverse osmosis+DTRO is used for concentration and reduction, MVR is used for evaporation and crystallization, the TDS concentration of concentrated water after treatment is 142000 mg/l, the recovery rate of the system is 84.5%, and the TDS of final water production is about 418 mg/l, which meets the design and reuse requirements. The sodium sulfate produced in the evaporation crystallization stage is about 4.9 t/h, and its purity is 99.12%, which can be used as chemical raw material.

When measuring the activity of unslaked lime by "DL/T 323-2010 method for determining the activity of unslaked lime for dry flue gas desulfurization", it was found that different results of unslaked lime activity were obtained by placing thermometers at different positions in thermally insulated container. The improvement measures of the shape of thermally insulated container, the position of thermometer, the position of stirrer and the sample injection equipment were put forward. The improved experimental equipment and method showed that the activity data of quicklime had a good reproducibility at ±1℃. The data detected by the improved experimental method can be of great significance to production.

Peptide-functionalized hydrogel is one of commonly used biomaterials to introduce hydrogel-induced vessel regeneration. Despite many reports about the discoveries of high-active peptides (or ligands) for regeneration, the study on the conjugating methods for the hydrogel functionalization with peptides is limited. Here, we compared the vasculogenic efficacy of the peptide-functionalized hydrogels prepared by two commonly used conjugating methods, 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) and Click methods, through cell models, organ-on-chips models, animal models, and RNA sequencing analysis. Two vascular-related cell types, the human umbilical vein endothelial cells (HUVECs) and the adipose-derived stem cells (ADSCs), have been cultured on the hydrogel surfaces prepared by EDC/Click methods. It showed that the hydrogels prepared by Click method supported the higher vasculogenic activities while the ones made by EDC method compromised the peptide activities on hydrogels. The vasculogenesis assays further revealed that hydrogels prepared by Click method promoted a better vascular network formation. In a critical ischemic hindlimb model, only the peptide-functionalized hydrogels prepared by Click method successfully salvaged the ischemic limb, significantly improved blood perfusion, and enhanced the functional recoveries (through gait analysis and animal behavior studies). RNA sequencing studies revealed that the hydrogels prepared by Click method significantly promoted the PI3K-AKT pathway activation compared to the hydrogels prepared by EDC method. All the results suggested that EDC method compromised the functions of the peptides, while Click method preserved the vascular regenerating capacities of the peptides on the hydrogels, illustrating the importance of the conjugating method during the preparation of the peptide-functionalized hydrogels.

ABSTRACTFlagella play a crucial role in the invasion process of Salmonella and function as a significant antigen that triggers host pyroptosis. Regulation of flagellar biogenesis is essential for both pathogenicity and immune escape of Salmonella. We identified the conserved and unknown function protein STM0435 as a new flagellar regulator. The ∆stm0435 strain exhibited higher pathogenicity in both cellular and animal infection experiments than the wild-type Salmonella. Proteomic and transcriptomic analyses demonstrated dramatic increases in almost all flagellar genes in the ∆stm0435 strain compared to wild-type Salmonella. In a surface plasmon resonance assay, purified STM0435 protein-bound c-di-GMP had an affinity of ~8.383 µM. The crystal structures of apo-STM0435 and STM0435&c-di-GMP complex were determined. Structural analysis revealed that R33, R137, and D138 of STM0435 were essential for c-di-GMP binding. A Salmonella with STM1987 (GGDEF protein) or STM4264 (EAL protein) overexpression exhibits completely different motility behaviours, indicating that the binding of c-di-GMP to STM0435 promotes its inhibitory effect on Salmonella flagellar biogenesis.

Abstract Age is a significant contributing factor to the occurrence and progression of cardiovascular disease (CVD). Pharmacological treatment can effectively alleviate CVD symptoms caused by aging. However, 90% of the drugs have failed in clinics because of the loss of drug effects or the occurrence of the side effects. One of the reasons is the disparity between animal models used and the actual physiological levels in humans. Therefore, we integrated multiple datasets from single‐cell and bulk‐seq RNA‐sequencing data in rats, monkeys, and humans to identify genes and pathways with consistent/differential expression patterns across these three species. An approach called “Cross‐species signaling pathway analysis” was developed to select suitable animal models for drug screening. The effectiveness of this method was validated through the analysis of the pharmacological predictions of four known anti‐vascular aging drugs used in animal/clinical experiments. The effectiveness of drugs was consistently observed between the models and clinics when they targeted pathways with the same trend in our analysis. However, drugs might have exhibited adverse effects if they targeted pathways with opposite trends between the models and the clinics. Additionally, through our approach, we discovered four targets for anti‐vascular aging drugs, which were consistent with their pharmaceutical effects in literatures, showing the value of this approach. In the end, software was established to facilitate the use of “Cross‐species signaling pathway analysis.” In sum, our study suggests utilizing bioinformatics analysis based on disease characteristics can help in choosing more appropriate animal models.

Abstract Objective This study aims to investigate the relationship between abnormal vaginal microecology and human papillomavirus (HPV) infection, as well as the squamous intraepithelial lesions (SIL) progression. Methods A total of 383 patients diagnosed with HPV infection in our hospital between March 2017 and February 2022 were selected as the experimental group. In addition, several volunteers (n = 898) who underwent physical examination during the same period were randomly selected as the control group. Subsequently, we conducted several investigations, such as HPV detection and gene typing, examined vaginal microecological imbalances, and performed cytological examinations to analyze the correlation between microecological changes, different types of HPV infection, and SIL progression. Results HPV detection primarily included single and high-risk types of HPV infections. Moreover, significant disparities in the vaginal microecological environment between patients with persistent HPV infection and the control group, as well as patients with low-grade and high-grade SIL (LSIL and HSIL), were observed. The regression analysis revealed a correlation between LSIL and microflora density, diversity, bacteriological vaginosis (BV), vulvovaginal candidiasis (VVC), trichomonas vaginalis (TV), sialidase, as well as Lactobacillus. In addition, we identified an association between HSIL and pH, flora density, diversity, BV, VVC, candida vaginitis (CV), leukocyte esterase, catalase, and Lactobacillus levels. Conclusion These findings revealed a significant association between abnormal vaginal microecology and both HPV infection and the SIL progression.

3D bioprinting technology is widely used to fabricate various tissue structures. However, the absence of vessels hampers the ability of bioprinted tissues to receive oxygen and nutrients as well as to remove wastes, leading to a significant reduction in their survival rate. Despite the advancements in bioinks and bioprinting technologies, bioprinted vascular structures continue to be unsuitable for transplantation compared to natural blood vessels. In addition, a complete assessment index system for evaluating the structure and function of bioprinted vessels in vitro has not yet been established. Therefore, in this review, we firstly highlight the significance of selecting suitable bioinks and bioprinting techniques as they two synergize with each other. Subsequently, focusing on both vascular-associated cells and vascular tissues, we provide a relatively thorough assessment of the functions of bioprinted vascular tissue based on the physiological functions that natural blood vessels possess. We end with a review of the applications of vascular models, such as vessel-on-a-chip, in simulating pathological processes and conducting drug screening at the organ level. We believe that the development of fully functional blood vessels will soon make great contributions to tissue engineering and regenerative medicine.

Objective: Many studies have demonstrated the heat effect from the holmium laser lithotripsy can cause persistent thermal injury to the ureter. The purpose of this study was to elucidate the use of a modified ureteral catheter with appropriate firing and irrigation to reduce the thermal injury to the “ureter” during the ureteroscopic holmium laser lithotripsy in vitro. Methods: An in vitro lithotripsy was performed using a modified catheter (5 Fr) as the entrance for the irrigation and the holmium laser fiber while using the remaining space in the ureteroscopic channel as an outlet. Different laser power settings (10 W, 20 W, and 30 W) with various firing times (3 s, 5 s, and 10 s) and rates of irrigation (15 mL/min, 20 mL/min, and 30 mL/min) were applied in the experiment. Temperature changes in the “ureter” were recorded with a thermometer during and after the lithotripsy. Results: During the lithotripsy, the local highest mean temperature was 60.3 °C and the lowest mean temperature was 26.7 °C. When the power was set to 10 w, the temperature was maintained below 43 °C regardless of laser firing time or irrigation flow. Regardless of the power or firing time selected, the temperature was below 43 °C at the rate of 30 mL/min. There was a significant difference in temperature decrease when continuous 3 s drainage after continuous firing (3 s, 5 s, or 10 s) compared to with not drainage (p

Abstract MR1-restricted T (MR1T) cells recognize microbial small molecule metabolites presented on the MHC Class I-like molecule MR1 and have been implicated in early effector responses to microbial infection. As a result, there is considerable interest in identifying chemical properties of metabolite ligands that permit recognition by MR1T cells, for consideration in therapeutic or vaccine applications. Here, we made chemical modifications to known MR1 ligands to evaluate the effect on MR1T cell activation. Specifically, we modified 6,7-dimethyl-8-d-ribityllumazine (DMRL) to generate 6,7-dimethyl-8-d-ribityldeazalumazine (DZ), and then further derivatized DZ to determine the requirements for retaining MR1 surface stabilization and agonistic properties. Interestingly, the IFN-γ response toward DZ varied widely across a panel of T cell receptor (TCR)-diverse MR1T cell clones; while one clone was agnostic toward the modification, most displayed either an enhancement or depletion of IFN-γ production when compared with its response to DMRL. To gain insight into a putative mechanism behind this phenomenon, we used in silico molecular docking techniques for DMRL and its derivatives and performed molecular dynamics simulations of the complexes. In assessing the dynamics of each ligand in the MR1 pocket, we found that DMRL and DZ exhibit differential dynamics of both the ribityl moiety and the aromatic backbone, which may contribute to ligand recognition. Together, our results support an emerging hypothesis for flexibility in MR1:ligand-MR1T TCR interactions and enable further exploration of the relationship between MR1:ligand structures and MR1T cell recognition for downstream applications targeting MR1T cells.

Summary: Myocardial infarction (MI) triggers an inflammatory response that transitions from pro-inflammatory to reparative over time. Restoring sympathetic nerves in the heart after MI prevents arrhythmias. This study investigated if reinnervation altered the immune response after MI. This study used quantitative multiplex immunohistochemistry to identify the immune cells present in the heart 2 weeks after ischemia-reperfusion. Two therapeutics stimulated reinnervation, preventing arrhythmias and shifting the immune response from inflammatory to reparative, with fewer pro-inflammatory macrophages and more regulatory T cells and reparative macrophages. Treatments did not alter macrophage phenotype in vitro, which suggested reinnervation contributed to the altered immune response.

Upon entering host cells, Salmonella quickly turns off flagella biogenesis to avoid recognition by the host immune system. However, it is not clear which host signal(s) Salmonella senses to initiate flagellum control. Here, we demonstrate that the acid signal can suppress flagella synthesis and motility of Salmonella, and this occurs after the transcription of master flagellar gene flhDC and depends on the anti-FlhDC factor YdiV. YdiV expression is activated after acid treatment. A global screen with ydiV promoter DNA and total protein from acid-treated Salmonella revealed a novel regulator of YdiV, the acid-related transcription factor CadC. Further studies showed that CadCC, the DNA binding domain of CadC, directly binds to a 33 nt region of the ydiV promoter with a 0.2 μM KD affinity. Furthermore, CadC could separate H-NS-ydiV promoter DNA complex to form CadC-DNA complex at a low concentration. Structural simulation and mutagenesis assays revealed that H43 and W106 of CadC are essential for ydiV promoter binding. No acid-induced flagellum control phenotype was observed in cadC mutant or ydiV mutant strains, suggesting that flagellum control during acid adaption is dependent on CadC and YdiV. The intracellular survival ability of cadC mutant strain decreased significantly compared with WT strain while the flagellin expression could not be effectively controlled in the cadC mutant strain when surviving within host cells. Together, our results demonstrated that acid stress acts as an important host signal to trigger Salmonella flagellum control through the CadC-YdiV-FlhDC axis, allowing Salmonella to sense a hostile environment and regulate flagellar synthesis during infection.

Abstract Emerging evidence has declared that Proteasome 26S subunit ATPase 2 (PSMC2) is involved in tumor progression. However, its role in breast cancer has not been investigated. Therefore, we sought to establish a correlation between breast cancer and PSMC2. PSMC2 expression in tissues was detected by immunohistochemistry. Loss-of-function study was used to evaluate the effects of PSMC2 knockdown in cell proliferation, apoptosis and migration. A gene microarray was performed to explore the potential downstream of PSMC2 with the help of Ingenuity Pathway Analysis (IPA). The effects of the PSMC2/PLAU axis on breast cancer were examined in vitro. Compared to para-cancer tissues, PSMC2 level was considerably elevated in breast cancer, which was significantly correlated with tumor grade. Knockdown of PSMC2 suppressed breast cancer progression in vitro and in vivo. The mechanistic research revealed that PSMC2 promotes the development and progression of human breast cancer through interacting with PLAU. Outcomes of our study showed that overexpression of PSMC2 provide tumorigenic and metastatic advantages in breast cancer, which may involve the regulation of PLAU. This study not only reveals a critical mechanism of breast cancer development, but also provides a promising therapeutic target for breast cancer treatment.

ABSTRACT Bacterial flagellin activates the host immune system and triggers pyroptosis. Salmonella reduces flagellin expression when it survives within host cells. Here, we found that the UMPylator YdiU significantly altered the Salmonella flagellar biogenesis process upon host cell entry. The expression levels of class II and class III flagellar genes, but not the class I flagellar genes flhDC, were dramatically increased in a ΔydiU strain compared to wild-type (WT) Salmonella in a host-simulating environment. A direct interaction between YdiU and FlhDC was detected by bacterial two-hybrid assay. Furthermore, YdiU efficiently catalyzed the UMPylation of FlhC but not FlhD, FliA, or FliC. UMPylation of FlhC completely eliminated its DNA-binding activity. In vivo experiments showed that YdiU was required and sufficient for Salmonella flagellar control within host cells. Mice infected with the ΔydiU strain died much earlier than WT strain-infected mice and developed much more severe inflammation and injury in organs and much higher levels of cytokines in blood, demonstrating that early host death induced by the ΔydiU strain is probably due to excessive inflammation. Our results indicate that YdiU acts as an essential factor of Salmonella to mediate host immune escape. IMPORTANCE Salmonella is an important facultative pathogen of foodborne illness and typhoid fever in humans. Flagella allow bacterial motility and are required for Salmonella to successfully invade the host cells. In parallel, flagellin triggers the host immune system. Salmonella reduces flagellar biogenesis to avoid detection within host cells by a largely unknown mechanism. Here, we report that the UMPylator YdiU inhibits flagellin expression in response to host signals in an UMPylation-dependent manner. The target of YdiU is the major flagellar transcription factor FlhDC. YdiU UMPylates the FlhC subunit on its Ser31 residue and prevents FlhDC from binding to flagellar genes, thus switching off flagellar biogenesis. Our results reveal a novel mechanism by which Salmonella adopts posttranslational modification to shut down flagellar synthesis as a strategy to achieve immune escape.

The photoreduction for hazardous Cr(VI) in industrial wastewater has been considered a “green” approach with low-cost and easy-to-go operation. SnS2 is a promising narrow bandgap photocatalyst, but its low charge carrier separation efficiency should be solved first. In this work, N-doped carbon quantum dots (CQDs) were prepared and loaded onto SnS2 nanoparticles via an in situ method. The resulting composite samples (NC@SnS2) were characterized, and their photocatalytic performance was discussed. SnS2 nanoparticles were obtained as hexagonal ones with a bandgap of 2.19 eV. The optimal doping level for NC@SnS2 was citric acid: urea:SnS2 = 1.2 mmol:1.8 mmol:3.0 mmol. It showed an average diameter of 40 nm and improved photocatalytic performance, compared to pure SnS2, following a pseudo-first-order reaction with a kinetic rate constant of 0.1144 min−1. Over 97% of Cr(VI) was photo-reduced after 30 min. It was confirmed that modification of SnS2 with CQDs can not only improve the light-harvesting ability but also stimulate the charge separation, which therefore can enhance the photoreactivity of SnS2 toward Cr(VI) reduction. The excellent stability of NC@SnS2 indicates that it is promising to be practically used in industrial wastewater purification.

ABSTRACT Iron limitation is a universal strategy of host immunity during bacterial infection. However, the mechanisms by which pathogens antagonize host nutritional immunity have not been fully elucidated. Here, we identified a requirement for the UMPylator YdiU for this process in Salmonella. The expression of YdiU was dramatically induced by the metal starvation signal. The intracellular iron content was much lower in the ΔydiU strain than in wild-type Salmonella, and the ΔydiU strain exhibited severe growth defect under metal deficiency environments. Genome-wide expression analyses revealed significantly decreased expression of iron uptake genes in ΔydiU strain compared with the wild-type strain. Interestingly, YdiU did not affect the expression level of the major iron uptake regulator Fur but directly UMPylated Fur on its H118 residue in vivo and in vitro. UMPylation destroyed the Fur dimer, promoted Fur aggregation, and eliminated the DNA-binding activity of Fur, thus abolishing the ability of Fur to inhibit iron uptake. Restricting Fur to the deUMPylated state dramatically eliminates Salmonella iron uptake in iron deficiency environments. In parallel, YdiU facilitates Salmonella survival within host cells by regulating the iron uptake pathway. IMPORTANCE Salmonella is the major pathogen causing bacterial enteric illness in both humans and animals. Iron availability is strictly controlled upon Salmonella entry into host cells. The mechanisms by which Salmonella balances the acquisition of sufficient iron while preventing a toxic overload has not been fully understood. Here, we reveal a novel regulation process of iron acquisition mediated by the UMPylator YdiU. Fur acts as the central regulator of bacterial iron homeostasis. YdiU UMPylates Fur on H118 and prevents Fur from binding to target DNA, thus activating the expression of iron uptake genes under iron-deficient conditions. We describe the first posttranslational modification-based regulation of Fur and highlight a potential mechanism by which Salmonella can adapt to eliminate host nutritional immunity.

The estimation of the degree of polarization of backscattered light and target light is the key to realize scattering removal in underwater polarimetric imaging. In this paper, a new polarization scattering removal method is proposed by realizing polarimetric calculation of the target light with each pixel of the scene automatically, which is conducive to the restoration of the details of underwater scene. The global model of pixel level is established by utilizing the gradient prior of the polarization information of the total radiance image. Different from the previous study that the degree of polarization of the target light is a constant, the global calculation method can solve the global variable image of the degree of polarization of the target light and it is used for reconstruction experiments of underwater real-world scene to verify the effectiveness of the algorithm. The experimental results demonstrate that the global pixel calculation method has obvious effect on image detail recovery of the underwater scene to realize the clear underwater vision. The influence of the backscattered light on underwater imaging is well suppressed and image contrast has been significantly improved, which provides a new method for enhancing performance of underwater polarimetric imaging with better vision.

Objective: To evaluate the efficacy and safety of Hengli® Chinese botulinum toxin type A (BTX-A; 100 U) in Chinese patients with overactive bladder.Methods: This study was a multicenter, randomized, double-blind, placebo-controlled trial in Chinese patients who were inadequately managed with anticholinergic medications. Eligible patients were randomized 2:1 to receive intradetrusor injections of Hengli® BTX-A (n = 144) or placebo (n = 72). The primary endpoint was the change in the number of daily micturition episodes at week 6 from baseline. The secondary efficacy endpoints included the average frequency of urgency and urinary incontinence (UI) episodes per day, urgency score, average micturition volume per day, OABSS, and QoL score.Results: In the Hengli® BTX-A group, there was a significantly greater reduction in the average number of micturition episodes per 24 h compared with the placebo group (3.28 vs. 1.43; p = 0.003). Moreover, there was a significantly greater improvement in the daily number of urgency episodes, micturition volume and OABSS score. An increased post-void residual urine volume, dysuria, and urinary tract infection represented adverse events (AEs) in the Hengli® BTX-A group. Most AEs were mild or moderate in severity. One patient in the BTX-A group initiated clean intermittent catheterization (CIC) during treatment.Conclusion: Hengli® BTX-A treatment was well-tolerated and resulted in significant improvements in OAB symptoms among Chinese patients inadequately managed by anticholinergics.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/clinicaltrials.prosearch.dhtml, Identifier: CTR20131190.

Purpose: We surveyed the benefit of dietary supplements to treat tinnitus and reported adverse effects. Method: A website was created for people with tinnitus to complete a variety of questions. Results: The 1,788 subjects who responded to questionnaires came from 53 different countries; 413 (23.1 %) reported taking supplements. No effect on tinnitus was reported in 70.7%, improvement in 19.0%, and worsening in 10.3%. Adverse effects were reported in 6% (n = 36), including bleeding, diarrhea, headache, and others. Supplements were reported to be helpful for sleep: melatonin (effect size, d = 1.228) and lipoflavonoid (d = 0.5244); emotional reactions: melatonin (d = 0.6138) and lipoflavonoid (d = 0.457); hearing: Ginkgo biloba (d = 0.3758); and concentration Ginkgo biloba (d = 0.3611). The positive, subjective reports should be interpreted cautiously; many might have reported a positive effect because they were committed to treatment and expected a benefit. Users of supplements were more likely to have loudness hyperacusis and to have a louder tinnitus. Conclusions: The use of dietary supplements to treat tinnitus is common, particularly with Ginkgo biloba, lipoflavonoids, magnesium, melatonin, vitamin B12, and zinc. It is likely that some supplements will help with sleep for some patients. However, they are generally not effective, and many produced adverse effects. We concluded that dietary supplements should not be recommended to treat tinnitus but could have a positive outcome on tinnitus reactions in some people. [ABSTRACT FROM AUTHOR]

Polyfluoroalkyl substances (PFASs) are persistent pollutants that may cause breast cancer. However, associations between exposure to PFASs and the risk of breast cancer are controversial. We retrieved studies on the association between PFASs—perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS)—and breast cancer risk in women from PubMed, Embase, and the Web of Science. The pooled odds ratios (ORs) or relative risks (RRs) and their 95% confidence intervals (CIs) were extracted or calculated from provided data. Moreover, subgroup and metaregression analyses were performed to distinguish the potential sources of heterogeneity between studies. Lastly, eight original studies were included in the meta-analysis. PFOA and PFHxS were positively correlated with breast cancer risk, and the pooled ORs (and 95% CIs) were 1.32 (1.19 and 1.46) and 1.79 (1.51 and 2.11), respectively. PFNA was negatively correlated with breast cancer risk and the pooled OR (and 95% CIs) was 0.76 (0.6 and 0.96), and PFOS was shown to have no correlation with breast cancer risk and the pooled OR (and 95% CIs) was 1.01 (0.87 and 1.17). All results were merged in a random-effects model with significant heterogeneities (I2 > 90%, p < 0.001). The results demonstrated that PFASs might be potential risk factors for breast cancer, and the compounds in low exposure levels could have a more harmful impact on human health.

Purpose: The purpose of the present study is to evaluate the changes over time of the Spatial Hearing Questionnaire (SHQ; Tyler, Perreau, & Ji, 2009) and the Speech, Spatial and Qualities of Hearing Scale (SSQ; Gatehouse & Noble, 2004) in adults with simultaneous bilateral cochlear implants by collecting data for 2 years after implantation. Method: Nineteen postlingual subjects participated in this study. Average age at implant was 63 years. The subjects' data were included in this retrospective analysis only if they completed both questionnaires. We compared subjects' SSQ and SHQ scores to word recognition and sound localization performances. Results: The study showed SHQ and SSQ scores continuously improved up to 1 year postimplantation, with the most improvement occurring within the first 6 months of implantation. After 1 year, the scores reached a plateau. This is consistent with laboratory tests from the same 19 subjects, and they showed high correlations (p < .05). The present study also showed a high degree of correlation between SHQ and SSQ scores. Conclusions: Both the SSQ and SHQ scores improved up to 12 months postimplantation, with the most improvement during the first 6 months of implantation. Both were consistent with laboratory tests. There was a high degree of correlation between SHQ and SSQ scores. [ABSTRACT FROM AUTHOR]

Purpose: To create a questionnaire focused on the primary activities impaired by tinnitus and therefore more sensitive to treatments. Method: Questions were developed on (a) emotions, (b) hearing, (c) sleep, and (d) concentration. A 20-item questionnaire was administered to 158 patients. First, confirmatory factor analysis was used to select 3 questions per domain. Second, factor analysis was used to evaluate the appropriateness of the 12-item questionnaire. Results: The analysis indicated that the selected questions successfully represented 4 independent domains. Scores were correlated with the Tinnitus Handicap Questionnaire (r = .77, p < .01) and loudness (r = .40, p < .01). The Sleep subscale correlated with the Pittsburgh Sleep Index (r = .68, p < .01); the Emotion subscale correlated with the Beck Inventory (r = .66, p < .01) and the Trait Anxiety questionnaire (r = .67, p < .01). The average scores went from 51% to 38% following treatment. Conclusion: The Tinnitus Primary Function Questionnaire is valid, reliable, and sensitive and can be used to determine the efficacy of clinical trials. [ABSTRACT FROM AUTHOR]

Summary: Sensing stressful conditions and adjusting the cellular metabolism to adapt to the environment are essential activities for bacteria to survive in variable situations. Here, we describe a stress-related protein, YdiU, and characterize YdiU as an enzyme that catalyzes the covalent attachment of uridine-5′-monophosphate to a protein tyrosine/histidine residue, an unusual modification defined as UMPylation. Mn2+ serves as an essential co-factor for YdiU-mediated UMPylation. UTP and Mn2+ binding converts YdiU to an aggregate-prone state facilitating the recruitment of chaperones. The UMPylation of chaperones prevents them from binding co-factors or clients, thereby impairing their function. Consistent with the recent finding that YdiU acts as an AMPylator, we further demonstrate that the self-AMPylation of YdiU padlocks its chaperone-UMPylation activity. A detailed mechanism is proposed based on the crystal structures of Apo-YdiU and YdiU-AMPNPP-Mn2+ and on molecular dynamics simulation models of YdiU-UTP-Mn2+ and YdiU-UTP-peptide. In vivo data demonstrate that YdiU effectively protects Salmonella from stress-induced ATP depletion through UMPylation.

The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells in ex vivo assays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule.

Abstract Pantothenate kinase‐associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease‐vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4′‐phosphopantetheine, normalized levels of the CoA‐, iron‐, and dopamine‐related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4′‐phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron–sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4′‐phosphopantetheine as a candidate therapeutic for PKAN.

Staphylococcus saprophyticus (S. saprophyticus) is one of the main pathogens that cause serious infection due to its acquisition of antibiotic resistance. The efflux pump decreases antibiotic abundance, and biofilm compromises the penetration of antibiotics. It has been reported that baicalin is a potential agent to inhibit efflux pumps, biofilm formation, and quorum-sensing systems. The purpose of this study was to investigate whether baicalin can inhibit S. saprophyticus biofilm formation and the quorum-sensing system by inhibiting the MsrA efflux pump. First, the mechanism of baicalin inhibiting efflux was investigated by the ethidium bromide (EtBr) efflux assay, measurement of ATP content, and pyruvate kinase (PK) activities. These results revealed that baicalin significantly reduced the efflux of EtBr, the ATP content, and the activity of PK. Moreover, its role in biofilm formation and the agr system was studied by crystal violet staining, confocal laser scanning microscopy, scanning electron microscopy, and real-time polymerase chain reaction. These results showed that baicalin decreased biofilm formation, inhibited bacterial aggregation, and downregulated mRNA transcription levels of the quorum-sensing system regulators agrA, agrC, RNAIII, and sarA. Correlation analysis indicated that there was a strong positive correlation between the efflux pump and biofilm formation and the agr system. We demonstrate for the first time that baicalin inhibits biofilm formation and the agr quorum-sensing system by inhibiting the efflux pump in S. saprophyticus. Therefore, baicalin is a potential therapeutic agent for S. saprophyticus biofilm-associated infections.

Purpose: To determine (a) changes in the Tinnitus Handicap Questionnaire (THQ) for patients using cochlear implants, (b) differences between patients who receive total or partial relief, and (c) identifiable characteristics of those who report tinnitus after implantation. Method: Pre- and postoperatively, 244 adults were administered the THQ when they reported tinnitus. Results: Of the 153 patients who had tinnitus preoperatively, 94 (61%) patients reported total suppression and 59 (39%) reported a partial reduction. In 91 patients who did not have tinnitus before implantation, 11 (12%) reported tinnitus postimplantation. The THQ score decreased from 41% preimplant to 30% postimplant. The largest reductions involved social handicap and hearing. Patients with a more severe hearing loss might be more likely to experience an exacerbation of their tinnitus. We were not able to clearly identify differences between patients who received total or partial relief and the characteristics of patients who reported tinnitus after implantation. Those who acquired tinnitus had the shortest duration hearing loss (5.6 years) and were the oldest (63 years). The average THQ score of patients getting tinnitus was 29%. Conclusions: Most tinnitus patients benefit from receiving a cochlear implant. [ABSTRACT FROM AUTHOR]

Purpose: We believe it is important to uncover tinnitus subgroups to identify subsets of patients most likely to benefit from different treatments. We review strategies for subgrouping based on etiology, subjective reports, the audiogram, psychoacoustics, imaging, and cluster analysis. Method: Preliminary results of a 2-step cluster analysis based on 246 participants from whom we had 26 categorical and 25 continuous variables were determined. Results: A 4-cluster solution suggested the following subgroups: (a) constant distressing tinnitus, (b) varying tinnitus that is worse in noise, (c) tinnitus patients who are copers and whose tinnitus is not influenced by touch (somatic modulation), and (d) tinnitus patients who are copers but whose tinnitus is worse in quiet environments. Conclusions: Subgroups of tinnitus patients can be identified by using statistical approaches. The subgroups we identify here represent a preliminary attempt at identifying such patients. One next step would be to explore clinical trials of tinnitus treatments based on subgroup analyses or on using subgroups in the selection criteria. [ABSTRACT FROM AUTHOR]

Identifying neurons that have functional opioid receptors is fundamental for the understanding of the cellular, synaptic and systems actions of opioids. Current techniques are limited to post hoc analyses of fixed tissues. Here we developed a fluorescent probe, naltrexamine-acylimidazole (NAI), to label opioid receptors based on a chemical approach termed ‘traceless affinity labeling’. In this approach, a high affinity antagonist naltrexamine is used as the guide molecule for a transferring reaction of acylimidazole at the receptor. This reaction generates a fluorescent dye covalently linked to the receptor while naltrexamine is liberated and leaves the binding site. The labeling induced by this reagent allowed visualization of opioid-sensitive neurons in rat and mouse brains without loss of function of the fluorescently labeled receptors. The ability to locate endogenous receptors in living tissues will aid considerably in establishing the distribution and physiological role of opioid receptors in the CNS of wild type animals.

[This corrects the article DOI: 10.1371/journal.pone.0120646.].