Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles.

Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.

Antimicrobial Activities of α-Helix and ß-Sheet Peptides against the Major Bovine Respiratory Disease Agent, Mannheimia haemolytica.

Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in cattle raised in North America. At the feedlot, cattle are subject to metaphylactic treatment with macrolides to prevent BRD, a practice that may promote antimicrobial resistance and has resulted in an urgent need for novel strategies. Mannheimia haemolytica is one of the major bacterial agents of BRD. The inhibitory effects of two amphipathic, α-helical (PRW4, WRL3) and one ß-sheet (WK2) antimicrobial peptides were evaluated against multidrug-resistant (MDR) M. haemolytica isolated from Alberta feedlots. WK2 was not cytotoxic against bovine turbinate (BT) cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All three peptides inhibited M. haemolytica, with WK2 being the most efficacious against multiple isolates. At 8-16 µg/mL, WK2 was bactericidal against Mh 330 in broth, and at 32 µg/mL in the presence of BT cells, it reduced the population by 3 logs CFU/mL without causing cytotoxic effects. The membrane integrity of Mh 330 was examined using NPN (1-N-phenylnaphthylamine) and ONPG (o-Nitrophenyl ß-D-galactopyranoside), with both the inner and outer membranes being compromised. Thus, WK2 may be a viable alternative to the use of macrolides as part of BRD prevention and treatment strategies.

Exposure to Secondhand Smoke Extract Increases Cisplatin Resistance in Head and Neck Cancer Cells.

Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers' saliva and treated with cisplatin (0.01-100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC50, and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells' capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.

The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP.

The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIPA52G point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48.

Intra-couple discordance in preconception syphilis screening for both spouses: a national and population-based survey in China, 2013-2018.

OBJECTIVE: The antenatal screening strategy remains inadequate for eliminating congenital syphilis. To further eliminate maternal fetal transmission, preconception syphilis screening is considered an option. In this study, we investigated syphilis seropositivity and intra-couple discordance among married couples planning a pregnancy in China to provide essential baseline evidence for preconception syphilis screening. DESIGN: Population-based survey. SETTING: National preconception registered data. POPULATION: Married Chinese couples planning conception within 6 months between 2013 and 2018. METHODS: Syphilis was screened using rapid plasma reagin (RPR); infection self-reporting and sociodemographic characteristics were collected through questionnaires and medical records, respectively. r 3.2.2 and arcgis 10.2 were used for statistical analyses and geographic mapping. MAIN OUTCOME MEASURES: RPR seropositivity. RESULTS: Among 31 955 041 couples, 29 737 172 (93.06%) had complete RPR results for both spouses; of those, 0.62% (186 100) were seropositive, with dramatic intra-couple discordance, with 0.33% positivity in wives, 0.24% positivity in husbands and 0.05% positivity in both spouses. Across time, both seropositivity and intra-couple discordance remained stable. Seropositivity in different regions varied significantly, with provincial rates ranging geographically from Tibet (0.8%) to Hebei (0.2%) (P < 0.05). Economic level was an independent factor for this regional variation, with seropositivity increasing as gross domestic product income decreased (P < 0.05). CONCLUSIONS: Intra-couple discordance in seropositivity for syphilis is notable among couples, with a considerable rate of pre-existing syphilis before pregnancy. Thus, screening both spouses during integrated preconception health care is recommended for further eliminating maternal-fetal transmission. TWEETABLE ABSTRACT: Intra-couple discordance in seropositivity for syphilis is notable among couples, with a considerable rate of pre-existing syphilis before pregnancy. Screening both spouses during integrated preconception health care is recommended to further eliminate maternal-fetal transmission.

The association between the vaginal microenvironment and fecundability: a register-based cohort study among Chinese women.

OBJECTIVE: To evaluate the association between the vaginal microenvironment and fecundability among women. DESIGN: Register-based nationwide cohort study. SETTING: Chinese National Free Pre-conception Check-up Project from 2015 to 2018. POPULATION: Our study included a total of 3 388 554 eligible women who were attempting to become pregnant. METHOD: We assessed the vaginal microenvironment at baseline by considering four indices: vaginal pH, clue cell examination, whiff test and vaginal cleanliness grading. If any of these indicators was abnormal, the vaginal microenvironment was defined as poor. Propensity score matching was used to control for potential confounders and reduce bias. Logistic models were used to estimate the fecundability odds ratios (FORs) after adjustment for covariates. MAIN OUTCOME MEASURES: Achievement of a pregnancy within 1 year. RESULTS: Of the total study population, 379 718 women (11.2%) had a poor vaginal microenvironment and their pregnancy rate after 1 year was significantly lower than the group with a normal microenvironment (71.8% versus 76.1%, P < 0.001). After adjusting for potential confounders, the women with a poor vaginal microenvironment were associated with a 9% reduction in fecundability compared with the normal microenvironment group (FOR 0.91, 95% CI 0.90-0.92). The adverse effects of a poor vaginal microenvironment were stronger among multipara (FOR 0.89, 95% CI 0.87-0.90) or women with irregular menstruation (FOR 0.86, 95% CI 0.84-0.89). CONCLUSION: There was a negative association between a poor vaginal microenvironment and the fecundability of women. These findings highlight the significance of assessing the vaginal microenvironment during pre-pregnancy health examinations. TWEETABLE ABSTRACT: Women with a poor vaginal microenvironment were associated with a reduction in fecundability.

Vaginal-perianal or vaginal-perineal compared with vaginal-rectal culture-based screening for Group B Streptococci (GBS) colonization during the third trimester of pregnancy: a systematic review and meta-analysis.

BACKGROUND: Screening for maternal anogenital Group B streptococci (GBS) colonization in pregnancy with initiation of intravenous intrapartum antibiotic prophylaxis as indicated has led to a significant reduction in the incidence of neonatal GBS infection. This study aims to evaluate the agreement between vaginal-perianal or vaginal-perineal culture and the more typically used vaginal-rectal culture for screening for maternal anogenital GBS colonization in the third trimester of pregnancy. METHODS: Eligible English-language studies published until January 2020 were retrieved from Scopus, Web of Science, PubMed, Embase, and ClinicalTrials.gov databases. Studies were compiled that assessed for GBS colonization utilizing vaginal-perianal or vaginal-perineal culture and vaginal-rectal culture during the third trimester of pregnancy. Nonoriginal research articles and studies that did not assess pregnant patients, did not use culture-based screening, or did not compare vaginal-perianal or vaginal-perineal culture with vaginal-rectal culture were excluded. The search identified 559 articles with three prospective cohort studies that met inclusion criteria, including 643 participants. Quality was assessed using the Newcastle-Ottawa Scale, and risk of bias was assessed using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Patient characteristics and associated pain with specimen collection were abstracted. Meta-analyses of both the raw agreement and the Cohen's kappa statistic were performed. RESULTS: Within the three included studies, the range of GBS detection was 17.6-34.0%, consistent with the anticipated prevalence of GBS colonization reported in earlier publications. For both raw agreement and Cohen's kappa coefficient, the test for heterogeneity was not significant, indicating low heterogeneity among studies. The pooled estimate of the raw agreement was 0.97 (95%CI 0.95-0.98) and of the Cohen's kappa coefficient was 0.91 (95% CI: 0.87-0.95), indicating (according to the Landis and Koch criteria) an "almost perfect" agreement between the compared clinical tests. In the two studies that assessed procedure-related patient discomfort, vaginal-rectal swabbing caused more discomfort. CONCLUSION: Use of vaginal-perineal culture for assessment of maternal GBS colonization is comparable to the more typically utilized vaginal-rectal culture and is associated with less discomfort.

[Active surveillance for thyroid micro-malignant nodules].

Objective: To evaluate the effect of ultrasound diagnosis of thyroid micro-malignant nodules and accumulate practical experience for the management of active surveillance for them, so as to avoid overtreatment. Methods: A total of 949 patients who were diagnosed with thyroid malignant nodules using ultrasonography, with the nodules being less than 1 cm in size and without regional lymph node metastasis or distant metastasis, were included. They were treated by the same surgeon of the Department of Head and Neck Surgery, Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to December 2020. 112 patients chose immediate surgery. The rest patients were asked to accept ultrasound examination every 6 months to 1 year. Follow-up endpoints: tumor size growth of 3 mm, tumor volume increase greater than 50%, lymph node metastasis or distant metastasis. Results: The median follow-up time was 19 months. 713 patients underwent surveillance for more than 6 months. Of the 713 patients, 570 (79.9%) were women, with mean age at 43.5 years old. Tumor progression was observed in 47 (6.6%) patients with a cumulative incidence of 2.7% (1 year), 7.2% (2 years) and 9.5% (3 years). In multivariate analysis, patient age [HR=0.508, 95%CI: 0.275-0.939, P=0.031], lesion number [HR=2.945, 95%CI: 1.593-5.444, P=0.001] and tumor size [HR=2.245, 95%CI: 1.202-4.192, P=0.011] at the beginning of observation were independent risk factors for tumor progression in patients with minimal thyroid malignant nodules during follow-up. During a median (range) active surveillance of 19 (6-80) months, 74 patients chose surgery during the surveillance. Among the 186 patients who underwent surgery, only 3 patients were diagnosed with fibrotic nodules in pathology, while the rest were papillary thyroid carcinoma. The ultrasound accuracy reached 98.4%(183/186). Conclusions: Ultrasonography is an effective method of diagnosing malignant thyroid nodules. Thyroid micro-malignant nodules progress slowly. As a result, it is safe to observe them instead of taking immediate surgery. Patient age, lesion number and tumor size at the beginning of observation are independent risk factors for the tumor progression of malignant nodules.

[Risk factors of residual tumor in single small hepatocellular carcinoma after thermal ablation treatment].

Objective: To evaluate the risk factors of residual tumor after thermal ablation in patients with small hepatocellular carcinoma. Methods: This was a retrospective study recruiting 107 patients diagnosed as single hepatocellular carcinoma with maximum diameter ≤3 cm from December 2009 to August 2015 in National Cancer Center. The cohort enrolled 81 males and 26 females, including 83 patients younger than 70 years old. All patients were treated with radiofrequency ablation or microwave ablation, and evaluated by CT or MRI after 4-6 weeks compared with baseline data. Potentially related factors were analyzed such as patients' characteristics, tumor location and adjacent, ablation pattern, hepatitis B/C infection. A multivariate logistic regression analysis was conducted for the independence of risk factors. Results: Six patients (5.6%) with residual tumor was detected in the whole population of 101 cases. Univariate analysis suggested that tumor adjacent to vascular structure, poor differentiation, AFP≥200 µg/L were the risk factors of residue disease (all P<0.05). Multivariate logistic regression suggested that pathological type of poorly differentiated tumor was the only independent risk factor (HR=2.26,95%CI 0.25-20.50, P=0.030). Conclusions: Poorly differentiated pathology is an independent predictive factor for residual disease in small hepatocellular carcinoma after thermal ablation. Such patients should be routinely followed up after operation.

NOMOGRAM COMBINING PREOPERATIVE ULTRASONOGRAPHY WITH CLINICAL FEATURES FOR PREDICTING LYMPH NODES POSTERIOR TO THE RIGHT RECURRENT LARYNGEAL NERVE METASTASIS IN PATIENTS WITH PAPILLARY THYROID CANCER.

Aim: To establish a nomogram combining preoperative ultrasonic and clinical features for predicting lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) metastasis in papillary thyroid carcinoma (PTC) patients. Methods: Preoperative ultrasonic and clinical variables of patients with PTC from 2014 to 2021 were retrospectively analyzed. The risk factors associated with LN-prRLN metastasis were identified and validated through a developed nomogram model based on univariate and multivariate logistic regression analysis. Results: A total of 615 patients (690 lesions) were enrolled for the training dataset and 207 patients (226 lesions) for the validation dataset with 54 (6.57%) patients developing LN-prRLN metastasis. Multivariate logistic regression analysis demonstrated that the preoperative ultrasound measurement of larger tumors (≥20 mm), higher TI-RADS category (category 5), and higher thyroglobulin level (9.86 ng/mL) in patients with PTC were predictive factors for LN-prRLN metastasis. The nomogram model was established and verified yielding a relatively good predictive performance in the training and validation dataset (AUC: 0.868 vs. 0.851). Conclusions: The nomogram combining preoperative ultrasonography with clinical features in this study is highly predictive of LN-prRLN metastasis in patients with PTC, which may provide more personalized recommendations for clinicians in preoperative decision-making for complete dissection of LN-prRLN.

Intermediate confounding in trio relationships: The importance of complete data in effect size estimation.

We present an important characteristic of trio models which may lead to bias and loss of power when one parent is unmodeled in trio analyses. Motivated by recent interest in estimating parental effects on postnatal and later-life phenotypes, we consider a causal model where each parent has both an effect on their child's phenotype which is mediated through the genotype transmitted to the child and a direct effect on the phenotype through the parentally provided environment. We derive the power and bias of models in which one parent's genotype is not modeled, showing that while the effect of the child's genotype is biased in the direction of the unmodeled parent's effect as expected, the estimated effect of the observed parent's genotype is also biased in the opposite direction. While this phenomenon may not be intuitive under the assumption of random mating, it can be explained by intermediate confounding of the child's genotype-phenotype effect. These observations have implications for the accurate estimation of maternal and paternal effects in trio data sets with missing genotype data.

Directional massless Dirac fermions in a layered van der Waals material with one-dimensional long-range order.

One or a few layers of van der Waals (vdW) materials are promising for applications in nanoscale electronics. Established properties include high mobility in graphene, a large direct gap in monolayer MoS2, the quantum spin Hall effect in monolayer WTe2 and so on. These exciting properties arise from electron quantum confinement in the two-dimensional limit. Here, we use angle-resolved photoemission spectroscopy to reveal directional massless Dirac fermions due to one-dimensional confinement of carriers in the layered vdW material NbSi0.45Te2. The one-dimensional directional massless Dirac fermions are protected by non-symmorphic symmetry, and emerge from a stripe-like structural modulation with long-range translational symmetry only along the stripe direction as we show using scanning tunnelling microscopy. Our work not only provides a playground for investigating further the properties of directional massless Dirac fermions, but also introduces a unique component with one-dimensional long-range order for engineering nano-electronic devices based on heterostructures of vdW materials.

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. METHODS AND RESULTS: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 µs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. CONCLUSIONS: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer.

OBJECTIVE: Mebendazole and other anti-parasitic drugs are being used off-prescription based on social media and unofficial accounts of their anti-cancer activity. The purpose of this study was to conduct a controlled evaluation of mebendazole's therapeutic efficacy in cell culture and in vivo models of ovarian cancer. The majority of ovarian cancers harbor p53 null or missense mutations, therefore the effects of p53 mutations and a mutant p53 reactivator, PRIMA-1MET (APR246) on mebendazole activity were evaluated. METHODS: Mebendazole was evaluated in cisplatin-resistant high grade serous stage 3C ovarian cancer patient derived xenograft (PDX) models: PDX-0003 (p53 null) and PDX-0030 (p53 positive), and on ovarian cancer cell lines: MES-OV (p53 R282W), ES2 (p53 S241F), A2780 (p53 wild type), SKOV3 parental (p53 null) and isogenic sublines, SKOV3 R273H p53 and SKOV3 R248W p53. Drug synergy and mechanisms were evaluated in cell cultures using isobolograms, clonogenic assays and western blots. Prevention of tumor establishment was studied in a MES-OV orthotopic model. RESULTS: Mebendazole inhibited growth of ovarian cancer cell cultures at nanomolar concentrations and PDXs at doses up to 50 mg/kg, and reduced orthotopic tumor establishment at 50 mg/kg. The mechanism of mebendazole was associated with p53-independent induction of p21 and tubule depolymerization. PRIMA-1MET also inhibited tumor establishment and worked synergistically with mebendazole in cell culture to inhibit growth and induce intrinsic apoptosis through a p53- and tubule destabilization-independent mechanism. CONCLUSION: This work demonstrates the therapeutic potential of repurposing mebendazole and supports clinical development of mebendazole for ovarian cancer therapy and maintenance.

Isolation and characterization of endophytic bacteria for controlling root rot disease of Chinese jujube.

AIM: Fusarium oxysporum is the primary pathogen causing root rot disease that severely affects cultivation of jujube fruit in the Xinjiang province of China. The aim of this study was to identify endophytic bacteria in healthy jujube organs that could effectively suppress F. oxysporum growth. METHODS AND RESULTS: Different plant organs (leaves, twigs and roots) were collected from healthy Chinese jujube cultivated in southern Xinjiang province of China. The endophytic bacterium Brevibacterium halotolerans JZ7 was selected for its strong antagonistic activity and growth-promoting characteristics. Gas-chromatography mass-spectrometry analysis showed that acetoin, 2,3-butanediol and fenretinide were the three dominant volatile organic compounds produced by strain JZ7. Fenretinide strongly suppressed spore germination of F. oxysporum in vitro. Pot experiments showed that strain JZ7 colonized both the roots and rhizosphere soil of Chinese jujube and significantly reduced F. oxysporum level in jujube rhizosphere soil. CONCLUSION: We demonstrated that B. halotolerans JZ7 can be developed into a biological control agent to combat root rot disease of Chinese jujube in the Xinjiang province of China. SIGNIFICANCE AND IMPACT OF THE STUDY: The suggested strategy for biological control of jujube root rot disease is fully in accordance with the current principles of sustainability.

Assessment of Streptococcus mutans biofilms on orthodontic adhesives over 7 days.

INTRODUCTION: The purpose of this study was to compare the metabolism of Streptococcus mutans biofilms after 1-7 days of growth on different orthodontic adhesives. METHODS: Specimens of 6 commercial orthodontic adhesives were fabricated in custom-made molds and polymerized using a light-emitting diode light-curing unit. Bioluminescent S mutans (UA159:JM10) biofilms were grown on ultraviolet-sterilized specimens for 1, 3, 5, and 7 days (n = 18 biofilms/d/product) in anaerobic conditions at 37°C. The metabolism of biofilms (relative luminescence unit [RLU]) was measured 0, 2, 4, and 6 minutes after exposure to D-luciferin solution using a microplate reader. A linear mixed-effects model was used to analyze the logarithm of RLU (log RLU). The model included fixed effects of products, days, and minutes. Tukey-Kramer post-hoc tests were then performed on the significant predictors of log RLU (α = 0.05). RESULTS: Days (P <0.0001) and minutes (P <0.0001) were independent predictors of log RLU, but the products were not (P = 0.5869). After adjusting for minutes, the log RLU was analyzed with a post-hoc test, and all differences between days were significant with the exceptions of day 3 from day 5 (P = 0.0731) and day 5 from day 7 (P = 0.8802). After adjusting for day, log RLU was analyzed with a post-hoc test and all differences in minutes were significant. CONCLUSIONS: No significant differences in the metabolism of S mutans biofilms were observed among the 6 orthodontic adhesives. Biofilms that were grown for 3 days demonstrated the highest levels of biofilm metabolism as evidenced by higher mean log RLU values relative to 1, 5, and 7-day growth durations.

[Studies of the norm of Karitane Parenting Confidence Scale(KPCS)among parents of infants in urban areas of China].

Objective: To establish the norm of the Chinese version of Karitane Parenting Confidence Scale (KPCS) in urban areas of China. Methods: From August to December 2017, the parents of 2 216 children (<36 months old) were selected from 15 cities (Beijing, Lianyungang, Hangzhou, Chengdu, Xi'an, Guangzhou, Changsha, Jinan, Guiyang, Ningbo, Dalian, Qinhuangdao, Maanshan, Chongqing and Wuhan) in 14 provinces by stratified random sampling. The general demographic characteristics and parents' parenting confidence were collected by a self-made questionnaire and KPCS Chinese version. The percentile norm was established. P3, P10 and P25 were used as the criteria to define the degree of lack of parenting confidence. Results: The age of mothers was (30.67±4.29). The age of the father was (32.50±4.99) years old. There were 726 (32.76%), 759 (34.25%) and 731 (32.99%) infants in 6-12, 12-23 and 24-35 months old groups. The total scores of P50, P25, P10 and P3 of KPCS (Chinese version) of infant parents in urban areas in China were 41, 38, 33, and 29 respectively. When the scores of parents were 34-37, 30-33, and ≤ 29, they were judged as mild, moderate, and severe lack of parenting confidence. There was no significant difference in the Chinese version of KPCS between parents of different age groups and parents of different gender (χ²=3.53, P=0.171; χ²=1.41, P=0.236). Each factor score≤P3 is defined as the boundary score, and the corresponding boundary scores of "parenting" "support" and "competence" were 13, 9, and 5 respectively. Conclusion: The Chinese version of KPCS can be used to assess the parenting confidence of infants in urban areas of China. It can used as one of the bases for scientific and objective evaluation of the parenting status of families.

Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53.

Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA-1MET drug inhibits growth and tumor establishment synergistically in a mutant-p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA-1MET were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty-eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high-grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA-1MET decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53-expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor-free rates in animals were 0% (controls), 25% (PRIMA1MET ), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1MET (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA-1MET alone and in combination for ovarian cancer maintenance therapy.

Effect of a bacteriophage T5virus on growth of Shiga toxigenic Escherichia coli and Salmonella strains in individual and mixed cultures.

A previously isolated a bacteriophage, vB_EcoS_AKFV33 of T5virus, demonstrated great potential in biocontrol of Shiga toxigenic Escherichia coli (STEC) O157. This study further evaluated its potential as a biocontrol agent in broth culture against other important non-O157 serogroups of STEC and Salmonella. AKFV33 was capable of lysing isolates of STEC serogroups O26 (n = 1), O145 (n = 1) and Salmonella enterica serovars (n = 6). In a broth culture microplate system, efficacy of AKFV33 for killing STEC O26:H11, O145:NM and Salmonella was improved (P < 0.05) at a lower multiplicity of infection and sampling time (6-10 h), when STEC O157:H7 was also included in the culture. This phage was able to simultaneously reduce numbers of STEC and Salmonella in mixtures with enhanced activity (P < 0.05) against O157:H7 and O26:H11, offering great promise for control of multiple zoonotic pathogens at both pre and post-harvest.

Transcriptomic and proteomic profiling response of methicillin-resistant Staphylococcus aureus (MRSA) to a novel bacteriocin, plantaricin GZ1-27 and its inhibition of biofilm formation.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a worrisome superbug, due to its wide distribution and multidrug resistance. To characterize effects of a newly identified plantaricin GZ1-27 on MRSA, transcriptomic and proteomic profiling of MRSA strain ATCC43300 was performed in response to sub-MIC (16 µg/mL) plantaricin GZ1-27 stress. In total, 1090 differentially expressed genes (padj < 0.05) and 418 differentially expressed proteins (fold change > 1.2, p < 0.05) were identified. Centralized protein expression clusters were predicted in biological functions (biofilm formation, DNA replication and repair, and heat-shock) and metabolic pathways (purine metabolism, amino acid metabolism, and biosynthesis of secondary metabolites). Moreover, a capacity of inhibition MRSA biofilm formation and killing biofilm cells were verified using crystal violet staining, scanning electron microscopy, and confocal laser-scanning microscopy. These findings yielded comprehensive new data regarding responses induced by plantaricin and could inform evidence-based methods to mitigate MRSA biofilm formation.